Overview of bipolar disorder
Bipolar disorder is a chronic and complex mood disorder that is characterized by an admixture of manic (bipolar mania), hypomanic and depressive (bipolar depression) episodes, with significant subsyndromal symptoms that commonly present between major mood episodes1. Ranked among the leading causes of worldwide disability2, bipolar I disorder has been consistently associated with significant medical and psychiatric comorbidity, premature mortality, high levels of functional disability and reduced quality of life3. The essential feature of bipolar I disorder requires the occurrence of at least one fully syndromal lifetime manic episode, although depressive episodes are common4. Bipolar II disorder requires the occurrence of at least one hypomanic episode and one major depressive episode; it is no longer considered a milder form of bipolar disorder as it is associated with considerable time spent depressed and with functional impairment that accompanies mood instability4. Bipolar disorder with mixed features is a complex presentation in which a mood episode from either the manic or depressive pole is complicated by the presence of subsyndromal but clinically significant symptoms from the opposite pole. Patients with bipolar depression have greater morbidity and mortality than patients with bipolar mania, with depressed patients having a higher risk of suicide, interepisode panic attack and psychosis5.
On the bipolar spectrum, bipolar depression is the leading cause of morbidity in patients with bipolar disorder6; at least 50% of patients initially present with a depressive episode7. Even with treatment, bipolar depression accounts for the majority of time spent unwell with the disorder and it is an important contributor to long-term dysfunction, psychosocial impairment and loss of work productivity. In light of reports that up to 10% of all visits to primary care are depression-related and as many as 64% of all clinical encounters for depression occur in this setting rather than in specialty care8, it is especially important for clinicians to be vigilant for symptoms of bipolar disorder in their patients. In settings other than primary care, clinicians treating patients with substance use disorders, women with mood symptoms during the pregnancy postpartum period, forensic populations, patients presenting for bariatric
surgery/obesity treatment and patients being treated at attention-deficit/hyperactivity disorder (ADHD) centers should also be attentive for the presence of bipolar depression since these conditions commonly present comorbidly. Understanding the challenges associated with bipolar depression requires understanding bipolar disorder in its entirety since fluctuating symptoms intermingle across the phases of illness to create a complex whole.
To identify articles that would be relevant to our review of bipolar depression, we conducted a multistep search of the literature cited in PubMed using the term “bipolar depression” and limiting the results to review articles; this search retrieved 687 entries. To ensure that entries specific to our interests were not missed, we additionally searched “bipolar depression” in conjunction with individual terms including prevalence, assessment, comorbidities, diagnosis, differential diagnosis and treatment. Reference lists from the articles we retrieved were manually searched for additional articles of relevance. English language articles that were published in peer-reviewed journals, with no date limitation, were included as sources for our review.
Lifetime and 12 month prevalence for bipolar I disorder have been estimated at 2.1% and 1.5%, respectively, based on criteria from the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)4; rates for men and women are similar3. The prevalence of bipolar disorder decreases with increasing age and education level, while its prevalence is higher in unemployed/disabled individuals than in employed individuals; prevalence does not appear to be consistently related to race/ethnicity or income9. Depressive and subsyndromal depressive symptoms are very common in bipolar disorder and it is noteworthy that patients spend considerably more time ill with depression (34% of the time) than with elevated/mixed symptoms (12% of the time)10.
patients who see primary care physicians for depression, the correct diagnosis for many may be bipolar disorder, with over 25% of patients from a family practice clinic who presented with anxiety or depression actually having a bipolar spectrum illness as diagnosed on a semistructured diagnostic interview11. Another primary-care-based study reported that of 72% of patients who screened positive for bipolar disorder on the Mood Disorder Questionnaire (MDQ)12 only 8% received the supporting diagnosis13. In light of evidence suggesting that 10% to 38% of patients with bipolar disorder are treated exclusively in primary care14, primary care providers should be alert for historical and emerging symptoms of bipolar disorder in undiagnosed patients, have expertise in providing ongoing treatment to diagnosed patients, and be knowledgeable about managing common medication-related side effects and disorder comorbidities.
Lifetime and 12 month prevalence of bipolar II disorder, a common bipolar phenotype that is related to chronic depression15, have been estimated at 1.1% and 0.8%, respectively, with briefer and less severe hypomanic episodes thought to be experienced by up to 4–6% of the population16. More than 90% of individuals who have a manic episode proceed to develop recurrent mood episodes and about 60% of manic episodes occur immediately before a major depressive episode4.
