case study of a schizophrenic patient

Module 11: Schizophrenia Spectrum and Other Psychotic Disorders

Case studies: schizophrenia spectrum disorders, learning objectives.

• Identify schizophrenia and psychotic disorders in case studies

Case Study: Bryant

Thirty-five-year-old Bryant was admitted to the hospital because of ritualistic behaviors, depression, and distrust. At the time of admission, prominent ritualistic behaviors and depression misled clinicians to diagnose Bryant with obsessive-compulsive disorder (OCD). Shortly after, psychotic symptoms such as disorganized thoughts and delusion of control were noticeable. He told the doctors he has not been receiving any treatment, was not on any substance or medication, and has been experiencing these symptoms for about two weeks. Throughout the course of his treatment, the doctors noticed that he developed a catatonic stupor and a respiratory infection, which was identified by respiratory symptoms, blood tests, and a chest X-ray. To treat the psychotic symptoms, catatonic stupor, and respiratory infection, risperidone, MECT, and ceftriaxone (antibiotic) were administered, and these therapies proved to be dramatically effective. [1]

Case Study: Shanta

Shanta, a 28-year-old female with no prior psychiatric hospitalizations, was sent to the local emergency room after her parents called 911; they were concerned that their daughter had become uncharacteristically irritable and paranoid. The family observed that she had stopped interacting with them and had been spending long periods of time alone in her bedroom. For over a month, she had not attended school at the local community college. Her parents finally made the decision to call the police when she started to threaten them with a knife, and the police took her to the local emergency room for a crisis evaluation.

Following the administration of the medication, she tried to escape from the emergency room, contending that the hospital staff was planning to kill her. She eventually slept and when she awoke, she told the crisis worker that she had been diagnosed with attention-deficit/hyperactive disorder (ADHD) a month ago. At the time of this ADHD diagnosis, she was started on 30 mg of a stimulant to be taken every morning in order to help her focus and become less stressed over the possibility of poor school performance.

After two weeks, the provider increased her dosage to 60 mg every morning and also started her on dextroamphetamine sulfate tablets (10 mg) that she took daily in the afternoon in order to improve her concentration and ability to study. Shanta claimed that she might have taken up to three dextroamphetamine sulfate tablets over the past three days because she was worried about falling asleep and being unable to adequately prepare for an examination.

Prior to the ADHD diagnosis, the patient had no known psychiatric or substance abuse history. The urine toxicology screen taken upon admission to the emergency department was positive only for amphetamines. There was no family history of psychotic or mood disorders, and she didn’t exhibit any depressive, manic, or hypomanic symptoms.

The stimulant medications were discontinued by the hospital upon admission to the emergency department and the patient was treated with an atypical antipsychotic. She tolerated the medications well, started psychotherapy sessions, and was released five days later. On the day of discharge, there were no delusions or hallucinations reported. She was referred to the local mental health center for aftercare follow-up with a psychiatrist. [2]

Another powerful case study example is that of Elyn R. Saks, the associate dean and Orrin B. Evans professor of law, psychology, and psychiatry and the behavioral sciences at the University of Southern California Gould Law School.

Saks began experiencing symptoms of mental illness at eight years old, but she had her first full-blown episode when studying as a Marshall scholar at Oxford University. Another breakdown happened while Saks was a student at Yale Law School, after which she “ended up forcibly restrained and forced to take anti-psychotic medication.” Her scholarly efforts thus include taking a careful look at the destructive impact force and coercion can have on the lives of people with psychiatric illnesses, whether during treatment or perhaps in interactions with police; the Saks Institute, for example, co-hosted a conference examining the urgent problem of how to address excessive use of force in encounters between law enforcement and individuals with mental health challenges.

Saks lives with schizophrenia and has written and spoken about her experiences. She says, “There’s a tremendous need to implode the myths of mental illness, to put a face on it, to show people that a diagnosis does not have to lead to a painful and oblique life.”

In recent years, researchers have begun talking about mental health care in the same way addiction specialists speak of recovery—the lifelong journey of self-treatment and discipline that guides substance abuse programs. The idea remains controversial: managing a severe mental illness is more complicated than simply avoiding certain behaviors. Approaches include “medication (usually), therapy (often), a measure of good luck (always)—and, most of all, the inner strength to manage one’s demons, if not banish them. That strength can come from any number of places…love, forgiveness, faith in God, a lifelong friendship.” Saks says, “We who struggle with these disorders can lead full, happy, productive lives, if we have the right resources.”

You can view the transcript for “A tale of mental illness | Elyn Saks” here (opens in new window) .

• Bai, Y., Yang, X., Zeng, Z., & Yang, H. (2018). A case report of schizoaffective disorder with ritualistic behaviors and catatonic stupor: successful treatment by risperidone and modified electroconvulsive therapy. BMC psychiatry , 18(1), 67. https://doi.org/10.1186/s12888-018-1655-5 ↵
• Henning A, Kurtom M, Espiridion E D (February 23, 2019) A Case Study of Acute Stimulant-induced Psychosis. Cureus 11(2): e4126. doi:10.7759/cureus.4126 ↵
• Modification, adaptation, and original content. Authored by : Wallis Back for Lumen Learning. Provided by : Lumen Learning. License : CC BY: Attribution
• A tale of mental illness . Authored by : Elyn Saks. Provided by : TED. Located at : https://www.youtube.com/watch?v=f6CILJA110Y . License : Other . License Terms : Standard YouTube License
• A Case Study of Acute Stimulant-induced Psychosis. Authored by : Ashley Henning, Muhannad Kurtom, Eduardo D. Espiridion. Provided by : Cureus. Located at : https://www.cureus.com/articles/17024-a-case-study-of-acute-stimulant-induced-psychosis#article-disclosures-acknowledgements . License : CC BY: Attribution
• Elyn Saks. Provided by : Wikipedia. Located at : https://en.wikipedia.org/wiki/Elyn_Saks . License : CC BY-SA: Attribution-ShareAlike
• A case report of schizoaffective disorder with ritualistic behaviors and catatonic stupor: successful treatment by risperidone and modified electroconvulsive therapy. Authored by : Yuanhan Bai, Xi Yang, Zhiqiang Zeng, and Haichen Yangcorresponding. Located at : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851085/ . License : CC BY: Attribution

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• My Account Login
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Open access
• Published: 24 February 2022

Systematic literature review of schizophrenia clinical practice guidelines on acute and maintenance management with antipsychotics

• Christoph U. Correll   ORCID: orcid.org/0000-0002-7254-5646 1 , 2 , 3 ,
• Amber Martin 4 ,
• Charmi Patel 5 ,
• Carmela Benson 5 ,
• Rebecca Goulding 6 ,
• Jennifer Kern-Sliwa 5 ,
• Kruti Joshi 5 ,
• Emma Schiller 4 &
• Edward Kim   ORCID: orcid.org/0000-0001-8247-6675 7  

Schizophrenia volume  8 , Article number:  5 ( 2022 ) Cite this article

14k Accesses

50 Citations

14 Altmetric

Metrics details

• Schizophrenia

Clinical practice guidelines (CPGs) translate evidence into recommendations to improve patient care and outcomes. To provide an overview of schizophrenia CPGs, we conducted a systematic literature review of English-language CPGs and synthesized current recommendations for the acute and maintenance management with antipsychotics. Searches for schizophrenia CPGs were conducted in MEDLINE/Embase from 1/1/2004–12/19/2019 and in guideline websites until 06/01/2020. Of 19 CPGs, 17 (89.5%) commented on first-episode schizophrenia (FES), with all recommending antipsychotic monotherapy, but without agreement on preferred antipsychotic. Of 18 CPGs commenting on maintenance therapy, 10 (55.6%) made no recommendations on the appropriate maximum duration of maintenance therapy, noting instead individualization of care. Eighteen (94.7%) CPGs commented on long-acting injectable antipsychotics (LAIs), mainly in cases of nonadherence (77.8%), maintenance care (72.2%), or patient preference (66.7%), with 5 (27.8%) CPGs recommending LAIs for FES. For treatment-resistant schizophrenia, 15/15 CPGs recommended clozapine. Only 7/19 (38.8%) CPGs included a treatment algorithm.

Similar content being viewed by others

A meta-analysis of effectiveness of real-world studies of antipsychotics in schizophrenia: Are the results consistent with the findings of randomized controlled trials?

Factors associated with successful antipsychotic dose reduction in schizophrenia: a systematic review of prospective clinical trials and meta-analysis of randomized controlled trials

The efficacy and heterogeneity of antipsychotic response in schizophrenia: A meta-analysis

Introduction.

Schizophrenia is an often debilitating, chronic, and relapsing mental disorder with complex symptomology that manifests as a combination of positive, negative, and/or cognitive features 1 , 2 , 3 . Standard management of schizophrenia includes the use of antipsychotic medications to help control acute psychotic episodes 4 and prevent relapses 5 , 6 , whereas maintenance therapy is used in the long term after patients have been stabilized 7 , 8 , 9 . Two main classes of drugs—first- and second-generation antipsychotics (FGA and SGA)—are used to treat schizophrenia 10 . SGAs are favored due to the lower rates of adverse effects, such as extrapyramidal effects, tardive dyskinesia, and relapse 11 . However, pharmacologic treatment for schizophrenia is complicated because nonadherence is prevalent, and is a major risk factor for relapse 9 and poor overall outcomes 12 . The use of long-acting injectable (LAI) versions of antipsychotics aims to limit nonadherence-related relapses and poor outcomes 13 .

Patient treatment pathways and treatment choices are determined based on illness acuity/severity, past treatment response and tolerability, as well as balancing medication efficacy and adverse effect profiles in the context of patient preferences and adherence patterns 14 , 15 . Clinical practice guidelines (CPG) serve to inform clinicians with recommendations that reflect current evidence from meta-analyses of randomized controlled trials (RCTs), individual RCTs and, less so, epidemiologic studies, as well as clinical experience, with the goal of providing a framework and road-map for treatment decisions that will improve quality of care and achieve better patients outcomes. The use of clinical algorithms or other decision trees in CPGs may improve the ease of implementation of the evidence in clinical practice 16 . While CPGs are an important tool for mental health professionals, they have not been updated on a regular basis like they have been in other areas of medicine, such as in oncology. In the absence of current information, other governing bodies, healthcare systems, and hospitals have developed their own CPGs regarding the treatment of schizophrenia, and many of these have been recently updated 17 , 18 , 19 . As such, it is important to assess the latest guidelines to be aware of the changes resulting from consideration of updated evidence that informed the treatment recommendations. Since CPGs are comprehensive and include the diagnosis as well as the pharmacological and non-pharmacological management of individuals with schizophrenia, a detailed comparative review of all aspects of CPGs for schizophrenia would have been too broad a review topic. Further, despite ongoing efforts to broaden the pharmacologic tools for the treatment of schizophrenia 20 , antipsychotics remain the cornerstone of schizophrenia management 8 , 21 . Therefore, a focused review of guideline recommendations for the management of schizophrenia with antipsychotics would serve to provide clinicians with relevant information for treatment decisions.

To provide an updated overview of United States (US) national and English language international guidelines for the management of schizophrenia, we conducted a systematic literature review (SLR) to identify CPGs and synthesize current recommendations for pharmacological management with antipsychotics in the acute and maintenance phases of schizophrenia.

Systematic searches for the SLR yielded 1253 hits from the electronic literature databases. After removal of duplicate references, 1127 individual articles were screened at the title and abstract level. Of these, 58 publications were deemed eligible for screening at the full-text level, from which 19 were ultimately included in the SLR. Website searches of relevant organizations yielded 10 additional records, and an additional three records were identified by the state-by-state searches. Altogether, this process resulted in 32 records identified for inclusion in the SLR. Of the 32 sources, 19 primary CPGs, published/issued between 2004 and 2020, were selected for extraction, as illustrated in the PRISMA diagram (Fig. 1 ). While the most recent APA guideline was identified and available for download in 2020, the reference to cite in the document indicates a publication date of 2021.

SLR systematic literature review.

Of the 19 included CPGs (Table 1 ), three had an international focus (from the following organizations: International College of Neuropsychopharmacology [CINP] 22 , United Nations High Commissioner for Refugees [UNHCR] 23 , and World Federation of Societies of Biological Psychiatry [WFSBP] 24 , 25 , 26 ); seven originated from the US; 17 , 18 , 19 , 27 , 28 , 29 , 30 , 31 , 32 three were from the United Kingdom (British Association for Psychopharmacology [BAP] 33 , the National Institute for Health and Care Excellence [NICE] 34 , and the Scottish Intercollegiate Guidelines Network [SIGN] 35 ); and one guideline each was from Singapore 36 , the Polish Psychiatric Association (PPA) 37 , 38 , the Canadian Psychiatric Association (CPA) 14 , the Royal Australia/New Zealand College of Psychiatrists (RANZCP) 39 , the Association Française de Psychiatrie Biologique et de Neuropsychopharmacologie (AFPBN) from France 40 , and Italy 41 . Fourteen CPGs (74%) recommended treatment with specific antipsychotics and 18 (95%) included recommendations for the use of LAIs, while just seven included a treatment algorithm Table 2 ). The AGREE II assessment resulted in the highest score across the CPGs domains for NICE 34 followed by the American Psychiatric Association (APA) guidelines 17 . The CPA 14 , BAP 33 , and SIGN 35 CPGs also scored well across domains.

Acute therapy

Seventeen CPGs (89.5%) provided treatment recommendations for patients experiencing a first schizophrenia episode 14 , 17 , 18 , 19 , 22 , 23 , 24 , 28 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 39 , 40 , 41 , but the depth and focus of the information varied greatly (Supplementary Table 1 ). In some CPGs, information on treatment of a first schizophrenia episode was limited or grouped with information on treating any acute episode, such as in the CPGs from CINP 22 , AFPBN 40 , New Jersey Division of Mental Health Services (NJDMHS) 32 , the APA 17 , and the PPA 37 , 38 , while the others provided more detailed information specific to patients experiencing a first schizophrenia episode 14 , 18 , 19 , 23 , 24 , 28 , 33 , 34 , 35 , 36 , 39 , 41 . The American Association of Community Psychiatrists (AACP) Clinical Tips did not provide any information on the treatment of schizophrenia patients with a first episode 29 .

There was little agreement among CPGs regarding the preferred antipsychotic for a first schizophrenia episode. However, there was strong consensus on antipsychotic monotherapy and that lower doses are generally recommended due to better treatment response and greater adverse effect sensitivity. Some guidelines recommended SGAs over FGAs when treating a first-episode schizophrenia patient (RANZCP 39 , Texas Medication Algorithm Project [TMAP] 28 , Oregon Health Authority 19 ), one recommended starting patients on an FGA (UNHCR 23 ), and others stated specifically that there was no evidence of any difference in efficacy between FGAs and SGAs (WFSBP 24 , CPA 14 , SIGN 35 , APA 17 , Singapore guidelines 36 ), or did not make any recommendation (CINP 22 , Italian guidelines 41 , NICE 34 , NJDMHS 32 , Schizophrenia Patient Outcomes Research Team [PORT] 30 , 31 ). The BAP 33 and WFBSP 24 noted that while there was probably no difference between FGAs and SGAs in efficacy, some SGAs (olanzapine, amisulpride, and risperidone) may perform better than some FGAs. The Schizophrenia PORT recommendations noted that while there seemed to be no differences between SGAs and FGAs in short-term studies (≤12 weeks), longer studies (one to two years) suggested that SGAs may provide benefits in terms of longer times to relapse and discontinuation rates 30 , 31 . The AFPBN guidelines 40 and Florida Medicaid Program guidelines 18 , which both focus on use of LAI antipsychotics, both recommended an SGA-LAI for patients experiencing a first schizophrenia episode. A caveat in most CPGs was that physicians and their patients should discuss decisions about the choice of antipsychotic and that the choice should consider individual patient factors/preferences, risk of adverse and metabolic effects, and symptom patterns 17 , 18 , 19 , 22 , 24 , 28 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 39 , 41 .

Most CPGs recommended switching to a different monotherapy if the initial antipsychotic was not effective or not well tolerated after an adequate antipsychotic trial at an appropriate dose 14 , 17 , 18 , 19 , 22 , 23 , 24 , 28 , 32 , 33 , 35 , 36 , 39 . For patients initially treated with an FGA, the UNHCR recommended switching to an SGA (olanzapine or risperidone) 23 . Guidance on response to treatment varied in the measures used but typically required at least a 20% improvement in symptoms (i.e. reduction in Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale scores) from pre-treatment levels.

Several CPGs contained recommendations on the duration of antipsychotic therapy after a first schizophrenia episode. The NJDMHS guidelines 32 recommended nine to 12 months; CINP 22 recommended at least one year; CPA 14 recommended at least 18 months; WFSBP 25 , the Italian guidelines 41 , and NICE 34 recommended 1 to 2 years; and the RANZCP 39 , BAP 33 , and SIGN 35 recommended at least 2 years. The APA 17 and TMAP 28 recommended continuing antipsychotic treatment after resolution of first-episode symptoms but did not recommend a specific length of therapy.

Twelve guidelines 14 , 18 , 22 , 24 , 28 , 30 , 31 , 33 , 34 , 35 , 36 , 39 , 40 (63.2%) discussed the treatment of subsequent/multiple episodes of schizophrenia (i.e., following relapse). These CPGs noted that the considerations guiding the choice of antipsychotic for subsequent/multiple episodes were similar to those for a first episode, factoring in prior patient treatment response, adverse effect patterns and adherence. The CPGs also noted that response to treatment may be lower and require higher doses to achieve a response than for first-episode schizophrenia, that a different antipsychotic than used to treat the first episode may be needed, and that a switch to an LAI is an option.

Several CPGs provided recommendations for patients with specific clinical features (Supplementary Table 1 ). The most frequently discussed group of clinical features was negative symptoms, with recommendations provided in the CINP 22 , UNHCR 23 , WFSBP 24 , AFPBN 40 , SIGN 35 , BAP 33 , APA 17 , and NJDMHS guidelines; 32 negative symptoms were the sole focus of the guidelines from the PPA 37 , 38 . The guidelines noted that due to limited evidence in patients with predominantly negative symptoms, there was no clear benefit for any strategy, but that options included SGAs (especially amisulpride) rather than FGAs (WFSBP 24 , CINP 22 , AFPBN 40 , SIGN 35 , NJDMHS 32 , PPA 37 , 38 ), and addition of an antidepressant (WFSBP 24 , UNHCR 23 , SIGN 35 , NJDMHS 32 ) or lamotrigine (SIGN 35 ), or switching to another SGA (NJDMHS 32 ) or clozapine (NJDMHS 32 ). The PPA guidelines 37 , 38 stated that the use of clozapine or adding an antidepressant or other medication class was not supported by evidence, but recommended the SGA cariprazine for patients with predominant and persistent negative symptoms, and other SGAs for those with full-spectrum negative symptoms. However, the BAP 33 stated that no recommendations can be made for any of these strategies because of the quality and paucity of the available evidence.

Some of the CPGs also discussed treatment of other clinical features to a limited degree, including depressive symptoms (CINP 22 , UNHCR 23 , CPA 14 , APA 17 , and NJDMHS 32 ), cognitive dysfunction (CINP 22 , UNHCR 23 , WFSBP 24 , AFPBN 40 , SIGN 35 , BAP 33 , and NJDMHS 32 ), persistent aggression (CINP 22 , WFSBP 24 , CPA 14 , AFPBN 40 , NICE 34 , SIGN 35 , BAP 33 , and NJDMHS 32 ), and comorbid psychiatric diagnoses (CINP 22 , RANZCP 39 , BAP 33 , APA 17 , and NJDMHS 32 ).

Fifteen CPGs (78.9%) discussed treatment-resistant schizophrenia (TRS); all defined it as persistent, predominantly positive symptoms after two adequate antipsychotic trials; clozapine was the unanimous first choice 14 , 17 , 18 , 19 , 22 , 23 , 24 , 28 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 39 . However, the UNHCR guidelines 23 , which included recommendations for treatment of refugees, noted that clozapine is only a reasonable choice in regions where white blood cell monitoring and specialist supervision are available, otherwise, risperidone or olanzapine are alternatives if they had not been used in the previous treatment regimen.

There were few options for patients who are resistant to clozapine therapy, and evidence supporting these options was limited. The CPA guidelines 14 therefore stated that no recommendation can be given due to inadequate evidence. Other CPGs discussed options (but noted there was limited supporting evidence), such as switching to olanzapine or risperidone (WFSBP 24 , TMAP 28 ), adding a second antipsychotic to clozapine (CINP 22 , NICE 34 , TMAP 28 , BAP 33 , Florida Medicaid Program 18 , Oregon Health Authority 19 , RANZCP 39 ), adding lamotrigine or topiramate to clozapine (CINP 22 , Florida Medicaid Program 18 ), combination therapy with two non-clozapine antipsychotics (Florida Medicaid Program 18 , NJDMHS 32 ), and high-dose non-clozapine antipsychotic therapy (BAP 33 , SIGN 35 ). Electroconvulsive therapy was noted as a last resort for patients who did not respond to any pharmacologic therapy, including clozapine, by 10 CPGs 17 , 18 , 19 , 22 , 24 , 28 , 32 , 35 , 36 , 39 .

Maintenance therapy

Fifteen CPGs (78.9%) discussed maintenance therapy to various degrees via dedicated sections or statements, while three others referred only to maintenance doses by antipsychotic agent 18 , 23 , 29 without accompanying recommendations (Supplementary Table 2 ). Only the Italian guideline provided no reference or comments on maintenance treatment. The CINP 22 , WFSBP 25 , RANZCP 39 , and Schizophrenia PORT 30 , 31 recommended keeping patients on the same antipsychotic and at the same dose on which they had achieved remission. Several CPGs recommended maintenance therapy at the lowest effective dose (NJDMHS 32 , APA 17 , Singapore guidelines 36 , and TMAP 28 ). The CPA 14 and SIGN 35 defined the lower dose as 300–400 mg chlorpromazine equivalents or 4–6 mg risperidone equivalents, and the Singapore guidelines 36 stated that the lower dose should not be less than half the original dose. TMAP 28 stated that given the relapsing nature of schizophrenia, the maintenance dose should often be close to the original dose. While SIGN 35 recommended that patients remain on the same antipsychotic that provided remission, these guidelines also stated that maintenance with amisulpride, olanzapine, or risperidone was preferred, and that chlorpromazine and other low-potency FGAs were also suitable. The BAP 33 recommended that the current regimen be optimized before any dose reduction or switch to another antipsychotic occurs. Several CPGs recommended LAIs as an option for maintenance therapy (see next section).

Altogether, 10/18 (55.5%) CPGs made no recommendations on the appropriate duration of maintenance therapy, noting instead that each patient should be considered individually. Other CPGs made specific recommendations: Both the Both BAP 33 and SIGN 35 guidelines suggested a minimum of 2 years, the NJDMHS guidelines 32 recommended 2–3 years; the WFSBP 25 recommended 2–5 years for patients who have had one relapse and more than 5 years for those who have had multiple relapses; the RANZCP 39 and the CPA 14 recommended 2–5 years; and the CINP 22 recommended that maintenance therapy last at least 6 years for patients who have had multiple episodes. The TMAP was the only CPG to recommend that maintenance therapy be continued indefinitely 28 .

Recommendations on the use of LAIs

All CPGs except the one from Italy (94.7%) discussed the use of LAIs for patients with schizophrenia to some extent. As shown in Table 3 , among the 18 CPGs, LAIs were primarily recommended in 14 CPGs (77.8%) for patients who are non-adherent to other antipsychotic administration routes (CINP 22 , UNHCR 23 , RANZCP 39 , PPA 37 , 38 , Singapore guidelines 36 , NICE 34 , SIGN 35 , BAP 33 , APA 17 , TMAP 28 , NJDMHS 32 , AACP 29 , Oregon Health Authority 19 , Florida Medicaid Program 18 ). Twelve CPGs (66.7%) also noted that LAIs should be prescribed based on patient preference (RANZCP 39 , CPA 14 , AFPBN 40 , Singapore guidelines 36 , NICE 34 , SIGN 35 , BAP 33 , APA 17 , Schizophrenia PORT 30 , 31 , AACP 29 , Oregon Health Authority 19 , Florida Medicaid Program 18 ).

