simple schizophrenia case study

Simple Schizophrenia: A Forgotten Diagnosis in Psychiatry

Affiliations.

• 1 Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
• 2 Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital.
• 3 Department of Psychiatry, School of Medicine and Medical Sciences, University College Dublin, St Vincent's University Hospital, Dublin, Ireland.
• 4 Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel.
• PMID: 31082962
• DOI: 10.1097/NMD.0000000000000936

Clustering of symptoms to characterize simple schizophrenia is still debated, and support is needed for the characterization of simple schizophrenia as a syndrome. We conducted a systematic review to identify all cases of simple schizophrenia published until December 2017. We identified 42 cases of simple schizophrenia, 57% of which met all three diagnostic criteria (ICD-10, DSM-4 research criteria, and Black and Boffeli's criteria for simple schizophrenia). The mean age at first contact with clinical services was 30.1 (SD = 11.6) years, with a mean delay of 7.4 (SD = 6.8) years from symptom onset to first presentation. An insidious onset and negative symptoms were characteristic features in all cases. Social withdrawal, alogia, blunted affect, lack of initiative/interest, and functional impairment were found in more than 85% of cases. Our findings contribute to greater awareness and understanding of simple schizophrenia, and have the potential to reawaken interest in this clinically distinct subgroup.

Publication types

• Systematic Review
• Schizophrenia* / classification
• Schizophrenia* / diagnosis
• Schizophrenia* / drug therapy
• Schizophrenia* / physiopathology

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Simple Schizophrenia Revisited: A Clinical, Neuropsychological, and Neuroimaging Analysis of Nine Cases

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Jordi Serra-Mestres, Carol A. Gregory, Subash Tandon, Alison J. Stansfield, Paul M. Kemp, Peter J. McKenna, Simple Schizophrenia Revisited: A Clinical, Neuropsychological, and Neuroimaging Analysis of Nine Cases, Schizophrenia Bulletin , Volume 26, Issue 2, 2000, Pages 479–493, https://doi.org/10.1093/oxfordjournals.schbul.a033467

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Simple schizophrenia is widely considered to be a controversial or even discredited entity. However, cases showing typical clinical features continue to be identified in surveys of schizophrenia patients. This article reports on nine patients who met proposed diagnostic criteria for simple schizophrenia. The patients all showed the classical features of social and occupational decline, as well as negative symptoms in the absence of clear-cut positive symptoms. A range of other symptoms, which were either nonspecific or fell short of psychotic phenomena, was also seen. Neuropsychological testing revealed evidence of general intellectual impairment plus deficits in executive function and memory. Computed tomography scans were normal or showed only minor abnormalities. All patients, however, showed abnormalities on single photon emission computerized tomography (SPECT), mainly affecting frontal and temporal regions. It is concluded that cases conforming to the original descriptions of simple schizophrenia continue to be seen and are still best understood as representing a form of schizophrenia.

• neuroimaging
• computed tomography
• single photon emission computed tomography
• neuropsychological tests
• psychotic disorders
• schizophrenia
• signs and symptoms
• executive functioning
• simple schizophrenia

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Simple schizophrenia: case report and review of the literature

Author information, affiliations.

• Efstratiou S 1
• Tzavaras N 2

Annals of General Psychiatry , 01 Jan 2010 , 9(Suppl 1): S183-S183 https://doi.org/10.1186/1744-859x-9-s1-s183   PMCID: PMC2991873

Abstract 

Free full text .

Sofia Efstratiou

1 Department of Psychiatry, General Hospital of Kilkis, NHS, Greece

2 University of Thrace, Greece

Nikolaos Tzavaras

3 Hellenic Psychiatric Association, Greece

Simple schizophrenia remains controversial. In this study we illustrate the diagnostic complexities of the disorder by emphasizing the importance of the criterion "progressive development of odd behaviour".

Materials and methods

We report the case of a 35-year-old man with "organic mental disorder". His medical and psychiatric history notes were peer reviewed and, neuropsychological assessments (WISC and Rorschach), blood tests, EEG and Computed tomography were carried out. Several psychiatric scales (SCID, BPRS, HDS-17, CAS and GAF and MMSE) were also used to establish diagnosis and to evaluate treatment changes. We reviewed the differential diagnosis of the case, the history of simple schizophrenia and its importance both to this case and to current thought about schizophrenia.

The patient had followed a social skills training program in a community setting for two years. His current state indicates IQ: 97, attention and concentration deficits, blunting of affect, inability to meet the demands of society and decline in overall performance (GAF: 41-50, CAS: 25). Neuroimaging and laboratory tests are normal. Furthermore he meets research criteria for simple deteriorative disorder or simple schizophrenia. He is been treated with aripiprazole now, with good response.

Conclusions

The review of the literature (historical articles, case reports, epidemiological and trancultural surveys, studies on reliability and validity and review articles) demonstrates the heterogeneity of the simple schizophrenia diagnosis oven the years. However there is a lack of developmental and psychopathological approaches that could provide a better understanding on the disorder. More case reports may contribute to that.

• Suzuki M, Nohara S, Hagino H, Takahashi T, Kawasaki Y, Yamashita I, Watanabe N, Seto H, Kurachi M. Prefrontal abnormalities in patients with simple schizophrenia: structural and functional brain-imaging studies in five cases. Psychiatry Res. 2005; 140 (2):157–71. 10.1016/j.pscychresns.2005.06.005. Epub 2005 Oct 21. [ Abstract ] [ CrossRef ] [ Google Scholar ]
• Serra-Mestres J, Gregory CA, Tandon S, Stansfield AJ, Kemp PM, McKenna PJ. Simple schizophrenia revisited: a clinical, neuropsychological, and neuroimaging analysis of nine cases. Schizophr Bull. 2000; 26 (2):479–93. [ Abstract ] [ Google Scholar ]
• Black DW, Boffeli TJ. Simple schizophrenia: past, present, and future. Am J Psychiatry. 1989; 146 (10):1267–73. [ Abstract ] [ Google Scholar ]
• Mack AH, Feldman JJ, Tsuang MT. A case of "pfropfschizophrenia": Kraepelin's bridge between neurodegenerative and neurodevelopmental conceptions of schizophrenia. Am J Psychiatry. 2002; 159 (7):1104–10. 10.1176/appi.ajp.159.7.1104. [ Abstract ] [ CrossRef ] [ Google Scholar ]

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CASE REPORT article

Early-onset schizophrenia with predominantly negative symptoms: a case study of a drug-naive female patient treated with cariprazine.

• Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary

Schizophrenia is a chronic and severe mental disorder characterized by positive, negative, and cognitive symptoms. Negative symptoms are usually present from the prodromal phase; early diagnosis and management of negative symptoms is a major health concern since an insidious onset dominated by negative symptoms is associated with a worse outcome. Antipsychotic medications, which are effective for treating positive symptoms, are generally ineffective for treating negative or cognitive symptoms. We present a 23-year-old woman showing severe symptoms at her first visit to our department. The patient’s parents reported that their daughter had experienced several years of psychosocial decline and putative psychiatric symptoms, but no medical attention had been previously sought; as such, the diagnosis of schizophrenia with predominantly negative symptoms was very much delayed. Early onset of schizophrenia, longer duration of untreated psychosis, and severe negative symptoms, which have limited treatment options, suggested a poor prognosis. We initiated monotherapy with cariprazine, a novel antipsychotic that has recently been proven efficacious in treating schizophrenia with predominantly negative symptoms. This report describes a 52-week cariprazine treatment regimen and follows the patient’s impressive clinical improvement confirmed by PANSS and CGI scores, and psychological tests.

Schizophrenia is a severe, chronic, and heterogeneous mental disorder that often has debilitating long-term outcomes. Its lifetime prevalence rate is estimated to be approximately 1% worldwide in the adult population ( Lehman et al., 2010 ). Onset generally occurs in late adolescence or early adulthood, with an average age of 18 years for men and 25 years for women. 1 The term early-onset schizophrenia (EOS) is used to refer to patients who are diagnosed with the disorder before this age. EOS is a severe, frequently disabling, and chronic condition with a prevalence approaching 0.5% in those younger than 18 years ( Hafner and Van der Heiden, 1997 ).

Schizophrenia is accompanied by a distortion of personality that affects fundamental mental and social functions, making everyday life extremely difficult for patients. Clinical symptoms are often classified in three main domains: positive symptoms, such as hallucinations, delusions, suspiciousness/persecution; negative symptoms, such as emotional withdrawal, blunted affect, and passive social withdrawal; and cognitive symptoms, such as impaired perception, learning, thinking, and memorizing. EOS may be accompanied by greater symptom severity, premorbid developmental impairment, ‘soft’ neurological signs (eg, clumsiness, motor incoordination), and a higher rate of substance abuse ( Hsiao and McClellan, 2008 ; Clemmensen et al., 2012 ; Immonen et al., 2017 ). Accordingly, diagnosis of EOS is often difficult and frequently delayed since onset is more commonly insidious than acute, which makes it difficult to differentiate EOS from underlying cognitive deficits, premorbid functional impairment, or other abnormalities ( Russell, 1994 ; Bartlet, 2014 ). Given this common delay in recognition of the disorder, the duration of untreated psychosis is often very long, further contributing to a poor outcome ( Penttila et al., 2014 ).

Although various hypotheses have been developed, the etiopathogenesis of schizophrenia and EOS is not fully understood ( McGuffin, 2004 ; Klosterkotter et al., 2011 ). 2 Among the rising and falling neurochemical theories, the dopamine hypothesis has remained a primary hypothesis guiding the treatment of schizophrenia. There are four dopaminergic pathways in the human brain: the mesolimbic, the mesocortical, the tuberoinfundibular, and the nigrostriatal. Positive symptoms of schizophrenia are associated with the hyperdopaminergic state of D 2 receptors in the mesolimbic area, while negative and cognitive symptoms are believed to be related to the hypodopaminergic dysregulation of the prefrontal cortex ( Stahl, 2003 ).

Negative symptoms of schizophrenia, which affect up to 60% of patients with schizophrenia ( Rabinowitz et al., 2013 ), form a complex clinical constellation of symptoms that challenge both diagnosis and treatment. By definition, negative symptoms mean the absence of normal functions. Negative symptoms are classified by their etiology as primary negative symptoms, which are core features of the disease itself, and secondary negative symptoms, which are consequences of positive symptoms, antipsychotic treatment, depression or extrapyramidal side effects. Five constructs have been accepted by general consensus as key aspects of negative symptoms: blunted affect, alogia, anhedonia, asociality, and avolition ( Marder and Galderisi, 2017 ). Patients with predominant negative symptoms lose their motivation, cannot function at school or work, and their interpersonal relationships severely decay. Due to impaired daily functioning and social amotivation, they may need constant care.

Although early intervention is associated with improvement in negative symptoms ( Boonstra et al., 2012 ), this may be challenging since negative symptoms develop slowly and may be difficult to detect or differentiate from other clinical features ( Kirkpatrick et al., 2001 ; Galderisi et al., 2018 ). Moreover, a more insidious onset predicts poorer outcome and more severe negative symptoms ( Kao and Liu, 2010 ; Immonen et al., 2017 ; Murru and Carpiniello, 2018 ). Diagnosis of patients with predominantly negative symptoms (lacking manifest psychotic signs) is often delayed, resulting in a longer duration of untreated psychosis. The length of untreated psychosis is closely related to poorer functional outcome ( Perkins et al., 2005 ).

Negative symptoms have traditionally had minimal response to antipsychotic treatment. First-generation antipsychotics are effective in treating positive symptoms, but negative symptom improvement is only evident when symptoms are secondary to positive symptoms. It was initially hoped that second-generation antipsychotics would target both positive and negative symptoms, but efficacy data have been disappointing. This was a large meta-analysis where only four second-generation drugs (amisulpride, risperidone, olanzapine, and clozapine) resulted to be more efficacious than first-generation antipsychotics in the overall change of symptoms, including positive and negative symptoms. The other examined second-generation antipsychotics were only as efficacious as first-generation antipsychotic agents ( Leucht et al., 2009 ). These studies were mainly conducted in patients with general symptoms of schizophrenia, therefore a secondary effect on negative symptoms could not be ruled out. Therefore negative symptom improvement cannot be considered a core component of atypicality ( Veerman et al., 2017 ). Previous studies have demonstrated that no drug had a beneficial effect on negative symptoms when compared to another drug ( Arango et al., 2013 ; Millan et al., 2014 ; Fusar-Poli et al., 2015 ), meaning that head to head comparisons of different agents among each other did not result in superiority of one drug to another. The latest comparison ( Krause et al., 2018 ) evaluated all studies that have been performed in the negative symptom population so far, and has found that amisulpride claimed superiority only to placebo, olanzapine was superior to haloperidol, but only in a small trial (n = 35), and cariprazine outperformed risperidone in a large well-controlled trial.

Hence cariprazine emerged as an agent of particular interest in regard to negative symptoms. Cariprazine is a dopamine D 3 /D 2 receptor partial agonist and serotonin 5-HT 1A receptor partial agonist. It has been hypothesized that cariprazine is the only antipsychotic that can block D 3 receptors in the living brain, thereby exhibiting functions that are related to D 3 blockade (e.g., improvement of negative symptoms) ( Stahl, 2016 ). In that large clinical trial including 460 patients with predominant negative symptoms and stable positive symptoms of schizophrenia, cariprazine was significantly more effective than risperidone in improving negative symptoms and patient functioning ( Nemeth et al., 2017 ).

Case Description

The 23-year-old female patient visited the Institute of Rare Diseases at our university with her parents. They had suspected for a long time that something was wrong with their daughter, but this was the first time they had asked for medical help. The patient was quiet and restrained since she did not speak much, her parents told us her story instead. Initially, the patient had done very well in a bilingual secondary school and was socially active with friends and peers. At the age of 15 years, her academic performance started to deteriorate, with her first problems associated with difficulty learning languages and memorizing. Her school grades dropped, and her personality started to gradually change. She became increasingly irritated, and was verbally and physically hostile toward her classmates, resorting to hitting and kicking at times. She was required to repeat a school year and subsequently dropped out of school at the age of 18 because she was unable to complete her studies. During these years, her social activity greatly diminished. She lived at home with her parents, did not go out with friends, or participate in relationships. Most of the time she was silent and unsociable, but occasionally she had fits of laughter without reason. Once the patient told her mother that she could hear the thoughts of others and was probably hearing voices as well. Slowly, her impulse-control problems faded; however, restlessness of the legs was quite often present.

