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Published: 06 November 2018

The challenges of living with bipolar disorder: a qualitative study of the implications for health care and research

Eva F. Maassen ORCID: orcid.org/0000-0003-0211-0994 1 , 2 ,
Barbara J. Regeer 1 ,
Eline J. Regeer 2 ,
Joske F. G. Bunders 1 &
Ralph W. Kupka 2 , 3

International Journal of Bipolar Disorders volume 6 , Article number: 23 ( 2018 ) Cite this article

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In mental health care, clinical practice is often based on the best available research evidence. However, research findings are difficult to apply to clinical practice, resulting in an implementation gap. To bridge the gap between research and clinical practice, patients’ perspectives should be used in health care and research. This study aimed to understand the challenges people with bipolar disorder (BD) experience and examine what these challenges imply for health care and research needs.

Two qualitative studies were used, one to formulate research needs and another to formulate healthcare needs. In both studies focus group discussions were conducted with patients to explore their challenges in living with BD and associated needs, focusing on the themes diagnosis, treatment and recovery.

Patients’ needs are clustered in ‘disorder-specific’ and ‘generic’ needs. Specific needs concern preventing late or incorrect diagnosis, support in search for individualized treatment and supporting clinical, functional, social and personal recovery. Generic needs concern health professionals, communication and the healthcare system.

Patients with BD address disorder-specific and generic healthcare and research needs. This indicates that disorder-specific treatment guidelines address only in part the needs of patients in everyday clinical practice.

Bipolar disorder (BD) is a major mood disorder characterized by recurrent episodes of depression and (hypo)mania (Goodwin and Jamison 2007 ). According to the Diagnostic and Statistical Manual 5 (DSM-5), the two main subtypes are BD-I (manic episodes, often combined with depression) and BD-II (hypomanic episodes, combined with depression) (APA 2014 ). The estimated lifetime prevalence of BD is 1.3% in the Dutch adult population (de Graaf et al. 2012 ), and BD is associated with high direct (health expenditure) and indirect (e.g. unemployment) costs (Fajutrao et al. 2009 ; Michalak et al. 2012 ), making it an important public health issue. In addition to the economic impact on society, BD has a tremendous impact on patients and their caregivers (Granek et al. 2016 ; Rusner et al. 2009 ). Even between mood episodes, BD is often associated with functional impairment (Van Der Voort et al. 2015 ; Strejilevich et al. 2013 ), such as occupational or psychosocial impairment (Huxley and Baldessarini 2007 ; MacQueen et al. 2001 ; Yasuyama et al. 2017 ). Apart from symptomatic recovery, treatment can help to overcome these impairments and so improve the person’s quality of life (IsHak et al. 2012 ).

Evidence Based Medicine (EBM), introduced in the early 1990s, is a prominent paradigm in modern (mental) health care. It strives to deliver health care based on the best available research evidence, integrated with individual clinical expertise (Sackett et al. 1996 ). EBM was introduced as a new paradigm to ‘de - emphasize intuition’ and ‘ unsystematic clinical experience’ (Guyatt et al. 1992 ) (p. 2420). Despite its popularity in principle (Barratt 2008 ), EBM has also been criticized. One such criticism is the ignorance of patients’ preferences and healthcare needs (Bensing 2000 ). A second criticism relates to the difficulty of adopting evidence-based treatment options in clinical practice (Bensing 2000 ), due to the fact that research outcomes measured in ‘the gold standard’ randomized-controlled trials (RCTs) seldom correspond to the outcomes clinical practice seeks and are not responsive to patients’ needs (Newnham and Page 2010 ). Moreover, EBM provides an overview on population level instead of individual level (Darlenski et al. 2010 ). Thus, adopting research evidence in clinical practice entails difficulties, resulting in an implementation gap.

To bridge the gap between research and clinical practice, it is argued that patients’ perspectives should be used in both health care and research. Patients have experiential knowledge about their illness, living with it in their personal context and their care needs (Tait 2005 ). This is valuable for both clinical practice and research as their knowledge complements that of health professionals and researchers (Tait 2005 ; Broerse et al. 2010 ; Caron-Flinterman et al. 2005 ). This source of knowledge can be used in the process of translating evidence into clinical practice (Schrevel 2015 ). Moreover, patient participation can enhance the clinical relevance of and support for research and the outcomes in practice (Abma and Broerse 2010 ). Hence, it is argued that these perspectives should be explicated and integrated into clinical guidelines, clinical practice, and research (Misak 2010 ; Rycroft-Malone et al. 2004 ).

Given the advantages of including patients’ perspectives, patients are increasingly involved in healthcare services (Bagchus et al. 2014 ; Larsson et al. 2007 ), healthcare quality (e.g. guideline development) (Pittens et al. 2013 ) and health-related research (e.g. agenda setting, research design) (Broerse et al. 2010 ; Boote et al. 2010 ; Elberse et al. 2012 ; Teunissen et al. 2011 ). However, patients’ perspectives on health care and on research are often studied separately. We argue that to be able to provide care focused on the patients and their needs, care and research must closely interact.

We hypothesize that the challenges BD patients experience and the associated care and research needs are interwoven, and that combining them would provide a more comprehensive understanding. We hypothesize that this more comprehensive understanding would help to close the gap between clinical practice and research. For this reason, this study aims to understand the challenges people with BD experience and examine what these challenges imply for healthcare and research needs.

To understand the challenges and needs of people with BD, we undertook two qualitative studies. The first aimed to formulate a research agenda for BD from a patient’s perspective, by gaining insights into their challenges and research needs. A second study yielded an understanding of the care needs from a patient’s perspective. In this article, the results of these two studies are combined in order to investigate the relationship between research needs and care needs. Challenges are defined as ‘difficulties patients face, due to having BD’. Care needs are defined as that what patients ‘desire to receive from healthcare services to improve overall health’ (Asadi-Lari et al. 2004 ) (p. 2). Research needs are defined as that what patients ‘desire to receive from research to improve overall health’.

Study on research needs

In this study, mixed-methods were used to formulate research needs from a patient’s perspective. First six focus group discussions (FGDs) with 35 patients were conducted to formulate challenges in living with BD and hopes for the future, and to formulate research needs arising from these difficulties and aspirations. These research needs were validated in a larger sample (n = 219) by means of a questionnaire. We have reported this study in detail elsewhere (Maassen et al. 2018 ).

Study on care needs

This study was part of a nationwide Dutch project to generate a practical guideline for BD: a translation of the existing clinical guideline to clinical practice, resulting in a standard of care that patients with BD could expect. The practical guideline (Netwerk Kwaliteitsontwikkeling GGZ 2017 ) was written by a taskforce comprising health professionals, patients. In addition to the involvement of three BD patients in the taskforce, a systematic qualitative study was conducted to gain insight into the needs of a broader group of patients.

Participants and data collection

To formulate the care needs of people with BD, seven FGDs were conducted, with a total of 56 participants, including patients (n = 49) and caregivers (n = 9); some participants were both patient and caregiver. The inclusion criteria for patients were having been diagnosed with BD, aged 18 years or older and euthymic at time of the FGDs. Inclusion criteria for caregivers were caring for someone with BD and aged 18 years or older. To recruit participants, a maximum variation sampling strategy was used to collect a broad range of care needs (Kuper et al. 2008 ). First, all outpatient clinics specialized in BD affiliated with the Dutch Foundation for Bipolar Disorder (Dutch: Kenniscentrum Bipolaire Stoornissen) were contacted by means of an announcement at regular meetings and by email if they were interested to participate. From these outpatient clinics, patients were recruited by means of flyers and posters. Second, patients were recruited at a quarterly meeting of the Dutch patient and caregiver association for bipolar disorder. The FGDs were conducted between March and May 2016.

The FGDs were designed to address challenges experienced in BD health care and areas of improvement for health care for people with BD. The FGDs were structured by means of a guide and each session was facilitated by two moderators. The leading moderator was either BJR or EFM, having both extensive experience with FGD’s from previous studies. The first FGD explored a broad range of needs. The subsequent six FGDs aimed to gain a deeper understanding of these care needs, and were structured according to the outline of the practical guideline (Netwerk Kwaliteitsontwikkeling GGZ 2017 ). Three chapters were of particular interest: diagnosis, treatment and recovery. These themes were discussed in the FGDs, two in each session, all themes three times in total. Moreover, questions on specific aspects of care formulated by the members of the workgroup were posed. The sessions took 90–120 min. The FGDs were audiotaped and transcribed verbatim. A summary of the FGDs was sent to the participants for a member check.

Data analysis

To analyze the data on challenges and needs, a framework for thematic analysis to identify, analyze and report patterns (themes) in qualitative data sets by Braun and Clarke ( 2006 ) was used. First, we familiarized ourselves with the data by carefully reading the transcripts. Second, open coding was used to derive initial codes from the data. These codes were provided to quotes that reflected a certain challenge or care need. Third, we searched for patterns within the codes reflecting challenges and within those reflecting needs. For both challenges and needs, similar or overlapping codes were clustered into themes. Subsequently, all needs were categorized as ‘specific’ or ‘generic’. The former are specific to BD and the latter are relevant for a broad range of psychiatric illnesses. Finally, a causal analysis provided a clear understanding of how challenges related to each other and how they related to the described needs.

To analyze the data on needs regarding recovery, four domains were distinguished, namely clinical, functional, social and personal recovery (Lloyd et al. 2008 ; van der Stel 2015 ). Clinical recovery refers to symptomatic remission; functional recovery concerns recovery of functioning that is impaired due to the disorder, particularly in the domain of executive functions; social recovery concerns the improvement of the patient’s position in society; personal recovery concerns the ability of the patient to give meaning to what had happened and to get a grip on their own life. The analyses were discussed between BR and EM. The qualitative software program MAX QDA 11.1.2 was used (MaxQDA).

Ethical considerations

According to the Medical Ethical Committee of VU University Medical Center, the Medical Research Involving Human Subjects Act does not apply to the current study. All participants gave written or verbal informed consent regarding the aim of the study and for audiotaping and its use for analysis and scientific publications. Participation was voluntary and participants could withdraw from the study at any time. Anonymity was ensured.

This section is in three parts. The first presents the participants’ characteristics. The second presents the challenges BD patients face, derived from both studies, and the disorder-specific care and research needs associated with these challenges. The third part describes the generic care needs that patients formulated.

Characteristics of the participants

In the study on care needs, 56 patients and caregivers participated. The mean age of the participants was 52 years (24–75), of whom 67.8% were women. The groups varied from four to sixteen participants, and all groups included men and women. Of all participants 87.5% was diagnosed with BD, of whom 48.9% was diagnosed with BD I. 3.5% was both caregivers and diagnosed with BD. Of 4 patients the age was missing, and from 6 patients the bipolar subtype.

Despite the fact that participants acknowledge the inevitable diagnostic difficulties of a complex disorder like BD, in both studies they describe a range of challenges in different phases of the diagnostic process (Fig. 1 ). Patients explained that the general practitioner (GP) and society in general did not recognize early-warning signs and mood swings were not well interpreted, resulting in late or incorrect diagnosis. Patients formulated a need for more research on what early-warning signs could be and on how to improve GPs’ knowledge about BD. Formulated care needs were associated with GPs using this knowledge to recognize early-warning signs in individual patients. One participant explained that certain symptoms must be noticed and placed in the right context:

Challenges with diagnosis (squares) including relating research needs (white circles) and care needs (grey circles). (1): mentioned in study on research needs; (2): mentioned in study on care needs. Dotted lines: division of challenges into sub challenges. Arrows: causal relation between challenges

I call it, ‘testing overflow of ideas’. [….] When it happens for the first time you yourself do not recognize it. Someone else close to you or the health professional, who is often not involved yet, must signal it. (FG6)

Moreover, these challenges are associated with the need to pay attention to family history and to use a multidisciplinary approach to diagnosis to benefit from multiple perspectives. The untimely recognition of early symptoms also results in another challenge: inadequate referral to the right specialized health professional. After referral, people often face a waiting list, again causing delay in the diagnostic process. These challenges result in the need for research on optimal referral systems and the care need for timely referral. One participant described her process after the GP decided to refer her:

But, yes, at that moment the communication wasn’t good at all. Because the general practitioner said: ‘she urgently has to be seen by someone’. Subsequently, three weeks went by, until I finally arrived at depression [department]. And at that department they said: ‘well, you are in the wrong place, you need to go to bipolar [department ]’. (FG1)

The challenge of being misdiagnosed is associated with the need to be able to ask for a second opinion and to have a timely and thorough diagnosis. On the one hand, it is important for patients that health professionals quickly understand what is going on, on the other hand that health professionals take the time to thoroughly investigate the symptoms by making several appointments.

From both studies, two main challenges related to the treatment of BD were derived (Fig. 2 ). The first is finding appropriate and satisfactory treatment. Participants explained that it is difficult to find the right medication and dosage that is effective and has acceptable side-effects. One participant illustrates:

Challenges with treatment (squares) including relating research needs (white circles) and care needs (grey circles). (1): mentioned in study on research needs; (2): mentioned in study on care needs. Dotted lines: division of challenges into sub challenges. Arrows: causal relation between challenges

I think, at one point, we have to choose, either overweight or depressed. (FG1)

Some participants said that they struggle with having to use medication indefinitely, including the associated medical checks. The difficult search for the right pharmacological treatment results in the need for research on long-term side-effects, on the mechanism of action of medicine and on the development of better targeted medication with fewer adverse side-effects. In care, patients would appreciate all the known information on the side-effects and intended effects. One participant explained the importance of being properly informed about medication:

I don’t read anything [about medication], because then I wouldn’t dare taking it. But I do think, when you explain it well, the advantages, the disadvantages, the treatment, the idea behind it, that would help a lot in compliance. (FG1)

A second aspect is the challenge of finding non-pharmacological therapies that fit patients’ needs. They said they and the health professionals often do not know which non-pharmacological therapies are available and effective:

But we found the carefarm ourselves Footnote 1 [….]. You have to search for yourself completely. Yes, I actually hoped that that would be presented to you, like: ‘this would be something for you’. (FG3)

Participants mentioned a variety of non-pharmacological therapies they found useful, namely cognitive behavior therapy (CBT), EMDR, running therapy, social-rhythm training, light therapy, mindfulness, psychotherapy, psychoeducation, and training in living with mood swings. They formulated the care need to receive an overview of all available treatment options in order to find a treatment best suited to their needs. They would appreciate research on the effectiveness of non-pharmacological treatments.

A third aspect within this challenge is finding the right balance between non-pharmacological and pharmacological treatment. Participants differed in their opinion about the need for medication. Whereas some participants stated that they need medication to function, others pointed out that they found non-pharmacological treatments effective, resulting in less or no medication use. They explained that the preferred balance can also change over time, depending on their mood. However, they experience a dominant focus on pharmacological treatment by the health professionals. To address this challenge, patients need support in searching for an appropriate balance.

Next to the challenge of finding appropriate and satisfactory treatment, a second treatment-related challenge is hospitalization. Participants often had a traumatic experience, due to seclusion, the authoritarian attitudes of clinical staff, and not involving their family. Patients therefore found it important to try preventing being hospitalized, for example by means of home treatment, which some participants experienced positively. Despite the challenges relating to hospitalization, participants did acknowledge that in some cases it cannot be avoided, in which case they urged for close family involvement, open communication and being treated by their own psychiatrist. Still, in the study on research needs, hospitalization did not emerge as an important research theme.

In both studies, participants described challenges in all four domains of recovery: clinical, functional, social and personal (Fig. 3 ). In relation to clinical recovery, participants struggled with the symptoms of mood episodes, the psychosis and the fear of a future episode. In contrast, some participants mentioned that they sometimes miss the hypomanic state they had experienced previously due to effective medical treatment. In the domain of functional recovery, participants contended with having to function below their educational level due to residual symptoms, such as cognitive problems, due to the importance of preventing stress in order to reduce the risk of a new episode, and because of low energy levels. This leads to the care need that health professionals should pay attention to the level of functioning of their patients.

Challenges with recovery (squares) including relating research needs (white circles) and care needs (grey circles). (1): mentioned in study on research needs; (2): mentioned in study on care needs. Dotted lines: division of challenges into sub challenges. Arrows: causal relation between challenges

In the domain of social recovery, participants described challenges with maintaining friendships, due to stigma, being unpredictable and with deciding when to disclose the disorder. The latter resulted in the care need for tips on disclosure. Moreover, patients experienced challenges with reintegration to work, due to colleagues’ lack of understanding, problems with functioning during an episode, the complicating policy of the (Dutch) Employee Insurance Agency Footnote 2 in relation to the fluctuating course of BD and the negative impact of stress. These challenges are associated with the care need that health professionals should pay attention to work and the need for research on how to improve the Social Security Agency’s policy.

