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Bipolar disorders

Affiliations.

• 1 Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada. Electronic address: [email protected].
• 2 Institute for Mental and Physical Health and Clinical Translation Strategic Research Centre, School of Medicine, Deakin University, Melbourne, VIC, Australia; Mental Health Drug and Alcohol Services, Barwon Health, Geelong, VIC, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, VIC, Australia; Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health, Melbourne, VIC, Australia; Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia.
• 3 Department of Psychiatry, Adult Division, Kingston General Hospital, Kingston, ON, Canada; Department of Psychiatry, Queen's University School of Medicine, Queen's University, Kingston, ON, Canada; Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
• 4 Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
• 5 Department of Psychiatry, Faculty of Medicine, University of Antioquia, Medellín, Colombia; Mood Disorders Program, Hospital Universitario San Vicente Fundación, Medellín, Colombia.
• 6 Copenhagen Affective Disorders Research Centre, Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen, Denmark; Department of Psychiatry, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
• 7 Discipline of Psychiatry, Northern Clinical School, University of Sydney, Sydney, NSW, Australia; Department of Academic Psychiatry, Northern Sydney Local Health District, Sydney, Australia.
• 8 Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
• 9 Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Dauten Family Center for Bipolar Treatment Innovation, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
• 10 Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.
• 11 Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.
• 12 Department of Psychiatry, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Psychiatric Research Unit, Psychiatric Centre North Zealand, Hillerød, Denmark.
• 13 Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London and South London and Maudsley National Health Service Foundation Trust, Bethlem Royal Hospital, London, UK.
• 14 Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
• PMID: 33278937
• DOI: 10.1016/S0140-6736(20)31544-0

Bipolar disorders are a complex group of severe and chronic disorders that includes bipolar I disorder, defined by the presence of a syndromal, manic episode, and bipolar II disorder, defined by the presence of a syndromal, hypomanic episode and a major depressive episode. Bipolar disorders substantially reduce psychosocial functioning and are associated with a loss of approximately 10-20 potential years of life. The mortality gap between populations with bipolar disorders and the general population is principally a result of excess deaths from cardiovascular disease and suicide. Bipolar disorder has a high heritability (approximately 70%). Bipolar disorders share genetic risk alleles with other mental and medical disorders. Bipolar I has a closer genetic association with schizophrenia relative to bipolar II, which has a closer genetic association with major depressive disorder. Although the pathogenesis of bipolar disorders is unknown, implicated processes include disturbances in neuronal-glial plasticity, monoaminergic signalling, inflammatory homoeostasis, cellular metabolic pathways, and mitochondrial function. The high prevalence of childhood maltreatment in people with bipolar disorders and the association between childhood maltreatment and a more complex presentation of bipolar disorder (eg, one including suicidality) highlight the role of adverse environmental exposures on the presentation of bipolar disorders. Although mania defines bipolar I disorder, depressive episodes and symptoms dominate the longitudinal course of, and disproportionately account for morbidity and mortality in, bipolar disorders. Lithium is the gold standard mood-stabilising agent for the treatment of people with bipolar disorders, and has antimanic, antidepressant, and anti-suicide effects. Although antipsychotics are effective in treating mania, few antipsychotics have proven to be effective in bipolar depression. Divalproex and carbamazepine are effective in the treatment of acute mania and lamotrigine is effective at treating and preventing bipolar depression. Antidepressants are widely prescribed for bipolar disorders despite a paucity of compelling evidence for their short-term or long-term efficacy. Moreover, antidepressant prescription in bipolar disorder is associated, in many cases, with mood destabilisation, especially during maintenance treatment. Unfortunately, effective pharmacological treatments for bipolar disorders are not universally available, particularly in low-income and middle-income countries. Targeting medical and psychiatric comorbidity, integrating adjunctive psychosocial treatments, and involving caregivers have been shown to improve health outcomes for people with bipolar disorders. The aim of this Seminar, which is intended mainly for primary care physicians, is to provide an overview of diagnostic, pathogenetic, and treatment considerations in bipolar disorders. Towards the foregoing aim, we review and synthesise evidence on the epidemiology, mechanisms, screening, and treatment of bipolar disorders.

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Diagnosis and treatment of patients with bipolar disorder: A review for advanced practice nurses

Ursula mccormick.

1 Medical Services, Centerstone of Indiana, Bloomington, Indiana

Bethany Murray

2 Indiana University School of Nursing, Columbus, Indiana

Brittany McNew

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 present; “bipolar disorder and nurse practitioner”; and “bipolar disorder and clinical nurse specialist.” Selected articles were relevant to adult outpatient care in the United States, with a prioritization of articles written by APNs or published in nursing journals.

Conclusions

BD has a substantial lifetime prevalence in the population at 4%. Because the manic or depressive symptoms of BD tend to be severe and recurrent over a patient's lifetime, the condition is associated with significant burden to the individual, caregivers, and society. Clinician awareness that BD may be present increases the likelihood of successful recognition and appropriate treatment. A number of pharmacological and nonpharmacological treatments are available for acute and maintenance treatments, with the prospect of achieving reduced symptom burden and increased functioning for many patients.

Implications for practice

Awareness of the disease burden, diagnostic issues, and management choices in BD has the potential to enhance outcome in substantial proportions of patients.

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 relationships (Valente & Kennedy, 2010 ). Although not as common as major depressive disorder (MDD), the lifetime prevalence of BD in the United States is substantial (estimated at approximately 4%), with similar rates regardless of race, ethnicity, and gender (Ketter, 2010 ; Merikangas et al., 2007 ). Long‐term outcomes are persistently suboptimal (Geddes & Miklowitz, 2013 ). The economic burden of BD to society is enormous, totaling almost $120 billion in the United States in 2009. These costs include the direct costs of treatment and indirect costs from reduced employment, productivity, and functioning (Dilsaver, 2011 ). Given the burden of illness to the individual and to society, there is an urgent need to improve the care of patients with BD.

There is a growing recognition of the substantial contribution that advanced practice nurses (APNs) such as nurse practitioners (NPs) and clinical nurse specialists (CNSs) can make in the recognition and care of patients with BD (Culpepper, 2010 ; Miller, 2006 ). Most patients with BD present initially to primary care providers, but—through a lack of resources or expertise—many do not receive an adequate evaluation for possible bipolar diagnosis (Manning, 2010 ). Early recognition can lead to earlier initiation of effective therapy, with beneficial effects on both the short‐term outcome and the long‐term course of the illness (Geddes & Miklowitz, 2013 ; Manning, 2010 ). Patients with BD are also likely to have other psychiatric and medical comorbidities, and, therefore, rely on their primary care provider for holistic care (Kilbourne et al., 2004 ; Krishnan, 2005 ). Finally, the importance of collaborative, team‐based care is increasingly recognized in managing BD. APNs, by their training and experience, are well suited to facilitate optimal patient care in collaboration with the other healthcare team members (Bauer et al., 2006 ; Chung et al., 2007 ). An especially important role for APNs within primary care lies in the care of the patient, while specialists manage the bipolar illness. It is essential that these two specialties collaborate in order to stay abreast of each other's current phase of treatment.

This review provides an up‐to‐date discussion of the principles and practices of managing BD in the primary care setting. Our emphasis is on holistic, team‐oriented, multimodal approaches to care, which is compatible with the experience and therapeutic orientation of APNs.

Diagnosis of BD

Definitions in bd.

Patients with BD experience recurrent episodes of pathologic mood states, characterized by manic or depressive symptoms, which are interspersed by periods of relatively normal mood (euthymia; Figure ​ Figure1; 1 ; Vieta & Goikolea, 2005 ). Formal definitions of manic and depressive symptoms are included in the recently updated Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ( DSM‐5 ; American Psychiatric Association, 2013 ). Notably, the depressive episodes of BD are defined by the same criteria as MDD in the DSM‐5 , so that distinguishing BD from MDD frequently depends on identifying a history of manic or hypomanic symptoms (Table 1 ).

Mood range and associated mood diagnosis (Vieta & Goikolea, 2005 ).

Diagnostic criteria for BD diagnoses: Overview of DSM‐5

Adapted from DSM‐5 (American Psychiatric Association, 2013 ). Readers are referred to the full DSM‐5 criteria published by the American Psychiatric Association ( 2013 ) for establishing a bipolar diagnosis.

There are two major types of BD. Bipolar I disorder (BD I) is defined by the presence of at least one episode of mania, whereas bipolar II disorder (BD II) is characterized by at least one episode of hypomania and depression. The main distinction between mania and hypomania is the severity of the manic symptoms: mania results in severe functional impairment, it may manifest as psychotic symptoms, and often requires hospitalization; hypomania does not meet these criteria (American Psychiatric Association, 2013 ).

The duration of mood episodes is highly variable, both between patients and in an individual patient over time, but, in general, a hypomanic episode may last days to weeks, a manic episode lasts weeks to months, and a depressive episode may last months to years (Benazzi, 2007 ; Manning, 2010 ; Valente & Kennedy, 2010 ). Although a history of depressive episodes is not required to make a diagnosis of BD I by the DSM‐5 criteria, in practice most patients do experience depressive episodes; however, depressive episodes are required for a diagnosis of BD II. Long‐term studies show that patients with BD, regardless of the subtype, experience symptomatic episodes of depression more frequently and for longer durations than manic or hypomanic episodes (Baldessarini et al., 2010 ; Geddes & Miklowitz, 2013 ; Judd et al., 2003 ; Valente & Kennedy, 2010 ).

While a mood episode may consist solely of manic or depressive symptoms, it may also include a combination of these symptoms. Such episodes are newly defined in DSM‐5 as either a manic or hypomanic episode with mixed features or a depressive episode with mixed features, depending on which symptoms are predominant (American Psychiatric Association, 2013 ; Table 1 ).