Our patient’s medical history was generally unremarkable. She lacked neurological or psychiatric signs. She had a tonsillectomy and adenotomy at age 7 years. Epilepsy was identified in the patient’s family history (father’s uncle). On physical examination, there were no signs of internal or neurological disease; body mass index was 21.5 (normal weight).

During the first psychiatric interview and examination, we found that our patient was alert and vigilant, but had trouble relating due to decreased integrity of consciousness. Her attention could be aroused or partially directed, and she had difficulty keeping a target idea. Autopsychic and allopsychic orientations were preserved. Longer thinking latencies and slowed movement responses were observed, sometimes with even cataleptic impressions. Cognitive functions, such as thinking, memory, and concept formation, were severely impaired, and we were unable to carry out some of our neurocognitive tests -such as the Addenbrooke’s Cognitive Examination ( Hsieh et al., 2013 ), the Toulouse-Pieron attention test (Kanizsa G1951), Bells test ( Gauthier et al., 1989 ) and the Trail Making Test- because of the patient’s denial of symptoms and refusal to cooperate.

She often looked aside and laughed frequently, suggesting the presence of perceptual disturbances, but she denied her symptoms when asked. In contrast to the periodic inappropriate laughing, apathy and anhedonia were markedly present. During the examination, the patient could not recall anything she would do or even think of with pleasure. According to the heteroanamnesis, she lost her interest in activities she used to like, did not go out with friends anymore, and showed no signs of joy or intimacy towards her family members either.

Along with the affective hyporesponsiveness, amotivation and a general psychomotor slowing were observed. Hypobulia, void perspectives, and lack of motivation were explored. Parental statements indicated that the patient’s social activity had continued to diminish, and her appearance and personal physical hygiene had deteriorated. When we initiated a conversation, the patient was negativistic and agitated. Her critical thinking ability was reduced, which led to inappropriate behavior (she, e.g., unexpectedly stood up and left the room while the examination was still ongoing). Considering her status, she was admitted to the clinic after her first visit.

After several differential diagnostic tests were performed (e.g., routine diagnostic laboratory parameters, immune serological analyses, electroencephalogram, magnetic resonance imaging, genetic testing), all the possible common and rare disorders, such as Huntington’s disease, Niemann Pick C disease, mitochondrial disorders, and autoimmune diseases, were ruled out.

At first contact, to differentiate the symptoms and severity of putative schizophrenia, we mapped the positive, negative, and general symptoms, as well as a clinical impression, using the Positive and Negative Syndrome Scale (PANSS), the Scale for Assessment of Negative Symptoms, and the Clinical Global Impressions-Severity (CGI-S) ( Groth-Marnat, 2009 ).

The patient had a very high PANSS total score, which corresponded to being considered “severely ill” or “among the most severely ill’ on the CGI-S ( Leucht et al., 2005 ). The PANSS score was derived dominantly from the negative items of the scale. Overall, her negative symptoms fulfilled criteria for predominantly negative symptoms, meaning that positive symptomatology was reduced, while negative symptoms were more explicit and dominated the clinical picture ( Riedel et al., 2005 ; Olie et al., 2006 ; Mucci et al., 2017 ). Baseline rating scale sores are presented in Table 1 .

Table 1 Summary of symptom scale scores at the time of admission to the hospital.

The diagnosis of EOS with predominantly negative symptoms was given and treatment with the antipsychotic agent cariprazine was initiated. The patient was hospitalized for 2 weeks following her arrival at the clinic. Cariprazine was started at the dose of 1.5 mg/day and titrated up to 4.5 mg/day over a 2-week period: the patient received 1.5 mg/day for the first 3 days, 3 mg/day from day 4 to day 12, and eventually 4.5 mg/day from day 13 onward. During these 2 weeks, which were spent in hospital, the patient’s explicit negative symptoms such as poverty of speech, psychomotor retardation, poor eye contact, and affective nonresponsiveness improved; however, delusions and hallucinatory perceptions did not fade significantly.

Two weeks after discharge, we saw the patient for her first outpatient visit. Significant clinical improvement was observed. The patient calmly cooperated during the examination, with no signs of agitation. She was oriented to time, place, and self, attention could be drawn and directed, and she was able to keep a target idea and change the subject. Although according to the family, perceptual disturbances were still present, laughing with no reason and looking aside were much less frequent, and restlessness of the legs had stopped; these symptoms were not observed during the examination. Psychomotoric negativism had improved greatly, the patient was more communicative, and she paid more attention to the activities of family members. The pace of speech was close to normal: the thinking latencies and slowed movement responses as observed at admission were not seen anymore. The patient had adequate reaction time to questions asked and could focus in the interview. Mild obstipation and somnolence in the evening were her main complaints. Apart from some tick-like eye closures, there was no pathological finding during physical and neurological examination. At this point, cariprazine was reduced to 3 mg per day.

At her second outpatient visit, which occurred 8 weeks after treatment initiation, further improvement was observed. According to her mother, the patient was more active and open at home. Neurological examination found that the alternating movements of her fingers were slightly slowed. Cariprazine 3 mg/day was continued with concomitant anticholinergic medication.

At the third outpatient visit, which occurred 16 weeks after the first contact, the patient’s overall symptoms, including cognitive functions, such as memory and abstract thinking, as well as functions in activities of daily living, had improved remarkably. She had started to participate in the family’s daily life, even taking responsibility for some household duties; further, she went to the hairdresser for the first time in years, a step forward from her previous state of self-neglect. She was probably still having auditory hallucinations, which she considered natural, and some extrapyramidal symptom (EPS)-like ruminating movements, like to-and-fro swinging of her trunk, were observed. She did not look aside any more and tics were no longer present. Compared with previous visits overall, she was very relaxed, retained eye contact, cooperated, and communicated adequately during the interview. She started to develop insight into her condition, and she told us that her “thoughts were not healthy.” At the last two visits, the synkinesis of the arms was reduced.

After 16 weeks of treatment, the patient’s PANSS Negative Subscale Score and PANSS factor score for negative symptoms (PANSS-FSNS) score were reduced by 44.44% and 41.31%, respectively. Recent studies have demonstrated that linking the percentage improvement of PANSS with CGI-S and -Improvement (CGI-I) scores shows that a 25–50% reduction of PANSS scores corresponds to clinically meaningful change ( Correll et al., 2011 ; Fusar-Poli et al., 2015 ). In acutely ill patients with predominantly positive symptoms who are more likely to respond well to treatment, the 50% cutoff would be a more clinically meaningful criterion; however, since even slight improvement might represent a clinically significant effect in a patient with atypical schizophrenia, the use of 25% cutoff is justified ( Correll et al., 2011 ; Fusar-Poli et al., 2015 ).

In this regard, the 44.44% (change from baseline: −20) and 41.31% (change from baseline: −19) improvement demonstrated on PANSS Negative Symptom subscale and PANSS-FSNS, respectively, are considered a clearly clinically relevant change. Beyond the impaired synkinesis and alternating movement of the arms and fingers, there were no other treatment-related physical dysfunctions. Change from baseline on the PANSS and CGI scales are shown over the course of treatment in Table 2 .

Table 2 Summary of symptom scale scores at weeks 16, 32, and 52.

Since our patient’s symptoms demonstrated strong improvement and tolerability was favorable, cariprazine therapy was continued. Improvement in both negative and positive symptoms was maintained over the course of treatment. At her later visits (32 and 52 weeks), PANSS total score was reduced to a level that was close to the minimum, and the decrease in negative symptom scores was considerable (PANSS-NSS=66.67% and PANS-FSNS=70.00% at both time points). The patient’s progress was also reflected in clinical and functional measurements, with the CGI-S score reduced to 2 (borderline mentally ill) and a CGI-I score of 1 (very much improved) indicating notable improvement.

Cariprazine has demonstrated broad spectrum efficacy in the treatment of positive and negative symptoms of schizophrenia. In a field where no treatment is available for difficult-to-treat negative symptoms, this case is unique and may have important implications for schizophrenia treatment. Despite experiencing approximately 8 years of untreated symptoms and functional impairment associated with predominantly negative symptom EOS, our 23-year-old female patient showed considerable symptomatic and functional improvement after several weeks of treatment with cariprazine. Given that the duration of untreated negative symptoms is associated with worse functional outcomes ( Boonstra et al., 2012 ), the remarkable improvement seen in this case shows how valuable cariprazine could be for patients with similar symptom presentations. Although it is not possible to generalize the observations and findings of this single case, it has the novelty of detecting a potential effect of cariprazine in a drug-naïve patient with marked negative symptoms of early-onset schizophrenia. To our knowledge, no cariprazine-related data has been published in this type of patients. A single case study is obviously far from being predictive for the efficacy of a drug, however, the results seen with this case are promising. With a dose recommended for patients with negative symptoms, our patient’s clinical condition, including positive, negative, and cognitive symptoms, as well as social functioning have improved notably, with the effect maintained for over 12 months. Generally, cariprazine has been well tolerated, with mild EPS observed after 8 weeks, but no metabolic, cardiac, or other side effects.

This case report suggests that the management of patients with EOS and prominent negative symptoms is achievable in everyday practice with cariprazine. More real-world clinical experience is needed to support this finding.

Data Availability Statement

All datasets generated for this study are included in the article/supplementary material.

Ethics Statement

Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

Author Contributions

All authors listed have made substantial, direct, and intellectual contribution to the work and approved it for publication.

This work was supported from Research and Technology Innovation Fund by the Hungarian National Brain Research Program (KTIA_NAP_ 2017-1.2.1-NKP-2017-00002). Editorial support for this case report was supported by funding from Gedeon Richter. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.

Acknowledgments

We are thankful to the patient and her family for giving us the opportunity to share her story in the form of a publication. Also, we acknowledge editorial assistance was provided by Carol Brown, MS, ELS, of Prescott Medical Communications Group, Chicago, Illinois, USA, a contractor of Gedeon Richter plc.

• ^ http://www.schizophrenia.com/szfacts.htm
• ^ https://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml

Arango, C., Garibaldi, G., Marder, S. R. (2013). Pharmacological approaches to treating negative symptoms: a review of clinical trials. Schizophr. Res. 150 (2-3), 346–352. doi: 10.1016/j.schres.2013.07.026

PubMed Abstract | CrossRef Full Text | Google Scholar

Bartlet, J. (2014). Childhood-onset schizophrenia: what do we really know? Health Psychol. Behav. Med. 2 (1), 735–747. doi: 10.1080/21642850.2014.927738

Boonstra, N., Klaassen, R., Sytema, S., Marshall, M., De Haan, L., Wunderink, L., et al. (2012). Duration of untreated psychosis and negative symptoms–a systematic review and meta-analysis of individual patient data. Schizophr. Res. 142 (1-3), 12–19. doi: 10.1016/j.schres.2012.08.017

Clemmensen, L., Vernal, D. L., Steinhausen, H. C. (2012). A systematic review of the long-term outcome of early onset schizophrenia. BMC Psychiatry 12, 150. doi: 10.1186/1471-244X-12-150

Correll, C. U., Kishimoto, T., Nielsen, J., Kane, J. M. (2011). Quantifying clinical relevance in the treatment of schizophrenia. Clin. Ther. 33 (12), B16–B39. doi: 10.1016/j.clinthera.2011.11.016

Fusar-Poli, P., Papanastasiou, E., Stahl, D., Rocchetti, M., Carpenter, W., Shergill, S., et al. (2015). Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials. Schizophr. Bull. 41 (4), 892–899. doi: 10.1093/schbul/sbu170

Galderisi, S., Mucci, A., Buchanan, R. W., Arango, C. (2018). Negative symptoms of schizophrenia: new developments and unanswered research questions. Lancet Psychiatry 5 (8), 664–677. doi: 10.1016/S2215-0366(18)30050-6

Gauthier, L., Dehaut, F., Joanette, Y. (1989). A quantitative and qualitative test for visual neglect. Int. J. Clin. Neuropsychol. 11 (2), 49–54. doi: 10.1016/j.neuropsychologia.2010.04.018

CrossRef Full Text | Google Scholar

Groth-Marnat, G. (2009). “Handbook of Psychological Assessment”. Fifth ed. (Hoboken, NJ: Wiley).

Google Scholar

Hafner, H., Van der Heiden, W. (1997). Epidemiology of schizophrenia. Can. J. Psychiatry 42 (2), 139–151. doi: 10.1177/070674379704200204

Hsiao, R., McClellan, J. (2008). Substance abuse in early onset psychotic disorders. J. Dual Diagn. 4 (1), 87–99. doi: 10.1300/J374v04n01_06

Hsieh, S., Schubert, S., Hoon, C., Mioshi, E., Hodges, J. R. (2013). Validation of the Addenbrooke’s Cognitive Examination III in frontotemporal dementia and Alzheimer’s disease. Dement Geriatr. Cognit. Disord. 36 (3-4), 242–250. doi: 10.1159/000351671

Immonen, J., Jaaskelainen, E., Korpela, H., Miettunen, J. (2017). Age at onset and the outcomes of schizophrenia: A systematic review and meta-analysis. Early Interv Psychiatry 11 (6), 453–460. doi: 10.1111/eip.12412

Kao, Y. C., Liu, Y. P. (2010). Effects of age of onset on clinical characteristics in schizophrenia spectrum disorders. BMC Psychiatry 10, 63. doi: 10.1186/1471-244X-10-63

Kirkpatrick, B., Buchanan, R. W., Ross, D. E., Carpenter, J. (2001). A separate disease within the syndrome of schizophrenia. Arch. Gen. Psychiatry 58 (2), 165–1671. doi: 10.1001/archpsyc.58.2.165

Klosterkotter, J., Schultze-Lutter, F., Bechdolf, A., Ruhrmann, S. (2011). Prediction and prevention of schizophrenia: what has been achieved and where to go next? World Psychiatry 10 (3), 165–174. doi: 10.1007/s00406-018-0869-3

Krause, M., Zhu, Y., Huhn, M., Schneider-Thoma, J., Bighelli, I., Nikolakopoulou, A., et al. (2018). Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis. Eur. Arch. Psychiatry Clin. Neurosci. 268 (7), 625–639. doi: 10.1007/s00406-018-0869-3

Lehman, A. F., Lieberman, J. A., Dixon, L. B., McGlashan, T. H., Miller, A. L., Perkins, D. O., et al. (2010). “Practice guideline for the treatment of patients with schizophrenia”, 2nd ed. American Psychiatric Association. Avaialble at: https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/schizophrenia.pdf .