For their personal recovery, participants struggled with acceptance of the disorder, due to shame, stigma, having to live by structured rules and disciplines, and the chronic nature of BD. This results in care needs for grief counselling and attention to acceptance and the need for research on the impact of being diagnosed with BD. Limited understanding within society also causes problems with acceptance, corresponding with the care need for education for caregivers and for research on how to increase social acceptance. Another challenge in personal recovery was discovering what recovery means and what constitute meaningful daily activities. Patients appreciated the support of health professionals in this area. One participant described the difficult search for the meaning of recovery:

I have been looking to recover towards the situation [before diagnosis] for a long time; that I could do what I always did and what I liked. But then I was confronted with the fact that I shouldn’t expect that to happen, or only with a lot of effort. (…) Then you start thinking, now what? A compromise. I don’t want to call that recovery, but it is a recovered, partly accepted, situation. But it is not recovery as I expected it to be. (FG5)

In general, participants considered frequent contact with a nurse or psychiatrist supportive, to help them monitor their mood and help them find (efficient) self-management strategies. Most participants appreciated the involvement of caregivers in the treatment and contact with peers.

Generic care needs

We have described BD-specific needs, but patients mentioned also mentioned several generic care needs. The latter are clustered into three categories. The first concerns the health professionals . Participants stressed the importance of a good health professional, who carefully listens, takes time, and makes them feel understood, resulting in a sense of connection. Furthermore, a good health professional treats beyond the guideline, and focuses on the needs of the individual patient. When there is no sense of connection, it should be possible to change to another health professional. The second category concerns communication between the patient and the health professional . Health professionals should communicate in an open, honest and clear way both in the early diagnostic phase and during treatment. Open communication facilitates individualized care, in which the patient is involved in decision making. In addition, participants wanted to be treated as a person, not as a patient, and according to a strength-based approach. The third category concerns needs at the level of the healthcare system . Participants struggled with the availability of the health professionals and preferred access to good care 24/7 and being able to contact their health professional quickly when necessary. Currently, according to the participants, the care system is not geared to the mood swings of BD, because patients often faced waiting lists before they could see a health professional.

Is adequate treatment also having a number from a mental health institution you can always call when you are in need, that you can go there? And not that you can go in three weeks, but on a really short notice. So at least a phone call. (FG3)

Participants were often frustrated by the limited collaboration between health professionals, within their own team, between departments of the organization, and between different organizations, including complementary health professionals. They would appreciate being able to merge their conventional and complementary treatment, with greater collaboration among the different health professionals. Furthermore, they would like continuity of health professionals as this improves both the diagnostic phase and treatment, and because that health professional gets to know the patient.

We hypothesized that research and care needs of patients are closely intertwined and that understanding these, by explicating patients’ perspectives, could contribute to closing the gap between research and care. Therefore, this study aimed to understand the challenges patients with BD face and examine what these imply for both healthcare and research. In the study on needs for research and in the study on care needs, patients formulated challenges relating to receiving the correct diagnosis, finding the right treatment, including the proper balance between non-pharmacological and pharmacological treatment, and to their individual search for clinical, functional, social and personal recovery. The formulated needs in both studies clearly reflected these challenges, leading to closely corresponding needs. Another important finding of our study is that patients not only formulate disorder-specific needs, but also many generic needs.

The needs found in our study are in line with the current literature on the needs of patients with BD, namely for more non-pharmacological treatment (Malmström et al. 2016 ; Nestsiarovich et al. 2017 ), timely recognition of early-warning signs and self-management strategies to prevent a new episode (Goossens et al. 2014 ), better information on treatment and treatment alternatives (Malmström et al. 2016 ; Neogi et al. 2016 ) and coping with grief (Goossens et al. 2014 ). Moreover, the need for frequent contact with health professionals, being listened to, receiving enough time, shared decision-making on pharmacological treatment, involving caregivers (Malmström et al. 2016 ; Fisher et al. 2017 ; Skelly et al. 2013 ), and the urge for better access to health care and continuity of health professionals (Nestsiarovich et al. 2017 ; Skelly et al. 2013 ) are confirmed by the literature. Our study added to this set of literature by providing insights in patients’ needs in the diagnostic process and illustrating the interrelation between research needs and care needs from a patient’s perspective.

The generic healthcare needs patients addressed in this study are clustered into three categories: the health professional , communication between the patient and the health professional and the health system. These categories all fit in a model of patient-centered care (PCC) by Maassen et al. ( 2016 ) In their review, patients’ perspectives on good care are compared with academic perspectives of PCC and a model of PCC is created comprising four dimensions: patient, health professional, patient – professional interaction and healthcare organization. All the generic needs formulated in this study fit into these four dimensions. The need to be treated as a person with strengths fits the dimension ‘patient’, and the need for a good health professional who carefully listens, takes time and makes them feel understood, resulting in a good connection with the professional, fits the dimension ‘health professional’ of this model. Furthermore, patients in this study stressed the importance of open communication in order to provide individualized care, which fits the dimension of ‘patient–professional interaction’. The urge for better access to health care, geared to patients’ mood swings and the need for better collaboration between health professionals and continuity of health professionals fits the dimension of ‘health care organization’ of the model. This study confirms the findings from the review and contributes to the literature stressing the importance of a patient-centered care approach (Mills et al. 2014 ; Scholl et al. 2014 ).

In the prevailing healthcare paradigm, EBM, the best available evidence should guide treatment of patients (Sackett et al. 1996 ; Darlenski et al. 2010 ). This evidence is translated into clinical and practical guidelines, which thus facilitate EBM and could be used as a decision-making tool in clinical practice (Skelly et al. 2013 ). For many psychiatric disorders, treatment is based on such disorder - specific clinical and practical guidelines. However, this disease-focused healthcare system has contributed to its fragmented nature Stange ( 2009 ) argues that this fragmented care system has expanded without the corresponding ability to integrate and personalize accordingly. We argue that acknowledging that disorder - specific clinical and practical guidelines address only parts of the care needs is of major importance, since otherwise important aspects of the patients’ needs will be ignored. Because there is an increasing acknowledgement that health care should be responsive to the needs of patients and should change from being disease-focused towards being patient-focused (Mead and Bower 2000 ; Sidani and Fox 2014 ), currently in the Netherlands generic practical guidelines are written on specific care themes (e.g. co-morbidity, side-effects, daily activity and participation). These generic practical guidelines address some of the generic needs formulated by the patients in our study. We argue that in addition to disorder-specific guidelines, these generic practical guidelines should increasingly be integrated into clinical practice, while health professionals should continuously be sensitive to other emerging needs. We believe that an integration of a disorder-centered and a patient-centered focus is essential to address all needs a patient.

Strengths, limitations and future research

This study has several strengths. First, it contributes to the literature on the challenges and needs of patients with BD. Second, the study is conducted from a patient’s perspective. Moreover, addressing this aim by conducting two separate studies enabled us to triangulate the data.

This study also has several limitations. First, this study reflects the challenges, care needs and research needs of Dutch patient with BD and caregivers. Despite the fact that a maximum variation sampling strategy was used to derive a broad range of challenges and needs throughout the Netherlands, the Dutch setting of the study may limit the transferability to other countries. To understand the overlap and differences between countries, similar research should be conducted in other contexts. Second, given the design of the study, we could not differentiate between patients and caregivers since they participated together in the FGDs. More patients than caregivers participated in the study. For a more in-depth understanding of the challenges and needs faced by caregivers, in future research separate FGDs should be conducted. Third, due to the fixed outline of the practical guideline used to conduct the FGDs, only the healthcare needs for diagnosis, treatment and recovery of BD are studied. Despite the fact that these themes might cover a broad range of health care, it could have resulted in overlooking certain needs in related areas of well-being. Therefore, future research should focus on needs outside of these themes in order to provide a complete set of healthcare needs.

Patients and their caregivers face many challenges in living with BD. Our study contributes to the literature on care and research needs from a patient perspective. Needs specific for BD are preventing late or incorrect diagnosis, support in search for individualized treatment, and supporting clinical, functional, social and personal recovery. Generic healthcare needs concern health professionals, communication and the healthcare system. This explication of both disorder-specific and generic needs indicates that clinical practice guidelines should address and integrate both in order to be responsive to the needs of patients and their caregivers.

Care farm: farms that combine agriculture and services for people with disabilities (Iancu 2013 ). These farms are used as interventions in mental care throughout Europe and the USA to facilitate recovery (Iancu et al. 2014 ).

A government agency involved in the implementation of employee insurance and providing labor market and data services.

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Maassen, E.F., Regeer, B.J., Regeer, E.J. et al. The challenges of living with bipolar disorder: a qualitative study of the implications for health care and research. Int J Bipolar Disord 6 , 23 (2018). https://doi.org/10.1186/s40345-018-0131-y

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Bipolar disorder.

Ankit Jain ; Paroma Mitra .

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Bipolar disorder, also known as bipolar affective disorder, is one of the top 10 leading causes of disability worldwide. Bipolar disorder is characterized by chronically occurring episodes of mania or hypomania alternating with depression and is often misdiagnosed initially. Treatment involves pharmacotherapy and psychosocial interventions, but mood relapse and incomplete response occur, particularly with depression. Continual reevaluation and treatment modification are commonly required during the long-term care of patients with bipolar disorder. Management of comorbid psychiatric and chronic medical conditions may also be necessary. This activity reviews the etiology, classification, evaluation, management, and prognosis of bipolar affective disorder, and it also highlights the role of the interprofessional team in managing and improving care for patients with this condition.

Recognize patterns of symptoms suggestive of bipolar disorder, its various subtypes, and related disorders.
Implement evidence-based management of bipolar disorder based on current published guidelines.
Select individualized pharmacotherapy plans and adjunct therapies for bipolar disorder and comorbidities.
Describe the necessity of an interprofessional holistic team approach that integrates psychiatric and medical healthcare in caring for patients with bipolar disorder to help achieve the best possible outcomes.
Introduction

Bipolar disorder (BD) is characterized by chronically occurring episodes of mania or hypomania alternating with depression and is often misdiagnosed initially.

Bipolar and related disorders include bipolar I disorder (BD-I), bipolar II disorder (BD-II), cyclothymic disorder, other specified bipolar and related disorders, and bipolar or related disorders, unspecified. The diagnostic label of "bipolar affective disorders" in the International Classification of Diseases 10th Revision (ICD-10) was changed to "bipolar disorders" in the ICD-11. The section on bipolar disorders in the ICD-11 is labeled "bipolar and related disorders," which is consistent with the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). [1]

A World Health Organization study showed "remarkably similar" international prevalence rates, severity, impact, and comorbidities of bipolar spectrum disorder, defined as BD-I, BD-II, and subthreshold bipolar. The aggregate lifetime prevalence of the bipolar spectrum was 2.4%. [2]

BD is often difficult to recognize because symptoms overlap with other psychiatric disorders, psychiatric and somatic comorbidity is common, and patients may lack insight into their conditions, particularly hypomania. Treatment involves pharmacotherapy and psychosocial interventions, but mood relapse and incomplete response occur, particularly with depression. Continual reevaluation and treatment modification are commonly required during the long-term care of these patients. Management of comorbid psychiatric and chronic medical conditions may also be necessary. This activity provides an overview of the etiology, classification, evaluation, and management of bipolar affective disorder.

Currently, the etiology of BD is unknown but appears to be due to an interaction of genetic, epigenetic, neurochemical, and environmental factors. Heritability is well established. [3] [4] [5] Numerous genetic loci have been implicated as increasing the risk of BD; the first was noted in 1987 with "DNA markers" on the short arm of chromosome 11. Since then, an association has been made between at least 30 genes and an increased risk of the condition. [6]

Although it is difficult to establish causation between life events and the development of BD, childhood maltreatment, particularly emotional abuse or neglect, has been linked to the later development of the condition. Other stressful life events associated with developing BD include childbirth, divorce, unemployment, disability, and early parental loss. [7] In adulthood, more than 60% of patients with BD report at least one "stressful life event" before a manic or depressive episode in the preceding 6 months. [6]

The etiology of BD is thought to involve imbalances in systems associated with monoaminergic neurotransmitters, particularly dopamine and serotonin, and intracellular signaling systems that regulate mood. However, no singular dysfunction of these neurotransmitter systems has been identified. [8]

In a recent neuroimaging review article, the ENIGMA Bipolar Disorder Working Group stated, "Overall, these studies point to a diffuse pattern of brain alterations including smaller subcortical volumes, lower cortical thickness and altered white matter integrity in groups of individuals with bipolar disorder compared to healthy controls." [9] Neuroimaging studies have also shown evidence of changes in functional connectivity. [10] [11]

Epidemiology

In the World Mental Health Survey Initiative, the use of mental health services for the bipolar spectrum (BD-I, BD-II, and subthreshold BD) concluded, “Despite cross-site variation in the prevalence rates of bipolar spectrum disorder, the severity, impact, and patterns of comorbidity were remarkably similar internationally.” The aggregate lifetime prevalence of BD-I was 0.6%, BD-II 0.4%, subthreshold BD 1.4%, and bipolar spectrum 2.4%. [2]

There are two peaks in the age of onset: 15-24 years and 45-54 years, with more than 70% of individuals manifesting clinical characteristics of the condition before 25 years of age. [12] [13] Bipolar disorder shows a relatively equal distribution across sex, ethnicity, and urban compared to rural areas. [7] [14]

Cyclothymia is associated with a lifetime prevalence of approximately 0.4-1% and a male-to-female ratio of 1:1. [15]

Pathophysiology

As with the etiology, the pathophysiology of BD is unknown and is thought to involve interactions between multiple genetic, neurochemical, and environmental factors. A recent neurobiology review article discusses in detail the “genetic components, signaling pathways, biochemical changes, and neuroimaging findings” in BD. [10]

Evidence supports a strong genetic component and an epigenetic contribution. Human studies have shown changes in brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in patients with BD, indicating neurotrophic signaling is a molecular mechanism associated with decreased neuroplasticity. Other proposed mechanisms include mitochondrial dysfunction, oxidative stress, immune-inflammatory imbalance, and compromised hypothalamic-pituitary-adrenal axis. Additionally, neuroimaging studies have shown “evidence of change in regional activity, functional connectivity, neuronal activity, and bioenergetics associated with BD,” and anatomic studies have revealed dendritic spine loss in the dorsolateral prefrontal cortex in the post-mortem brain tissue of patients with BD. [10] [16]

As mentioned, imbalances in systems associated with monoaminergic neurotransmitters, particularly dopamine and serotonin, and intracellular signaling systems that regulate mood are thought to be involved. However, no singular dysfunction of these neurotransmitter systems has been identified. [8]

History and Physical

Because bipolar disorder is a clinical diagnosis, making the correct diagnosis requires a comprehensive clinical assessment, including the directed patient interview, preferably supplemented by interviews of their relatives and the longitudinal course of their condition. Currently, there is no biomarker or neuroimaging study to aid in making the diagnosis.

Most patients with bipolar disorder are not correctly diagnosed until approximately 6 to 10 years after first contact with a healthcare provider, despite the presence of clinical characteristics of the condition. [17] Notably, misdiagnosing BD after first contact differs from not recognizing the transition from major depressive disorder (MDD), the most common index presentation, to BD. Estimates of patients transitioning to BD within three years of an MDD diagnosis range from 20-30%; therefore, clinicians must maintain an awareness of the potential for this transition when caring for patients with MDD who initially screened negative for BD. [18] Also, subthreshold hypomanic symptoms can occur in as many as 40% of patients with MDD. [19]

Although not highly sensitive and specific, self-report screening tools for BD may aid clinicians in making an accurate diagnosis. The most studied screening tools are the Mood Disorders Questionnaire (sensitivity 80%, specificity 70%) and the Hypomania Checklist 32 (sensitivity 82%, specificity 57%). [20] Positive results should motivate the clinician to conduct a thorough clinical assessment for bipolar disorder.