Thirteen CPGs (72.2%) recommended LAIs as maintenance therapy 18 , 19 , 24 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 39 , 40 . While five CPGs (27.8%), i.e., AFPBN 40 , RANZCP 39 , TMAP 28 , NJDMHS 32 , and the Florida Medicaid Program 18 recommended LAIs specifically for patients experiencing a first episode. While the CPA 14 did not make any recommendations regarding when LAIs should be used, they discussed recent evidence supporting their use earlier in treatment. Five guidelines (27.8%, i.e., Singapore 36 , NICE 34 , SIGN 35 , BAP 33 , and Schizophrenia PORT 30 , 31 ) noted that evidence around LAIs was not sufficient to support recommending their use for first-episode patients. The AFPBN guidelines 40 also stated that LAIs (SGAs as first-line and FGAs as second-line treatment) should be more frequently considered for maintenance treatment of schizophrenia. Four CPGs (22.2%, i.e., CINP 22 , UNHCR 23 , Italian guidelines 41 , PPA guidelines 37 , 38 ) did not specify when LAIs should be used. The AACP guidelines 29 , which evaluated only LAIs, recommended expanding their use beyond treatment for nonadherence, suggesting that LAIs may offer a more convenient mode of administration or potentially address other clinical and social challenges, as well as provide more consistent plasma levels.

Treatment algorithms

Only Seven CPGs (36.8%) included an algorithm as part of the treatment recommendations. These included decision trees or flow diagrams that map out initial therapy, durations for assessing response, and treatment options in cases of non-response. However, none of these guidelines defined how to measure response, a theme that also extended to guidelines that did not include treatment algorithms. Four of the seven guidelines with algorithms recommended specific antipsychotic agents, while the remaining three referred only to the antipsychotic class.

LAIs were not consistently incorporated in treatment algorithms and in six CPGs were treated as a separate category of medicine reserved for patients with adherence issues or a preference for the route of administration. The only exception was the Florida Medicaid Program 18 , which recommended offering LAIs after oral antipsychotic stabilization even to patients who are at that point adherent to oral antipsychotics.

Benefits and harms

The need to balance the efficacy and safety of antipsychotics was mentioned by all CPGs as a basic treatment paradigm.

Ten CPGs provided conclusions on benefits of antipsychotic therapy. The APA 17 and the BAP 33 guidelines stated that antipsychotic treatment can improve the positive and negative symptoms of psychosis and leads to remission of symptoms. These CPGs 17 , 33 as well as those from NICE 34 and CPA 14 stated that these treatment effects can also lead to improvements in quality of life (including quality-adjusted life years), improved functioning, and reduction in disability. The CPA 14 and APA 17 guidelines noted decreases in hospitalizations with antipsychotic therapy, and the APA guidelines 17 stated that long-term antipsychotic treatment can also reduce mortality. The UNHCR 23 and the Italian 41 guidelines noted that early intervention increased positive outcomes. The WFSBP 24 , AFPBN 40 , CPA 14 , BAP 33 , APA 17 , and NJDMHS 32 affirmed that relapse prevention is a benefit of continued/maintenance treatment.

Some CPGs (WFSBP 24 , Italian 41 , CPA 14 , and SIGN 35 ) noted that reduced risk for extrapyramidal adverse effects and treatment discontinuation were potential benefits of SGAs vs. FGAs.

The risk of adverse effects (e.g., extrapyramidal, metabolic, cardiovascular, and hormonal adverse effects, sedation, and neuroleptic malignant syndrome) was noted by all CPGs as the major potential harm of antipsychotic therapy 14 , 17 , 18 , 19 , 22 , 23 , 24 , 28 , 29 , 30 , 31 , 32 , 34 , 35 , 36 , 37 , 39 , 40 , 41 , 42 . These adverse effects are known to limit long-term treatment and adherence 24 .

This SLR of CPGs for the treatment of schizophrenia yielded 19 most updated versions of individual CPGs, published/issued between 2004 and 2020. Structuring our comparative review according to illness phase, antipsychotic type and formulation, response to antipsychotic treatment as well as benefits and harms, several areas of consistent recommendations emerged from this review (e.g., balancing risk and benefits of antipsychotics, preferring antipsychotic monotherapy; using clozapine for treatment-resistant schizophrenia). On the other hand, other recommendations regarding other areas of antipsychotic treatment were mostly consistent (e.g., maintenance antipsychotic treatment for some time), somewhat inconsistent (e.g., differences in the management of first- vs multi-episode patients, type of antipsychotic, dose of antipsychotic maintenance treatment), or even contradictory (e.g., role of LAIs in first-episode schizophrenia patients).

Consistent with RCT evidence 43 , 44 , antipsychotic monotherapy was the treatment of choice for patients with first-episode schizophrenia in all CPGs, and all guidelines stated that a different single antipsychotic should be tried if the first is ineffective or intolerable. Recommendations were similar for multi-episode patients, but factored in prior patient treatment response, adverse effect patterns, and adherence. There was also broad consensus that the side-effect profile of antipsychotics is the most important consideration when making a decision on pharmacologic treatment, also reflecting meta-analytic evidence 4 , 5 , 10 . The risk of extrapyramidal symptoms (especially with FGAs) and metabolic effects (especially with SGAs) were noted as key considerations, which are also reflected in the literature as relevant concerns 4 , 45 , 46 , including for quality of life and treatment nonadherence 47 , 48 , 49 , 50 .

Largely consistent with the comparative meta-analytic evidence regarding the acute 4 , 51 , 52 and maintenance antipsychotic treatment 5 effects of schizophrenia, the majority of CPGs stated there was no difference in efficacy between SGAs and FGAs (WFSBP 24 , CPA 14 , SIGN 35 , APA 17 , and Singapore guidelines 36 ), or did not make any recommendations (CINP 22 , Italian guidelines 41 , NICE 34 , NJDMHS 32 , and Schizophrenia PORT 30 , 31 ); three CPGs (BAP 33 , WFBSP 24 , and Schizophrenia PORT 30 , 31 ) noted that SGAs may perform better than FGAs over the long term, consistent with a meta-analysis on this topic 53 .

The 12 CPGs that discussed treatment of subsequent/multiple episodes generally agreed on the factors guiding the choices of an antipsychotic, including that the decision may be more complicated and response may be lower than with a first episode, as described before 7 , 54 , 55 , 56 .

There was little consensus regarding maintenance therapy. Some CPGs recommended the same antipsychotic and dose that achieved remission (CINP 22 , WFSBP 25 , RANZCP 39 , and Schizophrenia PORT 30 , 31 ) and others recommended the lowest effective dose (NJDMHS 32 , APA 17 , Singapore guidelines 36 , TMAP 28 , CPA 14 , and SIGN 35 ). This inconsistency is likely based on insufficient data as well as conflicting results in existing meta-analyses on this topic 57 , 58 , 59 .

The 15 CPGs that discussed TRS all used the same definition for this condition, consistent with recent commendations 60 , and agreed that clozapine is the primary evidence-based treatment choice 14 , 17 , 18 , 19 , 22 , 23 , 24 , 28 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 39 , reflecting the evidence base 61 , 62 , 63 . These CPGs also agreed that there are few options well supported by evidence for patients who do not respond to clozapine, with a recent meta-analysis of RCTs showing that electroconvulsive therapy augmentation may be the most evidence-based treatment option 64 .

One key gap in the treatment recommendations was how long patients should remain on antipsychotic therapy after a first episode or during maintenance therapy. While nine of the 17 CPGs discussing treatment of a first episode provided a recommended timeframe (varying from 1 to 2 years) 14 , 22 , 24 , 32 , 33 , 34 , 35 , 39 , 41 , the APA 17 and TMAP 28 recommended continuing antipsychotic treatment after resolution of first-episode symptoms but did not recommend a specific length of therapy. Similarly, six of the 18 CPGs discussing maintenance treatment recommended a specific duration of therapy (ranging from two to six years) 14 , 22 , 25 , 32 , 39 , while as many as 10 CPGs did not point to a firm end of the maintenance treatment, instead recommending individualized decisions. The CPGs not stating a definite endpoint or period of maintenance treatment after repeated schizophrenia episodes or even after a first episode of schizophrenia, reflects the different evidence types on which the recommendation is based. The RCT evidence ends after several years of maintenance treatment vs. discontinuation supporting ongoing antipsychotic treatment; however, naturalistic database studies do not indicate any time period after which one can safely discontinue maintenance antipsychotic care, even after a first schizophrenia episode 8 , 65 . In fact, stopping antipsychotics is associated not only with a substantially increased risk of hospitalization but also mortality 65 , 66 , 67 . In this sense, not stating an endpoint for antipsychotic maintenance therapy should not be taken as an implicit statement that antipsychotics should be discontinued at any time; data suggest the contrary.

A further gap exists regarding the most appropriate treatment of negative symptoms, such as anhedonia, amotivation, asociality, affective flattening, and alogia 1 , a long-standing challenge in the management of patients with schizophrenia. Negative symptoms often persist in patients after positive symptoms have resolved, or are the presenting feature in a substantial minority of patients 22 , 35 . Negative symptoms can also be secondary to pharmacotherapy 22 , 68 . Antipsychotics have been most successful in treating positive symptoms, and while eight of the CPGs provided some information on treatment of negative symptoms, the recommendations were generally limited 17 , 22 , 23 , 24 , 32 , 33 , 35 , 40 . Negative symptom management was a focus of the PPA guidelines, but the guidelines acknowledged that supporting evidence was limited, often due to the low number of patients with predominantly negative symptoms in clinical trials 37 , 38 . The Polish guidelines are also one of the more recently developed and included the newer antipsychotic cariprazine as a first-line option, which although being a point of differentiation from the other guidelines, this recommendation was based on RCT data 69 .

Another area in which more direction is needed is on the use of LAIs. While all but one of the 19 CPGs discussed this topic, the extent of information and recommendations for LAI use varied considerably. All CPGs categorized LAIs as an option to improve adherence to therapy or based on patient preference. However, 5/18 CPGs (27.8%) recommended the use of LAI early in treatment (at first episode: AFPBN 40 , RANZCP 39 , TMAP 28 , NJDMHS 32 , and Florida Medicaid Program 18 ) or across the entire illness course, while five others stated there was not sufficient evidence to recommend LAIs for these patients (Singapore 36 , NICE 34 , SIGN 35 , BAP 33 , and Schizophrenia PORT 30 , 31 ). The role of LAIs in first-episode schizophrenia was the only point where opposing recommendations were found across CPGs. This contradictory stance was not due to the incorporation of newer data suggesting benefits of LAIs in first episode and early-phase patients with schizophrenia 70 , 71 , 72 , 73 , 74 in the CPGs recommending LAI use in first-episode patients, as CPGs recommending LAI use were published between 2005 and 2020, while those opposing LAI use were published between 2011 and 2020. Only the Florida Medicaid CPG recommended LAIs as a first step equivalent to oral antipsychotics (OAP) after initial OAP response and tolerability, independent of nonadherence or other clinical variables. This guideline was also the only CPG to fully integrate LAI use in their clinical algorithm. The remaining six CPGs that included decision tress or treatment algorithms regarded LAIs as a separate paradigm of treatment reserved for nonadherence or patients preference rather than a routine treatment option to consider. While some CPGs provided fairly detailed information on the use of LAIs (AFPBN 40 , AACP 29 , Oregon Health Authority 19 , and Florida Medicaid Program 18 ), others mentioned them only in the context of adherence issues or patient preference. Notably, definitions of and means to determine nonadherence were not reported. One reason for this wide range of recommendations regarding the placement of LAIs in the treatment algorithm and clinical situations that prompt LAI use might be due to the fact that CPGs generally favor RCT evidence over evidence from other study designs. In the case of LAIs, there was a notable dissociation between consistent meta-analytic evidence of statistically significant superiority of LAIs vs OAPs in mirror-image 75 and cohort study designs 76 and non-significant advantages in RCTs 77 . Although patients in RCTs comparing LAIs vs OAPs were less severely ill and more adherent to OAPs 77 than in clinical care and although mirror-image and cohort studies arguably have greater external validity than RCTs 78 , CPGs generally disregard evidence from other study designs when RCT evidence exits. This narrow focus can lead to disregarding important additional data. Nevertheless, a most updated meta-analysis of all 3 study designs comparing LAIs with OAPs demonstrated consistent superiority of LAIs vs OAPs for hospitalization or relapse across all 3 designs 79 , which should lead to more uniform recommendations across CPGs in the future.

Only seven CPGs included treatment algorithms or flow charts to guide LAI treatment selection for patients with schizophrenia 17 , 18 , 19 , 24 , 29 , 35 , 40 . However, there was little commonality across algorithms beyond the guidance on LAIs mentioned above, as some listed specific treatments and conditions for antipsychotic switches, while others indicated that medication choice should be based on a patient’s preferences and responses, side effects, and in some cases, cost effectiveness. Since algorithms and flow charts facilitate the reception, adoption and implementation of guidelines, future CPGs should include them as dissemination tools, but they need to reflect the data and detailed text and be sufficiently specific to be actionable.

The systematic nature in the identification, summarization, and assessment of the CPGs is a strength of this review. This process removed any potential bias associated with subjective selection of evidence, which is not reproducible. However, only CPGs published in English were included and regardless of their quality and differing timeframes of development and publication, complicating a direct comparison of consensus and disagreement. Finally, based on the focus of this SLR, we only reviewed pharmacologic management with antipsychotics. Clearly, the assessment, other pharmacologic and, especially, psychosocial interventions are important in the management of individuals with schizophrenia, but these topics that were covered to varying degrees by the evaluated CPGs were outside of the scope of this review.

Numerous guidelines have recently updated their recommendations on the pharmacological treatment of patients with schizophrenia, which we have summarized in this review. Consistent recommendations were observed across CPGs in the areas of balancing risk and benefits of antipsychotics when selecting treatment, a preference for antipsychotic monotherapy, especially for patients with a first episode of schizophrenia, and the use of clozapine for treatment-resistant schizophrenia. By contrast, there were inconsistencies with regards to recommendations on maintenance antipsychotic treatment, with differences existing on type and dose of antipsychotic, as well as the duration of therapy. However, LAIs were consistently recommended, but mainly suggested in cases of nonadherence or patient preference, despite their established efficacy in broader patient populations and clinical scenarios in clinical trials. Guidelines were sometimes contradictory, with some recommending LAI use earlier in the disease course (e.g., first episode) and others suggesting they only be reserved for later in the disease. This inconsistency was not due to lack of evidence on the efficacy of LAIs in first-episode schizophrenia or the timing of the CPG, so that other reasons might be responsible, including possibly bias and stigma associated with this route of treatment administration. Lastly, gaps existed in the guidelines for recommendations on the duration of maintenance treatment, treatment of negative symptoms, and the development/use of treatment algorithms whenever evidence is sufficient to provide a simplified summary of the data and indicate their relevance for clinical decision making, all of which should be considered in future guideline development/revisions.

The SLR followed established best methods used in systematic review research to identify and assess the available CPGs for pharmacologic treatment of schizophrenia with antipsychotics in the acute and maintenance phases 80 , 81 . The SLR was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, including use of a prespecified protocol to outline methods for conducting the review. The protocol for this review was approved by all authors prior to implementation but was not submitted to an external registry.

Data sources and search algorithms

Searches were conducted by two independent investigators in the MEDLINE and Embase databases via OvidSP to identify CPGs published in English. Articles were identified using search algorithms that paired terms for schizophrenia with keywords for CPGs. Articles indexed as case reports, reviews, letters, or news were excluded from the searches. The database search was limited to CPGs published from January 1, 2004, through December 19, 2019, without limit to geographic location. In addition to the database sources, guideline body websites and state-level health departments from the US were also searched for relevant CPGs published through June 2020. A manual check of the references of recent (i.e., published in the past three years), relevant SLRs and relevant practice CPGs was conducted to supplement the above searches and ensure and the most complete CPG retrieval.

This study did not involve human subjects as only published evidence was included in the review; ethical approval from an institution was therefore not required.

Selection of CPGs for inclusion

Each title and abstract identified from the database searches was screened and selected for inclusion or exclusion in the SLR by two independent investigators based on the populations, interventions/comparators, outcomes, study design, time period, language, and geographic criteria shown in Table 4 . During both rounds of the screening process, discrepancies between the two independent reviewers were resolved through discussion, and a third investigator resolved any disagreement. Articles/documents identified by the manual search of organizational websites were screened using the same criteria. All accepted studies were required to meet all inclusion criteria and none of the exclusion criteria. Only the most recent version of organizational CPGs was included for data extraction.

Data extraction and synthesis

Information on the recommendations regarding the antipsychotic management in the acute and maintenance phases of schizophrenia and related benefits and harms was captured from the included CPGs. Each guideline was reviewed and extracted by a single researcher and the data were validated by a senior team member to ensure accuracy and completeness. Additionally, each included CPG was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. Following extraction and validation, results were qualitatively summarized across CPGs.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Data availability

The data that support the findings of the SLR are available from the corresponding author upon request.

Correll, C. U. & Schooler, N. R. Negative symptoms in schizophrenia: a review and clinical guide for recognition, assessment, and treatment. Neuropsychiatr. Dis. Treat. 16 , 519–534 (2020).

Article   PubMed   PubMed Central   Google Scholar  

Kahn, R. S. et al. Schizophrenia. Nat. Rev. Dis. Prim. 1 , 15067 (2015).

Article   PubMed   Google Scholar  

Millan, M. J. et al. Altering the course of schizophrenia: progress and perspectives. Nat. Rev. Drug Discov. 15 , 485–515 (2016).

Article   CAS   PubMed   Google Scholar  

Huhn, M. et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet 394 , 939–951 (2019).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Kishimoto, T., Hagi, K., Nitta, M., Kane, J. M. & Correll, C. U. Long-term effectiveness of oral second-generation antipsychotics in patients with schizophrenia and related disorders: a systematic review and meta-analysis of direct head-to-head comparisons. World Psychiatry 18 , 208–224 (2019).

Leucht, S. et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 379 , 2063–2071 (2012).

Carbon, M. & Correll, C. U. Clinical predictors of therapeutic response to antipsychotics in schizophrenia. Dialogues Clin. Neurosci. 16 , 505–524 (2014).

Correll, C. U., Rubio, J. M. & Kane, J. M. What is the risk-benefit ratio of long-term antipsychotic treatment in people with schizophrenia? World Psychiatry 17 , 149–160 (2018).

Emsley, R., Chiliza, B., Asmal, L. & Harvey, B. H. The nature of relapse in schizophrenia. BMC Psychiatry 13 , 50 (2013).

Correll, C. U. & Kane, J. M. Ranking antipsychotics for efficacy and safety in schizophrenia. JAMA Psychiatry 77 , 225–226 (2020).

Kane, J. M. & Correll, C. U. Pharmacologic treatment of schizophrenia. Dialogues Clin. Neurosci. 12 , 345–357 (2010).

Kane, J. M., Kishimoto, T. & Correll, C. U. Non-adherence to medication in patients with psychotic disorders: epidemiology, contributing factors and management strategies. World Psychiatry 12 , 216–226 (2013).

Correll, C. U. et al. The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J. Clin. Psychiatry 77 , 1–24 (2016).

Remington, G. et al. Guidelines for the pharmacotherapy of schizophrenia in adults. Can. J. Psychiatry 62 , 604–616 (2017).

American Psychiatric Association. Treatment recommendations for patients with schizophrenia. Am. J. Psychiatry 161 , 1–56 (2004).

Institute of Medicine (US) Committee to Advise the Public Health Service on Clinical Practice Guidelines, Field, M. J., & Lohr, K. N. (Eds.). Clinical Practice Guidelines: Directions for a New Program. (National Academies Press (US), 1990).

American Psychiatric Association. Practice Guideline for the Treatment of Patients With Schizophrenia , 3rd edn. (2021). https://doi.org/10.1176/appi.books.9780890424841 .

Florida Medicaid Drug Therapy Management Program. 2019–2020 Florida Best Practice Psychotherapeutic Medication Guidelines for Adults . (2020). Available at: https://floridabhcenter.org/wp-content/uploads/2021/04/2019-Psychotherapeutic-Medication-Guidelines-for-Adults-with-References_06-04-20.pdf .

Mental Health Clinical Advisory Group, Oregon Health Authority. Mental Health Care Guide for Licensed Practitioners and Mental Health Professionals. (2019). Available at: https://sharedsystems.dhsoha.state.or.us/DHSForms/Served/le7548.pdf .

Krogmann, A. et al. Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities. CNS Spectr. 24 , 38–69 (2019).

Fountoulakis, K. N. et al. The report of the joint WPA/CINP workgroup on the use and usefulness of antipsychotic medication in the treatment of schizophrenia. CNS Spectr . https://doi.org/10.1017/S1092852920001546 (2020).

Leucht, S. et al. CINP Schizophrenia Guidelines . (CINP, 2013). Available at: https://www.cinp.org/resources/Documents/CINP-schizophrenia-guideline-24.5.2013-A-C-method.pdf .

Ostuzzi, G. et al. Mapping the evidence on pharmacological interventions for non-affective psychosis in humanitarian non-specialised settings: A UNHCR clinical guidance. BMC Med. 15 , 197 (2017).

Hasan, A. et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, Part 1: Update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J. Biol. Psychiatry 13 , 318–378 (2012).

Hasan, A. et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, Part 2: Update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects. World J. Biol. Psychiatry 14 , 2–44 (2013).

Hasan, A. et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia - a short version for primary care. Int. J. Psychiatry Clin. Pract. 21 , 82–90 (2017).

Moore, T. A. et al. The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2006 update. J. Clin. Psychiatry 68 , 1751–1762 (2007).

Texas Medication Algorithm Project (TMAP). Texas Medication Algorithm Project (TMAP) Procedural Manual . (2008). Available at: https://jpshealthnet.org/sites/default/files/inline-files/tmapalgorithmforschizophrenia.pdf .

American Association of Community Psychiatrists (AACP). Clinical Tips Series, Long Acting Antipsychotic Medications. (2017). Accessed at: https://drive.google.com/file/d/1unigjmjFJkqZMbaZ_ftdj8oqog49awZs/view .

Buchanan, R. W. et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr. Bull. 36 , 71–93 (2010).

Kreyenbuhl, J. et al. The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2009. Schizophr. Bull. 36 , 94–103 (2010).

New Jersey Division of Mental Health Services. Pharmacological Practice Guidelines for the Treatment of Schizophrenia . (2005). Available at: https://www.state.nj.us/humanservices/dmhs_delete/consumer/NJDMHS_Pharmacological_Practice_Guidelines762005.pdf .

Barnes, T. R. et al. Evidence-based guidelines for the pharmacological treatment of schizophrenia: updated recommendations from the British Association for Psychopharmacology. J. Psychopharmacol. 34 , 3–78 (2020).

National Institute for Health and Care Excellence (NICE). Psychosis and schizophrenia in adults: prevention and management. (2014). Available at: http://www.nice.org.uk/guidance/cg178 .

Scottish Intercollegiate Guidelines Network (SIGN). Management of Schizophrenia: A National Clinical Guideline . (2013). Available at: https://www.sign.ac.uk/assets/sign131.pdf .

Verma, S. et al. Ministry of Health Clinical Practice Guidelines: Schizophrenia. Singap. Med. J. 52 , 521–526 (2011).

