research paper about bipolar depression

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• Published: 06 January 2020

Bipolar depression: a major unsolved challenge

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

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

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

Background: depression in bipolar disorder

Nosological uncertainties.

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

Current status of bipolar depression

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

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

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

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

Depression in overall morbidity

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

Morbidity and disability

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

Co-occurring psychiatric disorders

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

General-medical morbidity and mortality

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

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

Bipolar depression and suicide

Suicidal risks.

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

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

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

Suicide and treatment with antidepressants

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

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

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

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

Lithium treatment and suicide

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

Anticonvulsants and suicide

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

Antipsychotics and suicide

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

Other treatments and suicide

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

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

Treatment of bipolar depression

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

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

Antidepressants for bipolar depression

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

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

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

Antidepressants and mood switching

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

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

Mood-stabilizers

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

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

Second-generation antipsychotics

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

Other treatments

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

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

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

Conclusions

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

Availability of data and materials

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

Acharya N, Rosen AS, Polzer JP, et al. Duloxetine: meta-analyses of suicidal behaviors and ideation in clinical trials for major depressive disorder. J Clin Psychopharmacol. 2006;26(6):587–94.

Article   CAS   PubMed   Google Scholar  

Agosti V, Stewart JW. Hypomania with and without dysphoria: comparison of comorbidity and clinical characteristics of respondents from a national community sample. J Affect Disord. 2008;108(1–2):177–82.

Article   PubMed   Google Scholar  

Ahmedani BK, Simon GE, Stewart C, et al. Healthcare contacts in the year before suicide death. J Gen Int Med. 2014;29(6):870–7.

Article   Google Scholar  

Almeida OP, Hankey GJ, Yeap BB, Golledge J, Flicker L. Older men with bipolar disorder: clinical associations with early and late illness. Int J Geriatr Psychiatry. 2018;33(12):1613–9.

Altshuler LL, Sugar CA, McElroy SL, et al. Switch rates during acute treatment for bipolar II depression with lithium, sertraline, or the two combined: randomized, double-blind comparison. Am J Psychiatry. 2017;174(3):266–76.

Amsterdam JD, Shults J. Efficacy and safety of long-term fluoxetine vs. lithium monotherapy of bipolar II disorder: randomized, double-blind, placebo-substitution study. Am J Psychiatry. 2010;167(7):792–800.

Article   PubMed   PubMed Central   Google Scholar  

Angst J, Angst F, Gerber-Werder R, Gamma A. Suicide in 406 mood-disorder patients with and without long-term medication: a 40 to 44 years’ follow-up. Arch Suicide Res. 2005;9(3):279–300.

Arvilommi P, Suominen K, Mantere O, Valtonen H, Leppamaki S, Isometsa E. Predictors of long-term work disability among patients with type I and II bipolar disorder: prospective 18-month follow-up study. Bipolar Disord. 2015;17(8):821–35.

Bachmann S. Epidemiology of suicide and the psychiatric perspective. Int J Environ Res Public Health. 2018;15(7):E1425–47.

Bahji A, Hawken ER, Sepehry AA, Cabrera CA, Vázquez GH. ECT beyond unipolar major depression: systematic review and meta-analysis of electroconvulsive therapy in bipolar depression. Acta Psychiatr Scand. 2019;139(3):214–26.

CAS   PubMed   Google Scholar  

Baldessarini RJ. Chemotherapy in psychiatry. 3rd ed. New York: Springer Press; 2013.

Book   Google Scholar  

Baldessarini RJ, Tondo L. Lithium and suicidal risk. Bipolar Disord. 2008;10(1):114–5.

Baldessarini RJ, Tondo L. Suicidal risks during treatment of bipolar disorder patients with lithium versus anticonvulsants. Pharmacopsychiatry. 2009;42(2):72–5.

Baldessarini RJ, Tondo L, Davis P, et al. Decreased risk of suicides and attempts during long-term lithium treatment: meta-analytic review. Bipolar Disord. 2006;8(5):625–39.

Baldessarini RJ, Henk H, Sklar A, Chang J, Leahy L. Psychotropic medications for patients with bipolar disorder in the United States: polytherapy and adherence. Psychiatr Serv. 2008;59(10):1175–83.

Baldessarini RJ, Salvatore P, Khalsa HM, et al. Morbidity in 303 first-episode bipolar I disorder patients. Bipolar Disord. 2010a;12(3):264–70.

Baldessarini RJ, Tondo L, Ghiani C, Lepri B. Illness risk following rapid vs. gradual discontinuation of antidepressants. Am J Psychiatry. 2010b;167(8):934–41.

Baldessarini RJ, Vieta E, Calabrese JR, Tohen M, Bowden C. Bipolar depression: overview and commentary. Harv Rev Psychiatry. 2010c;18(3):143–57.

Baldessarini RJ, Undurraga J, Vázquez GH, et al. Predominant recurrence polarity among 928 adult international bipolar I disorder patients. Acta Psychiatr Scand. 2012;125(4):293–302.

Baldessarini RJ, Faedda GL, Offidani E, et al. Antidepressant-associated mood-switching and transition from unipolar major depression to bipolar disorder. J Affect Disord. 2013;148(1):129–35.

Baldessarini RJ, Tondo L, Visioli C. First-episode types in bipolar disorder: predictive associations with later illness. Acta Psychiatr Scand. 2014;129(5):383–92.

Baldessarini RJ, Pérez J, Salvatore P, Trede K, Maggini C. Chapt 1: History of bipolar manic-depressive disorder. In: Yildiz A, Nemeroff C, Ruiz P, editors. The bipolar book: history, neurobiology, and treatment. New York: Oxford University Press; 2015. p. 3–20.

Chapter   Google Scholar  

Baldessarini RJ, Tondo L, Pinna N, Nuñez GH, Vázquez GH. Suicidal risk factors in major affective disorders. Br J Psychiatry. 2019a;215(4):621–6.

Baldessarini RJ, Tondo L, Vázquez GH. Pharmacological treatment of adult bipolar disorder. Mol Psychiatry. 2019b;24(2):198–217.

Baldessarini RJ, Tondo L, Vázquez GH. Chapt 4: Unmet needs in psychiatry: bipolar depression. In: Pompili M, McIntyre RS, Fiorillo A, Sartorius N, editors. New directions in psychiatry. New York: Springer Press; 2020.

Google Scholar  

Barbui C, Esposito E, Cipriani A. Selective serotonin reuptake inhibitors and risk of suicide: systematic review of observational studies. CMAJ. 2009;180(3):291–7.

Barbuti M, Pacchiarotti I, Vieta E, et al. Antidepressant-induced hypomania/mania in patients with major depression: evidence from the BRIDGE-II-MIX study. J Affect Disord. 2017;219(9):187–92.

Beasley CM Jr, Dornseif BE, Bosomworth JC, et al. Fluoxetine and suicide: meta-analysis of controlled trials of treatment for depression. BMJ. 1991;303(3804):685–92.

Bond DJ, Noronha M, Kauer-Sant’Anna M, Lam RW, Yatham LN. Antidepressant-associated mood elevations in bipolar II disorder compared with bipolar I disorder and major depressive disorder: systematic review and meta-analysis. J Clin Psychiatry. 2008;69(10):1589–601.

Bouwkamp CG, de Kruiff ME, van Troost TM, et al. Interpersonal and social rhythm group therapy for patients with bipolar disorder. Int J Group Psychother. 2013;63:97–115.

Braun C, Bschor T, Franklin J, Baethge C. Suicides and suicide attempts during long-term treatment with antidepressants: meta-analysis of 29 placebo-controlled studies including 6934 patients with major depressive disorder. Psychother Psychosom. 2016;85(3):171–9.

Bridge JA, Iyengar S, Salary CB, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: meta-analysis of randomized controlled trials. JAMA. 2007;297(15):1683–96.

Brietzke E, Mansur RB, McIntyre RS. Impact of inequalities in healthcare on the mortality risk of individuals with severe mental illnesses. Braz J Psychiatry. 2017;39(3):193–4.

Brown GK, Ten Have T, Henriques GR, Xie SX, Hollander JE, Beck AT. Cognitive therapy for the prevention of suicide attempts: randomized controlled trial. JAMA. 2005;294(5):563–70.

Brown EB, McElroy SL, Keck PE Jr, et al. Seven-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. J Clin Psychiatry. 2006;67(7):1025–33.

Bschor T. Lithium in the treatment of major depressive disorder. Drugs. 2014;74(8):855–62.

Bschor T, Angst J, Azorin JM, et al. Are bipolar disorders underdiagnosed in patients with depressive episodes? Results of the multicenter BRIDGE screening study in Germany. J Affect Disord. 2012;142(1–3):45–52.

Carbon M, Hsieh C-H, Kane JM, Correll CU. Tardive dyskinesia prevalence in the period of second-generation antipsychotic use, meta-analysis. J Clin Psychiatry. 2017;78(3):e264–78.

Centorrino F, Masters GA, Talamo A, Baldessarini RJ, Öngür D. Metabolic syndrome in psychiatrically hospitalized patients treated with antipsychotics and other psychotropics. Hum Psychopharmacol. 2012;27(5):521–6.

Chen TY, Kamali M, Chu CS, Yeh CB, Huang M, Mao WC, Lin Y, Chen YW, Tseng PT, Hsu CY. Divalproex and its effect on suicide risk in bipolar disorder: systematic review and meta-analysis of multinational observational studies. J Affect Disord. 2019;245(2):812–8.

Chesney E, Goodwin GM, Fazel S. Risks of all-cause and suicide mortality in mental disorders: meta-review. World Psychiatry. 2014;13(2):153–60.

Cimpianu CL, Strube W, Falkai P, Palm U, Hasan A. Vagus nerve stimulation in psychiatry: systematic review of the available evidence. J Neural Transm. 2017;124(1):145–58.

Cipriani A, Pretty H, Hawton K, Geddes JR. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: systematic review of randomized trials. Am J Psychiatry. 2005;162(10):1805–19.

Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ Clin Res. 2013;346(6):f3646–59.

Conway CR, Kumar A, Xiong W, Bunker M, Aaronson ST, Rush AJ. Chronic vagus nerve stimulation significantly improves quality of life in treatment-resistant major depression. J Clin Psychiatry. 2018;79(5):52–9.

Correll CU, Detraux J, De Lepeleire J, De Hert M. Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression, or bipolar disorder. World Psychiatry. 2015;14(20):119–36.

Correll CU, Solmi M, Veronese N, et al. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale, meta-analysis of 3,211,768 patients and 113,383,368 controls. World Psychiatry. 2017;16(2):163–80.

Cuellar AK, Johnson SL, Winters R. Distinctions between bipolar and unipolar depression. Clin Psychol Rev. 2005;25(3):307–39.

De Dios C, Ezquiaga E, Garcia A, Soler B, Vieta E. Time spent with symptoms in a cohort of bipolar disorder outpatients in Spain: prospective, 18-month follow-up study. J Affect Disord. 2010;125(1–3):74–81.

Dhir A. Investigational drugs for treating major depressive disorder. Expert Opin Investig Drugs. 2017;26(1):9–24.

Dickerson F, Origoni A, Schroeder J, et al. Natural cause mortality in persons with serious mental illness. Acta Psychiatr Scand. 2018;137(5):371–9.

Drancourt N, Etain B, Lajnef M, Henry C, Raust A, Cochet B, Mathieu F, Gard S, Mbailara K, Zanouy L, Kahn JP, Cohen RF, Wajsbrot-Elgrabli O, Leboyer M, Scott J, Bellivier F. Duration of untreated bipolar disorder: missed opportunities on the long road to optimal treatment. Acta Psychiatr Scand. 2013;127(2):136–44.

Earley W, Burgess MV, Rekeda L, et al. Cariprazine treatment of bipolar depression: randomized double-blind placebo-controlled, phase-3 study. Am J Psychiatry. 2019;176(6):439–48.

FDA (US Food and Drug Administration). Antiepileptic drugs and suicidality 2008. Anticon, https://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm192556.pdf . Accessed 22 Dec 2018.

Felber W, Bauer M, Lewitzka U, Müller-Oerlinghausen B. Lithium clinics in Berlin and Dresden: 50-year experience. Pharmacopsychiatry. 2018;51(5):166–71.

Filkowski MM, Sheth SA. Deep brain stimulation for depression: emerging indication. Neurosurg Clin N Am. 2019;30(2):243–56.

Fink M, Kellner CH, McCall WV. Role of ECT in suicide prevention. J ECT. 2014;30(1):5–9.

Fornaro M, Solmi M, Veronese N, et al. Burden of mood-disorder/cerebrovascular disease comorbidity: essential neurobiology, psychopharmacology, and physical activity interventions. Int Rev Psychiatry. 2017;29(5):425–35.

Forte A, Baldessarini RJ, Tondo L, Vázquez G, Pompili M, Girardi P. Long-term morbidity in bipolar-I, bipolar-II, and major depressive disorders. J Affect Disord. 2015;178(6):71–8.

Forte A, Buscaioni A, Fiorillo A, Pompili M, Baldessarini RJ. Suicidal risk following hospital discharge: review. Harv Rev Psychiatry. 2019;27(4):209–16.

PubMed   Google Scholar  

Fountoulakis KN, Vieta E, Young A, et al. Unmet needs in the treatment of bipolar disorder and recommendations for future research. Int J Neuropsychopharmacol. 2017;20(2):196–205.

Frye MA, Ha K, Kanba S, et al. International consensus group on depression prevention in bipolar disorder. J Clin Psychiatry. 2011;72(10):1295–310.

Gadad BS, Jha MK, Czysz A, et al. Peripheral biomarkers of major depression and antidepressant treatment response: current knowledge and future outlooks. J Affect Disord. 2018;233(6):3–14.