A significant diagnostic challenge is distinguishing between unipolar and bipolar depression because episodes of unipolar major depression and bipolar depression have the same general diagnostic criteria. Clinicians must inquire about past manic, hypomanic, and depressive episodes in patients presenting with symptoms of a depressive episode. Inquiry into past hypomanic or manic episodes is particularly important for patients with early onset of their first depressive episode (ie, in patients younger than 25 years), a high number of lifetime depressive episodes (5 or more episodes), and a family history of bipolar disorder. These findings in the patient’s history have been shown to increase the likelihood of a bipolar rather than a unipolar diagnosis. [21]

Other factors increasing the likelihood of a diagnostic change from MDD to BD include the presence of psychosis, unresponsiveness to antidepressants, the induction of manic or hypomanic symptoms by antidepressant drug treatment, and polymorbidity, defined as 3 or more comorbid conditions. [18] [22]

General DSM-5 Diagnostic Criteria for Bipolar and Related Disorders (American Psychiatric Association. Diagnostic and StatisticalManual of Mental Disorders 5th edition (DSM-5). Arlington, VA: American Psychiatric Publishing; 2013)

BD-I : Criteria met for at least one manic episode, which might have been preceded or followed by a hypomanic episode or major depressive episode (hypomanic or major depressive episodes are not required for the diagnosis).

BD-II : Criteria met for at least one current or past hypomanic episode and a major depressive episode; no manic episodes.

Cyclothymic disorder : Hypomanic symptoms that do not meet the criteria for hypomanic episodes and depressive symptoms that do not meet the criteria for major depressive episodes in numerousperiods (at least half the time) for at least 2 years (1 year in those aged ≤18 years); criteria for major depressive, manic, or hypomanic episodes have never been met.

Specified bipolar and related disorders : Bipolar-like phenomena that do not meet the criteria for BD-I, BD-II, or cyclothymic disorder due to insufficient duration or severity, ie, 1) short-duration hypomanic episodes and major depressive disorder, 2) hypomanic episodes with insufficient symptoms and major depressive episode, 3) hypomanic episode without a prior major depressive episode, and 4) short-duration cyclothymia.

Unspecified bipolar and related disorders : Characteristic symptoms of bipolar and related disorders that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning but do not meet the full criteria for any category previously mentioned.

The symptoms and episodes used to diagnose these disorders must not be related to the physiological effects of a substance or general medical condition.

BD-I and BD-II can be further specified as rapid cycling or seasonal patterns and whether the episodes have psychotic features, catatonia, anxious distress, melancholic features, or peripartum onset. Rapid cycling refers to 4 or more distinct mood episodes during a 12-month period.

Mood-congruent delusions may be present in either a depressive or manic episode, including delusions of guilt or grandiose delusions of power and wealth. Psychotic features, by definition, are absent in hypomanic episodes.

To better account for "mixed features," the current diagnostic criteria implements specifiers. Manic or hypomanic episodes with mixed features meet the full criteria for mania or hypomania and have at least 3 of the following signs or symptoms: depressed mood, anhedonia, psychomotor retardation, fatigue, excessive guilt, or recurrent thoughts of death. Major depressive episodes with mixed features meet the full criteria for a major depressive episode and have at least 3 of the following signs or symptoms: expansive mood, grandiosity, increased talkativeness, flight of ideas, increased goal-directed activity, indulgence in activities with a high potential for "painful consequences," and decreased need for sleep. The mixed features must be present during "most days."

DSM-5 Diagnostic Criteria for Bipolar I Disorder

For a diagnosis of BD-I, it is necessary to meet the following criteria for a manic episode. The manic episode may have been preceded by and may be followed by hypomanic or major depressive episodes (hypomanic or major depressive episodes are not required for the diagnosis).

A manic episode is defined as a distinct period of persistently elevated or irritable mood with increased activity or energy lasting for at least 7 consecutive days or requiring hospitalization. The presence of 3 or more of the following is required to qualify as a manic episode. If the mood is irritable, at least 4 of the following must be present:

Inflated self-esteem or grandiosity
Decreased need for sleep
A compulsion to keep talking or being more talkative than usual
Flight of ideas or racing thoughts
High distractibility
Increased goal-directed activity (socially, at work or school, or sexually) or psychomotor agitation (non-goal-directed activity)
Excessive involvement in activities that have a high potential for painful consequences, such as engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments

The episode is not attributable to the physiological effects of a substance or general medical condition.

The symptoms of a manic episode are markedly more severe than those of a hypomanic episode and result in impaired social or occupational functioning or require hospitalization.

DSM-5 Diagnostic Criteria for Bipolar II Disorder

For a diagnosis of BD-II, it is necessary to have met the criteria for at least one current or past hypomanic episode and a major depressive episode without a manic episode (see below for major depressive episode criteria).

A hypomanic episode is defined as a distinct period of persistently elevated or irritable mood with increased activity or energy lasting for at least 4 consecutive days. The presence of 3 or more of the following is required to qualify as a hypomanic episode. If the mood is irritable, at least 4 of the following must be present:

The episode is an unequivocal change in functioning, uncharacteristic of the person and observable by others. Also, the episode is not severe enough to cause marked impairment, is not due to the physiological effects of a substance or general medical condition, and there is no psychosis (if present, this is mania by definition).

DSM-5 Diagnostic Criteria for a Major Depressive Episode

The presence of 5 or more of the following symptoms daily or nearly every day for a consecutive 2-week period that is a change from baseline or previous functioning:

Subjective report of depressed mood most of the day (or depressed mood observed by others)
Anhedonia most of the day
Significant weight loss when not dieting or weight gain or decrease or increase in appetite
Insomnia or hypersomnia
Psychomotor agitation or retardation
Fatigue or loss of energy
Feelings of worthlessness or excessive or inappropriate guilt
Decreased concentration or indecisiveness
Recurrent thoughts of death, recurrent suicidal ideation without a specific plan

To meet the criteria, at least one of the symptoms must be depressed mood or anhedonia, the symptoms must not be attributable to a substance or general medical condition, and it causes functional impairment (eg, social or occupational).

Possible Secondary Cause of Bipolar Disorder

The following characteristics may heighten the clinical suspicion for a possible secondary cause in patients with signs and symptoms associated with bipolar disorder: older than 50 at the first onset of symptoms, abnormal vital signs or neurological examination, a recent change in health status or medications temporally associated with symptom onset, unusual response or unresponsiveness to appropriate treatments, and no personal or family history of a psychiatric disorder.

Recommended initial evaluation for a possible secondary cause includes a urine drug screen, complete blood count with blood smear, comprehensive metabolic panel, thyroid function tests, and vitamin B and folate levels.

Treatment / Management

Although numerous clinical practice guidelines exist for the treatment and management of bipolar disorder, there is not enough consistency to generate a ‘meta-consensus’ model. [23] Authors of a recent systematic review concluded, “The absence of a uniform language and recommendations in current guidelines may be an additional complicating factor in the implementation of evidence-based treatments in BD.” [24] The following is an abbreviated synthesis of guidelines published by the National Institute for Health and Care Excellence (NICE), British Association for Psychopharmacology, International College of Neuro-Psychopharmacology (CINP), Canadian Network for Mood and Anxiety Treatments (CANMAT), International Society for Bipolar Disorders (ISBD), and Indian Psychiatric Society (IPS). [25] [26] [27] [28] [29]

Manic Episode

Mania is considered a medical emergency and often requires psychiatric hospitalization. Initial treatment is aimed at stabilization of the potentially or acutely agitated patient to help de-escalate distress, mitigate potentially dangerous behavior, and facilitate the patient assessment and evaluation. When possible, a calming environment with minimal stimuli should be provided. Adjunctive benzodiazepines may be used concomitantly with mood stabilizers and antipsychotic drugs to reduce agitation and promote sleep.

The patient’s current medications must be considered. For example, a second drug is recommended if the patient presents while the condition is already managed with lithium monotherapy. Also, antidepressants are usually tapered and discontinued in a manic phase. First-line monotherapy includes a mood stabilizer, such as lithium or valproate, or an antipsychotic, such as aripiprazole, asenapine, cariprazine, quetiapine, or risperidone.

Add another medication if symptoms are inadequately controlled, or the mania is very severe. Combination treatments include lithium or valproate with either aripiprazole, asenapine, olanzapine, quetiapine, or risperidone. Electroconvulsive therapy (ECT) may be considered as monotherapy or as part of combination therapy in patients whose mania is particularly severe or treatment-resistant and in women with severe mania who are pregnant.

Valproate should not be used for women of childbearing potential due to the unacceptable risk to the fetus of teratogenesis and impaired intellectual development.

Hypomanic Episodes

By definition, hypomanic episodes are not severe enough to cause marked impairment, and there is no psychosis; therefore, these episodes can be managed in an ambulatory setting. Pharmacotherapy is similar to that for mania, but higher doses may be required for the latter.

Acute Bipolar Depression

Suicidal and self-harm risk has priority in managing patients with bipolar disorder who present with an acute depressive episode because most suicide deaths in patients with BD occur during this phase. Patients may or may not require hospitalization.

For patients not already taking long-term medication for BD, first-line monotherapy includes quetiapine, olanzapine, or lurasidone (has not been studied in acute bipolar mania). Combination treatment with olanzapine-fluoxetine, lithium plus lamotrigine, and lurasidone plus lithium or valproate may also be considered.

Consider cognitive behavioral therapy (CBT) as an add-on to pharmacotherapy. However, never consider CBT as monotherapy because there is minimal evidence to support psychological treatments without pharmacotherapy in treating acute bipolar depression.

Also, consider adding ECT for refractory bipolar depression or as a first-line treatment in the presence of psychotic features and a high risk of suicide.

For patients presenting with a depressive episode while taking long-term medication (breakthrough episode), make sure their current treatments are likely to protect them from a manic relapse (eg, mood stabilizer or antipsychotic). When applicable, check the medication dose, patient adherence, drug-drug interactions, and serum concentrations. Also, inquire about current stressors, alcohol or substance use, and psychosocial intervention adherence.

Generally, treatment options for BD-II depression are similar to those for BD-I depression.

Antidepressant medications should not be used as monotherapy in most patients with bipolar disorder, as available evidence does not support their efficacy, and there is a risk of a switch to mania or mood instability during an episode of bipolar depression. Antidepressants can be administered adjunctively to mood stabilizers (eg, lithium and lamotrigine) and second-generation antipsychotics.

Maintenance Treatment

Most patients with bipolar disorder will require maintenance treatment for many years, possibly lifelong, to prevent recurrent episodes and restore their pre-illness functioning. The current recommendation is for continuous rather than intermittent treatment, with treatments that were effective during the acute phase often continued initially to prevent early relapse. Mood stabilizers and atypical antipsychotics alone or in combination are the mainstays of maintenance pharmacotherapy.

There is substantial evidence showing lithium monotherapy’s effectiveness against manic, depressive, and mixed relapse. Additionally, lithium is associated with a decreased risk of suicide in patients with BD. Monitoring during treatment, including serum lithium concentrations, is a standard of care.

In addition to the individualized pharmacotherapy plan, essential components of maintenance treatment include medication adherence, primary prevention and treatment for psychiatric and medical comorbidities, and psychotherapy when appropriate. Suicidality surveillance is critical throughout the maintenance phase.

Differential Diagnosis

The differential diagnosis of bipolar disorder includes other conditions characterized by depression, impulsivity, mood lability, anxiety, cognitive dysfunction, and psychosis. The most common differential diagnoses are MDD, schizophrenia, anxiety disorders, substance use disorders, borderline personality disorder, and in the pediatric age group, attention-deficit/hyperactivity disorder and oppositional defiant disorder. [18] [30]

Bipolar disorder is one of the top 10 leading causes of disability worldwide. [31] A recent meta-analysis showed that patients with BD “experienced reduced life expectancy relative to the general population, with approximately 13 years of potential life lost.” Additionally, patients with bipolar disorder showed a greater reduction in lifespan relative to the general population than patients with common mental health disorders, including anxiety and depressive disorders, and life expectancy was significantly lower in men with BD than in women with BD. [32] A different meta-analysis showed that all-cause mortality in patients with BD is double that expected in the general population. Natural deaths occurred over 1.5 times greater in BD, comprised of an “almost double risk of deaths from circulatory illnesses (heart attacks, strokes, etc) and 3 times the risk of deaths from respiratory illness (COPD, asthma, etc).” Unnatural deaths occurred approximately 7 times more often than in the general population, with an increased suicide risk of approximately 14 times and an increased risk of other violent deaths of almost 4 times. Deaths by all causes studied were similarly increased in men and women. [33] A more recent systematic review of the association between completed suicide and bipolar disorder showed an approximately 20- to 30-fold greater suicide rate in bipolar disorder than in the general population. [34]

Complications

Individuals with bipolar disorder show a markedly increased risk of premature death due to the increased risk of suicide and medical comorbidities, including cardiovascular, respiratory, and endocrine causes. [35] More than half of patients are overweight or obese, which appears to be independent of treatment with weight-promoting psychotropic medications. [36] One-third of patients with bipolar disorder also meet the criteria for metabolic syndrome, which increases the risks of heart disease and stroke. [37] Additionally, attempted suicides are more common among patients with concurrent metabolic syndrome. [37] Comorbid overweight and obesity are associated with a more severe course, an increased lifetime number of depressive and manic episodes, poorer response to pharmacotherapy, and heightened suicide risk. [22] [38] Migraine is also associated with bipolar disorder. [39]

Psychiatric comorbidity is present in 50 to 70% of patients with BD. Of those diagnosed with the condition, 70% to 90% meet the criteria for generalized anxiety disorder, social anxiety disorder, or panic disorder, and 30 to 50% for alcohol and other substance use disorders. [40] [41] [42] Psychiatric comorbidities in patients with bipolar disorder are associated with a more severe course, more frequent depressive and manic episodes, and reduced quality of life. [22] Up to half of patients with BD have a comorbid personality disorder, particularly borderline personality disorder, and 10 to 20% have a binge eating disorder, leading to more frequent mood episodes and higher rates of suicidality and alcohol and substance use disorders. [43] [44]

Deterrence and Patient Education

Psychoeducation delivered individually or in a group setting is recommended for patients and family members and may include teaching to detect and manage prodromes of depression and mania, enhance medication adherence, and improve lifestyle choices. Patients are encouraged to avoid stimulants like caffeine, minimize alcohol consumption, exercise regularly, and practice appropriate sleep hygiene. [28] Providers are encouraged to maximize the therapeutic alliance, convey empathy, allow patients to participate in treatment decisions, and consistently monitor symptoms, which have been shown to reduce suicidal ideation, improve treatment outcomes, and increase patient satisfaction with care. [28] [45] Patients may also benefit from case management or care coordination services to help connect them to community-based resources, such as support groups, mental health centers, and substance use treatment programs.

Enhancing Healthcare Team Outcomes

The goal of treatment for patients with bipolar disorder is a full functional recovery (a return to pre-illness baseline functioning). This goal can best be achieved by integrating psychiatric and medical healthcare using an interprofessional team approach to manage BD and comorbid psychiatric and medical conditions. [46] Interprofessional healthcare teams may consist of any combination of the following: case manager, primary care clinician, psychiatrist, psychiatric nurse practitioner, psychiatric physician assistant, psychiatric nurse specialist, social worker, psychologist, and pharmacist.

Ideally, a consistent long-term alliance will form between the patient, their family, and healthcare team members to provide pharmacotherapy management, psychoeducation, ongoing monitoring, and psychosocial support. [26] Also, patients with bipolar disorder and co-occurring alcohol or substance use disorders may benefit from the involvement of an addiction specialist, as there is evidence that effective treatment can improve outcomes. [47] Pharmacists must perform medication reconciliation to ensure there are no drug-drug interactions that could inhibit effective care and report any concerns they have to the prescriber or their nursing staff. Furthermore, collaborative care models have shown efficacy in improving outcomes when used to treat patients with BD. Key elements include patient psychoeducation, using evidence-based treatment guidelines; collaborative decision-making by patients and their healthcare provider(s); and supportive technology to support monitoring and patient follow-up. [46] [48] [49]

An interprofessional approach is a mainstay in treating patients with bipolar disorder. An interprofessional team that provides a holistic and integrated approach to patient care can help achieve the best possible outcomes with the fewest adverse events. [Level 5]

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Disclosure: Ankit Jain declares no relevant financial relationships with ineligible companies.

Disclosure: Paroma Mitra declares no relevant financial relationships with ineligible companies.

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Bipolar I disorder: a qualitative study of the viewpoints of the family members of patients on the nature of the disorder and pharmacological treatment non-adherence

Nasim Mousavi 1 ,
Marzieh Norozpour ORCID: orcid.org/0000-0002-8894-9178 1 ,
Zahra Taherifar 2 ,
Morteza Naserbakht 3 &
Amir Shabani 3

BMC Psychiatry volume 21 , Article number: 83 ( 2021 ) Cite this article

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Bipolar disorder is a common psychiatric disorder with a massive psychological and social burden. Research indicates that treatment adherence is not good in these patients. The families’ knowledge about the disorder is fundamental for managing their patients’ disorder. The purpose of the present study was to investigate the knowledge of the family members of a sample of Iranian patients with bipolar I disorder (BD-I) and to explore the potential reasons for treatment non-adherence.