CAS   Google Scholar  

Szulc, A. et al. Recommendations for the treatment of schizophrenia with negative symptoms. Standards of pharmacotherapy by the Polish Psychiatric Association (Polskie Towarzystwo Psychiatryczne), part 1. Rekomendacje dotyczace leczenia schizofrenii z. objawami negatywnymi. Stand. farmakoterapii Polskiego Tow. Psychiatrycznego, czesc 1. 53 , 497–524 (2019).

Google Scholar  

Szulc, A. et al. Recommendations for the treatment of schizophrenia with negative symptoms. Standards of pharmacotherapy by the Polish Psychiatric Association (Polskie Towarzystwo Psychiatryczne), part 2. Rekomendacje dotyczace leczenia schizofrenii z. objawami negatywnymi. Stand. farmakoterapii Polskiego Tow. Psychiatrycznego, czesc 2. 53 , 525–540 (2019).

Galletly, C. et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders. Aust. N. Z. J. Psychiatry 50 , 410–472 (2016).

Llorca, P. M. et al. Guidelines for the use and management of long-acting injectable antipsychotics in serious mental illness. BMC Psychiatry 13 , 340 (2013).

De Masi, S. et al. The Italian guidelines for early intervention in schizophrenia: development and conclusions. Early Intervention Psychiatry 2 , 291–302 (2008).

Article   Google Scholar  

Barnes, T. R. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J. Psychopharmacol. 25 , 567–620 (2011).

Correll, C. U. et al. Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia: systematic overview and quality appraisal of the meta-analytic evidence. JAMA Psychiatry 74 , 675–684 (2017).

Galling, B. et al. Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis. World Psychiatry 16 , 77–89 (2017).

Pillinger, T. et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry 7 , 64–77 (2020).

Rummel-Kluge, C. et al. Second-generation antipsychotic drugs and extrapyramidal side effects: a systematic review and meta-analysis of head-to-head comparisons. Schizophr. Bull. 38 , 167–177 (2012).

Angermeyer, M. C. & Matschinger, H. Attitude of family to neuroleptics. Psychiatr. Prax. 26 , 171–174 (1999).

CAS   PubMed   Google Scholar  

Dibonaventura, M., Gabriel, S., Dupclay, L., Gupta, S. & Kim, E. A patient perspective of the impact of medication side effects on adherence: results of a cross-sectional nationwide survey of patients with schizophrenia. BMC Psychiatry 12 , 20 (2012).

McIntyre, R. S. Understanding needs, interactions, treatment, and expectations among individuals affected by bipolar disorder or schizophrenia: the UNITE global survey. J. Clin. Psychiatry 70 (Suppl 3), 5–11 (2009).

Tandon, R. et al. The impact on functioning of second-generation antipsychotic medication side effects for patients with schizophrenia: a worldwide, cross-sectional, web-based survey. Ann. Gen. Psychiatry 19 , 42 (2020).

Zhang, J. P. et al. Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis. Int. J. Neuropsychopharmacol. 16 , 1205–1218 (2013).

Zhu, Y. et al. Antipsychotic drugs for the acute treatment of patients with a first episode of schizophrenia: a systematic review with pairwise and network meta-analyses. Lancet Psychiatry 4 , 694–705 (2017).

Kishimoto, T. et al. Relapse prevention in schizophrenia: a systematic review and meta-analysis of second-generation antipsychotics versus first-generation antipsychotics. Mol. Psychiatry 18 , 53–66 (2013).

Leucht, S. et al. Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, Bayesian meta-analysis, and meta-regression of efficacy predictors. Am. J. Psychiatry 174 , 927–942 (2017).

Samara, M. T., Nikolakopoulou, A., Salanti, G. & Leucht, S. How many patients with schizophrenia do not respond to antipsychotic drugs in the short term? An analysis based on individual patient data from randomized controlled trials. Schizophr. Bull. 45 , 639–646 (2019).

Zhu, Y. et al. How well do patients with a first episode of schizophrenia respond to antipsychotics: a systematic review and meta-analysis. Eur. Neuropsychopharmacol. 27 , 835–844 (2017).

Bogers, J. P. A. M., Hambarian, G., Michiels, M., Vermeulen, J. & de Haan, L. Risk factors for psychotic relapse after dose reduction or discontinuation of antipsychotics in patients with chronic schizophrenia. A systematic review and meta-analysis. Schizophr. Bull. Open 46 , Suppl 1 S326 (2020).

Tani, H. et al. Factors associated with successful antipsychotic dose reduction in schizophrenia: a systematic review of prospective clinical trials and meta-analysis of randomized controlled trials. Neuropsychopharmacology 45 , 887–901 (2020).

Uchida, H., Suzuki, T., Takeuchi, H., Arenovich, T. & Mamo, D. C. Low dose vs standard dose of antipsychotics for relapse prevention in schizophrenia: meta-analysis. Schizophr. Bull. 37 , 788–799 (2011).

Howes, O. D. et al. Treatment-resistant schizophrenia: treatment response and resistance in psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am. J. Psychiatry 174 , 216–229 (2017).

Masuda, T., Misawa, F., Takase, M., Kane, J. M. & Correll, C. U. Association with hospitalization and all-cause discontinuation among patients with schizophrenia on clozapine vs other oral second-generation antipsychotics: a systematic review and meta-analysis of cohort studies. JAMA Psychiatry 76 , 1052–1062 (2019).

Siskind, D., McCartney, L., Goldschlager, R. & Kisely, S. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br. J. Psychiatry 209 , 385–392 (2016).

Siskind, D., Siskind, V. & Kisely, S. Clozapine response rates among people with treatment-resistant schizophrenia: data from a systematic review and meta-analysis. Can. J. Psychiatry 62 , 772–777 (2017).

Wang, G. et al. ECT augmentation of clozapine for clozapine-resistant schizophrenia: a meta-analysis of randomized controlled trials. J. Psychiatr. Res. 105 , 23–32 (2018).

Tiihonen, J., Tanskanen, A. & Taipale, H. 20-year nationwide follow-up study on discontinuation of antipsychotic treatment in first-episode schizophrenia. Am. J. Psychiatry 175 , 765–773 (2018).

Taipale, H. et al. Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophr. Res . 197 , 274–280 (2018).

Taipale, H. et al. 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20). World Psychiatry 19 , 61–68 (2020).

Carbon, M. & Correll, C. U. Thinking and acting beyond the positive: the role of the cognitive and negative symptoms in schizophrenia. CNS Spectr. 19 (Suppl 1), 38–52 (2014).

PubMed   Google Scholar  

Krause, M. et al. Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis. Eur. Arch. Psychiatry Clin. Neurosci. 268 , 625–639 (2018).

Kane, J. M. et al. Effect of long-acting injectable antipsychotics vs usual care on time to first hospitalization in early-phase schizophrenia: a randomized clinical trial. JAMA Psychiatry 77 , 1217–1224 (2020).

Schreiner, A. et al. Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia. Schizophr. Res. 169 , 393–399 (2015).

Subotnik, K. L. et al. Long-acting injectable risperidone for relapse prevention and control of breakthrough symptoms after a recent first episode of schizophrenia. A randomized clinical trial. JAMA Psychiatry 72 , 822–829 (2015).

Tiihonen, J. et al. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am. J. Psychiatry 168 , 603–609 (2011).

Zhang, F. et al. Efficacy, safety, and impact on hospitalizations of paliperidone palmitate in recent-onset schizophrenia. Neuropsychiatr. Dis. Treat. 11 , 657–668 (2015).

Kishimoto, T., Nitta, M., Borenstein, M., Kane, J. M. & Correll, C. U. Long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies. J. Clin. Psychiatry 74 , 957–965 (2013).

Kishimoto, T. et al. Effectiveness of long-acting injectable vs oral antipsychotics in patients with schizophrenia: a meta-analysis of prospective and retrospective cohort studies. Schizophr. Bull. 44 , 603–619 (2018).

Kishimoto, T. et al. Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials. Schizophr. Bull. 40 , 192–213 (2014).

Kane, J. M., Kishimoto, T. & Correll, C. U. Assessing the comparative effectiveness of long-acting injectable vs. oral antipsychotic medications in the prevention of relapse provides a case study in comparative effectiveness research in psychiatry. J. Clin. Epidemiol. 66 , S37–41 (2013).

Kishimoto, T., Hagi, K., Kurokawa, S., Kane, J. M. & Correll, C. U. Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre-post studies. Lancet Psychiatry 8 , 387–404 (2021).

Cook, D. J., Mulrow, C. D. & Haynes, R. B. Systematic reviews: synthesis of best evidence for clinical decisions. Ann. Intern. Med. 126 , 376–380 (1997).

Higgins, J. P. T. & Green, S. Cochrane Collaboration Handbook for Systematic Reviews of Interventions . (The Cochrane Collaboration and John Wiley & Sons, Ltd, 2008).

Download references

Acknowledgements

This study received financial funding from Janssen Scientific Affairs.

Open Access funding enabled and organized by Projekt DEAL.

Author information

Authors and affiliations.

The Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY, USA

• Christoph U. Correll

Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA

Charité Universitätsmedizin Berlin, Department of Child and Adolescent Psychiatry, Berlin, Germany

Evidera, Waltham, MA, USA

Amber Martin & Emma Schiller

Janssen Scientific Affairs, LLC, Titusville, NJ, USA

Charmi Patel, Carmela Benson, Jennifer Kern-Sliwa & Kruti Joshi

Goulding HEOR Consulting Inc., Vancouver, BC, Canada

Rebecca Goulding

Biohaven Pharmaceuticals, New Haven, CT, USA

You can also search for this author in PubMed   Google Scholar

Contributions

C.C., A.M., R.G., C.P., C.B., K.J., J.K.S., E.S. and E.K. contributed to the conception and the design of the study. A.M., R.G. and E.S. conducted the literature review, including screening, and extraction of the included guidelines. All authors contributed to the interpretations of the results for the review; A.M. and C.C. drafted the manuscript and all authors revised it critically for intellectual content. All authors gave their final approval of the completed manuscript.

Corresponding author

Correspondence to Christoph U. Correll .

Ethics declarations

Competing interests.

C.C. has received personal fees from Alkermes plc, Allergan plc, Angelini Pharma, Gedeon Richter, Gerson Lehrman Group, Intra-Cellular Therapies, Inc, Janssen Pharmaceutica/Johnson & Johnson, LB Pharma International BV, H Lundbeck A/S, MedAvante-ProPhase, Medscape, Neurocrine Biosciences, Noven Pharmaceuticals, Inc, Otsuka Pharmaceutical Co, Inc, Pfizer, Inc, Recordati, Rovi, Sumitomo Dainippon Pharma, Sunovion Pharmaceuticals, Inc, Supernus Pharmaceuticals, Inc, Takeda Pharmaceutical Company Limited, Teva Pharmaceuticals, Acadia Pharmaceuticals, Inc, Axsome Therapeutics, Inc, Indivior, Merck & Co, Mylan NV, MedInCell, and Karuna Therapeutics and grants from Janssen Pharmaceutica, Takeda Pharmaceutical Company Limited, Berlin Institute of Health, the National Institute of Mental Health, Patient Centered Outcomes Research Institute, and the Thrasher Foundation outside the submitted work; receiving royalties from UpToDate; and holding stock options in LB Pharma. A.M., R.G., and E.S. were all employees of Evidera at the time the study was conducted on which the manuscript was based. C.P., C.B., K.J., J.K.S., and E.K. were all employees of Janssen Scientific Affairs, who hold stock/shares, at the time the study was conducted.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary information, reporting summary, rights and permissions.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ .

Reprints and permissions

About this article

Cite this article.

Correll, C.U., Martin, A., Patel, C. et al. Systematic literature review of schizophrenia clinical practice guidelines on acute and maintenance management with antipsychotics. Schizophr 8 , 5 (2022). https://doi.org/10.1038/s41537-021-00192-x

Download citation

Received : 26 February 2021

Accepted : 02 November 2021

Published : 24 February 2022

DOI : https://doi.org/10.1038/s41537-021-00192-x

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Psychosis superspectrum ii: neurobiology, treatment, and implications.

• Roman Kotov
• William T. Carpenter
• Katherine G. Jonas

Molecular Psychiatry (2024)

Antipsychotic Discontinuation through the Lens of Epistemic Injustice

• Helene Speyer
• Lene Falgaard Eplov

Community Mental Health Journal (2024)

Delphi panel to obtain clinical consensus about using long-acting injectable antipsychotics to treat first-episode and early-phase schizophrenia: treatment goals and approaches to functional recovery

• Celso Arango
• Andrea Fagiolini

BMC Psychiatry (2023)

Machine learning methods to predict outcomes of pharmacological treatment in psychosis

• Lorenzo Del Fabro
• Elena Bondi
• Paolo Brambilla

Translational Psychiatry (2023)

Comparison of clinical outcomes in patients with schizophrenia following different long-acting injectable event-driven initiation strategies

• Carmela Benson
• Panagiotis Mavros

Schizophrenia (2023)

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

• Dermatology
• Gastroenterology
• Geriatric Medicine and Gerontology
• Gynecology and Obstetrics
• Heart and Vascular
• Neurology and Neurosurgery
• Ophthalmology
• Orthopaedics
• Otolaryngology–Head and Neck Surgery
• Physical Medicine and Rehabilitation
• Plastic and Reconstructive Surgery
• Psychiatry and Behavioral Sciences
• Pediatric Specialties
• Pediatric Diabetes and Endocrinology
• Pediatrics Florida
• Pediatric Gastroenterology and GI Surgery
• Pediatric Heart
• Pediatrics Maryland/DC
• Pediatric Neurology & Neurosurgery
• Pediatric Orthopaedics
• Physician Affiliations
• Health Care Technology
• High-Value Health Care
• Clinical Research Advancements
• Precision Medicine Excellence
• Patient Safety

Case Study Illustrates How Schizophrenia Can Often Be Overdiagnosed

Share Fast Facts

Study shows how schizophrenia can often be over diagnosed. Learn how. Click to Tweet

Study author Russell Margolis, director of the Johns Hopkins Schizophrenia Center, answers questions on misdiagnosis of the condition and reiterates the importance of thorough examination.

It’s not uncommon for an adolescent or young adult who reports hearing voices or seeing things to be diagnosed with schizophrenia, but using these reports alone can contribute to the disease being overdiagnosed, says  Russell Margolis , clinical director of the Johns Hopkins Schizophrenia Center. 

Many clinicians consider hallucinations as the sine qua non, or essential condition, of schizophrenia, he says. But even a true hallucination might be part of any number of disorders — or even within the range of normal. To diagnose a patient properly, he says, “There’s no substitute for taking time with patients and others who know them well. Trying to [diagnose] this in a compressed, shortcut kind of way leads to error.”

A case study he shared recently in the  Journal of Psychiatric Practice  illustrates the problem. Margolis, along with colleagues Krista Baker, schizophrenia supervisor at Johns Hopkins Bayview Medical Center, visiting resident Bianca Camerini, and Brazilian psychiatrist Ary Gadelha, described a 16-year-old girl who was referred to the Early Psychosis Intervention Clinic at Johns Hopkins Bayview for a second opinion concerning the diagnosis and treatment of suspected schizophrenia.

The patient made friends easily but had some academic difficulties. Returning to school in eighth grade after a period of home schooling, she was bullied, sexually groped and received texted death threats. She then began to complain of visions of a boy who harassed her, as well as three tall demons. The visions waxed and waned in relation to stress at school. The Johns Hopkins consultants determined that this girl did not have schizophrenia (or any other psychotic disorder), but that she had anxiety. They recommended psychotherapy and viewing herself as a healthy, competent person, instead of a sick one. A year later, the girl reported doing well: She was off medications and no longer complained of these visions.

Margolis answers  Hopkins Brain Wise ’s questions.

Q: How are anxiety disorders mistaken for schizophrenia?

A:  Patients often say they have hallucinations, but that doesn’t always mean they’re experiencing a true hallucination. What they may mean is that they have very vivid, distressing thoughts — in part because hallucinations have become a common way of talking about distress, and partly because they may have no other vocabulary with which to describe their experience. 

Then, even if it  is  a true hallucination, there are features of the way psychiatry has come to be practiced that cause difficulties. Electronic medical records are often designed with questionnaires that have yes or no answers. Sometimes, whether the patient has hallucinations is murky, or  possible —  not yes or no. Also, one can’t make a diagnosis based just on a hallucination; the diagnosis of disorders like schizophrenia is based on a constellation of symptoms. 

Q: How often are patients in this age range misdiagnosed?

A:  There’s no true way to know the numbers. Among a very select group of people in our consultation clinic where questions have been raised, about half who were referred to us and said to have schizophrenia or a related disorder did not. That is not generalizable.

Q:   Why does that happen?

A:  There is a lack of attention to the context of symptoms and other details, and there’s also a tendency to take patients literally. If a patient complains about x, there’s sometimes a pressure to directly address x. In fact, that’s not appropriate medicine. It is very important to pay attention to a patient’s stated concerns, but to place these concerns in the bigger picture. Clinicians can go too far in accepting at face value something that needs more exploration. 

Q: What lessons do you hope to impart by publishing this case?

A:  I want it to be understood that the diagnosis of schizophrenia has to be made with care. Clinicians need to take the necessary time and obtain the necessary information so that they’re not led astray. Eventually, we would like to have more objective measures for defining our disorders so that we do not need to rely totally on a clinical evaluation. 

Learn more about Russell Margolis’ research regarding the challenges of diagnosing schizophrenia .

• About Johns Hopkins Medicine
• Contact Johns Hopkins Medicine
• Centers & Departments
• Maps & Directions
• Find a Doctor
• Patient Care
• Terms & Conditions of Use
• Privacy Statement

Connect with Johns Hopkins Medicine

Join Our Social Media Communities >

Clinical Connection

• Otolaryngology—Head and Neck Surgery
• Contact Johns Hopkins

© The Johns Hopkins University, The Johns Hopkins Hospital, and Johns Hopkins Health System. All rights reserved.

Privacy Policy and Disclaimer

• Search Menu
• Advance Articles
• Author Guidelines
• Submission Site
• Open Access Policy
• Self-Archiving Policy
• About Schizophrenia Bulletin Open
• About University of Maryland School of Medicine
• About the Maryland Psychiatric Research Center
• Editorial Board
• Advertising & Corporate Services
• Journals Career Network
• Journals on Oxford Academic
• Books on Oxford Academic

Article Contents

Introduction.

• Conclusions
• Acknowledgments
• < Previous

Inpatient Treatment of People With Schizophrenia: Quantifying Clinical Change Using the Health of the Nation Outcome Scales

• Article contents
• Figures & tables
• Supplementary Data

Barbara Lay, Patrik Roser, Wolfram Kawohl, Inpatient Treatment of People With Schizophrenia: Quantifying Clinical Change Using the Health of the Nation Outcome Scales, Schizophrenia Bulletin Open , Volume 2, Issue 1, January 2021, sgab030, https://doi.org/10.1093/schizbullopen/sgab030

• Permissions Icon Permissions

Schizophrenia can require hospital inpatient care in crisis periods or times of severe symptoms, although the length of hospital stays has been considerably reduced in the last few decades. Evidence on individual outcomes under routine psychiatric practice conditions is sparse. This study aims to evaluate the outcomes of inpatient treatment in patients with schizophrenia using the reliable and clinically significant change approach. We used routinely collected Health of the Nation Outcome Scales (HoNOS) data to assess the extent to which and the areas where symptomatic and functional improvement was achieved. Data from 1783 schizophrenia patients admitted to a large psychiatric centre in Switzerland were examined.

Mean HoNOS total score dropped from 17.9 to 11.7 (effect size 0.8) during treatment; the greatest improvements were achieved regarding symptomatic problems and aggressive, agitated behavior. According to the reliable change index formula, 24.5% of patients were to be considered improved, 73.3% unchanged and 2.2% deteriorated. In total, 56.6% were discharged from the hospital in a subclinical or mild functional state. The degree of individual improvement and time to achieve maximum symptom reduction varied considerably, depending on the patients’ functional state at admission, as did the length of hospital stay (median 28 days). Rates of readmission within 28 days (17.8%) were significantly lower in patients with clinically significant improvement, discharged in better clinical condition. These findings support reconsidering (length of) inpatient treatment within the overall framework of meaningful clinical change and subsequent treatment needs in patients with schizophrenia.

Schizophrenia is a particularly severe disorder and one of the leading causes of disability worldwide. According to the Global Burden of Disease study 2016, schizophrenia was ranked as the 12th most disabling disorder globally. 1 Long-term outcome studies report that a large number of schizophrenia patients have residual symptoms between episodes (13%−48%) or a chronic course of illness (10%−40% 2 , 3 ). Moreover, schizophrenia is often associated with co-occurring mental or behavioral disorders and other medical conditions. 4 Impairment in daily life is thus significant, with major implications for independence of residence, ability to work and social interactions. 5 , 6 Life-long mental health care and support therefore remains vital for most individuals with schizophrenia.

Despite the development of drug treatments and of community-based alternatives to psychiatric hospital care in the last decades, readmissions to hospital due to clinical deterioration are still frequent in the treatment of schizophrenia. A recent meta-analysis reported that more than half (55%) of all first episode psychosis (FEP) patients required hospitalisation over an average follow-up of 7 years after FEP. 7 Moreover, the proportion of people with FEP who were readmitted to a psychiatric hospital remained stable over time (1966–2017). Findings based on a number of longitudinal studies from German-speaking countries actually suggested that patients suffering from schizophrenia are more (or most) likely to be “high utilizers” of inpatient psychiatric services. 8–11 In Switzerland, treatment for an ICD-10 F2 main diagnosis currently accounts for about one fifth of all inpatient admissions (19.4% in 2019) according to national psychiatry statistics covering the 42 acute care psychiatric hospitals in Switzerland. 12

Hospital-based treatment, however, has been efficiently reduced in most high-income countries for many years. In the European Union, psychiatric care beds in hospitals decreased on average per 100 000 inhabitants from 74.9 in 2008 to 68.0 in 2018. 13 For individuals with schizophrenia length of stay in the hospital (LOS) was considerably reduced. In Switzerland, for example, LOS has decreased by half for patients with psychoses in the space of three decades 14 and is now below the OECD average. 15 This development has been driven by several factors: concerns about the counter-productive effects of reduced autonomy, availability of alternative treatment options, service users’ preferences, and, not least, increasing pressure to cut public expenditure on health care, particularly in view of the fact that hospitalizations account for a large share of health care costs. 7 , 16

Nevertheless, it is widely acknowledged that hospital admissions are unavoidable in people with an acute exacerbation of psychosis that cannot be managed safely in an outpatient setting. According to the German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN) S3-guideline for schizophrenia, “inpatient psychiatric-psychotherapeutic treatment is offered if patients require particular diagnostic and therapeutic measures or need the special protection of the hospital because they pose an acute risk to themselves or others” ( 17 , p. 79), and it is recommended “that hospitalizations are short and planned, if possible” ( 17 , p. 78). A guideline cannot precisely specify “short” (LOS) of course, that is, how long it will take to reduce the risk of self-harm or harm to others, positive psychotic symptoms, aggression or agitation to a degree that allows safely discharging a patient into the community. In clinical practice, it is most often at the attending psychiatrist’s discretion, who, in coordination with a multiprofessional team, performs this clinical evaluation, based on his/her own judgement and experience. Routine clinical data are rarely used as a standard for the evaluation process.

Despite the vital role hospital admission still plays in the treatment of schizophrenia, information on the magnitude of individual change (compared to initial symptoms, behavior problems or functional disabilities) achieved in clinical inpatient settings is still scant. In particular, it is not fully understood how length of hospital care translates into symptomatic and functional improvement in patients with psychoses. Moreover, important questions regarding the effects of shortening LOS on clinical outcomes remain unanswered, for example, questions regarding the necessary and sufficient LOS to ensure clinically meaningful change, or the patient groups most likely to benefit from a shorter hospital stay. Therefore, the extent to which LOS may be further reduced whilst still resulting in clinically relevant outcomes and meeting the needs of the patients concerned is a matter of ongoing dispute.

