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

Eva f maassen, barbara j regeer, eline j regeer, joske f g bunders, ralph w kupka.

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Received 2018 Jun 6; Accepted 2018 Aug 22; Collection date 2018.

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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:

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)

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

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:

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

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

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 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 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.

Authors’ contributions

EFM designed the study, contributed to the data collection, managed the analysis and wrote the first draft of the manuscript. BJR designed the study and contributed to the data collection, data analysis, and writing of the manuscript. JFGB contributed to the study design and critical revision of the manuscript. EJR contributed to the study conception and critical revision of the manuscript. RWK contributed to the study design, acquisition of data, and critical revision of the manuscript. All authors contributed to the final manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

The authors received no financial support for the research.

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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.

Contributor Information

Eva F. Maassen, Phone: +31 (0)6 13861504, Email: [email protected]

Barbara J. Regeer, Email: [email protected]

Eline J. Regeer, Email: [email protected]

Joske F. G. Bunders, Email: [email protected]

Ralph W. Kupka, Email: [email protected]

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Bipolar depression: a major unsolved challenge

• Ross J. Baldessarini   ORCID: orcid.org/0000-0001-9718-8211 1 , 2 ,
• Gustavo H. Vázquez 2 , 3 &
• Leonardo Tondo 1 , 2 , 4  

International Journal of Bipolar Disorders volume  8 , Article number:  1 ( 2020 ) Cite this article

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Depression in bipolar disorder (BD) patients presents major clinical challenges. As the predominant psychopathology even in treated BD, depression is associated not only with excess morbidity, but also mortality from co-occurring general-medical disorders and high suicide risk. In BD, risks for medical disorders including diabetes or metabolic syndrome, and cardiovascular disorders, and associated mortality rates are several-times above those for the general population or with other psychiatric disorders. The SMR for suicide with BD reaches 20-times above general-population rates, and exceeds rates with other major psychiatric disorders. In BD, suicide is strongly associated with mixed (agitated-dysphoric) and depressive phases, time depressed, and hospitalization. Lithium may reduce suicide risk in BD; clozapine and ketamine require further testing. Treatment of bipolar depression is far less well investigated than unipolar depression, particularly for long-term prophylaxis. Short-term efficacy of antidepressants for bipolar depression remains controversial and they risk clinical worsening, especially in mixed states and with rapid-cycling. Evidence of efficacy of lithium and anticonvulsants for bipolar depression is very limited; lamotrigine has long-term benefit, but valproate and carbamazepine are inadequately tested and carry high teratogenic risks. Evidence is emerging of short-term efficacy of several modern antipsychotics (including cariprazine, lurasidone, olanzapine-fluoxetine, and quetiapine) for bipolar depression, including with mixed features, though they risk adverse metabolic and neurological effects.

Background: depression in bipolar disorder

Nosological uncertainties.

Debate concerning Kraepelin’s broadly inclusive concept of manic-depressive illness (MDI) continued to 1980 with a first formal separation of a distinct bipolar disorder (BD) with mania from nonbipolar major depressive disorder (MDD) in DSM-III (Trede et al. 2005 ; Baldessarini et al. 2015 ). Tension continues between lumping mood syndromes and separating various depressive and bipolar subtypes, and considering a “spectrum” of disorders ranging from more or less pure depression to archetypical BD, leading to profound therapeutic ambiguities (Cuellar et al. 2005 ; Goodwin and Jamison 2007 ; Baldessarini 2013 ; Yildiz et al. 2015 ; Tondo et al. 2018 ).

Current status of bipolar depression

Adequate understanding, timely diagnosis, and effective short- and long-term treatment of depressive episodes in BD patients are critically important but remarkably insufficiently resolved (Baldessarini et al. 2010c ). Clinical significance of bipolar depression is underscored by strong association with overall morbidity, other co-occurring psychiatric conditions (notably anxiety and substance-abuse disorders), disability, and excess mortality owing largely to suicide in young patients and intercurrent medical illness in older patients (Ösby et al. 2001 , 2018 ; Tondo et al. 2014 , 2016 ; Baldessarini et al. 2020 ).