Rapid cycling is a term describing the occurrence of at least four mood episodes within 1 year. Identification of rapid cycling is important, because these patients are less responsive to treatment. Rapid cycling should be considered a “red flag” that indicates the need for referral to specialist care.

Diagnostic criteria for BD

Successful assessment and treatment by the healthcare team requires knowledge of the episodic nature of BD. Diagnosis of a full‐blown manic episode may be relatively straightforward. If presenting to primary care, these patients may require immediate referral to specialist hospital care because of the risk of harm to self or others. However, more common in the primary care setting is the presentation of patients with depressive symptoms, who require a differentiation between BD and MDD (Cerimele, Chwastiak, Chan, Harrison, & Unutzer, 2013 ; Sasdelli et al., 2013 ). For this reason, all patients presenting with depressive symptoms should be assessed for a history of manic or hypomanic symptoms (Cerimele et al., 2013 ; Sasdelli et al., 2013 ; Valente & Kennedy, 2010 ).

Use of a bipolar screening tool is a time‐efficient first step in diagnosis, to be followed by a confirmatory clinical interview. The Mood Disorder Questionnaire (MDQ, Table 2 ) and the Composite International Diagnostic Interview, version 3.0 (CIDI 3.0), are commonly used screening tools in which scores above specific cut‐off values raise a suspicion of BD (Hirschfeld et al., 2000 ; Kessler & Ustun, 2004 ). Web‐based and electronic screening tools are also being developed with the aim of greater time efficiency (Gaynes et al., 2010 ; Gill, Chen, Grimes, & Klinkman, 2012 ). A comprehensive recent review of the screening tools in BD is provided by Hoyle, Elliott, and Comer ( 2015 ). While screening tools can help to recognize patients likely to have BD and can improve the efficiency of the clinical interview, it is important to note that case‐finding tools are not infallible and cannot replace the interview.

The Mood Disorder Questionnaire

Adapted from Hirschfeld et al. ( 2000 ).

The clinical interview should aim to establish the following (Manning, 2010 ; Price & Marzani‐Nissen, 2012 ):

• ▪ The presence of past or current episodes of manic or depressive symptoms, as described in DSM‐5
• ▪ The duration and severity of these episodes, including the presence of suicidal or homicidal ideation
• ▪ The impact of mood episodes on functioning in work, social, and family roles
• ▪ The presence of comorbidities (such as substance abuse, personality disorder, and anxiety disorder including posttraumatic stress disorder)
• ▪ The history of treatments administered and the response to treatments
• ▪ The family history.

In cases of continued diagnostic uncertainty, a formal diagnosis of BD may require a consultation with an experienced primary care physician, psychiatrist, psychologist, or APN to confirm the presence of DSM‐5 criteria, as well as to categorize the bipolar subtype that is present. The clinical interview, besides establishing the bipolar diagnosis, represents an important element in treatment planning, by helping to select the optimal medication(s) and the optimal site of treatment—either within primary care or by involving specialist psychiatric support. Finally, continued interviews over the course of treatment will help establish rapport and trust with the patient that encourages communication and enhances treatment adherence (Zolnierek & Dimatteo, 2009 ). Open dialogue between the healthcare worker and patient represents an essential element of patient interviews.

Other elements of the patient interview should include a physical examination and laboratory tests, with the particular aim to exclude disorders that can mimic bipolar symptoms, for example, hypothyroidism or hyperthyroidism, infection, and substance misuse (Krishnan, 2005 ). Psychiatric disorders (e.g., panic disorder, posttraumatic stress disorder) other than MDD can also mimic symptoms of BD and these should be considered in the differential diagnosis (Goldberg, 2010 ).

In establishing a BD diagnosis, it can be very informative to ask family members or close friends to provide a description of the patient's symptoms (with, of course, the patient's consent). Lack of insight is a characteristic of patients with BD, and hypomanic symptoms, in particular, may not be considered a manifestation of the illness by the patient. This is also an opportunity to assess the burden that family or friends may be experiencing as well as their current relationships with the patient (National Collaborating Centre for Mental Health [UK], 2006 ).

Misdiagnosis and underdiagnosis

Because MDD is more common than BD, and because MDD and BD have similar symptoms, it is very common for BD to be misdiagnosed as MDD (Manning, 2010 ; Miller, 2006 ). In one study, over 60% of patients who were eventually diagnosed with BD had previously been misdiagnosed with MDD.

A number of adverse consequences can result from the misdiagnosis and underdiagnosis of BD (Hirschfeld, 2007 ; Manning, 2010 ; McCombs, Ahn, Tencer, & Shi, 2007 ). Most importantly, patients with BD who are misdiagnosed with MDD may be treated with conventional antidepressant monotherapy. Compared with appropriately treated patients, such patients are less likely to respond, are at increased risk of a switch to mania, and may experience an acceleration of mood cycling (Manning, 2010 ; Miller, 2006 ; Sidor & Macqueen, 2011 ; Vieta & Valenti, 2013 ).

Sharing the diagnosis

Discussing the diagnosis with the patient is critical to laying a foundation for effective treatment. The acceptance of a BD diagnosis may be difficult and often occurs over time. The initial diagnosis is frequently provisional, and requires additional observations or confirmatory historical information. It can also be expected that patients will show resistance to the diagnosis, possibly because of the social stigma of having a mental illness. One of the best tools to facilitate acceptance of the diagnosis is motivational interviewing, which is a form of counseling that elicits and strengthens the patient's motivation for change through a process of collaboration and rapport. Motivational interviewing was developed for patients with an alcohol or drug problem, but has been applied more broadly in recent years (Laakso, 2012 ). Having patience and persistence in helping patients to “own” their BD, and take responsibility for managing it, is an important objective in motivational interviewing (Laakso, 2012 ).

Pharmacotherapy

Pharmacological treatment is fundamental for successfully managing patients with BD. For acute episodes, the objective is symptom reduction, with the ultimate goal of full remission. For maintenance treatment, the goal is to prevent the recurrences of mood episodes. Medications used in the treatment of BD include mood stabilizers (e.g., lithium, valproate, lamotrigine, and carbamazepine), atypical antipsychotics, and conventional antidepressants (Geddes & Miklowitz, 2013 ; Hirschfeld, Bowden, & Gitlin, 2002 ). Table 3 lists the medications that are approved by the U.S. Food and Drug Administration (FDA) in treating the different phases of BD.

Medications with FDA indication for treatment of BD

*Also used adjunctively but not FDA indicated.

A, adjunctive to a mood stabilizer; C, combination therapy with another mood stabilizer, antipsychotic, or antidepressant; M, monotherapy; RLAI risperidone long‐acting injectable; X, recommended in guidelines but not FDA indicated.

Mood stabilizers

Lithium was the first agent to be used in the treatment of BD. Although it has many limitations, including a delayed onset of action in the treatment of acute mania, limited efficacy in the treatment of bipolar depression, and a narrow therapeutic window, lithium still has an important role today (Geddes, Burgess, Hawton, Jamison, & Goodwin, 2004 ; Hirschfeld et al., 2002 ). In particular, lithium has shown efficacy in preventing recurrence of manic episodes and it is the only medication correlated with a reduced risk of suicide in BD. A study that reduced the lithium dosage (to increase its tolerability) reported no benefit from using lithium plus optimized personalized treatment when compared to optimized personalized treatment alone (Nierenberg et al., 2013 ).

Sodium valproate is the most commonly used mood stabilizer. It has a more rapid onset of action than lithium for the acute treatment of mania, and was superior to placebo as an acute therapy in the largest study performed to date (Bowden et al., 1994 ), but the evidence for its efficacy as a maintenance treatment for mania is not so robust (Geddes et al., 2010 ; Kessing, Hellmund, Geddes, Goodwin, & Andersen, 2011 ). Placebo‐controlled studies of carbamazepine describe significant efficacy in acute mania (Weisler, Kalali, & Ketter, 2004 ; Weisler et al., 2005 ). In the absence of long‐term controlled studies, a naturalistic study over an average of 10 years reported that carbamazepine is efficacious in most patients (Chen & Lin, 2012 ). Lamotrigine, in contrast to the other mood stabilizers, is more effective for preventing the recurrence of depressive than manic episodes of BD (Vieta & Valenti, 2013 ). Lamotrigine has also been investigated for the treatment of acute bipolar depression, but the evidence for efficacy is less convincing (Geddes, Calabrese, & Goodwin, 2009 ). A study of lamotrigine in acute mania reported no significant difference from placebo (Frye et al., 2000 ).

There are a number of safety and tolerability concerns with mood stabilizers that impact their long‐term use. Lithium requires regular monitoring of blood levels, because the therapeutic window is narrow. Lithium can cause progressive renal insufficiency and thyroid toxicity. After initial assessment of renal and thyroid functions, repeat monitoring of renal and thyroid functions every 6 months is recommended to ensure normal functioning (Price & Heninger, 1994 ). The most common adverse events associated with lithium include tremors as well as gastrointestinal problems such as nausea, vomiting, and diarrhea. Hepatotoxicity is the most common serious adverse event associated with valproate (risk: 1/20,000); other adverse effects include nausea, dizziness, somnolence, lethargy, infection, tinnitus, and cognitive impairment. Monitoring is required for hematologic abnormalities including low platelet count, low white blood count, and, in some cases, bone marrow suppression during valproate therapy (Martinez, Russell, & Hirschfeld, 1998 ). Carbamazepine is associated with reduced tolerability during rapid dose titration and its potential for interaction with other psychiatric and nonpsychiatric medications further limits its use (Grunze et al., 2009 ). Carbamazepine has an FDA boxed warning for agranulocytosis and aplastic anemia and is associated in approximately 10% of patients with the formation of a benign rash. Lamotrigine, which is overall the best‐tolerated medication in this class, can cause a rash like the Stevens–Johnson rash. Lamotrigine has been studied specifically in relation to fetal cleft palate formation; however, the evidence remains unconvincing. Fetal exposure to valproate, carbamazepine, and lithium can be teratogenic (Connolly & Thase, 2011 ; Dodd & Berk, 2004 ; Geddes & Miklowitz, 2013 ; Hirschfeld et al., 2002 ; Tatum, 2006 ).