With the adoption of quality control processes, routine outcome monitoring has been implemented nationwide in many countries, including Switzerland, to promote the evaluation of mental health services performance. Measuring clinically meaningful change during treatment is a key part of this. For the evaluation of such data, performance indicators have been proposed and statistically explored. 18 , 19 On the basis of these methods several studies have been carried out recently in the Netherlands and Italy, yielding results for large patient samples treated in community mental health services, 20 integrated mental health institutions, 18 a medical psychiatric unit of a general hospital, 21 and child mental health facilities. 22 Such evaluations go far beyond the conventional use of statistical significance tests (to compare pre-post treatment group means), shifting the focus from “is there any difference” to “how big is the difference.” These studies examined outcomes on a service level, however, thus covering a broad range of mental disorders, rather than focusing on people with psychoses.

In the present study, we sought to apply these indicators of treatment outcome to an unselected sample of patients who received inpatient treatment for schizophrenia or related disorders. To determine clinical change during inpatient treatment we used HoNOS (Health of the Nation Outcome Scale) data collected in everyday clinical practice. Specifically, this study aimed:

to assess the extent to which, and in what areas, symptomatic and functional improvement is achieved in this patient group in terms of categorical indicators of clinically meaningful change and pre-post treatment differences;

to study how treatment outcomes relate to the length of inpatient stay,

and how outcomes relate to the risk of hospital readmission shortly after discharge.

Ethical approval for this secondary analysis of health-related patient data was obtained from the Swiss Ethics Committees on research involving humans (EKNZ ID 2020-01804).

Sample—Data Basis

Between January 1, 2016 and December 31, 2019, a total of 11 876 people received inpatient treatment in the Department of Psychiatry and Psychotherapy of the Psychiatric Services Aargau (PDAG). The PDAG comprise all mental health services in the Swiss Canton of Aargau, a catchment area of around 690 000 inhabitants. The PDAG, within which the Department of Psychiatry and Psychotherapy covers the mental health care for adults, have a mandate to provide acute mental health care for the whole population. This study included all patients aged between 18 and 65 years who had been treated for schizophrenia or related disorders (main diagnosis ICD-10 F2). In total, 2249 inpatient admissions meeting the inclusion criteria during the index period were identified ( basic sample ).

Inpatient Treatment

The treatment of schizophrenia in the PDAG includes pharmacological and nonpharmacological therapeutic interventions according to the DGPPN S3 guideline for schizophrenia. The nonpharmacological treatment particularly consists of psychoeducational and psychotherapeutic interventions, cognitive and social skills training, occupational and exercise therapy as well as family and community interventions, provided by a multiprofessional treatment team. In the case of severely aggressive and agitated behavior in combination with the high risk of self-harm or harm to others, de-escalating interventions including seclusion and/or parenteral medication may be required.

Data Collection

The patients’ sociodemographic, diagnostic, and treatment-related data were extracted from the electronic medical database of the PDAG. All psychiatric hospitals in Switzerland are obliged to report data on admissions, discharges, and treatment measures in a standardized form to the Federal Office of Statistics. The completeness of these documents is regularly monitored. The hospital doctors in charge of a given patient are responsible for diagnostic assessments and for completing the documentation.

Within the framework of the national quality assurance programme (ANQ), 12 psychiatric hospitals are moreover committed to evaluating the inpatient treatment the patients received. The Health of the Nation Outcome Scale (HoNOS), 23 an internationally established instrument for the assessment of clinical problems and social functioning of patients with mental illness, is used in this study to evaluate treatment outcomes. The Swiss ANQ provides an anchored version of the HoNOS, however the raters had no special training. The HoNOS ratings were made by the attending doctors within the first three days after admission to the hospital (t1) and within the last three days before leaving the hospital (t2).

The HoNOS comprises 12 items covering four key areas of functioning: behavior, impairment, symptoms, and social functioning. Each of the 12 items is rated on a 0–4 scale of severity (0 = no problem; 1 = minor problem requiring no action; 2 = mild problem but definitely present; 3 = moderately severe problem; 4 = severe to very severe problem). Reference time period for the assessment are the previous 7 days.

The reliability of the HoNOS has been reported to be fair to good. 19 , 24 , 25 Validity in terms of congruence with responses on conceptually similar instruments, like CGI, GAF, BPRS (convergent validity) and sensitivity to change was found to be satisfactory. 25 , 26 Normative data from a functional population are lacking for this instrument. 22

We excluded from the current analysis HoNOS ratings in which more than 3 rateable items were left uncompleted, because there were doubts about the adherence to assessment guidelines and clinical validity of such evaluations (t1: N = 5; t2: N = 3; 460 measures missing completely). Thus, HoNOS measures were available for N = 2244 (99.8% of the basic sample) upon admission and for N = 1786 (79.4%) upon discharge. In 1783 patients (79.3%) a HoNOS assessment had been made at admission and at discharge ( study sample ).

In cases in which a HoNOS evaluation had ≤3 missing items, we imputed the missing values using the Weighted mean approach proposed by Gale and others. This approach is regarded as highly useful for predicting missing item scores accurately in routinely used depression scales 27 and has been found to yield more accurate predictions for HoNOS data in modelling studies than other techniques of imputation. 28 Considering that these studies were based on patient samples with a wide range of mental health conditions within general psychiatry, we generated new HoNOS item weights from our database (confined to schizophrenia patients). HoNOS measures that contained a full set of valid scores (t1: N = 1445; t2: N = 1490) were used to establish the item weights for the 12 items. Missing item values were then replaced by the resultant weighted mean scores of all completed items.

Dropout Analysis

A dropout analysis comparing clinical aspects of patients with (study sample) and without HoNOS discharge assessments (dropouts) revealed statistically significant group differences in several clinical aspects.

Most importantly, of the 463 dropouts, 431 (93.1%) had left the psychiatric hospital within 7 days after admission. According to the ANQ guidelines a second HoNOS assessment was not required for these cases during the index period of this study, which is why second HoNOS assessments were not available.

Regarding relevant clinical aspects of patients without HoNOS t2 assessments, 61.2% of them had been in the hospital only for crisis intervention (vs. 20.7% of the study sample), and 45.4% had left the hospital against medical advice (vs. 17.7%). A higher percentage of the dropout group was male (66.1% vs. 60.5%). Moreover, the dropout group was on average 4.5 years younger (36.2y vs. 40.7y). Overall, almost one in four patients had a substance use disorder as a comorbid condition. In the dropout group, however, comorbidity with substance use disorders was, at 27.6%, more prevalent than in the study sample (20.4%).

Regarding the HoNOS ratings at admission, there were statistically significant, albeit small differences between the dropout and study sample on all HoNOS items except item 11 (living conditions). Therefore, the HoNOS t1 scores of the basic sample are presented in Table 2 , in addition to those of the study sample.

Indicators of Treatment Outcome

Mean d ifference ∆t1 − t2 and e ffects s ize (es)..

As a statistical indicator of change under treatment we computed the standardized mean difference between HoNOS scores at admission and at discharge (effect size; ES), which is the most commonly used effect indicator to denote within-group effect size in treatment outcome research. 18 Positive values of ∆t1 − t2 indicate a lower level of severity in this study, while negative values indicate a higher level of severity at t2, compared with t1.

Classification of Severity.

To analyze outcomes beyond conventional pre-post tests of differences on a group level we used further (clinical) criteria. The HoNOS were constructed to be as independent as possible, with each item rating representing a clinical judgement of severity in itself. We therefore classified “severity” based on the number of individual items with a certain severity score, instead of using cut-offs based on the total score. We used the criteria suggested by Parabiaghi 20 to discriminate between four categories: a score of ≥3 on at least one HoNOS item was adopted to discriminate between “severe” and “nonsevere” cases. Subjects with a score of ≥3 on at least two HoNOS items were classified as “very severe.” Nonsevere subjects were regarded as “subclinical” if they had scores <2 on all items. Subjects were classified as “mild” if they had a score of 2 on at least one item. Thus, the sample was stratified into four severity groups, both at admission and at discharge.

Reliable Change Index (RCI).

The RCI, developed by Jacobson & Truax, 29 is a psychometric criterion used to decide whether the change in an individual’s score is statistically significant or not, based on how reliable the measure is. For measures based on the Jacobson–Truax method, ecological validity has been established 30 and they are widely used to determine meaningful individual improvement. In the present study we specified a 95% confidence level which equates to a RCI of ≥1.96. We estimated the standard error of measurement using the reliability statistic for the HoNOS total score (Cronbach’s α = 0.713). On this basis we calculated the RCI adopting the formula of Jacobson & Truax. The resulting RCI of 10.5 means that an individual change score greater than this would occur in less than 5% of the cases through the fluctuations of imprecise measuring alone. Differences in HoNOS scores at admission and at discharge within the range of +11 and −11 were therefore classified as “no reliable change,” whereas change scores of +11 or above are regarded as significant improvement and change scores of −11 or below as significant deterioration.

Considering that some prior studies 18 , 20 , 31 are based on a RCI change threshold of ≥8, we furthermore analyzed our data using this less stringent cut-off. These results will be included in the tables to allow for comparability.

Reliable and C linically S ignificant C hange (RCSC).

To study statistical significance of change together with the symptomatic and functional state in which the patient had left the hospital, we combined the two criteria “level of severity” (as described above) and “RCI.” Thus, we determined the proportion of patients whose HoNOS total score not only had improved significantly, but whose scores also had moved out of the category of “severe” cases to a mild or subclinical level of severity at t2.

Similarly, the proportion of patients with significantly deteriorated change scores who had moved from a “nonsevere” to a “severe” group was determined. This was the case in only a small minority of the sample (39; 2.2%). We therefore merged this group with the RCSC group “unchanged” in the further analyses.

Statistical Analysis

Effect size statistics in the present study are calculated within a repeated measures design. Therefore, we used the formula for correlated measures applying Psychometrica 32 to compute ES with 95% confidence intervals. Test results are considered statistically significant at P < .05, two-tailed.

To compare patients with and without a HoNOS discharge assessment (dropout analysis) regarding clinical patient characteristics we used independent samples t -tests (HoNOS items; age) and chi 2 -tests (categorical variables). To test changes in HoNOS measures during inpatient treatment (t2 compared to t1) we applied paired t -tests.

To operationalize “use of inpatient psychiatric treatment” we specified two key parameters: “length of inpatient stay” LOS and “time to inpatient readmission.” LOS, which does not usually have a normal distribution and is extremely right-skewed in our data as well, was analyzed using nonparametric tests (dropout comparisons: Mann–Whitney U tests; differences in LOS between HoNOS outcome categories: Mann–Whitney U tests, Kruskal–Wallis tests). In addition, we explored the kind of association between HoNOS outcome measures and LOS by displaying ∆t1 − t2 and RCI change rates graphically. To this end the (ranked) LOS data were split up into 10 equally large subsections (deciles). Thus, each decile comprised 1/10 of the sample, corresponding to an increase in LOS of 10 percentage points.

For the analysis of “time to readmission” we used a sub-sample, namely patients who had been discharged from the hospital before September 30, 2019 ( N = 1671). This selection was made (in this analysis only) to ensure a sufficiently long follow-up period after discharge in all cases. We assessed whether a patient had been readmitted to the psychiatric hospital within a 28-day period following discharge. Readmission to hospital within 28 days is considered to be related to outcome, and serves in some countries as an indicator of the quality of care. 30 We examined the effect of the HoNOS-based indicators of outcome on the readmission risk using logistic regression analysis. Statistical analyses were performed using SPSS version 26.0 (IBM 2019).

Sample Characteristics

The descriptive statistics for the basic sample of 2249 patients are displayed in Table 1 . The majority of patients included in this study were admitted for a schizophrenic disorder (ICD-10 F20). In 31% of this sample the admission had been compulsory, 23% left the psychiatric hospital against medical advice. Regarding their sociodemographic background, the sample (mainly men; mean age: 40 years) is characterized by a high rate of people dependent on social welfare payments (46%) and living alone (73%).

Characteristics of the Basic Sample ( N = 2249)

a Age range: 18–65 years.

Change in HoNOS Scores Before and After Inpatient Treatment

A comparison of mean HoNOS scores at admission (t1) with those at discharge (t2) is shown in Table 2 . Between the two time points there was a statistically significant decrease in levels of severity across the 12 HoNOS scales; the HoNOS total score declined from 17.9 to 11.7 ( P < .001). In terms of effect size (ES), the magnitude of change, however, was only small in 8 of the 12 HoNOS scales, whereas in three scales (“aggression/overactivity,” “depressive symptoms,” “other mental health problems”) the ES value exceeded 0.5, which means that the sample moved half of the standard deviation in the asymptomatic direction on these scales. With an ES of 0.8, changes in the HoNOS scale “problems associated with hallucinations and delusions” and in the HoNOS total score, overall, were most pronounced.

Comparison of HoNOS Scores at Admission (t1) and at Discharge (t2)

SD, standard deviation.

ES, effect size ( d repeated measures); 95% confidence interval.

Δt1 – t2, differences t1 – t2 (positive values indicate lower = improved t2 scores).

Assessing the extent to which symptomatic or functional improvement is achieved we found marked differences in some of the HoNOS scales, depending on the level of severity at admission ( figure 1 ). Whereas patients who had been classified as “severe” or “very severe” at admission showed greatest improvement during treatment regarding the item “hallucinations and delusions,” there were only minor effects in the mild severity group. In the “very severe” group, improvement regarding ’other mental health problems’ ranged second. In the “mild severity” group the most pronounced improvement was found in “aggression/overactivity” and “depressive symptoms.” Across all levels of severity, “aggressive, overactive” behavior problems had improved at discharge. However, in the “mild” and “severe group” results also suggest that “problems with occupation and activities” had deteriorated at discharge rather than improved.

Mean change in HoNOS scores (Δ t1 − t2), by severity level at admission (t1).

Table 3 shows the proportion of patients moving (at t2) into another severity group according to the severity criteria defined above (left columns), who showed reliable change according to the RCI (centre columns), or reliable and clinically significant change according to the RCSC (right columns), broken down by severity grouping at t1.

Categorical Shift t1 – t2 and Clinical Change Indices of HoNOS Scores ( N = 1783)

RCI 95% , reliable change index, 95% confidence level.

RCSC 95% , reliable clinically significant change, 95% confidence level.

Categorical Shift.

The clinical condition at admission had been classified as very severe in 1167 subjects (65.5%), as severe in 369 (20.7%), and as mild in 247 (13.9% including 1% subclinical states). The comparison of t1 and t2 rates shows that, in total, the rate of 86.2% admitted with “severe or very severe” functional impairment (score of ≥3 in at least one HoNOS item) has been reduced by half at discharge (43.4%). Within the 247 “nonsevere” cases at admission, 72.9% had remained in this category at t2, whereas a categorical shift to a “severe” condition was found in 27.1%. Within the group of 1536 “severe” cases at admission, 46.0 % were still classified as “severe” at discharge, whereas a categorical shift to a “nonsevere” condition was found in 54.0%.

Reliable Change.

The relationship between the pairwise individual HoNOS total scores at t1 and t2 is depicted in supplementary figure 1S . According to the RCI determined for this sample, no reliable change (i.e., change beyond what could be attributed to measurement error or chance) was observed in 73.3% of the sample (dots within the 95% confidence limits). In a small number of patients, 2.2% of the sample, HoNOS total scores had significantly deteriorated by t2, whereas in 24.5% a significant improvement was found (RCI ≥ 11). If the less stringent threshold “change of at least 8 points” were to be applied, this would have resulted in a rate of 52.1% being classified as “unchanged,” whereas 4.6% would be classified as worsened and 43.3% as improved.

When RCI rates are stratified according to the “severity of the clinical condition at admission,” significant deterioration is found in a small minority of cases across all categories of severity at t1. Rates of significantly improved patients (RCI ≥ 11) clearly increased with a higher severity level at t1: whereas in the “mild severity” group the HoNOS total score significantly decreased in 4.0%, we found 8.9% in the “severe” group and 33.7% in the “very severe” group. It is obvious, however, that in mild or subclinical conditions a major decrease in HoNOS scores is basically impossible.

Reliable and Clinically Significant Change.

Not all who underwent a reliable significant change between t1 and t2, were fully recovered in the sense that they no longer were classified as “severe” cases according to the above classification of severity. We found reliable and clinically significant change in 17.9% of this sample. The RCSC rate was at 24.2% highest in the “very severe” group at t1. This means that for almost one in four patients in this group the HoNOS total score had been reduced by 11 points or more and severity of symptoms had reached a mild or subclinical level (at a cut-off of 8 points, the corresponding RCSC recovery rates are 30.5% in the total sample, and 36.7% in the “very severe” group).

Treatment Outcome and Length of Inpatient Stay (LOS)

The average length of stay in hospital in the study sample was 28.0 days (median; mean 36.9; SD 30.4). In 10% of the sample inpatient treatment took longer than 76 days, and in some cases more than 200 days. A higher level of severity at admission was found to be associated with a longer hospital stay: whereas the LOS in patients who had been classified as “subclinical/mild” was 24.0 days (median), it was 26.0 days in the “severe” and 29.0 days in the “very severe” group (LOS differences statistically significant; P = .013).

Regarding the outcome criterion RCI the group comparison showed that time in hospital was, at 26.0 days (median), shortest in the “no reliable change” group. “Reliably improved” patients stayed 5.5 days longer, that is, on average 31.5 days, in inpatient treatment. In the small group of “reliably deteriorated” patients, the LOS was 34.0 days ( P < .001).

This corresponds, by and large, to the LOS ascertained for the RCSC groups: Patients with reliable and clinically significant change were in the hospital for 31.0 days on average, whereas in the “unchanged or deteriorated” group LOS was 27.0 days ( P = .001).

To further explore how change in HoNOS scores varies with LOS, we compared outcomes across the 10 decile subsections according to the LOS distribution. Supplementary figure 2S gives the extent of improvement (∆t1 − t2 HoNOS total score) achieved within each decile group, in total (red line), and stratified by level of severity at t1. The mean ∆t1 − t2 scores averaged at 1.9 in the “subclinical/mild,” 3.4 in the “severe” and 7.9 in the “very severe” group.

As to the total sample, results suggest that improvement was highest in patients who had spent 22–27 days in the psychiatric hospital. Up to this point, HoNOS scores increasingly improved with longer LOS. Marked improvement was also achieved with longer hospital stays, but no greater improvement was found in these patients.

A closer look at the three severity groups shows that the improvement “curve” closely follows this pattern in the “very severe” group. This is not unexpected, considering that this group accounts for 65.5% of the total sample. HoNOS improvements in the “very severe” group were considerably higher throughout all LOS deciles than those of the lower severity groups, peaking at 10.3 points (∆t1 − t2) in patients who spent 22–27 days in the hospital. Regarding the “severe” group, the findings suggest that a maximum improvement is already reached after 18–21 days. After 35 days of inpatient stay only small improvements (<2.9 points) are found (apart from the outlier at LOS “77+”). In the “subclinical mild” group, which showed the least pronounced changes throughout, the maximum improvement of 4.1 points occurs even earlier, after 10–13 days. Longer inpatient stay in this severity group was associated with only very small improvement and, after 77 days, even deterioration in clinical problems.

In the same way, outcome in terms of RCI rates was compared across LOS deciles. Supplementary figure 3S gives the rate of patients whose HoNOS scores had been classified as reliably improved, unchanged, or worsened within in each time section. This comparison reveals that rates of “reliably improved” patients increased steadily up to 31.2% at LOS 22–27 days and varied between 24.9% and 32.0% after that. Regarding the “unchanged” group which represent a majority (73.3%) of the whole sample, rates run counter to the above, decreasing from 85.6% to 67.3% up to a LOS of 22–27 days. “Reliably deteriorated” patients were found to be almost evenly distributed across any LOS time (rates between 1.5% and 3.8%).

Treatment Outcome and Hospital Readmission

Readmission to hospital soon after discharge is an undesirable course of treatment, in general suggesting that the patient did not remain stable, thus being widely used as a proxy of “relapse.” We therefore sought to examine how the HoNOS-based clinical change indices are related to readmission within 28 days of discharge. In total 17.6% were readmitted within 28 days. Results suggest that this rate is directly related to the level of severity at discharge ( supplementary table 1S ): for those who had been discharged in a clinical condition that had been classified as “very severe,” this readmission rate was (at 26.0%) three times that of patients discharged in a “subclinical” level of severity (7.8%).

All clinical change indices were significantly linked to the likelihood of early readmission as well. Regarding the RCI, results suggest that there was an almost 50% decrease in the odds of being readmitted within 28 days given reliable clinical improvement at discharge (OR 0.52; compared to RCI “unchanged”). For the RCSC group “reliable and clinically significant change” this risk had decreased even further (OR 0.33). The regression coefficients of all clinical change indices suggest that the risk of being readmitted within 28 days after discharge is significantly lower in “improved,” compared to “unchanged” clinical conditions, whereas no such statistical differences were found between “unchanged” and “deteriorated” clinical conditions.

The present study examines the outcome of inpatient psychiatric treatment of people with schizophrenia and related disorders. We analyzed a data-set of 2249 inpatient admissions to a large Swiss psychiatric service to determine the magnitude of individual clinical change and its relationship to LOS.

Symptomatic and Functional Status at Admission

Most of these patients had been admitted to the psychiatric hospital in a severely impaired functional status; adopting the criteria suggested by Parabiaghi, 20 86.1% were classified as severe or very severe. By comparison, the overall level of severity at admission was, with a mean HoNOS total score of 17.9, similar to that reported from Medical Psychiatric Units in the Netherlands (16.2; 21 ). In patients admitted to community mental health services presenting with psychosis, less severe clinical problems were found at initial assessment in a large observational study from the UK (HoNOS total score 11.1; 33 ) as well as in large-scale studies on “mixed” samples attending community mental health services in Italy and the Netherlands (11.6 31 ; 12.4 18 ). Initial scores in these studies are quite close to the mean HoNOS score of our study sample at discharge, or even lower (8.9 34 ). A comparatively higher level of severity (22.9), however, was reported by a Swiss psychiatric hospital specialized in treating “heavy-users” for patients with an ICD-10 F2 main diagnosis. 35 Even if comparisons between patient populations should be made with due caution, these initial scores seem to suggest that opting for inpatient treatment reflects a higher overall level of clinical problems. The current analysis shows that symptomatic problems (hallucinations, delusions) were of primary importance for admission to hospital treatment.

Clinically Meaningful Change

To examine mental health outcome, pre-post differences are usually analyzed relying on statistical significance alone, which does not allow us to draw conclusions on the relevance of clinical outcomes. Measures based on the Jacobson-Truax method therefore have been recommended to evaluate the extent of individual change. In the present study a reliable change was achieved in 24.5% of the sample during treatment.

There are only few studies in psychiatry that have examined treatment effects using HoNOS measures in this way. A recent study on the functional status and healthcare needs of 50 patients with complex medical and psychiatric morbidity reported reliable improvement in 8% of this sample. 21 The results of a modelling study based on data from Australian mental health services indicated a rate of 38.0% significantly improved (and 60.8% without significant change) in adults in acute inpatient settings. 19 In a large-scale study evaluating community mental health services in Italy, rates of 14.4% improved, 82.5% stable, and 3.2% worsened have been reported at RCI 95% for the subgroup of patients who had been classified as “severe”. 20 In all these studies samples of mixed cases were analyzed. This suggests that the relatively large proportion of patients who did not show meaningful change during treatment in our study (73.3%) is not a result that specifically characterizes the treatment outcome of patients with psychosis. Considering that in community mental health settings “stabilization” of a patient alone can be regarded as a favorable outcome, whereas in inpatient treatment the efficient reduction of acute symptoms has priority, a higher rate of reliably improved patients, however, is to be expected in inpatient treatment.