Clinical challenges include difficult and often long-delayed diagnostic differentiation of depression as an initial presentation of BD vs. a manifestation of nonbipolar MDD. Accurate diagnosis and appropriate treatment typically are delayed by 6–8 years, and even longer following juvenile onset (Post et al. 2010 ; Bschor et al. 2012 ; Drancourt et al. 2013 ; Tondo et al. 2014 ). Depression is initially considered as unipolar MDD in as many as 40% of patients later diagnosed with BD (Stensland et al. 2008 ; Shen et al. 2018 ). Such uncertainty is heightened as depression is the most prevalent presenting polarity in BD, (Goodwin and Jamison 2007 ; Baldessarini et al. 2014 ; Yildiz et al. 2015 ). Moreover, excess future depression in BD can be anticipated by initial episodes of anxiety or mixed-states as well as of depression (Baldessarini et al. 2012 , 2014 , 2020 ).

BD patients commonly fear, seek to avoid, to report, and to seek clinical help for depression. Contrarily, they may not recognize moderate increases of mood, energy, activity, or libido as hypomanic symptoms as clinically relevant, and may even prefer such states. Diagnostic uncertainty is especially likely early in the illness-course and without corroborating information from a family member or close friend (Vöhringer and Perlis 2016 ).

In perhaps 12–17% of cases, BD is not recognized until there is a mood “switch” into hypomania or mania (“[hypo]mania”), either spontaneously or with exposure to a mood-elevating substance (Tondo et al. 2010 ; Baldessarini et al. 2013 ; Barbuti et al. 2017 ). Other indirect factors suggesting a diagnosis of BD include: (a) familial mania, psychosis, “nervous breakdown,” or psychiatric hospitalization; (b) early illness-onset, commonly with depression; (c) cyclothymic temperament; (d) multiple recurrences (e.g., ≥ 4 depressive episodes within 10 years); (e) depression with prominent agitation, anger, insomnia, irritability, talkativeness, other “mixed” or hypomanic features, or psychotic symptoms; (f) clinical “worsening,” especially with mixed features during an antidepressant treatment; (g) suicidal ideation and acts; and (h) substance abuse (Tondo et al. 2014 ; Vöhringer and Perlis 2016 ).

Depression in overall morbidity

Of note, overall time in depressive phases of BD, and duration of depressive episodes are much greater than in mania or hypomania (“[hypo]mania”) (Kupka et al. 2007 ; De Dios et al. 2010 ). Moreover, morbidity has been surprisingly high in BD despite supposedly effective treatment. Indeed, BD patients averaged 45% of time ill during long-term follow-up, and depression accounted for 72% of time-ill, and somewhat more with BD-II (81%) than BD-I (70%) (Forte et al. 2015 ) (Table  1 ).

Morbidity and disability

Given the high proportion of time in depression among BD patients, depression is likely to be associated with dysfunction and disability, including limited academic achievement and decreased employment success. Perhaps 80% of BD patients experience some work-loss, and 30–40% experience prolonged unemployment during adult working years—much of that disability associated with depression (Zimmerman et al. 2010 ; Arvilommi et al. 2015 ).

Co-occurring psychiatric disorders

Psychiatric conditions commonly encountered in BD patients include substance-abuse and anxiety disorders, as well as various personality disorders and temperament types (Goodwin and Jamison 2007 ; Pavlova et al. 2015 ; Preti et al. 2016 ; Messer et al. 2017 ; Stokes et al. 2017 ; Vázquez et al. 2017b ; Post et al. 2018 ). Such concomitant conditions may meet standard diagnostic criteria, but whether they should be considered separate, “co-morbid” disorders vs. expressions of the range of psychopathology of BD remains unresolved (Yildiz et al. 2015 ; Vázquez et al. 2017b ). Multiple diagnoses risk contributing to complexity and potential incoherence of treatment choices to compromise clinical care.

General-medical morbidity and mortality

BD patients have increased risk of many general-medical disorders, including vascular conditions, with increased morbidity, disability and diminished longevity (McIntyre et al. 2007 ; Correll et al. 2017 ; Fornaro et al. 2017 ). In addition, obesity, diabetes, migraine, and some infectious diseases are more prevalent among BD patients (McIntyre et al. 2007 ; Almeida et al. 2018 ). With BD, risk of myocardial infarction was 37% greater (88% among women), stroke 60%, and congestive heart failure nearly 230% greater than in age-matched general populations (Wu et al. 2015 ; Fornaro et al. 2017 ; Tsai et al. 2017 ). Cardiovascular diseases are particularly frequent in association with BD disorder (Table  2 ) (Correll et al. 2017 ). Mediating factors include obesity, inactivity, diabetes or metabolic syndrome, and increased inflammatory factors—all with increased prevalence among BD patients (Vancampfort et al. 2013 ; Halaris 2017 ; Tsai et al. 2017 ), and at least in part attributable to treatments which may contribute to these risks (Baldessarini 2013 ; Correll et al. 2015 ).