Atypical antipsychotics

The atypical antipsychotics were developed in the modern era of psychopharmacology; all agents in this class have been studied by randomized controlled trials in the treatment of BD (Derry & Moore, 2007 ; Yatham et al., 2013 ). For the treatment of acute bipolar mania, all approved atypical antipsychotics (also called “second‐generation” antipsychotics) demonstrate efficacy and acceptable safety. For acute bipolar depression, however, few atypical antipsychotics have demonstrated efficacy. Only quetiapine (immediate‐release [IR] and extended‐release [XR] formulations) has proven efficacy as monotherapy for treating acute depressive episodes of BD I or BD II (Table 3 ; Calabrese et al., 2005 ; Suppes et al., 2010 ; Thase et al., 2006 ). A fixed‐dose combination of olanzapine and fluoxetine has demonstrated efficacy for treating acute depressive episodes of BD I (Tohen et al., 2003 ) and lurasidone has recently received FDA approval as monotherapy or adjunctive therapy (with either lithium or valproate) in BD I but not BD II (Loebel et al., 2014a , 2014b ).

For the maintenance treatment of BD I, FDA‐approved atypical antipsychotics include aripiprazole, olanzapine, quetiapine (IR and XR), risperidone long‐acting injection (LAI), and ziprasidone; these agents are approved either as monotherapy or as adjunctive therapy in combination with a mood stabilizer. A recent meta‐analysis of trials of the atypical antipsychotics in maintenance treatment concluded that aripiprazole, olanzapine, quetiapine (IR or XR), and risperidone LAI monotherapy were statistically superior to placebo for treating manic or mixed episodes, while quetiapine alone was also significantly effective against recurrence of depressive episodes (Vieta et al., 2011 ).

The safety and tolerability profiles of the atypical antipsychotics have been well characterized in patients with BD. A number of safety issues are associated with these drugs as a class, including sedation/somnolence, metabolic effects (e.g., weight gain, hyperglycemia, and dyslipidemia), and extrapyramidal side effects (EPS). The relative risk of these effects differs between individual atypical antipsychotics. For example, the risk of adverse metabolic effects is reported to be greatest with olanzapine and lowest with ziprasidone, and intermediate with quetiapine and risperidone (Perlis, 2007 ). Adjunctive therapies that include atypical antipsychotics in combination with other agents (usually mood stabilizers) are also associated with a greater risk of adverse events than monotherapies (Smith, Cornelius, Warnock, Tacchi, & Taylor, 2007 ). Given the propensity of atypical antipsychotics to adversely affect weight, lipid levels, and other metabolic parameters, it is important to monitor patients regularly (Hirschfeld et al., 2002 ; The Management of Bipolar Disorder Working Group, 2010 ).

Conventional antidepressants

The proper use of conventional antidepressants is an area of controversy in the treatment of BD (Pacchiarotti et al., 2013 ). The main concern in using antidepressants as monotherapy in patients with bipolar depression is the risk of precipitating a switch to mania/hypomania, which is estimated to occur in between 3% and 15% of cases (Pacchiarotti et al., 2013 ; Tondo, Baldessarini, Vazquez, Lepri, & Visioli, 2013 ; Vazquez, Tondo, & Baldessarini, 2011 ). Another unresolved issue is whether maintenance treatment that includes antidepressants is effective for the prevention of recurrence (Pacchiarotti et al., 2013 ; Vazquez et al., 2011 ). If conventional antidepressants are used, it is recommended to combine them with a mood stabilizer or an atypical antipsychotic, and to taper the antidepressant dose following remission of the episode (Amit & Weizman, 2012 ; Connolly & Thase, 2011 ; Hirschfeld et al., 2002 ; Yatham et al., 2013 ). Contemporary guidelines recommend selective serotonin reuptake inhibitors (SSRIs) or bupropion rather than selective serotonin‐norepinephrine reuptake inhibitors (SNRIs) or tricyclics, as SSRIs and bupropion are less likely to cause manic switch. While full consensus is currently absent, there is wide agreement that antidepressant monotherapy should be avoided in patients with BD I and patients with BD II with two or more concomitant core manic symptoms, while antidepressants should be avoided entirely in patients with rapid cycling or those being treated for a mixed episode (Pacchiarotti et al., 2013 ).

Psychosocial treatments

Psychosocial treatments, including individual psychotherapies as well as educational and supportive group therapies, are increasingly considered an integral part of the treatment of BD (Connolly & Thase, 2011 ; Geddes & Miklowitz, 2013 ). Common components of psychosocial treatments are education about the disease and a focus on treatment adherence and self‐care. Interestingly, among the psychosocial treatments, the strongest evidence for effectiveness is for group psychoeducation of patients and caregivers (Colom et al., 2009 ; Reinares et al., 2008 ). Long‐term benefits of this approach include a reduction in days with symptoms and in days hospitalized (Colom et al., 2009 ).

Two other psychotherapies with evidence to support their effectiveness are BD‐specific cognitive behavioral psychotherapy (Jones et al., 2012 ) and interpersonal and social rhythm therapy (Frank et al., 2005 ). Interpersonal and social rhythm therapy is an intervention designed to increase the regularity of patients’ daily routines, based on the concept that disruption of circadian rhythms is a underlying feature of mood disorders (Frank, Swartz, & Boland, 2007 ). These therapies can help patients improve adherence to their medication, enhance their ability to recognize triggers to mood episodes, and develop strategies for early intervention. Combining BD‐specific adjunctive psychotherapies with pharmacological therapy has been shown to significantly reduce relapse rates (Scott, Colom, & Vieta, 2007 ).

Peer support

BD impacts all aspects of a person's life, causing severe disruption to relationships, employment, and education. Peer support can be very helpful in dealing with the consequences of these effects through sharing of experiences, where patients can discover that others have had similar experiences and can have hope for recovery, stability, and a satisfying life. Support groups, sponsored by national organizations, may be available locally or regionally. There is also a wealth of resources available online (Table 4 ).

Web resources for BD

Major challenges in the management of patients with BD

A number of commonly encountered challenges can contribute to suboptimal outcomes in BD. An awareness of these challenges and the implementation of proactive strategies can help to maximize adherence to care and the benefits of treatment.

Nonadherence

Medication nonadherence is a significant problem in primary care medicine generally, and in patients with BD in particular. Experience from other areas of medicine suggests that nonadherence may be widely unrecognized (Ho, Bryson, & Rumsfeld, 2009 ). Validated scales for gauging nonadherence include the Morisky Adherence Scale, although this is not widely adopted in clinical practice (Morisky, Ang, Krousel‐Wood, & Ward, 2008 ). Reasons for nonadherence among patients with BD include the following: a denial of the diagnosis, especially in those with predominant mania; a lack of belief that the medications being offered are necessary or effective; and a wish to avoid the real or imagined adverse effects of medications (Devulapalli et al., 2010 ). Additional practical factors, including poor access to health care and limited resources to support treatment costs, can also affect adherence (Kardas, Lewek, & Matyjaszczyk, 2013 ).

Nonadherence is probably the most significant factor contributing to poor treatment outcome in BD (Hassan & Lage, 2009 ; Lew, Chang, Rajagopalan, & Knoth, 2006 ), which leads to increased emergency room visits and hospitalization (Hassan & Lage, 2009 ; Lage & Hassan, 2009 ; Lew et al., 2006 ; Rascati et al., 2011 ). Investing more time and resources to work with patients during symptom‐free periods is likely to be cost saving by reducing the utilization of these high‐cost resources (Zeber et al., 2008 ).

Comorbid psychiatric disorders

The complexity in treating patients with BD is increased by the high rates of cooccurring psychiatric disorders, in particular anxiety disorders and substance use disorders (Grant et al., 2005 ; Krishnan, 2005 ). The importance of these cooccurring conditions cannot be overstated; they are associated with both exacerbations of BD and poor treatment outcomes (Grant et al., 2005 ; Kessler et al., 1996 ). Although it may be prudent to refer such patients to specialist care, the first critical step is to make a correct diagnosis and to help these patients to accept the problem and the need for treatment.

Comorbid medical disorders

Patients with BD have an elevated prevalence of medical morbidities, including obesity, diabetes, cardiovascular disease, and hepatitis (Kilbourne et al., 2004 ; Krishnan, 2005 ). A comorbidity of increasingly recognized importance is obstructive sleep apnea (OSA), which causes sleep disturbance that can trigger mood episodes (Soreca, Levenson, Lotz, Frank, & Kupfer, 2012 ). A recent study reported OSA in over 20% of patients with BD, which the authors mention may be an underestimate of the true prevalence (Kelly, Douglas, Denmark, Brasuell, & Lieberman, 2013 ). The authors concluded that unrecognized OSA may play a major role in the mortality and morbidity of BDs. All patients diagnosed with a BD should be screened with an OSA questionnaire.

The burden of medical disorders may be increased by the adverse effects of BD treatment, by cooccurring substance misuse or by decrements in self‐care secondary to BD itself (McIntyre, 2009 ). For example, depression typically deprives patients of the motivation and energy to engage in treatment for chronic medical conditions. Early recognition and treatment of medical disorders in patients with BD has been shown to have a major beneficial effect on all‐cause mortality (Crump, Sundquist, Winkleby, & Sundquist, 2013 ).