Some methodological aspects should also be borne in mind. The proportion of “improved” (unchanged, worsened) patients immediately depends on the stringency of the criterion for RCI that is applied. As is the case in all statistical hypothesis testing, where the significance level for a test is chosen by the researcher, there is no universal reference value. We used a 95% confidence level because it is most commonly used, but it is clear that a lower threshold would produce a higher proportion of patients who can be considered “improved.” Moreover, it has been argued that the RCI is a conservative measure, quickly resulting in a large proportion of “unchanged” patients. 18 , 19 , 31 It is an asset of the RCI, however, that it explicitly addresses the issue of measurement error, so that we can be reasonably confident that the observed changes are statistically reliable and reflect real improvement, rather than spurious differences. The baseline level of symptom severity is a further factor affecting the likelihood of achieving “improvement.” In the present sample, a large minority of 15.1% had an initial HoNOS score of <11 and were thus factually unable to pass the threshold of reliable change. On the basis of the data available, it is uncertain whether in these mild forms of symptom or functional severity inpatient admission could have been prevented.

The majority of this sample showed most pronounced improvements regarding problems with hallucinations and delusions. Also, with regard to other mental health problems, depressed mood and aggressive behavior, substantial changes were identified. This suggests that inpatient treatment was effective in reducing particularly symptomatic and behavioral problems, that is, those domains in which these patients had scored highest at admission and upon which inpatient treatment of individuals with schizophrenia often primarily concentrates. An evaluation of the effectiveness of routine NHS care in the UK recently showed an outcome profile across the 12 HoNOS scales that is very similar to the one found in the current study, with most notable improvements in the “hallucinations” and “other mental and behavior problems” scales for patients with psychotic mental illnesses. 33 Greatest improvement in symptom domains in which pretest severity was highest is a finding, however, that has been repeatedly reported in the literature. 18 , 33 , 34 , 36 Regarding the further HoNOS scales we found only small effects. As to self-injury and physical illness this could possibly be explained by low prevalence at admission. As to cognitive problems as well as social problems, we can only speculate: difficulties in social and occupational functioning might have been not so much in focus as targets in acute admissions; but it could also mean that these are problem areas that are particularly difficult to change during short inpatient treatment, or that are particularly difficult to change in individuals with psychosis.

The small group of patients (2.2%) whose mental health status significantly deteriorated during inpatient treatment demands our special attention. Further research efforts will be required to understand the key factors behind such worsening and to better address their treatment needs.

Treatment Outcome and LOS

Overall, the HoNOS total score improved on average by 6.2 points (ES 0.79). This reduction is within the range other studies (of mostly “mixed” samples with only few or no psychotic patients) have found, which reported reduction in HoNOS scores ranging between 4.6 and 7.9 (ES 0.6−1.58 21 , 35–37 ) after inpatient treatment.

Results of this analysis suggest that routine inpatient treatment was effective. Nevertheless, one might ask whether equivalent outcomes would also have been achieved with shorter inpatient stays. The current study cannot conclusively answer this question, as a well-controlled trial would be necessary, but it may provide a more differentiated picture than the usual analyses of LOS predictors do, in which clinical change during treatment is typically not addressed.

According to the present data hospital stay was on average 4 days longer in patients who achieved reliable and clinically significant change, but the time at which the improvement peak is reached strongly depends on initial symptom severity: Patients with schizophrenia admitted in a very severe clinical condition reached the point of optimal improvement in health and social functioning on average 12 days later than those admitted with only mild clinical problems. In previous research factors related to clinical severity and poor social functioning were usually associated with longer LOS 38 , 39 ; this is corroborated by the present findings.

The relation between patient outcome and LOS raises the question of the role and the contribution of the tarification system being applied. Reimbursement of in-hospital treatments in Switzerland is regulated by a payment system based on diagnosis-related groups which provides incentives for early discharge of patients in the form of declining daily reimbursements with longer LOS. The impact of this reimbursement system on the quality of care and patient outcomes has not yet been fully understood. 39–41 Especially with regard to severe mental illness it is still unclear whether it is associated with reduced LOS or improved efficacy of inpatient treatment.

Case study: treatment-resistant schizophrenia

WELLCOME CENTRE HUMAN NEUROIMAGING/SCIENCE PHOTO LIBRARY

Learning objectives

After reading this article, individuals should be able to:

• Describe the management of schizophrenia;
• Understand pharmaceutical issues that occur during treatment with antipsychotics, especially clozapine ;
• Explain how the Mental Health Act 1983 impacts on care;
• Understand the importance of multidisciplinary and patient-centred care in managing psychosis.

Around 0.5–0.7% of the UK population is living with schizophrenia. Of these individuals, up to one-third are classified as treatment-resistant. This is defined as schizophrenia that has not responded to two different antipsychotics ​[1,2]​ .

Clozapine is the most effective treatment for such patients ​[3]​ . It is recommended by the National Institute for Health and Care Excellence (NICE)[4], and is the only licensed medicine for this patient group ​[4,5]​ . For treatment-responsive patients, there should be a collaborative approach when choosing a treatment ​[4]​ . More information on the recognition and management of schizophrenia can be found in a previous article here , and in accompanying case studies  here . 

This case study aims to explore a patient’s journey in mental health services during a relapse of schizophrenia. It also aims to highlight good practice for communicating with patients with severe mental illness in all settings, and in explaining the role of clozapine. 

Case presentation

Mr AT is a male, aged 26 years, who has been diagnosed with paranoid schizophrenia. He moved to the UK with his family from overseas five years ago. He lives with his parents in a small flat in London. His mother calls the police after he goes missing, finding his past two months’ medication untouched. 

He is found at an airport, attempting to go through security without a ticket. He is confused and paranoid about the police asking him to come with them. 

He is taken to A&E and is medically cleared (see Box 1) ​[6]​ . 

Box 1: Common differentials for psychotic symptoms

Medical conditions can present as psychosis. These include:

• Intoxication/effects of drugs (cannabis, stimulants, opioids, corticosteroids);
• Cerebrovascular disease;
• Temporal lobe epilepsy.

Mr AT’s history is taken by a psychiatrist, and his crisis plan sought (as per NICE recommendations) but he does not have one ​[7]​ .

He has been under the care of mental health services for two years and disputes his diagnosis of paranoid schizophrenia. He was admitted to a psychiatric hospital 18 months ago where he was prescribed the antipsychotic amisulpride at 600mg daily. 

He is teetotal, smokes ten cigarettes a day and smokes cannabis every day. His BMI is 26 and he has hypercholesterolaemia (total cholesterol = 6.1mmol/L, reference range <5mmol/L) but all other tests are normal. 

He has no allergies. His only medication is amisulpride 600mg each morning, which he does not take. 

Medicines reconciliation

Mr AT is transferred to a psychiatric ward and placed under Section 2 of the Mental Health Act , allowing detention for up to 28 days for assessment and treatment (see Box 2).

Box 2: The Mental Health Act 1983

This legislation allows for the detention and treatment of patients with serious mental illness, where urgent care is required. This is often referred to as “sectioning”.

It includes regulations about treatment against a patient’s consent to safeguard patients’ liberty, which become more stringent with longer detentions.

Patients may only be given medication to treat their mental illness without their consent and may refuse physical health treatment. 

He denies any mental illness and tells the team they are conspiring with MI6. He is visibly experiencing auditory hallucinations: seen by him talking to himself and looking to empty corners of the room. Amisulpride is re-prescribed at 300mg, which he declines to take. 

A pharmacy technician completes a medicines reconciliation and contacts the care coordinator. The technician provides information about Mr AT’s treatment and feels he is still unwell as he has continued to express paranoid beliefs about his neighbours and MI6.

The ward pharmacist speaks to the patient. As per NICE guidance on medicines adherence , they adopt a non-judgemental attitude ​[8]​ . Mr AT is provided with information on the benefits and side effects of the medication and is asked open questions regarding his reluctance to take it. For more information on non-adherence to medicines and mental illness, see Box 3 ​[9]​ .

Box 3: Medicines adherence and mental health

Adherence to medication is similar for both physical and mental health medicines: only about 50% of patients are adherent. 

Side effects and lack of involvement in decision making often lead to poor adherence. 

In mental illness, other factors are: 

• Denial of illness (poor ‘insight’); 
• Lack of contact by services;
• Cultural factors, such as family, religious or personal beliefs around mental illness or medication.

Mr AT reports gynaecomastia and impotence, and says that he will not take any antipsychotics as they are “poison designed by MI6”, although is unable to concentrate on the discussion owing to hearing voices. 

He is prescribed clonazepam 1mg twice daily owing to his distress, which is to be reduced as treatment controls his psychosis. He is offered nicotine replacement therapy but decides to use an e-cigarette on the ward. 

He is unable to weigh up information to make decisions owing to his chaotic thinking and is felt to not have capacity to make decisions on his treatment. The team debates what treatment to offer.

Patient preference

Mr AT refuses all options presented to him. A decision is made to administer against his will and aripiprazole is chosen as it is less likely to cause hyperprolactinaemia and sexual dysfunction. He then agrees to take tablets “if it will get me out of hospital”. 

After eight weeks of treatment with orodispersible aripiprazole 15mg, Mr AT is able have a more coherent conversation, but is hallucinating and distressed. He is clearly under treated. The pharmacist attempts to complete a side-effect rating scale ( Glasgow Antipsychotic Side-effect Scale [GASS] ) but he declines. He is pacing around the ward in circles: it is felt he may be experiencing akathisia (restlessness) — a common side effect of antipsychotics (see  Table 1 ). 

Treatment review

The team feels clozapine is the best option owing to the treatment failure of two antipsychotics.  

The team suggests this to Mr AT. He refuses, stating the ward is experimenting on him with new medication and he refuses to take another antipsychotics. 

The pharmacist meets the patient with an occupational therapist to discuss what his goals are. Mr AT states he wants to go to college to become a carpenter. They discuss routes to achieve this, which all involve the first step of leaving hospital and the conclusion that clozapine is the best way to achieve this. The pharmacist clarifies the patient’s aripiprazole will not continue once clozapine is established. They leave information about clozapine with the patient and offer to return to discuss it further. 

Mr AT agrees to take clozapine a week later (see Box 4) ​[10–14]​ . Aripiprazole is tapered and stopped.

Box 4: Clozapine characteristics

Clozapine significantly prolongs life and improves quality of life ​[10]​ . Delaying clozapine is associated with poorer outcomes for patients ​[11]​ . 

Clozapine is under-prescribed owing to healthcare professionals’ anxiety and unfamiliarity around its use ​[12–14]​ .

It causes neutropenia in up to 3% of patients so regular monitoring is required . Twice-weekly monitoring is needed if neutrophils are <2 x10 9 /L. Most patients should stop clozapine if neutrophils are <1.5×10 9 /L. These ranges can differ from some laboratory definitions of neutropenia. 

Other side effects include sedation, hypersalivation and weight gain. See  Table 2  for red flags for serious side effects. 

Clozapine is titrated up slowly to avoid cardiovascular complications. A treatment break of >48 hours warrants specialist advice for a retitration plan. 

The pharmacist meets with Mr AT to discuss clozapine. He is told that this is likely to be a long-term treatment. The pharmacist acknowledges that the patient disagrees with his diagnosis, but this treatment is likely to prevent him from returning to hospital. 

He is started on clozapine at 12.5mg at night, which is slowly increased. Pre- and post-dose monitoring of his vital signs is completed. 

On day nine of the titration, his pulse is 115bpm. He otherwise feels well and blood tests show no signs of myocarditis (see   Table 2), so the titration is continued but slowed.

After 3 weeks he is taking 150mg twice daily of clozapine and his symptoms have significantly improved: he is regularly bathing, not visibly hallucinating and engaging with staff.

The pharmacy technician completes a GASS form. Mr AT reports constipation, hypersalivation and sedation. 

A pharmacist meets the patient to reiterate important counselling points, and discuss questions he may have about his treatment and how to manage side effects. Medication changes are made with the patients’ input: 

• His constipation is monitored with a stool chart and he is started on senna 15mg at night;
• He is started on hyoscine hydrobromide 300 micrograms at night for salivation;
• He is switched to clozapine 300mg once daily at night to simplify his regime and reduce daytime sedation. His clonazepam is reduced and stopped.

Smoking is discussed owing to tobacco’s role as an enzyme inducer (more information on tobacco smoking and its potential drug interactions can be found in a previous article here ). Mr AT states he will continue to use an e-cigarette for now. He is informed that if he starts smoking again, his clozapine may become less effective and he should immediately inform his team. 

He is discharged a few weeks later via a home treatment team and attends a clinic once weekly. On each attendance, he has a full blood count taken and analysed on site. He is assessed by a pharmacy technician and nurse for side effects and adherence to treatment, and his smoking status is clarified. 

The technician asks what he thinks the clozapine has done for him. Mr AT states he is still unsure about having a mental illness, but recognises that clozapine has helped him out of hospital and intends to continue taking it. 

Good practice in the pharmaceutical care of psychosis involves:

• Active patient involvement in discussions on treatment decisions;
• Regular review of treatment: discussing efficacy, side effects and the patient’s view and understanding of treatment; 
• Multidisciplinary approaches to helping patients choose treatment;
• For patients who dispute their diagnosis and the need for treatment, open dialogue is important. Such discussions should involve the patient’s goals, which are likely to be shared by the team (rapid discharge, preventing admissions, reducing distress); 
• Information about treatment should be provided regularly in both written and verbal form;
• Where appropriate, involve carers/next of kin in decision making and information sharing. 

Important points

• Schizophrenia affects 1 in 200 people, meaning such patients will present regularly in all settings;
• Patients with acute psychosis, who are in recovery, may be managed by specialist teams, who are the best source of information for a patient’s care;
• Collaborating with the patient on a viable long-term treatment plan improves adherence;
• Clozapine is recommended where two antipsychotics have failed;
• Clozapine is a high-risk medicine, but the risks are manageable;
• Hydrocarbons produced by smoking (but not nicotine replacement therapy, e-cigarettes or chewing tobacco) induce the enzyme CYP1A2, which reduces clozapine levels markedly (up to 20–60%). Starting or stopping smoking could precipitate relapse or induce toxicity, respectively.
• 1 Conley RR, Kelly DL. Management of treatment resistance in schizophrenia. Biological Psychiatry. 2001; 50 :898–911. doi: 10.1016/s0006-3223(01)01271-9
• 2 Gillespie AL, Samanaite R, Mill J, et al. Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review. BMC Psychiatry. 2017; 17 . doi: 10.1186/s12888-016-1177-y
• 3 Taylor DM. Clozapine for Treatment-Resistant Schizophrenia: Still the Gold Standard? CNS Drugs. 2017; 31 :177–80. doi: 10.1007/s40263-017-0411-6
• 4 Psychosis and schizophrenia in adults: prevention and management. NICE. 2014. https://www.nice.org.uk/guidance/cg178/ (accessed Jan 2022).
• 5 Clozaril 25 mg tablets. Electronic medicines compendium. 2020. https://www.medicines.org.uk/emc/product/4411/smpc (accessed Jan 2022).
• 6 Psychosis and schizophrenia: what else might it be? NICE. 2020. https://cks.nice.org.uk/topics/psychosis-schizophrenia/diagnosis/differential-diagnosis/ (accessed Jan 2022).
• 7 Service user experience in adult mental health: improving the experience of care for people using adult NHS mental health services. NICE. 2011. https://www.nice.org.uk/guidance/cg136/ (accessed Jan 2022).
• 8 Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence . NICE. 2009. https://www.nice.org.uk/guidance/cg76/ (accessed Jan 2022).
• 9 Taylor D, Barnes T, Young A. The Maudsley Prescribing Guidelines in Psychiatry . 13th ed. Hoboken, New Jersey: : Wiley 2018.
• 10 Meltzer HY, Burnett S, Bastani B, et al. Effects of Six Months of Clozapine Treatment on the Quality of Life of Chronic Schizophrenic Patients. PS. 1990; 41 :892–7. doi: 10.1176/ps.41.8.892
• 11 Üçok A, Çikrikçili U, Karabulut S, et al. Delayed initiation of clozapine may be related to poor response in treatment-resistant schizophrenia. International Clinical Psychopharmacology. 2015; 30 :290–5. doi: 10.1097/yic.0000000000000086
• 12 Whiskey E, Barnard A, Oloyede E, et al. An Evaluation of the Variation and Underuse of Clozapine in the United Kingdom. SSRN Journal. 2020. doi: 10.2139/ssrn.3716864
• 13 Nielsen J, Dahm M, Lublin H, et al. Psychiatrists’ attitude towards and knowledge of clozapine treatment. J Psychopharmacol. 2009; 24 :965–71. doi: 10.1177/0269881108100320
• 14 Verdoux H, Quiles C, Bachmann CJ, et al. Prescriber and institutional barriers and facilitators of clozapine use: A systematic review. Schizophrenia Research. 2018; 201 :10–9. doi: 10.1016/j.schres.2018.05.046
• This article was corrected on 31 January 2022 to clarify that tobacco is an enzyme inducer, not an enzyme inhibitor

Useful structured introduction to the subject for clinical purposes

Thank you Amrit for your feedback, we are pleased that you found this article useful.

Michael Dowdall, Executive Editor, Research & Learning

Please note that smoking causes enzyme INDUCTION not INHIBITION as stated. (Via aromatic polyhydrocarbons, not nicotine)

Hi James. Thank you for bringing this to our attention. This has now been corrected. Hannah Krol, Deputy Chief Subeditor

Only with Herbal formula I was able to cure my schizophrenia Illness with the product I purchase from Dr Sims Gomez Herbs A Clinic in South Africa

  Cancel reply

You must be logged in to post a comment.

You might also be interested in…

Bridging the mental health gap: the role of pharmacists 

More than 100 extra pharmacists employed in mental health community teams since 2019/2020

More than 40% of people with ADHD waiting at least two years to access mental health service, study finds

• Editorial Policy
• Privacy and Cookie Policy

• What is Schizophrenia?
• Modern Treatments
• Who Is At Risk?
• Facts and Figures

Information Sheets

• Schizophrenia and dangerous behaviour
• How is schizophrenia diagnosed?
• A brief history of schizophrenia
• Recovery strategies
• Disclosure – telling other people about your schizophrenia
• Can you recover from schizophrenia?
• Coping with stress
• Managing medication
• Preparing for relapses
• Coping with side effects of medication
• Schizophrenia and diet
• Organising your time
• Self monitoring your schizophrenia
• Understanding voices
• Coping with voices
• Understanding negative symptoms
• Treatments for negative symptoms
• Self help for negative symptoms
• Help from the Jobcentre
• Writing a CV (resumé)
• What kind of work can I do?
• Sources of help for job searching
• Volunteering
• Work experience
• Job Interview techniques
• Holding down a job
• Case study: Martin’s story
• Information for carers
• Self Help for Paranoia
• Treatments for Paranoia in Schizophrenia
• Understanding Paranoia
• Information for doctors and health workers
• Staying out of debt
• Dealing with existing debt
• Schizophrenia and Physical Health
• Exercise and Schizophrenia
• Schizophrenia and street drugs
• Schizophrenia and Alcohol
• Depression and Schizophrenia
• What can be done about depression in schizophrenia
• Labelling in Schizophrenia
• Schizophrenia and Language
• Stigma in Schizophrenia
• The Anti-Psychiatry Movement
• Cognitive Symptoms of Schizophrenia
• Schizophrenia: A Christian Perspective
• Religious and Spiritual Delusions in Schizophrenia
• Sleep problems
• The Science of Sleep in Schizophrenia
• Richard Dadd
• Ivor Gurney
• Daniel McNaghten
• Henry J Deutschendorf
• Dr William Chester Minor
• Recent Developments in the Treatment of Schizophrenia
• Guidance for Journalists

Get Involved

If you would like to get involved with Living with Schizophrenia’s work then please leave your details.

We are always looking for people to write about their experiences of schizophrenia, to contribute ideas and tips and oversee our work.

Leave your email and location and details of how schizophrenia has affected you and we will be in touch.

Case Study: Schizophrenia and Work: Martin’s Story

Martin had been out of work for several years following a prolonged psychotic episode which began when he was studying at university. He desperately wanted to get into work but found that employers treated his prolonged absence “on the sick” with suspicion. He thought that if he could do a period of work experience that would show prospective employers that he was capable of working again but he was afraid that if he did it might affect his benefits.

So Martin made an appointment to see the Disability Employment Advisor at the Jobcentre to discuss his plans. She was understanding and helpful and explained that a work placement would not affect his benefits as long as it was done as part of the Jobcentre’s own scheme. She also told him that the scheme would pay his travel-to work expenses while he was on the placement.

Job-searching

Next Martin researched local employers using the internet and the local press, looking for companies that might have vacancies in the sort of clerical and administrative work he thought he could do. Then he called the companies by ‘phone and speaking to the person on the switchboard checked that he had the correct postal address for them and asked the name of the person in charge of recruiting. It is vital to be able to write to a named person rather than just the Human Resources Manager.

Martin had already spent a lot of time on his CV so now he compiled a covering letter to go with it. It took him about a month to work up his CV and covering letter using books that he got from the local library. He also managed to get advice from a local back-to-work scheme recommended by the Disability Employment Advisor at the Jobcentre. Martin knew that it was essential that his letter and CV had the maximum impact.

Martin sent his CV and letter off to six employers and then waited about a week before calling them up on the ‘phone. He asked to speak to the person he had written to but if the person on the switchboard asked the reason for his call he simply said that he was calling to follow up a letter he had written.

After approaching about 20 employers in this way he finally found one who said there could be an opening for work experience in a couple of months time. So over the next three months Martin kept in touch with the company by ‘phone once a month just to let them know that he was still keen on coming to work for them.

The interview

Finally the company asked him in for an interview. Before going to the interview Martin prepared really well in advance by researching the company well and trying to anticipate the sorts of questions he would be asked. He also went to the local library and took out some books on interview techniques and managed to get on a one day course on interview skills that the Jobcentre had told him about. This included a mock interview which he found particularly useful.

The day of the interview arrived and Martin was very nervous but he was up early and washed and dressed. To be sure of being on time he left an hour early and checked out the location of the office. Then he went to Starbucks for a coffee while he waited. This gave him an opportunity to flick through his notes and prepare on some of the answers he had been working on. He made sure that he was punctual and well groomed and did his best to present himself well at the interview.

Despite being really well prepared walking through the front door of the office was one of the hardest things that he had done for years. But the receptionist was polite and could not have been more helpful. She made him feel welcome and even offered him a coffee (which he declined).

The Human Resources Manager who interviewed Martin was very professional but quickly put him at his ease. He asked questions about his education at school, his hobbies and pastimes and his qualifications and then came the bit that Martin had been dreading when the HR Manager asked him why he had dropped out of college. Martin explained that he had had a breakdown caused by too much stress while he was at college. He went on to explain that although it was a bad breakdown it was behind him now and that with the help of his family and friends and his doctor he had been able to make a really strong recovery. He also explained that in some ways the experience had made him a stronger person and that he had matured as a result of it.

As the end of the interview approached Martin was sure that he had flunked it but the interviewer told him that he had been successful and asked him to start on Monday. Martin was delighted to be offered a period of three months unpaid work experience during which he would work for two days a week at their local office doing clerical and administrative work.

Martin was walking on air when he left the office. All his hard work had been worth it.

The next day Martin called the Disability Employment Advisor at the local Jobcentre to tell them about the offer and see how his benefits would be affected. She confirmed that his benefits wouldn’t be affected as long as he only worked for 16 hours a week.

The placement

For the next three months Martin worked hard at his placement. He made sure that he got all the basics right: being punctual and well groomed every day. At work he was helpful and got on well with the other workers. Although he was very shy at first he soon learned the importance of making small talk with his colleagues and building good working relationships.