Garay RP, Zarate CA Jr, Charpeaud T, et al. Investigational drugs in recent clinical trials for treatment-resistant depression. Expert Rev Neurother. 2017;17(6):593–609.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381(9878):1672–82.

Ghaemi SN, Wingo AF, Filkowski MA, Baldessarini RJ. Long-term antidepressant treatment in bipolar disorder: meta-analyses of benefits and risks. Acta Psychiatr Scand. 2008;118(5):347–56.

Ghaemi SN, Ostacher MM, El-Mallakh RS, et al. Antidepressant discontinuation in bipolar depression: randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry. 2010;71(4):372–80.

Gibbons RD, Hur K, Brown CH, Mann JJ. Relationship between antiepileptic drugs and suicide attempts in patients with bipolar disorder. Arch Gen Psychiatry. 2009;66(12):1354–60.

Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM. Antidepressants for bipolar depression: systematic review of randomized, controlled trials. Am J Psychiatry. 2004;161(9):1537–47.

Gitlin MJ. Antidepressants in bipolar depression: an enduring controversy. Int J Bipolar Disord. 2018;6(1):25–31.

Goodwin FK, Jamison KR. Manic-depressive illness. 2nd ed. New York: Oxford University Press; 2007.

Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee J, Revicki D. Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA. 2003;290(11):1467–73.

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(6):495–553.

Grady SE, Marsh TA, Tenhouse A, Klein K. Ketamine for the treatment of major depressive disorder and bipolar depression: review of the literature. Ment Health Clin. 2017;7(1):16–23.

Grunebaum MF, Ellis SP, Keip JG, et al. Ketamine vs. midazolam in bipolar depression with suicidal thoughts. Bipolar Disord. 2017;19(3):176–83.

Halaris A. Inflammation-associated co-morbidity between depression and cardiovascular disease. Curr Top Behav Neurosci. 2017;31(11):45–70.

Hällgren J, Ösby U, Westman J, Gissler M. Mortality trends in external causes of death in people with mental health disorders in Sweden, 1987-2010. Scand J Public Health. 2018;47(2):121–6.

Hammad TA, Laughren TP, Racoosin JA. Suicide rates in short-term randomized controlled trials of newer antidepressants. J Clin Psychopharmacol. 2006;26(2):203–7.

Hjorthøj C, Drivsholm-Østergaard ML, Eriksen-Benros M, et al. Association between alcohol and substance use disorders and all-cause and cause-specific mortality in schizophrenia, bipolar disorder, and unipolar depression: nationwide, prospective, register-based study. Lancet Psychiatry. 2015;2(9):801–8.

Isometsä ET. Suicide in bipolar I disorder in Finland: psychological autopsy findings from the National Suicide Prevention Project in Finland. Arch Suicide Res. 2005;9(3):251–60.

Itagaki K, Takebayashi M, Shibasaki C, et al. Factors associated with relapse after a response to electroconvulsive therapy in unipolar versus bipolar depression. J Affect Disord. 2017;208(1):113–9.

Kessler RC, Berglund P, Borges G, Nock M, Wang PS. Trends in suicide ideation, plans, gestures, and attempts in the US, 1990–1992 to 2001–2003. JAMA. 2005;293(20):2487–95.

Khan A, Khan SR, Leventhal RM, Brown WA. Symptom reduction and suicide risk among patients treated with placebo in antipsychotic clinical trials: analysis of the FDA database. Am J Psychiatry. 2001;158(9):1449–54.

Khan A, Khan SR, Hobus J, et al. Differential pattern of response in mood symptoms and suicide risk measures in severely ill depressed patients assigned to citalopram with placebo or citalopram combined with lithium: role of lithium levels. J Psychiatr Res. 2011;45(11):1489–96.

Koukopoulos A, Reginaldi D, Tondo L, Visioli C, Baldessarini RJ. Course sequences in bipolar disorder: depressions preceding or following manias or hypomanias. J Affect Disord. 2013;151(1):105–10.

Kupka RW, Altshuler LL, Nolen WA, et al. Three times more days depressed than manic or hypomanic in both bipolar I and bipolar II disorder. Bipolar Disord. 2007;9(5):531–5.

Large M, Swaraj S. Suicide, substance use and natural causes are respectively the most important causes of mortality in the first year post discharge from psychiatric hospitals. Evid Based Ment Health. 2018;21(2):e8–9.

Laughren TP. Proceedings of a meeting of the Psychopharmacology Drug Advisory Committee (PDAC) concerning suicidal risk in trials of antidepressant drugs in juvenile and adult patients, 2006. http://www.fda.gov/ohrms/dockets/ac/06/briefing//2006-4272b1-01-fda.pdf . Accessed 22 Dec 2018.

Lauterbach E, Felber W, Müller-Oerlinghausen B, et al. Adjunctive lithium treatment in the prevention of suicidal behavior in depressive disorders: randomized, placebo-controlled, one-year trial. Acta Psychiatr Scand. 2008;118(6):469–79.

Lewitzka U, Bauer M, Felber W, Müller-Oerlinghausen B. Antisuicidal effect of lithium: current state of research and its clinical implications for the long-term treatment of affective disorders. Nervenärzt. 2013;84(3):294–306.

Li XB, Tang YL, Wang CY, de Leon J. Clozapine for treatment-resistant bipolar disorder: systematic review. Bipolar Disord. 2015;17(3):235–47.

Liu B, Zhang Y, Fang H, et al. Efficacy and safety of long-term antidepressant treatment for bipolar disorders: meta-analysis of randomized controlled trials. J Affect Disord. 2017a;223(12):41–8.

Liu X, Agerbo E, Li J, Meltzer-Brody S, Bergink V, Munk-Olsen T. Depression and anxiety in the postpartum period and risk of bipolar disorder: Danish nationwide register-based cohort study. J Clin Psychiatry. 2017b;78(5):e469–76.

Lovas DA, Schuman-Olivier Z. Mindfulness-based cognitive therapy for bipolar disorder: systematic review. J Affect Disord. 2018;240:247–61.

Maj M, Pirozzi R, Magliano L, Fiorillo A, Bartoli L. Agitated, “unipolar” major depression: prevalence, phenomenology and outcome. J Clin Psychiatry. 2006;67(5):712–9.

Marangell LB, Dennehy EB, Wisniewski SR, et al. Case-control analyses of the impact of pharmacotherapy on prospectively observed suicide attempts and completed suicides in bipolar disorder. J Clin Psychiatry. 2008;69(6):916–22.

Martinez-Botella G, Salituro FG, Harrison BL, et al. Neuroactive steroids: SAGE-217, a clinical next-generation neuroactive steroid positive allosteric modulator of the GABA A receptor. J Med Chem. 2017;60(18):7810–9.

McCauley E, Berk MS, Asarnow JR, et al. Efficacy of dialectical behavioral therapy for adolescents at high risk for suicide: randomized clinical trial. JAMA Psychiatry. 2018;75(8):777–85.

McElroy SL, Weisler RH, Chan W, et al. Double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry. 2010;71(2):163–74.

McGirr A, Vöhringer PA, Ghaemi SN, Lam RW, Yatham LN. Safety and efficacy of adjunctive second generation antidepressant therapy with a mood-stabilizer or an atypical antipsychotic in acute bipolar depression: systematic review and meta-analysis of randomized placebo-controlled trials. Lancet Psychiatry. 2016;3(12):1138–46. https://doi.org/10.1016/s2215-0366(16)30264-4) .

McIntyre RS, Soczynska JK, Beyer JL, et al. Medical comorbidity in bipolar disorder: reprioritizing unmet needs. Curr Opin Psychiatry. 2007;20(4):406–16.

McMahon K, Herr NR, Zerubavel N, Hoertel N, Neacsiu AD. Psychotherapeutic treatment of bipolar depression. Psychiatr Clin N Am. 2016;39(1):35–56.

Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: international suicide prevention trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82–91.

Messer T, Lammers G, Müller-Siecheneder F, Schmidt RF, Latifi S. Substance abuse in patients with bipolar disorder: systematic review and meta-analysis. Psychiatry Res. 2017;253(7):338–50.

Möller HJ. Is there evidence for negative effects of antidepressants on suicidality in depressive patients? Systematic review. Eur Arch Psychiatry Clin Neurosci. 2006;256(8):476–96.

Müller-Oerlinghausen B, Ahrens B, Felber W. Suicide-preventive and mortality-reducing effect of lithium. In: Bauer M, Grof P, Müller-Oerlinghausen B, editors. Lithium in neuropsychiatry. London: Informa Healthcare; 2006. p. 79–192.

Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry. 2001;158:906–12.

Nierenberg AA, Alpert JE, Gardner-Schuster EE, Seay S, Mischoulon D. Vagus nerve stimulation: 2-year outcomes for bipolar versus unipolar treatment-resistant depression. Biol Psychiatry. 2008;64(6):455–60.

Nock MK, Borges G, Bromet EJ, et al. Cross-national prevalence and risk factors for suicidal ideation, plans and attempts. Br J Psychiatry. 2008;192(2):98–105.

Olfson M, Wall M, Wang S, Crystal S, Liu SM, Gerhard T, Blanco C. Short-term suicide risk after psychiatric hospital discharge. JAMA Psychiatry. 2016;73(11):1119–26.

Oquendo MA, Galfalvy HC, Currier D, et al. Treatment of suicide attempters with bipolar disorder: randomized clinical trial comparing lithium and valproate in the prevention of suicidal behavior. Am J Psychiatry. 2011;168(10):1050–6.

Ösby U, Brandt L, Correia N, Ekbom A, Sparén P. Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry. 2001;58(9):844–50.

Ösby U, Westman J, Hällgren J, Gissler M. Mortality trends in cardiovascular causes in schizophrenia, bipolar and unipolar mood disorder in Sweden 1987–2010. Eur J Pub Health. 2018;26(5):867–71.

Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. International Society for Bipolar Disorders (ISBD) Task-Force report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013;170(11):1249–62.

Parsaik AK, Singh B, Khosh-Chashm D, Mascarenhas SS. Efficacy of ketamine in bipolar depression: systematic review and meta-analysis. J Psychiatr Pract. 2015;21(6):427–35.

Pavlova B, Perlis RH, Uher R. Lifetime prevalence er of anxiety disorders in people with bipolar disorder: systematic review and meta-analysis. Lancet Psychiatry. 2015;2(8):710–7.

Perugi G, Medda P, Toni C, et al. Role of electroconvulsive therapy (ECT) in bipolar disorder: effectiveness in 522 patients with bipolar depression, mixed-state, mania and catatonic features. Curr Neuropharmacol. 2017;15(3):359–71.

Pompili M, Baldessarini RJ, Forte A, et al. Do atypical antipsychotics have antisuicidal effects? A hypothesis-generating overview. Int J Mol Sci. 2016;17(10):E1700–13.

Article   PubMed   CAS   Google Scholar  

Post RM, Leverich GS, Kupka RW, et al. Early-onset bipolar disorder and treatment delay are risk factors for poor outcome in adulthood. J Clin Psychiatry. 2010;71(7):864–72.

Post RM, Leverich GS, McElroy S, et al. Prevalence of Axis-II comorbidities in bipolar disorder: relationship to mood-state. Bipolar Disord. 2018;20(4):303–12.

Preti A, Vrublevska J, Veroniki AA, Huedo-Medina TB, Fountoulakis KN. Prevalence, impact and treatment of generalized anxiety disorder in bipolar disorder: systematic review and meta-analysis. Evid Based Ment Health. 2016;19(3):73–81.

Ragguett RM, McIntyre RS. Cariprazine for the treatment of bipolar depression: a review. Expert Rev Neurother. 2019;19(4):317–23.

Ragguett RM, Rong C, Kratiuk K, McIntyre RS. Rapastinel: investigational NMDA-R modulator for major depressive disorder: evidence to date. Expert Opin Investig Drugs. 2019;28(2):113–9.

Reinares M, Rosa AR, Franco C, et al. Systematic review on the role of anticonvulsants in the treatment of acute bipolar depression. Int J Neuropsychopharmacol. 2013;16(2):485–96.

Roberts E, Cipriani A, Geddes JR, Nierenberg AA, Young AH. Evidence for lithium in suicide prevention. Br J Psychiatry. 2017;211(6):396–7.

Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. New Engl J Med. 2007;356(17):1711–22.

Salcedo S, Gold AK, Sheikh S, et al. Empirically supported psychosocial interventions for bipolar disorder: current state of the research. J Affect Disord. 2016;201(9):203–14.

Salloum NC, Walker MC, Gangwani S, Conway CR. Emergence of mania in two middle-aged patients with a history of unipolar, treatment-refractory depression receiving vagus nerve stimulation. Bipolar Disord. 2017;19(1):60–4.

Sani G, Fiorillo A. Use of lithium in mixed states. CNS Spectr. 2019. https://doi.org/10.1017/S1092852919001184 . (in press) .

Saunders KE, Hawton K. Clinical assessment and crisis intervention for the suicidal bipolar disorder patient. Bipolar Disord. 2013;15(5):575–83.

Schatzberg AF. A word to the wise about intranasal esketamine. Am J Psychiatry. 2019;176(6):422–4.

Schneider-Thoma J, Efthimiou O, Huhn M, et al. Second-generation antipsychotic drugs and short-term mortality: systematic review and meta-analysis of randomized placebo-controlled trials. Lancet Psychiatry. 2018;5(8):653–63.

Scott LJ. Brexanolone: first global approval. Drugs. 2019;79(7):779–83.

Selle V, Schalkwijk S, Vázquez GH, Baldessarini RJ. Treatments for acute bipolar depression: meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium, and second-generation antipsychotics. Pharmacopsychiatry. 2014;47(2):43–52.