Women of childbearing age

Women are at high risk of BD recurrence during pregnancy, especially if medications are discontinued, as well as during the postpartum period. Balancing the risk of medications against the need to prevent a mood episode requires active collaboration between the healthcare providers and the patient (McKenna et al., 2005 ). Teratogenicity is a potential risk with most of the mood stabilizers; lamotrigine may be an exception, but there are no well‐controlled studies in humans to confirm this. Atypical antipsychotics, with the exception of lurasidone, are rated FDA pregnancy category C, meaning that they have not been shown to be either safe or unsafe for use during pregnancy; lurasidone is classed in pregnancy category B based on current data.

Suicide rates in BD are the highest among the psychiatric disorders (Chen & Dilsaver, 1996 ; Tondo, Isacsson, & Baldessarini, 2003 ). The lifetime incidence of at least one suicide attempt was reported in one study to be 29% in patients with BD, compared to 16% for MDD (Chen & Dilsaver, 1996 ). Other studies have reported even higher rates of suicide attempts of 25%–60% during the course of BD, with suicide completion rates of 14%–60% (Sublette et al., 2009). The primary healthcare team should monitor all patients with BD for suicidality, especially those with persistent depressive or mixed‐mood symptoms, and immediately refer any patient at high‐risk for suicide to specialist care (Tondo et al., 2003 ).

Alcohol abuse in patients with BD is associated with further elevation in the risk of suicide, particularly in the presence of concurrent drug use disorders. A study that investigated this association concluded that higher suicide attempt rates in patients with BD I and alcoholism were mostly explained by higher aggression scores, while the higher rates of attempted suicide associated with other drug use disorders appeared to be the result of higher impulsiveness, hostility, and aggression (Sublette et al., 2009). This study, similar to previous reports, found that earlier age of bipolar onset increased the likelihood that alcohol use disorder would be associated with suicide attempts. Effective clinical management of substance use disorders has the potential to reduce the risk of suicidal behavior in these patients with BD.

BD continues to represent a substantial burden to patients, their care providers, and society. Management of BD poses a challenge to all healthcare providers, including the APNs. A suspicion of BD increases the likelihood of successful diagnosis. Emphasis should be placed on accurately identifying manic, hypomanic, and depressive episodes. A number of pharmacological and nonpharmacological treatments are available for acute and maintenance treatments. Healthcare providers should be aware of the efficacy and safety profiles of each of these agents, with the aim to achieve the most effective utilization of the approaches available in the management of patients with BD. An awareness of these aspects in BD—disease burden, diagnostic issues, and management choices—can enhance outcome in substantial proportions of patients. In summary, Table 5 provides a useful overview of the principles to consider when providing care for patients with BD.

Principles of providing care for patients with BD

Red flags indicating need for specialist involvement:

▪ Suicidality

▪ Pregnancy and postpartum

▪ Severe psychiatric comorbidity (e.g., substance dependence, anxiety)

▪ History of treatment resistance (e.g., multiple hospitalizations)

▪ Rapid‐cycling pattern.

Adapted from Culpepper ( 2010 ).

Funding Editorial support was provided by Bill Wolvey of PAREXEL, funded by AstraZeneca.

Disclosure Ursula McCormick has received personal fees from AstraZeneca and Sunovian. Bethany Murray and Brittany McNew report no conflicts of interest.