Leucht, S., Kane, J. M., Kissling, W., Hamann, J., Etschel, E., Engel, R. R. (2005). What does the PANSS mean? Schizophr. Res. 79 (2-3), 231–238. doi: 10.1016/j.schres.2005.04.008

Leucht, S., Corves, C., Arbter, D., Engel, R. R., Li, C., Davis, J. M. (2009). Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373 (9657), 31–41. doi: 10.1016/S0140-6736(08)61764-X

Marder, S. R., Galderisi, S. (2017). The current conceptualization of negative symptoms in schizophrenia. World Psychiatry 16 (1), 14–24. doi: 10.1002/wps.20385

McGuffin, P. (2004). Nature and nurture interplay: schizophrenia. Psychiatr. Prax 31 Suppl 2, S189–S193. doi: 10.1055/s-2004-834565

Millan, M. J., Fone, K., Steckler, T., Horan, W. P. (2014). Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. Eur. Neuropsychopharmacol. 24 (5), 645–692. doi: 10.1016/j.euroneuro.2014.03.008

Mucci, A., Merlotti, E., Ucok, A., Aleman, A., Galderisi, S. (2017). Primary and persistent negative symptoms: Concepts, assessments and neurobiological bases. Schizophr. Res. 186, 19–28. doi: 10.1016/j.schres.2016.05.014

Murru, A., Carpiniello, B. (2018). Duration of untreated illness as a key to early intervention in schizophrenia: A review. Neurosci. Lett. 669, 59–67. doi: 10.1016/j.neulet.2016.10.003

Nemeth, G., Laszlovszky, I., Czobor, P., Szalai, E., Szatmari, B., Harsanyi, J., et al. (2017). Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet 389 (10074), 1103–1113. doi: 10.1016/S0140-6736(17)30060-0

Olie, J. P., Spina, E., Murray, S., Yang, R. (2006). Ziprasidone and amisulpride effectively treat negative symptoms of schizophrenia: results of a 12-week, double-blind study. Int. Clin. Psychopharmacol. 21 (3), 143–151. doi: 10.1097/01.yic.0000182121.59296.70

Penttila, M., Jaaskelainen, E., Hirvonen, N., Isohanni, M., Miettunen, J. (2014). Duration of untreated psychosis as predictor of long-term outcome in schizophrenia: systematic review and meta-analysis. Br. J. Psychiatry 205 (2), 88–94. doi: 10.1192/bjp.bp.113.127753

Perkins, D. O., Gu, H., Boteva, K., Lieberman, J. A. (2005). Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am. J. Psychiatry 162 (10), 1785–1804. doi: 10.1176/appi.ajp.162.10.1785

Rabinowitz, J., Werbeloff, N., Caers, I., Mandel, F. S., Stauffer, V., Menard, F., et al. (2013). Negative symptoms in schizophrenia–the remarkable impact of inclusion definitions in clinical trials and their consequences. Schizophr. Res. 150 (2-3), 334–338. doi: 10.1016/j.schres.2013.06.023

Riedel, M., Muller, N., Strassnig, M., Spellmann, I., Engel, R. R., Musil, R., et al. (2005). Quetiapine has equivalent efficacy and superior tolerability to risperidone in the treatment of schizophrenia with predominantly negative symptoms. Eur. Arch. Psychiatry Clin. Neurosci. 255 (6), 432–437. doi: 10.1007/s00406-005-0622-6

Russell, ,. A. T. (1994). The Clinical Presentation of Childhood-Onset Schizophrenia. Schizophr. Bull. 20 (4), 631–646. doi: 10.1093/schbul/20.4.631

Stahl, S. M. (2003). Describing an atypical antipsychotic: Receptor binding and its role in pathophysiology. Prim Care Companion J. Clin. Psychiatry 5 (Suppl 3), 9–13.

Stahl, S. M. (2016). Mechanism of action of cariprazine. CNS Spectr. 21 (2), 123–127. doi: 10.1017/S1092852916000043

Veerman, S. R. T., Schulte, P. F. J., de Haan, L. (2017). Treatment for Negative Symptoms in Schizophrenia: A Comprehensive Review. Drugs 77 (13), 1423–1459. doi: 10.1007/s40265-017-0789-y

Keywords: cariprazine, schizophrenia, negative symptoms, early-onset schizophrenia, second-generation antipsychotic

Citation: Molnar MJ, Jimoh IJ, Zeke H, Palásti Á and Fedor M (2020) Early-Onset Schizophrenia With Predominantly Negative Symptoms: A Case Study of a Drug-Naive Female Patient Treated With Cariprazine. Front. Pharmacol. 11:477. doi: 10.3389/fphar.2020.00477

Received: 24 October 2019; Accepted: 26 March 2020; Published: 23 April 2020.

Reviewed by:

Copyright © 2020 Molnar, Jimoh, Zeke, Palásti and Fedor. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Maria Judit Molnar, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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

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• v.62(4); Fall 2010

Language: English | French

Case Report: Schizophrenia Discovered during the Patient Interview in a Man with Shoulder Pain Referred for Physical Therapy

Purpose: The purpose of this case report is to demonstrate the importance of a thorough patient interview. The case involves a man referred for physical therapy for a musculoskeletal dysfunction; during the patient interview, a psychiatric disorder was recognized that was later identified as schizophrenia. A secondary purpose is to educate physical therapists on the recognizable signs and symptoms of schizophrenia.

Client description: A 19-year-old male patient with chronic shoulder, elbow, and wrist pain was referred for physical therapy. During the interview, the patient reported that he was receiving signals from an electronic device implanted in his body.

Measures and outcome: The physical therapist's initial assessment identified a disorder requiring medical referral. Further management of the patient's musculoskeletal dysfunction was not appropriate at this time.

Intervention: The patient was referred for further medical investigation, as he was demonstrating signs suggestive of a psychiatric disorder. The patient was diagnosed with schizophrenia by a psychiatrist and was prescribed Risperdal.

Implications: This case study reinforces the importance of a thorough patient interview by physical therapists to rule out non-musculoskeletal disorders. Patients seeking neuromusculoskeletal assessment and treatment may have undiagnosed primary or secondary psychiatric disorders that require recognition by physical therapists and possible medical referral.

RÉSUMÉ

Objectif : L'objectif de cette étude de cas consiste à démontrer l'importance de réaliser des entrevues en profondeur avec les patients. Le cas étudié concerne un homme dirigé vers la physiothérapie en raison d'une dysfonction musculosquelettique. Au cours de l'entrevue avec ce patient, un problème psychiatrique a été décelé; par la suite, de la schizophrénie a été diagnostiquée. Le deuxième objectif de cette étude de cas est d'éduquer et de sensibiliser les physiothérapeutes aux signes et aux symptômes aisément reconnaissables de la schizophrénie.

Description du client : Le patient est un jeune homme de 19 ans qui souffre de douleurs chroniques à l'épaule, au coude et au poignet et qui avait été dirigé en physiothérapie. Au cours de l'entrevue, le patient a déclaré qu'il recevait des signaux provenant d'un appareil électronique implanté dans son corps.

Mesures et résultats : L'évaluation préliminaire du physiothérapeute a permis d'identifier un problème qui nécessitait que le patient soit redirigé vers un médecin. Une gestion plus poussée de la dysfonction musculosquelettique de ce patient a été jugée inappropriée à cette étape.

Intervention : Le patient a été dirigé vers une investigation médicale plus approfondie, puisqu'il manifestait des signes de possibles problèmes psychiatriques. Le patient a par la suite été diagnostiqué comme schizophrène et on lui a prescrit du Risperdal.

Implication : Cette étude de cas vient réaffirmer l'importance, pour le physiothérapeute, de procéder à des entrevues approfondies avec les patients pour s'assurer qu'il n'y a pas d'autres problèmes que les seules dysfonctions musculosquelettiques. Les patients qui souhaitent obtenir une évaluation et un traitement musculosquelettique peuvent souffrir aussi d'un problème psychiatrique primaire ou secondaire non diagnostiqué qui exige d'être reconnu par le physiothérapeute et qui nécessitera vraisemblablement une attention médicale ultérieure.

INTRODUCTION

A recent US study demonstrated that less than one-third of diagnoses provided to physical therapists by primary-care physicians are specific. 1 The same study illustrated that physical therapists must assume a greater diagnostic role and must routinely provide medical screening and differential diagnosis of pathology during the examination. 1 Similarly, studies conducted in Australia and Canada have concluded that the majority of referrals for physical therapy are not provided with a specific diagnosis. 2 , 3 Medical screening is important, since physical therapists are increasingly functioning as the primary contact for patients with neuromusculoskeletal dysfunctions, 4 , 5 which means a greater likelihood of encountering patients with non-musculoskeletal disorders, including psychiatric disorders.

As demonstrated by the World Health Organization's International Classification of Functioning, Disability and Health, it is imperative to take an individual's psychological state into account, since disorders in this area can lead to disability. 6 Many psychiatric conditions are commonly encountered in physical therapy practice; for example, depression, anxiety, and fear-avoidance have all been associated with low back, neck, and widespread musculoskeletal pain. 7 – 9 These psychiatric disorders have been identified both as risk factors for musculoskeletal dysfunction and as an important secondary psychosocial aspect of disablement. 7 – 10 It is therefore important for physical therapists to consider the primary and secondary roles of psychopathology in disability.

Although various models of primary-care physical therapy have demonstrated physical therapists' expertise in the realm of neuromusculoskeletal dysfunctions, there is a need for increased competencies in academic, clinical, and affective domains. 5 Few et al. propose a hypothesis-oriented algorithm for symptom-based diagnosis through which physical therapists can arrive at a diagnostic impression. 11 This algorithm takes into account the various causes of pathology, including psychogenic disorders. 11 Although additional research is necessary to validate Few et al.'s algorithm, it provides one model that considers underlying pathologies in determining the appropriateness of physical therapy intervention. 11 The present case report further illustrates the importance of considering the patient's affective and psychological state in order to more effectively screen for and identify psychiatric disorders that require medical referral.

The purpose of this case report is to demonstrate the importance of a thorough patient interview. We present the case of a man, referred for physical therapy for a musculoskeletal dysfunction, who was determined during the patient interview to have an undiagnosed psychiatric disorder, later identified as schizophrenia. In addition, this report is intended to educate physical therapists about the recognizable signs and symptoms of schizophrenia.

CASE DESCRIPTION

The patient was a 19-year-old male university student. His recreational activities included skateboarding, snowboarding, break dancing, and weight training. The patient first sought medical attention from a sport medicine physician in January 2006, when he reported right lateral wrist pain since falling and hitting the ulnar aspect of his wrist while skateboarding in October 2005. Plain film radiographs taken after the injury were negative, and the patient did not receive any treatment. The physician found no wrist swelling, minimal tenderness over the ulnar aspect of the right wrist, full functional strength, and minimally restricted range of motion (ROM). The patient was given ROM exercises and was diagnosed with a right wrist contusion.

Over the next 22 months, the patient returned to the same sport medicine clinic 10 times, reporting pain in his wrist, shoulder, elbow, knee, ankle, and neck. He stated that the elbow, wrist, and shoulder injuries were due to falls while skateboarding and snowboarding or to overuse during weight training; some injuries had no apparent cause. Over the course of his medical care, the patient followed up with three different physicians at the same clinic. He was diagnosed by these physicians, in order of occurrence, with (1) right wrist contusion and sprain; (2) right wrist impingement and left wrist strain; (3) right shoulder supraspinatus tendinopathy; (4) right peroneal overuse injury and strain; (5) disuse adhesions of the right peroneals and right hip adhesions; (6) right ankle neuropathic pain secondary to nerve injury and sprain and right-knee patellofemoral pain syndrome (PFPS); (7) neuropathic pain of the right peroneal nerve; (8) trauma-induced left-knee PFPS; (9) ongoing post-traumatic left-knee PFPS; and (10) right levator scapula strain, chronic right infraspinatus strain, right elbow ulnar ridge contusion, and right wrist chronic distal ulnar impingement secondary to malaligned triangular fibrocartilage complex (TFCC).

After his tenth visit to a physician, the patient was referred for physical therapy for chronic right levator scapula strain and right supraspinatus strain. During the interview, the patient stated that he had right shoulder pain because of a snowboarding injury sustained 1 year earlier and because of a fall onto the lateral right shoulder 2 years ago. Aggravating activities to the shoulder included pull-ups, rowing, and free weights. No position or movement alleviated his pain, and the pain did not fluctuate over the course of the day. His sleep was disturbed only when lying on the right shoulder. The patient was in generally good health, but he said that his right wrist and left knee occasionally felt cold for no apparent reason. He denied experiencing any loss of sensation, decreased blood flow, or numbness or tingling in the knee and wrist. The patient said he believed that his knee and wrist became cold as a result of electromagnetic impulses sent to the joint via an electrical implant in his body and that this device was the cause of his ongoing shoulder pain.

According to the patient, this device had been implanted into his body 2 years earlier by a government organization (the Central Intelligence Agency, the US government, or the US Army) to control his actions. Electromagnetic impulses generated by the implant had caused his falls and injuries; they also caused his joints to become cold or painful when he was doing something “they” did not want him to do, such as break dancing, snowboarding, skateboarding, or exercising. The patient also believed that many other people unknowingly had implants; he claimed that friends, neighbours, professors, and strangers were “working with them” and that they “emotionally abuse[d]” him by giving signs such as kicking a leg back to let him know he was being watched. Furthermore, he indicated that he often received commands telling him to harm his friends or family and that these orders came either from the electrical implant or from the people he claimed were emotionally abusing him. He therefore distanced himself from some friends because he did not want to follow through with these commands. I asked the patient if he felt he would harm himself or others because of his psychotic-like symptoms. He denied any desire to inflict harm on himself or others. Had he posed a threat to himself or others, he would have been “formed” (i.e., committed to a psychiatric facility by the appropriate medical professional).

The patient's past medical and family history were unremarkable. He did not use any prescription or over-the-counter medications, but he felt his thoughts about electrical implants were decreased by the use of marijuana, which he used socially. He was a non-smoker and a social consumer of alcohol. He had a normal gait and appeared comfortable in an unsupported seated position. He denied any weight changes, bowel or bladder problems, night pain, or difficulty breathing.

PHYSICAL EXAMINATION

The patient reported a maximum verbal numeric pain rating scale (NPRS) score of 8/10 and a minimum score of 0/10, with pain usually present in the shoulder. In a double-blind, placebo-controlled, multi-centre chronic pain study, when the baseline NPRS raw score fluctuated by 0 points, the sensitivity and specificity were 95.32% and 31.80% respectively; 12 , 13 when there was a 4-point raw score change, the sensitivity and specificity were 35.92% and 96.92% respectively. 12 The patient stated that when he experienced shoulder pain, it was located on the anterior, posterior, and lateral aspects of his shoulder and radiated down to his elbow and wrist. He reported 0/10 shoulder pain while seated.