This study was conducted by qualitative content analysis. In-depth interviews were held and open-coding inductive analysis was performed. A thematic content analysis was used for the qualitative data analysis.

The viewpoints of the family members of the patients were categorized in five themes, including knowledge about the disorder, information about the medications, information about the treatment and the respective role of the family, reasons for pharmacological treatment non-adherence, and strategies applied by families to enhance treatment adherence in the patients. The research findings showed that the family members did not have enough information about the nature of BD-I, which they attributed to their lack of training on the disorder. The families did not know what caused the recurrence of the disorder and did not have sufficient knowledge about its prescribed medications and treatments. Also, most families did not know about the etiology of the disorder.

The lack of knowledge among the family members of patients with BD-I can have a significant impact on relapse and treatment non-adherence. These issues need to be further emphasized in the training of patients’ families. The present findings can be used to re-design the guidelines and protocols in a way to improve treatment adherence and avoid the relapse of BD-I symptoms.

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Bipolar I disorder (BD-I) is a chronic and recurrent psychiatric disorder in which a person has a manic episode for 1 week, which may present before or after hypomanic or major depressive episodes [ 1 ].

BD-I is accompanied by chronic stress, disability, increased risk of sudden mood swings, higher rates of comorbid disorders and moral, financial, and legal problems. The disorder is ranked the sixth debilitating disease according to the World Health Organization (WHO). BD-I is considered the most expensive mental disorder in terms of the health and behavioral care required by the patients and the burden on governmental institutions and insurance companies [ 2 , 3 , 4 ]. According to a report by the Central Bank of the Islamic Republic of Iran, the average annual income of an Iranian household in 2012 was 209,050,000 Rials. The direct annual cost of one BD-I patient consists of 10% of this average family income [ 5 ].

BD-I affects the patient’s life and has long-term consequences that are visible in the patient’s social performance and quality of life [ 6 , 7 ]. Severe impairment in job performance is observed in about 30% of the patients with BD-I. In such cases, functional improvement falls substantially behind symptom improvement [ 1 ].

Pharmacological treatment is the first-line treatment for BD-I. Evidence shows that about 40% of patients with BD-I do not have good medication adherence, which translates into a higher probability of symptom relapse, hospitalization, and increased suicide risk [ 8 ]. In a study in Tehran, Iran, poor treatment adherence was noticed in about 30% of BD-I patients [ 9 ]. Another study from Iran [ 10 ] also reported the prevalence of poor compliance in BD-I patients after the first episode of mania as 38.1% during a 17-month follow-up period. Therefore, it is of great importance to better understand and investigate the underlying reasons for treatment non-adherence in BD-I patients.

Given the changes implemented in health care systems over the last two decades and the resultant focus on community-based services, the role of families in caring for BD-I patients has become more prominent [ 6 ]. The insufficient knowledge of families about the disorder, its symptoms, and medications has made the management of BD-I more difficult and eventually imposes additional costs on them [ 6 ]. The higher is the cost imposed on the family, the more likely is it for the family members to show adverse reactions to the BD-I patients, which itself leads to a higher chance of disorder relapse [ 3 ].

In Iran, the general public is acquainted with various types of psychiatric illnesses through mass media and public educational websites such as the website of the Iranian Psychiatric Association ( https://iranmentalhealth.com ) and other Persian public written sources. Patients with BD-I and their families become familiar with the treatment process after consulting a general practitioner, a psychiatrist, or a psychologist, and, if necessary, the patients are admitted to the hospital through a psychiatrist. In addition to medical treatment, they receive the necessary training and information about their treatment process in the hospital. Furthermore, an association called ABR (Association of Mental Health Promotion), with an active website ( http://abrcharity.ir ), independently monitors patients, including those with bipolar disorder, after discharge.

Many studies have examined the views and roles of patients with BD-I and their caregivers and also the importance of family awareness and its impact on medication adherence. Tacchi & Scott [ 11 ] and Veligan et al. [ 12 ] suggest that the family members’ beliefs about the nature of BD-I and the information they have about the disorder affect the patient’s medication adherence. The review of literature showed no precise studies conducted to explore the knowledge, information, and opinions of family members of BD-I patients about the disorder and the causes of their medication non-adherence.

In a previous study in Iran [ 13 ], the authors held qualitative interviews with the family members of patients with BD-I and reported that treatment non-adherence is a major problem in these patients. They also reported that the patients and their families did not have sufficient knowledge about the nature of this disorder. Considering these findings about the insufficient knowledge of the family members of BD-I patients and the high rate of treatment non-adherence, it is necessary to conduct more studies to investigate the possible causes of treatment non-adherence and families’ knowledge and beliefs about this disorder in Iran. This study was thus carried out to explore the viewpoints of the family members of BD-I patients about the nature of this disorder and the potential causes of treatment non-adherence. The results can be used for revising the psychoeducation guidelines for BD-I patients, as clinical guidelines mandate the inclusion of psychoeducation in the treatment plan adopted for these patients. The results can also be used to design a protocol to address the disorder relapse, which can have substantial consequences in terms of reducing healthcare costs.

The findings of this study are reported according to the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist [ 14 ].

Study samples’ characteristics

The participants were the family members of patients diagnosed with BD-I. The patients had been admitted to Iran Psychiatry Hospital in Tehran, Iran, and were receiving pharmacological treatments.

This study used purposive sampling to select the participants. From November 2017 to April 2018, 12 patients were interviewed by two psychiatrists based on the DSM-5 criteria [ 1 ] and received the diagnosis of BD-I. Then these diagnoses were confirmed by A.SH. and their families were invited to participate in the study.

None of the family members refused to participate in the study and they all completed the entire course of the study. The mean age of the participants was 50.83 years. There were three male (25%) and nine female (75%) participants (Table 1 ). Table 2 shows further details on patients’ characteristics.

Data collection

After diagnosing patients with BD-I, and obtaining the written consent of the family members of patients to participate in this study, data were collected by in-depth interviews from family members of patients, conducted at the hospital’s conference hall. No one else was present at the time of the interviews except for the interviewer and the participant. Each interview lasted approximately 20 min and was digitally recorded for subsequent analyses. Two female PhD candidates (N. M. and M. N.) in clinical psychology at the University of Social Welfare and Rehabilitation Sciences, Tehran, Iran, who had already received training on the implementation of qualitative studies, held the interviews. They did not know any of the participants. The interviewers introduced themselves to the participants before the beginning of each interview. The interview questions were provided by the authors. The interviews were held only once and were not repeated. Data saturation was reached with 12 participants, and no further participants were interviewed after reaching this number. Data saturation occurs when no new information is obtained by conducting further interviews [ 15 ].

Data analysis

Thematic analysis was used for the qualitative data analysis [ 16 , 17 ]. To this end, the six steps proposed by Clark and Brown [ 17 ] were used.

The raw data derived from the interviews were used for the analysis. The content of the interviews were transcribed verbatim immediately after each interview. Field notes were made during the interviews and were reviewed in this stage. Three authors (M. N., N. M., and Z. T.) read the interviews several times for immersing in the data and getting familiar with it. Line-by-line coding was then applied to generate the initial codes. These steps were performed manually by the three authors without using any computer programs. One author encoded each interview and the interview was then read by another author and encoded again. The individually-extracted codes were then integrated and modified, if necessary.

In the next step, by linking the codes together, their common patterns and concepts were extracted and potential themes and subthemes were identified, keeping the research questions in mind. The data related to the themes were then collected and examined to verify the accuracy of the themes and subthemes, which resulted in five final themes.

Several statements were selected from the interviews as examples and are reported in the results section. To preserve participants’ anonymity, their names and ages are not mentioned in the results; instead, they are represented by random numbers.

Taking into account comprehensiveness, homogeneity, and overlap, the components of the family members’ viewpoints on the nature of the disorder and the reasons for pharmacological treatment non-adherence were categorized into five themes, including knowledge about the disorder, information about the medications, information about the treatment and the respective role of the family, reasons for pharmacological treatment non-adherence, and strategies applied by families to enhance treatment adherence in the patients.

Each of the themes contained several subthemes, which were themselves made up of some open codes. These subthemes contained recurrent codes and concepts that shared a common meaning.

Table 3 presents the themes, subthemes and examples of some of the codes.

Theme one: knowledge about the disorder

Most interviewees did not have sufficient or accurate knowledge about the nature of BD-I, the signs and symptoms of depression and mania cycles, and the outcome of the disorder. They mentioned the lack of training or inadequate training (especially by healthcare providers) as the main cause of insufficient knowledge about BD-I. Additionally, most families did not have a good understanding of the etiology of BD-I.

Some of them considered BD-I as a genetic abnormality, while others considered factors such as adolescent maltreatment, parents’ unusual conditions during sexual intercourse, and the lack of proper training before parenthood as potential causes of BD-I.

Participant No. 5 (a patient’s wife): “I was told that he has a nervous problem.” Participant No. 3 (a patient‘s mother): "I have a theory about having babies. I think that not everyone should have children. The husband and wife should be screened and monitored for two years to see if they understand the matter clearly. Do you see these anomalies now? ... These shameful movies they watch … The person is not feeling well when raising their kid … From an Islamic point of view, from a human’s point of view, both the husband and wife need to be monitored. Their food and other things should also be monitored to see if they can have a healthy baby.”

Participant No. 7 (a patient’s mother): "Because this boy is always impressed by me, sometimes I tell myself, maybe I didn’t fully understand him during his puberty. Sometimes I blame myself, as he has said this many times. I always blame myself … . Sometimes he says, ‘You did this to me, that’s why I’m sick now and take drugs’. For example, when hitting puberty, in the first or second year of high school, he used to get up late and so he got to school very late. Then the school’s principal complained to me, ‘Why is he late again?’ And he says, ‘Why did you wake me up early in the morning? You did this to me.” Participant No. 10 (a patient’s mother), referring to her son's divorce: "That's why he's so broken.” Participant No. 11 (a patient’s sister): "Bipolar disorder has a genetic background. I think there would be no one out there who suffered from the disorder unless they got the genes. It is a genetic disorder, but it emerges when a patient experiences a series of shocking events. Well, some have higher potentials, such as those who get very angry. I mean, the anger itself is not part of the disorder, but in angry people, shocking events affect the patient more rapidly.”

Theme two: information about the medications

Many family members had a misconception about the treatment of the disorder and the effects of psychotropic medications on the patients. In other words, they were unable to accurately identify the therapeutic effects of the administered medications and the time it took for the patients to show signs of improvement. Also, some participants were unaware of the side-effects of the prescribed medications. Some mentioned side-effects like memory loss and drug addiction; however, almost all the participants believed that pharmacological treatment is necessary for the patients despite the side-effects.

Participant No. 1 (a patient’s mother): "The problem of her running away from home with her boyfriend was a big burden for us, but as the prescribed meds began to show their effectiveness, this problem was gradually solved and we finally managed to put up with her aggressiveness and other problems. That is, we were saying to ourselves, ‘This is a period of angriness; we had better not said this, not done that’... We thought the medication was working. But now they’ve told me, ‘No, your patient has not recovered at all, has not been cured.”

Participant No. 1 (a patient's mother): "Her first psychiatrist, who has been visiting her for eight years, was frequently asking if she studies, watches TV or goes to work at all. ‘Whenever she goes back to these routines, then she has recovered,’ the therapist would say. Recently, she’s always been saying, ‘I would love to go to work’ and so on. Once, her employer told her to do some cleaning, and she had responded, ‘I’m not your servant.’ She suddenly broke it off and said, ‘I won’t go to work anymore.’ She didn’t sleep at all, saying, ‘I work so much, but I don’t feel exhausted at all.’ We were also excited and thought ‘Yeah, so this doctor's meds have been good; she’s getting back to normal, she’s working,’ She was frequently organizing her closet, like an obsession.”

Participant No. 3 (a patient’s mother): “I can’t remember the side-effects but I’ve heard about them in classes. My daughter is taking lithium now but she gets these chills. Her stomach is not well. Its side-effects are such that they affect her memory. However, when we compare the pros and cons, we have to take it. "

Theme three: information about the treatment

The regular intake of medications, stress control, work, exercise, regular visits to a psychiatrist or psychologist, and the need to provide insight into the patient’s illness through education were noted by the families in this part. Some participants believed that psychotherapy sessions cannot help treat this disorder while some had completely false or superstitious beliefs about treatment of the disorder.

Participant No. 4 (a patient's son): "Our patient doesn’t accept justifications. When you bring them to classes and convince them that ‘You are sick, and you have to take this medication because of this and that, and we have evidence that you have this disorder,’ and then we show it to them, prove it like in the movies, say that this disorder is serious because of so and so reasons, I think, it would be much easier.”

Participant No. 1 (a patient’s mother): "They sent us to get counseling. Of course, my daughter did not cooperate and didn’t come with. So, I got an appointment under my name to get information and find out how to deal with this disorder. Then the psychologist said, 'No, your daughter is diagnosed with bipolar disorder; this is an acute illness. Counseling does not work for her. She should take medications –a lot of them. And since the doc said those words, we withdrew from counseling altogether.”

Participant No. 5 (a patient’s wife): "My mother-in-law says, ‘If God gives him a baby, he’ll be fine.’ Because his ex-wife also failed to bear a child for him.”

Theme four: information about the role of the family in the treatment

Most families defined their role as helping the patient recover and adhere to their treatment, reminding them to take the medications, encouraging them to go to the doctor, not leaving them alone, and doing whatever they wanted to do so that things went as the patient wished. The patients also appeared to feel guilty when their families tried to comfort them, and this pattern was observed in several of the participants in this study.

Participant No. 6 (a patient’s husband): "We should put up with her, love her, not argue about what she says, listen to her, get her to do exercise to keep busy. I'm here now and I brought her with me too instead of leaving her alone to think about stuff.”

Participant No. 2 (a patient’s mother): "You should be good to them, listen to them, make home a peaceful environment, and not argue.”

Participant No. 8 (a patient’s wife): “I don't know. If he just thinks that everything is okay, all will be okay; but such feelings don’t last forever.”

Participant No. 2 (a patient’s mother): "I tell him to take his meds on time … Say, ‘Let's go to the park to take a look around ... Don't stay at home too much. God is merciful; it won’t be that bad’ … I talk to him, I comfort him sometimes, tell him that I’m ill too because I feel your pain.’ I really do. I’ve been crying alone at home many times. God, what will happen at the end?"(She cries).

Theme five: reasons for pharmacological treatment non-adherence

As for this theme, the participants noted issues that were mostly about the comments made by other people, including relatives or care-providers, such as doctors or specialists in other disciplines. An interesting observation was made by a participant who mentioned a celebrity talking on TV about the inefficiency of medications; following these comments, the patient had stopped taking his medications. Another issue was that the families’ constant changing of the patient’s physician contributed to their medication non-adherence. Another reason noted for non-adherence was that the patients did not suffer from mania symptoms and found that it was not so crucial for them to take the medications. Additionally, some patients reported the physical discomfort and weakness (e.g., impotence) experienced as side-effects of the prescribed medications a reason for their medication non-adherence.

Participant No. 2 (a patient’s mother): "She didn't take the meds for seven to eight months. Her friend had told her ‘Your eyes look different. When you take the medicine, your eyes turn into a strange shape. Get rid of them.’ After seven months, her disease relapsed.”

Participant No. 6 (a patient’s husband): "If we go to a party somewhere and someone asks her, ‘Oh, you take drugs?’ … But that person is not aware of the matter, cause she might look all well, and that person doesn’t know what’s actually happening in my wife’s mind, who then has to admit that she is alright."

Participant No. 7 (a patient’s mother): "At one point at work, some colleagues told him, ‘You will become addicted to the medicines, you will get sick.’ Then, he put the medicines aside and became pessimistic about his work. ‘This job has made me sick,’ so he said and left his job all of a sudden. He had a great job, not a difficult one. He could manage it by himself very easily.”

Participant No. 3 (a patient’s mother): “My son had gone to a doctor to remove the corn on his feet. The doctor had checked his medicine prescriptions and asked, ‘What are these you’re taking? You won’t be able to conceive a baby in the future. It’ll affect you poorly’ and so on. My son keeps repeating what the doctor told him.”

Participant No. 1 (a patient’s mother): "That emergency nurse who came to our house told us to change her doctor. Since then, she has kept repeating this sentence. She threw out all her medicines.”