With many general-medical disorders, BD patients have more adverse clinical outcomes and diminished life-expectancy, with all-cause mortality up to 15-times above general population rates, and rising (McIntyre et al. 2007 ; Ösby et al. 2018 ; Hällgren et al. 2018 ; Staudt-Hansen et al. 2019 ). Life-expectancy with BD is reduced by 12–15 years (Chesney et al. 2014 ). Factors associated with this decreased longevity include co-occurring substance abuse, smoking, and being overweight, unmarried, and having limited access to adequate medical care (Hjorthøj et al. 2015 ; Brietzke et al. 2017 ; Dickerson et al. 2018 ). The decreased longevity may be particularly associated with depression (Dickerson et al. 2018 ).

Bipolar depression and suicide

Suicidal risks.

The reported international annual suicide rate averages 15.4/100,000 (0.015%/year), with wide regional variation (WHO 2018 ). The standardized mortality ratio (SMR) for suicide in BD is about 20 (Baldessarini et al. 2019a ). By diagnosis, suicide risk ranks: bipolar disorders (BD-I = BD-II; especially with mixed or psychotic features) ≥ severe major depressive disorder with hospitalization > moderate depression among outpatients (Bachmann 2018 ; Hällgren et al. 2018 ; Baldessarini et al. 2019a ). Risk for suicide and attempts is especially high in days following discharge from psychiatric hospitalization, in association with delay or lack of appropriate aftercare (Olfson et al. 2016 ; Large and Swaraj 2018 ; Forte et al. 2019 ).

In mood-disorder patients depressive-dysphoric phases are more associated with suicide than other illness states, especially if accompanied by mixed (hypomanic) features, co-occurring substance abuse, and following previous suicidal acts (Tondo et al. 1999 , 2018 ; Baldessarini et al. 2019b ). General population rates of suicide attempts average 0.2–0.6% per year, or approximately 36-times the suicide rate, and over 1%/year in BD (Kessler et al. 2005 ; Nock et al. 2008 ; Tondo et al. 2016 ; Baldessarini et al. 2019b ). The ratio of suicide attempts/suicides (A/S), an index of lethality lower with more lethal intent or method, is only 5–10 in BD and MDD, or about five-times above lower than that for the general population (Tondo and Baldessarini 2015 ; Baldessarini et al. 2019b ).

Among both BD-I and BD-II patients, especially with mixed or psychotic features, risk of suicidal behavior is among the highest of all psychiatric disorders despite supposedly effective treatments (Baldessarini et al. 2019b ). This disparity almost certainly reflects great difficulty of treating depressive and mixed states in BD (Baldessarini et al. 2010c ; Saunders and Hawton 2013 ; Forte et al. 2015 ). The remarkably prolonged delay of recognition and intervention in BD, sometimes for more than a decade, contrasts strikingly with observations that half of long-term risk of suicidal acts among BD patients occurred within the first 2–3 years of illness (Tondo and Baldessarini 2014 , 2015 ).

Suicide and treatment with antidepressants

Suicide cannot be “treated” but only prevented (Table  3 ). Research on treatments aimed at suicide prevention, not surprisingly, is very limited because of clinical and ethical problems arising if an inactive or ineffective treatment, such as placebo, were compared to an experimental intervention, with death as a potential outcome. In addition, it is virtually impossible to know when a suicide has been prevented, whereas suicidal acts or surrogate measures can be counted. Rarity of suicide, even among psychiatric patients, encourages research reliance on more prevalent measures related to suicide, including suicidal ideation, threats, self-injurious acts, or emergency interventions. However, the typically distant relationship of such measures to suicide limits their value in testing for therapeutic effects on suicide itself. Relating treatments to suicidal risks is further complicated by uncertain long-term adherence to recommended treatments (Isometsä 2005 ; Simon and Hales 2012 ; Baldessarini 2013 ; Ahmedani et al. 2014 ). Treatments for BD considered for possible suicide-prevention include antidepressants, anticonvulsants and lithium, antipsychotics, ECT, and psychosocial interventions (Table  3 ).