Shelton RC, Stahl SM. Risperidone and paroxetine given singly and in combination for bipolar depression. J Clin Psychiatry. 2004;65:1715–9.

Shen H, Zhang L, Xu C, Zhu J, Chen M, Fang Y. Analysis of misdiagnosis of bipolar disorder in an outpatient setting. Shanghai Arch Psychiatry. 2018;30(2):93–101.

Sidor MM, MacQueen GM. Update on antidepressant use in bipolar depression. Curr Psychiatry Rep. 2012;14(6):696–704.

Simon RI, Hales RE, editors. Textbook of suicide assessment and management. 2nd ed. Washington, DC: American Psychiatric Press; 2012.

Smith KA, Cipriani A. Lithium and suicide in mood disorders: updated meta-review on the scientific literature. Bipolar Disord. 2017;19(7):575–86.

Solmi M, Veronese N, Zaninoto L, et al. Lamotrigine compared to placebo and other agents with antidepressant activity in patients with unipolar and bipolar depression: comprehensive meta-analysis of efficacy and safety outcomes in short-term trials. CNS Spectr. 2016;21(5):403–18.

Song J, Sjolander A, Joas E, et al. Suicidal behavior during lithium and valproate treatment: a within-individual 8-year prospective study of 50,000 patients with bipolar disorder. Am J Psychiatry. 2017;174(8):795–802.

Staudt-Hansen P, Frahm-Laursen M, Grøntved S, Puggard-Vogt-Straszek S, Licht RW, Nielsen RE. Increasing mortality gap for patients diagnosed with bipolar disorder: nationwide study with 20 years of follow-up. Bipolar Disord. 2019;21(3):270–5.

Stensland MD, Schultz JF, Frytak JR. Diagnosis of unipolar depression following initial identification of bipolar disorder: common and costly misdiagnosis. J Clin Psychiatry. 2008;69(5):749–58.

Stokes PRA, Kalk NJ, Young AH. Bipolar disorder and addictions: the elephant in the room. Br J Psychiatry. 2017;211(3):132–4.

Suzuki M, Dallaspezia S, Locatelli C, Uchiyama M, Colombo C, Benedetti F. Does early response predict subsequent remission in bipolar depression treated with repeated sleep deprivation combined with light therapy and lithium? J Affect Disord. 2018;229(3):371–6.

Tamayo JM, Zarate CA Jr, Vieta E, Vázquez GH, Tohen M. Level of response and safety of pharmacological monotherapy in the treatment of acute bipolar I disorder phases: systematic review and meta-analysis. Int J Neuropsychopharmacol. 2010;13(6):813–32.

Tarsy D, Lungu C, Baldessarini RJ. Epidemiology of tardive dyskinesia before and during the era of modern antipsychotic drugs. In: Weiner WJ, Tolosa E, editors. Hyperkinetic movement disorders. In Aminoff MJ, Boller F, Swaab DF, editors. Handbook of clinical neurology. Edinburgh: Elsevier Press; 2010. p. 601–16.

Taylor DM, Cornelius V, Smith L, Young AH. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis. Acta Psychiatr Scand. 2014;130(6):452–68.

Thies-Flechtner K, Müller-Oerlinghausen B, Seibert W, Walther A, Greil W. Effect of prophylactic treatment on suicide risk in patients with major affective disorders: data from a randomized prospective trial. Pharmacopsychiatry. 1996;29(3):103–7.

Tiihonen J, Wahlbeck K, Lönnqvist J, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalization due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ. 2006;333(7561):224–9.

Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60(11):1079–88.

Tondo L, Baldessarini RJ. Reduction of suicidal behavior in bipolar disorder patients during long-term treatment with lithium. In: Koslow SH, Ruiz P, Nemeroff CB, editors. Concise guide to understanding suicide: epidemiology pathophysiology and prevention. Cambridge: Cambridge University Press; 2014. p. 217–28.

Tondo L, Baldessarini RJ. Chapt 37: Suicide in bipolar disorder. In: Yildiz A, Nemeroff C, Ruiz P, editors. The bipolar book: history, neurobiology, and treatment. New York: Oxford University Press; 2015. p. 509–28.

Tondo L, Baldessarini RJ. Antisuicidal effects in mood disorders: are they unique to lithium? Pharmacopsychiatry. 2018;51(5):177–88.

Tondo L, Baldessarini RJ, Hennen J, Floris G, Silvetti F, Tohen M. Lithium treatment and risk of suicidal behavior in bipolar disorder patients. J Clin Psychiatry. 1998;59(8):405–14.

Tondo L, Baldessarini RJ, Hennen J, et al. Suicide attempts in major affective disorder patients with comorbid substance use disorders. J Clin Psychiatry. 1999;60(2):63–9.

Tondo L, Hennen J, Baldessarini RJ. Reduced suicide risk with long-term lithium treatment in major affective illness: meta-analysis. Acta Psychiatr Scand. 2001;104(3):163–72.

Tondo L, Lepri B, Baldessarini RJ. Suicidal status during antidepressant treatment in 789 Sardinian patients with major affective disorder. Acta Psychiatr Scand. 2008;118(2):106–15.

Tondo L, Vázquez GH, Baldessarini RJ. Mania associated with antidepressant-treatment: comprehensive meta-analytic review. Acta Psychiatr Scand. 2010;121(6):404–14.

Tondo L, Baldessarini RJ, Vázquez GH, Lepri B, Visioli C. Clinical responses to antidepressants among 1036 acutely depressed patients with bipolar or unipolar major affective disorders. Acta Psychiatr Scand. 2013;127(5):355–64.

Tondo L, Visioli C, Preti A, Baldessarini RJ. Bipolar disorders following initial depression: modeling predictive clinical factors. J Affect Disord. 2014;167(10):44–9.

Tondo L, Pompili M, Forte A, Baldessarini RJ. Suicide attempts in bipolar disorders: comprehensive review of 101 reports. Acta Psychiatr Scand. 2016;133(3):174–86.

Tondo L, Vázquez GH, Pinna M, Vaccotto PA, Baldessarini RJ. Characteristics of depressive and bipolar patients with mixed features. Acta Psychiatr Scand. 2018;138(3):243–52.

Trede K, Salvatore P, Baethge C, Gerhard A, Maggini C, Baldessarini RJ. Manic-depressive illness: evolution in Kraepelin’s textbook, 1883–1926. Harv Rev Psychiatry. 2005;13(3):155–78.

Tsai SY, Lee CH, Chen PH, et al. Risk factors for early cardiovascular mortality in patients with bipolar disorder. Psychiatry Clin Neurosci. 2017;71(10):716–24.

Tseng PT, Chen YW, Tu KY, et al. Light therapy in the treatment of patients with bipolar depression: meta-analytic study. Eur Neuropsychopharmacol. 2016;26(6):1037–47.

Undurraga J, Baldessarini RJ, Valenti M, et al. Bipolar depression: clinical correlates of receiving antidepressants. J Affect Disord. 2012;139(1):89–93.

Vancampfort D, Vansteelandt K, Correll CU, et al. Metabolic syndrome and metabolic abnormalities in bipolar disorder: meta-analysis of prevalence rates and moderators. Am J Psychiatry. 2013;170(3):265–74.

Vázquez GH, Tondo L, Baldessarini RJ. Comparison of antidepressant responses in patients with bipolar vs. unipolar depression: meta-analytic review. Pharmacopsychiatry. 2011;44(1):21–6.

Vázquez GH, Tondo L, Undurraga J, Baldessarini RJ. Overview of antidepressant treatment of bipolar depression. Int J Neuropsychopharmacol. 2013;16(7):1673–85.

Vázquez GH, Tondo L, Undurraga J, Zaratiegui R, Selle V, Baldessarini RJ. Pharmacological treatment of bipolar depression. Adv Psychiatr Treatment. 2014;20(1):193–201.

Vázquez GH, Holtzman J, Tondo L, Baldessarini RJ. Efficacy and tolerability of treatments for bipolar depression. J Affect Disord. 2015;183(9):258–62.

Vázquez GH, Camino S, Tondo L, Baldessarini RJ. Potential novel treatments for bipolar depression: ketamine, fatty acids, anti-inflammatory agents, and probiotics. CNS Neurol Disord Drug Targets. 2017a;16(8):858–69.

Vázquez GH, Forte A, Camino S, Tondo L, Baldessarini RJ. Chapt 17: Psychiatric comorbidity in bipolar disorder: treatment implications: anxiety syndromes and substance abuse. In: Carvalho E, Vieta E, editors. The treatment of bipolar disorder: integrative treatment strategies and future directions. New York: Oxford University Press; 2017b. p. 225–54.

Viktorin A, Lichtenstein P, Thase ME, et al. Risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer. Am J Psychiatry. 2014;171(10):1067–673.

Vöhringer PA, Perlis RH. Discriminating between bipolar disorder and major depressive disorder. Psychiatr Clin N Am. 2016;39(1):1–10.

Wasserman D, Rihmer Z, Rujescu D, et al. European Psychiatric Association (EPA) guidance on suicide treatment and prevention. Eur Psychiatry. 2012;27(2):129–41.

WHO (World Health Organization). International suicide rates, 2018. http://www.who.int/gho/mental_health/suicide_rates_crude/en/ . Accessed 3 Dec 2018.

Widge AS, Malone DA Jr, Dougherty DD. Closing the loop on deep brain stimulation for treatment-resistant depression. Front Neurosci. 2018;12(3):1–9.

Wilkinson ST, Sanacora G. A new generation of antidepressants: update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. Drug Discov Today. 2019;24(2):606–15.

Wilkinson ST, Ballard ED, Bloch MH, et al. Effect of a single dose of intravenous ketamine on suicidal ideation: systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175(2):150–8.

Wu SI, Chen SC, Liu SI, et al. Relative risk of acute myocardial infarction in people with schizophrenia and bipolar disorder: population-based cohort study. PLoS ONE. 2015;10(8):e013463.

Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97–170.

Yerevanian BI, Koek RJ, Mintz J. Bipolar pharmacotherapy and suicidal behavior: lithium, divalproex and carbamazepine. J Affect Disord. 2007;103(1–3):23–8.

Yildiz A, Nemeroff C, Ruiz P, editors. The bipolar book: history, neurobiology, and treatment. New York: Oxford University Press; 2015.

Young AH, McElroy SL, Bauer M, et al. Double-blind, placebo-controlled study (EMBOLDEN I) of quietapine and lithium monotherapy in adults in the acute phase of bipolar depression. J Clin Psychiatry. 2010;71(2):150–62.

Zalsman G, Hawton K, Wasserman D, et al. Suicide prevention strategies revisited: 10-year systematic review. Lancet Psychiatry. 2016;3(7):646–59.

Zimmerman M, Galione JN, Chelminski I, Young D, Dalrymple K, Ruggero CJ. Sustained unemployment in psychiatric outpatients with bipolar disorder: frequency and association with demographic variables and comorbid disorders. Bipolar Disord. 2010;12(7):720–6.

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

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

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Research Article

The Dynamics of Mood and Coping in Bipolar Disorder: Longitudinal Investigations of the Inter-Relationship between Affect, Self-Esteem and Response Styles

* E-mail: [email protected]

Affiliation School of Psychology, Bangor University, Bangor, United Kingdom

Affiliation School of Psychological Sciences, University of Manchester, Manchester, United Kingdom

Affiliation Greater Manchester West NHS Trust, Manchester, United Kingdom

Affiliation Department of Psychology and Neuropsychology, University of Maastricht, Maastricht, The Netherlands

Affiliation Centre for Biostatistics, Institute of Population Health, University of Manchester, Manchester, United Kingdom

Affiliation Institute of Psychology, Health and Society, University of Liverpool, Liverpool, United Kingdom

• Hana Pavlickova, 
• Filippo Varese, 
• Angela Smith, 
• Inez Myin-Germeys, 
• Oliver H. Turnbull, 
• Richard Emsley, 
• Richard P. Bentall

• Published: April 26, 2013
• https://doi.org/10.1371/journal.pone.0062514
• Reader Comments

Previous research has suggested that the way bipolar patients respond to depressive mood impacts on the future course of the illness, with rumination prolonging depression and risk-taking possibly triggering hypomania. However, the relationship over time between variables such as mood, self-esteem, and response style to negative affect is complex and has not been directly examined in any previous study – an important limitation, which the present study seeks to address.

In order to maximize ecological validity, individuals diagnosed with bipolar disorder (N = 48) reported mood, self-esteem and response styles to depression, together with contextual information, up to 60 times over a period of six days, using experience sampling diaries. Entries were cued by quasi-random bleeps from digital watches. Longitudinal multilevel models were estimated, with mood and self-esteem as predictors of subsequent response styles. Similar models were then estimated with response styles as predictors of subsequent mood and self-esteem. Cross-sectional associations of daily-life correlates with symptoms were also examined.

Cross-sectionally, symptoms of depression as well as mania were significantly related to low mood and self-esteem, and their increased fluctuations. Longitudinally, low mood significantly predicted rumination, and engaging in rumination dampened mood at the subsequent time point. Furthermore, high positive mood (marginally) instigated high risk-taking, and in turn engaging in risk-taking resulted in increased positive mood. Adaptive coping (i.e. problem-solving and distraction) was found to be an effective coping style in improving mood and self-esteem.

Conclusions

This study is the first to directly test the relevance of response style theory, originally developed to explain unipolar depression, to understand symptom changes in bipolar disorder patients. The findings show that response styles significantly impact on subsequent mood but some of these effects are modulated by current mood state. Theoretical and clinical implications are discussed.