• American Psychiatric Association . (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: American Psychiatric Association. [ Google Scholar ]
• Amit, B. H. , & Weizman, A. (2012). Antidepressant treatment for bipolar depression: An update . Depression Research and Treatment , 2012 , 684725. doi: 10.1155/2012/684725 . [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Baldessarini, R. J. , Salvatore, P. , Khalsa, H. M. , Gebre‐Medhin, P. , Imaz, H. , Gonzalez‐Pinto, A. , … Tohen, M. (2010). Morbidity in 303 first‐episode bipolar I disorder patients . Bipolar Disorders , 12 , 264–270. doi: 10.1111/j.1399-5618.2010.00812.x . [ PubMed ] [ Google Scholar ]
• Bauer, M. S. , McBride, L. , Williford, W. O. , Glick, H. , Kinosian, B. , Altshuler, L. , … Sajatovic, M. (2006). Collaborative care for bipolar disorder: Part II. Impact on clinical outcome, function, and costs . Psychiatric Services , 57 ( 7 ), 937–945. doi: 10.1176/appi.ps.57.7.937 . [ PubMed ] [ Google Scholar ]
• Benazzi, F. (2007). Bipolar II disorder: Epidemiology, diagnosis and management . CNS Drugs , 21 ( 9 ), 727–740. [ PubMed ] [ Google Scholar ]
• Bowden, C. L. , Brugger, A. M. , Swann, A. C. , Calabrese, J. R. , Janicak, P. G. , Petty, F. , … Frazer, A. (1994). Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group . Journal of the American Medical Association , 271 , 918–924. [ PubMed ] [ Google Scholar ]
• Calabrese, J. R. , Keck, P. E., Jr. , Macfadden, W. , Minkwitz, M. , Ketter, T. A. , Weisler, R. H. , … Mullen, J. (2005). A randomized, double‐blind, placebo‐controlled trial of quetiapine in the treatment of bipolar I or II depression . American Journal of Psychiatry , 162 , 1351–1360. doi: 10.1176/appi.ajp.162.7.1351 . [ PubMed ] [ Google Scholar ]
• Cerimele, J. M. , Chwastiak, L. A. , Chan, Y. F. , Harrison, D. A. , & Unutzer, J. (2013). The presentation, recognition and management of bipolar depression in primary care . Journal of General Internal Medicine , 28 , 1648–1656. doi: 10.1007/s11606-013-2545-7 . [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chen, Y. W. , & Dilsaver, S. C. (1996). Lifetime rates of suicide attempts among subjects with bipolar and unipolar disorders relative to subjects with other Axis I disorders . Biological Psychiatry , 39 , 896–899. doi: 10.1016/0006-3223(95)00295-2 . [ PubMed ] [ Google Scholar ]
• Chen, C. H. , & Lin, S. K. (2012). Carbamazepine treatment of bipolar disorder: A retrospective evaluation of naturalistic long‐term outcomes . BMC Psychiatry , 12 , 47. doi: 10.1186/1471-244X-12-47 . [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chung, H. , Culpepper, L. , de Wester, J. N. , de Wester, J. N. , Grieco, R. , Kaye, N. S. , … Ross, R. (2007). Challenges in recognition, clinical management, and treatment of bipolar disorders at the interface of psychiatric medicine and primary care . Current Psychiatry , 6 ( 11 ). Retrieved from http://www.currentpsychiatry.com/education-center/education-center/article/challenges-in-recognition-clinical-management-and-treatment-of-bipolar-disorder-at-the-interface-of-psychiatric-medicine-and-primary-care/a3b717e8fc79bbb15d27bf9352f872f5.html . [ Google Scholar ]
• Colom, F. , Vieta, E. , Sanchez‐Moreno, J. , Goikolea, J. M. , Popova, E. , Bonnin, C. M. , & Scott, J. (2009). Psychoeducation for bipolar II disorder: An exploratory, 5‐year outcome subanalysis . Journal of Affective Disorders , 112 ( 1–3 ), 30–35. doi: 10.1016/j.jad.2008.03.023 . [ PubMed ] [ Google Scholar ]
• Connolly, K. R. , & Thase, M. E. (2011). The clinical management of bipolar disorder: A review of evidence‐based guidelines . Primary Care Companion for CNS Disorders , 13 , pii: PCC.10r01097. doi: 10.4088/PCC.10r01097 . [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Crump, C. , Sundquist, K. , Winkleby, M. A. , & Sundquist, J. (2013). Comorbidities and mortality in bipolar disorder: A Swedish national cohort study . JAMA Psychiatry , 70 , 931–939. doi:1714400[pii];10.1001/jamapsychiatry.2013.1394. [ PubMed ] [ Google Scholar ]
• Culpepper, L. (2010). The role of primary care clinicians in diagnosing and treating bipolar disorder . Primary Care Companion to the Journal of Clinical Psychiatry , 12 ( Suppl 1 ), 4–9. doi: 10.4088/PCC.9064su1c.01 . [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Derry, S. , & Moore, R. A. (2007). Atypical antipsychotics in bipolar disorder: Systematic review of randomised trials . BMC Psychiatry , 7 , 40. doi:1471‐244X‐7‐40. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Devulapalli, K. K. , Ignacio, R. V. , Weiden, P. , Cassidy, K. A. , Williams, T. D. , Safavi, R. , … Sajatovic, M. (2010). Why do persons with bipolar disorder stop their medication? Psychopharmacology Bulletin , 43 , 5–14. Retrieved from PM:21150842. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Dilsaver, S. C. (2011). An estimate of the minimum economic burden of bipolar I and II disorders in the United States: 2009 . Journal of Affective Disorders , 129 , 79–83. doi: 10.1016/j.jad.2010.08.030 . [ PubMed ] [ Google Scholar ]
• Dodd, S. , & Berk, M. (2004). The pharmacology of bipolar disorder during pregnancy and breastfeeding . Expert Opinion on Drug Safety , 3 , 221–229. doi: 10.1517/eods.3.3.221.31074 . [ PubMed ] [ Google Scholar ]
• Frank, E. , Swartz, H. A. , & Boland, E. (2007). Interpersonal and social rhythm therapy: An intervention addressing rhythm dysregulation in bipolar disorder . Dialogues in Clinical Neuroscience , 9 , 325–332. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Frank, E. , Kupfer, D. J. , Thase, M. E. , Mallinger, A. G. , Swartz, H. A. , Fagiolini, A. M. , … Monk, T. (2005). Two‐year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder . Archives of General Psychiatry , 62 , 996–1004. doi: 10.1001/archpsyc.62.9.996 . [ PubMed ] [ Google Scholar ]
• Frye, M. A. , Ketter, T. A. , Kimbrell, T. A. , Dunn, R. T. , Speer, A. M. , Osuch, E. A. , … Post, R. M. (2000). A placebo‐controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders . Journal of Clinical Psychopharmacology , 20 , 607–614. [ PubMed ] [ Google Scholar ]
• Gaynes, B. N. , DeVeaugh‐Geiss, J. , Weir, S. , Gu, H. , MacPherson, C. , Schulberg, H. C. , … Rubinow, D. R. (2010). Feasibility and diagnostic validity of the M‐3 checklist: A brief, self‐rated screen for depressive, bipolar, anxiety, and post‐traumatic stress disorders in primary care . Annals of Family Medicine , 8 , 160–169. doi: 10.1370/afm.1092 . [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Geddes, J. R. , Burgess, S. , Hawton, K. , Jamison, K. , & Goodwin, G. M. (2004). Long‐term lithium therapy for bipolar disorder: Systematic review and meta‐analysis of randomized controlled trials . American Journal of Psychiatry , 161 , 217–222. [ PubMed ] [ Google Scholar ]
• Geddes, J. R. , Calabrese, J. R. , & Goodwin, G. M. (2009). Lamotrigine for treatment of bipolar depression: Independent meta‐analysis and meta‐regression of individual patient data from five randomised trials . British Journal of Psychiatry , 194 , 4–9. doi: 10.1192/bjp.bp.107.048504 . [ PubMed ] [ Google Scholar ]
• Geddes, J. R. , Goodwin, G. M. , Rendell, J. , Azorin, J. M. , Cipriani, A. , Ostacher, M. J. , … Juszczak, E. (2010). Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): A randomised open‐label trial . Lancet , 375 , 385–395. doi: 10.1016/S0140-6736(09)61828-6 . [ PubMed ] [ Google Scholar ]
• Geddes, J. R. , & Miklowitz, D. J. (2013). Treatment of bipolar disorder . Lancet , 381 , 1672–1682. doi: 10.1016/S0140-6736(13)60857-0 . [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Gill, J. M. , Chen, Y. X. , Grimes, A. , & Klinkman, M. S. (2012). Using electronic health record‐based tools to screen for bipolar disorder in primary care patients with depression . Journal of the American Board of Family Medicine , 25 ( 3 ), 283–290. doi: 10.3122/jabfm.2012.03.110217 . [ PubMed ] [ Google Scholar ]
• Goldberg, J. F. (2010). Differential diagnosis of bipolar disorder . CNS Spectrums , 15 ( 2 Suppl 3 ), 4–7. [ PubMed ] [ Google Scholar ]
• Grant, B. F. , Stinson, F. S. , Hasin, D. S. , Dawson, D. A. , Chou, S. P. , Ruan, W. J. , & Huang, B. (2005). Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: Results from the National Epidemiologic Survey on Alcohol and Related Conditions . Journal of Clinical Psychiatry , 66 , 1205–1215. [ PubMed ] [ Google Scholar ]
• Grunze, H. , Vieta, E. , Goodwin, G. M. , Bowden, C. , Licht, R. W. , Moller, H. J. , & Kasper, S. (2009). The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: Update 2009 on the treatment of mania . World Journal of Biological Psychiatry , 10 , 85–116. doi: 10.1080/15622970902823202 . [ PubMed ] [ Google Scholar ]
• Hassan, M. , & Lage, M. J. (2009). Risk of rehospitalization among bipolar disorder patients who are nonadherent to antipsychotic therapy after hospital discharge . American Journal of Health‐System Pharmacy , 66 , 358–365. doi: 10.2146/ajhp080374 . [ PubMed ] [ Google Scholar ]
• Hirschfeld, R. M. (2007). Screening for bipolar disorder . American Journal of Managed Care , 13 ( 7 Suppl ), S164–S169. [ PubMed ] [ Google Scholar ]
• Hirschfeld, R. M. , Bowden, C. L. , & Gitlin, M. J. (2002). Practice guideline for the treatment of patients with bipolar disorder . American Psychiatric Association . Retrieved from http://dbsanca.org/docs/APA_Bipolar_Guidelines.1783155.pdf . [ Google Scholar ]
• Hirschfeld, R. M. , Williams, J. B. , Spitzer, R. L. , Calabrese, J. R. , Flynn, L. , Keck, P. E., Jr. , … Zajecka, J. (2000). Development and validation of a screening instrument for bipolar spectrum disorder: The Mood Disorder Questionnaire . American Journal of Psychiatry , 157 , 1873–1875. [ PubMed ] [ Google Scholar ]
• Ho, P. M. , Bryson, C. L. , & Rumsfeld, J. S. (2009). Medication adherence: Its importance in cardiovascular outcomes . Circulation , 119 , 3028–3035. doi: 10.1161/CIRCULATIONAHA.108.768986 . [ PubMed ] [ Google Scholar ]
• Hoyle, S. , Elliott, L. , & Comer, L. (2015). Available screening tools for adults suffering from bipolar affective disorder in primary care: An integrative literature review . Journal of the American Association of Nurse Practitioners , 27 , 280–289. [ PubMed ] [ Google Scholar ]
• Jones, S. , Mulligan, L. D. , Law, H. , Dunn, G. , Welford, M. , Smith, G. , & Morrison, A. P. (2012). A randomised controlled trial of recovery focused CBT for individuals with early bipolar disorder . BMC Psychiatry , 12 , 204. doi:1471‐244X‐12‐204. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Judd, L. L. , Akiskal, H. S. , Schettler, P. J. , Coryell, W. , Endicott, J. , Maser, J. D. , … Keller, M. B. (2003). A prospective investigation of the natural history of the long‐term weekly symptomatic status of bipolar II disorder . Archives of General Psychiatry , 60 , 261–269. [ PubMed ] [ Google Scholar ]
• Kardas, P. , Lewek, P. , & Matyjaszczyk, M. (2013). Determinants of patient adherence: A review of systematic reviews . Frontiers in Pharmacology , 4 , 91. doi: 10.3389/fphar.2013.00091 . [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Kelly, T. , Douglas, L. , Denmark, L. , Brasuell, G. , & Lieberman, D. Z. (2013). The high prevalence of obstructive sleep apnea among patients with bipolar disorders . Journal of Affective Disorders , 151 ( 1 ), 54–58. doi:S0165-0327(13)00426-6[pii];10.1016/j.jad.2013.05.047. [ PubMed ] [ Google Scholar ]
• Kessing, L. V. , Hellmund, G. , Geddes, J. R. , Goodwin, G. M. , & Andersen, P. K. (2011). Valproate v. lithium in the treatment of bipolar disorder in clinical practice: Observational nationwide register‐based cohort study . British Journal of Psychiatry , 199 , 57–63. doi: 10.1192/bjp.bp.110.084822 . [ PubMed ] [ Google Scholar ]
• Kessler, R. C. , Nelson, C. B. , McGonagle, K. A. , Edlund, M. J. , Frank, R. G. , & Leaf, P. J. (1996). The epidemiology of co‐occurring addictive and mental disorders: Implications for prevention and service utilization . American Journal of Orthopsychiatry , 66 ( 1 ), 17–31. [ PubMed ] [ Google Scholar ]
• Kessler, R. C. , & Ustun, T. B. (2004). The World Mental Health (WMH) Survey Initiative Version of the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI) . International Journal of Methods in Psychiatric Research , 13 , 93–121. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Ketter, T. A. (2010). Diagnostic features, prevalence, and impact of bipolar disorder . Journal of Clinical Psychiatry , 71 , e14. doi: 10.4088/JCP.8125tx11c . [ PubMed ] [ Google Scholar ]
• Kilbourne, A. M. , Cornelius, J. R. , Han, X. , Pincus, H. A. , Shad, M. , Salloum, I. , … Haas, G. L. (2004). Burden of general medical conditions among individuals with bipolar disorder . Bipolar Disorders , 6 , 368–373. doi: 10.1111/j.1399-5618.2004.00138.x . [ PubMed ] [ Google Scholar ]