Strong association of suicidal behavior or acts with depression suggests that treatment with antidepressants might reduce suicidal risk, though most studies have yielded inconsistent evidence. Most were not designed to test for suicidal behavior as an explicit outcome measure rather than as an incidental and passively reported “adverse event” (Möller 2006 ; Tondo and Baldessarini 2015 ; Baldessarini et al. 2020 ). Too, some patients can worsen clinically when given an antidepressant, and the treated depressive episode can be accompanied by agitation, dysphoria, restlessness, irritability, anger, insomnia, behavioral disinhibition, or other mixed features, with increased risk of suicidal behavior (Tondo et al. 1999 , 2018 ; Maj et al. 2006 ; Simon and Hales 2012 ; Pacchiarotti et al. 2013 ). In addition, abrupt or rapid discontinuation of antidepressant treatment markedly increases early risk of new depression, and might increase suicidal risk (Baldessarini et al. 2010b ).

Several studies have found only minor associations of antidepressant treatment and suicidal behaviors, mainly with MDD (Beasley et al. 1991 ; Acharya et al. 2006 ; Möller 2006 ; Tondo et al. 2008 ; Khan et al. 2011 ; Tondo and Baldessarini 2015 ; Braun et al. 2016 ). Other findings noted increased risk of suicidal acts in juveniles and young adults but decreased risk in older adults (Hammad et al. 2006 ; Laughren et al. 2006 ; Bridge et al. 2007 ; Barbui et al. 2009 ; Saunders and Hawton 2013 ; Braun et al. 2016 ). However, most such studies lacked explicit, validated, predefined outcome measures pertinent to suicide.

In our experience, emergence of new suicidal behaviors among mood-disordered adults treated with sustained antidepressant treatment in clinical settings was infrequent, involving perhaps 5/1000 patients/year (Tondo et al. 2008 ). Nevertheless, risks of clinical worsening with antidepressants, as well as the possibility that acute depression may be the initial episode of BD, should be considered and monitored at any age, especially early in antidepressant treatment.

Lithium treatment and suicide

An association of reduced risk of suicides and attempts during long-term treatment with lithium in BD is supported consistently by most (Müller-Oerlinghausen et al. 2006 ; Baldessarini and Tondo 2008 ; Tondo and Baldessarini 2014 , 2015 , 2018 ; Roberts et al. 2017 ; Smith and Cipriani 2017 ; Felber et al. 2018 ), but not all studies (Marangell et al. 2008 ; Oquendo et al. 2011 ). At least 10 placebo-controlled, randomized trials not specifically designed with suicide risk as the primary outcome measure, but involving more than 110,000 person-years of risk, found five- to sixfold reductions in suicidal acts (Tondo et al. 1998 , 2001 ; Angst et al. 2005 ; Cipriani et al. 2005 ; Baldessarini et al. 2006 ; Lauterbach et al. 2008 ; Khan et al. 2011 ). Based on such studies, several expert reports recommend long-term lithium treatment to limit risk of suicidal behavior in BD patients (Wasserman et al. 2012 ; Lewitzka et al. 2013 ; Yatham et al. 2018 ).

Anticonvulsants and suicide

Few studies directly compare suicidal risks during treatment with alternatives to lithium, including anticonvulsants, and findings are largely inconsistent and inconclusive (Thies-Flechtner et al. 1996 ; Goodwin et al. 2003 ; Yerevanian et al. 2007 ; Baldessarini and Tondo 2009 ; Chen et al. 2019 ). The FDA ( 2008 ) proposed that some anticonvulsants may even be associated with increased risk of suicidal behavior, at least in epilepsy patients, though probably not in psychiatric applications (Yerevanian et al. 2007 ; Gibbons et al. 2009 ). Meta-analysis of suicidal behavior with lithium vs. several anticonvulsants (mainly valproate) in six direct comparisons involving over 30,000 patients found nearly three-fold greater reductions with lithium (Baldessarini and Tondo 2009 ).