As the end of his placement approached Martin wondered if he would be offered a permanent position. He asked the HR Manager about this but sadly he was told that there were no permanent vacancies at that time so when the end of his placement came Martin had mixed feelings. On the one hand he was disappointed that the work experience had not turned into a permanent job but on the other hand he had had three months experience in the workplace and had something to put on his CV to demonstrate to other employers that he could work. And most importantly he had that all important reference from a well respected local employer.

But that isn’t quite the end of the story. Martin continued searching for a job without success for another six months but continued to keep in touch with the HR Manager he had worked for during his work experience. One day he saw in the local press that they were advertising for a clerical assistant so he called them and explained that he was still jobsearching and would be available for this position. The HR Manager was very pleased to hear from him and said that he would call him back. The next day Martin got a call asking him to go in for an interview straight away and was offered the job.

Martin called the Jobcentre Plus helpline and found out what benefits he would be entitled to while he was working and was pleased to find out that he would be better off in work.

Martin has now been employed in his new job for two years and is delighted to be living an independent lifestyle free of the benefits culture he was in before. It has had its difficulties though. For instance Martin found that his illness had left him emotionally very sensitive and that he found it difficult to cope if his work was criticised. But he knew that this was something he had to learn to live with and gradually he managed to learn new social skills that helped him to cope better and at the same time helped him in other areas of his life.

Martin has enjoyed the structure that the new job has brought to his life. He enjoys the work and the social contact that the job entails. He has made new friends and above all his self-esteem has grown vastly. Now when people ask him what he does for a living he no longer has to say that he is unemployed.

Some Key Points from Martin’s Story:

• Research the local job market really well
• Before writing to a firm call to check the postal address.
• Find out the name of the person in charge of recruitment. Writing to a named person makes sure your letter gets read.
• You can’t spend enough time preparing your CV and cover letter. Get as much help as you can from books, the library etc.
• When making follow up calls avoid Mondays and Fridays as these are busy days for people in business. Similarly don’t call too early in the morning or after 3.30 pm and don’t call around lunchtime.
• When making follow up calls be prepared for few false starts but use these to develop your technique. Treat the first half a dozen calls as practice calls.
• Don’t pester firms with too frequent follow up calls. Once every three weeks is about right.
• Be prepared for disappointment and don’t feel let down by it.
• Before going for an interview research the firm really well. Google and Google News and the local press are useful sources.
• It is perfectly normal to be nervous at an interview. Try to minimise the nerves by making sure you have planned and prepared well and getting a good night’s sleep beforehand.
• At the interview you may be asked about your illness. Be honest but there is no need to disclose your diagnosis at this stage unless you are asked directly: a broad brush explanation such as “a breakdown” is sufficient.

LWS Speaking Out

Read what Living with Schizophrenia has to say about topical issues in mental health

Schizophrenia and Cancer

Out of area placements, schizophrenia and heat related deaths, schizophrenia is a major cause of homelessness, shortage of doctors in the nhs, speaking out archives.

Living with schizophrenia was set up by people who have direct personal experience of the condition using their own personal funds and relies on donations to continue its work. We do not get grants from any public body or commercial organisation: we rely on people like you supporting our work.

Subscribe to our mailing list

View our Privacy and Cookie Policy .

Living with Schizophrenia is a trading style of LWS (UK) CIC a Community Interest Company registered in England no. 7492057 Copyright © 2024 Living With Schizophrenia . All rights reserved. Web Design by Priority Pixels . Terms of use , Privacy and Cookie Policy , Website acceptable use policy

• Frontiers in Psychiatry
• Schizophrenia
• Research Topics

Case Reports in Schizophrenia and Psychotic Disorders: 2023

Total Downloads

Total Views and Downloads

About this Research Topic

Frontiers in Psychiatry is proud to present our Case Reports series. Our case reports aim to highlight unique cases of patients that present with an unexpected/unusual diagnosis, including complexity and differential diagnosis and/or co-morbid diagnoses, treatment outcome, or clinical course. Case reports ...

Keywords : schizophrenia, case reports, psychotic, disorders

Important Note : All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

Topic Editors

Topic coordinators, recent articles, submission deadlines, participating journals.

Manuscripts can be submitted to this Research Topic via the following journals:

total views

• Demographics

No records found

total views article views downloads topic views

Top countries

Top referring sites, about frontiers research topics.

With their unique mixes of varied contributions from Original Research to Review Articles, Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author.

• Special Issues
• Conferences
• Turkish Journal of Analysis and Number Theory Home
• Current Issue
• Browse Articles
• Editorial Board
• Abstracting and Indexing
• Aims and Scope
• American Journal of Applied Psychology Home
• Social Science
• Medicine & Healthcare
• Earth & Environmental
• Agriculture & Food Sciences
• Business, Management & Economics
• Biomedical & Life Science
• Mathematics & Physics
• Engineering & Technology
• Materials Science & Metallurgy
• Quick Submission
• Apply for Editorial Position
• Propose a special issue
• Launch a new journal
• Authors & Referees
• Advertisers
• Open Access

• Full-Text PDF
• Full-Text HTML
• Full-Text Epub
• Full-Text XML
• Mona Zein. Case Study of Schizophrenia in A Young Adult Male. American Journal of Applied Psychology . Vol. 10, No. 1, 2022, pp 20-30. https://pubs.sciepub.com/ajap/10/1/4 ">Normal Style
• Zein, Mona. 'Case Study of Schizophrenia in A Young Adult Male.' American Journal of Applied Psychology 10.1 (2022): 20-30. ">MLA Style
• Zein, M. (2022). Case Study of Schizophrenia in A Young Adult Male. American Journal of Applied Psychology , 10 (1), 20-30. ">APA Style
• Zein, Mona. 'Case Study of Schizophrenia in A Young Adult Male.' American Journal of Applied Psychology 10, no. 1 (2022): 20-30. ">Chicago Style

Case Study of Schizophrenia in A Young Adult Male

This report presents a special case of a highly educated and intelligent patient diagnosed with simple schizophrenia and depression. This patient attended psychotherapy sessions regularly with the therapist (the author) which helped him to express his thoughts and ventilate his emotions. This report aims is to reinforce the importance of psychotherapy and family interventions in the management of a schizophrenic patient. The patient has adequate insight into the effects of schizophrenia on his self-reflection that have ended up leaving him frustrated with poor achievements in life. The patient’s symptoms were tracked using rehabilitative approaches and techniques. Counseling with the patient and his family completed 50 sessions treatment period. This resulted in a significant improvement in the patient's and family's functioning because they were able to recognize their problems, find appropriate solutions, and place them into action. The therapeutic experience of the schizophrenic patient is presented in this report.

1. Introduction

Schizophrenia is a severe and chronic mental illness that affects approximately 1% of the population, characterized by a complex of clinical syndromes and a wide range of psychopathologic manifestations 1 . Symptoms of schizophrenia are classified into positive and negative categories, including distortions in thinking, concentration, cognition, emotions, language, and sense of self, motivation, and behavioral abnormalities 2 , 3 . It is a disease that markedly affects social and occupational functioning, interpersonal relationship, and morbidity 4 . Schizophrenic patients believe they have lost the touch with reality and may also lose interest in the most fundamental demands of existence. When these symptoms are treated with antipsychotics, including both typical and atypical, as well as psychotherapy and psychosocial, most persons with schizophrenia recover significantly over time. 2

Schizophrenia is a debilitating neuropsychiatric and long course disorder, covering alterations in thought manifested in the failure to understand reality, The sufferer often lacks the connection with real-world and lives in an imaginary world perception manifested in false belief, confusion, auditory hallucination, and emotions 5 , 6 , 7 , cognitive deficits have been shown to have a consequential impact on prolonged functionality. Cognitive deficits include predicaments with attention, executive function, memory, and metacognition 8 . Schizophrenia is often misunderstood as a split personality by many people 9 , and is heavily populated in the Egyptian Mental Health hospitals; so, it is important to understand what the disorder is about to provide the best course of treatment for the patients. 10

Symptoms of schizophrenia can be divided into positives, such as delusions (having false beliefs), and hallucinations (hearing voices and seeing things), disorganized and negatives, such as (blunted affect, tiredness, apathy, alogia, avolition), A person who has at least two of the above symptoms for about one month will be diagnosed as a schizophrenic patient 13 .

The disorganized symptoms may occur depending on the patient's previous characteristics and the duration of the disorder, in addition, the chronic cumulative consequences of schizophrenia are often severe and long-lasting with marked social disengagement. 6 . The lack of sufficient knowledge about the condition increases the occurrence of frequent relapses due to poor drug compliance, negative side effects, negative expressed emotions, and problematic coping strategies which lead the patient to become socially isolated and a burden to the family 14 . According to systematic reviews, family intervention reduces re-hospitalization and makes the family's life easier. 15 . Not all the domains of schizophrenia are presented by the patients, but a patient may have some symptoms in each category.

Collaboration with patients, caregivers, and treatment providers is required to better understand schizophrenia. 16 . The onset of the disorder mostly begins in the second decade, and while the symptoms vary from one patient to another, the consequences are usually severe and long-lasting. Women are more likely than men to develop schizophrenia in late adolescence and early adulthood 17 . It usually appears between the ages of 15 years to 35 years. 18 .

Men's incidence peaks b at 15 and 25 years of age, whereas women's incidence peaks at 25 and 35 years of age.

The exact etiology of schizophrenia remains uncertain, there are many theories, but there is still no consensus 19 , 20 , however, different theories are presented for understanding its pathophysiology. This includes genetic theory, dopaminergic theory specifically the increased presynaptic dopamine synthesis which contributes to altered chemistry and structure of the brain in the mesolimbic system, which is responsible for positive symptoms, whereas the mesocortical pathway responsible for negative symptoms complemented by the glutamatergic hypothesis which considers changes in prefrontal neuronal connectivity involving glutamatergic neurotransmission at NMDA receptor 11 , 12 , non-developmental theory, and psychosocial theory. Biological vulnerability, severe stress, poor coping skills, and the lack of social support are all thought to be contributors to the development of schizophrenia. 21

Many other psychiatric disturbances share the characteristics of schizophrenia. 22 . On the contrary, many studies have found that schizophrenia patients are prone to comorbidities. Depression has a significant impact on schizophrenic patients, despite its high prevalence and frequent under diagnosis. The prevalence of depression in schizophrenia patients varies widely over the world, ranging from 7% to 70%, with a median of 25%. 23 . There is plenty of evidence in the literature about the impact of depressive symptoms on the quality of life in schizophrenic patients 24 . There is plenty of evidence in the literature concerning the effect of depressive symptoms on schizophrenic patients' quality of life. Anxiety and depressive symptoms presented by schizophrenic patients require special attention schizophrenic, as these manifestations have a major influence on their quality of life than schizophrenia's negative and positive symptoms 25 , but with proper treatment, mortality associated with depression can decrease about 70%. 26

Comprehensive treatment programs for schizophrenia should include a variety of ongoing services, such as medication administration, access to proper psychosocial therapy, housing and employment assistance, and financial resources 27 , 28 .

Specific therapeutic approaches have a considerable improvement to the quality of schizophrenic patient’s lives. The goals of the treatment program focus on the elimination of symptoms, relapse of disorder, and improving the quality of life. Antipsychotics medications are the cornerstone in pharmacotherapy for their effectiveness in reducing symptoms and risk of relapse. They are further divided into two main classes: Typical antipsychotics and atypical antipsychotics, but they may be associated with many undesirable effects. 29 . The new generation of antipsychotics medications has been proven to have fewer side effects as compared to the conventional typical antipsychotics. After treating the acute symptom, many schizophrenia patients experience major functional and social deficits, necessitating follow-up with a psychotherapist to address the remaining symptoms.

Many researchers were concerned because of the recurrent nature of the condition and the severity of functional psychosocial deficits led to a greater focus on the necessity of empirically validated psychotherapies that can support recovery beyond symptom reduction. 28 , 30 , 31 , 32 . They help schizophrenic patients in learning how to live effectively with vulnerabilities, eliminate symptoms, improve interpersonal and social adaptation impairments, and enhance overall life functioning 33 . The outcomes of the treatment work towards achieving life milestones, staying safe from destructive behaviors, increasing physical activity, improving quality of life, finding work, developing a positive sense of self, and developing psychosocial skills 34 , 35 . It is recommended to have continuous treatment for all diagnosed patients. 36 , 37

This report presents a case of an adult man diagnosed with simple schizophrenia and depression. The aims of this report are: (A) to demonstrate the importance of individualistic psychotherapy interventions (B) to illustrates the positive outcomes of the psychotherapy interventions on the improvement of the patient's life (C) to emphasize the importance of family therapy in schizophrenia patient treatment (D) to illustrate the influence of life experience particularly based on child abuse, education, and intelligence on the prognosis of the illness.

2. Case Report

The client’s profile including the history of personal, medical, family, and social was prepared through psychotherapy sessions.

Personal history Mr. X presented for treatment of simple schizophrenia, is a 34-year-old, Muslim, Egyptian male, with a high level of education, unemployed, right-handed. The patient’s birth was by normal delivery. He was born in the seventh month of pregnancy in Saudi Arabia on the 12th of December 1986, and he has a twin brother, Single, who lives with his father, stepmother, and his siblings.

The patient claimed that he remembers every detail of his early life, he reported that his developmental phases were normal and rapid, he could speak and walk at the age of one. He reported having the habit of nail-biting from the age of five till the age of eleven, he reported being a quiet child. He reported he was being abused emotionally and physically by his father, receiving punishment for no reason, and when he screamed, he had been beaten up more aggressively. He reported he never hit or harm his siblings or other children. He reported being neglected and abandoned by his both parents, he stated he had been complaining from inequality and maltreatment from his parents since his childhood, his father prefers his twin brother over him, while his mother was preferring his elder sister, he started seeing how his parents treat his siblings led him to isolate himself, feeling depressed, and frustrated. 38 , 39 , 40 , 41 , 42 , 43

He reported having poor physical health, he wasn’t eating properly as a child, and his parents never cared for him. He reported suffering from constipation most of the time, consistently complaining of having the anal worm since he was two years old till the age five, he stated he was using the toilet bidet, pushing it hard inside his anus area to get rid of the anal worm, he stated his mother sometimes was helping him in this removal process. 44 , 45 , 46 .

He reported he used to stay most of the time alone, imagining good scenarios where he plays with other children happily, and buying his favorite toys during his childhood, he reported that he never had classmates or friends. 47

He reported being bullied in his elementary school. 48 . He reported he liked the taste of salt, so he used to add a lot of salt to his food, he liked its taste to an extent that he was tasting his urine. 49 . He reported having homosexual orientation since his childhood and when he grew up he was involved in random homosexual relationships through online websites and applications, he stated that he imagines himself having sex with the same sex during his masturbation, he stated that he never was in a relationship with a girl because he feels inadequate to fulfill a girl needs, besides he decided since he knew his medical condition that he will not marry not to transfer the psychosis genes to his children, so he stated that he stops himself from thinking of having any emotional or sexual relationship with girls, whenever it comes to his mind. 50 , 51 , 52 , 53

Regarding the patient’s premorbid personality, he was an Introvert with nearly no friends, reacts to stress by isolation and dissociation. Muslim, Believer, without practicing. The patient reached puberty at the age of 11 years with male gender identity and role, and homosexual orientation. Regarding the patient’s educational record, he entered a private school at age 6, with very poor relations with teachers and peers, he was an excellent student with excellent scholastic achievements until he reached the university, his academic performance started to be very poor during the first year of college that it took him almost 9 years to get his bachelor’s degree of engineering. 54

Regarding the patient’s work record, he worked as an engineer in a private company for two years, but they fired him from work because of his intense hand shivers while doing any work tasks, and his low volume voice, and a small amount of speech due to the side effects of antipsychotic medications. 55

The case medical history was identified with schizophrenia characterized by a history of characterized by a history of psychotic episodes in which he displayed signs and symptoms of schizophrenia, but the patient is currently having no positive symptoms (delusions, hallucinations, disorganized speech, or behavior). Recently he has been diagnosed with simple schizophrenia, he represents negative symptoms including the inability to express emotions, indifference, slurred speech, communication difficulties, and withdrawal from social situations and relationship. The patient reported 16-year history characterized by ongoing persecutory delusions, as well as auditory and visual hallucinations, the condition started 16 years ago, since 2005, he reported that it started one year after losing the academic performance in college, continuous fights, and clashes with his family especially his father. He reported experiencing auditory and visual hallucinations. He started writing an unknown language 56 , drawing awkward sketches, creating a religion, visually hallucinating seeing pictures on the walls, talking to them as if they are real, also auditory hallucinations hearing voices, and engaging himself in conversations involving his family and strangers. He claimed to hear people talking about him and insulting him, a few of whom he knew. Therefore, he was suspicious of others and uncomfortable. As a result, he spent the night with an imaginative friend and refused to get along with his family because he felt unsafe either at home or outside. The content of his thoughts revealed delusions of persecution, visual and auditory hallucinations. 57

He became depressed most of the time, staying always alone in his room with spontaneous bouts of crying and continuous death wishes with a sense of worthlessness. Also, he lost his interest in previously pleasurable activities, decreased sleep hours by nearly 3h per day with a marked decrease in his appetite up to that he lost 10 kgs within a month. The patient also had proper insight since the beginning of treatment. He reported that one month later to his hallucinations, he informed his family about his strange issues, but at the beginning, they didn't believe him, so he was left without treatment. He reported that his family claimed that they don’t notice anything wrong with him other than being different and having odd behaviors, he reported his family were so neglectful of his torture and didn’t care to treat him, so he tried to seek professional help himself behind them and decided to take the medications prescribed by the psychiatrist at the age of 18 behind his family who wasn’t admitting his disorder. 58 , 59 .

He reported the first psychiatrists he visited didn’t diagnose him correctly then finally he went to another psychiatrist who diagnosed him with schizophrenia. Two months later, he started taking the medications regularly and he felt much better under medications, finally, his family believed that he has schizophrenia and supported him financially to be treated. He reported having the medications on time until he felt some undesirable side effects, so he went to a private psychiatric hospital from the age of 25 till now. He reported the symptoms became increasingly debilitating over time, negatively affecting his relationship with his family, especially his father and stepmother. He reported he wasn’t hospitalized at any period of his life, meanwhile, during the recent period of treatment, the patient developed complaints of acute Prostate Hyperplasia, so he started to follow up under the guidance of an Andrology specialist, he also complained of experiencing fine tremors which resulted as side effects from having the antipsychotic medications. 60

He reported that he stopped taking the medications regularly to avoid such complications, and sometimes he forgets to take them, he reported being depressed and isolated at times when he stops or changes the medications for better ones. In the four months leading up to his appointment with the therapist, he stopped taking the prescribed medications to avoid its complications. 61

The patient had shown signs of medical adherence issues since he had Prostate Hyperplasia, he stated multiple times he was concerned about the side effects of medications and believed it is the reason for his suffering during masturbation or while having sex, so he was therefore placed under directly observed therapy at home. 62 , 63 , 64 , his lifestyle data showed that he is a heavy smoker and uses drugs, particularly Hash and Alcohol. 65 , 66

The patient reported he didn’t undergo electroconvulsive therapy (ECT), because the psychiatrist didn’t prescribe it. He reported also he had never been in any psychotherapy before. He was brought by his sister who is reliable, living with the patient, very concerned about his behavior and case to the therapist for his attempts suicide many times during the past period, his sister reported he is mentally abnormal for the past 16 years with irregularly taking antipsychotics under the guidance of the psychiatrist, she reported two weeks before to the visit to the psychotherapist, which was on (5th of September of 2020), he became depressed all day with recurrent bouts of spontaneous crying and persistent sense of worthlessness, with noticeably decreased sleep hours than usual, decreased social interaction with his family than usual, loss of interests in watching TV and staying with his siblings, especially his sister whom he prefers among other siblings. Meanwhile, his sister also reported recently she discovered him being involved in random homosexual relationships which ended up leaving him with HIV, she also stated he had experienced horrible physical abuse by a gang, whom he contacted online through a dating website to have sexual affairs after reaching the agreed place, they caught him and beaten him up causing profound injuries all over his body till he bled profusely, his siblings insisted to perform blood tests to find out if he had used any illegal drugs or not before the onset of his current symptoms and the patient’s blood samples showed his infection with HIV and drug use. Moreover, his sister reported currently he feels angry, suffocated, being isolated at home, and developed a marked decrease in appetite with persistent death wishes.

When the patient was first seen by the therapist, the patient exhibited complaints of difficulties sleeping, loss of appetite, depressed mood, and affect constricted among the relevant indications. Meanwhile, he was dressing properly and exhibited appropriate behavior. He reported attempts to commit suicide because he wanted to die 67 , 68 , 69 , 70 , 71 , especially after knowing that he got infected with HIV, stating that he never had a life and will never have, besides being upset for causing a lot of trouble to his family, so he wants to die to make them relieved and happy with their own lives 72 . The patient did not display positive symptoms like delusions or hallucinations during the period of treatment with the therapist. He reported being preoccupied with spirituality and believes he has an imagined and unique place, people, language, and religion including different prayers and rituals that he created himself to feel safe away from that abusive world. He was practicing an unknown religion although he claims to believe in God.

Family history there was a family history of both mental and physical illnesses. The patient’s parents are non-consanguineous, his father is 65-year-old, from a high-grade position in a private job, he stated his father is aggressive, unfair, stubborn, neglectful, nervous, hardworking, dominant, organized, assertive, and serious, he stated he never could talk to him, he reported having a poor relationship with his father with a relevant medical and psychiatric history, he reported his uncle is a schizophrenic patient who is totally collapsed and hospitalized for more than 10 years ago. He reported his mother with a relevant medical but non-psychiatric history who was a highly educated housewife and died 10 years ago at the age of 56 years due to breast cancer, and asthma, he reported his mother was kind-hearted, calm, fair, caring, generous, honest, family-oriented, sensitive, religious, flexible, wise, and friendly. He had a harmonious relationship with his mother. The patient is a twin at third in the series of 3 siblings (1 sister and 2 brothers). The patient’s sister is a 38-year-old, high educated, worker, single, diagnosed with bipolar disorder, and he has a harmonious relationship with his sister. The twin brother is highly educated, single with features of schizoid personality disorder, and he has a harmonious relationship with him. The elder brother is 37-year-old, high educated, married with two twin’s offspring, and living abroad with Irrelevant PH, he has a very poor relationship with him.

Social history revealed he lives in an apartment with his siblings while his father, and stepmother live in a separate apartment in the same building. The family has vast social contact with their other maternal and paternal relatives. He didn’t have any friends in the past but currently, he has very few friends.

Psychological assessments were used to formulate the appropriate treatment and management plan

Rationale 1: To assess the severity of psychopathology

The positive and negative syndrome scale (PANSS) for schizophrenia 73 : positive signs are absent, whereas negative symptoms are present, according to the results of the tests. The scores were moderate in both the affective blunting and anhedonia-asociality, mild in both alogia, avolition-apathy, and absence of attentional impairment.

The Schizotypal Personality Questionnaire (SPQ): The presence of schizotypal traits is indicated by test results. Unusual perceptual experiences are presented in the cognitive-perceptual area. High social anxiety and constricted effect were presented in the interpersonal aspect and absence of disorganization which includes odd behavior and odd speech.

Beck Depression Inventory (BDI): test findings indicated the presence of mild depression.

Personality diagnostic questionnaire-4 (PDQ-4): The results of the test pointed to a possible diagnosis of schizotypal personality, depressed personality, and avoidant personality.

Rationale 2: To assess Cognitive Functioning

Eysenck Personality Questionnaire (EPQ): tested showed low scores on psychoticism, and extroversion, and high scores on neuroticism, and Impulsivity.

Stanford-Binet Intelligence Scales (SB-5): test findings showed the full-scale Intelligence quotient score (132) which is classified as gifted or very advanced intelligence level.