• Krishnan, K. R. (2005). Psychiatric and medical comorbidities of bipolar disorder . Psychosomatic Medicine , 67 , 1–8. doi: 10.1097/01.psy.0000151489.36347.18 . [ PubMed ] [ Google Scholar ]
• Laakso, L. J. (2012). Motivational interviewing: Addressing ambivalence to improve medication adherence in patients with bipolar disorder . Issues in Mental Health Nursing , 33 , 8–14. doi: 10.3109/01612840.2011.618238 . [ PubMed ] [ Google Scholar ]
• Lage, M. J. , & Hassan, M. K. (2009). The relationship between antipsychotic medication adherence and patient outcomes among individuals diagnosed with bipolar disorder: A retrospective study . Annals of General Psychiatry , 8 , 7. doi: 10.1186/1744-859X-8-7 . [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Lew, K. H. , Chang, E. Y. , Rajagopalan, K. , & Knoth, R. L. (2006). The effect of medication adherence on health care utilization in bipolar disorder . Managed Care Interface , 19 , 41–46. [ PubMed ] [ Google Scholar ]
• Loebel, A. , Cucchiaro, J. , Silva, R. , Kroger, H. , Hsu, J. , Sarma, K. , & Sachs, G. (2014a). Lurasidone monotherapy in the treatment of bipolar I depression: A randomized, double‐blind, placebo‐controlled study . American Journal of Psychiatry , 171 , 160–168. doi: 10.1176/appi.ajp.2013.13070984 . [ PubMed ] [ Google Scholar ]
• Loebel, A. , Cucchiaro, J. , Silva, R. , Kroger, H. , Sarma, K. , Xu, J. , & Calabrese, J. R. (2014b). Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: A randomized, double‐blind, placebo‐controlled study . American Journal of Psychiatry , 171 , 169–177. doi: 10.1176/appi.ajp.2013.13070985 . [ PubMed ] [ Google Scholar ]
• Manning, J. S. (2010). Tools to improve differential diagnosis of bipolar disorder in primary care . Primary Care Companion to the Journal of Clinical Psychiatry , 12 ( Suppl 1 ), 17–22. doi: 10.4088/PCC.9064su1c.03 . [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Martinez, J. M. , Russell, J. M. , & Hirschfeld, R. M. (1998). Tolerability of oral loading of divalproex sodium in the treatment of mania . Depression and Anxiety , 7 , 83–86. doi:10.1002/(SICI)1520‐6394(1998)7:2<83::AID‐DA6>3.0.CO;2‐6. [ PubMed ] [ Google Scholar ]
• McCombs, J. S. , Ahn, J. , Tencer, T. , & Shi, L. (2007). The impact of unrecognized bipolar disorders among patients treated for depression with antidepressants in the fee‐for‐services California Medicaid (Medi‐Cal) program: A 6‐year retrospective analysis . Journal of Affective Disorders , 97 ( 1–3 ), 171–179. doi: 10.1016/j.jad.2006.06.018 . [ PubMed ] [ Google Scholar ]
• McIntyre, R. S. (2009). Understanding needs, interactions, treatment, and expectations among individuals affected by bipolar disorder or schizophrenia: The UNITE global survey . Journal of Clinical Psychiatry , 70 ( Suppl 3 ), 5–11. doi: 10.4088?JCP.7075su1c.02. [ PubMed ] [ Google Scholar ]
• McKenna, K. , Koren, G. , Tetelbaum, M. , Wilton, L. , Shakir, S. , Diav‐Citrin, O. , … Einarson, A. (2005). Pregnancy outcome of women using atypical antipsychotic drugs: A prospective comparative study . Journal of Clinical Psychiatry , 66 , 444–449. [ PubMed ] [ Google Scholar ]
• Merikangas, K. R. , Akiskal, H. S. , Angst, J. , Greenberg, P. E. , Hirschfeld, R. M. , Petukhova, M. , & Kessler, R. C. (2007). Lifetime and 12‐month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication . Archives of General Psychiatry , 64 , 543–552. doi: 10.1001/archpsyc.64.5.543 . [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Miller, K. (2006). Bipolar disorder: Etiology, diagnosis, and management . Journal of the American Association of Nurse Practitioners , 18 , 368–373. 10.1111/j.1745-7599.2006.00148.x . [ PubMed ] [ Google Scholar ]
• Morisky, D. E. , Ang, A. , Krousel‐Wood, M. , & Ward, H. J. (2008). Predictive validity of a medication adherence measure in an outpatient setting . Journal of Clinical Hypertension , 10 , 348–354. [ PMC free article ] [ PubMed ] [ Google Scholar ] Retracted
• National Collaborating Centre for Mental Health (UK) . (2006). Bipolar disorder: The management of bipolar disorder in adults, children and adolescents, in primary and secondary care. Living with bipolar disorder: Interventions and lifestyle advice . British Psychological Society . Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK55353/ [ PubMed ] [ Google Scholar ]
• Nierenberg, A. A. , Friedman, E. S. , Bowden, C. L. , Sylvia, L. G. , Thase, M. E. , Ketter, T. , … Calabrese, J. R. (2013). Lithium treatment moderate‐dose use study (LiTMUS) for bipolar disorder: A randomized comparative effectiveness trial of optimized personalized treatment with and without lithium . American Journal of Psychiatry , 170 , 102–110. doi: 10.1176/appi.ajp.2012.112060751 . [ PubMed ] [ Google Scholar ]
• Pacchiarotti, I. , Bond, D. J. , Baldessarini, R. J. , Nolen, W. A. , Grunze, H. , Licht, R. W. , … Vieta, E. (2013). The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders . American Journal of Psychiatry , 170 , 1249–1262. doi: 10.1176/appi.ajp.2013.13020185 . [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Perlis, R. H. (2007). Treatment of bipolar disorder: The evolving role of atypical antipsychotics . American Journal of Managed Care , 13 ( 7 Suppl ), S178–S188. Retrieved from PM:18041879. [ PubMed ] [ Google Scholar ]
• Price, L. H. , & Heninger, G. R. (1994). Lithium in the treatment of mood disorders . New England Journal of Medicine , 331 , 591–598. doi: 10.1056/NEJM199409013310907 . [ PubMed ] [ Google Scholar ]
• Price, A. L. , & Marzani‐Nissen, G. R. (2012). Bipolar disorders: A review . American Family Physician , 85 , 483–493. doi:d10089. Retrieved from PM:22534227. [ PubMed ] [ Google Scholar ]
• Rascati, K. L. , Richards, K. M. , Ott, C. A. , Goddard, A. W. , Stafkey‐Mailey, D. , Alvir, J. , … Mychaskiw, M. (2011). Adherence, persistence of use, and costs associated with second‐generation antipsychotics for bipolar disorder . Psychiatric Services , 62 , 1032–1040. doi: 10.1176/appi.ps.62.9.1032 . [ PubMed ] [ Google Scholar ]
• Reinares, M. , Colom, F. , Sanchez‐Moreno, J. , Torrent, C. , Martinez‐Aran, A. , Comes, M. , … Vieta, E. (2008). Impact of caregiver group psychoeducation on the course and outcome of bipolar patients in remission: a randomized controlled trial . Bipolar Disorders , 10 , 511–519. doi: 10.1155/2013/548349 . [ PubMed ] [ Google Scholar ]
• Sasdelli, A. , Lia, L. , Luciano, C. C. , Nespeca, C. , Berardi, D. , & Menchetti, M. (2013). Screening for bipolar disorder symptoms in depressed primary care attenders: comparison between Mood Disorder Questionnaire and Hypomania Checklist (HCL‐32) . Psychiatry Journal , 2013 , 548349. doi: 10.1155/2013/548349 . [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Scott, J. , Colom, F. , & Vieta, E. (2007). A meta‐analysis of relapse rates with adjunctive psychological therapies compared to usual psychiatric treatment for bipolar disorders . International Journal of Neuropsychopharmacology , 10 , 123–129. doi: 10.1017/S1461145706006900 . [ PubMed ] [ Google Scholar ]
• Sidor, M. M. , & Macqueen, G. M. (2011). Antidepressants for the treatment of bipolar depression: A systematic review and meta‐analysis . Journal of Clinical Psychiatry , 72 ( 2 ), 156–167. doi: 10.4088/JCP.09r05385gre . [ PubMed ] [ Google Scholar ]
• Smith, L. A. , Cornelius, V. , Warnock, A. , Tacchi, M. J. , & Taylor, D. (2007). bipolar mania: A systematic review and meta‐analysis of co‐therapy vs. monotherapy . Acta Psychiatrica Scandinavica , 115 , 12–20. doi: 10.1111/j.1600-0447.2006.00912.x . [ PubMed ] [ Google Scholar ]
• Soreca, I. , Levenson, J. , Lotz, M. , Frank, E. , & Kupfer, D. J. (2012). Sleep apnea risk and clinical correlates in patients with bipolar disorder . Bipolar Disorders , 14 ( 6 ), 672–676. doi: 10.1111/j.1399-5618.2012.01044.x . [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Sublette, M. E. , Carballo, J. J. , Moreno, C. , Galfalvy, H. C. , Brent, D. A. , Birmaher, B. , …Oquendo, M. A. (2009). Substance use disorders and suicide attempts in bipolar subtypes . Journal of Psychiatric Research , 43 ( 3 ), 230–238. doi:S0022-3956(08)00114-3[pii];10.1016/j.jpsychires.2008.05.001. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Suppes, T. , Datto, C. , Minkwitz, M. , Nordenhem, A. , Walker, C. , & Darko, D. (2010). Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of bipolar depression . Journal of Affective Disorders , 121 ( 1–2 ), 106–115. doi: 10.1016/j.jad.2009.10.007 . [ PubMed ] [ Google Scholar ]
• Tatum, W. O. (2006). Use of antiepileptic drugs in pregnancy . Expert Review of Neurotherapeutics , 6 , 1077–1086. doi: 10.1586/14737175.6.7.1077 . [ PubMed ] [ Google Scholar ]
• Thase, M. E. , Macfadden, W. , Weisler, R. H. , Chang, W. , Paulsson, B. , Khan, A. , & Calabrese, J. R. (2006). Efficacy of quetiapine monotherapy in bipolar I and II depression: A double‐blind, placebo‐controlled study (the BOLDER II study) . Journal of Clinical Psychopharmacology , 26 ( 6 ), 600–609. doi: 10.1097/01.jcp.0000248603.76231.b7 . [ PubMed ] [ Google Scholar ]
• The Management of Bipolar Disorder Working Group . (2010). VA/DoD clinical practice guidelines for management of bipolar disorder in adults Washington, DC: Department of Veterans Affairs, Department of Defense. [ Google Scholar ]
• Tohen, M. , Vieta, E. , Calabrese, J. , Ketter, T. A. , Sachs, G. , Bowden, C. , … Breier, A. (2003). Efficacy of olanzapine and olanzapine‐fluoxetine combination in the treatment of bipolar I depression . Archives of General Psychiatry , 60 , 1079–1088. doi: 10.1001/archpsyc.60.11.1079 . [ PubMed ] [ Google Scholar ]
• Tondo, L. , Baldessarini, R. J. , Vazquez, G. , Lepri, B. , & Visioli, C. (2013). Clinical responses to antidepressants among 1036 acutely depressed patients with bipolar or unipolar major affective disorders . Acta Psychiatrica Scandinavica , 127 , 355–364. doi: 10.1111/acps.12023 . [ PubMed ] [ Google Scholar ]
• Tondo, L. , Isacsson, G. , & Baldessarini, R. (2003). Suicidal behaviour in bipolar disorder: Risk and prevention . CNS Drugs , 17 , 491–511. [ PubMed ] [ Google Scholar ]
• Valente, S. M. , & Kennedy, B. L. (2010). End the bipolar tug‐of‐war . Nurse Practitioner , 35 , 36–45. doi: 10.1097/01.NPR.0000367933.64526.3e . [ PubMed ] [ Google Scholar ]
• Vazquez, G. , Tondo, L. , & Baldessarini, R. J. (2011). Comparison of antidepressant responses in patients with bipolar vs. unipolar depression: A meta‐analytic review . Pharmacopsychiatry , 44 , 21–26. doi: 10.1055/s-0030-1265198 . [ PubMed ] [ Google Scholar ]
• Vieta, E. , & Goikolea, J. M. (2005). Atypical antipsychotics: Newer options for mania and maintenance therapy . Bipolar Disorders , 7 ( Suppl 4 ), 21–33. doi: 10.1111/j.1399-5618.2005.00212.x . [ PubMed ] [ Google Scholar ]
• Vieta, E. , Gunther, O. , Locklear, J. , Ekman, M. , Miltenburger, C. , Chatterton, M. L. , … Paulsson, B. (2011). Effectiveness of psychotropic medications in the maintenance phase of bipolar disorder: A meta‐analysis of randomized controlled trials . International Journal of Neuropsychopharmacology , 14 , 1029–1049. doi: 10.1017/S1461145711000885 . [ PubMed ] [ Google Scholar ]
• Vieta, E. , & Valenti, M. (2013). Pharmacological management of bipolar depression: treatment, maintenance, and prophylaxis . CNS Drugs , 27 , 515–529. doi: 10.1007/s40263-013-0073-y . [ PubMed ] [ Google Scholar ]
• Weisler, R. H. , Kalali, A. H. , & Ketter, T. A. (2004). A multicenter, randomized, double‐blind, placebo‐controlled trial of extended‐release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes . Journal of Clinical Psychiatry , 65 , 478–484. Retrieved from PM:15119909. [ PubMed ] [ Google Scholar ]
• Weisler, R. H. , Keck, P. E., Jr. , Swann, A. C. , Cutler, A. J. , Ketter, T. A. , & Kalali, A. H. (2005). Extended‐release carbamazepine capsules as monotherapy for mania in bipolar disorder: A multicenter, randomized, double‐blind, placebo‐controlled trial . Journal of Clinical Psychiatry , 66 , 323–330. [ PubMed ] [ Google Scholar ]
• Yatham, L. N. , Kennedy, S. H. , Parikh, S. V. , Schaffer, A. , Beaulieu, S. , Alda, M ., … Berk, M. (2013). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: Update 2013 . Bipolar Disorders , 15 , 1–44. doi: 10.1111/bdi.12025 . [ PubMed ] [ Google Scholar ]
• Zeber, J. E. , Copeland, L. A. , Good, C. B. , Fine, M. J. , Bauer, M. S. , & Kilbourne, A. M. (2008). Therapeutic alliance perceptions and medication adherence in patients with bipolar disorder . Journal of Affective Disorders , 107 , 53–62. doi: 10.1016/j.jad.2007.07.026 . [ PubMed ] [ Google Scholar ]
• Zolnierek, K. B. , & Dimatteo, M. R. (2009). Physician communication and patient adherence to treatment: A meta‐analysis . Medical Care , 47 ( 8 ), 826–834. doi: 10.1097/MLR.0b013e31819a5acc . [ PMC free article ] [ PubMed ] [ Google Scholar ]