Antipsychotics and suicide

Antipsychotic drugs remain little-evaluated for effects on suicidal behavior (Simon and Hales 2012 ). However, one study found no difference in relatively short-term risk of suicides or attempts during treatment of > 10,000 psychotic patients with either first- or second-generation antipsychotics (FGAs or SGAs) vs. placebo (Khan et al. 2001 ). In addition, mortality risk was not increased in nearly 109,000 schizophrenia subjects given antipsychotic drugs (Schneider-Thoma et al. 2018 ), but was greater without antipsychotic treatment in another study of over 2200 such patients (Tiihonen et al. 2006 ). The InterSePT study comparing suicide-related behavior in schizophrenia patients at high risk for suicide provided strong support for an antisuicidal effect of clozapine compared to olanzapine (Meltzer et al. 2003 ). Clozapine has not been evaluated adequately in the treatment of BD patients, although it may have antimanic or mood-stabilizing effects (Li et al. 2015 ). Studies of SGAs with antidepressant effects in BD patients, in particular, require assessment for effects on suicide.

Other treatments and suicide

Evidence is growing that the glutamate NMDA-receptor antagonist ketamine and its active S -enantiomer (esketamine) can exert rapid, short-term reduction of suicidal ideation along with rapid reduction of symptoms of depression, including in BD patients, although effects on suicidal behavior are uncertain (Parsaik et al. 2015 ; Grunebaum et al. 2017 ; Wilkinson et al. 2018 ). There is considerable uncertainty about how to continue use of racemic or S -ketamine following initial benefits, and some concern that its discontinuation may provoke adverse clinical responses (Schatzberg 2019 ). ECT often appears to be lifesaving in suicidal emergencies but lacks evidence of sustained antisuicidal efficacy (Fink et al. 2014 ). Other methods of external electrical or magnetic stimulation of brain, vagal nerve stimulation, and deep brain stimulation are being investigated or introduced for the treatment of otherwise treatment-resistant depression but remain to be tested adequately for specific effects on suicidal behavior, particularly in BD.

Additional interventions of potential value include emergency hospitalization (Zalsman et al. 2016 ) as well as psychotherapies, in particular cognitive-behavioral, dialectic, and interpersonal methods, which can improve depressive symptoms and may reduce suicidal risk (Brown et al. 2005 ; Zalsman et al. 2016 ; McCauley et al. 2018 ; Baldessarini et al. 2020 ). However, results from studies of psychosocial interventions may be limited by the self-selection of patients who adhere to such prolonged treatments.

Treatment of bipolar depression

As noted, depressive, dysthymic, and mixed states account for the majority of illness-burden in BD, and are strongly predicted by initial depressive, mixed, or anxious episodes (Goodwin and Jamison 2007 ; Yildiz et al. 2015 ; Forte et al. 2015 ; Baldessarini et al. 2014 , 2019a ). Remarkably few treatments are proved to be highly and consistently effective in acute episodes of bipolar depression, and there is even less evidence supporting substantial long-term protection from recurrences (Table  4 ). In particular, there is continued controversy about the value and risks of antidepressant drugs in bipolar depression (Pacchiarotti et al. 2013 ; McGirr et al. 2016 ). Lack of highly effective treatments encourages widespread drug-combinations and other off-label treatments largely untested for effectiveness and safety.

Relative paucity of experimental treatment studies for bipolar depression may reflect a broadly accepted view that “major depression” is similar in its clinical characteristics as well as treatment responses in BD and MDD (Baldessarini 2013 ). Instead, their characteristics differ, e.g., in family history, sex-distribution, onset-age, long-term diagnostic stability, episode duration, recurrence rates, and treatment-responses (Baldessarini et al. 2010a , c ). The assumption of similarity probably contributes to the rarity of direct comparisons of treatment responses with depression in BD vs. MDD, and leaves bipolar depression as a leading challenge for psychiatric therapeutics (Goodwin et al. 2016 ; Baldessarini et al. 2019b , 2020 ).

Antidepressants for bipolar depression

Ease and relative safety of treating depressive episodes with modern antidepressants, and strenuous efforts to minimize or avoid depression by BD patients and clinicians, have made antidepressants the leading treatment provided to BD patients (Baldessarini et al. 2008 , 2019b ). Nevertheless, there is a striking paucity of therapeutic experimentation and inconsistent findings, despite more than a half-century of use of antidepressant drugs to treat “depression,” with particularly serious gaps regarding dysthymia and dysphoria, mixed features, and long-term prophylaxis for bipolar depression (Ghaemi et al. 2008 , 2010 ; Sidor and MacQueen 2012 ; Baldessarini 2013 ; Pacchiarotti et al. 2013 ; Fountoulakis et al. 2017 ; Liu et al. 2017a ; Gitlin 2018 ). Many experts advise caution in using antidepressants, particularly for BD-I patients to avoid potentially dangerous mood-switches, and encourage their use, if necessary, only with mood-stabilizing agents or SGAs, and without current mixed features or agitation (Pacchiarotti et al. 2013 ; Tondo et al. 2013 ; Goodwin et al. 2016 ; Yatham et al. 2018 ).