Standing posture was assessed in the frontal and sagittal planes. 14 The patient had a mild forward head posture and internally rotated glenohumeral joints in the sagittal plane. The frontal-plane analysis revealed a slight elevation of the right shoulder and level iliac crests. Such visual assessment of cervical and lumbar lordosis has an intrarater reliability of k =0.50 but an interrater reliability of k =0.16. 15

In the frontal plane, the right scapula was abducted four finger-widths from the mid-thoracic spine, and the left scapula was abducted three finger-widths. The scapulas were superiorly rotated bilaterally. Surface palpation of the acromial angle, inferior angle, and spine of the scapula differed less than 0.98 cm, 0.46 cm, and 0.67 cm, respectively, from the actual bony location, with a 95% confidence interval. 16 There was visible hypertrophy of the pectoralis major muscle bilaterally. Active and passive ROM were tested for the shoulders as recommended by Magee. 14 The patient had full bilateral active ROM, with minimal pain at end-range flexion and abduction that was not increased with overpressure in accordance with Magee. 14 He had full passive ROM with no pain reported.

Manual muscle testing based on Hislop and Montgomery revealed 4/5 strength of external rotation at 0° and 45° of abduction, with pain reported along the anterolateral shoulder. 17 Testing also showed 3/5 strength and no pain with resisted abduction with the arm at the side at approximately 30° of abduction. 18 Manual muscle testing is a useful clinical assessment tool, although a recent literature review suggested that further testing is required for scientific validation. 18 Palpation of the shoulder, as described by Hoppenfeld, revealed slight tenderness over the greater tubercle, as well as along the length of the levator scapula muscle. 19

Special tests were negative for the sulcus sign, Speed's test, the drop arm test, and the empty can test, as described by Magee. 14 Research shows that Speed's test has a sensitivity and specificity of 32% and 61% for biceps and labral pathology respectively; 20 the drop arm test has a sensitivity of 27% and a specificity of 88% as a specific test for rotator cuff tears, and the empty can test has a sensitivity of 44% and a specificity of 90% in diagnosing complete or partial rotator cuff tears. 20 , 21 The Neer and Hawkins-Kennedy impingement tests were both negative. 14 According to a meta-analysis by Hegedus et al., the Neer test is 79% sensitive and 53% specific, while the Hawkins-Kennedy test is 79% sensitive and 59% specific, for impingement. 21

I (NS) diagnosed the patient with mild supraspinatus tendinosis, with no evidence of tearing of the rotator cuff muscles, based on the following findings drawn from the patient interview: shoulder pain aggravated by pull-ups, rowing, and free weights; increased pain when lying on the affected shoulder. Additional significant findings from the physical examination included full shoulder active ROM with minimal pain at end-range flexion and abduction; pain along the anterior lateral shoulder with resisted testing of external rotation at 0° and 45° of abduction; negative drop arm and empty can tests; and tenderness over the greater tubercle of the humerus. The musculoskeletal dysfunction did not explain the level of pain reported by the patient (maximum NPRS 8/10), nor was the physical examination able to reproduce the exact location of the reported shoulder pain or the elbow, wrist, and knee pain described by the patient.

I was concerned about a serious pathology or a psychological disorder, given that this 19-year-old had made 10 medical appointments over 22 months for 6 different regions of the body; in my experience of examining and treating patients between the ages of 18 and 25, the frequency of the appointments and the variation in afflicted body parts are not typical of a young patient. The patient's description of his shoulder pain, in terms of location and severity, was not reproducible by physical examination. Throughout our interview, the patient did not maintain good eye contact, spoke in a monotone voice, and had an overall flat affect. Even when he described his beliefs about implants and government control, his voice and demeanour remained expressionless. The patient described persecutory delusions, command hallucinations, and social isolation from friends and family, all of which are signs of psychosis according to the Diagnostic and Statistical Manual of Mental Health . 22

Based on the findings from the patient interview and the physical examination, the patient did have symptoms consistent with a known musculoskeletal dysfunction; however, the undiagnosed and uncontrolled psychiatric symptoms made it more appropriate to refer him back to the physician for evaluation and treatment of his psychosis than to provide physical therapy intervention for his shoulder dysfunction. Furthermore, because research shows that the rate of suicide among patients with schizophrenia can range from 2% or 4% to as high as 15% 23 , 24 and that the rate of suicide is highest among patients close to the date of diagnosis, early recognition is crucial. 23

INTERVENTION

Based on the findings from the patient interview and the signs and symptoms of psychiatric disorders, I explained to the patient that there was a need for further medical investigation. Although the patient did not agree with this initial assessment, he did consent to a follow-up with the referring physician.

I spoke to the referring physician in person and explained to him my findings from the patient interview, specifically the patient's belief that he had electrical implants in his body. I also pointed out the patient's affect and the limited physical findings during the physical examination. I provided the physician with some direct quotes from the patient to demonstrate the level of psychosis he was presenting with. I stated my conclusion that the patient was suffering from some form of psychosis that precluded physical therapy treatment for his shoulder at that time. The referring physician was quite concerned about the patient and called him during our meeting to arrange a follow-up medical appointment.

The physician examined the patient, made similar observations, concurred with my assessment, and concluded that the patient was experiencing some form of psychosis. The plan of care involved referral to a psychiatrist, follow-up with the physician, and explaining to the patient that physical therapy would not be appropriate at this time because of the presence of a serious psychiatric disorder. The patient did not believe that he had a psychiatric disorder, but he was willing to follow up with a psychiatrist. The physician noted that the patient was not a threat to himself or others and that he did not report having homicidal or suicidal thoughts.

The patient followed up with the psychiatrist 11 days after his appointment with the physician. He was diagnosed with schizophrenia and started on a daily dose of risperidone (Risperdal). The patient was also instructed to follow up with the psychiatrist every second week to ensure compliance with the medication and to discuss progress. Further details of the psychiatric assessment and treatment were not available for this case report. Outcomes are also unavailable for this case report, since follow-up by the physical therapist was not possible.

Case Summary

This case report describes a 19-year-old man referred to physical therapy with shoulder, wrist, and knee pain who was later diagnosed with a psychiatric disorder. After completing a thorough patient interview and physical examination, I concluded that the patient was suffering from an undiagnosed psychiatric disorder that required medical referral. The interview revealed that the patient had delusions about electrical devices' being implanted in his body and was experiencing various forms of hallucination. The patient was promptly referred for medical consult and was diagnosed with schizophrenia by a psychiatrist.

Patient Symptoms and Schizophrenia

Schizophrenia is a psychiatric disorder affecting between 0.5% and 1.5% of adults worldwide, with a slightly greater prevalence in men. 22 The age of onset may be from 5 to 60 years; however, more than 50% of first episodes occur between the ages of 15 and 24. 22 , 25 , 26 An earlier onset is more common among men, while later onset is more common among women. 25 Schizophrenia shows a higher incidence in individuals born in urban areas than in those born in rural areas. 22 , 25 Because the patient in the present case fell into several of these categories (male, born in an urban area, experienced onset of symptoms around age 17) and presented with clear symptoms of a psychiatric disorder (delusions, hallucinations), schizophrenia seemed the most likely diagnosis.

The signs and symptoms of schizophrenia are classified as either positive or negative. 22 Positive symptoms are an excess of normal function and include delusions, hallucinations, and disorganized speech; 22 , 27 negative symptoms are a deficiency of normal function and include limited goal-directed behaviour (avolition), limited fluency and productivity of speech and thought, and a flat affect. 22 , 27 The diagnosis of schizophrenia requires the presence of at least two of these positive or negative symptoms lasting at least 6 months. 22 , 27 In this case, the patient presented with delusions (e.g., electrical implants trying to control his and others' actions), including persecutory delusions (e.g., “they are emotionally abusing me”), hallucinations (e.g., hearing voices, seeing signs), and a flat affect. Since the patient was enrolled in university at the time of diagnosis, his cognitive function is assumed to be well preserved. The patient reported no change in symptoms for 2 years.

Schizophrenia is subdivided into five types: paranoid, disorganized, catatonic, undifferentiated, and residual (see Table ​ Table1 1 ). 22 , 28 Based on these observations and on the literature, the patient's symptoms were suggestive of paranoid schizophrenia, 22 which is the most prevalent form of schizophrenia in most parts of the world. 22

Schizophrenia Subtypes 6

The aetiology of schizophrenia remains unknown. 29 , 30 There is a strong genetic predisposition. 29 , 30 Patients who experience the onset of schizophrenia before age 22 are 10 times more likely to have a history of a complicated caesarean birth than patients with a later onset of schizophrenia, which suggests a possible neurodevelopmental factor in early-onset schizophrenia. 31 Mild childhood head injuries may play a role in the expression of schizophrenia in families with a strong genetic predisposition to this disorder. 32 Psychological stress has also been implicated in the onset of schizophrenia, since it often precipitates the first psychotic episode or increases the likelihood of a relapse. 33 , 34 In this case, the patient described a family “break-up” which may have precipitated the onset of psychosis. Details about his childhood head injuries and the circumstances of his birth were not obtained. After being diagnosed with schizophrenia, the patient revealed to the referring physician that his father had experienced something similar when he was younger, which may point to a genetic predisposition.

There are no conclusive diagnostic tests for schizophrenia. 22 However, imaging studies have suggested neurophysiologic changes as an associated finding. Volumetric magnetic resonance imaging (MRI) studies of patients with schizophrenia have demonstrated an overall reduction in grey matter; an increase in white matter; decreased size of the amygdala, hippocampus, and parahippocampus; an overall reduction in brain volume; and larger lateral ventricles relative to a control group. 35 – 37

Psychiatric Disorders as They Relate to Musculoskeletal Dysfunction

As primary-care practitioners, physical therapists may encounter patients with possible psychiatric disorders such as schizophrenia. However, the physical therapy literature on psychiatric disorders as they relate to musculoskeletal disorders focuses mainly on low back pain (LBP). 7 , 8 In an examination of a large number of physical and psychological factors, one prospective case-control study points to the importance of psychological variables as a risk factor for chronic LBP and widespread musculoskeletal pain. 8 Previous research has also concurred with this study in implicating psychological variables as risk factors for LBP and neck pain. 9 , 10 These articles provide a link between psychological disorders and patients seeking physical therapy for musculoskeletal dysfunctions.

In this case report, the physical examination was suggestive of a mild supraspinatus tendinosis, but this did not explain the severity of pain reported by the patient or the referral of pain to the elbow, wrist, and knee. One of the limitations of the physical examination was that there was not sufficient time to perform physical examination of the elbow, wrist, and knee. The patient's undiagnosed and uncontrolled psychiatric symptoms took priority over the musculoskeletal dysfunction and required immediate medical referral without physical therapy intervention. Because of the inconsistencies between interview and physical examination, as well as the patient's perception that an electrical implant was causing his musculoskeletal pain, there is a possibility that at least some of his musculoskeletal symptoms may have been manifestations of his psychiatric disorder.

Effective Patient Interviews

The medical literature indicates that 50% of all mental illness is recognized during the interview process as part of medical assessment by the primary-care physician. 38 As physical therapists embrace their role as providers of primary care, 4 , 5 they must rely on their skills in patient interviewing and physical examination to rule out medical pathology. Improved assessment skills by the physical therapist may help to identify primary or secondary medical pathologies that have not previously been diagnosed. Within the peer-reviewed literature, a number of case studies demonstrate identification of non-musculoskeletal or visceral pathology that can manifest as musculoskeletal disorders; 39 – 41 these case studies are examples of how physical therapists can perform an initial assessment, identify a medical pathology that precludes treatment, and make an appropriate referral. During a patient interview, physical therapists must be well aware of the psychological and psychosocial aspects of the examination to identify relevant aspects of the patient's demeanour (e.g., appropriate self-care) and emotional state (e.g., inappropriate affect). The patient interview should consist of non-leading, open-ended questions about how pain in multiple areas is related and how it is caused. Furthermore, physical therapists should avoid rationalizing the patient's symptoms during the interview process. At a minimum, patients should be permitted to speak about and describe their symptoms in a way that is meaningful to them.

Schizophrenia and Primary Care

Schizophrenia is most often initially recognized by the primary-care physician. 42 Psychiatrists, psychologists, and even the lay community have also been noted in the literature as making the initial identification. 43 – 45 Although conspicuously absent from the literature on the initial identification of schizophrenia, physical therapists are in a position to be important first-contact care providers who can make the initial identification of schizophrenia, and other psychiatric disorders, through effective patient interviews. Although labelling patients as having a psychiatric disorder is outside physical therapists' scope of practice, the diagnostic process is not exclusive to any one profession. In this case, the process of diagnosis, which involves assessing the patient, grouping findings, interpreting the data, and identifying the patient's problems, led me to conclude that the primary dysfunction was psychiatric in nature. 46 This process, which Few et al. call “diagnostic reasoning,” is well within physical therapists' scope of practice and is something we constantly engage in during our daily clinical practice. 11 Diagnostic reasoning involves taking into account all of the possible pathological structures and determining the most likely cause of the patient's symptoms. In practice, expert clinicians do not follow standardized protocols; 46 rather, they pay attention to cues provided by the patient, recognize patterns, and test hypotheses to arrive at a probable cause for the patient's symptoms. 11

IMPLICATIONS AND FUTURE DIRECTIONs

The medical literature has identified gaps in the knowledge of primary-care physicians, specifically a lack of awareness of the symptoms and epidemiology of schizophrenia. 28 To facilitate early recognition, referral, and diagnosis of schizophrenia, the medical literature has suggested increased collaboration among family physicians and mental-health professionals, as well as ongoing mental-health training for family physicians. 47 , 48 Physical therapists should also heed these suggestions. A study in the physical therapy literature recommends mental-health training for recognizing the symptoms of depression in a population with LBP; 7 the same study, conducted in Australia, concluded that physical therapists' ability to recognize depressive symptoms in an outpatient setting was poor. 7

An initial step to address these gaps could be a position paper that draws on the medical literature to inform physical therapists about the presence, prevalence, signs, and symptoms of common psychiatric disorders. As well, future research needs to focus on the incidence of musculoskeletal signs and symptoms in patients with common psychiatric disorders.

KEY MESSAGES

What is already known on this topic.

To the authors' knowledge, there are no known studies in the literature describing a case of a patient referred to physical therapy for musculoskeletal dysfunction who was later diagnosed with schizophrenia.