• Research article
• Open access
• Published: 08 February 2021

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.

Peer Review reports

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

Diagnostic and statistical manual of mental disorders. Fifth edition (DSM-5). Arlington: American Psychiatric Association; 2013.

Kaushik P, Bhatia M. Burden and quality of life in spouses of patients with schizophrenia and bipolar disorder. Delhi Psychiatry J. 2013;16(1):83-9.

Maji KR SMSRKS, Maji KR, Sood M, Sagar R, Khandelwal SK. No Title. 2012 Mar 18 [cited 2020 mar 16];58(2). Available from: http://www.ncbi.nlm.nih.gov/pubmed/21421638 .

Zergew A, Hailemariam D, Alem A, Kebede D. A longitudinal comparative analysis of economic and family caregiver burden due to bipolar disorder. Afr J Psychiatry. 2008;11(3):191–8.

Article   Google Scholar  

Shirkhoda SA. The investigation of the amount of cost for bipolar disorder type I and its related factors during the 1-year follow-up for the hospitalized patients in Iran educational-therapeutic psychiatric center [dissertaion]. Iran University of Medical Sciences ;2014.

Jönsson PD, Skärsäter I, Wijk H, Danielson E. Experience of living with a family member with bipolar disorder. Int J Ment Health Nurs. 2011;20(1):29–37.

Shabani A, Ahmadzad-Asl M, Zangeneh K, Teimurinejad S, Kokar S, Taban M, et al. Quality of life in patients with bipolar I disorder: is it related to disorder outcome? Acta Med Iran 2013:51(6):386-93.

Clatworthy J, Bowskill R, Rank T, Parham R, Horne R. Adherence to medication in bipolar disorder: a qualitative study exploring the role of patients’ beliefs about the condition and its treatment. Bipolar Disord 2007;9(6):656-64.

Sharifi A, Shabani A, Ahmadzadasl M. The pattern of adherence in patients with bipolar I disorder; an eight weeks study: Iranian Journal of Psychiatry and Behav Sci 2009;3(2):39-43.

Shabani A, Eftekhar M. Non Compliance After First Episode of Manic or Mixed Mood State: A 17-Month Follow-up. 2007;1(2):46-49.

Tacchi M-J, Scott J. Improving adherence in schizophrenia and bipolar disorders: Wiley; 2005;7:24-31.

Velligan D, Weiden P, Sajatovic M, Scott J, Carpenter D, Ross R, et al. Expert Consensus Panel on Adherence Problems in Serious and Persistent Mental Illness. The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry 2009;70(suppl 4):1-46.

Shabani A, Sobhani S, Tahmasebi N, Ghahramani S, Dejman M: How family caregivers of patients with bipolar disorder conceptualize caring problems: a qualitative study, unpublished.

Tong A, Sainsbury P, Craig J. Consolidated criteria for reporting qualitative research (COREQ): a 32-item checklist for interviews and focus groups. Int J Qual Health Care 2007;19(6):349-57.

Fusch PI, Ness LR. Are we there yet? Data saturation in qualitative research. Qual Rep. 2015;20(9):1408.

Clarke V, Braun V. Using thematic analysis in counselling and psychotherapy research: A critical reflection. Couns Psychother Res 2018;18(2):107-10.

Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol 2006;3(2):77-101.

Chakrabarti S. Treatment-adherence in bipolar disorder: a patient-centred approach. World J Psychiatry 2016;6(4):399.

Shamsaei F, Mohammadkhan Kermanshahi S, Vanaki Z. Survey of Family Caregiver Needs of Patients with Bipolar Disorder. Avicenna J Clin Med 2010;17(3):57-63.

Rahmani F, Ebrahimi H, Ranjbar F, Asghari E. The effect of group psychoeducational program on attitude toward mental illness in family caregivers of patients with bipolar disorder. Hayat. 2016;21(4):65-79.

MacDonald L, Chapman S, Syrett M, Bowskill R, Horne R. Improving medication adherence in bipolar disorder: A systematic review and meta-analysis of 30 years of intervention trials. J Affect Disord 2016;194:202-21.

Wright JH. Cognitive-behavior therapy for severe mental illness: An illustrated guide: American Psychiatric Pub; 2009.

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.

Fisher A, Manicavasagar V, Sharpe L, Laidsaar-Powell R, Juraskova I. A qualitative exploration of patient and family views and experiences of treatment decision-making in bipolar II disorder. J Ment Health 2018;27(1):66-79.

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.

Proudfoot JG, Parker GB, Benoit M, Manicavasagar V, Smith M, Gayed A. What happens after diagnosis? Understanding the experiences of patients with newly-diagnosed bipolar disorder. Health Expect 2009;12(2):120-9.

Crowe M, Inder M, Carlyle D, Wilson L, Whitehead L, Panckhurst A, et al. Feeling out of control: a qualitative analysis of the impact of bipolar disorder. J Psychiatr Ment Health Nurs 2012;19(4):294-302.

Weiss RD, Greenfield SF, Najavits LM, Soto JA, Wyner D, Tohen M, et al. Medication compliance among patients with bipolar disorder and substance use disorder. J Clin Psychiatry 1998;59(4):172-4.

Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002;59(6):530-7.

Judd LL, Schettler PJ, Akiskal HS, Maser J, Coryell W, Solomon D, et al. Long-term symptomatic status of bipolar I vs. bipolar II disorders. Int J Neuropsychopharmacol 2003;6(2):127-37.

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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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Zahra Taherifar

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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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DOI : https://doi.org/10.1186/s12888-020-03008-x

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• 1 Precision Medicine Center of Excellence in Mood Disorders, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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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.