Well-designed, controlled, monotherapy trials of antidepressants for acute bipolar depression are surprisingly few, vary in size and quality, and yield inconsistent findings (Table  4 ) (Vázquez et al. 2011 ; Tondo et al. 2013 ; Gitlin 2018 ; Yatham et al. 2018 ). Two large trials found no additional improvement in bipolar depression by adding paroxetine or bupropion to mood-stabilizing or antipsychotic drugs (Sachs et al. 2007 ; McElroy et al. 2010 ). Two meta-analyses including these and the few other relevant trials supported possible efficacy of various antidepressants in bipolar depression (Gijsman et al. 2004 ; Vázquez et al. 2013 ); another did not (Sidor and MacQueen 2012 ). Several direct comparisons found similar antidepressant responses in depressed BD and MDD patients (Vázquez et al. 2011 ). Another comparison of clinical responses in large samples of depressed BD-I, BD-II, or MDD patients also found only minor differences in response or remission and low risk of mood-switching in these disorders, provided that subjects with agitation or even minor mixed features were excluded (Tondo et al. 2013 ).

Impressions that antidepressants may be less effective in acute bipolar depression than in MDD may, to some extent, reflect adverse effects of treatment, including worsening of agitation, anger, or dysphoria, interpreted as failure of depression to respond (Tondo et al. 2013 ). Our findings from available randomized, controlled trials support the impression that antidepressant treatment has yielded a significant, 32% superiority over placebo for acute bipolar depression, with moderately high heterogeneity of outcomes (Table  4 ). Despite this limited and inconsistent body of research, it is evidently widely assumed clinically that antidepressants may be appropriate for some BD patients, and especially safe for BD-II depression (Baldessarini et al. 2008 ; Amsterdam and Shults 2010 ; Undurraga et al. 2012 ; Altshuler et al. 2017 ; Gitlin 2018 ). Selection of BD candidates for clinical antidepressant treatment may usefully be guided by previous beneficial and tolerated responses, relatively less severe or nonrapidly cycling illness, relatively few previous depressions, lack of switching from depression to mania, or of current agitation or even minor mixed features (Pacchiarotti et al. 2013 ; Tondo et al. 2013 ; Baldessarini et al. 2019b ). Research on biomarkers associated with response to antidepressants is ongoing and may help in identifying more effective treatments for various types of depression (Gadad et al. 2018 ).

Antidepressants and mood switching

There is widespread concern that antidepressant treatment for bipolar depression risks switching into potentially dangerous agitation or mania, especially in BD-I (Bond et al. 2008 ; Undurraga et al. 2012 ). Such risk is more associated with the long-term BD course-pattern of depression followed by mania before a stable interval (“DMI”) than the opposite (“MDI”) (Koukopoulos et al. 2013 ). However, it is difficult to distinguish spontaneous from antidepressant-associated switching in BD, mean rates of which are similar (13.8% [12.2–15.3] vs. 15.3% [14.5–16.1]) (Tondo et al. 2010 ). Though it is plausible to expect mood-stabilizing and antipsychotic drugs to prevent mood-switching with antidepressants, required randomized comparisons are lacking (Tondo et al. 2010 ; Baldessarini et al. 2019b ). Trials of antidepressants have found little difference in risk of new mania between antidepressants and placebo, with or without a mood-stabilizer included, although exposure times were short (Liu et al. 2017a ). However, one study found that switching in BD was 2.8-times greater within 9 months after adding an antidepressant, but not if a mood-stabilizer also was used (Viktorin et al. 2014 ), and switching risk was increased in the rare long-term trials with an antidepressant included in treatment (Ghaemi et al. 2008 ).

An evident clinical consensus is that antidepressants be used for BD only cautiously, with short-acting agents given in moderate, slowly increased doses, briefly, and with effective mood-stabilizing co-treatment, while monitoring for emerging hypomania. It seems prudent that antidepressants, especially tricyclics and some SNRIs, be used very cautiously for bipolar depression, especially in BD-I patients, and perhaps avoided altogether with a history of mood-switching during antidepressant treatment, rapid-cycling without antidepressant treatment, or if mixed symptoms are present (Tondo et al. 2010 ; Pacchiarotti et al. 2013 ).