Participant No. 3 (a patient’s mother): “Since the beginning of the new year, he’s began to no longer take his medications. In Khandevaneh, Footnote 1 Mr. Mehran Ghafourian (a famous Iranian actor) said, ‘I was in a bad mood ... I had depression. I put the medications aside and started exercising.’ My son stopped taking his medicines on hearing those words. I asked him many times to go see a doctor but he said no. He continued to not take his medicines and then his disorder worsened. He was frequently beating us up until we took him to the hospital with the help of the police.”

Participant No. 3 (a patient’s mother): “There was a child psychiatrist on a TV talk. We took our son to her office. We used to visit a counselor as well. The psychiatrist prescribed him some medications. We didn’t know what the medications were. He was taking his medicines. In the middle of therapy, we stopped it. Then, my son-in-law, who is a doctor, said ‘Dr. A -his professor- is a very good doctor.’ My son used to go to Dr. A. earlier when he was a college student. He was taking medicines and he believed in him so much. Then again, my eldest daughter, who is a physician, said ‘Dr. B. is a very helpful therapist. All the doctors, engineers, and educated people go to visit him.’ Then he went there ... And two years ago, I took him to Dr. S. too, to help him get rid of his substance abuse." (This participant named seven different doctors).

Participant No. 4 (a patient’s son) discussed the reasons for the patient’s refusal to take the medications and said: "Well, he doesn't actually believe in the disorder being a real one (in the manic episode). Maybe now he takes the pill in front of you, but you know that it is not something that bothers him. You take pills more easily if you have actual pain, but when you don’t, you ask yourself ‘Why do I have to take all these pills?”

Participant No. 11 (a patient’s sister): “We can note the poor behaviors of those around him. He considers any weaknesses he experiences (e.g., sexual problems) a side-effect of the medicines he’s taking. And he’s linking everything to the medicines and thinking they’re going to make him different from the others.”

The findings of this study regarding the viewpoints of the family members of patients with BD-I were categorized into five themes. Although qualitative studies do not allow for the identification of the extent and relative importance of every condition, recurrent themes and concepts stated by the participants at different individual and social levels were extracted.

Research suggests that there is a relationship between families’ knowledge and beliefs about the disorder and the patients’ medication adherence [ 12 ]. The attitudes and knowledge of the family members have a significant influence on the patient’s own beliefs and attitudes and affect the patient’s decision about treatment compliance [ 18 ]. In agreement with previous studies [ 19 , 20 ], the family caretakers in this study were shown to lack sufficient information and knowledge about the nature of BD-I. In addition, many participants had inaccurate or false information and insisted on these false beliefs. A review study on treatment acceptance found that brief interventions focused on relapse prevention and psychoeducation-based interventions have the greatest impact on relapse prevention [ 21 ]. Maintaining the patients’ circadian rhythms (especially sleep rhythm), controlling activity levels, verifying and controlling initial symptoms of mania and depressive episodes, and not using narcotics or stimulants have been recommended in approved psychotherapy protocols for bipolar patients [ 22 ]. Nonetheless, the participants in this study did not discuss any of these important factors. The lack of knowledge about these important issues among families can have a significant impact on relapse and treatment non-adherence in the patients. These points need to be further emphasized in training patients’ families.

In a qualitative study on bipolar patients and their families, Peters, Pontin, Lobban, and Morriss [ 23 ] found that the viewpoints of patients and their families play an important role in managing the disorder; however, the families usually get despondent about participating in this process, and their perception was that some mental health workers believe that family involvement makes their work more complicated. Meanwhile, the present study showed that, in Iran, families do not have enough information about their role in preventing disorder relapse and attribute their patient’s relapse only to factors such as medication withdrawal, unemployment, lack of community support, and financial problems. Most of them believed that if everything goes as the patient wishes, the disorder will not relapse.

Furthermore, the participants did not have adequate information about the non-pharmacological treatment options available for this disorder and the role that psychologists can play in helping the patients enhance their medication adherence and prevent the symptoms of relapse. A variety of behavioral, cognitive, and emotion-focused interventions are used in the management of bipolar disorders [ 22 ]. Nevertheless, the participants did not have sufficient knowledge about these treatments. The observation that many psychologists in Iran appear unwilling to participate in the treatment of bipolar disorder patients seems to play a role in this lack of knowledge. According to Farhoudian et al. [ 24 ], only about 1.5% of all the studies on psychiatric disorders conducted in Iran between 1973 and 2003 involved bipolar and cyclothymic patients. In a qualitative study on bipolar-II patients and their families, Fisher et al. [ 25 ] found that the number of resources available to patients for deciding about their treatment has increased and their priorities have been given increasing attention; yet, the patients’ and their families’ preferences are not fully considered.

Similar to the studies carried out by Jönsson, Wijk, Skärsäter & Danielson [ 26 ] and Shamsaei, Mohamad Khan Kermanshahi, and Vanaki [ 27 ], in the present study, the patients and their families were struggling with the acceptance, understanding, and management of the disorder. According to the participants, the families’ lack of insight into the patients’ disorder contributed significantly to their medication non-adherence. This finding is in line with Scott and Pope’s [ 28 ] research, but Delmas, Proudfoot, Parker, and Manicavasagar [ 29 ] stated that the rejection of treatment is a complex issue that depends on various factors.

Some of the results of this study are consistent with the findings reported by Clatworthy, Bowskill, Rank, Parham, and Horne [ 8 ], who noted that deliberate treatment non-adherence is associated with factors such as patients’ concerns about the prescribed medications and their side-effects in the case of continuous consumption. Proudfoot et al. [ 30 ] stated that the side-effects of medications, coping with unpleasant symptoms, the extent of awareness about the nature of the disorder, and the reactions to it as well as the stigma associated with the disorder affect the patient’s life path. Besides, these symptoms have a permanent impact on the disorder relapse [ 31 ]. The findings showed that the interaction of the disorder, patient, medications, psychiatric attitude, and cultural attitude with non-compliance is very complex [ 32 ].

In addition to the themes mentioned, there were some interesting results concerning the response process in all the interviews. For example, the majority of the participants only reported symptoms of the manic episode, while two major studies [ 33 , 34 ] have shown that people with bipolar I and II (especially type II) disorders spend most of their symptomatic days with depression. Patients suffer greatly during the depressive episodes but have elevated or irritable moods during the manic episode; in contrast, families find the mania symptoms more annoying and disruptive to themselves. This duality can negatively impact reaching a common understanding with the patient about visiting the doctor and taking medications. Moreover, the fact that some families do not have enough information about the depressive episode can eventuate in neglecting the patient’s need to take medications during this phase, which can then adversely affect medication adherence. These results are somewhat contradictory to the results of a previous study [ 29 ], which reported that both patients and their family members report symptoms of mania and hypomania to their physicians less often, as some of them enjoy the manic symptoms. Family members feel relieved when they see that their patient is happy and shows mania symptoms. A major cause of this discrepancy in findings may be the differences in the study populations. While Delmas et al. [ 29 ] studied patients with bipolar I and II, the present study examined only patients with BD-I. The discrepancy may also partially originate from cultural differences. It seems that when there is a pattern of greater attention to objective and apparent symptoms, very important mental symptoms such as suicidal thoughts, whether during the mania or depressive episode, are neglected by families.

This study showed that families with a higher educational and socioeconomic status tend to seek psychiatric care from different psychiatrists. Frequently changing the treating psychiatrist can cause treatment non-adherence in the patients. Furthermore, as the family members of such patients falsely think that they have greater medical information, they are more likely to encourage the patient to stop taking their prescribed medications.

A major limitation of this study was that most participants were the mothers of the patients, as it was hard to find other family members of the patients to participate in the study. For example, only one child of a patient and one sister were among the participants. Also, all the participants were from Tehran and were selected from one hospital; therefore, the generalization of the results to other cities in Iran should be pursued with caution.

The authors suggest using the findings of this qualitative study regarding the knowledge of the family members of patients with bipolar I disorder (BD-I) as well as the dominating cultural beliefs to design further quantitative studies. The quantitative assessment of individual, familial, and social reasons for treatment non-adherence is also a recommendation for future research. Conducting similar studies on the family members of patients with other types of bipolar disorder with an attention to the different processes and outcomes involved is also recommended. Since there are different ethnicities and subcultures in Iran, the results obtained by examining the residents of the country’s capital city cannot be generalized to the population of other cities and towns, and it is necessary to repeat the study in other populations in order to get familiar with other viewpoints in Iran.

Overall, the results of this study contribute to the emerging qualitative research on bipolar disorder and provide the readers with an insight into the viewpoints of the family members of patients with BD-I. Some inaccurate information might have been observed in participants’ statements due to some deeply-rooted cultural attitudes and beliefs and their correction may require extensive interventions.

The results of this study can be used to compile educational content for patients with bipolar disorder and their families as well as for psychologists, psychiatrists, psychiatry assistants, and hospital health workers.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

A popular comedy show on Iranian television

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Peters S, Pontin E, Lobban F, Morriss R. Involving relatives in relapse prevention for bipolar disorder: a multi-perspective qualitative study of value and barriers. BMC Psychiatry 2011;11(1):172.

Farhoudian A, Rad Goodarzi R, Rahimi Movaghar A, Sharifi V, Mohammadi MR, Sahimi Izadian E, et al. Trend of Researches in the Field of Psychiatric Disorders in Iran. Iran J Psychiatry Clin Psychol 2007;12(4):327-36.

Jönsson PD, Wijk H, Skärsäter I, Danielson E. Persons living with bipolar disorder—their view of the illness and the future. Issues Mental Health Nurs 2008;29(11):1217-36.27.

Shamsaei F, Mohamad khan Kermanshahi S, Vanaki Z. Meaning of Health from the Perspective of Family Member Caregiving to Patients with Bipolar Disorder. Journal of Mazandaran University of Medical Sciences. 2012;22(90):52-65.

Scott J, Pope M. Nonadherence with mood stabilizers: prevalence and predictors. J Clin Psychiatry 2002;63(5):384-390.

Delmas K, Proudfoot J, Parker G, Manicavasagar V. Recoding past experiences: A qualitative study of how patients and family members adjust to the diagnosis of bipolar disorder. J Nerv Ment Dis 2011;199(2):136-9.

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Acknowledgements

The authors express their gratitude to all the staff of Iran Psychiatry Hospital for their generous cooperation in the study.

This research is funded by the Mental Health Research Center of Iran University of Medical Sciences (grant number 95–01–121-27963).

The views expressed are those of the authors and not necessarily those of the Mental Health Research Center of Iran University of Medical Sciences. The funders had no role in the study design, data collection and analysis, interpretation, decision to publish or the writing and preparation of the manuscript.

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Nasim Mousavi & Marzieh Norozpour

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Zahra Taherifar

Faculty of Behavioral Sciences and Mental Health, Tehran Psychiatry Institute, Iran University of Medical Sciences, Tehran, Islamic Republic of Iran

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NM, MN and ASH conceived the study idea and design. NM, and MN conducted the interviews. NM, MN and ZT conducted transcription and data analysis. NM, MNA and ZT interpreted and presented the results, and contributed to the manuscript. ASH supervised the research activities and contributed to the interpretation of results. NM, MN and ZT wrote the manuscript. All authors have read, edited and approved the final manuscript for submission.

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Mousavi, N., Norozpour, M., Taherifar, Z. et al. Bipolar I disorder: a qualitative study of the viewpoints of the family members of patients on the nature of the disorder and pharmacological treatment non-adherence. BMC Psychiatry 21 , 83 (2021). https://doi.org/10.1186/s12888-020-03008-x

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Diagnosis and management of bipolar disorders

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1 Precision Medicine Center of Excellence in Mood Disorders, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
2 Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Correspondence to: F S Goes fgoes1{at}jhmi.edu

Bipolar disorders (BDs) are recurrent and sometimes chronic disorders of mood that affect around 2% of the world’s population and encompass a spectrum between severe elevated and excitable mood states (mania) to the dysphoria, low energy, and despondency of depressive episodes. The illness commonly starts in young adults and is a leading cause of disability and premature mortality. The clinical manifestations of bipolar disorder can be markedly varied between and within individuals across their lifespan. Early diagnosis is challenging and misdiagnoses are frequent, potentially resulting in missed early intervention and increasing the risk of iatrogenic harm. Over 15 approved treatments exist for the various phases of bipolar disorder, but outcomes are often suboptimal owing to insufficient efficacy, side effects, or lack of availability. Lithium, the first approved treatment for bipolar disorder, continues to be the most effective drug overall, although full remission is only seen in a subset of patients. Newer atypical antipsychotics are increasingly being found to be effective in the treatment of bipolar depression; however, their long term tolerability and safety are uncertain. For many with bipolar disorder, combination therapy and adjunctive psychotherapy might be necessary to treat symptoms across different phases of illness. Several classes of medications exist for treating bipolar disorder but predicting which medication is likely to be most effective or tolerable is not yet possible. As pathophysiological insights into the causes of bipolar disorders are revealed, a new era of targeted treatments aimed at causal mechanisms, be they pharmacological or psychosocial, will hopefully be developed. For the time being, however, clinical judgment, shared decision making, and empirical follow-up remain essential elements of clinical care. This review provides an overview of the clinical features, diagnostic subtypes, and major treatment modalities available to treat people with bipolar disorder, highlighting recent advances and ongoing therapeutic challenges.

Introduction

Abnormal states of mood, ranging from excesses of despondency, psychic slowness, diminished motivation, and impaired cognitive functioning on the one hand, and exhilaration, heightened energy, and increased cognitive and motoric activity on the other, have been described since antiquity. 1 However, the syndrome in which both these pathological states occur in a single individual was first described in the medical literature in 1854, 2 although its fullest description was made by the German psychiatrist Emil Kraepelin at the turn of the 19th century. 3 Kraepelin emphasized the periodicity of the illness and proposed an underlying trivariate model of mood, thought (cognition), and volition (activity) to account for the classic forms of mania and depression and the various admixed presentations subsequently know as mixed states. 3 These initial descriptions of manic depressive illness encompassed most recurrent mood syndromes with relapsing remitting course, minimal interepisode morbidity, and a wide spectrum of “colorings of mood” that pass “without a sharp boundary” from the “rudiment of more severe disorders…into the domain of personal predisposition.” 3 Although Kraepelin’s clinical description of bipolar disorder (BD) remains the cornerstone of today’s clinical description, more modern conceptions of bipolar disorder have differentiated manic depressive illness from recurrent depression, 4 partly based on differences in family history and the relative specificity of lithium carbonate and mood stabilizing anticonvulsants as anti-manic and prophylactic agents in bipolar disorder. While the boundaries of bipolar disorder remain a matter of controversy, 5 this review will focus on modern clinical conceptions of bipolar disorder, highlighting what is known about its causes, prognosis, and treatments, while also exploring novel areas of inquiry.

Sources and selection criteria

PubMed and Embase were searched for articles published from January 2000 to February 2023 using the search terms “bipolar disorder”, “bipolar type I”, “bipolar type II”, and “bipolar spectrum”, each with an additional search term related to each major section of the review article (“definition”, “diagnosis”, “nosology”, “prevalence”, “epidemiology”, “comorbid”, “precursor”, “prodrome”, “treatment”, “screening”, “disparity/ies”, “outcome”, “course”, “genetics”, “imaging”, “treatment”, “pharmacotherapy”, “psychotherapy”, “neurostimulation”, “convulsive therapy”, “transmagnetic”, “direct current stimulation”, “suicide/suicidal”, and “precision”). Searches were prioritized for systematic reviews and meta-analyses, followed by randomized controlled trials. For topics where randomized trials were not relevant, searches also included narrative reviews and key observational studies. Case reports and small observations studies or randomized controlled trials of fewer than 50 patients were excluded.

Modern definitions of bipolar disorder

In the 1970s, the International Classification of Diseases and the Diagnostic and Statistical Manual of Mental Disorders reflected the prototypes of mania initially described by Kraepelin, following the “neo-Kraepelinian” model in psychiatric nosology. To meet the primary requirement for a manic episode, an individual must experience elevated or excessively irritable mood for at least a week, accompanied by at least three other typical syndromic features of mania, such as increased activity, increased speed of thoughts, rapid speech, changes in esteem, decreased need for sleep, or excessive engagement in impulsive or pleasurable activities. Psychotic symptoms and admission to hospital can be part of the diagnostic picture but are not essential to the diagnosis. In 1994, Diagnostic and Statistical Manual of Mental Disorders , fourth edition (DSM-IV) carved out bipolar disorder type II (BD-II) as a separate diagnosis comprising milder presentations of mania called hypomania. The diagnostic criteria for BD-II are similar to those for bipolar disorder type I (BD-I), except for a shorter minimal duration of symptoms (four days) and the lack of need for significant role impairment during hypomania, which might be associated with enhanced functioning in some individuals. While the duration criteria for hypomania remain controversial, BD-II has been widely accepted and shown to be as common as (if not more common than) BD-I. 6 The ICD-11 (international classification of diseases, 11th revision) included BD-II as a diagnostic category in 2019, allowing greater flexibility in its requirement of hypomania needing to last several days.