Citation: Pavlickova H, Varese F, Smith A, Myin-Germeys I, Turnbull OH, Emsley R, et al. (2013) The Dynamics of Mood and Coping in Bipolar Disorder: Longitudinal Investigations of the Inter-Relationship between Affect, Self-Esteem and Response Styles. PLoS ONE 8(4): e62514. https://doi.org/10.1371/journal.pone.0062514

Editor: Xiang Yang Zhang, Baylor College of Medicine, United States of America

Received: November 22, 2012; Accepted: March 21, 2013; Published: April 26, 2013

Copyright: © 2013 Pavlickova et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This research was supported by a studentship for A. Smith from the Economic and Social Research Council ( www.esrc.ac.uk ) and a studentship for H. Pavlickova from the National Institute for Social Care and Health Research, the Welsh Assembly Government ( www.wales.gov.uk/nischr ; Project ref.: HS/09/004), and Betsi Cadwaladr University Health Board (BCUHB) Charitable Funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Attempts to understand the psychological mechanisms underlying bipolar disorder are made difficult by the multidimensional, dynamic and fluctuating nature of the symptoms experienced by patients. For example, although the term ‘bipolar disorder’ implies that depression and mania lie at opposite ends on a spectrum of affect, cross-sectional comparisons indicate that these two groups of symptoms lie on separate dimensions of psychopathology, so that patients can be simultaneously depressed and manic [1] , explaining why patients sometimes present with mixed episodes [2] . It has been reported that mood in bipolar patients can fluctuate chaotically over short periods of time [3] , and longitudinal studies have shown that, within individuals, manic and depressive symptoms vary relatively independently with each other, although with a small but statistically significant positive correlation between them [4] , again explaining why mixed episodes are sometimes observed. The implication of these observations is that psychological studies of bipolar patients should ideally be conducted with sophisticated designs that take into account the complex cross-sectional and longitudinal structure of symptoms, so that covariations between symptoms and psychological processes can be adequately detected.

Problems of self-esteem and related processes seem to be particularly evident in bipolar disorder; almost a century ago, Kreapelin [5] described in detail how manic grandiosity sharply contrasts with low self-esteem and withdrawal during periods of depression. More recent research on the psychological mechanisms in bipolar disorder has focused on self-related cognitive processes already implicated in unipolar depression, for example as proposed in theories by Beck [6] and by Abramson et al. [7] . These studies have shown that individuals with bipolar disorder often present with a negative attributional (explanatory) style [8] , a negative self-concept, and dysfunctional attitudes towards the self [9] , [10] , [11] , [12] . In contrast to Kraepelin’s earlier observations, cross-sectional comparisons suggest that these pessimistic cognitive biases may be evident across all phases of bipolar disorder [13] .

However, a somewhat different picture has emerged from studies employing longitudinal designs or studies examining symptoms rather than episodes. These studies have indicated that bipolar disorder is associated with substantial instability in affective and self-related processes. Pronounced daily fluctuations in self-esteem have been observed in studies of remitted patients [14] , those in depressive episode [13] , and also in studies of individuals assessed by questionnaire measures to be at high-risk of bipolar disorder [15] . Further, low self-esteem in persons with bipolar disorder prospectively predicts worsening of affective, particularly depressive, symptoms [10] , [16] , [17] . In a longitudinal study [18] , where patients were assessed every 6 months, although self-esteem correlated positively with current mania and negatively with current depression, negative self-esteem predicted both future depressive and future manic symptoms. Other self-related cognitive measures administered in the study, although correlating with current symptoms, did not predict future symptoms.

In a similar vein, pronounced fluctuations of affect in bipolar disorder have been indicated by studies of high-risk student samples [15] , [19] , subsyndromal individuals [20] , remitted bipolar patients [14] , and those currently in manic and depressive episode [13] . Notably, affect and self-esteem appear to fluctuate in concert and hence to be tightly linked [21] , [22] .

One way of examining shifts in mood and self-esteem is in the context of the coping mechanisms or response styles individuals employ as a response to low, or elevated, mood. In her work on unipolar depression, Nolen-Hoeksema [23] argued that these mechanisms include rumination, problem solving, distraction activities and risk-taking. In a factor-analytic study by Knowles et al. [24] , problem-solving and distraction loaded on a single factor they labeled active coping.

A number of studies have found that rumination predicts onset and severity of depression in unipolar patients [25] , [26] , [27] . Expanding on the original theory, Thomas and Bentall [28] hypothesized that, whilst at times rumination may exacerbate depressive mood in bipolar patients, at other times it may instigate vigorous attempts to avoid negative mood by engaging in high-risk activities resulting, in turn, in hypomania or full-blown mania. Thomas et al. [29] found high levels of rumination in remitted bipolar patients compared to controls, and high levels of self-reported active coping (problem solving and distraction activities) and risk-taking in manic patients compared to controls. Van der Gucht et al. [13] found high levels of rumination in patients in all phases of bipolar disorder, including remission, but again that self-reported risk-taking was elevated only in currently manic patients. Only one study has examined response styles in relation to daily life experiences and fluctuations in mood and self-esteem [15] . In this experience sampling study of high-risk sample of students selected by questionnaire, higher levels of rumination were associated with lower self-esteem, even though no differences in rumination between the low-risk and high-risk groups were identified.

Insight into the temporal dynamics of response styles in relation to other variable psychological processes such as mood and self-esteem has been precluded by the cross-sectional designs employed in most previous studies of bipolar disorder.

Therefore, the aim of the present study was to examine processes specific to bipolar disorder. First, we investigated cross-sectional associations between symptoms of depression and mania with daily life correlates (i.e. affect and self-esteem) and coping styles (rumination, risk-taking and adaptive coping). We predicted that symptoms of depression would be associated with low mood and self-esteem, and more pronounced fluctuations of both. In addition, we expected depressive symptoms to be related to increased levels of rumination. As to symptoms of mania, we predicted associations with increased mood, self-esteem, and their fluctuations. Furhtermore, mania was expected to be associated with risk-taking.

Second, this study sought to examine prospective associations between mood, self-esteem and response styles in two ways: a) whether mood and self-esteem at time T−1 predict engagement in response styles at the subsequent time point. We expected that low mood and self-esteem at time T−1 would predict increased levels of rumination at time T. In turn, high mood and self-esteem would predict increased risk-taking at time T; b) whether engaging in coping styles at time T−1 influences mood and self-esteem at time T. We expected that engaging in rumination would lead to decreased mood and self-esteem, whilst engaging in risk-taking would improve mood and self-esteem.

Materials and Methods

Ethical approval was obtained from the Leeds (East) Research Ethics Committee and the University of Manchester Senate Ethics Committee. Inclusion criteria for inception into the study were a) diagnosis of bipolar affective disorder, b) currently receiving outpatient care, c) ability to speak/read English, and d) ability to complete the self-report measures independently. Participants were excluded from the study if they met diagnostic criteria for schizophrenia, schizoaffective disorder, primary substance misuse disorder, or had a history of post-natal depression with no hypomania/mania according to DSM-IV [30] . Potential participants were approached via secondary care and self-help groups: 129 covering letters were posted by consultant psychiatrists, resulting in 40 responses, out of which 7 individuals withdrew prior to interview, 5 after receiving further information. Out of the 28 participants commencing the study, 5 dropped out, and 23 completed the study. In addition, consultant psychiatrists approached prospective participants during clinics (N unknown), out of which 3 withdrew after gaining further information, and 24 completed the study. Only one participant was recruited via self-help groups. A total of 48 participants diagnosed with bipolar disorder provided written informed consent and were included into the study: 28 were in a remission, 12 were currently depressed, and 8 currently hypomanic. Participants’ characteristics are described in Table 1 . All participants completed the Structured Clinical Interview for Axis I DSM-IV Disorders [31] .

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https://doi.org/10.1371/journal.pone.0062514.t001

Instruments

1. clinical measures..

To assess symptom levels at the beginning of the study, participants completed two clinical measures in a face-to-face interview.

The Hamilton rating scale for depression [HRSD, 32] consists of 17 items rated by the interviewer on a 0–4 scale with higher scores indicating more sever depressive symptomatology. The HRSD shows inter-rater reliability coefficients up to 0.90 [32] , and good validity and reliability [33] .

The Bech-Refaelson Mania Scale, Modified Version [MAS, 34] is widely used to assess symptoms of mania and designed to be administered alongside the HRSD. Each of its 11 items is rated on a five-point scale, resulting in a total score ranging between 0–44. The scale shows a high inter-observer reliability and an acceptable level of consistency across items [34] .

2. Psychological measures.

All variables pertaining to the psychological processes of concern in this study were derived from experience sampling method (ESM) diaries that participants were asked to complete over a six-day period.

Experience sampling method. The experience sampling method (ESM, [35] ) is a repeated self-assessment procedure completed in participants’ natural environments and thus advantageous over classically administered self-report questionnaires for its high ecological validity [36] . Its validity, reliability and feasibility have been demonstrated in a number of clinical populations, such as in samples of individuals with diagnosis of schizophrenia [37] , [38] , depression [39] , [40] , panic disorder [41] and bipolar disorder [42] , [43] , [44] .

Participants received a pre-programmed digital wristwatch emitting 10 bleeps a day in quasi-random intervals (between 7.30 a.m. and 10.30 p.m.) and six pocketsize diaries to be completed over the period of six days (i.e. one dairy to be completed per each study day). The diary booklet consisted of 10 self-report forms (one per beep), and each comprised scales assessing mood, self-esteem, and styles of coping with depressive mood. Participants received a thorough explanation of the method during a briefing session. To ensure that participants understood the method, they were asked to fill in one form in a trial booklet during the briefing. During the 6-day study period, participants were contacted by telephone to ascertain that they had managed to comply with the procedure, and were thoroughly debriefed after completion of the study. Only participants who completed more than 20 valid responses (i.e. an entry between 5 minutes prior and 15 minutes after the beep) were included in the analyses [45] . This resulted in exclusion of two participants (both females, mean age 59, with depression ratings of 0, 0 and mania ratings of 1 and 2.

Experience Sampling Method Variables

The items included in the ESM self-assessment forms were all rated on 7-point Likert scales and used to define the following variables:

Momentary self-esteem and self-esteem fluctuations.

Four items in the self-report form assessed momentary self-esteem (i.e. “I am a failure”, “I am ashamed of myself”, “I like myself”, and “I am a good person”). Using the Kaiser criterion, principal component analysis (PCA) on the raw within-participant scores revealed one factor accounting for 63% of the total variance. Both negative and positive items showed a strong loading on the factor (positive items<−.68; negative items >.80) and high internal consistency after reversing the two negative items scores (Cronbach’s α = .79). The momentary self-esteem score was defined as the mean score of the four items. Each fluctuation in self-esteem was defined as the absolute difference in the ratings of self-esteem between consecutive time points, with higher scores reflecting more intense fluctuations.

Positive and negative affect, and mood fluctuations.

Nine items assessing momentary positive (e.g. “I feel cheerful”) and negative (e.g. “I feel sad”) affect were used. PCA confirmed two separate factors (eigenvalues >1) together accounting for 66% of variance. The positive affect (PA) factor consisted of four items (“cheerful”, “excited”, “relaxed” and “satisfied”; Cronbach’s α = .82) and the negative affect (NA) factor incorporated five items (“lonely”, “anxious”, “sad”, “irritated” and “guilty”; Cronbach’s α = .86). Fluctuation in mood was defined as the absolute moment-to-moment change in ratings of a) positive mood, and b) negative mood; that is, at each time point two variables were obtained, fluctuation in positive mood and fluctuation in negative mood; higher values reflected more pronounced fluctuations.

Assessment of responses to depression.

Based on the revised version of Nolen-Hoeksema’s Response Style Questionnaire [23] , [24] , the self-assessment forms contained eight items evaluating participants’ coping and response strategies for depression (e.g. “Since the last bleep I have thought about the bad things that have happened to me.”) rated on a 7-point Likert scale ranging from −3 (Disagree) to +3 (Agree). Due to bimodal distribution of the scores suggesting that a portion of participants misunderstood the scale as 0 indicating ‘no engagement’, we have recoded all responses rated negatively (i.e. −3, −2, and −1) as 0. Consistent with previous studies [13] , [24] , PCA confirmed three independent factors accounting for 72% of the variance: rumination (2 items with loadings >.90; Cronbach’s α = .82), adaptive coping (4 distraction and problem-solving items with loadings >.59; Cronbach’s α = .72) and risk-taking (2 items with loadings >.91; Cronbach’s α = .84).

Data Analyses

The structure of ESM data allows for the investigation of longitudinal associations between ESM variables using regression methods, i.e. testing whether ESM variables at a given beep (i.e. T) are predicted by responses at the previous beep (T−1). The longitudinal nature of these data implies that ESM data have a hierarchical structure (i.e. ESM entries at each beep are clustered within participants); therefore the assumption of the independence of residuals required for linear models is violated. Multilevel modeling adequately account for this type of violations [46] , [47] , [48] . Data were analyzed with the XTREG module of STATA version 12.0 using maximum likelihood estimation. As a number of variables (i.e. symptoms of depression and mania, and all response styles) were severely positively skewed, bootstrapping (1000 iterations) was utilized, the recommended procedure when the assumptions of normality are violated [49] .