What This Study Adds

This case report contributes to the existing literature on physical therapists functioning as competent providers of primary care who have the knowledge and skills needed to rule out non-musculoskeletal pathology. It also educates physical therapists about the signs and symptoms of schizophrenia.

Shah N, Nakamura Y. Case report: schizophrenia discovered during the patient interview in a man with shoulder pain referred for physical therapy. Physiother Can. 2010;62:308–315

Schizophrenia case studies: putting theory into practice

This article considers how patients with schizophrenia should be managed when their condition or treatment changes.

DR P. MARAZZI/SCIENCE PHOTO LIBRARY

Treatments for schizophrenia are typically recommended by a mental health specialist; however, it is important that pharmacists recognise their role in the management and monitoring of this condition. In ‘ Schizophrenia: recognition and management ’, advice was provided that would help with identifying symptoms of the condition, and determining and monitoring treatment. In this article, hospital and community pharmacy-based case studies provide further context for the management of patients with schizophrenia who have concurrent conditions or factors that could impact their treatment.

Case study 1: A man who suddenly stops smoking

A man aged 35 years* has been admitted to a ward following a serious injury. He has been taking olanzapine 20mg at night for the past three years to treat his schizophrenia, without any problems, and does not take any other medicines. He smokes 25–30 cigarettes per day, but, because of his injury, he is unable to go outside and has opted to be started on nicotine replacement therapy (NRT) in the form of a patch.

When speaking to him about his medicines, he appears very drowsy and is barely able to speak. After checking his notes, it is found that the nurses are withholding his morphine because he appears over-sedated. The doctor asks the pharmacist if any of the patient’s prescribed therapies could be causing these symptoms.

What could be the cause?

Smoking is known to increase the metabolism of several antipsychotics, including olanzapine, haloperidol and clozapine. This increase is linked to a chemical found in cigarettes, but not nicotine itself. Tobacco smoke contains aromatic hydrocarbons that are inducers of CYP1A2, which are involved in the metabolism of several medicines [1] , [2] , [3] . Therefore, smoking cessation and starting NRT leads to a reduction in clearance of the patient’s olanzapine, leading to increased plasma levels of the antipsychotic olanzapine and potentially more adverse effects — sedation in this case.

Patients who want to stop, or who inadvertently stop, smoking while taking antipsychotics should be monitored for signs of increased adverse effects (e.g. extrapyramidal side effects, weight gain or confusion). Patients who take clozapine and who wish to stop smoking should be referred to their mental health team for review as clozapine levels can increase significantly when smoking is stopped [3] , [4] .

For this patient, olanzapine is reduced to 15mg at night; consequently, he seems much brighter and more responsive. After a period on the ward, he has successfully been treated for his injury and is ready to go home. The doctor has asked for him to be supplied with olanzapine 15mg for discharge along with his NRT.

What should be considered prior to discharge?

It is important to discuss with the patient why his dose was changed during his stay in hospital and to ask whether he intends to start smoking again or to continue with his NRT. Explain to him that if he wants to begin, or is at risk of, smoking again, his olanzapine levels may be impacted and he may be at risk of becoming unwell. It is necessary to warn him of the risk to his current therapy and to speak to his pharmacist or mental health team if he does decide to start smoking again. In addition, this should be used as an opportunity to reinforce the general risks of smoking to the patient and to encourage him to remain smoke-free.

It is also important to speak to the patient’s community team (e.g. doctors, nurses), who specialise in caring for patients with mental health disorders, about why the olanzapine dose was reduced during his stay, so that they can then monitor him in case he does begin smoking again.

Case 2: A woman with constipation

A woman aged 40 years* presents at the pharmacy. The pharmacist recognises her as she often comes in to collect medicine for her family. They are aware that she has a history of schizophrenia and that she was started on clozapine three months ago. She receives this from her mental health team on a weekly basis.

She has visited the pharmacy to discuss constipation that she is experiencing. She has noticed that since she was started on clozapine, her bowel movements have become less frequent. She is concerned as she is currently only able to go to the toilet about once per week. She explains that she feels uncomfortable and sick, and although she has been trying to change her diet to include more fibre, it does not seem to be helping. The patient asks for advice on a suitable laxative.

What needs to be considered?

Constipation is a very common side effect of clozapine . However, it has the potential to become serious and, in rare cases, even fatal [5] , [6] , [7] , [8] . While minor constipation can be managed using over-the-counter medicines (e.g. stimulant laxatives, such as senna, are normally recommended first-line with stool softeners, such as docusate, or osmotic laxatives, such as lactulose, as an alternative choice), severe constipation should be checked by a doctor to ensure there is no serious bowel obstruction as this can lead to paralytic ileus, which can be fatal [9] . Symptoms indicative of severe constipation include: no improvement or bowel movement following laxative use, fever, stomach pain, vomiting, loss of appetite and/or diarrhoea, which can be a sign of faecal impaction overflow.

As the patient has been experiencing this for some time and is only opening her bowels once per week, as well as having other symptoms (i.e. feeling uncomfortable and sick), she should be advised to see her GP as soon as possible.

The patient returns to the pharmacy again a few weeks later to collect a prescription for a member of their family and thanks the pharmacist for their advice. The patient was prescribed a laxative that has led to resolution of symptoms and she explains that she is feeling much better. Although she has a repeat prescription for lactulose 15ml twice per day, she says she is not sure whether she needs to continue to take it as she feels better.

What advice should be provided?

As she has already had an episode of constipation, despite dietary changes, it would be best for the patient to continue with the lactulose at the same dose (i.e. 15ml twice daily), to prevent the problem occurring again. Explain to the patient that as constipation is a common side effect of clozapine, it is reasonable for her to take laxatives before she gets constipation to prevent complications.

Pharmacists should encourage any patient who has previously had constipation to continue taking prescribed laxatives and explain why this is important. Pharmacists should also continue to ask patients about their bowel habits to help pick up any constipation that may be returning. Where pharmacists identify patients who have had problems with constipation prior to starting clozapine, they can recommend the use of a prophylactic laxative such as lactulose.

Case 3: A mother is concerned for her son who is talking to someone who is not there

A woman has been visiting the pharmacy for the past 3 months to collect a prescription for her son, aged 17 years*. In the past, the patient has collected his own medicine. Today the patient has presented with his mother; he looks dishevelled, preoccupied and does not speak to anyone in the pharmacy.

His mother beckons you to the side and expresses her concern for her son, explaining that she often hears him talking to someone who is not there. She adds that he is spending a lot of time in his room by himself and has accused her of tampering with his things. She is not sure what she should do and asks for advice.

What action can the pharmacist take?

It is important to reassure the mother that there is help available to review her son and identify if there are any problems that he is experiencing, but explain it is difficult to say at this point what he may be experiencing. Schizophrenia is a psychotic illness which has several symptoms that are classified as positive (e.g. hallucinations and delusions), negative (e.g. social withdrawal, self-neglect) and cognitive (e.g. poor memory and attention).

Many patients who go on to be diagnosed with schizophrenia will experience a prodromal period before schizophrenia is diagnosed. This may be a period where negative symptoms dominate and patients may become isolated and withdrawn. These symptoms can be confused with depression, particularly in younger people, though depression and anxiety disorders themselves may be prominent and treatment for these may also be needed. In this case, the patient’s mother is describing potential psychotic symptoms and it would be best for her son to be assessed. She should be encouraged to take her son to the GP for an assessment; however, if she is unable to do so, she can talk to the GP herself. It is usually the role of the doctor to refer patients for an assessment and to ensure that any other medical problems are assessed. 

Three months later, the patient comes into the pharmacy and seems to be much more like his usual self, having been started on an antipsychotic. He collects his prescription for risperidone and mentions that he is very worried about his weight, which has increased since he started taking the newly prescribed tablets. Although he does not keep track of his weight, he has noticed a physical change and that some of his clothes no longer fit him.

What advice can the pharmacist provide?

Weight gain is common with many antipsychotics [10] . Risperidone is usually associated with a moderate chance of weight gain, which can occur early on in treatment [6] , [11] , [12] . As such, the National Institute for Health and Care Excellence recommends weekly monitoring of weight initially [13] . As well as weight gain, risperidone can be associated with an increased risk of diabetes and dyslipidaemia, which must also be monitored [6] , [11] , [12] . For example, the lipid profile and glucose should be assessed at 12 weeks, 6 months and then annually [12] .

The pharmacist should encourage the patient to attend any appointments for monitoring, which may be provided by his GP or mental health team, and to speak to his mental health team about his weight gain. If he agrees, the pharmacist could inform the patient’s mental health team of his weight gain and concerns on his behalf. It is important to tackle weight gain early on in treatment, as weight loss can be difficult to achieve, even if the medicine is changed.

The pharmacist should provide the patient with advice on healthy eating (e.g. eating a balanced diet with at least five fruit and vegetables per day) and exercising regularly (e.g. doing at least 150 minutes of moderate-intensity activity or 75 minutes of vigorous-intensity activity per week), and direct him to locally available services. The pharmacist can record the adverse effect on the patient’s medical record, which will help flag this in the future and thus help other pharmacists to intervene should he be prescribed risperidone again.

*All case studies are fictional.

Useful resources

• Mind — Schizophrenia
• Rethink Mental Illness — Schizophrenia
• Mental Health Foundation — Schizophrenia
• Royal College of Psychiatrists — Schizophrenia
• NICE guidance [CG178] — Psychosis and schizophrenia in adults: prevention and management
• NICE guidance [CG155] — Psychosis and schizophrenia in children and young people: recognition and management
• British Association for Psychopharmacology — Evidence-based guidelines for the pharmacological treatment of schizophrenia: updated recommendations from the British Association for Psychopharmacology

About the author

Nicola Greenhalgh is lead pharmacist, Mental Health Services, North East London NHS Foundation Trust

[1] Chiu CC, Lu ML, Huang MC & Chen KP. Heavy smoking, reduced olanzapine levels, and treatment effects: a case report. Ther Drug Monit 2004;26(5):579–581. doi: 10.1097/00007691-200410000-00018

[2] de Leon J. Psychopharmacology: atypical antipsychotic dosing: the effect of smoking and caffeine. Psychiatr Serv 2004;55(5):491–493. doi: 10.1176/appi.ps.55.5.491

[3] Mayerova M, Ustohal L, Jarkovsky J et al . Influence of dose, gender, and cigarette smoking on clozapine plasma concentrations. Neuropsychiatr Dis Treat 2018;14:1535–1543. doi: 10.2147/NDT.S163839

[4] Ashir M & Petterson L. Smoking bans and clozapine levels. Adv Psychiatr Treat 2008;14(5):398–399. doi: 10.1192/apt.14.5.398b

[5] Young CR, Bowers MB & Mazure CM. Management of the adverse effects of clozapine. Schizophr Bull 1998;24(3):381–390. doi: 10.1093/oxfordjournals.schbul.a033333

[6] Taylor D, Barnes TRE & Young AH. The Maudsley Prescribing Guidelines in Psychiatry . 13th edn. London: Wiley Blackwell; 2018

[7] Oke V, Schmidt F, Bhattarai B et al . Unrecognized clozapine-related constipation leading to fatal intra-abdominal sepsis — a case report. Int Med Case Rep J 2015;8:189–192. doi: 10.2147/IMCRJ.S86716

[8] Hibbard KR, Propst A, Frank DE & Wyse J. Fatalities associated with clozapine-related constipation and bowel obstruction: a literature review and two case reports. Psychosomatics 2009;50(4):416–419. doi: 10.1176/appi.psy.50.4.416

[9] Medicines and Healthcare products Regulatory Agency. Clozapine: reminder of potentially fatal risk of intestinal obstruction, faecal impaction, and paralytic ileus. 2020. Available from: https://www.gov.uk/drug-safety-update/clozapine-reminder-of-potentially-fatal-risk-of-intestinal-obstruction-faecal-impaction-and-paralytic-ileus (accessed April 2020)

[10] Leucht S, Cipriani A, Spineli L et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013;382(9896):951–962. doi: 10.1016/S0140-6736(13)60733-3

[11] Bazire S. Psychotropic Drug Directory . Norwich: Lloyd-Reinhold Communications LLP; 2018

[12] Cooper SJ & Reynolds GP. BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment. J Psychopharmacol 2016;30(8):717–748. doi: 10.1177/0269881116645254

[13] National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management. Clinical guideline [CG178]. 2014. Available from: https://www.nice.org.uk/guidance/cg178 (accessed April 2020)

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Understanding Schizophrenia: A Case Study

Schizophrenia is characterized mainly, by the gross distortion of reality, withdrawal from social interaction, disorganization and fragmentation of perception, thoughts and emotions. Insight is an important concept in clinical psychiatry, a lack of insight is particularly common in schizophrenia patient. Previous studies reported that between 50-80% of patients with schizophrenia do not believe, they have a disorder. By the help of psychological assessment, we can come to know an individual's problems especially in cases, where patient is hesitant or has less insight into illness. Assessment is also important for the psychological management of the illness. Knowing the strengths and weaknesses of that particular individual with psychological analysis tools can help to make better plan for the treatment. The present study was designed to assess the cognitive functioning, to elicit severity of psychopathology, understanding diagnostic indicators, personality traits that make the individual vulnerable to the disorder and interpersonal relationship in order to plan effective management. Schizophrenia is a chronic disorder, characterized mainly by the gross distortion of reality, withdrawal from social interaction, and disorganization and fragmentation of perception, thought and emotion. Approximately, 1% world population suffering with the problem of Schizophrenia. Both male and female are almost equally affected with slight male predominance. Schizophrenia is socioeconomic burden with suicidal rate of 10% and expense of 0.02-1.65% of GDP spent on treatment. Other co-morbid factors associated with Schizophrenia are diabetes, Obesity, HIV infection many metabolic disorders etc. Clinically, schizophrenia is a syndrome of variables symptoms, but profoundly disruptive, psychopathology that involves cognition, emotion, perception, and other aspects of behavior. The expression of these manifestations varies across patients and over the time, but the effect of the illness is always severe and is usually long-lasting. Patients with schizophrenia usually get relapse after treatment. The most common cause for the relapse is non-adherent with the medication. The relapse rate of schizophrenia increases later time on from 53.7% at 2 years to

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• Published: 04 June 2024

Psychiatric adverse events following COVID-19 vaccination: a population-based cohort study in Seoul, South Korea

• Hong Jin Kim   ORCID: orcid.org/0000-0002-8162-9585 1 ,
• Min-Ho Kim   ORCID: orcid.org/0000-0003-4909-2308 2 ,
• Myeong Geun Choi 3 &
• Eun Mi Chun   ORCID: orcid.org/0000-0001-9616-2722 3  

Molecular Psychiatry ( 2024 ) Cite this article

277 Accesses

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• Bipolar disorder
• Schizophrenia

Evidence has suggested an increased risk of psychiatric manifestations following viral infections including coronavirus disease-2019 (COVID-19). However, psychiatric adverse events (AEs) after COVID-19 vaccination, which were documented in case reports and case series, remain unclear. This study is aimed to investigate the psychiatric AEs after COVID-19 vaccination from a large population-based cohort in Seoul, South Korea. We recruited 50% of the Seoul-resident population randomly selected from the Korean National Health Insurance Service (KNHIS) claims database on 1, January, 2021. The included participants ( n  = 2,027,353) from the Korean National Health Insurance Service claims database were divided into two groups according to COVID-19 vaccination. The cumulative incidences per 10,000 of psychiatric AEs were assessed on one week, two weeks, one month, and three months after COVID-19 vaccination. Hazard ratios (HRs) and 95% Confidence interval (CIs) of psychiatric AEs were measured for the vaccinated population. The cumulative incidence of depression, anxiety, dissociative, stress-related, and somatoform disorders, sleep disorders, and sexual disorders at three months following COVID-19 vaccination were higher in the vaccination group than no vaccination group. However, schizophrenia and bipolar disorders showed lower cumulative incidence in the vaccination group than in the non-vaccinated group. Depression (HR [95% CI] = 1.683 [1.520–1.863]), anxiety, dissociative, stress-related, and somatoform disorders (HR [95% CI] = 1.439 [1.322–1.568]), and sleep disorders (HR [95% CI] = 1.934 [1.738–2.152]) showed increased risks after COVID-19 vaccination, whereas the risks of schizophrenia (HR [95% CI] = 0.231 [0.164–0.326]) and bipolar disorder (HR [95% CI] = 0.672 [0.470–0.962]). COVID-19 vaccination increased the risks of depression, anxiety, dissociative, stress-related, and somatoform disorders, and sleep disorders while reducing the risk of schizophrenia and bipolar disorder. Therefore, special cautions are necessary for administering additional COVID-19 vaccinations to populations vulnerable to psychiatric AEs.