Burden of illness
The significant burdens of bipolar disorder for individual patients, caregivers and society are the result of the interaction of social factors with both economic factors (socioeconomic) and factors related to individual thoughts and behaviors (psychosocial). In the US in 2015, the total estimated direct (e.g. treatment-related costs, inpatient and outpatient services) and indirect (e.g. lost productivity for patients and caregivers, unemployment) cost of bipolar I disorder was $202.1 billion dollars, with indirect costs far exceeding direct costs17. Due to the pervasiveness of depressive symptoms over time and higher indirect costs, a greater proportion of the overall costs of bipolar disorder are attributed to depressive symptoms than to manic or mixed symptoms; manic and mixed symptoms account for higher direct costs because of higher inpatient treatment expenses10.
The burden of bipolar depression in the workplace is consequential. Patients with bipolar disorder and at least one past-year depressive episode had greater levels of absenteeism, presenteeism and total lost work days than patients with only manic/hypomanic episodes during the past year18. Further, unemployed individuals with bipolar disorder compared with those who are employed had significantly greater severity of depressive, but not manic, symptoms and employed individuals with at least one major depressive episode missed an additional 4 days of work per months than those without depressive symptoms19. Beyond the workplace, depressive symptoms related to bipolar disorder are associated with considerable impairment in domains of individual functioning (e.g. social, household, interpersonal relationships) and quality of life9,20,21. Subsyndromal depression, which is almost ubiquitous between major mood episodes, has also been associated with poorer outcomes among patients with bipolar disorder22.
Course of bipolar illness and clinical characteristics
Classically characterized as a cyclical disorder with full manic or depressive episodes separated by periods of euthymia, bipolar disorder is more accurately described as having a chronic and subtle course of mood disturbances with residual symptoms, emotional dysregulation, circadian rhythm sleep disturbances, cognitive impairment, and greater risk of psychiatric and medical comorbidity between mood episodes23(Figure 1). The progressive course of bipolar disorder, in conjunction with its cognitive, functional and medical repercussions, has been acknowledged for almost a century, with a more recent focus on the effects of neuroprogression (pathological central nervous system reorganization) on psychosocial functioning and perhaps even premature aging1,24.
Figure 1. Bipolar disorder: a dimensional approach.
chart database evaluation of 1130 patients with bipolar disorder found that the average depressive episode was 5.2 months and 50% longer than the average manic episode, which lasted 3.5 months25. The first episode of bipolar disorder usually occurs before the age of 30 years. In a study of more than 1000 patients, over 60% of patients experienced onset before the age of 18 years, with early onset associated with greater rates of comorbid anxiety disorders and substance abuse, more recurrences, shorter periods of euthymia, and greater likelihood of suicide attempts26. In at least 50% of patients, bipolar disorder initially presents with a depressive episode7, which commonly results in a misdiagnosis of unipolar depression and the potential for mistreatment with antidepressant monotherapy27.
For bipolar I and II disorders, the proportion of time spent ill (e.g. major or minor depression, mania or hypomania, anxiety or mixed bipolar states) was found to be similarly high (44% and 43%, respectively), with major or minor depression the predominant morbidity in both disorders (70% and 81%, respectively)28. Naturalistic data strongly support the concept that the longitudinal course of bipolar disorder is expressed as a dimensional spectrum involving the complete range of depressive and manic symptom severity, greater depressive than manic morbidity, and frequent subsyndromal symptoms from both affective poles29,30. Subsyndromal, minor depressive and hypomanic symptoms combined (29.9%) are found to be nearly three times more frequent in bipolar disorder than syndromal-level major depressive and manic symptoms (11.2%); longer initial episodes, episodes with depression only and cycling polarity predicted greater chronicity during long-term follow-up, as did comorbid drug-use disorder30.
Among patients with bipolar disorder, the annual rate of attempted and completed suicide is 3.9% and 1.4%, respectively, which is considerably higher than corresponding rates in the general population (0.5% and 0.02%, respectively)31. Further, the risk of suicide is higher for bipolar patients experiencing a depressive episode or mixed state than for patients with pure mania10,32. For bipolar patients, depression-related risk factors for suicide attempt include multiple hospitalizations for depression and having suicidal thoughts while depressed; conversely, a past suicide attempt has also been shown to be predictive of an increased amount of time spent depressed, more severe depression and suicidal ideation33.