Mood-stabilizers

Several anticonvulsants have been used widely for BD, based on secure evidence of short-term antimanic effects (carbamazepine and valproate) or long-term reduction of risk of depressive recurrences (lamotrigine) (Baldessarini 2013 ; Geddes and Miklowitz 2013 ; Reinares et al. 2013 ). Such treatment choices are encouraged by seeming simpler than treatment with lithium (Baldessarini 2013 ; Vázquez et al. 2014 ). For divalproex monotherapy, 4 small trials suggest possible value in acute bipolar depression (Table  4 ), but it remains FDA-unapproved for depression or long-term treatment in BD. Evidence that lamotrigine is effective in acute bipolar depression rests on pooling inconsistent data, including from individually failed trials vs. placebo (Table  4 ) (Solmi et al. 2016 ). Lamotrigine is FDA-approved only for long-term prophylaxis in BD, with partial effectiveness against recurrences of depression but little efficacy against acute or recurrent mania (Frye et al. 2011 ; Baldessarini 2013 ). Moreover, slow dose-increases to avoid potentially serious dermatological reactions limit practicality of off-label use of lamotrigine in acute bipolar depression. Evidence concerning carbamazepine for short- or long-term use for bipolar depression is very limited (Table  4 ), and controlled trials for other anticonvulsants in BD are lacking (Reinares et al. 2013 ; Selle et al. 2014 ).

Despite use of lithium as a fundamental treatment for BD for more than six decades, and its position as a first-line treatment in some expert guidelines (Goodwin et al. 2016 ; Yatham et al. 2018 ), it remains virtually untested for acute bipolar depression. Lithium was included as a third-arm of a trial in acute bipolar depression designed primarily to test quetiapine, with little benefit (Table  4 ) (Young et al. 2010 ). Nevertheless, lithium has some long-term effectiveness against recurrences of bipolar depression as well as greater prophylactic effects against [hypo]mania (Baldessarini 2013 ; Bschor 2014 ; Yatham et al. 2018 ), and benefits in mixed episodes in BD (Sani and Fiorillo 2019 ). Moreover, as noted, lithium may reduce risk of suicide substantially in BD patients (Tondo et al. 2001 ; Baldessarini et al. 2006 ; Cipriani et al. 2013 ; Tondo and Baldessarini  2014 , 2018 ; Song et al. 2017 ).

Second-generation antipsychotics

SGAs, including cariprazine, lurasidone, olanzapine-fluoxetine, and quetiapine are currently the only FDA-approved medicines for short-term treatment of acute depressive episodes in BD (Baldessarini 2013 ; Selle et al. 2014 ; Earley et al. 2019 ; Ragguett and McIntyre 2019 ). Of these, only quetiapine has outperformed placebo consistently in several trials, with similar results for doses of 300 vs. 600 mg/day, and only the lower dose is FDA-approved (McElroy et al. 2010 ). Olanzapine-fluoxetine was superior to placebo, whereas olanzapine alone was less effective (Tohen et al. 2003 ). Unsurprisingly, as both olanzapine and quetiapine are antimanic, they have yielded somewhat lower risks of mood-switching than placebo (Selle et al. 2014 ). Most of these responses in acute bipolar depression have been modest (Table  4 ), and possible long-term protective effects require further study. Of note, beneficial effects in bipolar depression are not a class-effect of all SGAs (Taylor et al. 2014 ). In effective doses, antipsychotics risk adverse effects that include excessive sedation as well as distressing restlessness (akathisia) (Brown et al. 2006 ; Tamayo et al. 2010 ). Although risks of tardive dyskinesia with most SGAs are far lower than with FGAs (Tarsy et al. 2010 ; Carbon et al. 2017 ), their greatly increasing use and broadening indications may risk increased numbers of cases of even this uncommon adverse outcome (Pompili et al. 2016 ). Moreover, risks of weight-gain, type-2 diabetes, and other features of metabolic syndrome (hyperlipidemia, hypertension) are encountered with some SGAs (particularly olanzapine and quetiapine), sometimes rapidly (Centorrino et al. 2012 ; Baldessarini 2013 ; Vázquez et al. 2015 ). These medically important adverse effects tend to limit the potential value of SGAs for prophylactic treatment against recurrences of bipolar depression (Vázquez et al. 2014 , 2015 ; Fountoulakis et al. 2017 ). In summary, cariprazine, lurasidone, and quetiapine, as well as olanzapine-fluoxetine are effective in acute bipolar depression, though with some risks, and they need further testing for long-term, prophylactic effects against bipolar depression.