Rationale 3: To elicit diagnostic indicators and personality traits

(A). Objective Tests: The Minnesota Multiphasic Personality Inventory (MMPI): the results of the test revealed a valid and interpretable profile. His scores were high in Depression, Schizophrenia, and Social Introversion, while the score was low on the Masculinity/Femininity subscale which refers to his homosexual tendencies, poor identification with stereotypical male gender roles, and Moderate in psychasthenia.

(B). Projective Tests: Goodenough–Harris Draw-a-Person Test (DAPT): The patient was found to be very intelligent, with male inadequacy, poor social skills, poor interpersonal relationships, dependency, oral erotic tendencies, sexual role conflict, sexual inadequacy and difficulties, depressed mood, psychotic tendency, anxiety, impulsivity, insecurity, lack of status and low self-esteem, preoccupation with sex to compensate for weakness feelings, according to the test results.

The Thematic Apperception Test (TAT): By using TAT techniques, it was interpreted the development of the disorder was due to family circumstances and within the family itself. his father had abused the patient emotionally, psychologically, and physically. The father used to name-calling him, cursing at him in public and in private most of the time, yelling at him, insulting him, constantly rejecting his thoughts, ideas, and opinions, making him doubt his feelings and thoughts, and even his sanity, by manipulating the truth, neglecting his basic needs, being mistreated and always blamed for everything happens in his surroundings, which disappointed him and led to his isolation, uncertainty, and depression. Cards revealed the patient is constantly seeking to achieve more than is reasonable given his current resources, especially regarding his high intelligence level, but due to the disorder and the side effects of antipsychotics, the failure to meet goals becomes more likely, resulting in frustration. He could possibly be having an unusual thought pattern, which is frequently triggered by the existence of unmet demands. Cards revealed also he had been forced to do activities he never enjoyed in his past, having difficulties concentrating, and achieve higher competence growing old, difficulties living and communicating with other people, feeling depressed and guilty, experiencing isolation and abandonment. Sexual difficulties in establishing a man-woman relationship because he feels inadequate, he seemed to have homosexuality which was revealed from his attitudes toward members of the same sex. He also appeared to have an excessive internalization of feelings, preferring to externalize them which was manifested in his attitudes toward some external controlling forces, leading him to anxiety. Cards revealed his struggles with authority especially with the paternal figure while having positive feelings and attitudes towards his maternal figure. He appeared to be prone to abnormal behavior, which is most likely caused by mediational dysfunction. He also seemed to have features of obsessive-compulsive disorder. He seemed to have so unique imaginative abilities. He lacks the hope and the motives to live effectively, which led him to the path of self-destructive behaviors, he seemed to be in a need to better control his impulses, also his attitude toward death was calm and quiet, revealing his desire to die peacefully, he doesn't fear death, as he thinks that death is eternal peace. He has negative attitudes toward his body images, he thinks he lacks physical attractiveness, and his body shape is distorted which led to the presence of anxiety and insecurity.

Therapeutic interventions

A structured clinical interview was conducted with the patient and his siblings based on the DSM-IV-TR to provide comprehensive coverage of Axis I disorders. 74 , 75 . The psychotherapy period lasted 9 months and consisted of weekly sessions

The first therapeutic approach is family therapy which is important due to the fact the patient spends most of his time with his family who would be primarily responsible for providing support, medication, several factors, and activities in the patient’s life. The patient's family reported that they feel guilty because they are unknowledgeable of the patient needs and how can they help him. The aim of applying family therapy was to increase the collective family collaboration and enhance the relationships, which is extremely beneficial for the patient. Therefore, it was crucial to provide family therapy intervention to improve their coping, problem-solving skills, and enhance their communication skills with each other, because poor family care affects the patient’s situation negatively. The family therapy resulted in effective stress reduction, which could significantly influence relapse rates. Additionally, they could aid the patient in emotional processing and cognitive reappraisal, thereby enhancing his overall mental and psychological states. Throughout the years, the finding of more than 50 studies indicated that family therapy has a positive impact on the patient’s recovery and reduces rates of readmission, relapses, and the improvement of the patient clinically. 76 , 77

The second therapeutic approach is Psychodynamic therapy , which considers an important individual treatment modality for schizophrenics provided in combination with pharmacotherapy. 78 , 79 , Journal of the American Psychoanalytic Association , 34 (4), 799-834." class="coltj"> 80 , Nature , 328 (6133), 753-753." class="coltj"> 81 , Social Work , 33 (5), 465-467." class="coltj"> 82 , 83 , 84 . According to the psychodynamic approach, Schizophrenia develops because of the ego's disintegration. The ego will be ‘broken apart' by its attempt to maintain the desires of Id, leaving the Id in full control of the psyche, and the person eventually loses contact with reality. They regress to a state of ‘primary narcissism’ where they are ruled by their animal instincts, unable of regulating their behaviors, and hallucinating due to their inability to distinguish between their imaginations and reality 85 . The main goal of applying this approach was to elicit his past emotional experiences and improve his self-awareness so that he could recognize how they influenced his current mental state and behaviors, foster new positive relationship experiences, identifying his conflicts and defense mechanisms that have preceded his pathologic mental state. The interventions included variety of strategies, such as explorative insight-oriented, free association, supportive and directive activity, Interpretation of transference, dreams, and resistance phenomena, all of which were applied in a flexible manner, 86 . In addition, the family psychodynamics were considered through a deep understanding of the complex dynamics of blame and guilt in psychosis which allowed the therapist to better deal with the patient and his family members and help them with the difficult interpersonal processes 87 . Psychoanalysis was a highly effective therapy for treating the patient's deep-seated psychological issues. 88 , 89 , 90

The third therapeutic approach is cognitive-behavioral therapy (CBT), which was applied to provide the patient with several tools that could decrease the intensity of the negative symptoms, increase social skills, maintain a higher living quality, enhance his ability to function independently and effectively, reduced daily life stress, managing anxiety, and depression 91 . Techniques of CBT used are Simulation and Roleplaying, Cognitive restructuring of the style in which the person views himself and the others and gets rid of negative automatic thoughts and negative unrealistic assumptions, Ice Breaking, Guided discovery, Engaging, Goal Setting (Smart Goals), Graded Exposure Assignments, Behavioral Coping Skills (Activity scheduling and behavior activation), Behavioral experiments in which he could form a hypothesis then perform a mini-experiment to determine to what extent are his assumptions true, which could be highly beneficial with psychotic symptoms, Rehearsals, and Practices, ABC Model, Mindfulness Practice, Relaxation and Stress reduction tools.

CBT techniques were effective with the patient, it helped him to understand and cope with difficulties, struggles, and situations that he finds challenging for him. Educated him how to set appropriate and realistic goals, developed a wider understanding of his mental condition and cognitive functioning, ability reconstruction, symptom reduction, and management, reduced negative schemas, effective management for stressful situations, changing cognitive biases by using therapy-assisted disconfirmation strategies, as well as through a detailed consideration of the entire body of data. 92 , 93 , Schizophrenia Research , 98 (1-3), 1-7." class="coltj"> 94 , 95 , 96 .

The fourth psychosocial approach is social skills training . Schizophrenia patients can improve their interpersonal skills when given structured behavioral training that focuses on well-defined actions, contexts, and issues 97 . The patient had deficiencies in the skills necessary for daily activities. He was provided social skills training to help him improve his social interactions that are necessary to live independently. Skills training plans included behaviorally based instruction, employment skills, self-care, relationships, medications and symptoms management skills, communication skills, positive reinforcement, role modeling, rehearsing, and corrective feedback to function effectively in life 98 . It was provided opportunities to the patient for practice in implementing abilities in a real-world setting. The patient practiced these skills with the therapist first multiple times while getting feedback, then he started applying them in real-life settings. The skills developed during the sessions were generalized to other situations important to the patient's daily life, resulting in significant effects on proximal assessments. 30 , 99 , 100 , 101 , 102

The fifth psychosocial approach is Psychoeducation , which emphasizes coping strategies, and empowerment ability 103 , 104 . Psychoeducation helped the patient and his family to understand the disorder, as the better informed the patient and caregivers are, the better the patient's and caregivers' health outcomes. They were also educated on positive reinforcement techniques, the management of medications and crisis, timely and flexible perception of current experiences, family conflicts, communication, and the social and clinical needs for the patient. Psychoeducation programs were effective in explaining symptoms, treatment options, recovery, and services that can help. The psychoeducation strategies included written information, videos, websites, meetings, and discussions. The psychoeducation was beneficial for the patient and all family members to communicate better and solve problems. Mental Health Services Research , 1 (4), 223-230." class="coltj"> 105 , ChemInform , 42 (34), no-no." class="coltj"> 106 , 107 , 108

The sixth psychosocial approach is Psychosocial Interventions for Alcohol and Substance Use Disorders which are considered an important part of any comprehensive substance abuse treatment plan for promoting behavior change, they were applied to help the patient realize how his substance usage puts him at risk and to encourage him to cut back or stop using drugs.

Psychosocial Interventions were implemented intensively and individually. Aimed at utilizing the relationship between the therapist and the patient to promote positive changes in the patient's drug-taking behaviors as well as other aspects of cognition and mood. 109 , 110 , 111 , 112 , 113 .

Psychosocial programs included motivational enhancement (MI), brief interventions (BIs) for alcohol and tobacco, behavioral techniques that emphasize engagement in therapy, coping strategies, relapse prevention training (RP), contingency management (CM),feedback, accepting responsibility, counselling, list of options, sympathy, and self-efficacy and integration 114 , 115 , 116 . The Psychosocial Interventions were effective in the management of the patient's consumption of alcohol and drug use. 102 , 117 , 118 . It resulted in an 80% reduction in alcohol consumption and completely quitting substance use. 119 , 120 , 121 , 122 , 123 , 124

Finally, the psychotherapy interventions were effective in the management of the patient, without intervention and treatment, the patient’s brain would keep deteriorating, his ventricles would expand, and his brain will shrink till he loses most of his cognitive functions, Therefore, it is important for all who are diagnosed with schizophrenia to have early prevention, recognition of early signs, receiving the proper psychotherapy interventions, receiving the proper and appropriate medications from the start of the diagnosis.

Progress and outcomes:

Over the 9-month individualistic and family therapy period. The patient's disorder progressed in an ‘episodic with stable deficiency pattern’. Psychotherapy interventions were effective in achieving life milestones, decreasing negative symptoms of schizophrenia, depression, and anxiety, improving his physical activity, cognitive abilities, and raising his awareness about the disorder and its complications. His communication skills have improved effectively with his family and others. He could feel a positive sense of self, body image, security, and normalize his thought patterns. Quality of life has improved and safety from harmful and destructive behaviors is achieved, he learned to cope with stressful situations, and identify early warning signs of relapse to be able to manage the disorder. The patient complied and was on medication, His complaining behavior was managed to keep him functioning normally at home and in society.

3. Discussion

This report presents a case of simple schizophrenia, which meets all ICD-10 and DSM-5 criteria and seems like a typical insidious psychosocial deterioration without obvious psychotic symptoms 125 . Simple schizophrenia is described mostly by negative schizophrenia symptoms, including anhedonia-asociality, avolition-apathy, affective flattening, or blunting, alogia, inattentiveness 126 , 127 , 128 the patient had most of these symptoms, along with self-neglect which is one of the most specific and observable simple schizophrenia symptoms 129 , 130 , 131 , Therefore, simple schizophrenia is insidious and life-destructive mental disorder. Through this publication, I focused on the importance of both the individualistic psychotherapy and family therapy interventions in treating a case diagnosed with simple schizophrenia who was similar to the other patients who are often brought into psychotherapy sessions by their relatives as in this case 132 , 133 , 134 , 135 . Also, focused on confirming the positive outcomes of psychotherapy and family interventions in the treatment of a patient who demonstrates negative symptoms, along with the antipsychotics under the supervision of a psychiatrist. The patient's biography and history, as reported by him and his siblings, could probably justify and fundaments the etiology of the schizophrenia prodromal opens with supposedly stress-induced acute psychotic episodes. Experiencing child abuse, poor parenting behaviors familiar negligence, double-bind communication, psychiatric disorders in the family. He lived under considerable situational-related stress since his early childhood; this impacted his overall functioning and led him to be defiant against authority figures, blaming family members for his problems, which resulted in poor interpersonal relationships, all such factors were potential triggers for his schizophrenia and depression 136 , 137 , 138 , 139 , 140 . The patient seemed to be slow, having troubles with social interactions since early childhood leading to increased social isolation 141 . Identical social withdrawal and interests were lost in this case after losing his high academic achievements. Identical social withdrawal and interests were lost in this case after losing his high academic achievements 142 . He seemed to have difficulty speaking due to disorganized thinking (alogia), so he doesn’t like to talk much especially in social situations. Unfortunately, almost every case diagnosed with schizophrenia end up with total social life and functional breakdown. 131 . The patient seemed to have a good level of attention, concentration and visual-motor coordination. Due to his lack of impulse control, he appeared to have a difficulty modulating emotions which results in striving for immediate gratification of impulses and sensation-seeking, which was manifested in his desires to have random homosexual relationships, alcohol, and drug use. He seemed to be experiencing unusual thought content, but those thoughts are far from delusional thinking along with some odd behaviors 143 , 144 . He seemed to be experiencing episodes of muttering, unmotivated laugh and anger manifested in his inability to feel or express pleasure (anhedonia). He seemed to have depression-anxiety alike symptoms 145 , 146 , 147 , 148 , 149 manifested in a decreased sense of purpose and lacking motivation (avolition). He seemed to have a negative self-perception that led to a pessimistic view of himself and the world. He seemed also to be dissatisfied, insecure, restless, irritable, inadequate, inferior, and disappointed. The outcomes of psychotherapy interventions were successful and effective because of his ability in self-reflection and abstract thinking due to his high intelligence level.

The therapeutic approaches as well as physical and psychological improvements were successful, and the patient was able to live a healthy life, along with medication usage. Finally, this case shows the importance of this kind of individual and multi-holistic approach on the management of schizophrenic patients 1 , 150 , 151 , 152 , because only in that way the psychotherapists can maximize the effectiveness of the interventions.

4. Conclusion

Schizophrenia is a very frequent mental disorder, and one of the most severe and impairing medical disorders. A diagnosis of simple schizophrenia and depression was considered in this case. In this case, the disorder progressed gradually and peaked during a vital stage of life, the adolescence phase. The age of onset for the patient was at the age of 18 which was the most critical period for him regarding his educational, occupational, and social development, the consequences of the disorders led to a lifelong deficit. psychotherapy interventions were effective in the management and reduction of the negative symptoms and depression after conducting 50 sessions. In this case, the stress on the family and lack of awareness about the condition were important factors in the disorder's progression, his family was instructed to accommodate the surroundings in the home setting to improve the patient's comfort. He became normal, engaged himself in social situations effectively, improved his interpersonal relationship, and could find a suitable job, due to his high cognitive level, the patient has appropriate and adequate insight into his condition, which is a good prognosis factor. The bad prognostic factors are the lack of family support and the long duration of the disorder. It is important to mention that to maintain anonymity, I have concealed specific details about his life and family's occupations.

Ethical Considerations

This study violates no ethical considerations. The participant signed written consent before starting this research, and anonymity was applied to ensure confidentiality and beneficence. The participant also had the right to refuse to participate or not continue when started.

Conflict of Interests

Regarding the publication of this paper, the author claims no conflict of interest.

Published with license by Science and Education Publishing, Copyright © 2022 Mona Zein

Cite this article:

Normal style, chicago style.

• Google-plus

A Sometimes Overlooked Schizophrenia and Psychosis Symptom

For some, emotions can feel iced..

Updated May 5, 2024 | Reviewed by Abigail Fagan

• What Is Psychosis?
• Find counselling to treat psychosis
• Changes to emotional experience such as emotional blunting is common in schizophrenia.
• A systematic review suggests that art and body-focused therapies may help with emotional blunting.
• New and emerging medications have also shown to be promising in addressing this symptom.

In her Ted Talk, "My Journey Through Schizophrenia and Homelessness" (2006), Bethany Yeiser describes her experience of schizophrenia. She courageously details how her thinking changed and became clouded by beliefs that she would be a prophet and menacing voices. After a battle involving hospitalizations and times of being unhoused, she made a remarkable recovery and now advocates for others while sharing her own story.

Early in her talk, she says, "My heart was like ice." This experience of emotional flatness or blunted affect is common in schizophrenia. On the outside, it can look like a still face, on the inside it can feel like a disconnection. This is one of several schizophrenia symptoms known as negative symptoms, things like loss of motivation , social withdrawal, and flatness.

While not as well-known as the hallmark symptoms of hallucinations and delusions in schizophrenia, research shows that this set of symptoms might better predict a person's functioning (Milev et al., 2005). These symptoms can affect a person's relationships and joy in life. Yet perhaps because these symptoms are sometimes less apparent than others, they often go untreated.

Psychotherapy Approaches

That said, psychotherapy techniques involving focus on the body and the use of art in therapy are effective in treating negative symptoms including emotional blunting in schizophrenia (Isabelina et al., 2023). Research on the use of time and negative symptoms has also uncovered that less productive use of time is often linked with increased negative symptoms (D’Anna et al., 2023). While it is difficult to draw the arrow of causation here, behavior activation might also be a target in treating negative symptoms.

A study of Recovery-Oriented Cognitive Therapy (CT-R) for individuals living with a schizophrenia spectrum disorder with a high level of negative symptoms found a decrease in negative symptoms after the six-month treatment (Grant et al., 2017). This is particularly interesting as CT-R has taken a non-traditional focus in treating serious mental illness. By focusing on cultivating what is called the 'adaptive mode,' or a mindset bent toward how the person is at their best while also invigorating aspirations, the treatment takes a recovery-oriented approach.

New Medications

While the majority of medications currently in use to treat schizophrenia, with the possible exception of clozapine, have not been found effective in treating negative symptoms, newer and investigational medications are showing more positive results. These newer medications appear to have somewhat different mechanisms of action than most antipsychotics .

The medication lumateperone, for example, appears to target glutamate, a neurotransmitter that has been considered in its role of negative symptoms (Gruber et al., 2014) in addition to dopamine and serotonin. This medication has shown some positive effects on negative symptoms of schizophrenia (Tarzian et al., 2023).

Other investigational medications with entirely novel mechanisms of action including KarTX, which is expected to be released later this year are also showing promising effects on negative symptoms like emotion blunting (Horan et al, 2023).

The recent research focus on the long-neglected challenge of negative symptoms in schizophrenia is encouraging. With innovative interventions, more individuals facing this blunting may have an opportunity for an increased quality of life and a sense of connection.

D’Anna, G., Zarbo, C., Cardamone, G., Zamparini, M., Calza, S., Rota, M., ... & de Girolamo, G. (2023). Interplay between negative symptoms, time spent doing nothing, and negative emotions in patients with schizophrenia spectrum disorders: results from a 37-site study. Schizophrenia , 9 (1), 63.

Grant, P. M., Bredemeier, K., & Beck, A. T. (2017). Six-month follow-up of recovery-oriented cognitive therapy for low-functioning individuals with schizophrenia. Psychiatric Services , 68 (10), 997-1002.

Gruber, O., Chadha Santuccione, A., & Aach, H. (2014). Magnetic resonance imaging in studying schizophrenia, negative symptoms, and the glutamate system. Frontiers in psychiatry , 5 , 32.

Horan, William P., et al. "Potential impact of KarXT on negative symptoms in acute schizophrenia: An analysis of pooled data from 3 trials." CNS Summit (2023).

Milev, P., Ho, B. C., Arndt, S., & Andreasen, N. C. (2005). Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. American Journal of Psychiatry , 162 (3), 495-506.

Tarzian, M., Ndrio, M., Chique, B., Serai, J., Thalackal, B., Lau, J., ... & Serai, J. K. (2023). Illuminating Hope for Mental Health: A Drug Review on Lumateperone. Cureus , 15 (9).

Yeiser, B. (2016). My Journey Through Schizophrenia and Homelessness. Ted Talk. My journey through schizophrenia and homelessness | Bethany Yeiser | TEDxCincinnati (youtube.com)

Jennifer Gerlach, LCSW, is a psychotherapist based in Southern Illinois who specializes in psychosis, mood disorders, and young adult mental health.

• Find a Therapist
• Find a Treatment Center
• Find a Psychiatrist
• Find a Support Group
• Find Online Therapy
• International
• New Zealand
• South Africa
• Switzerland
• Asperger's
• Bipolar Disorder
• Chronic Pain
• Eating Disorders
• Passive Aggression
• Personality
• Goal Setting
• Positive Psychology
• Stopping Smoking
• Low Sexual Desire
• Relationships
• Child Development
• Therapy Center NEW
• Diagnosis Dictionary
• Types of Therapy

Understanding what emotional intelligence looks like and the steps needed to improve it could light a path to a more emotionally adept world.

• Emotional Intelligence
• Gaslighting
• Affective Forecasting
• Neuroscience

Downregulation of miR-29a as a possible diagnostic biomarker for schizophrenia

• Original Article
• Open access
• Published: 05 May 2024
• Volume 51 , article number  617 , ( 2024 )

Cite this article

You have full access to this open access article

• Parya Alizadeh Khosroshahi 1 ,
• Hamidreza Ashayeri   ORCID: orcid.org/0000-0002-2593-9810 2 ,
• Mohammad Ghanbari 3 ,
• Ayyoub Malek   ORCID: orcid.org/0000-0002-6545-2935 4 ,
• Sara Farhang   ORCID: orcid.org/0000-0001-8552-138X 4 , 5 &
• Mehdi Haghi   ORCID: orcid.org/0000-0001-8400-4209 1  

108 Accesses

Explore all metrics

MicroRNAs (miRNAs) are epigenetic factors regulating many genes involved in brain development. Dysregulation of miRNA could result in dysregulation of genes which may contribute to diseases affecting the brain and behavior (e.g., schizophrenia). miR-29 family is a miRNA family contributing to brain maturation. miR-29 knockout in animal studies is reported to correlate with psychiatric disorders very similar to those seen in schizophrenia. In this study, we aimed to evaluate the miR-29a level in patients with schizophrenia and its potential value in the diagnosis of schizophrenia.

Materials and methods

The serum sample of 42 patients with schizophrenia and 40 healthy subjects were obtained from the Azeri Recent onset/Acute phase psychosis Survey (ARAS) Cohort study. After preparations, the expression level of miR-29a was investigated by real-time PCR. The SPSS and GraphPad prism software were used to analyze the relation between miR-29a level and clinical parameters and its potential as a biomarker for the diagnosis of schizophrenia.

Our study showed a significantly lower miR-29a level in patients compared to healthy controls ( p  = 0.0012). Furthermore, miR-29a level was significantly lower in some types of schizophrenia ( p  = 0.024). miR-29a level was not related to sex, age, or heredity ( p  > 0.05). miR-29a also showed 80% specificity and 71.43% sensitivity in the diagnosis of schizophrenia.

Downregulation of miR-29a in schizophrenia is significantly related to the development of this illness. It might have the potential as a biomarker for schizophrenia.

Similar content being viewed by others

Altered expression of microRNA-223 in the plasma of patients with first-episode schizophrenia and its possible relation to neuronal migration-related genes

miRNAs as potential diagnostic biomarkers and pharmacogenomic indicators in psychiatric disorders

Deregulated microRNA expression in biospecimens from patients diagnosed with schizophrenia and bipolar disorder as a disease biomarker

Avoid common mistakes on your manuscript.

Introduction

Schizophrenia affects thinking, behaviors, and feelings. The prevalence is around 1% of the population [ 1 ] but it is one of the mental illnesses capable of disrupting lives of patients and people around them. The diagnosis of schizophrenia includes a spectrum of symptoms that are classified into two categories: positive and negative symptoms [ 2 ]. Both genetic and environmental factors play major roles in the pathogenesis of schizophrenia. According to monozygotic and dizygotic twin studies, the inheritance rate of schizophrenia is estimated to be approximately 97% indicating the importance of genes in the incidence of this disease [ 3 ]. Environmental factors like childhood experiences [ 4 ], migration [ 5 ], and cannabis use [ 6 ] also increase the chance of schizophrenia. Increased dopamine levels play a role in the pathophysiology of schizophrenia and drugs that antagonize D2 receptors reveal some of the symptoms [ 7 , 8 ]. Despite all current treatment options, 10 to 30% of patients show resistance to pharmacologic treatments [ 9 ]. These imply that other mechanisms might be involved and a better understanding of the pathogenesis and pathophysiology of disorder is needed for the early detection and development of effective therapeutic strategies.