The other significant difference between the two major diagnostic systems has been their consideration of mixed symptoms. Mixed states, initially described by Kraepelin as many potential concurrent combinations of manic and depressive symptoms, were more strictly defined by DSM as a week or more with full syndromic criteria for both manic and depressive episodes. In DSM-5, this highly restrictive criterion was changed to encompass a broader conception of subsyndromal mixed symptoms (consisting of at least three contrapolar symptoms) in either manic, hypomanic, or depressive episodes. In ICD-11, mixed symptoms are still considered to be an episode, with the requirement of several prominent symptoms of the countervailing mood state, a less stringent requirement that more closely aligns with Kraepelin's broader conception of mixed states. 7

Epidemiology

Using DSM-IV criteria, the National Comorbidity Study replication 6 found similar lifetime prevalence rates for BD-I (1.0%) and BD-II (1.1%) among men and women. Subthreshold symptoms of hypomania (bipolar spectrum disorder) were more common, with prevalence rate estimates of 2.4%. 6 Incidence rates, which largely focus on BD-I, have been estimated at approximately 6.1 per 100 000 person years (95% confidence interval 4.7 to 8.1). 8 Estimates of the incidence and lifetime prevalence of bipolar disorder show moderate variations according to the method of diagnosis (performed by lay interviewers in a research context v clinically trained interviews) and the racial, ethnic, and demographic context. 9 Higher income, westernized countries have slightly higher rates of bipolar disorder, 10 which might reflect a combination of westernized centricity in the specific idioms used to understand and elicit symptoms, as well as a greater knowledge, acceptance, and conceptualization of emotional symptoms as psychiatric disorders.

Causes of bipolar disorder

Like other common psychiatric disorders, bipolar disorder is likely caused by a complex interplay of multiple factors, both at the population level and within individuals, 11 which can be best conceptualized at various levels of analysis, including genetics, brain networks, psychological functioning, social support, and other biological and environmental factors. Because knowledge about the causes of bipolar disorder remains in its infancy, for pragmatic purposes, most research has followed a reductionistic model that will ultimately need to be synthesized for a more coherent view of the pathophysiology that underlies the condition.

Insights from genetics

From its earliest descriptions, bipolar disorder has been observed to run in families. Indeed, family history is the strongest individual risk factor for developing the disorder, with first degree relatives having an approximately eightfold higher risk of developing bipolar disorder compared with the baseline population rates of ~1%. 12 While family studies cannot separate the effects of genetics from behavioral or cultural transmission, twin and adoption studies have been used to confirm that the majority of the familial risk is genetic in origin, with heritability estimates of approximately 60-80%. 13 14 There have been fewer studies of BD-II, but its heritability has been found to be smaller (~46%) 15 and closer to that of more common disorders such as major depressive disorder or generalized anxiety. 15 16 Nevertheless, significant heritability does not necessarily imply the presence of genes of large effect, since the genetic risk for bipolar disorder appears likely to be spread across many common variants of small effect sizes. 16 17 Ongoing studies of rare variations have found preliminary evidence for variants of slightly higher effect sizes, with initial evidence of convergence with common variations in genes associated with the synapse and the postsynaptic density. 18 19

While the likelihood that the testing of single variants or genes will be useful for diagnostic purposes is low, analyses known as polygenic risk studies can sum across all the risk loci and have some ability to discriminate cases from controls, albeit at the group level rather than the individual level. 20 These polygenic risk scores can also be used to identify shared genetic risk factors across other medical and psychiatric disorders. Bipolar disorder has strong evidence for common variant based coheritability with schizophrenia (genetic correlation (r g ) 0.69) and major depressive disorder (r g 0.48). BD-I has stronger coheritability with schizophrenia compared with BD-II, which is more strongly genetically correlated with major depressive disorder (r g 0.66). 16 Lower coheritability was observed with attention deficit hyperactivity disorder (r g 0.21), anorexia nervosa (0.20), and autism spectrum disorder (r g 0.21). 16 These correlations provide evidence for shared genetic risk factors between bipolar disorder and other major psychiatric syndromes, a pattern also corroborated by recent nationwide registry based family studies. 12 14 Nevertheless, despite their potential usefulness, polygenic risk scores must currently be interpreted with caution given their lack of populational representation and lingering concerns of residual confounds such as gene-environment correlations. 21

Insights from neuroimaging

Similarly to the early genetic studies, small initial studies had limited replication, leading to the formation of large worldwide consortiums such as ENIGMA (enhancing neuroimaging genetics through meta-analysis) which led to substantially larger sample sizes and improved reproducibility. In its volumetric analyses of subcortical structures from MRI (magnetic resonance imaging) of patients with bipolar disorder, the ENIGMA consortium found modest decreases in the volume of the thalamus (Cohen’s d −0.15), the hippocampus (−0.23), and the amygdala (−0.11), with an increased volume seen only in the lateral ventricles (+0.26). 22 Meta-analyses of cortical regions similarly found small reductions in cortical thickness broadly across the parietal, temporal, and frontal cortices (Cohen’s d −0.11 to −0.29) but no changes in cortical surface area. 23 In more recent meta-analyses of white matter tracts using diffuse tension imaging, widespread but modest decreases in white matter integrity were found throughout the brain in bipolar disorder, most notably in the corpus callosum and bilateral cinguli (Cohen’s d −0.39 to −0.46). 24 While these findings are likely to be highly replicable, they do not, as yet, have clinical application. This is because they reflect differences at a group level rather than an individual level, 25 and because many of these patterns are also seen across other psychiatric disorders 26 and could be either shared risk factors or the effects of confounding factors such as medical comorbidities, medications, co-occurring substance misuse, or the consequences (rather than causes) of living with mental illness. 27 Efforts to collate and meta-analyze large samples utilizing longitudinal designs 28 task based, resting state functional MRI measurents, 29 as well as other measures of molecular imaging (magnetic resonance spectroscopy and positron emission tomography) are ongoing but not as yet synthesized in large scale meta-analyses.

Environmental risk factors

Because of the difficulty in measuring and studying the relevant and often common environmental risk factors for a complex illness like bipolar disorder, there has been less research on how environmental risk factors could cause or modify bipolar disorder. Evidence for intrauterine risk factors is mixed and less compelling than such evidence in disorders like schizophrenia. 30 Preliminary evidence suggests that prominent seasonal changes in solar radiation, potentially through its effects on circadian rhythm, can be associated with an earlier onset of bipolar disorder 31 and a higher likelihood of experiencing a depressive episode at onset. 31 However, the major focus of environmental studies in bipolar disorder has been on traumatic and stressful life events in early childhood 32 and in adulthood. 33 The effects of such adverse events are complex, but on a broad level have been associated with earlier onset of bipolar disorder, a worse illness course, greater prevalence of psychotic symptoms, 34 substance misuse and psychiatric comorbidities, and a higher risk of suicide attempts. 32 35 Perhaps uniquely in bipolar disorder, evidence also indicates that positive life events associated with goal attainment can also increase the risk of developing elevated states. 36

Comorbidity

Bipolar disorder rarely manifests in isolation, with comorbidity rates indicating elevated lifetime risk of several co-occurring symptoms and comorbid disorders, particularly anxiety, attentional disorders, substance misuse disorders, and personality disorders. 37 38 The causes of such comorbidity can be varied and complex: they could reflect a mixed presentation artifactually separated by current diagnostic criteria; they might also reflect independent illnesses; or they might represent the downstream effects of one disorder increasing the risk of developing another disorder. 39 Anxiety disorders tend to occur before the frank onset of manic or hypomanic symptoms, suggesting that they could in part reflect prodromal symptoms that manifest early in the lifespan. 37 Similarly, subthreshold and syndromic symptoms of attention deficit/hyperactivity disorder are also observed across the lifespan of people with bipolar disorder, but particularly in early onset bipolar disorder. 40 On the other hand, alcohol and substance misuse disorders occur more evenly before and after the onset of bipolar disorder, consistent with a more bidirectional causal association. 41

The association between bipolar disorder and comorbid personality disorders is similarly complex. Milder manifestations of persistent mood instability (cyclothymia) or low mood (dysthymia) have previously been considered to be temperamental variants of bipolar disorder, 42 but are now classified as related but separate disorders. In people with persistent emotional dysregulation, making the diagnosis of bipolar disorder can be particularly challenging, 43 since the boundaries between longstanding mood instability and phasic changes in mood state can be difficult to distinguish. While symptom overlap can lead to artificially inflated prevalence rates of personality disorders in bipolar disorder, 44 the elevated rates of most personality disorders in bipolar disorder, particularly those related to emotional instability, are likely reflective of an important clinical phenomenon that is understudied, particularly with regard to treatment implications. 45 In general, people with comorbidities tend to have greater symptom burden and functional impairment and have lower response rates to treatment. 46 47 Data on approaches to treat specific comorbid disorders in bipolar disorder are limited, 48 49 and clinicians are often left to rely on their clinical judgment. The most parsimonious approach is to treat primary illness as fully as possible before considering additional treatment options for remaining comorbid symptoms. For certain comorbidities, such as anxiety symptoms and disorders of attention, first line pharmacological treatment—namely, antidepressants and stimulants, should be used with caution, since they might increase the long term risks of mood switching or overall mood instability. 50 51

Like other major mental illnesses, bipolar disorder is also associated with an increased prevalence of common medical disorders such as obesity, hyperlipidemia, coronary artery disease, chronic obstructive pulmonary disease, and thyroid dysfunction. 52 These have been attributed to increase risk factors such as physical inactivity, poor nutrition, smoking, and increased use of addictive substances, 53 but some could also be consequences of specific treatments, such as the atypical antipsychotics and mood stabilizers. 54 Along with poor access to care, this medical burden likely accounts for much of the increased standardized mortality (approximately 2.6 times higher) in people with bipolar disorder, 55 highlighting the need to utilize treatments with better long term side effect profiles, and the need for better integration with medical care.

Precursors and prodromes: who develops bipolar disorder?

While more widespread screening and better accessibility to mental health providers should in principle shorten the time to diagnosis and treatment, early manifestation of symptoms in those who ultimately go on to be diagnosed with bipolar disorder is generally non-specific. 56 In particular, high risk offspring studies of adolescents with a parent with bipolar disorder have found symptoms of anxiety and attentional/disruptive disorders to be frequent in early adolescence, followed by higher rates of depression and sleep disturbance in later teenage years. 56 57 Subthreshold symptoms of mania, such as prolonged increases in energy, elated mood, racing thoughts, and mood lability are also more commonly found in children with prodromal symptoms (meta-analytic prevalence estimates ranging from 30-50%). 58 59 Still, when considered individually, none of these symptoms or disorders are sensitive or specific enough to accurately identify individuals who will transition to bipolar disorder. Ongoing approaches to consider these clinical factors together to improve accuracy have a promising but modest ability to identify people who will develop bipolar disorder, 60 emphasizing the need for further studies before implementation.

Screening for bipolar disorder

Manic episodes can vary from easily identifiable prototypical presentations to milder or less typical symptoms that can be challenging to diagnose. Ideally, a full diagnostic evaluation with access to close informants is performed on patients presenting to clinical care; however, evaluations can be hurried in routine clinical care, and the ability to recall previous episodes might be limited. In this context, the use of screening scales can be a helpful addition to clinical care, although screening scales must be regarded as an impetus for a confirmatory clinical interview rather than a diagnostic instrument by themselves. The two most widely used and openly available screening scales are the mood disorders questionnaire (based on the DSM-IV criteria for hypomania) 61 and the hypomania check list (HCL-32), 62 that represent a broader overview of symptoms proposed to be part of a broader bipolar spectrum.

Racial/ethnic disparities

Although community surveys using structured or semi-structured diagnostic instruments, have provided little evidence for variation across ethnic groups, 63 64 observational studies based on clinical diagnoses in healthcare settings have found a disproportionately higher rate of diagnosis of schizophrenia relative to bipolar disorder in black people. 65 Consistent with similar disparities seen across medicine, these differences in clinical diagnoses are likely influenced by a complex mix of varying clinical presentations, differing rates of comorbid conditions, poorer access to care, greater social and economic burden, as well as the potential effect of subtle biases of healthcare professionals. 65 While further research is necessary to identify driving factors responsible for diagnostic disparities, clinicians should be wary of making a rudimentary diagnosis in patients from marginalized backgrounds, ensuring comprehensive data gathering and a careful diagnostic formulation that incorporates shared decision making between patient and provider.

Bipolar disorder is a recurrent illness, but its longitudinal course is heterogeneous and difficult to predict. 46 66 The few available long term studies of BD-I and BD-II have found a consistent average rate of recurrence of 0.40 mood episodes per year in historical studies 67 and 0.44 mood episodes per year in more recent studies. 68 The median time to relapse is estimated to be 1.44 years, with higher relapse rates seen in BD-I (0.81 years) than in BD-II (1.63 years) and no differences observed with respect to age or sex. 1 2 In addition to focusing on episodes, an important development in research and clinical care of bipolar disorder has been the recognition of the burden of subsyndromal symptoms. Although milder in severity, these symptoms can be long lasting, functionally impairing, and can themselves be a risk factor for episode relapse. 69 Recent cohort studies have also found that a substantial proportion of patients with bipolar disorder (20-30%) continue to have poor outcomes even after receiving guideline based care. 46 70 Risk factors that contribute to this poor outcome include transdiagnostic indicators of adversity such as substance misuse, low educational attainment, socioeconomic hardship, and comorbid disorders. As expected, those with more severe past illness activity, including those with rapid cycling, were also more likely to remain symptomatically and psychosocially impaired. 46 71 72

The primary focus of treating bipolar disorder has been to manage the manic, mixed, or depressive episodes that present to clinical care and to subsequently prevent recurrence of future episodes. Owing to the relapse remitting nature of the illness, randomized controlled trials are essential to determine treatment efficacy, as the observation of clinical improvement could just represent the ebbs and flows of the natural history of the illness. In the United States, the FDA (Food and Drug Administration) requires at least two large scale placebo controlled trials (phase 3) to show significant evidence of efficacy before approving a treatment. Phase 3 studies of bipolar disorder are generally separated into short term studies of mania (3-4 weeks), short term studies for bipolar depression (4-6 weeks), and longer term maintenance studies to evaluate prophylactic activity against future mood episodes (usually lasting one year). Although the most rigorous evaluation of phase 3 studies would be to require two broadly representative and independent randomized controlled trials, the FDA permits consideration of so called enriched design trials that follow participants after an initial response and tolerability has been shown to an investigational drug. Because of this initial selection, such trials can be biased against comparator agents, and could be less generalizable to patients seen in clinical practice.

A summary of the agents approved by the FDA for treatment of bipolar disorder is in table 1 , which references the key clinical trials demonstrating efficacy. Figure 1 and supplementary table 1 are a comparison of treatments for mania, depression, and maintenance. Effect sizes reflect the odds ratios or relative risks of obtaining response (defined as ≥50% improvement from baseline) in cases versus controls and were extracted from meta-analyses of randomized controlled trials for bipolar depression 86 and maintenance, 94 as well as a network meta-analysis of randomized controlled trials in bipolar mania. 73 Effect sizes are likely to be comparable for each phase of treatment, but not across the different phases, since methodological differences exist between the three meta-analytic studies.

FDA approved medications for bipolar disorder

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Summary of treatment response rates (defined as ≥50% improvement from baseline) of modern clinical trials for acute mania, acute bipolar depression, and long term recurrence. Meta-analytic estimates were extracted from recent meta-analyses or network meta-analyses of acute mania, 73 acute bipolar depression, 86 and bipolar maintenance studies 94

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Acute treatment of mania

As mania is characterized by impaired judgment, individuals can be at risk for engaging in high risk, potentially dangerous behaviors that can have substantial personal, occupational, and financial consequences. Therefore, treatment of mania is often considered a psychiatric emergency and is, when possible, best performed in the safety of an inpatient unit. While the primary treatment for mania is pharmacological, diminished insight can impede patients' willingness to accept treatment, emphasizing the significance of a balanced therapeutic approach that incorporates shared decision making frameworks as much as possible to promote treatment adherence.