• ↵ . Falret’s discovery: the origin of the concept of bipolar affective illness. Translated by M. J. Sedler and Eric C. Dessain. Am J Psychiatry 1983;140:1127-33. doi: 10.1176/ajp.140.9.1127 OpenUrl CrossRef PubMed Web of Science
• ↵ Kraepelin E. Manic-depressive Insanity and Paranoia. Translated by R. Mary Barclay from the Eighth German. Edition of the ‘Textbook of Psychiatry.’ 1921.
• Merikangas KR ,
• Akiskal HS ,
• Koukopoulos A ,
• Jongsma HE ,
• Kirkbride JB ,
• Rowland TA ,
• Kessler RC ,
• Kazdin AE ,
• Aguilar-Gaxiola S ,
• WHO World Mental Health Survey collaborators
• Bergen SE ,
• Kuja-Halkola R ,
• Larsson H ,
• Lichtenstein P
• Smoller JW ,
• Lichtenstein P ,
• Sjölander A ,
• Mullins N ,
• Forstner AJ ,
• O’Connell KS ,
• Palmer DS ,
• Howrigan DP ,
• Chapman SB ,
• Pirooznia M ,
• Murray GK ,
• McGrath JJ ,
• Hickie IB ,
• ↵ Mostafavi H, Harpak A, Agarwal I, Conley D, Pritchard JK, Przeworski M. Variable prediction accuracy of polygenic scores within an ancestry group. Loos R, Eisen MB, O’Reilly P, eds. eLife 2020;9:e48376. doi: 10.7554/eLife.48376 OpenUrl CrossRef PubMed
• Westlye LT ,
• van Erp TGM ,
• Costa Rica/Colombia Consortium for Genetic Investigation of Bipolar Endophenotypes
• Pauling M ,
• ENIGMA Bipolar Disorder Working Group
• Schnack HG ,
• Ching CRK ,
• ENIGMA Bipolar Disorders Working Group
• Goltermann J ,
• Hermesdorf M ,
• Dannlowski U
• Gurholt TP ,
• Suckling J ,
• Lennox BR ,
• Bullmore ET
• Marangoni C ,
• Hernandez M ,
• Achtyes ED ,
• Agnew-Blais J ,
• Gilman SE ,
• Upthegrove R ,
• ↵ Etain B, Aas M. Childhood Maltreatment in Bipolar Disorders. In: Young AH, Juruena MF, eds. Bipolar Disorder: From Neuroscience to Treatment . Vol 48. Current Topics in Behavioral Neurosciences. Springer International Publishing; 2020:277-301. doi: 10.1007/7854_2020_149
• Johnson SL ,
• Weinberg BZS
• Stinson FS ,
• Costello CG
• Klein & Riso LP DN
• Sandstrom A ,
• Perroud N ,
• de Jonge P ,
• Bunting B ,
• Nierenberg AA
• Hantouche E ,
• Vannucchi G
• Zimmerman M ,
• Ruggero CJ ,
• Chelminski I ,
• Leverich GS ,
• McElroy S ,
• Mignogna KM ,
• Balling C ,
• Dalrymple K
• Kappelmann N ,
• Stokes PRA ,
• Jokinen T ,
• Baldessarini RJ ,
• Faedda GL ,
• Offidani E ,
• Viktorin A ,
• Launders N ,
• Osborn DPJ ,
• Roshanaei-Moghaddam B ,
• De Hert M ,
• Detraux J ,
• van Winkel R ,
• Lomholt LH ,
• Andersen DV ,
• Sejrsgaard-Jacobsen C ,
• Skjelstad DV ,
• Gregersen M ,
• Søndergaard A ,
• Brandt JM ,
• Van Meter AR ,
• Youngstrom EA ,
• Taylor RH ,
• Ulrichsen A ,
• Strawbridge R
• Hafeman DM ,
• Merranko J ,
• Hirschfeld RM ,
• Williams JB ,
• Spitzer RL ,
• Adolfsson R ,
• Benazzi F ,
• Regier DA ,
• Johnson KR ,
• Akinhanmi MO ,
• Biernacka JM ,
• Strakowski SM ,
• Goldberg JF ,
• Schettler PJ ,
• Coryell W ,
• Scheftner W ,
• Endicott J ,
• Zarate CA Jr . ,
• Matsuda Y ,
• Fountoulakis KN ,
• Zarate CA Jr .
• Bowden CL ,
• Brugger AM ,
• The Depakote Mania Study Group
• Calabrese JR ,
• Depakote ER Mania Study Group
• Weisler RH ,
• Kalali AH ,
• Ketter TA ,
• SPD417 Study Group
• Keck PE Jr . ,
• Cutler AJ ,
• Caffey EM Jr . ,
• Grossman F ,
• Eerdekens M ,
• Jacobs TG ,
• Grundy SL ,
• The Olanzipine HGGW Study Group
• Versiani M ,
• Ziprasidone in Mania Study Group
• Sanchez R ,
• Aripiprazole Study Group
• McIntyre RS ,
• Panagides J
• Calabrese J ,
• McElroy SL ,
• EMBOLDEN I (Trial 001) Investigators
• EMBOLDEN II (Trial D1447C00134) Investigators
• Lamictal 606 Study Group
• Lamictal 605 Study Group
• Keramatian K ,
• Chakrabarty T ,
• Nestsiarovich A ,
• Gaudiot CES ,
• Neijber A ,
• Hellqvist A ,
• Paulsson B ,
• Trial 144 Study Investigators
• Schwartz JH ,
• Szegedi A ,
• Cipriani A ,
• Salanti G ,
• Dorsey ER ,
• Rabbani A ,
• Gallagher SA ,
• Alexander GC
• Cerqueira RO ,
• Yatham LN ,
• Kennedy SH ,
• Parikh SV ,
• Højlund M ,
• Andersen K ,
• Correll CU ,
• Ostacher M ,
• Schlueter M ,
• Geddes JR ,
• Mojtabai R ,
• Nierenberg AA ,
• Goodwin GM ,
• Agomelatine Study Group
• Vázquez G ,
• Baldessarini RJ
• Altshuler LL ,
• Cuijpers P ,
• Miklowitz DJ ,
• Efthimiou O ,
• Furukawa TA ,
• Strawbridge R ,
• Tsapekos D ,
• Hodsoll J ,
• Vinberg M ,
• Kessing LV ,
• Forman JL ,
• Miskowiak KW
• Lewandowski KE ,
• Sperry SH ,
• Torrent C ,
• Bonnin C del M ,
• Martínez-Arán A ,
• Bonnín CM ,
• Tamura JK ,
• Carvalho IP ,
• Leanna LMW ,
• Karyotaki E ,
• Individual Patient Data Meta-Analyses for Depression (IPDMA-DE) Collaboration
• Vipulananthan V ,
• Hurlemann R ,
• UK ECT Review Group
• Haskett RF ,
• Mulsant B ,
• Trivedi MH ,
• Wisniewski SR ,
• Espinoza RT ,
• Vazquez GH ,
• McClintock SM ,
• Carpenter LL ,
• National Network of Depression Centers rTMS Task Group ,
• American Psychiatric Association Council on Research Task Force on Novel Biomarkers and Treatments
• Levkovitz Y ,
• Isserles M ,
• Padberg F ,
• Blumberger DM ,
• Vila-Rodriguez F ,
• Thorpe KE ,
• Williams NR ,
• Sudheimer KD ,
• Bentzley BS ,
• Konstantinou G ,
• Toscano E ,
• Husain MM ,
• McDonald WM ,
• International Consortium of Research in tDCS (ICRT)
• Sampaio-Junior B ,
• Tortella G ,
• Borrione L ,
• McAllister-Williams RH ,
• Gippert SM ,
• Switala C ,
• Bewernick BH ,
• Hidalgo-Mazzei D ,
• Mariani MG ,
• Fagiolini A ,
• Swartz HA ,
• Benedetti F ,
• Barbini B ,
• Fulgosi MC ,
• Burdick KE ,
• Diazgranados N ,
• Ibrahim L ,
• Brutsche NE ,
• Sinclair J ,
• Gerber-Werder R ,
• Miller JN ,
• Vázquez GH ,
• Franklin JC ,
• Ribeiro JD ,
• Turecki G ,
• Gunnell D ,
• Hansson C ,
• Pålsson E ,
• Runeson B ,
• Pallaskorpi S ,
• Suominen K ,
• Ketokivi M ,
• Hadzi-Pavlovic D ,
• Stanton C ,
• Lewitzka U ,
• Severus E ,
• Müller-Oerlinghausen B ,
• Rogers MP ,
• Li+ plus Investigators
• Manchia M ,
• Michel CA ,
• Auerbach RP
• Altavini CS ,
• Asciutti APR ,
• Solis ACO ,
• Casañas I Comabella C ,
• Riblet NBV ,
• Young-Xu Y ,
• Shortreed SM ,
• Rossom RC ,
• Amsterdam JD ,
• Brunswick DJ
• Gustafsson U ,
• Marangell LB ,
• Bernstein IH ,
• Karanti A ,
• Kardell M ,
• Collins FS ,
• Armstrong K ,
• Concato J ,
• Singer BH ,
• Ziegelstein RC
• ↵ Holmes JH, Beinlich J, Boland MR, et al. Why Is the Electronic Health Record So Challenging for Research and Clinical Care? Methods Inf Med 2021;60(1-02):32-48. doi: 10.1055/s-0041-1731784
• García Rodríguez LA ,
• Cantero OF ,
• Martinotti G ,
• Dell’Osso B ,
• Di Lorenzo G ,
• REAL-ESK Study Group
• Palacios J ,
• DelBello MP ,
• Husain MI ,
• Chaudhry IB ,
• Subramaniapillai M ,
• Jones BDM ,
• Daskalakis ZJ ,
• Carvalho AF ,
• ↵ Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition Recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2016;30:495-553. doi: 10.1177/0269881116636545 OpenUrl CrossRef PubMed
• Verdolini N ,
• Del Matto L ,
• Regeer EJ ,
• Hoogendoorn AW ,
• Harris MG ,
• WHO World Mental Health Survey Collaborators