Psychiatric comorbidities

Multiple psychiatric comorbidities, including ADHD, anxiety, personality disorders, eating disorder and substance use disorders interfere with the diagnosis and treatment of bipolar depression, and likely contribute to increased disease morbidity and mortality, including increased suicide risk64,65. Psychiatric comorbidity is reported in 90% of patients with bipolar I or II disorder9, with anxiety, impulse control and substance use disorders found to be two to three times more prevalent than in the general population9,66. Comorbid anxiety and bipolar disorder is specifically associated with earlier age of the first depressive episode, greater number of depressive episodes, fewer days well, longer time to recovery from a depressive episode, shorter time to relapse, poor role functioning and reduced quality of life67,68.

At least 50% of adults with bipolar disorder experience substance use disorders at some point in their lives69, making this both an important comorbidity and a potential differential diagnosis criterion. Similar to comorbid obesity, substance use disorder is thought to be associated with an aberrant reward–motivation neural network55. The prognosis for substance use disorder is mainly predicted by the number and severity of comorbid episodes of bipolar depression. People with alcohol use disorder are at four times greater risk of having bipolar disorder than are people without alcohol use disorder; illicit drug users have a five times greater risk of having bipolar disorder than nonusers70. Patients with these comorbid disorders have a much greater burden of illness than other patients, with sequelae including delayed recovery from mood episodes, increased suicidality, functional impairment, decreased medication adherence and decreased quality of life70.

It is of additional concern that a comorbid syndrome of bipolar disorder and ADHD appears to be common, although more studies are needed to clarify its diagnostic validity and treatment approach. Comorbid ADHD and bipolar disorder, which is present in up to 47% of adult ADHD populations and 21% of bipolar disorder populations, has a more severe course of illness compared with that of bipolar disorder alone, and high rates of comorbidity with other psychiatric disorders71.

Comorbid eating disorders, which are particularly associated with the depressive phases of bipolar disorder72, have a much higher prevalence for patients with bipolar disorder (range, 6–27%) than for individuals in the general population (4–10%)73,74. Binge eating behavior is an important consideration for clinicians since it may serve as an early predictor of eating disorders in patients with bipolar spectrum disorder75.


Given the high number of comorbid conditions and differential diagnoses associated with bipolar disorder, correct diagnosis is a challenge for healthcare professionals. In a survey of bipolar patients involved with National Depressive and Manic–Depressive Association support groups, 69% reported that they were initially misdiagnosed by psychiatrists, with a mean of 3.5 other diagnoses received and 4 psychiatrists consulted before an accurate diagnosis was received76. For 60% of patients, the misdiagnosis was MDD, with women more likely than men to receive an MDD diagnosis (68% vs. 43%). Only 20% of patients with bipolar disorder and a depressive episode are diagnosed with bipolar disorder within the first year of seeking treatment77; the mean delay between the onset of illness and diagnosis is 5 to 10 years78. Primary care physicians treat approximately half of all patients with mental illness79, and among patients who screened positive for bipolar disorder, the diagnosis was missed by primary care physicians 78% of the time80. Given the progressive nature of bipolar disorder, timely and accurate diagnosis is extremely important and clinicians should be especially attentive to symptoms that are suggestive of the disorder.

Diagnostic criteria require that patients with bipolar depression have a history of at least one manic episode and present with either a depressed mood most of the day, nearly every day, or loss of interest and pleasure in all activities (anhedonia); additional symptoms may include weight loss, insomnia, psychomotor agitation or retardation, feelings of worthlessness or guilt, decreased ability to concentrate, and recurrent thoughts of death or suicidal ideation4. Depressive symptoms must be severe enough to cause clinically significant distress and impairment in social or occupational functioning. Diagnosis can be complicated because the criteria for a bipolar depressive episode are the same as those for a unipolar depressive episode, making an accurate history of mania or hypomania the crucial differentiating factor. In addition, while patients are typically troubled by depressive symptoms, they may not recognize that manic or hypomanic symptoms are also part of the illness so an incomplete symptomatic profile may be reported to the clinician, further clouding the diagnostic picture.