Multilevel regression models were employed as follows:

• We investigated the daily life correlates of depressive and manic symptoms measured at baseline. Separate multilevel regression models were estimated for the following dependent variables: PA, NA, SE, fluctuations of PA, fluctuations of NA, fluctuations of SE, rumination, active-copying and risk-taking. For each model, symptoms of depression and mania were entered as independent variables.
• We examined whether PA, NA and SE predicted subsequent response style behaviors. Response style items were phrased “Since the last bleep…” in the diary booklets and as such, assessed coping behaviours between successive time points T−1 and T. For the purpose of the present analyses they were treated as time T items. Separate multilevel regression models were estimated for each independent variable (i.e. PA, NA and SE) as measured at T−1 and response styles (i.e. rumination, active copying and risk-taking) at time T were entered into the models as dependent variables. We controlled for the confounding effect of response style at the previous time point (T−1), as well as for the baseline symptoms of depression and mania.
• We tested whether response styles predicted subsequent levels of PA, NA, and SE. Separate multilevel regression models were estimated for each dependent variable (i.e. PA, NA and SE) at time T with response styles (rumination, adaptive copying, and risk-taking) at time T−1 as predictors. We controlled for the confounding effect of PA, NA and SE at the previous beep, and symptoms of depression and mania measured at a baseline.

Are Symptoms of Depression (HRSD) and Mania (MAS) Associated?

In preliminary analyses, we first examined the distributions of depression (HRSD) and mania (MAS) scores, and their associations. As previous studies found a weak, but significant correlation between symptoms of depression and mania [4] , [50] , we first examined the relatedness of the two scores. Correlation analyses in the present study did not reach statistical significance, r s  = 0.18, p = .23. Nevertheless, in the following analyses both symptoms were controlled for simultaneously.

i. Are symptoms of depression and mania associated with daily life correlates?

Although our main goal was to investigate the longitudinal relationship between variables, the cross-sectional associations were examined first, see Table 2 . First, we investigated whether positive and negative mood, and self-esteem were related to symptom ratings. Statistical analyses were carried out for momentary level of each variable (i.e. PA, NA, SE) as well as their fluctuations. We found that both depression and mania were associated with higher momentary negative affect (p<.001), lower momentary positive affect (p<.001), and lower momentary self-esteem (p<.01), as well as with more pronounced fluctuations of all variables (all p s <.001).

https://doi.org/10.1371/journal.pone.0062514.t002

We also examined the associations between symptom ratings and response style scores (i.e. rumination, adaptive coping, and risk-taking). Depression was significantly associated with higher levels of rumination, adaptive coping and risk-taking (all ps <.001), whilst mania was significantly associated only with increased levels of risk-taking (p<.001; Table 2 ).

ii. Does affect and self-esteem at time T-1 predict response styles at time T?

The main aim of the present study was to examine associations between affect, self-esteem, and response styles over time. We first examined how affect and self-esteem influenced the way individuals engaged in response styles, and then (in the next section), how response styles affected subsequent mood and self-esteem.

First, the predictive properties of each affect and self-esteem variable at each time point (T−1) on rumination at the subsequent time point (T) was investigated ( Table 3 , upper rows). Multilevel regression analyses revealed that negative affect was associated with increased rumination (p<.001), whereas positive affect (p<.001) and self-esteem (p<.001) were associated with decreases in ruminative thinking at the subsequent time point. When all predictors were entered into the model simultaneously, only affect remained a significant predictor of subsequent rumination: positive affect was associated with a decrease (p<.01), whilst negative affect with an increase (p<.001) of rumination ( Table 3 lower rows).

https://doi.org/10.1371/journal.pone.0062514.t003

None of the independent variables was significantly associated with adaptive coping (all p s = ns; Table 3 ).

Finally, we examined whether affect and self-esteem at time T−1 predicted risk-taking at time T ( Table 3 , upper rows). Risk-taking was significantly predicted by high positive (p<.01), and low negative mood (p<.01) at the previous time point, but only positive affect (p = .071) remained marginally associated with risk-taking when all predictors were entered into the model simultaneously ( Table 3 , lower rows).

iii. Do response styles assessed at T-1 predict affect and self-esteem at T?

Multilevel regression models were estimated to examine whether response styles to depression predicted changes in positive affect, negative affect and self-esteem at subsequent time points. When separate models were estimated for a model with positive affect as the dependent variable, adaptive coping (p<.05), and risk taking (p<.01) at the previous time point significantly predicted an increase in positive affect (both p s <.05), whilst rumination significantly predicted a decrease in self-esteem, and only marginally in positive affect (p = .05). All predictors were significantly associated with positive affect when entered into the model simultaneously (all p s <.05, Table 4 ).

https://doi.org/10.1371/journal.pone.0062514.t004

When separate models were estimated with negative affect as the outcome variable, no significant associations were revealed. Nevertheless, in a model with all response styles entered into the model simultaneously, a marginally significant relationship between rumination at time T−1 and negative affect at the subsequent time point was found (p = .079).

In a model with self-esteem as the dependent variable, no significant associations with response styles at the previous time point were revealed. When all predictors were entered into the model simultaneously, adaptive coping at time T-1 significantly predicted an increase in self-esteem at time T (p<.05).

iv. Follow-up analyses.

In order to examine whether any of the identified relationships were moderated by symptoms of depression or mania, an interaction term between each predictor and symptoms was added into each of the models described in ii) and iii) above with all relevant predictors entered simultaneously. Each model was calculated twice, first with interactions between symptoms of depression and the predictors, followed by a similar model with interactions between symptoms of mania and the predictors. For example, in the case of the model with positive affect as a dependent variable and all three response styles as predictors, three interaction terms were added (between each response style and ratings of depression). A similar model was then calculated with interaction terms between each response style and ratings of mania.

Only one model yielded a significant baseline symptom × predictor interaction. A significant interaction term between symptoms of mania and levels of rumination (β = 0.02, SE = 0.01, p<.01, CI [.01.04]), was found when positive affect was the dependent variable. Additional analyses indicated that rumination led to a decrease in positive affect in individuals with low symptoms of mania at baseline (β = −.27, SE = .04, p<.001, CI [−.35 −.19]) but not in those with high symptoms of mania at baseline. No other significant interaction terms were identified (all p s>.05).

The present study is a novel investigation of the prospective relationships between affect, self-esteem and response styles in individuals diagnosed with bipolar disorder. It tests Nolen-Hoeksema’s [23] response style theory and its later adaptations [24] , [28] , originally formulated to explain the course of unipolar depression using longitudinal data from bipolar patients to examine the impact of psychological variables on response styles and, subsequently, the effect of response styles on psychological variables. The experience sampling method employed in this study allowed the capture of these dynamic relationships, which cannot be assessed using more conventional cross-sectional designs.

Before reviewing the main results, we will comment first on the observed cross-sectional relationships between mood and self-esteem in daily life and baseline symptoms of depression and mania. It was expected that low self-esteem and high negative affect would be associated with symptoms of depression, whereas high positive affect and self-esteem would relate to symptoms of mania. Further, we predicted that increased fluctuations of these processes would be related to both symptoms. Our expectations regarding associations with depression were confirmed, and in line with previous literature. Here, associations between depression and negative mood, as well as its instability, have been consistently reported in studies of high risk students [19] , [24] , [51] , subclinical samples [20] and bipolar patients [13] , [52] . Similarly, previous findings have indicated an association between depression and self-esteem [16] , as well as instability of self-esteem in high risk student [15] and patient studies [14] .

Contrary to our expectations, symptoms of mania showed similar associations with mood and self-esteem as depression (i.e. mania was associated with low mood and self-esteem, and their increased instability), although the effect found was smaller. In contrast to our findings, previous studies have found mania to be related to high mood [51] , and self-esteem comparable to that of controls [13] . Yet, our findings are not the first of its kind. An earlier factor analytic study suggested dysphoria to be the strongest component of mania [53] , and underlying negativity of affect and self-concept during mania have been suggested by studies employing implicit assessments [14] , [54] .

The discrepancy between the present study and previous reports, both employing explicit assessments, might be related to methodological differences. For example, a number of studies employed comparisons of different phases of bipolar disorder, rather than investigating associations of psychological measures with symptoms (e.g. [13] ), an approach complicated by frequent co-existence of depressive and manic symptoms. Another explanation might be related to age differences between examined populations. Several previous studies employed high-risk student populations, and it is likely that personal context of students is considerably different to that of adults with a history of severe mental illness. Although both kinds of studies may be tapping the same underlying vulnerabilities, their expression might be changing across the course of life. The present study is methodologically advantageous in that it has employed patients, representative of bipolar phenomenology, and utilized a longitudinal and ecologically valid assessment and robust statistical methods controlling for covariation of symptoms and non-normality of data.

The increased fluctuations in affect and self-esteem seen in relation to symptoms of depression and mania in the present study suggests that the fluctuations we have observed in remitted patients in previous studies [13] , [24] may have been the consequence of subsyndromal symptoms.

In respect of associations between symptoms and response styles, we expected that rumination would be associated with depression, and risk-taking with mania. Indeed, symptoms of depression were related to increased rumination, an observation that is consistent with Nolen-Hoeksema’s [23] original response style theory, and with findings from bipolar high-risk [24] , [28] , [55] , and patient studies [13] , [29] . The association observed between depressive symptoms and adaptive coping was unexpected, as an earlier patient study found adaptive coping to be related to mania rather than depression [29] . The disparity might reflect the differences between the retrospective questionnaire assessments employed by Thomas et al. [29] and the more ecologically valid experience sampling method utilized in the current study. Finally, risk-taking was positively associated with symptoms of depression as well as mania. Although we did not predict an association between depression and risk-taking, similar cross-sectional relationships have been reported previously [14] , [24] , [29] .

The main aim of the present study was to examine the unique associations between momentary mood, self-esteem and coping styles, and vice versa, whilst controlling for symptoms of depression and mania. To our knowledge, this is the first study to prospectively investigate Nolen-Hoeksema’s [23] response style hypothesis, utilizing measures of response styles in daily life. It was predicted that both low mood and low self-esteem would prompt rumination at a subsequent time point, whilst positive mood and high self-esteem might trigger risky behaviors. The hypotheses were mostly confirmed, with a number of implications requiring comment. As noted, previous cross-sectional studies reported an association between rumination and symptoms of depression. The present findings suggest that high levels of negative, and low levels of positive affect instigate the subsequent engagement in rumination and that, in turn, rumination impacts most robustly via the dampening of positive mood. Furthermore, rumination led to decrease in positive affect only in individuals with few symptoms of mania, whilst no effect was found in those with manic symptoms. These findings are in line with Nolen-Hoeksema’s notion that rumination as such does not cause depression, but rather moderates already depressive mood [56] . The null finding regarding the causal role of self-esteem potentially points to the precedence of affect over cognitive psychological processes in affective disorders, but further investigations are warranted, and this conjecture should be viewed with caution.

The findings regarding risk-taking have both theoretical and clinical implications. Although risk-taking have been found to be related to symptoms of depression and mania cross-sectionally, in a prospective design, positive, rather than negative, mood led to greater risk taking when controlling for the effect of symptoms (although the association reached only marginal significance). In turn, engaging in risk-taking resulted in improvements of mood. In a similar vein, Thomas et al. [29] and Van der Gucht [13] reported higher levels of risk-taking, as measured by questionnaire, in manic participants compared to controls. The failure to detect an association between risk-taking and negative affect, then, implies that this response style might not necessarily act as a defense against low mood as proposed previously [28] , but rather is associated with an increased emotional and behavioral reactivity to reward stimuli as proposed by the behavioural activation theory of mania [57] , [58] , [59] . This account is consistent with recent neuroimaging studies, which have pointed to the abnormal processing of reward stimuli in bipolar patients and at-risk samples [60] , [61] , [62] .

In her original theory, Nolen-Hoeksama (1991) suggested that engaging in distraction (which, along with problem-solving, was incorporated into adaptive coping in this and some previous studies) ameliorates depressive symptoms. Moreover, Nolen-Hoeksema argued that employing healthy coping strategies such as problem solving may be prevented by rumination. Our findings support these hypotheses only partially. Although in the current study neither mood, nor self-esteem instigated subsequent engagement in adaptive coping, employing this coping style led to substantial improvements in mood and self-esteem at the following time point. Furthermore, adaptive coping was found to be an effective strategy even when controlling for other coping strategies. Hence, adaptive coping appears to be a top-down strategy, that can be deliberately employed to improve one’s affective state, an observation that is consistent with earlier studies showing its effectiveness in natural and laboratory conditions [25] , [56] .

A number of limitations should be acknowledged. Despite methodological advantages of experience sampling method over classical self-report assessments [45] , some authors have raised concerns regarding participants’ compliance with, and hence reliability of, the pencil-and-paper protocol of experience sampling, favoring the use of electronic diaries [63] , [64] , [65] . Whilst this might be an important limitation in studies employing predetermined entries, previous studies have demonstrated comparable, and relatively high, compliance in electronic and paper diary studies, when using a random-entry design [66] , [67] , [68] , also employed in the present study. Further, it is possible that utilizing different time lags in the predictive analyses would have led to different results.

The findings have a number of clinical implications. Various psychotherapies operate by means of modifying coping strategies – though often using different methods (for review, see [69] ); the response style theory has been found to provide a useful framework for understanding the utility of coping styles. Our findings highlight the importance of therapeutic strategies to ameliorate rumination in bipolar patients, and also the potential value of psychoeducational methods of reducing risk taking in response to incipient manic symptoms. The observation that risk-taking prompted by positive affect leads to a further escalation of affect points to the need to interrupt this cycle during the earliest phase of a hypomanic episode. Existing cognitive behavior therapy strategies which have been shown to be effective already address these issues to some degree [70] . The results regarding adaptive coping are promising as they imply that individuals with severe illness retain some ability to effectively regulate their mood.

Author Contributions

Contributed to revising manuscript critically for important intellectual content: IM-G AS FV OT RPB RE HP. Conceived and designed the experiments: AS IM-G RPB. Performed the experiments: AS. Analyzed the data: FV HP RE. Wrote the paper: HP RPB OT IM-G FV RE.