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Introduction.

In the unprecedented era of coronavirus disease-2019 (COVID-19), the global outbreak of COVID-19 has had an unpredictable and heterogeneous impact on the healthcare system worldwide [ 1 , 2 ]. Especially in mental illness, COVID-19 showed an increased risk of mental health problems together with lockdown, social distancing, and uncertain causes [ 3 , 4 ]. There have been growing concerns that the COVID-19 pandemic has increasingly had a detrimental effect on long-term mental health at an early stage in the development of vaccines [ 5 , 6 ].

The rapid development of COVID-19 vaccines, ranging from mRNA-based vaccines (BNT162b2, mRNA-1273) to viral vector vaccines (cDNA-based vaccines; AZD1222, JNJ-78436735), has contributed to overcoming the COVID-19 pandemic in the view of severity and mortality [ 1 , 7 ]. However, it has also given rise to new issues such as post-COVID-19 sequelae and vaccine-related adverse events (AEs) [ 2 , 5 , 6 , 7 , 8 , 9 , 10 ]. With their issues, mental health is still an unsolved concern in the post-COVID-19 era [ 4 , 6 ]. Many studies have focused on the correlation between mental health and COVID-19 breakthrough [ 11 ]. However, mental illness as a result of the COVID-19 vaccine itself, specifically post-vaccination psychiatric AEs was not well-studied, with scant evidence in the literature, which was documented primarily in the form of case reports and case series [ 12 , 13 , 14 , 15 ].

In this study, we investigated the psychiatric AEs including schizophrenia, depression, bipolar disorder, anxiety, dissociative, stress-related, and somatoform disorders, sleep disorders, and sexual disorders after COVID-19 vaccination from a population-based cohort using the Korean National Health Insurance Service (KNHIS) claims database in Seoul, South Korea.

Materials and methods

The concept and protocol of this study were approved by the Institutional Review Board (IRB) of our institute, which waived the requirement for informed consent because data analyses were performed retrospectively using anonymized data derived from the South Korean NHIS database.

Data source

We used the KNHIS claims database to recruit a randomly selected 50% of the population residing in Seoul on 1 January 2021 with their diagnostic records up to 31 December 2021. The process of selecting a random 50% of the population in Seoul was carried out by the KNHIS system. After authorization by KNHIS, the data collection was performed in November 2022. The psychiatric AEs included schizophrenia, mood disorders (depression, and bipolar disorder), anxiety, dissociative, stress-related, and somatoform disorders (anxiety disorders, obsessive-compulsive disorder, reacting to severe stress, and adjustment disorders, conversion disorders, somatoform disorders, and other neurotic disorders), sleep disorders, eating disorders, and sexual disorders using the International Classification of Diseases (ICD) Tenth Revision codes after the index date. This population-based cohort study was also conducted by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [ 16 ].

Study population

A total of 4,348,412 individuals living in Seoul, South Korea, constituting 50% of the population, were included and investigated as of January 1, 2021. Individuals under 20 years (n = 144,525) were excluded, leaving 4,203,887 individuals for analysis. We initially divided into two groups based on COVID-19 vaccination and defined as vaccinated group as individuals who received two doses of the COVID-19 vaccine. For the 3,839,014 vaccinated population, we excluded 1,684,625 individuals who did not receive a second dose by 1, October 2021. For 364,873 unvaccinated population, we excluded 13,890 individuals who died on 1, October 2021. The diagnostic records for the year preceding the index date were traced to investigate the causal relationship between vaccine administration and AEs. The occurrence of the target psychiatric disorders was defined as receiving a primary diagnosis of the disease from the day following the index date. Individuals who had received a primary or secondary diagnosis of any target disease for a year prior to index date were excluded from the study. We finally included the participants defined by two groups in this study: the vaccinated group (n = 1,718,999) and the non-vaccinated group (n = 308,354) (Fig.  1 ).

Flowchart of this study.

Outcome measurements

The primary outcome measure was the cumulative incidence of psychiatric AEs per 10,000 population at one week, two weeks, one month, and three months between two groups. The secondary outcome measures were risks of psychiatric target AEs for COVID-19 vaccination using the odd ratios (ORs) and hazard ratios (HRs). Furthermore, subgroup analyses were also conducted based on gender, age, the number of COVID-19 vaccine doses, the vaccine type (mRNA vaccine, cDNA vaccine, and heterologous vaccination), health insurance level, presence of diabetes mellitus (DM), hypertension (HTN), hyperlipidemia, and chronic obstructive pulmonary disease (COPD). Age, gender, insurance level, Charlson’s comorbidity index (CCI), presence of DM, HTN, hyperlipidemia, and COPD, and prior COVID-19 infection history were extracted using their ICD-19 codes, which were suggested by Sundararajan et al. [ 17 ]. The presence of comorbid diseases (i.e., DM, HTN, hyperlipidemia, and COPD), categories of CCI, and the prior COVID-19 infection history were determined based on receiving a primary or secondary diagnosis at least twice within one year before the index date. The National Health Insurance (NHI) premium was used as a proxy for income, as it is proportional to monthly income, encompassing both earnings and capital gains. The income quantiles of the enrolled participants were subdivided into three groups (low-, middle- and high-income groups in medical aid enrollees and the 0–33, 34–66, and 67–100 centiles of NHI enrollees). Detailed information for ICD-10 codes used for analysis is presented in Supplementary Table  1 .

Statistical analysis

Statistical analysis was performed using the SAS Enterprise Guide (version 8.3., SAS Institute, Cary, NC, USA). A normal distribution was confirmed with the Kolmogorov–Smirnov test. Baseline patient characteristics and comorbidities were reported as means ± standard deviation for continuous variables and ratio for categorical variables. Student’s t test was performed for continuous variables and the chi-square test for categorical variables. The cumulative incidence was calculated per 10,000 populations. To identify the association between COVID-19 vaccination and psychiatric AEs, a multiple logistic regression model was used for ORs, corresponding to 95% CIs. Cox proportional hazards regression was used to estimate the HRs and 95% CIs. Two-sided p values of 0.05 or less were considered to indicate statistical significance.

The participants’ characteristics

In total, 2,027,353 subjects were included in this study. Among them, 308,354 (15.21%) had not received the COVID-19 vaccine (i.e., non-vaccinated subjects, no vaccination group in this study), whereas 1,718,999 (84.79%) were vaccinated against COVID-19 (i.e., vaccinated subjects, the vaccinated group in this study). The baseline characteristics of the vaccinated and non-vaccinated groups are presented in Table  1 .

The cumulative incidences per 10,000 of psychiatric AEs following the COVID-19 vaccination

The cumulative incidence of the psychiatric AEs at three months was 0.51 (95% CI, 0.40–0.62) vs 1.98 (95% CI, 1.48–2.47) for schizophrenia, 18.30 (95% CI, 17.66-18.93) vs 14.24 (95% CI, 12.91–15.57) for depression, 0.79 (95% CI, 0.66–0.92) vs 1.39 (95% CI, 0.98–1.81) for bipolar disorder, 28.41 (95% CI, 27.62–29.21) vs 20.27 (95% CI, 18.68–21.86) for anxiety, dissociative, stress-related, and somatoform disorders, 0.30 (95% CI, 0.22–0.38) vs 0.32 (95% CI, 0.12–0.53) for eating disorder, 28.85 (95% CI, 28.05–29.96) vs 12.19 (95% CI, 10.96–13.43) for sleep disorders, 0.27 (95% CI, 0.19–0.34) vs 0.03 (95% CI, 0.00–0.10) for sexual disorders between the vaccinated group and non-vaccinated group. Therefore, the cumulative incidences of schizophrenia ( p  < 0.001) and bipolar disorder ( p  = 0.002) were significantly lower in the vaccinated group than in the non-vaccinated group. Meanwhile, depression ( p  < 0.001), anxiety, dissociative, stress-related, and somatoform disorders ( p  < 0.001), sleep disorders ( p  < 0.001), and sexual disorders ( p  = 0.007) showed significantly higher cumulative incidence in the vaccinated group than in the non-vaccinated group. There was no statistical difference in the cumulative incidence of eating disorders at three months between the two groups ( p  = 0.724). Detailed information of cumulative incidence was presented in Table  2 .

The cumulative incidences per 10,000 of psychiatric AEs according to vaccine types

Our data was also stratified by vaccine type including vaccination using mRNA-based vaccine only (only mRNA vaccine), vaccination using cDNA-based vaccine only (only cDNA vaccine), and heterologous vaccination, which were compared by non-vaccinated group. For decreased incidences of schizophrenia and bipolar disorder following COVID-19 vaccination, schizophrenia showed the lowest cumulative incidence at three months in the case of heterologous vaccination (0.42; 95% CI, 0.05–0.79) compared to other vaccine types with statistical significances ( p  < 0.001). The lowest cumulative incidence of bipolar disorder at three months was observed in the case of vaccination using only cDNA vaccine (0.39; 95% CI, 0.23-0.55) with a statistical difference ( p  < 0.001). For increased incidences of depression, anxiety, dissociative, stress-related, and somatoform disorders, sleep disorders, and sexual disorders following COVID-19 vaccination, the highest cumulative incidence of depression at three months was significantly observed in heterologous vaccination (23.31; 95% CI, 20.56–26.05) compared to other vaccine types ( p  < 0.001). However, the cumulative incidence of depression at three months was lower in the case of vaccination using only cDNA vaccine (12.26; 95% CI, 11.37–13.15) than in the non-vaccinated group (14.24; 95% CI, 12.91–15.57) with statistical differences ( p  = 0.014). The incidence of anxiety, dissociative, stress-related, and somatoform disorders was significantly observed to be highest in the case of heterologous vaccination (31.75; 95% CI, 28.55–34.95), followed by only mRNA vaccination (29.13; 95% CI, 28.08–30.18) and only cDNA vaccination (26.53; 95% CI, 25.22–27.83) ( p  < 0.001). The incidence of sleep disorders at three months was significantly observed to be high level in both cases of only cDNA vaccination (34.78; 95% CI, 33.28–36.28), and heterologous vaccination (32.09; 95% CI, 28.87–35.31), followed by only mRNA vaccination (24.98; 95% CI, 24.00–25.96) ( p  < 0.001). The cumulative incidences of sexual disorders showed no statistical differences up to one month ( p  > 0.05). At three months, the sexual disorder showed differences in cumulative incidence according to vaccine types ( p  = 0.04). There was no statistical difference in the cumulative incidence of eating disorders at three months ( p  = 0.785) according to vaccine types. The cumulative incidences of psychiatric AEs according to vaccine type are presented in Fig.  2 and Supplementary Table  2 .

a Schizophrenia. b Depression. c Bipolar disorder. d Anxiety, dissociative, stress-related, and somatoform disorders. e Sleep disorder. f Sexual disorders.

The risks of psychiatric AEs following the COVID-19 vaccination

In the Cox proportional hazard model in this study, the HR for COVID-19 vaccination was 0.231 (95% CI, 0.164–0.326) for schizophrenia, 1.683 (95% CI, 1.520–1.863) for depression, 0.672 (95% CI, 0.470–0.962) for bipolar disorder, 1.439 (95% CI, 1.322–1.568) for anxiety, dissociative, stress-related, and somatoform disorders, 0.796 (95% CI, 0.395–1.604) for eating disorders, 1.934 (95% CI, 1.738–2.152) for sleep disorders, and 6.556 (95% CI, 0.890–48.296) for sexual disorders. Therefore, COVID-19 vaccination significantly decreased the risks of occurrence for schizophrenia and bipolar disorder, while significantly increasing the risks for depression, anxiety, dissociative, stress-related, and somatoform disorders, and sleep disorders. There was no effect of COVID-19 vaccination on the occurrence of eating disorders and sexual disorders (Fig.  3a ).

a The risks of psychiatric adverse events (AEs) according to COVID-19 vaccination. b The risks of psychiatric adverse events according to the COVID-19 vaccine types.

In the multivariate logistic model in this study, the ORs of target psychiatric AEs, except for bipolar disorder at one week, two weeks, and one month showed statistical significance, indicating similar patterns for HRs in the Cox proportional hazard model. For bipolar disorder, the OR showed 1.166 (95% CI, 0.240–5.670; p  = 0.849) at one week, 0.946 (95% CI, 0.304–2.949; p  = 0.924) at two weeks, 0.982 (95% CI, 0.463–2.079; p  = 0.962) at one month, and 0.674 (95% CI, 0.471–0.964; p  = 0.031). The detailed information for ORs of target psychiatric AEs was described in Supplementary Table  3 .