The three main classes of anti-manic treatments are lithium, mood stabilizing anticonvulsants (divalproate and carbamazepine), and antipsychotic medications. Almost all antipsychotics are effective in treating mania, with the more potent dopamine D2 receptor antagonists such as risperidone and haloperidol demonstrating slightly higher efficacy ( fig 1 ). 73 In the United States, the FDA has approved the use of all second generation antipsychotics for treating mania except for lurasidone and brexpriprazole. Compared with mood stabilizing medications, second generation antipsychotics have a faster onset of action, making them a first line treatment for more severe manic symptoms that require rapid treatment. 99 The choice of which specific second generation antipsychotic to use depends on a balance of efficacy, tolerability concerns, and cost considerations (see table 1 ). Notably, the FDA has placed a black box warning on all antipsychotics for increasing the risk of cerebral vascular accidents in the elderly. 100 While this was primarily focused on the use of antipsychotics in dementia, this likely class effect should be taken into account when considering the use of antipsychotics in the elderly.

Traditional mood stabilizers, such as lithium, divalproate, and carbamazepine are also effective in the treatment of active mania ( fig 1 ). Since lithium also has a robust prophylactic effect (see section on prevention of mood episodes below) it is often recommended as first line treatment and can be considered as monotherapy when rapid symptom reduction is not clinically indicated. On the other hand, other anticonvulsants such as lamotrigine, gabapentin, topiramate, and oxcarbazepine have not been found to be effective for the treatment of mania or mixed episodes. 101 Although the empirical evidence for polypharmacy is limited, 102 combination treatment in acute mania, usually consisting of a mood stabilizer and a second generation antipsychotic, is commonly used in clinical practice despite the higher burden of side effects. Following resolution of an acute mania, consideration should be given to transitioning to monotherapy with an agent with proven prophylactic activity.

Pharmacological approaches to bipolar depression

Depressed episodes are usually more common than mania or hypomania, 103 104 and often represent the primary reason for individuals with bipolar disorder to seek treatment. Nevertheless, because early antidepressant randomized controlled trials did not distinguish between unipolar and bipolar depressive episodes, it has only been in the past two decades that large scale randomized controlled trials have been conducted specifically for bipolar depression. As such trials are almost exclusively funded by pharmaceutical companies, they have focused on the second generation antipsychotics and newer anticonvulsants still under patent. These trials have shown moderate but robust effects for most recent second generation antipsychotics, five of which have received FDA approval for treating bipolar depression ( table 1 ). No head-to-head trials have been conducted among these agents, so the choice of medication depends on expected side effects and cost considerations. For example, quetiapine has robust antidepressant efficacy data but is associated with sedation, weight gain, and adverse cardiovascular outcomes. 105 Other recently approved medications such as lurasidone, cariprazine, and lumateperone have better side effect profiles but show more modest antidepressant activity. 106

Among the mood stabilizing anticonvulsants, lamotrigine has limited evidence for acute antidepressant activity, 107 possibly owing to the need for an 8 week titration to reach the full dose of 200 mg. However, as discussed below, lamotrigine can still be considered for mild to moderate acute symptoms owing to its generally tolerable side effect profile and proven effectiveness in preventing the recurrence of depressive episodes. Divalproate and carbamazepine have some evidence of being effective antidepressants in small studies, but as there has been no large scale confirmatory study, they should be considered second or third line options. 86 Lithium has been studied for the treatment of bipolar depression as a comparator to quetiapine and was not found to have a significant acute antidepressant effect. 88

Antidepressants

Owing to the limited options of FDA approved medications for bipolar depression and concerns of metabolic side effects from long term second generation antipsychotic use, clinicians often resort to the use of traditional antidepressants for the treatment of bipolar depression 108 despite the lack of FDA approval for such agents. Indeed, recent randomized clinical trials of antidepressants in bipolar depression have not shown an effect for paroxetine, 89 109 bupropion, 109 or agomelatine. 110 Beyond the question of efficacy, another concern regarding antidepressants in bipolar disorder is their potential to worsen the course of illness by either promoting mixed or manic symptoms or inducing more subtle degrees of mood instability and cycle acceleration. 111 However, the risk of switching to full mania while being treated with mood stabilizers appears to be modest, with a meta-analysis of randomized clinical trials and clinical cohort studies showing the rates of mood switching over an average follow-up of five months to be approximately 15.3% in people with bipolar disorder treated on antidepressants compared with 13.8% in those without antidepressant treatment. 111 The risk of switching appears to be higher in the first 1-2 years of treatment in people with BD-I, and in those treated with a tricyclic antidepressant 112 or the dual reuptake inhibitor venlafaxine. 113 Overall, while the available data have methodological limitations, most guidelines do not recommend the use of antidepressants in bipolar disorder, or recommend them only after agents with more robust evidence have been tried. That they remain so widely used despite the equivocal evidence base reflects the unmet need for treatment of depression, concerns about the long term side effects of second generation antipsychotics, and the challenges of changing longstanding prescribing patterns.

Pharmacological approaches to prevention of recurrent episodes

Following treatment of the acute depressive or manic syndrome, the major focus of treatment is to prevent future episodes and minimize interepisodic subsyndromal symptoms. Most often, the medication that has been helpful in controlling the acute episode can be continued for prevention, particularly if clinical trial evidence exists for a maintenance effect. To show efficacy for prevention, studies must be sufficiently long to allow the accumulation of future episodes to occur and be potentially prevented by a therapeutic intervention. However, few long term treatment studies exist and most have utilized enriched designs that likely favor the drug seeking regulatory approval. As shown in figure 1 , meta-analyses 94 show prophylactic effect for most (olanzapine, risperidone, quetiapine, aripiprazole, asenapine) but not all (lurasidone, paliperidone) recently approved second generation antipsychotics. The effect sizes are generally comparable with monotherapy (odds ratio 0.42, 95% confidence interval 0.34 to 0.5) or as adjunctive therapy (odds ratio 0.37, 95% confidence interval 0.25 to 0.55). 94 Recent studies of lithium, which have generally used it as a (non-enriched) comparator drug, show a comparable protective effect (odds ratio 0.46, 95% confidence interval 0.28 to 0.75). 94 Among the mood stabilizing anticonvulsant drugs, a prophylactic effect has also been found for both divalproate and lamotrigine ( fig 1 and supplementary table 1), although only the latter has been granted regulatory approval for maintenance treatment. While there are subtle differences in effect sizes in drugs approved for maintenance ( fig 1 and table 1 ), the overlapping confidence intervals and methodological differences between studies prevent a strict comparison of the effect measures.

Guidelines often recommend lithium as a first line agent given its consistent evidence of prophylaxis, even when tested as the disadvantaged comparator drug in enriched drug designs. Like other medications, lithium has a unique set of side effects and ultimately the decision about which drug to use among those which are efficacious should be a decision carefully weighed and shared between patient and provider. The decision might be re-evaluated after substantial experience with the medication or at different stages in the long term treatment of bipolar disorder (see table 1 ).

Psychotherapeutic approaches

The frequent presence of residual symptoms, often associated with psychosocial and occupational dysfunction, has led to renewed interest in psychotherapeutic and psychosocial approaches to bipolar disorder. Given the impairment of judgment seen in mania, psychotherapy has more of a supportive and educational role in the treatment of mania, whereas it can be more of a primary focus in the treatment of depressive states. On a broad level, psychotherapeutic approaches effective for acute depression, such as cognitive behavioral therapy, interpersonal therapy, behavioral activation, and mindfulness based strategies, can also be recommended for acute depressive states in individuals with bipolar disorder. 114 Evidence for more targeted psychotherapy trials for bipolar disorder is more limited, but meta-analyses have found evidence for decreased recurrence (odds ratio 0.56; 95% confidence interval 0.43 to 0.74) 115 and improvement of subthreshold interepisodic depressive and manic symptoms with cognitive behavioral therapy, family based therapy, interpersonal and social rhythm therapy, and psychoeducation. 115 Recent investigations have also focused on targeted forms of psychotherapy to improve cognition 116 117 118 as well as psychosocial and occupational functioning. 119 120 Although these studies show evidence of a moderate effect, they remain preliminary, methodologically diverse, and require replication on a larger scale. 121

The implementation of evidence based psychotherapy as a treatment faces several challenges, including clinical training, fidelity monitoring, and adequate reimbursement. Novel approaches, leveraging the greater tractability of digital tools 122 and allied healthcare workers, 123 are promising means of lessening the implementation gap; however, these approaches require validation and evidence of clinical utility similar to traditional methods.

Neurostimulation approaches

For individuals with bipolar disorder who cannot tolerate or do not respond well to standard pharmacotherapy or psychotherapeutic approaches, neurostimulation techniques such as repetitive transcranial magnetic stimulation or electric convulsive therapy should be considered as second or third line treatments. Electric convulsive therapy has shown response rates of approximately 60-80% in severe acute depressions 124 125 and 50-60% in cases with treatment resistant depression. 126 These response rates compare favorably with those of pharmacological treatment, which are likely to be closer to ~50% and ~30% in subjects with moderate to severe depression and treatment resistant depression, respectively. 127 Although the safety of electric convulsive therapy is well established, relatively few medical centers have it available, and its acceptability is limited by cognitive side effects, which are usually short term, but which can be more significant with longer courses and with bilateral electrode placement. 128 While there have been fewer studies of electric convulsive therapy for bipolar depression compared with major depressive disorder, it appears to be similarly effective and might show earlier response. 129 Anecdotal evidence also suggests electric convulsive therapy that is useful in refractory mania. 130

Compared with electric convulsive therapy, repetitive transcranial magnetic stimulation has no cognitive side effects and is generally well tolerated. Repetitive transcranial magnetic stimulation acts by generating a magnetic field to depolarize local neural tissue and induce excitatory or inhibitory effects depending on the frequency of stimulation. The most studied FDA approved form of repetitive transcranial magnetic stimulation applies high frequency (10 Hz) excitatory pulses to the left prefrontal cortex for 30-40 minutes a day for six weeks. 131 Like electric convulsive therapy, repetitive transcranial magnetic stimulation has been primarily studied in treatment resistant depression and has been found to have moderate effect, with about one third of patients having a significant treatment response compared with those treated with pharmacotherapy. 131 Recent innovations in transcranial magnetic stimulation have included the use of a novel, larger coil to stimulate a larger degree of the prefrontal cortex (deep transcranial magnetic stimulation), 132 and a shortened (three minutes), higher frequency intermittent means of stimulation known as theta burst stimulation that appears to be comparable to conventional (10 Hz) repetitive transcranial magnetic stimulation. 133 A preliminary trial has recently assessed a new accelerated protocol of theta burst stimulation marked by 10 sessions a day for five days. It found that theta burst stimulation had a greater effect on people with treatment resistant depression compared with treatment as usual, although larger studies are needed to confirm these findings. 134

Conventional repetitive transcranial magnetic stimulation (10 Hz) studies in bipolar disorder have been limited by small sample sizes but have generally shown similar effects compared with major depressive disorder. 135 However, a proof of concept study of single session theta burst stimulation did not show efficacy in bipolar depression, 136 reiterating the need for specific trials for bipolar depression. Given the lack of such trials in bipolar disorder, repetitive transcranial magnetic stimulation should be considered a potentially promising but as yet unproven treatment for bipolar depression.

The other major form of neurostimulation studied in both unipolar and bipolar depression is transcranial direct current stimulation, an easily implemented method of delivering a low amplitude electrical current to the prefrontal area of the brain that could lead to local changes in neuronal excitability. 137 Like repetitive transcranial magnetic stimulation, transcranial direct current stimulation is well tolerated and has been mostly studied in unipolar depression, but has not yet generated sufficient evidence to be approved by a regulatory agency. 138 Small studies have been performed in bipolar depression, but the results have been mixed and require further research before use in clinical settings. 137 138 139 Finally, the evidence for more invasive neurostimulation studies such as vagal nerve stimulation and deep brain stimulation remains extremely limited and is currently insufficient for clinical use. 140 141

Treatment resistance in bipolar disorder

As in major depressive disorder, the use of term treatment resistance in bipolar disorder is controversial since differentiating whether persistent symptoms are caused by low treatment adherence, poor tolerability, the presence of comorbid disorders, or are the result of true treatment resistance, is an essential but often challenging clinical task. Treatment resistance should only be considered after two or three trials of evidence based monotherapy, adjunctive therapy, or both. 142 In difficult-to-treat mania, two or more medications from different mechanistic classes are typically used, with electric convulsive therapy 143 and clozapine 144 being considered if more conventional anti-manic treatments fail. In bipolar depression, it is common to combine antidepressants with anti-manic agents, despite limited evidence for efficacy. 145 Adjunctive therapies such as bright light therapy, 146 the dopamine D2/3 receptor agonist pramipexole, 147 and ketamine 148 149 have shown promising results in small open label trials that require further study.

Treatment considerations to reduce suicide in bipolar disorder

The risk of completed suicide is high across the subtypes of bipolar disorder, with estimated rates of 10-15% across the lifespan. 150 151 152 Lifetime rates of suicide attempts are much higher, with almost half of all individuals with bipolar disorder reporting at least one attempt. 153 Across a population and, often within individuals, the causes of suicide attempts and completed suicides are likely to be multifactorial, 154 affected by various risk factors, such as symptomatic illness, environmental stressors, comorbidities (particularly substance misuse), trait impulsivity, interpersonal conflict, loneliness, or socioeconomic distress. 155 156 Risk is highest in depressive and dysphoric/mixed episodes 157 158 and is particularly high in the transitional period following an acute admission to hospital. 159 Among the available treatments, lithium has potential antisuicidal properties. 160 However, since suicide is a rare event, with very few to zero suicides within a typical clinical trial, moderate evidence for this effect emerges only in the setting of meta-analyses of clinical trials. 160 Several observational studies have shown lower mortality in patients on lithium treatment, 161 but such associations might not be causal, since lithium is potentially fatal in overdose and is often avoided by clinicians in patients at high risk of suicide.

The challenge of studying scarce events has led most studies to focus on the reduction of the more common phenomena of suicidal ideation and behavior as a proxy for actual suicides. A recent such multisite study of the Veterans Affairs medical system included a mixture of unipolar and bipolar disorder and was stopped prematurely for futility, indicating no overall effect of moderate dose lithium. 162 Appropriate limitations of this study have been noted, 163 164 including difficulties in recruitment, few patients with bipolar disorder (rather than major depressive disorder), low levels of compliance with lithium therapy, high rates of comorbidity, and a follow-up of only one year. Nevertheless, while the body of evidence suggests that lithium has a modest antisuicidal effect, its degree of protection and utility in complex patients with comorbidities and multiple risk factors remain matters for further study. Treatment of specific suicidal risk in patients with bipolar disorder must therefore also incorporate broader interventions based on the individual’s specific risk factors. 165 Such an approach would include societal interventions like means restriction 166 and a number of empirically tested suicide focused psychotherapy treatments. 167 168 Unfortunately, the availability of appropriate training, expertise, and care models for such treatments remains limited, even in higher income countries. 169

More scalable solutions, such as the deployment of shortened interventions via digital means could help to overcome this implementation gap; however, the effectiveness of such approaches cannot be assumed and requires empirical testing. For example, a recent large scale randomized controlled trial of an abbreviated online dialectical behavioral therapy skills training program was paradoxically associated with slightly increased risk of self-harm. 170

Treatment consideration in BD-II and bipolar spectrum conditions

Because people with BD-II primarily experience depressive symptoms and appear less likely to switch mood states compared with individuals with BD-I, 50 171 there has been a greater acceptance of the use of antidepressants in BD-II depression, including as monotherapy. 172 However, caution should be exercised when considering the use of antidepressants without a mood stabilizer in patients with BD-II who might also experience high rates of mood instability and rapid cycling. Such individuals can instead respond better to newer second generation antipsychotic agents such as quetiapine 173 and lumateperone, 93 which are supported by post hoc analyses of these more recent clinical trials with more BD-II patients. In addition, despite the absence of randomized controlled trials, open label studies have suggested that lithium and other mood stabilizers can have similar efficacy in BD-II, especially in the case of lamotrigine. 174

Psychotherapeutic approaches such as psychoeducation, cognitive behavioral therapy, and interpersonal and social rhythm therapy have been found to be helpful 115 and can be considered as the primary form of treatment for BD-II in some patients, although in most clinical scenarios BD-II is likely to occur in conjunction with psychopharmacology. While it can be tempting to consider BD-II a milder variant of BD-I, high rates of comorbid disorders, rapid cycling, and adverse consequences such as suicide attempts 175 176 highlight the need for clinical caution and the provision of multimodal treatment, focusing on mood improvement, emotional regulation, and better psychosocial functioning.