• View Article
• Google Scholar
• 5. Kraepelin E (1921) Manic-depressive insanity and paranoia. Barclay RM, translator. Edinburgh: Livingstone.
• 7. Abramson LY, Alloy LB, Metalsky GI (1988) The cognitive diathesis-stress theories of depression: Towards and evaluation of the theories’ validities. In: Alloy LB, editor. Cognitive Processes in Depression. New York: Guilford.
• 30. American Psychiatric Association (1994) Diagnostic and statistical manual for mental disorders, 4th edition. Washington DC: Author.
• 31. First M, Spitzer R, Gibbon M, Williams J (1995) Structured clinical interview for Axis I DSM-IV disorders. Washington DC: American Psychiatric Association Press.
• 33. Rehm LP (1988) Assessment of depression. In: Bellack AS, Hersen M, editors. Behavioral Assessment : A Practical Handbook 3rd Edition. Oxford: Permagon. 313–364.
• 35. Csikszentmihalyi M, Larson R (1987) Validity and reliability of the Experience Sampling Method. Journal of Nervous and Mental Disease 175.
• 38. Myin-Germeys I, van Os J (2007) Stress-reactivity in psychosis: Evidence for an affective pathway to psychosis. Clinical Psychology Review: 409–424.
• 43. Kwapil TR, Barrantes-Vidal N, Armistead MS, Hope GA, Brown LH, et al.. (2011) The expression of bipolar spectrum psychopathology in daily life. Journal of Affective Disorders 130.
• 44. Walsh MA, Royal A, Brown LH, Barrantes-Vidal N, Kwapil TR (in press) Looking for bipolar spectrum psychopathology: identification and expression in daily life. Comprehensive Psychiatry.
• 45. Delespaul P (1995) Assessing schizophrenia in daily life: The Experience Sampling Method. Maastricht, the Netherlands: Universitaire Pers Maastricht.
• 47. Hox JJ (2010) Multilevel analysis: Techniques and applications. Hove: Routledge.
• 48. Twisk JWR (2006) Applied Multilevel Analysis. New York: Cambridge University Press.
• 49. Mooney CZ, Duval RD (1993) Bootstrapping: A non-parametric approach to statistical inference. Newbury Park, CA: Sage Publications.
• 50. Pavlickova H, Varese F, Turnbull O, Scott J, Morriss R, et al. (under review) Symptom-specific self-referential cognitive processes in bipolar disorder: A longitudinal analysis. Psychological Medicine.
• 69. Roth A, Fonagy P (2005) What works for whom: A critical review of psychotherapy research. London: Guildford Press.

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• Systematic Review
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• Published: 20 July 2022

The serotonin theory of depression: a systematic umbrella review of the evidence

• Joanna Moncrieff 1 , 2 ,
• Ruth E. Cooper 3 ,
• Tom Stockmann 4 ,
• Simone Amendola 5 ,
• Michael P. Hengartner 6 &
• Mark A. Horowitz 1 , 2  

Molecular Psychiatry volume  28 ,  pages 3243–3256 ( 2023 ) Cite this article

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A Correspondence to this article was published on 16 June 2023

A Comment to this article was published on 16 June 2023

The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT 1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n  = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use ( n  = 1869). Two meta-analyses of overlapping studies examining the 5-HT 1A receptor (largest n  = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n  = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers ( n  = 566), but weak evidence of an effect in those with a family history of depression ( n  = 75). Another systematic review ( n  = 342) and a sample of ten subsequent studies ( n  = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study ( n  = 115,257) and one collaborative meta-analysis ( n  = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.

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Introduction.

The idea that depression is the result of abnormalities in brain chemicals, particularly serotonin (5-hydroxytryptamine or 5-HT), has been influential for decades, and provides an important justification for the use of antidepressants. A link between lowered serotonin and depression was first suggested in the 1960s [ 1 ], and widely publicised from the 1990s with the advent of the Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants [ 2 , 3 , 4 ]. Although it has been questioned more recently [ 5 , 6 ], the serotonin theory of depression remains influential, with principal English language textbooks still giving it qualified support [ 7 , 8 ], leading researchers endorsing it [ 9 , 10 , 11 ], and much empirical research based on it [ 11 , 12 , 13 , 14 ]. Surveys suggest that 80% or more of the general public now believe it is established that depression is caused by a ‘chemical imbalance’ [ 15 , 16 ]. Many general practitioners also subscribe to this view [ 17 ] and popular websites commonly cite the theory [ 18 ].

It is often assumed that the effects of antidepressants demonstrate that depression must be at least partially caused by a brain-based chemical abnormality, and that the apparent efficacy of SSRIs shows that serotonin is implicated. Other explanations for the effects of antidepressants have been put forward, however, including the idea that they work via an amplified placebo effect or through their ability to restrict or blunt emotions in general [ 19 , 20 ].

Despite the fact that the serotonin theory of depression has been so influential, no comprehensive review has yet synthesised the relevant evidence. We conducted an ‘umbrella’ review of the principal areas of relevant research, following the model of a similar review examining prospective biomarkers of major depressive disorder [ 21 ]. We sought to establish whether the current evidence supports a role for serotonin in the aetiology of depression, and specifically whether depression is associated with indications of lowered serotonin concentrations or activity.

Search strategy and selection criteria

The present umbrella review was reported in accordance with the 2009 PRISMA statement [ 22 ]. The protocol was registered with PROSPERO in December 2020 (registration number CRD42020207203) ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=207203 ). This was subsequently updated to reflect our decision to modify the quality rating system for some studies to more appropriately appraise their quality, and to include a modified GRADE to assess the overall certainty of the findings in each category of the umbrella review.

In order to cover the different areas and to manage the large volume of research that has been conducted on the serotonin system, we conducted an ‘umbrella’ review. Umbrella reviews survey existing systematic reviews and meta-analyses relevant to a research question and represent one of the highest levels of evidence synthesis available [ 23 ]. Although they are traditionally restricted to systematic reviews and meta-analyses, we aimed to identify the best evidence available. Therefore, we also included some large studies that combined data from individual studies but did not employ conventional systematic review methods, and one large genetic study. The latter used nationwide databases to capture more individuals than entire meta-analyses, so is likely to provide even more reliable evidence than syntheses of individual studies.

We first conducted a scoping review to identify areas of research consistently held to provide support for the serotonin hypothesis of depression. Six areas were identified, addressing the following questions: (1) Serotonin and the serotonin metabolite 5-HIAA–whether there are lower levels of serotonin and 5-HIAA in body fluids in depression; (2) Receptors - whether serotonin receptor levels are altered in people with depression; (3) The serotonin transporter (SERT) - whether there are higher levels of the serotonin transporter in people with depression (which would lower synaptic levels of serotonin); (4) Depletion studies - whether tryptophan depletion (which lowers available serotonin) can induce depression; (5) SERT gene – whether there are higher levels of the serotonin transporter gene in people with depression; (6) Whether there is an interaction between the SERT gene and stress in depression.

We searched for systematic reviews, meta-analyses, and large database studies in these six areas in PubMed, EMBASE and PsycINFO using the Healthcare Databases Advanced Search tool provided by Health Education England and NICE (National Institute for Health and Care Excellence). Searches were conducted until December 2020.

We used the following terms in all searches: (depress* OR affective OR mood) AND (systematic OR meta-analysis), and limited searches to title and abstract, since not doing so produced numerous irrelevant hits. In addition, we used terms specific to each area of research (full details are provided in Table  S1 , Supplement). We also searched citations and consulted with experts.

Inclusion criteria were designed to identify the best available evidence in each research area and consisted of:

Research synthesis including systematic reviews, meta-analysis, umbrella reviews, individual patient meta-analysis and large dataset analysis.

Studies that involve people with depressive disorders or, for experimental studies (tryptophan depletion), those in which mood symptoms are measured as an outcome.

Studies of experimental procedures (tryptophan depletion) involving a sham or control condition.

Studies published in full in peer reviewed literature.

Where more than five systematic reviews or large analyses exist, the most recent five are included.

Exclusion criteria consisted of:

Animal studies.

Studies exclusively concerned with depression in physical conditions (e.g. post stroke or Parkinson’s disease) or exclusively focusing on specific subtypes of depression such as postpartum depression, depression in children, or depression in bipolar disorder.

No language or date restrictions were applied. In areas in which no systematic review or meta-analysis had been done within the last 10 years, we also selected the ten most recent studies at the time of searching (December 2020) for illustration of more recent findings. We performed this search using the same search string for this domain, without restricting it to systematic reviews and meta-analyses.

Data analysis

Each member of the team was allocated one to three domains of serotonin research to search and screen for eligible studies using abstract and full text review. In case of uncertainty, the entire team discussed eligibility to reach consensus.

For included studies, data were extracted by two reviewers working independently, and disagreement was resolved by consensus. Authors of papers were contacted for clarification when data was missing or unclear.

We extracted summary effects, confidence intervals and measures of statistical significance where these were reported, and, where relevant, we extracted data on heterogeneity. For summary effects in the non-genetic studies, preference was given to the extraction and reporting of effect sizes. Mean differences were converted to effect sizes where appropriate data were available.

We did not perform a meta-analysis of the individual meta-analyses in each area because they included overlapping studies [ 24 ]. All extracted data is presented in Table  1 . Sensitivity analyses were reported where they had substantial bearing on interpretation of findings.

The quality rating of systematic reviews and meta-analyses was assessed using AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews) [ 25 ]. For two studies that did not employ conventional systematic review methods [ 26 , 27 ] we used a modified version of the AMSTAR-2 (see Table  S3 ). For the genetic association study based on a large database analysis we used the STREGA assessment (STrengthening the REporting of Genetic Association Studies) (Table  S4 ) [ 28 ]. Each study was rated independently by at least two authors. We report ratings of individual items on the relevant measure, and the percentage of items that were adequately addressed by each study (Table  1 , with further detail in Tables  S3 and S4 ).

Alongside quality ratings, two team members (JM, MAH) rated the certainty of the results of each study using a modified version of the GRADE guidelines [ 29 ]. Following the approach of Kennis et al. [ 21 ], we devised six criteria relevant to the included studies: whether a unified analysis was conducted on original data; whether confounding by antidepressant use was adequately addressed; whether outcomes were pre-specified; whether results were consistent or heterogeneity was adequately addressed if present; whether there was a likelihood of publication bias; and sample size. The importance of confounding by effects of current or past antidepressant use has been highlighted in several studies [ 30 , 31 ]. The results of each study were scored 1 or 0 according to whether they fulfilled each criteria, and based on these ratings an overall judgement was made about the certainty of evidence across studies in each of the six areas of research examined. The certainty of each study was based on an algorithm that prioritised sample size and uniform analysis using original data (explained more fully in the supplementary material), following suggestions that these are the key aspects of reliability [ 27 , 32 ]. An assessment of the overall certainty of each domain of research examining the role of serotonin was determined by consensus of at least two authors and a direction of effect indicated.

Search results and quality rating

Searching identified 361 publications across the 6 different areas of research, among which seventeen studies fulfilled inclusion criteria (see Fig.  1 and Table  S1 for details of the selection process). Included studies, their characteristics and results are shown in Table  1 . As no systematic review or meta-analysis had been performed within the last 10 years on serotonin depletion, we also identified the 10 latest studies for illustration of more recent research findings (Table  2 ).

Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagramme.

Quality ratings are summarised in Table  1 and reported in detail in Tables  S2 – S3 . The majority (11/17) of systematic reviews and meta-analyses satisfied less than 50% of criteria. Only 31% adequately assessed risk of bias in individual studies (a further 44% partially assessed this), and only 50% adequately accounted for risk of bias when interpreting the results of the review. One collaborative meta-analysis of genetic studies was considered to be of high quality due to the inclusion of several measures to ensure consistency and reliability [ 27 ]. The large genetic analysis of the effect of SERT polymorphisms on depression, satisfied 88% of the STREGA quality criteria [ 32 ].

Serotonin and 5-HIAA

Serotonin can be measured in blood, plasma, urine and CSF, but it is rapidly metabolised to 5-hydroxyindoleacetic acid (5-HIAA). CSF is thought to be the ideal resource for the study of biomarkers of putative brain diseases, since it is in contact with brain interstitial fluid [ 33 ]. However, collecting CSF samples is invasive and carries some risk, hence large-scale studies are scarce.

Three studies fulfilled inclusion criteria (Table  1 ). One meta-analysis of three large observational cohort studies of post-menopausal women, revealed lower levels of plasma 5-HT in women with depression, which did not, however, reach statistical significance of p  < 0.05 after adjusting for multiple comparisons. Sensitivity analyses revealed that antidepressants were strongly associated with lower serotonin levels independently of depression.

Two meta-analyses of a total of 19 studies of 5-HIAA in CSF (seven studies were included in both) found no evidence of an association between 5-HIAA concentrations and depression.

Fourteen different serotonin receptors have been identified, with most research on depression focusing on the 5-HT 1A receptor [ 11 , 34 ]. Since the functions of other 5-HT receptors and their relationship to depression have not been well characterised, we restricted our analysis to data on 5-HT 1A receptors [ 11 , 34 ]. 5-HT 1A receptors, known as auto-receptors, inhibit the release of serotonin pre-synaptically [ 35 ], therefore, if depression is the result of reduced serotonin activity caused by abnormalities in the 5-HT 1A receptor, people with depression would be expected to show increased activity of 5-HT 1A receptors compared to those without [ 36 ].