The risks of psychiatric AEs according to the COVID-19 vaccine type

We further assessed the risks of target psychiatric AEs according to the COVID-19 vaccine. For schizophrenia and bipolar disorder which were observed to have lower occurrences following COVID-19 vaccination, the HRs of schizophrenia were 0.239 (95% CI, 0.163–0.352) in only mRNA vaccination, 0.218 (95% CI, 0.138–0.343) in only cDNA vaccination, and 0.227 (95% CI, 0.091–0.566) in heterologous vaccination with statistical significances. On the other hand, the HR of bipolar disorder was statistically significant only in the case of only cDNA vaccination (0.339; 95% CI, 0.196–0.587). For depression, anxiety, dissociative, stress-related, and somatoform disorders, and sleep disorders which were observed to have higher occurrences following COVID-19 vaccination, the HRs of depression (1.777; 95% CI, 1.527–2.067), anxiety, dissociative, stress-related, and somatoform disorders (1.521; 95% CI, 1.338–1.729), and sleep disorders (2.080; 95% CI, 1.855–2.332) showed the highest levels in the case of heterologous vaccination with statistical significances, respectively. There were no statistical differences in risks of eating disorders and sexual disorders according to vaccine types (Fig.  3b ).

The ORs of target psychiatric AEs, except for bipolar disorder at one week, two weeks, and one month also showed statistical significance, indicating similar patterns for HRs in the Cox proportional hazard model. For bipolar disorder, the OR for only cDNA vaccination showed 1.581 (95% CI, 0.172–14.496; p  = 0.685) at one week, 0.459 (95% CI, 0.073–2.893; p  = 0.407) at two weeks, 0.191 (95% CI, 0.039–0.939; p  = 0.042) at one month, and 0.340 (95% CI, 0.197–0.589; p  < 0.001). The detailed information for ORs of target psychiatric AEs according to vaccine types was described in Supplementary Table  3 .

Subgroup analysis for psychiatric AEs based on gender, age, insurance level, and CCI

As age increases, the risks of schizophrenia (HR, 1.027; 95% CI, 1.016–1.039) and sleep disorders (HR, 1.014; 95% CI, 1.012–1.016) significantly increase and the risks of depression (HR, 0.969; 95% CI, 0.966–0.971), bipolar disorder (HR, 0.982; 95% CI, 0.971–0.993), anxiety, dissociative, stress-related, somatoform disorders (HR, 0.988; 95% CI, 0.986–0.990) significantly decrease. Considering the HR values, age does not seem to largely affect the risk of psychiatric AEs. For the insurance level, the HR of schizophrenia at the high insurance level was 0.593 ( p  = 0.007) with statistical differences compared to the low insurance level. The HRs of depression at the high insurance level and middle insurance level were respectively 0.904 ( p  = 0.014) and 0.824 ( p  < 0.001) with statistical differences. There were no statistical differences in other psychiatric disorders for the insurance levels. For CCI, a higher score of CCI more than 2 significantly increased the risks of depression (HR, 1.393; 95% CI, 1.217–1.596), anxiety, dissociative, stress-related, somatoform disorders (HR, 1.440; 95% CI, 1.306–1.587), and sleep disorders (HR, 1.315; 95% CI, 1.198–1.444) than zero score of CCI. Based on these results, women are mostly susceptible to psychiatric AEs (except for sexual disorders) compared to men. Detailed information for Cox proportional hazard model for psychiatric AEs was presented in Supplementary Table  4 .

The post-sequelae of COVID-19 and vaccine-related AEs have globally been concerns for mental illness, ranging from mild signs of mental symptoms to psychiatric disorders [ 18 ]. During the prolonged COVID-19 pandemic, there has been an emerging trend in complications of COVID-19 infection and vaccination, intensifying the psychosocial burdens [ 5 , 18 , 19 ]. Despite the considerable clinical benefits of the COVID-19 vaccination, it paradoxically made managing psychiatric disorders more challenging due to the contradictory outcomes associated with COVID-19 vaccination [ 11 , 13 , 14 , 15 , 18 , 19 , 20 , 21 ]. Here, we conducted a population-based retrospective cohort study for psychiatric AEs after COVID-19 vaccination in Seoul, South Korea. From our cohort between 1,718,999 vaccinated subjects and 308,354 non-vaccinated subjects, we found that the vaccinated subjects showed a significantly higher incidence of depression, anxiety, dissociative, stress-related, and somatoform disorders, sleep disorders, and sexual disorders and a significantly lower incidence of schizophrenia and bipolar disorder than the non-vaccinated subjects. Furthermore, COVID-19 vaccination increased risks of depression, anxiety, dissociative, stress-related, and somatoform disorders and sleep disorders but reduced risks of schizophrenia and bipolar disorder.

Some evidence between COVID-19 and mental illness has gradually grown since the most common symptoms of the long-COVID-19 pandemic were depression/anxiety, psychotic disorder, and cognitive impairment (called brain fog) experienced by 22% of patients within 6 months after COVID-19 infections [ 4 , 14 ]. However, there have been contradictory reports between mental illness and COVID-19 vaccinations. Chaudhuri et al. reported that vaccination significantly alleviated psychological distress measured by the General Health Questionnaire in the UK Household Longitudinal cohort study [ 18 ]. Meanwhile, Balasubramanian et al. reviewed the reports of psychiatric AEs to COVID-19 vaccines, which illustrated 14 cases of psychiatric reactions including psychosis, depression, and anxiety, dissociative, stress-related, and somatoform disorders [ 15 ]. To our knowledge, there are scarce studies on the association between vaccines and psychiatric AEs. Therefore, our population-based cohort study provides robust evidence for the psychiatric AEs after COVID-19 vaccinations. Furthermore, our study provided risks of psychiatric AEs according to vaccine type, revealing that the psychiatric disorders (depression, anxiety, dissociative, stress-related, and somatoform disorders, and sleep disorders) with increased risks due to COVID-19 vaccination showed the highest risk in the case of heterogeneous vaccination. Meanwhile, occurrences of schizophrenia consistently decreased risks according to vaccine type but bipolar disorder showed significantly decreased risks from only cDNA vaccination.

Two representative mood disorders, depression, and bipolar disorders, showed contrasting trends for COVID-19 vaccination. The serotonin theory is that depression is caused by an alternation of the hypothalamic-pituitary-adrenal (HPA) axis, particularly serotonin (5-hydroxytryptamine or 5-HT) [ 22 , 23 , 24 ]. Along with this theory, the selective serotonin reuptake inhibitor is currently the main drug to treat depression [ 22 ]. Serotonin, known as a neurotransmitter, is important to immune systems as the regulator of immune responses and inflammatory processes by central and peripheral mechanisms [ 22 , 24 ]. For reports of COVID-19 vaccines, the association between adrenal crisis and COVID-19 vaccination has been suggested with the possible risk of heterologous vaccination [ 25 , 26 ] Therefore, COVID-19 may alternate the HPA axis, which can potentially increase the risk of depression from our study. In our study, HR for bipolar disorder was found to be 0.672 (95% CI, 0.470–0.962) in association with COVID-19 vaccination. However, this result was primarily caused by only cDNA vaccination with a notable lower HR of 0.339 (95% CI, 0.196–0.587). Interestingly, other types of COVID-19 vaccinations did not demonstrate a significant impact on the occurrences of bipolar disorder. These distinctive findings suggested that the differential effects along with vaccine types may be underestimated in mental illness, particularly bipolar disorder [ 12 , 27 ].

The immune response mediated by COVID-19 vaccination manifests in a variety of ways across different sites in our body [ 28 ]. Trougakos et al. described that the AEs following COVID-19 vaccination may related to the proinflammatory action of the lipid nanoparticles or the delivered mRNA and proinflammatory effects of the produced antigens-spike protein and/or its peptides fragments [ 29 ]. The COVID-19 vaccination activated proinflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor-α mediated by CD4 + T cells [ 28 ]. Many immune-related factors have been suggested for the expression of psychosis [ 13 ]. The hyperinflammatory status can increase dopamine with N-inhibition of methyl-d-aspartate receptor (NMDAR), which leads to psychosis [ 30 ]. Furthermore, an autoimmune response caused by the spike protein and encoded viral protein in the vaccine can be a potential factor in the manifestation of schizophrenia [ 31 , 32 ]. Of many vaccination methods, Lee et al. described that the heterologous vaccination enhanced B cells and CD4 + T cell responses [ 33 ]. Proinflammatory effects can be exacerbated by preexisting inflammatory conditions after administration of mRNA lipid nanoparticles [ 29 ]. This heightened immune response may influence the occurrence of schizophrenia, as presented in our study. However, the profound pathophysiological mechanisms should be performed in future translational research [ 27 ].

Anxiety and stress-related disorders are the main concerns for COVID-19 infection and vaccination, which were widely studied from fear to vaccine hesitancy [ 34 ]. Conversion disorders, characterized by paralysis, sensory disturbances, and seizures are associated with alternation of brain function networks [ 35 ]. Our study showed increased risks of anxiety, dissociative, stress-related, and somatoform disorders, and sleep disorders, which were heightened by heterologous vaccination. Most patients who were infected with COVID-19 experienced chronic fatigue with mild cognitive impairment (i.e., brain fog) [ 21 , 35 , 36 ]. Abel et al. described that COVID-19 infection increased the risks of fatigue and sleep disorders from the UK primary care data [ 21 ]. The mechanism is thought to be caused by a decrease in cerebral blood flow, and it is similar to neuropsychiatric disorders affected by inflammatory processes and immune responses [ 37 ]. Since COVID-19 vaccination is also associated with immune responses, both clinicians and vaccinated subjects should be cautious of these manifestations, especially anxiety, dissociative, stress-related, and somatoform disorders, and sleep disorders that can also be affected by COVID-19 vaccination in our study. Therefore, the COVID-19 vaccination increases the manifestation of neurosis-related disorders but decreases that of psychosis-related disorders.

With the increasing evidence of extrapulmonary manifestations including neurological and psychiatric symptoms, COVID-19 infection as well as vaccination may affect the central and peripheral nervous system with profound cellular and molecular mechanisms [ 6 , 38 , 39 ]. The spike protein, especially brain-infiltrating SARS-CoV-2 spike protein has been suggested as an important target for the development of neurological and psychiatric disorders. Several mechanisms involved in spike protein have been proposed at the mice level such as TLR2-mediated depression, TLR4-mediated cognitive dysfunction, and anxiety mediated by non-cell autonomous hippocampal neuronal cell deaths by inducing IL-1β from glial cells [ 40 ]. Importantly, a recent study suggested that mRNA vaccines have slippery sequences inducing +1 ribosomal frameshifting products after vaccinations as a consequence of N 1 -methylpseudouridine-induced ribosome stalling [ 41 ]. Although the pathogenesis remains unclear, our study suggests that neuroinflammation caused by spike proteins may contribute to occurrences of some psychiatric AEs such as depression and anxiety, dissociative, stress-related, and somatoform disorders. Therefore, future translational research may provide the pathophysiological differences between psychosis and neurosis from the COVID-19 vaccination.

To supplement our hypothesis regarding the mechanism of action after COVID-19 vaccination, we tried further study using the gene sets enrichment analysis (Supplementary Table  5 ). We found that schizophrenia-related genes share the enrichment pathway for bile acid metabolism. Bile acids prevent the binding of spike protein with angiotensin-converting enzyme II (ACE2) and modulate the expression of ACE2, suggesting the protective role [ 42 ]. Our study also showed that COVID-19 vaccination reduced risks of schizophrenia. For depression, as an increased risk after COVID-19 vaccination, the results were shown for the deep interaction of spike protein-related factors such as NLRP3 inflammasome [ 40 ]. This supports that the presence of the spike protein plays a crucial role in the manifestation of diseases after COVID-19 vaccination. Regarding the neurosis, the Rap1 signaling was observed as an enrichment pathway in the genes of neuroticisms. It regulates MAPK pathways that are important for SARS-CoV-2 virus replication [ 43 , 44 ]. However, these findings will have to be validated by future experimental studies.

This study has several limitations. First, we collected the claims data based on ICD-19 codes, which led to potential errors regarding mismatching or misclassification could have occurred. Second, previous studies have suggested the impact of poverty rates on mental disorders but there are differences in the baseline characteristics between the two groups in this study [ 45 , 46 ]. Although propensity score matching could be a statistical option to overcome this limitation, the real-world data is scarce on the psychiatric AEs following the COVID-19 vaccination so future studies through the process of propensity score matching should be addressed for COVID-19 vaccine-related psychiatric AEs. Meanwhile, both schizophrenia and bipolar disorders often manifest at a young age (under 20 years old) [ 47 ]. However, our study protocol didn’t include the adolescent population group because our study protocol has been approved by our IRB to analyze adults more than 20 years old. Furthermore, the COVID-19 vaccination for adolescents in South Korea has been authorized since October 2021, which made it impossible to collect COVID-19 vaccine-related AEs of the population under 20 years old in our study protocol. Thus, future studies for adolescents considering the manifestation of psychiatric disorders will be needed on COVID-19 vaccine-related AEs. Third, we measured psychiatric AEs up to three months following COVID-19 vaccination. This study did not contain the long-term follow-up COVID-19 vaccine-associated AEs. Last, despite being a population-based study targeting the population in Seoul, South Korea, it cannot be generalized to the entire population, globally since psychiatric disorders could be related to ethnic and genetic backgrounds. Therefore, a global-scale real-world study for adverse events of COVID-19 vaccination will be important in the future.

In conclusion, this population-based cohort study revealed that COVID-19 vaccination differentially affects occurrences of psychiatric disorders. It increased the risks of depression, anxiety, dissociative, stress-related, and somatoform disorders, and sleep disorders while reducing the incidence and risk of schizophrenia and bipolar disorder. Our findings suggested that the relationship between COVID-19 vaccination and mental illness may be underestimated along with the complexity of its impact on mental health. Thus, close observation and special caution are necessary for administering additional COVID-19 vaccinations to populations vulnerable to psychiatric AEs.

Data availability

The datasets analyzed during the current study are available through an application to the National Health Insurance Service, South Korea. This protects the confidentiality of the data and ensures that Information Governance is robust.

Lundberg-Morris L, Leach S, Xu Y, Martikainen J, Santosa A, Gisslén M, et al. Covid-19 vaccine effectiveness against post-covid-19 condition among 589 722 individuals in Sweden: population based cohort study. Bmj. 2023;383:e076990.