Environment affects gene expression and probability of schizophrenia increases if a person with high genetic risk is exposed to environmental risk factors [ 10 ]. Epigenetic mechanisms explain the interaction between genetics and the environment at a molecular level. Many studies in the field of epigenetics have focused on microRNAs (miRNAs) due to their important mechanism in the post-transcriptional regulation of genes and their effect on the development of many diseases without any change of DNA sequence. Also, there is a reciprocal action between miRNAs and other epigenetic pathways such as DNA methylation which makes miRNA-epigenetic feedback loop in physiological processes [ 11 ]. The mature miRNAs are small noncoding RNA molecules (19–23 nucleotides length) that interact with RNA-inducing silencing complex (RISC) and are able to suppress numerous genes via attaching to 3’ UTR region of mRNAs. This leads to the prevention of mRNA translation or mRNA breakage via the enzymatic activity of RISC [ 12 ]. Also, many miRNAs show tissue-specific expression patterns and are released from normal or abnormal cells via extracellular vesicles into circulation. Change in the level of specific miRNAs in body fluids may be related to the abnormality of specific cells or organs in the body [ 13 ].

Many of these miRNAs regulate genes which play a vital role in the pathophysiology of the central nervous system thereby; dysregulation of these miRNAs can be the origin of abnormal pathways in the development of mental disorders such as schizophrenia [ 14 ]. For example, miR-9 and miR-4467 regulate the genes that engage in the regulation of neurotrophin signaling, neuronal differentiation, and nervous system development. Downregulation of miR-9 and upregulation of miR-4467 show a potential diagnostic biomarker in the blood of patients with schizophrenia [ 15 ]. miR-29 family are highly noticed because they correlate with the late stage of brain maturation. The role of miR-29 dysregulation is revealed in several neurodegenerative diseases such as Alzheimer’s [ 16 ], Huntington’s, ataxia phenotype [ 17 ], and Parkinson’s disease [ 18 ]. Also, miR-29 knockout in mice is associated with psychiatric disorders very similar to those seen in autism, epilepsy, and schizophrenia [ 19 ]. The expression pattern and diagnostic biomarker potential of miR-29 in schizophrenia patients’ serum is not clear yet. However, it is essential to evaluate miR-29a expression pattern and biomarker potential role in patients with schizophrenia due to the crucial role of miR-29a in neuronal differentiation, neurological recovery, axon branching, neural cell survival, and synaptic plasticity [ 17 , 20 , 21 , 22 , 23 ]. The aim of this study was to evaluate miR-29a expression level in the serum of schizophrenia patients compared to normal ones. In this research, we also evaluated the potential biomarker role of miR-29a in patients with schizophrenia.

Sample preparation

This study was performed within the framework of ARAS study. The Azeri Recent onset/Acute phase psychosis Survey (ARAS) [ 24 ] is a prospective cohort of Iranian patients with first episode psychosis. This study meets international ethical standards, including the Declaration of Helsinki, and was approved by the Iranian national ethical committee (IR.NIMAD.REC.1396.101). Patients diagnosed with schizophrenia based on Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria were enrolled. They were drug naïve or within the first month of starting the medication. After obtaining written informed consent from patients and their legal caregivers, the blood samples of 42 patients with schizophrenia and 40 controls were prepared from Razi hospital (Tabriz, Iran) and immediately stored at -80℃. The control sample involved students or staff of the hospital volunteered to give blood sample for research purpose. Beside the self-report of medical and psychiatric history, a clinical interview evaluated them for major psychiatric disorders and the samples were used if there was no psychiatric condition reported or detected.

RNA isolation

Total RNA was isolated from serum specimens by using trizol in room temperature based on the manufacturer’s protocol (ziaviz, Iran). The quantity of RNA was assessed by a nanodrop spectrophotometer (Thermo Fisher Scientific, Waltham, USA). RNA samples were stored at -80˚C until complementary DNA (cDNA) synthesis. According to manufacturer’s instructions, approximately 250 µg of total RNA was used as template for cDNA synthesis using add script cDNA synthesis kit (add bio, Korea). For specific cDNA synthesis from target miR-29a and U6 mRNA, specific stem-loop primers were designed which have been illustrated in Table  1 . U6 was used as the housekeeping gene for data normalization.

Quantitative real-time PCR (qRT-PCR)

For qRT-PCR, specific primers were designed which have been detailed in Table  1 . qRT-PCR was performed by using SYBR green MasterMix (Amplicon, Odense, Denmark) on a Light Cycler® 96 Real-Time PCR system (Roche Molecular Systems, Pleasanton, USA). A total volume of 10 µl containing 5 µl MasterMix, 0.3 µl of forward and reverse primers for miR-29a and 0.5 µl of forward and reverse primers for U6, 2.4 µl DNase/RNase free H2O for miR-29a and 2 µl DNase/RNase free H2O for U6, and 2 µl of cDNA was used in each reaction. Amplification was performed with the following settings: 15 min at 95˚C, followed by 45 cycles of 30 s at 95˚C, 30 s at 60˚C and 30 s at 72˚C. All reactions were repeated three times and miR-29a relative expression was evaluated by using the comparative cycle threshold (Ct) method. Then, miR-29a expression levels were normalized to U6 expression levels and difference between miR-29a and U6 Ct values (ΔCt) was calculated for each sample. Finally, miR-29a expression levels in patients and control people were determined by calculating 2 −∆Ct .

Statistical analysis

SPSS statistics version 26 and GraphPad Prism 9 software were used for statistical analysis. Non-parametric Mann-Whitney and Kruskal Wallis tests were performed to examine expression level and association between miR-29a expression and clinical characteristics of patients with schizophrenia. Receiver operation curve (ROC) was used for evaluating sensitivity and specificity of miR-29a as a potential diagnostic biomarker. The 95% confidence interval (CI) was used and p-values less than 0.05 were considered as significant.

Patient characteristics

A total of 82 subjects (42 patients with schizophrenia and 40 healthy individuals) were included in this research. Thirty (71.43%) patients were male and twelve (28.57%) were female and in healthy control individuals 20 were male and 20 were female. The mean age for patients was 31 (SD = ± 13.85 years) and for healthy individuals was 26.4 (SD = ± 6.1 years). Based on DSM-IV schizophrenia classification, approximately 23 patients (54.76%) had paranoid type, 9 patients (21.43%) had disorganized type, and 10 patients (23.81%) had undifferentiated type of schizophrenia. In terms of the familial background, 8 patients (19%) had heredity and 34 patients (81%) had non-heredity form of schizophrenia (Table  2 .). While 15% of patients was taking no medication, the majority of them were receiving antipsychotic treatment at the time of assessment: risperidone (42.5%), olanzapine (22.5%), quetiapine (5%) aripiprazole (7.5%) and haloperidol (7.5%).

The expression of miR-29 in serums of patients with schizophrenia

The expression level of miR-29a in serum of patients with schizophrenia and healthy individuals were assessed by qRT-PCR. Our results revealed that the expression level of miRNA-29a is significantly decreased in serum of schizophrenic patients compared to serum of healthy individuals (p-value = 0.0012) (Fig.  1 ).

Expression of miR-29a in serum of patients with schizophrenia compared to healthy subjects. CON: healthy controls, SCH: schizophrenia

Association between miR-29a expression levels and clinical parameters

Our results demonstrated that there was a significant association between miR-29a expression level and the types of schizophrenia so that, the expression of miR-29a significantly decreased in serum samples of paranoid type compared to disorganized and undifferentiated types of schizophrenia (p-value = 0.024). However, there was no significant association between miR-29a expression and other clinical features including age, gender, and inheritance ( p  > 0.05).

The serum expression level of miR-29a as a potential biomarker of schizophrenia

The ROC analysis was performed to evaluate miR-29a potentials as a diagnostic biomarker for schizophrenia. Our result revealed a sensitivity and specificity of 80% and 71.43%, respectively (p-value = 0.0015). The area under curve (AUC) was 0.7506 (Fig.  2 . and Table  3 ).

The ROC curve analysis showed a sensitivity and specificity of 80% and 71.43%, respectively. The AUC is 0.7506. AUC: area under the curve, ROC: receiver operation curve

In present study, we revealed significant downregulation of miR-29a in serum of patients with schizophrenia compared to healthy controls (p-value = 0.0012). This miR-29a downregulation was significantly correlated with paranoid type than other main types including disorganized and undifferentiated forms of disease (p-value = 0.024). Also, we concluded that low level of miR-29a in serum can be used as a potential biomarker in diagnosis of schizophrenia (sensitivity = 80% and specificity = 71.43%). Our findings are consistent with previous study by perkins et al. (2007) in which they showed downregulation of 15 miRNAs including miR-29a and miR-29c in postmortem prefrontal cortex tissue study of 15 individuals with schizophrenia ( n  = 13) or schizoaffective disorder ( n  = 2) compared to 21 unaffected individuals (patients miR-29a level was 0.82 fold the unaffected subjects miR-29a level) [ 25 ]. Another study by Akif Camkurt et al. (2016) investigated miR-29a-3p serum levels between 16 schizophrenic patients and 16 normal controls report a significantly higher level of miR-29a-3p in patients compared to normal subjects (p-value < 0.001) [ 26 ].

Several target genes and molecular pathways of miR-29 are known in brain disorders, which indicate the important role of miR-29 in the brain development. miR-29 family includes miR-29a, miR-29b-1, miR-29b-2 and miR-29c [ 19 ]. The mature sequences of these miRNAs are highly conserved in human, mouse and rat. This indicate their common mechanisms in regulation of genes which have crucial role in neurodegeneration and neuronal survival [ 27 ]. The mechanism in which miR-29a dysregulation is associated with schizophrenia is not known and need to deep molecular studies. However, recent researches highlight several molecular pathways of miR-29 in brain maturation and neurofunctional disorders. Shioya et al. demonstrated that miR-29 regulates navigator 3 (NAV3) gene which is a regulator of axon guidance. Downregulation of miR-29a is associated with increased level of NAV3 in Alzheimer disease brains [ 28 ]. Since NAV3 has is part of neural navigator gene family like NAV1 and NAV 2, dysregulation in NAV 3 expression can lead to abnormal neural growth and play a role is disease such as autism spectrum disorders [ 29 ] or Alzheimer disease.

Downregulation of miR-29a is also associated with neural cell death [ 17 ]. Roshan et al. revealed that in Spinocerebellar ataxias 17, downregulation of miR-29a and miR-29b lead to elevation of their target genes; β-secretase 1 (BACE1), p53 upregulated modulator of apoptosis (PUMA), and BAK which result in cytochrome releasing and neuronal apoptosis [ 30 ]. It is demonstrated that miR-29 by targeting PTEN expression stimulates AKT signaling pathway which has an important role in neural stem/progenitor cells (NSPCs) selfrenewing during brain damage [ 31 ]. Ling Yang et al. revealed that in Parkinson’s disease, miR-29a by targeting of mitochondrial antiviral signaling protein (MAVS) prevents MPP+-induced cell death and inflammation. Therefore, miR-29a has neuroprotective role against inflammation and oxidative stress which are common feature of neuropsychiatric disorders such as schizophrenia, autism, and depression [ 32 ]. A recent research that carried out in mice model, revealed DNMT3A as a direct target of miR-29, has an important role in postnatal mammalian brain development and its upregulation during knock out of miR-29 associated with neurobehavioral sequelae as seen in autism spectrum disorders, epilepsy, and schizophrenia [ 19 ]. DNA methyltransferase DNMT3A is responsible for de novo non-canonical CH (non-CG where H = A, C, T) methylation which is increased in the postnatal brain at birth and then severely decreased several weeks later [ 33 ]. Regulation of DNMT3A depends on miR-29 expression pattern in postnatal brain during lifespan so that downregulation of miR-29 associated with increased CH methylation in genes such as CHL1, FZD3, and SOX5 which are associated with schizophrenia [ 19 ]. A Meta-analysis has shown that synaptophysin levels reduce in prefrontal cortical cortex and hippocampus of schizophrenic patients [ 34 ]. Postmortem studies and genetic evidences show a reduced synaptic plasticity in schizophrenia [ 35 ]. Therefore, miR-29 family regulate neuronal activity and synaptic function during lifespan. Downregulation of miR-29 in serum of patients can cause impairment in neural and synaptic activity in schizophrenia. However precise mechanisms and molecular pathways of miR-29 downregulation in schizophrenia need to more studies.

There are very limited reports about patients with psychotic deriders from the Middle east, including Iran. The main strength of this study was the nature of the sample, standard diagnostic tools and the timing of blood sampling. However, results might be limited with the cross-sectional design, and using blood samples. For future studies we recommend using larger sample size and including further clinical outcome to determine value of microRNA levels as a screening tool, considering effect of treatment on microRNA levels, and using lumbar puncture samples for a more accurate investigation of conditions which effect brain.

In conclusion, results of this study showed that miR-29a is significantly downregulated in serums of patients with schizophrenia compared to healthy individuals. Also, low level of miR-29a in serum of schizophrenic patients was significantly associated with paranoid type of schizophrenia. According to ROC analysis, we concluded that miR-29a may be considered as a potential diagnostic biomarker in patients with schizophrenia.

Data availability

The data that support the findings of this study are available from the corresponding authors, Sara Farhang or Mehdi Haghi, upon reasonable request.

Abbreviations

Azeri Recent onset/Acute phase psychosis Survey

area under curve

β-secretase 1

Complementary DNA

confidence interval

mitochondrial antiviral signalling protein

messenger RNA

neural stem/progenitor cell

p53 upregulated modulator of apoptosis qRT-PCR :Qualitative real-time polymerase chain reaction

Receiver operation curve

Velligan DI, Rao S (2023) The Epidemiology and Global Burden of Schizophrenia. J Clin Psychiatry, 84(1)

Hany M et al Schizophrenia , in StatPearls . 2023, StatPearls Publishing Copyright © 2023, StatPearls Publishing LLC.: Treasure Island (FL)

Clarke MC et al (2009) Evidence for an interaction between familial liability and prenatal exposure to infection in the causation of schizophrenia. Am J Psychiatry 166(9):1025–1030

Article   PubMed   Google Scholar  

Matheson SL et al (2013) Childhood adversity in schizophrenia: a systematic meta-analysis. Psychol Med 43(2):225–238

Article   CAS   PubMed   Google Scholar  

Henssler J et al (2020) Migration and schizophrenia: meta-analysis and explanatory framework. Eur Arch Psychiatry Clin Neurosci 270(3):325–335

Marconi A et al (2016) Meta-analysis of the Association between the Level of Cannabis Use and risk of psychosis. Schizophr Bull 42(5):1262–1269

Article   PubMed   PubMed Central   Google Scholar  

Shen LH, Liao MH, Tseng YC (2012) Recent advances in imaging of dopaminergic neurons for evaluation of neuropsychiatric disorders. J Biomed Biotechnol 2012:p259349

Article   Google Scholar  

Brisch R et al (2014) The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. Front Psychiatry 5:47

PubMed   PubMed Central   Google Scholar  

Patel KR et al (2014) Schizophrenia: overview and treatment options. P t 39(9):638–645

Robinson N, Bergen SE (2021) Environmental risk factors for Schizophrenia and bipolar disorder and their relationship to genetic risk: current knowledge and future directions. Front Genet 12:686666

Yao Q, Chen Y, Zhou X (2019) The roles of microRNAs in epigenetic regulation. Curr Opin Chem Biol 51:11–17

Bushati N, Cohen SM (2007) microRNA functions. Annu Rev Cell Dev Biol 23:175–205

Ortiz-Quintero B (2020) Extracellular MicroRNAs as Intercellular Mediators and noninvasive biomarkers of Cancer. Cancers (Basel), 12(11)

Hussein M, Magdy R (2021) MicroRNAs in central nervous system disorders: current advances in pathogenesis and treatment. Egypt J Neurol Psychiatry Neurosurg 57(1):36

Jin M et al (2021) Alterations in the expression levels of mir-9-5p and miR-4467 in Peripheral blood of patients with first-episode Schizophrenia. Research Square

Müller M et al (2016) MicroRNA-29a is a candidate biomarker for Alzheimer’s Disease in Cell-Free Cerebrospinal Fluid. Mol Neurobiol 53(5):2894–2899

Roshan R et al (2014) Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice. RNA 20(8):1287–1297

Article   CAS   PubMed   PubMed Central   Google Scholar  

Bai X et al (2017) Downregulation of blood serum microRNA 29 family in patients with Parkinson’s disease. Sci Rep 7(1):5411

Swahari V et al (2021) MicroRNA-29 is an essential regulator of brain maturation through regulation of CH methylation. Cell Rep 35(1):108946

Gao Y et al (2020) MicroRNA–29a promotes the neural differentiation of rat neural stem/progenitor cells by targeting KLF4. Mol Med Rep 22(2):1008–1016

Yang W, Sun P (2020) Promoting functions of microRNA-29a/199B in neurological recovery in rats with spinal cord injury through inhibition of the RGMA/STAT3 axis. J Orthop Surg Res 15(1):427

Li H et al (2014) MicroRNA-29a modulates axon branching by targeting doublecortin in primary neurons. Protein Cell 5(2):160–169

Volpicelli F et al (2019) The microRNA-29a modulates serotonin 5-HT7 receptor expression and its effects on hippocampal neuronal morphology. Mol Neurobiol 56(12):8617–8627

Farhang S et al (2022) ARAS recent onset acute phase psychosis survey, a prospective observational cohort of first episode psychosis in Iran—the cohort profile. Schizophrenia 8(1):101

Perkins DO et al (2007) microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol 8(2):1–11

Camkurt MA et al (2016) Investigation of Dysregulation of several MicroRNAs in Peripheral blood of Schizophrenia patients. Clin Psychopharmacol Neurosci 14(3):256–260

Kriegel AJ et al (2012) The miR-29 family: genomics, cell biology, and relevance to renal and cardiovascular injury. Physiol Genom 44(4):237–244

Article   CAS   Google Scholar  

Shioya M et al (2010) Aberrant microRNA expression in the brains of neurodegenerative diseases: miR-29a decreased in Alzheimer disease brains targets neurone navigator 3. 36(4):320–330Neuropathology and applied neurobiology

Powers RM, Hevner RF, Halpain S (2022) The Neuron navigators: structure, function, and evolutionary history. Front Mol Neurosci 15:1099554

Roshan R et al (2012) Regulation of BACE1 by miR-29a/b in a cellular model of Spinocerebellar Ataxia 17. RNA Biol 9(6):891–899

Gao Y et al (2019) miR–29 promotes the proliferation of cultured rat neural stem/progenitor cells via the PTEN/AKT signaling pathway. Mol Med Rep 20(3):2111–2118

CAS   PubMed   PubMed Central   Google Scholar  

Williams JA et al (2022) Inflammation and brain structure in Schizophrenia and other Neuropsychiatric disorders: a mendelian randomization study. JAMA Psychiatry 79(5):498–507

Lister R et al (2013) Global epigenomic reconfiguration during mammalian brain development. Science 341(6146):1237905

Osimo EF et al (2019) Synaptic loss in schizophrenia: a meta-analysis and systematic review of synaptic protein and mRNA measures. Mol Psychiatry 24(4):549–561

Forsyth JK, Lewis DA (2017) Mapping the consequences of impaired synaptic plasticity in Schizophrenia through Development: an integrative model for diverse clinical features. Trends Cogn Sci 21(10):760–778

Download references

Acknowledgements

The Azeri Recent onset/Acute phase psychosis Survey (ARAS) was funded by the Iranian National Institute for Medical Research Development (NIMAD). The study was in part supported by the Research Center for Psychiatry and Behavioral Sciences at Tabriz University of Medical Sciences.

Tabriz University of Medical Sciences.

Author information

Authors and affiliations.

Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran

Parya Alizadeh Khosroshahi & Mehdi Haghi

Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

Hamidreza Ashayeri

Clinical Research Development Center, Mohammad Kermanshahi and Farabi Hospitals, Imam Khomeini, Kermanshah University of Medical Sciences, Kermanshah, Iran

Mohammad Ghanbari

University Medical Center Groningen, University of Groningen, University Center for Psychiatry, Groningen, The Netherlands

Ayyoub Malek & Sara Farhang

Research center of psychiatry and behavioral sciences, Tabriz university of medical sciences, Tabriz, Iran

Sara Farhang

You can also search for this author in PubMed   Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and by P.A, A.M. Analysis were performed by M.H. The first draft of the manuscript was written by S.F. & H.A. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Sara Farhang or Mehdi Haghi .

Ethics declarations

Ethical approval.

This study meets international ethical standards, including the Declaration of Helsinki, and was approved by the Iranian national ethical committee (IR.NIMAD.REC.1396.101).

Consent to participate

Informed consent was obtained from all individual participants included in this study.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .

Reprints and permissions

About this article

Khosroshahi, P.A., Ashayeri, H., Ghanbari, M. et al. Downregulation of miR-29a as a possible diagnostic biomarker for schizophrenia. Mol Biol Rep 51 , 617 (2024). https://doi.org/10.1007/s11033-024-09428-2

Download citation

Received : 25 January 2024

Accepted : 08 March 2024

Published : 05 May 2024

DOI : https://doi.org/10.1007/s11033-024-09428-2

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Schizophrenia
• Epigenetics
• Non-coding RNA
• Real-time PCR

Advertisement

• Find a journal
• Publish with us
• Track your research

We couldn’t find any results matching your search.

Please try using other words for your search or explore other sections of the website for relevant information.

We’re sorry, we are currently experiencing some issues, please try again later.

Our team is working diligently to resolve the issue. Thank you for your patience and understanding.

News & Insights

Teva And Medincell Say Phase 3 SOLARIS Study In Schizophrenia Met Primary Goal

May 08, 2024 — 07:34 am EDT

Written by RTTNews.com for RTTNews  ->

(RTTNews) - Teva Pharmaceuticals, a U.S. affiliate of Teva Pharmaceutical Industries Ltd. (TEVA), and Medincell Wednesday said the Phase 3 SOLARIS study evaluating TEV-'749 in adult patients with schizophrenia met its primary goal.

The study achieved clinically meaningful and statistically significant reductions for the high, medium, and low dose groups versus placebo in the Positive and Negative Syndrome Scale (PANSS) total score, a widely used assessment tool for schizophrenia symptom severity.

Further, TEV-'749 was well tolerated, with no incidence of post-injection delirium/sedation syndrome (PDSS) observed to date.

The long-term safety of TEV-'749 and incidence of PDSS are also being evaluated in the SOLARIS open-label study with safety data topline readout expected in the second half of 2024.

The views and opinions expressed herein are the views and opinions of the author and do not necessarily reflect those of Nasdaq, Inc.

Stocks mentioned

More related articles.

This data feed is not available at this time.

Sign up for the TradeTalks newsletter to receive your weekly dose of trading news, trends and education. Delivered Wednesdays.

To add symbols:

• Type a symbol or company name. When the symbol you want to add appears, add it to My Quotes by selecting it and pressing Enter/Return.
• Copy and paste multiple symbols separated by spaces.

These symbols will be available throughout the site during your session.

Your symbols have been updated

Edit watchlist.

• Type a symbol or company name. When the symbol you want to add appears, add it to Watchlist by selecting it and pressing Enter/Return.

Opt in to Smart Portfolio

Smart Portfolio is supported by our partner TipRanks. By connecting my portfolio to TipRanks Smart Portfolio I agree to their Terms of Use .