Two meta-analyses satisfied inclusion criteria, involving five of the same studies [ 37 , 38 ] (see Table  1 ). The majority of results across the two analyses suggested either no difference in 5-HT 1A receptors between people with depression and controls, or a lower level of these inhibitory receptors, which would imply higher concentrations or activity of serotonin in people with depression. Both meta-analyses were based on studies that predominantly involved patients who were taking or had recently taken (within 1–3 weeks of scanning) antidepressants or other types of psychiatric medication, and both sets of authors commented on the possible influence of prior or current medication on findings. In addition, one analysis was of very low quality [ 37 ], including not reporting on the numbers involved in each analysis and using one-sided p-values, and one was strongly influenced by three studies and publication bias was present [ 38 ].

The serotonin transporter (SERT)

The serotonin transporter protein (SERT) transports serotonin out of the synapse, thereby lowering the availability of serotonin in the synapse [ 39 , 40 ]. Animals with an inactivated gene for SERT have higher levels of extra-cellular serotonin in the brain than normal [ 41 , 42 , 43 ] and SSRIs are thought to work by inhibiting the action of SERT, and thus increasing levels of serotonin in the synaptic cleft [ 44 ]. Although changes in SERT may be a marker for other abnormalities, if depression is caused by low serotonin availability or activity, and if SERT is the origin of that deficit, then the amount or activity of SERT would be expected to be higher in people with depression compared to those without [ 40 ]. SERT binding potential is an index of the concentration of the serotonin transporter protein and SERT concentrations can also be measured post-mortem.

Three overlapping meta-analyses based on a total of 40 individual studies fulfilled inclusion criteria (See Table  1 ) [ 37 , 39 , 45 ]. Overall, the data indicated possible reductions in SERT binding in some brain areas, although areas in which effects were detected were not consistent across the reviews. In addition, effects of antidepressants and other medication cannot be ruled out, since most included studies mainly or exclusively involved people who had a history of taking antidepressants or other psychiatric medications. Only one meta-analysis tested effects of antidepressants, and although results were not influenced by the percentage of drug-naïve patients in each study, numbers were small so it is unlikely that medication-related effects would have been reliably detected [ 45 ]. All three reviews cited evidence from animal studies that antidepressant treatment reduces SERT [ 46 , 47 , 48 ]. None of the analyses corrected for multiple testing, and one review was of very low quality [ 37 ]. If the results do represent a positive finding that is independent of medication, they would suggest that depression is associated with higher concentrations or activity of serotonin.

Depletion studies

Tryptophan depletion using dietary means or chemicals, such as parachlorophenylalanine (PCPA), is thought to reduce serotonin levels. Since PCPA is potentially toxic, reversible tryptophan depletion using an amino acid drink that lacks tryptophan is the most commonly used method and is thought to affect serotonin within 5–7 h of ingestion. Questions remain, however, about whether either method reliably reduces brain serotonin, and about other effects including changes in brain nitrous oxide, cerebrovascular changes, reduced BDNF and amino acid imbalances that may be produced by the manipulations and might explain observed effects independent of possible changes in serotonin activity [ 49 ].

One meta-analysis and one systematic review fulfilled inclusion criteria (see Table  1 ). Data from studies involving volunteers mostly showed no effect, including a meta-analysis of parallel group studies [ 50 ]. In a small meta-analysis of within-subject studies involving 75 people with a positive family history, a minor effect was found, with people given the active depletion showing a larger decrease in mood than those who had a sham procedure [ 50 ]. Across both reviews, studies involving people diagnosed with depression showed slightly greater mood reduction following tryptophan depletion than sham treatment overall, but most participants had taken or were taking antidepressants and participant numbers were small [ 50 , 51 ].

Since these research syntheses were conducted more than 10 years ago, we searched for a systematic sample of ten recently published studies (Table  2 ). Eight studies conducted with healthy volunteers showed no effects of tryptophan depletion on mood, including the only two parallel group studies. One study presented effects in people with and without a family history of depression, and no differences were apparent in either group [ 52 ]. Two cross-over studies involving people with depression and current or recent use of antidepressants showed no convincing effects of a depletion drink [ 53 , 54 ], although one study is reported as positive mainly due to finding an improvement in mood in the group given the sham drink [ 54 ].

SERT gene and gene-stress interactions

A possible link between depression and the repeat length polymorphism in the promoter region of the SERT gene (5-HTTLPR), specifically the presence of the short repeats version, which causes lower SERT mRNA expression, has been proposed [ 55 ]. Interestingly, lower levels of SERT would produce higher levels of synaptic serotonin. However, more recently, this hypothesis has been superseded by a focus on the interaction effect between this polymorphism, depression and stress, with the idea that the short version of the polymorphism may only give rise to depression in the presence of stressful life events [ 55 , 56 ]. Unlike other areas of serotonin research, numerous systematic reviews and meta-analyses of genetic studies have been conducted, and most recently a very large analysis based on a sample from two genetic databanks. Details of the five most recent studies that have addressed the association between the SERT gene and depression, and the interaction effect are detailed in Table  1 .

Although some earlier meta-analyses of case-control studies showed a statistically significant association between the 5-HTTLPR and depression in some ethnic groups [ 57 , 58 ], two recent large, high quality studies did not find an association between the SERT gene polymorphism and depression [ 27 , 32 ]. These two studies consist of  by far the largest and most comprehensive study to date [ 32 ] and a high-quality meta-analysis that involved a consistent re-analysis of primary data across all conducted studies, including previously unpublished data, and other comprehensive quality checks [ 27 , 59 ] (see Table  1 ).

Similarly, early studies based on tens of thousands of participants suggested a statistically significant interaction between the SERT gene, forms of stress or maltreatment and depression [ 60 , 61 , 62 ], with a small odds ratio in the only study that reported this (1.18, 95% CI 1.09 to 1.28) [ 62 ]. However, the two recent large, high-quality studies did not find an interaction between the SERT gene and stress in depression (Border et al [ 32 ] and Culverhouse et al.) [ 27 ] (see Table  1 ).

Overall results

Table  3 presents the modified GRADE ratings for each study and the overall rating of the strength of evidence in each area. Areas of research that provided moderate or high certainty of evidence such as the studies of plasma serotonin and metabolites and the genetic and gene-stress interaction studies all showed no association between markers of serotonin activity and depression. Some other areas suggested findings consistent with increased serotonin activity, but evidence was of very low certainty, mainly due to small sample sizes and possible residual confounding by current or past antidepressant use. One area - the tryptophan depletion studies - showed very low certainty evidence of lowered serotonin activity or availability in a subgroup of volunteers with a family history of depression. This evidence was considered very low certainty as it derived from a subgroup of within-subject studies, numbers were small, and there was no information on medication use, which may have influenced results. Subsequent research has not confirmed an effect with numerous negative studies in volunteers.

Our comprehensive review of the major strands of research on serotonin shows there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity. Most studies found no evidence of reduced serotonin activity in people with depression compared to people without, and methods to reduce serotonin availability using tryptophan depletion do not consistently lower mood in volunteers. High quality, well-powered genetic studies effectively exclude an association between genotypes related to the serotonin system and depression, including a proposed interaction with stress. Weak evidence from some studies of serotonin 5-HT 1A receptors and levels of SERT points towards a possible association between increased serotonin activity and depression. However, these results are likely to be influenced by prior use of antidepressants and its effects on the serotonin system [ 30 , 31 ]. The effects of tryptophan depletion in some cross-over studies involving people with depression may also be mediated by antidepressants, although these are not consistently found [ 63 ].

The chemical imbalance theory of depression is still put forward by professionals [ 17 ], and the serotonin theory, in particular, has formed the basis of a considerable research effort over the last few decades [ 14 ]. The general public widely believes that depression has been convincingly demonstrated to be the result of serotonin or other chemical abnormalities [ 15 , 16 ], and this belief shapes how people understand their moods, leading to a pessimistic outlook on the outcome of depression and negative expectancies about the possibility of self-regulation of mood [ 64 , 65 , 66 ]. The idea that depression is the result of a chemical imbalance also influences decisions about whether to take or continue antidepressant medication and may discourage people from discontinuing treatment, potentially leading to lifelong dependence on these drugs [ 67 , 68 ].

As with all research synthesis, the findings of this umbrella review are dependent on the quality of the included studies, and susceptible to their limitations. Most of the included studies were rated as low quality on the AMSTAR-2, but the GRADE approach suggested some findings were reasonably robust. Most of the non-genetic studies did not reliably exclude the potential effects of previous antidepressant use and were based on relatively small numbers of participants. The genetic studies, in particular, illustrate the importance of methodological rigour and sample size. Whereas some earlier, lower quality, mostly smaller studies produced marginally positive findings, these were not confirmed in better-conducted, larger and more recent studies [ 27 , 32 ]. The identification of depression and assessment of confounders and interaction effects were limited by the data available in the original studies on which the included reviews and meta-analyses were based. Common methods such as the categorisation of continuous measures and application of linear models to non-linear data may have led to over-estimation or under-estimation of effects [ 69 , 70 ], including the interaction between stress and the SERT gene. The latest systematic review of tryptophan depletion studies was conducted in 2007, and there has been considerable research produced since then. Hence, we provided a snapshot of the most recent evidence at the time of writing, but this area requires an up to date, comprehensive data synthesis. However, the recent studies were consistent with the earlier meta-analysis with little evidence for an effect of tryptophan depletion on mood.

Although umbrella reviews typically restrict themselves to systematic reviews and meta-analyses, we aimed to provide the most comprehensive possible overview. Therefore, we chose to include meta-analyses that did not involve a systematic review and a large genetic association study on the premise that these studies contribute important data on the question of whether the serotonin hypothesis of depression is supported. As a result, the AMSTAR-2 quality rating scale, designed to evaluate the quality of conventional systematic reviews, was not easily applicable to all studies and had to be modified or replaced in some cases.

One study in this review found that antidepressant use was associated with a reduction of plasma serotonin [ 26 ], and it is possible that the evidence for reductions in SERT density and 5-HT 1A receptors in some of the included imaging study reviews may reflect compensatory adaptations to serotonin-lowering effects of prior antidepressant use. Authors of one meta-analysis also highlighted evidence of 5-HIAA levels being reduced after long-term antidepressant treatment [ 71 ]. These findings suggest that in the long-term antidepressants might produce compensatory changes [ 72 ] that are opposite to their acute effects [ 73 , 74 ]. Lowered serotonin availability has also been demonstrated in animal studies following prolonged antidepressant administration [ 75 ]. Further research is required to clarify the effects of different drugs on neurochemical systems, including the serotonin system, especially during and after long-term use, as well as the physical and psychological consequences of such effects.

This review suggests that the huge research effort based on the serotonin hypothesis has not produced convincing evidence of a biochemical basis to depression. This is consistent with research on many other biological markers [ 21 ]. We suggest it is time to acknowledge that the serotonin theory of depression is not empirically substantiated.

Data availability

All extracted data is available in the paper and supplementary materials. Further information about the decision-making for each rating for categories of the AMSTAR-2 and STREGA are available on request.

Coppen A. The biochemistry of affective disorders. Br J Psychiatry. 1967;113:1237–64.

Article   CAS   PubMed   Google Scholar  

American Psychiatric Association. What Is Psychiatry? 2021. https://www.psychiatry.org/patients-families/what-is-psychiatry-menu .

GlaxoSmithKline. Paxil XR. 2009. www.Paxilcr.com (site no longer available). Last accessed 27th Jan 2009.

Eli Lilly. Prozac - How it works. 2006. www.prozac.com/how_prozac/how_it_works.jsp?reqNavId=2.2 . (site no longer available). Last accessed 10th Feb 2006.

Healy D. Serotonin and depression. BMJ: Br Med J. 2015;350:h1771.

Article   Google Scholar  

Pies R. Psychiatry’s New Brain-Mind and the Legend of the “Chemical Imbalance.” 2011. https://www.psychiatrictimes.com/view/psychiatrys-new-brain-mind-and-legend-chemical-imbalance . Accessed March 2, 2021.

Geddes JR, Andreasen NC, Goodwin GM. New Oxford Textbook of Psychiatry. Oxford, UK: Oxford University Press; 2020.

Book   Google Scholar  

Sadock BJ, Sadock VA, Ruiz P. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 10th Editi. Lippincott Williams & Wilkins (LWW); 2017.

Cowen PJ, Browning M. What has serotonin to do with depression? World Psychiatry. 2015;14:158–60.

Article   PubMed   PubMed Central   Google Scholar  

Harmer CJ, Duman RS, Cowen PJ. How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry. 2017;4:409–18.

Yohn CN, Gergues MM, Samuels BA. The role of 5-HT receptors in depression. Mol Brain. 2017;10:28.

Hahn A, Haeusler D, Kraus C, Höflich AS, Kranz GS, Baldinger P, et al. Attenuated serotonin transporter association between dorsal raphe and ventral striatum in major depression. Hum Brain Mapp. 2014;35:3857–66.

Amidfar M, Colic L, Kim MWAY-K. Biomarkers of major depression related to serotonin receptors. Curr Psychiatry Rev. 2018;14:239–44.

Article   CAS   Google Scholar  

Albert PR, Benkelfat C, Descarries L. The neurobiology of depression—revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms. Philos Trans R Soc Lond B Biol Sci. 2012;367:2378–81.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Pilkington PD, Reavley NJ, Jorm AF. The Australian public’s beliefs about the causes of depression: associated factors and changes over 16 years. J Affect Disord. 2013;150:356–62.

Article   PubMed   Google Scholar  

Pescosolido BA, Martin JK, Long JS, Medina TR, Phelan JC, Link BG. A disease like any other? A decade of change in public reactions to schizophrenia, depression, and alcohol dependence. Am J Psychiatry. 2010;167:1321–30.

Read J, Renton J, Harrop C, Geekie J, Dowrick C. A survey of UK general practitioners about depression, antidepressants and withdrawal: implementing the 2019 Public Health England report. Therapeutic Advances in. Psychopharmacology. 2020;10:204512532095012.