Article   PubMed   PubMed Central   Google Scholar  

Lee DS, Kim JW, Lee KL, Jung YJ, Kang HW. Adverse events following COVID-19 vaccination in South Korea between February 28 and August 21, 2021: a nationwide observational study. Int J Infect Dis. 2022;118:173–82.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Moreno C, Wykes T, Galderisi S, Nordentoft M, Crossley N, Jones N, et al. How mental health care should change as a consequence of the COVID-19 pandemic. Lancet Psychiatry. 2020;7:813–24.

Jefsen OH, Kolbaek P, Gil Y, Speed M, Dinesen PT, Sonderskov KM, et al. COVID-19 vaccine willingness amongst patients with mental illness compared with the general population. Acta Neuropsychiatr. 2021;33:273–6.

Article   PubMed   Google Scholar  

Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27:601–15.

Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26:1017–32.

Article   CAS   PubMed   Google Scholar  

Barouch DH. Covid-19 vaccines - immunity, variants, boosters. N Engl J Med. 2022;387:1011–20.

Wang W, Wang CY, Wang SI, Wei JC. Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: a retrospective cohort study from the TriNetX US collaborative networks. EClinicalMedicine. 2022;53:101619.

Patone M, Handunnetthi L, Saatci D, Pan J, Katikireddi SV, Razvi S, et al. Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection. Nat Med. 2021;27:2144–53.

Buchan SA, Seo CY, Johnson C, Alley S, Kwong JC, Nasreen S, et al. Epidemiology of Myocarditis and Pericarditis Following mRNA vaccination by vaccine product, schedule, and interdose interval among adolescents and adults in Ontario, Canada. JAMA Netw Open. 2022;5:e2218505.

Sun HL, Zhao YJ, Sha S, Li XH, Si TL, Liu YF, et al. Depression and anxiety among caregivers of psychiatric patients during the late stage of the COVID-19 pandemic: a perspective from network analysis. J Affect Disord. 2024;344:33–40.

Kita A, Fuyuno Y, Matsuura H, Yamaguchi Y, Okuhira K, Kimoto S. Psychiatric adverse reaction to COVID-19 vaccine booster presenting as first-episode acute mania with psychotic features: A case report. Psychiatry Res Case Rep. 2023;2:100143.

Google Scholar  

Grover S, Rani S, Kohat K, Kathiravan S, Patel G, Sahoo S, et al. First episode psychosis following r eceipt of first dose of COVID-19 vaccine: a case report. Schizophr Res. 2022;241:70–1.

Harrison PJ, Taquet M. Neuropsychiatric disorders following SARS-CoV-2 infection. Brain. 2023;146:2241–7.

Balasubramanian I, Faheem A, Padhy SK, Menon V. Psychiatric adverse reactions to COVID-19 vaccines: a rapid review of published case reports. Asian J Psychiatr. 2022;71:103129.

von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Bmj. 2007;335:806–8.

Article   Google Scholar  

Sundararajan V, Henderson T, Perry C, Muggivan A, Quan H, Ghali WA. New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality. J Clin Epidemiol. 2004;57:1288–94.

Chaudhuri K, Howley P. The impact of COVID-19 vaccination for mental well-being. Eur Econ Rev. 2022;150:104293.

Penninx B, Benros ME, Klein RS, Vinkers CH. How COVID-19 shaped mental health: from infection to pandemic effects. Nat Med. 2022;28:2027–37.

Nishimi K, Neylan TC, Bertenthal D, Seal KH, O’Donovan A. Association of psychiatric disorders with incidence of SARS-CoV-2 breakthrough infection among vaccinated adults. JAMA Netw Open. 2022;5:e227287.

Abel KM, Carr MJ, Ashcroft DM, Chalder T, Chew-Graham CA, Hope H, et al. Association of SARS-CoV-2 Infection With Psychological distress, psychotropic prescribing, fatigue, and sleep problems among UK primary care patients. JAMA Netw Open. 2021;4:e2134803.

Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, et al. Major depressive disorder. Nat Rev Dis Primers. 2016;2:16065.

Vieta E, Berk M, Schulze TG, Carvalho AF, Suppes T, Calabrese JR, et al. Bipolar disorders. Nat Rev Dis Primers. 2018;4:18008.

Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry. 2023;28:3243–56.

Maguire D, McLaren DS, Rasool I, Shah PM, Lynch J, Murray RD. ChAdOx1 SARS-CoV-2 vaccination: a putative precipitant of adrenal crises. Clin Endocrinol. 2023;99:470–3.

Article   CAS   Google Scholar  

Markovic N, Faizan A, Boradia C, Nambi S. Adrenal crisis secondary to COVID-19 vaccination in a patient with hypopituitarism. AACE Clin Case Rep. 2022;8:171–3.

Cozzolino A, Hasenmajer V, Newell-Price J, Isidori AM. COVID-19 pandemic and adrenals: deep insights and implications in patients with glucocorticoid disorders. Endocrine. 2023;82:1–14.

Li C, Lee A, Grigoryan L, Arunachalam PS, Scott MKD, Trisal M, et al. Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine. Nat Immunol. 2022;23:543–55.

Trougakos IP, Terpos E, Alexopoulos H, Politou M, Paraskevis D, Scorilas A, et al. Adverse effects of COVID-19 mRNA vaccines: the spike hypothesis. Trends Mol Med. 2022;28:542–54.

Tang SW, Helmeste D, Leonard B. Inflammatory neuropsychiatric disorders and COVID-19 neuroinflammation. Acta Neuropsychiatrica. 2021;33:165–77.

Yonker LM, Swank Z, Bartsch YC, Burns MD, Kane A, Boribong BP, et al. Circulating spike protein detected in Post-COVID-19 mRNA vaccine myocarditis. Circulation. 2023;147:867–76.

Yesilkaya UH, Sen M, Tasdemir BG. A novel adverse effect of the BNT162b2 mRNA vaccine: first episode of acute mania with psychotic features. Brain Behav Immun Health. 2021;18:100363.

Lee HK, Go J, Sung H, Kim SW, Walter M, Knabl L, et al. Heterologous ChAdOx1-BNT162b2 vaccination in Korean cohort induces robust immune and antibody responses that includes Omicron. iScience. 2022;25:104473.

McNeil A, Purdon C. Anxiety disorders, COVID-19 fear, and vaccine hesitancy. J Anxiety Disord. 2022;90:102598.

Espay AJ, Aybek S, Carson A, Edwards MJ, Goldstein LH, Hallett M, et al. Current concepts in diagnosis and treatment of functional neurological disorders. JAMA Neurol. 2018;75:1132–41.

Morin CM, Drake CL, Harvey AG, Krystal AD, Manber R, Riemann D, et al. Insomnia disorder. Nat Rev Dis Primers. 2015;1:15026.

Theoharides TC, Stewart JM, Hatziagelaki E, Kolaitis G. Brain “fog,” inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin. Front Neurosci. 2015;9:225.

Khayat-Khoei M, Bhattacharyya S, Katz J, Harrison D, Tauhid S, Bruso P, et al. COVID-19 mRNA vaccination leading to CNS inflammation: a case series. J Neurol. 2022;269:1093–106.

Theoharides TC. Could SARS-CoV-2 spike protein be responsible for long-COVID syndrome? Mol Neurobiol. 2022;59:1850–61.

Fontes-Dantas FL, Fernandes GG, Gutman EG, De Lima EV, Antonio LS, Hammerle MB, et al. SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice. Cell Rep. 2023;42:112189.

Mulroney TE, Pöyry T, Yam-Puc JC, Rust M, Harvey RF, Kalmar L, et al. N 1 -methylpseudouridylation of mRNA causes +1 ribosomal frameshifting. Nature. 2024;625:189–94.

Fiorucci S, Urbani G, Biagioli M, Sepe V, Distrutti E, Zampella A. Bile acids and bile acid activated receptors in the treatment of Covid-19. Biochem Pharmacol. 2023;115983. https://doi.org/10.1016/j.bcp.2023.115983 .

Zhang YL, Wang RC, Cheng K, Ring BZ, Su L. Roles of Rap1 signaling in tumor cell migration and invasion. Cancer Biol Med. 2017;14:90–9.

Hadzega D, Babisova K, Hyblova M, Janostiakova N, Sabaka P, Janega P, et al. Analysis of transcriptomics data from COVID-19 patients: a pilot research. Folia Microbiol. 2024;69:155–64.

Das-Munshi J, Chang CK, Bakolis I, Broadbent M, Dregan A, Hotopf M, et al. All-cause and cause-specific mortality in people with mental disorders and intellectual disabilities, before and during the COVID-19 pandemic: cohort study. Lancet Reg Health Eur. 2021;11:100228.

Bennett JE, Pearson-Stuttard J, Kontis V, Capewell S, Wolfe I, Ezzati M. Contributions of diseases and injuries to widening life expectancy inequalities in England from 2001 to 2016: a population-based analysis of vital registration data. Lancet Public Health. 2018;3:e586–97.

Ortiz-Orendain J, Gardea-Resendez M, Castiello-de Obeso S, Golebiowski R, Coombes B, Gruhlke PM, et al. Antecedents to first episode psychosis and mania: comparing the initial prodromes of schizophrenia and bipolar disorder in a retrospective population cohort. J Affect Disord. 2023;340:25–32.

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Department of Orthopedic Surgery, Inje University Sanggye Paik Hospital, College of Medicine, Inje University, Seoul, Republic of Korea

Hong Jin Kim

Informatization Department, Ewha Womans University Seoul Hospital, Seoul, Republic of Korea

Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, School of Medicine, Ewha Womans University, Seoul, Republic of Korea

Myeong Geun Choi & Eun Mi Chun

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EMC conceptualized the study. HJK, M-HK, and EMC designed the study. HJK, M-HK, and EMC analyzed and interpreted the data. M-HK acquired the data. HJK and EMC drafted the manuscript. HJK, M-HK, MGC, and EMC critically reviewed the work. MGC verified the data in the study. All authors had full access to all the data and had final responsibility for the decision to submit for publication.

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Correspondence to Eun Mi Chun .

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The study protocol was approved by the Institutional Review Board of our institute (IRB No.: EUMC 2022-07-003), which waived the requirement for informed consent because data analyses were performed retrospectively using anonymized data derived from the South Korean NHIS database.

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Kim, H.J., Kim, MH., Choi, M.G. et al. Psychiatric adverse events following COVID-19 vaccination: a population-based cohort study in Seoul, South Korea. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02627-0

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Published : 04 June 2024

DOI : https://doi.org/10.1038/s41380-024-02627-0

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Stolen Remains Found in Plastic Bag Traced to Woman Born 160 Years Ago

Skeletal remains found in Oxnard, Calif., in 1985 have been identified as those of Gertrude Elliott-Littlehale, a musician whose grave was desecrated after her death in 1915.

By Johnny Diaz

In October 1985, partial skeletal remains were found in a plastic bag in the Channel Islands Harbor in Oxnard, Calif., northwest of Los Angeles. The authorities determined that they belonged to a woman who died when she was between 35 and 50 years old, but nothing else about her was known and, for decades, the trail went cold.

Nearly 40 years later, the woman once again has a name. She was Gertrude Elliott-Littlehale, a musician who was born in 1864, lived in San Francisco and died in 1915. And at one point decades ago, her grave was robbed and her skull was taken, according to Othram, the forensic laboratory that announced the identification of her remains last week.

The break in the case came after scientists were able to build a DNA profile from the remains. Investigators tracked down living potential relatives and collected a reference sample from one of them, leading to the identification.

David Mittelman, the chief executive of Othram, said in an interview on Monday that his company had worked on century-old cases before, and that “we have worked with DNA that is sometimes in very terrible shape” because of chemical damage and heat damage.

“The circumstances are very unusual though,” he said of Ms. Elliott-Littlehale’s case. “A grave robbery, the theft of the skull.”

“We use a process we developed called forensic-grade genome sequencing,” Mr. Mittelman said, “and this is a robust forensic DNA test method that works broadly on challenging DNA. So we had no trouble in this case. It was far from the worst we have seen, in terms of DNA quality.”

Such advance forensic genetic genealogy techniques were still decades in the future in 1985, when the Ventura County Sheriff’s Office began puzzling over the remains that had been found in a plastic bag in Oxnard. Without leads, the investigation eventually went cold.

In 2016, information about the case was added to the National Missing and Unidentified Persons System as case UP15170.

Investigators eventually developed a clay facial reconstruction of the woman and shared images of it with the public, hoping to generate new leads. Despite this and other “extensive efforts by law enforcement investigators to identify the woman,” Othram said in a statement, “no matches were found.”

In May 2023, the Ventura County Sheriff’s Office cold case unit, in collaboration with the Ventura County Medical Examiner’s Office, submitted forensic evidence to Othram to determine whether advanced DNA testing could help identify the woman.

Othram scientists were able to extract DNA from the evidence provided by the sheriff’s office and used it to “conduct extensive genetic genealogy research.” That, Othram said, produced new leads, including potential relatives, and ultimately led to the identification of Ms. Elliott-Littlehale.

A few biographical details have since surfaced.

A native of Stockton, Calif., she graduated from high school when she was 16, attended the New England Conservatory of Music in Boston before continuing her musical studies in Paris, according to a news article about her death , from appendicitis, in The Stockton Daily Independent. She lived in San Francisco with her husband, James M. Littlehale, and their daughter, who was 7 when her mother died.

A capsule profile in the March 1905 edition of The Wasp, a weekly magazine published in San Francisco, described her as “an accomplished musician, a delightful conversationalist and an observant traveler” who had returned after a period of “travel and residence in Europe” to teach voice lessons.

Mr. Mittelman said that Ms. Elliot-Littlehale traveled weekly from San Francisco to Stockton, Calif., where she was part of something called the Saturday Afternoon Musical Club, he added. The lab shared a color image of her based on a black-and-white image provided by her family that showed Ms. Elliott-Littlehale in a patterned scarf and a bonnet covering her light brown hair.

She was buried after “brief and simple services” at a family mausoleum in a cemetery in Stockton, The Daily Independent reported . Decades later, investigators received a tip that a grave had been robbed and a skull was taken, Othram said.

“This was Elliot-Littlehale’s grave that had been disturbed,” the company said. It was not clear when her grave was desecrated.

It was also not immediately clear what would become of her remains. The Ventura County Sheriff’s Office’s lead detective in the case was not available on Monday.

Ms. Elliot-Littlehale’s case was the 38th one where California officials have publicly identified an individual using Othram’s technology, the company said.

Kirsten Noyes contributed research.

Johnny Diaz is a reporter for The Times covering breaking news from Miami. More about Johnny Diaz

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