Precision medicine: can it be applied to improve the care of bipolar disorder?

The recent focus on precision medicine approaches to psychiatric disorders seeks to identify clinically relevant heterogeneity and identify characteristics at the level of the individual or subgroup that can be leveraged to identify and target more efficacious treatments. 1 177 178

The utility of such an approach was originally shown in oncology, where a subset of tumors had gene expression or DNA mutation signatures that could predict response to treatments specifically designed to target the aberrant molecular pathway. 179 While much of the emphasis of precision medicine has been on the eventual identification of biomarkers utilizing high throughput approaches (genetics and other “omics” based measurements), the concept of precision medicine is arguably much broader, encompassing improvements in measurement, potentially through the deployment of digital tools, as well as better conceptualization of contextual, cultural, and socioeconomic mechanisms associated with psychopathology. 180 181 Ultimately, the goal of precision psychiatry is to identify and target driving mechanisms, be they molecular, physiological, or psychosocial in nature. As such, precision psychiatry seeks what researchers and clinicians have often sought: to identify clinically relevant heterogeneity to improve prediction of outcomes and increase the likelihood of therapeutic success. The novelty being not so much the goals of the overarching approach, but the increasing availability of large samples, novel digital tools, analytical advances, and an increasing armamentarium of biological measurements that can be deployed at scale. 177

Although not unique to bipolar disorder, several clinical decision points along the life course of bipolar disorder would benefit from a precision medicine approach. For example, making an early diagnosis is often not possible based on clinical symptoms alone, since such symptoms are usually non-specific. A precision medicine approach could also be particularly relevant in helping to identify subsets of patients for whom the use of antidepressants could be beneficial or harmful. Admittedly, precision medicine approaches to bipolar disorder are still in their infancy, and larger, clinically relevant, longitudinal, and reliable phenotypes are needed to provide the infrastructure for precision medicine approaches. Such data remain challenging to obtain at scale, leading to renewed efforts to utilize the extant clinical infrastructure and electronic medical records to help emulate traditional longitudinal analyses. Electronic medical records can help provide such data, but challenges such as missingness, limited quality control, and potential biases in care 182 need to be resolved with carefully considered analytical designs. 183

Emerging treatments

Two novel atypical antipsychotics, amilsupride and bifeprunox, are currently being tested in phase 3 trials ( NCT05169710 and NCT00134459 ) and could gain approval for bipolar depression in the near future if these pivotal trials show a significant antidepressant effect. These drugs could offer advantages such as greater antidepressant effects, fewer side effects, and better long term tolerability, but these assumptions must be tested empirically. Other near term possibilities include novel rapid antidepressant treatments, such as (es)ketamine that putatively targets the glutamatergic system, and has been recently approved for treatment resistant depression, but which have not yet been tested in phase 3 studies in bipolar depression. Small studies have shown comparable effects of intravenous ketamine, 149 184 in bipolar depression with no short term evidence of increased mood switching or mood instability. Larger phase 2 studies ( NCT05004896 ) are being conducted which will need to be followed by larger phase 3 studies. Other therapies targeting the glutamatergic system have generally failed phase 3 trials in treatment resistant depression, making them unlikely to be tested in bipolar depression. One exception could be the combination of dextromethorphan and its pharmacokinetic (CYP2D6) inhibitor bupropion, which was recently approved for treatment resistant depression but has yet to be tested in bipolar depression. Similarly, the novel GABAergic compound zuranolone is currently being evaluated by the FDA for the treatment of major depressive disorder and could also be subsequently studied in bipolar depression.

Unfortunately, given the general efficacy for most patients of available treatments, few scientific and financial incentives exist to perform large scale studies of novel treatment in mania. Encouraging results have been seen in small studies of mania with the selective estrogen receptor modulator 185 tamoxifen and its active metabolite endoxifen, both of which are hypothesized to inhibit protein kinase C, a potential mechanistic target of lithium treatment. These studies remain small, however, and anti-estrogenic side effects have potentially dulled interest in performing larger studies.

Finally, several compounds targeting alternative pathophysiological mechanisms implicated in bipolar disorder have been trialed in phase 2 academic studies. The most studied has been N -acetylcysteine, a putative mitochondrial modulator, which initially showed promising results only to be followed by null findings in larger more recent studies. 186 Similarly, although small initial studies of anti-inflammatory agents provided impetus for further study, subsequent phase 2 studies of the non-steroidal agent celecoxib, 187 the anti-inflammatory antibiotic minocycline, 187 and the antibody infliximab (a tumor necrosis factor antagonist) 188 have not shown efficacy for bipolar depression. Secondary analyses have suggested that specific anti-inflammatory agents might be effective only for a subset of patients, such as those with elevated markers of inflammation or a history of childhood adversity 189 ; however, such hypotheses must be confirmed in adequately powered independent studies.

Several international guidelines for the treatment of bipolar disorder have been published in the past decade, 102 190 191 192 providing a list of recommended treatments with efficacy in at least one large randomized controlled trial. Since effect sizes tend to be moderate and broadly comparable across classes, all guidelines allow for significant choice among first line agents, acknowledging that clinical characteristics, such as history of response or tolerability, severity of symptoms, presence of mixed features, or rapid cycling can sometimes over-ride guideline recommendations. For acute mania requiring rapid treatment, all guidelines prioritize the use of second generation antipsychotics such as aripiprazole, quetiapine, risperidone, asenapine, and cariprazine. 102 192 193 Combination treatment is considered based on symptom severity, tolerability, and patient choice, with most guidelines recommending lithium or divalproate along with a second generation antipsychotic for mania with psychosis, severe agitation, or prominent mixed symptoms. While effective, haloperidol is usually considered a second choice option owing to its propensity to cause extrapyramidal symptoms. 102 192 193 Uniformly, all guidelines agree on the need to taper antidepressants in manic or mixed episodes.

For maintenance treatment, guidelines are generally consistent in recommending lithium if tolerated and without relative contraindications, such as baseline renal disease. 194 The second most recommended maintenance treatment is quetiapine, followed by aripiprazole for patients with prominent manic episodes and lamotrigine for patients with predominant depressive episodes. 194 Most guidelines recommend considering prophylactic properties when initially choosing treatment for acute manic episodes, although others suggests that acute maintenance treatments can be cross tapered with maintenance medications after several months of full reponse. 193

For bipolar depression, recent guidelines recommend specific second generation antipsychotics such as quetiapine, lurasidone, and cariprazine 102 192 193 For more moderate symptoms, consideration is given to first using lamotrigine and lithium. Guidelines remain cautious about the use of antidepressants (selective serotonin reuptake inhibitors, venlafaxine, or bupropion) in patients with BP-I, restricting them to second or third line treatments and always in the context of an anti-manic agent. However, for patients with BP-II and no rapid cycling, several guidelines allow for the use of carefully monitored antidepressant monotherapy.

Bipolar disorder is a highly recognizable syndrome with many effective treatment options, including the longstanding gold standard therapy lithium. However, a significant proportion of patients do not respond well to current treatments, leading to negative consequences, poor quality of life, and potentially shortened lifespan. Several novel treatments are being developed but limited knowledge of the biology of bipolar disorder remains a major challenge for novel drug discovery. Hope remains that the insights of genetics, neuroimaging, and other investigative modalities could soon be able to inform the development of rational treatments aimed to mitigate the underlying pathophysiology associated with bipolar disorder. At the same time, however, efforts are needed to bridge the implementation gap and provide truly innovative and integrative care for patients with bipolar disorder. 195 Owing to the complexity of bipolar disorder, few patients can be said to be receiving optimized care across the various domains of mental health that are affected in those with bipolar disorder. Fortunately, the need for improvement is now well documented, 196 and concerted efforts at the scale necessary to be truly innovative and integrative are now on the horizon.

Questions for future research

Among adolescents and young adults who manifest common mental disorders such as anxiety or depressive or attentional disorders, who will be at high risk for developing bipolar disorder?

Can we predict the outcomes for patients following a first manic or hypomanic episode? This will help to inform who will require lifelong treatment and who can be tapered off medications after sustained recovery.

Are there reliable clinical features and biomarkers that can sufficiently predict response to specific medications or classes of medication?

What are the long term consequences of lifelong treatments with the major classes of medications used in bipolar disorder? Can we predict and prevent medical morbidity caused by medications?

Can we understand in a mechanistic manner the pathophysiological processes that lead to abnormal mood states in bipolar disorder?

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

Contributors: FSG performed the planning, conduct, and reporting of the work described in the article. FSG accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

Competing interests: I have read and understood the BMJ policy on declaration of interests and declare no conflicts of interest.

Patient involvement: FSG discussed of the manuscript, its main points, and potential missing points with three patients in his practice who have lived with longstanding bipolar disorder. These additional viewpoints were incorporated during the drafting of the manuscript.

Provenance and peer review: Commissioned; externally peer reviewed.

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IMAGES

(PDF) The challenges of living with bipolar disorder: a qualitative
(PDF) Bipolar disorder and aging
(PDF) Bipolar Depression: Overview and Commentary
(PDF) Editorial: a new journal in bipolar disorders
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(PDF) Neuropsychology of bipolar disorder

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COMMENTS

PDF Diagnosis and management of bipolar disorders
This article provides an overview of the clinical features, diagnostic subtypes, and major treatment modalities for bipolar disorder, a recurrent and sometimes chronic mood disorder. It also explores the causes, prognosis, and novel areas of inquiry for bipolar disorder research.
(PDF) Bipolar Disorder: From Pathophysiology to Treatment
Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which ...
The Diagnosis and Management of Bipolar I and II Disorders
Making the Diagnosis. The first step toward the accurate diagnosis of BP-I or BP-II disorder is identifying current or past manic, hypomanic, and depressive epi-sodes. Diagnostic criteria for these types of mood episodes, and clinical probes for identi-fying key symptoms, are provided in Table 1.12 With this information, speci c bipo-fi lar ...
Bipolar Disorder
Bipolar I disorder is defined by the presence of overt manic episodes with a range of manifestations, including overconfidence, grandi-osity, talkativeness, extreme disinhibition, irritability ...
Articles
Bipolar disorder is a broad diagnostic construct associated with significant phenotypic and genetic heterogeneity challenging progress in clinical practice and discovery research. Prospective studies of well-c... Anne Duffy and Paul Grof. International Journal of Bipolar Disorders 2024 12:12.
Bipolar disorders
Bipolar disorders are a group of chronic mental disorders that include bipolar I disorder and bipolar II disorder ().Bipolar I disorder is defined by the presence of a syndromal, manic episode, and has an estimated global lifetime prevalence of 0·6-1·0%. 1 Bipolar II disorder is defined by the presence of a syndromal, hypomanic episode and a major depressive episode, and has an estimated ...
Full article: Bipolar depression: the clinical characteristics and
Prevalence. Lifetime and 12 month prevalence for bipolar I disorder have been estimated at 2.1% and 1.5%, respectively, based on criteria from the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Citation 4; rates for men and women are similar Citation 3.The prevalence of bipolar disorder decreases with increasing age and education level, while its prevalence ...
Mapping the scientific research on bipolar disorder: A scientometric
Bipolar disorder (BD) is a severe psychiatric illness with an increasing prevalence worldwide. Although the pathological mechanism of and pharmacological interventions for BD have been extensively investigated in preclinical and clinical studies, a scientometric analysis of the developmental trends, interdisciplinary frontiers, and research hotspots in this field has not yet been conducted.
REVIEW Diagnosis and treatment of patients with bipolar disorder: A
Purpose: This review article provides an overview of the frequency, burden of illness, diagnosis, and treatment of bipolar disorder (BD) from the perspective of the advanced practice nurses (APNs). Data sources: PubMed searches were conducted using the following keywords: "bipolar disorder and primary care," restricted to dates 2000 to ...
A Review of Bipolar Disorder in Adults
Epidemiology. Bipolar I disorder starts on average at 18 years and bipolar II disorder at 22 years. 9,14 A community study using the Mood Disorder Questionnaire (MDQ) revealed a prevalence of 3.7 percent. 15 The National Comorbidity Study showed onset typically between 18 and 44, with higher rates between 18 and 34 than 35 and 54. 1 In a survey of members of the DBSA, more than half of the ...
(PDF) Bipolar Disorder
Abstract. Bipolar disorder is a severe, complicated, and often misunderstood disorder that can have serious impacts on a person's quality of life, sense of self-worth, and overall health. This ...
Diagnosis and treatment of patients with bipolar disorder: A review for
Introduction. Bipolar disorder (BD) is a chronic illness associated with severely debilitating symptoms that can have profound effects on both patients and their caregivers (Miller, 2006).BD typically begins in adolescence or early adulthood and can have life‐long adverse effects on the patient's mental and physical health, educational and occupational functioning, and interpersonal ...
PDF BIPOLAR DISORDER
What causes bipolar disorder? Men and women are equally likely to have bipolar disorder, and it can affect people from any background and at any age. However, it is most common between the ages of 15 to 35 years. The exact cause that leads to some people developing bipolar disorder is not known, but there are factors that play a part in causing
The challenges of living with bipolar disorder: a qualitative study of
Bipolar disorder (BD) is a major mood disorder characterized by recurrent episodes of depression and (hypo)mania (Goodwin and Jamison 2007).According to the Diagnostic and Statistical Manual 5 (DSM-5), the two main subtypes are BD-I (manic episodes, often combined with depression) and BD-II (hypomanic episodes, combined with depression) (APA 2014).
Bipolar Disorder
Bipolar disorder, also known as bipolar affective disorder, is one of the top 10 leading causes of disability worldwide. Bipolar disorder is characterized by chronically occurring episodes of mania or hypomania alternating with depression and is often misdiagnosed initially. Treatment involves pharmacotherapy and psychosocial interventions, but ...
PDF Bipolar Disorder
Bipolar disorder is a mental illness that can be chronic (persistent or constantly reoccurring) or episodic (occurring occasionally and at irregular intervals). People sometimes refer to bipolar disorder with the older terms "manic-depressive disorder" or "manic depression.". Everyone experiences normal ups and downs, but with bipolar ...
(PDF) Bipolar disorder: an overview
PDF | Bipolar disorder (BD) is a chronic disorder characterised by abnormal mood changes and fluctuation in energy levels. The disease is characterised... | Find, read and cite all the research ...
Bipolar I disorder: a qualitative study of the viewpoints of the family
Bipolar disorder is a common psychiatric disorder with a massive psychological and social burden. Research indicates that treatment adherence is not good in these patients. The families' knowledge about the disorder is fundamental for managing their patients' disorder. The purpose of the present study was to investigate the knowledge of the family members of a sample of Iranian patients ...
Diagnosis and management of bipolar disorders
Bipolar disorders (BDs) are recurrent and sometimes chronic disorders of mood that affect around 2% of the world's population and encompass a spectrum between severe elevated and excitable mood states (mania) to the dysphoria, low energy, and despondency of depressive episodes. The illness commonly starts in young adults and is a leading cause of disability and premature mortality.
(PDF) BIPOLAR DISORDER IN ADULTS
Bipolar disorder is the 6th leading cause of disability in the developed world among those between the ages 15 and 44 years age groups. Serotonin is one of the neurotransmitter in the brain, and ...

The challenges of living with bipolar disorder: a qualitative study of the implications for health care and research

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Bipolar I disorder: a qualitative study of the viewpoints of the family members of patients on the nature of the disorder and pharmacological treatment non-adherence

Study samples’ characteristics

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Theme one: knowledge about the disorder

Theme two: information about the medications

Theme three: information about the treatment

Theme four: information about the role of the family in the treatment

Theme five: reasons for pharmacological treatment non-adherence

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Diagnosis and management of bipolar disorders

Introduction

Sources and selection criteria

Modern definitions of bipolar disorder

Epidemiology

Causes of bipolar disorder

Insights from genetics

Insights from neuroimaging

Environmental risk factors

Comorbidity

Precursors and prodromes: who develops bipolar disorder?

Screening for bipolar disorder

Racial/ethnic disparities

Acute treatment of mania

Pharmacological approaches to bipolar depression

Antidepressants

Pharmacological approaches to prevention of recurrent episodes

Psychotherapeutic approaches

Neurostimulation approaches

Treatment resistance in bipolar disorder

Treatment considerations to reduce suicide in bipolar disorder

Treatment consideration in BD-II and bipolar spectrum conditions

Precision medicine: can it be applied to improve the care of bipolar disorder?

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