Google Scholar  

Demasi M, Gøtzsche PC. Presentation of benefits and harms of antidepressants on websites: A cross-sectional study. Int J Risk Saf Med. 2020;31:53–65.

Jakobsen JC, Gluud C, Kirsch I. Should antidepressants be used for major depressive disorder? BMJ Evidence-Based. Medicine. 2020;25:130–130.

Moncrieff J, Cohen D. Do antidepressants cure or create abnormal brain states? PLoS Med. 2006;3:e240.

Kennis M, Gerritsen L, van Dalen M, Williams A, Cuijpers P, Bockting C. Prospective biomarkers of major depressive disorder: a systematic review and meta-analysis. Mol Psychiatry. 2020;25:321–38.

Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.

Fusar-Poli P, Radua J. Ten simple rules for conducting umbrella reviews. Evid Based Ment Health. 2018;21:95–100.

Pollock M, Fernandes RM, Becker LA, Pieper D, Hartling L. Chapter V: Overviews of Reviews. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., editors. Cochrane Handbook for Systematic Reviews of Interventions version 6.2,. version 6.Cochrane; 2021.

Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008.

Huang T, Balasubramanian R, Yao Y, Clish CB, Shadyab AH, Liu B, et al. Associations of depression status with plasma levels of candidate lipid and amino acid metabolites: a meta-analysis of individual data from three independent samples of US postmenopausal women. Mol Psychiatry. 2020;2020. https://doi.org/10.1038/s41380-020-00870-9 .

Culverhouse RC, Saccone NL, Horton AC, Ma Y, Anstey KJ, Banaschewski T, et al. Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression. Mol Psychiatry. 2018;23:133–42.

Little J, Higgins JPT, Ioannidis JPA, Moher D, Gagnon F, von Elm E, et al. STrengthening the REporting of Genetic Association Studies (STREGA)— An Extension of the STROBE Statement. PLoS Med. 2009;6:e1000022.

Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schünemann HJ. What is quality of evidence and why is it important to clinicians? BMJ. 2008;336:995–8.

Yoon HS, Hattori K, Ogawa S, Sasayama D, Ota M, Teraishi T, et al. Relationships of cerebrospinal fluid monoamine metabolite levels with clinical variables in major depressive disorder. J Clin Psychiatry. 2017;78:e947–56.

Kugaya A, Seneca NM, Snyder PJ, Williams SA, Malison RT, Baldwin RM, et al. Changes in human in vivo serotonin and dopamine transporter availabilities during chronic antidepressant administration. Neuropsychopharmacology. 2003;28:413–20.

Border R, Johnson EC, Evans LM, Smolen A, Berley N, Sullivan PF, et al. No support for historical candidate gene or candidate gene-by-interaction hypotheses for major depression across multiple large samples. Am J Psychiatry. 2019;176:376–87.

Ogawa S, Tsuchimine S, Kunugi H. Cerebrospinal fluid monoamine metabolite concentrations in depressive disorder: A meta-analysis of historic evidence. J Psychiatr Res. 2018;105:137–46.

Nautiyal KM, Hen R. Serotonin receptors in depression: from A to B. F1000Res. 2017;6:123.

Rojas PS, Neira D, Muñoz M, Lavandero S, Fiedler JL. Serotonin (5‐HT) regulates neurite outgrowth through 5‐HT1A and 5‐HT7 receptors in cultured hippocampal neurons. J Neurosci Res. 2014;92:1000–9.

Kaufman J, DeLorenzo C, Choudhury S, Parsey RV. The 5-HT1A receptor in Major Depressive Disorder. Eur Neuropsychopharmacol. 2016;26:397–410.

Nikolaus S, Müller H-W, Hautzel H. Different patterns of 5-HT receptor and transporter dysfunction in neuropsychiatric disorders – a comparative analysis of in vivo imaging findings. Rev Neurosci. 2016;27:27–59.

Wang L, Zhou C, Zhu D, Wang X, Fang L, Zhong J, et al. Serotonin-1A receptor alterations in depression: A meta-analysis of molecular imaging studies. BMC Psychiatry. 2016;16:1–9.

Kambeitz JP, Howes OD. The serotonin transporter in depression: Meta-analysis of in vivo and post mortem findings and implications for understanding and treating depression. J Affect Disord. 2015;186:358–66.

Meyer JH. Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatry Neurosci. 2007;32:86–102.

PubMed   PubMed Central   Google Scholar  

Mathews TA, Fedele DE, Coppelli FM, Avila AM, Murphy DL, Andrews AM. Gene dose-dependent alterations in extraneuronal serotonin but not dopamine in mice with reduced serotonin transporter expression. J Neurosci Methods. 2004;140:169–81.

Shen H-W, Hagino Y, Kobayashi H, Shinohara-Tanaka K, Ikeda K, Yamamoto H, et al. Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters. Neuropsychopharmacology. 2004;29:1790–9.

Hagino Y, Takamatsu Y, Yamamoto H, Iwamura T, Murphy DL, Uhl GR, et al. Effects of MDMA on extracellular dopamine and serotonin levels in mice lacking dopamine and/or serotonin transporters. Curr Neuropharmacol. 2011;9:91–5.

Zhou Z, Zhen J, Karpowich NK, Law CJ, Reith MEA, Wang D-N. Antidepressant specificity of serotonin transporter suggested by three LeuT-SSRI structures. Nat Struct Mol Biol. 2009;16:652–7.

Gryglewski G, Lanzenberger R, Kranz GS, Cumming P. Meta-analysis of molecular imaging of serotonin transporters in major depression. J Cereb Blood Flow Metab. 2014;34:1096–103.

Benmansour S, Owens WA, Cecchi M, Morilak DA, Frazer A. Serotonin clearance in vivo is altered to a greater extent by antidepressant-induced downregulation of the serotonin transporter than by acute blockade of this transporter. J Neurosci. 2002;22:6766–72.

Benmansour S, Cecchi M, Morilak DA, Gerhardt GA, Javors MA, Gould GG, et al. Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level. J Neurosci. 1999;19:10494–501.

Horschitz S, Hummerich R, Schloss P. Down-regulation of the rat serotonin transporter upon exposure to a selective serotonin reuptake inhibitor. Neuroreport. 2001;12:2181–4.

Young SN. Acute tryptophan depletion in humans: a review of theoretical, practical and ethical aspects. J Psychiatry Neurosci. 2013;38:294–305.

Ruhe HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry. 2007;12:331–59.

Fusar-Poli P, Allen P, McGuire P, Placentino A, Cortesi M, Perez J. Neuroimaging and electrophysiological studies of the effects of acute tryptophan depletion: A systematic review of the literature. Psychopharmacology. 2006;188:131–43.

Hogenelst K, Schoevers RA, Kema IP, Sweep FCGJ, aan het Rot M. Empathic accuracy and oxytocin after tryptophan depletion in adults at risk for depression. Psychopharmacology. 2016;233:111–20.

Weinstein JJ, Rogers BP, Taylor WD, Boyd BD, Cowan RL, Shelton KM, et al. Effects of acute tryptophan depletion on raphé functional connectivity in depression. Psychiatry Res. 2015;234:164–71.

Moreno FA, Erickson RP, Garriock HA, Gelernter J, Mintz J, Oas-Terpstra J, et al. Association study of genotype by depressive response during tryptophan depletion in subjects recovered from major depression. Mol. Neuropsychiatry. 2015;1:165–74.

Munafò MR. The serotonin transporter gene and depression. Depress Anxiety. 2012;29:915–7.

Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003;301:386–9.

Kiyohara C, Yoshimasu K. Association between major depressive disorder and a functional polymorphism of the 5-hydroxytryptamine (serotonin) transporter gene: A meta-analysis. Psychiatr Genet. 2010;20:49–58.

Oo KZ, Aung YK, Jenkins MA, Win AK. Associations of 5HTTLPR polymorphism with major depressive disorder and alcohol dependence: A systematic review and meta-analysis. Aust N. Z J Psychiatry. 2016;50:842–57.

Culverhouse RC, Bowes L, Breslau N, Nurnberger JI, Burmeister M, Fergusson DM, et al. Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression. BMC Psychiatry. 2013;13:1–12.

Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited. Arch Gen Psychiatry. 2011;68:444.

Sharpley CF, Palanisamy SKA, Glyde NS, Dillingham PW, Agnew LL. An update on the interaction between the serotonin transporter promoter variant (5-HTTLPR), stress and depression, plus an exploration of non-confirming findings. Behav Brain Res. 2014;273:89–105.

Bleys D, Luyten P, Soenens B, Claes S. Gene-environment interactions between stress and 5-HTTLPR in depression: A meta-analytic update. J Affect Disord. 2018;226:339–45.

Delgado PL. Monoamine depletion studies: implications for antidepressant discontinuation syndrome. J Clin Psychiatry. 2006;67:22–26.

CAS   PubMed   Google Scholar  

Kemp JJ, Lickel JJ, Deacon BJ. Effects of a chemical imbalance causal explanation on individuals’ perceptions of their depressive symptoms. Behav Res Ther. 2014;56:47–52.

Lebowitz MS, Ahn W-K, Nolen-Hoeksema S. Fixable or fate? Perceptions of the biology of depression. J Consult Clin Psychol. 2013;81:518.

Zimmermann M, Papa A. Causal explanations of depression and treatment credibility in adults with untreated depression: Examining attribution theory. Psychol Psychother. 2020;93:537–54.

Maund E, Dewar-Haggart R, Williams S, Bowers H, Geraghty AWA, Leydon G, et al. Barriers and facilitators to discontinuing antidepressant use: A systematic review and thematic synthesis. J Affect Disord. 2019;245:38–62.

Eveleigh R, Speckens A, van Weel C, Oude Voshaar R, Lucassen P. Patients’ attitudes to discontinuing not-indicated long-term antidepressant use: barriers and facilitators. Therapeutic Advances in. Psychopharmacology. 2019;9:204512531987234.

Harrell FE Jr. Regression Modeling Strategies: With Applications to Linear Models, Logistic and Ordinal Regression, and Survival Analysis. Springer, Cham; 2015.

Schafer JL, Kang J. Average causal effects from nonrandomized studies: a practical guide and simulated example. Psychol Methods. 2008;13:279–313.

Pech J, Forman J, Kessing LV, Knorr U. Poor evidence for putative abnormalities in cerebrospinal fluid neurotransmitters in patients with depression versus healthy non-psychiatric individuals: A systematic review and meta-analyses of 23 studies. J Affect Disord. 2018;240:6–16.

Fava GA. May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance. Therapeutic Adv Psychopharmacol. 2020;10:2045125320970325.

Kitaichi Y, Inoue T, Nakagawa S, Boku S, Kakuta A, Izumi T, et al. Sertraline increases extracellular levels not only of serotonin, but also of dopamine in the nucleus accumbens and striatum of rats. Eur J Pharm. 2010;647:90–6.

Gartside SE, Umbers V, Hajós M, Sharp T. Interaction between a selective 5‐HT1Areceptor antagonist and an SSRI in vivo: effects on 5‐HT cell firing and extracellular 5‐HT. Br J Pharmacol. 1995;115:1064–70.

Bosker FJ, Tanke MAC, Jongsma ME, Cremers TIFH, Jagtman E, Pietersen CY, et al. Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats: role of serotonin synthesis. Neurochem Int. 2010;57:948–57.

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There was no specific funding for this review. MAH is supported by a Clinical Research Fellowship from North East London NHS Foundation Trust (NELFT). This funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

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JM conceived the idea for the study. JM, MAH, MPH, TS and SA designed the study. JM, MAH, MPH, TS, and SA screened articles and abstracted data. JM drafted the first version of the manuscript. JM, MAH, MPH, TS, SA, and REC contributed to the manuscript’s revision and interpretation of findings. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author). SA declares no conflicts of interest. MAH reports being co-founder of a company in April 2022, aiming to help people safely stop antidepressants in Canada. MPH reports royalties from Palgrave Macmillan, London, UK for his book published in December, 2021, called “Evidence-biased Antidepressant Prescription.” JM receives royalties for books about psychiatric drugs, reports grants from the National Institute of Health Research outside the submitted work, that she is co-chairperson of the Critical Psychiatry Network (an informal group of psychiatrists) and a board member of the unfunded organisation, the Council for Evidence-based Psychiatry. Both are unpaid positions. TS is co-chairperson of the Critical Psychiatry Network. RC is an unpaid board member of the International Institute for Psychiatric Drug Withdrawal.

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Moncrieff, J., Cooper, R.E., Stockmann, T. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry 28 , 3243–3256 (2023). https://doi.org/10.1038/s41380-022-01661-0

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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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Bipolar disorder.

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Last Update: February 20, 2023 .

• Continuing Education Activity

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

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

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

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

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

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

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

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

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

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

• Epidemiology

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

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

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

• Pathophysiology

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

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

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

• History and Physical

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

DSM-5 Diagnostic Criteria for Bipolar I Disorder

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

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

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

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

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

DSM-5 Diagnostic Criteria for Bipolar II Disorder

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

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

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

DSM-5 Diagnostic Criteria for a Major Depressive Episode

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

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

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

Possible Secondary Cause of Bipolar Disorder

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

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

• Treatment / Management

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

Manic Episode

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

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

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

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

Hypomanic Episodes

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

Acute Bipolar Depression

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

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

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

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

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

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

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

Maintenance Treatment

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

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

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

• Differential Diagnosis

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

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

• Complications

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

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

• Deterrence and Patient Education

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

• Enhancing Healthcare Team Outcomes

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

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

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

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

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

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Jain A, Mitra P. Bipolar Disorder. [Updated 2023 Feb 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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