Other treatments

Growing numbers of novel pharmacological treatments for depression are under investigation; some may be of value in BD, including drugs that act at synaptic transmission systems mediated by amino acid neurotransmitters glutamate and GABA. They include the NMDA-glutamate receptor antagonist ketamine and newer pharmacologically similar agents (e.g., apimostinel, rapastinel) (Dhir 2017 ; Garay et al. 2017 ; Grady et al. 2017 ; Grunebaum et al. 2017 ; Ragguett et al. 2019 ; Wilkinson and Sanacora 2019 ). Given apparent association of postpartum mood disorders and BD (Liu et al. 2017b ), neurosteroids that interact with GABA A receptors and found effective for postpartum depression (e.g., brexanolone) may be of interest for bipolar depression (Martinez-Botella et al. 2017 ; Scott 2019 ). Agents of less certain value include polyunsaturated fatty acids, anti-inflammatory agents, and probiotics (Vázquez et al. 2017a ).

Among nonpharmacological treatments, acute bipolar depression is responsive to ECT (Itagaki et al. 2017 ; Perugi et al. 2017 ; Bahji et al. 2019 ), although optimal treatment to follow successful ECT remains uncertain. Other biomedical treatments may be of value in bipolar depression. Intense light therapy and sleep deprivation are plausible candidates that require adequate testing in BD (Tseng et al. 2016 ; Suzuki et al. 2018 ). Vagal nerve stimulation (VNS) is FDA-approved for treatment-resistant depression, with evidence of efficacy in depression of BD and MDD (Cimpianu et al. 2017 ; Conway et al. 2018 ), though with some risk of inducing mania (Salloum et al. 2017 ). Repeated transcranial magnetic stimulation (rTMS) and various forms of electrical stimulation of brain from the surface or through stereotaxically placed deep-brain electrodes remain experimental for bipolar depression (Nierenberg et al. 2008 ; Vázquez et al. 2017a ; Widge et al. 2018 ; Filkowski and Sheth 2019 ).

Finally, several manual-based, replicable forms of psychotherapy, alone or added to antidepressants, have shown promise for treating BD patients (Bouwkamp et al. 2013 ; McMahon et al. 2016 ; Salcedo et al. 2016 ; Lovas and Schuman-Olivier 2018 ; Yatham et al. 2018 ).

Conclusions

Depression, dysthymia, and dysphoria in BD represent major, only partially solved, clinical challenges (Table  5 ). As the main unresolved illness in treated BD, bipolar depression is associated with excess morbidity as well as mortality from co-occurring general-medical disorders and very high suicide risk. Suicide risk in BD exceeds general-population rates by 20-fold and is strongly associated with depressive phases, especially with mixed or psychotic features. Treatments proposed to reduce suicide risk notably include lithium. Treatment of bipolar depression is far less well investigated than MDD, and the value and tolerability of standard antidepressants for bipolar depression remain controversial. Evidence of efficacy in bipolar depression of mood-stabilizing agents, including lithium and several anticonvulsants (except lamotrigine, long-term) remains far less substantial than for several SGAs. All available pharmacological treatments used for bipolar depression have limited efficacy and risk adverse metabolic or neurological effects. Overall, we strongly encourage renewed efforts to consider bipolar depression as distinct from depression in MDD and to seek more effective treatments especially for long-term prophylaxis aimed at reducing morbidity and mortality.

Availability of data and materials

Relevant data are provided in the tables within the report and in the references cited.

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Supported by a grant from the Bruce J. Anderson Foundation and the McLean Private Donors Psychiatric Research Fund (to RJB), and by a grant from the Aretaeus Foundation of Rome (to LT).

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Baldessarini, R.J., Vázquez, G.H. & Tondo, L. Bipolar depression: a major unsolved challenge. Int J Bipolar Disord 8 , 1 (2020). https://doi.org/10.1186/s40345-019-0160-1

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Received : 24 August 2019

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DOI : https://doi.org/10.1186/s40345-019-0160-1

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