The DSM-5 also provides a mixed features specifier that can be applied to manic or hypomanic episodes that have depressive features and, conversely, to depressive episodes that have manic features. Patients must meet the full criteria for a manic/hypomanic episode or depressive episode and concurrently have at least three symptoms emanating from the opposite pole. Approximately 25–35% of patients have been identified as having mixed features as part of a depressive mood episode in either bipolar disorder or unipolar depression81. Accurate diagnosis is important since mixed features in either illness are associated with greater illness complexity, reduced treatment response, lack of response to antidepressants, worse outcomes and increased risk of suicide82. In bipolar disorder, even mood episodes that appear to be purely depressive have at least subtle manic-like symptoms, such as distractibility, racing thoughts, irritation and agitation, that are present in up to two thirds of patients83. Specific recommendations for managing mixed features are limited and there are currently no approved treatments82.

Differential diagnosis

The diagnosis of bipolar disorder can be challenging because the first episode of mood disturbance in bipolar disorder is usually depression, not mania, and most patients seek treatment for depressive symptoms84–86. Initial misdiagnosis of patients with bipolar disorder results in delay of appropriate treatment and the potential for mistreatment with antidepressant monotherapy, which may subsequently increase the risk of recurrence and chronicity in this progressive disorder27,84. The primary differential diagnoses are major depression, anxiety disorders, ADHD, personality disorder, drug and alcohol misuse, schizophrenia, in addition to consequences of trauma/brain injury.

Although nothing can replace careful clinical assessment, screening tools may help to identify bipolar disorder or rule out an incorrect diagnosis in primary care and clinical practice. For example, the MDQ is an easy-to-use self-report instrument consisting of 13 questions that assess clustering of symptoms and functional impairment in bipolar disorder12,16,87. When used with follow-up questioning and evaluation, the MDQ has been shown to have good sensitivity (∼70%) and specificity (∼90%) for diagnosing bipolar disorder12,87. Advanced practice registered nurses reported that screening depressed patients with validated screening tools could reduce the time to correct diagnosis and treatment of bipolar depression88, suggesting that screening tools may improve diagnostic accuracy in primary care.

Unipolar depression

Misdiagnosis of unipolar depression in patients with bipolar depression is a common and challenging problem. Of patients with bipolar disorder, a majority are initially misdiagnosed with MDD, leading to the possibility of incorrect treatment and poor outcomes (Figure 2)76.

Figure 2. Unipolar or bipolar depression?Display full size

Since the diagnostic criteria for a major depressive episode are the same in bipolar depression and MDD, with no single constellation of symptoms diagnostic for either disorder, clinicians should be aware that specific symptoms have a higher probability of being associated with each diagnosis (Figure 3)7.

Figure 3. Symptoms with potential diagnostic utility in bipolar and unipolar depression1,7.Display full size

In patients from academic centers followed up for at least 1 year in the National Institute of Mental Health Collaborative Depression Study, approximately 25% of patients initially diagnosed with MDD subsequently experienced a manic or hypomanic episode, resulting in a revised diagnosis of bipolar I or II disorder89. The presence of subthreshold hypomania predicted progression from unipolar depression to bipolar depression. Misdiagnosis as unipolar depression is more likely when patients present to clinicians during a depressive episode since unipolar depression is more common and it is difficult to retrospectively establish a manic/hypomanic history90. Misdiagnosis as unipolar depression is also more likely if the patient is evaluated early in the course of illness, since the first bipolar mood episodes are likely to be depressive, or if there is no validating information from family/caregivers or friends91,92. Patients with greater number of failed antidepressant trials are more likely to have bipolar disorder7, which is a clinical concern since the use of monotherapy antidepressants in bipolar depression is not backed by a strong evidence base, although it is an exceedingly common practice. Concerns pertaining to the use of antidepressant treatment without mood stabilizing treatment include the possibility of increased acute risk of switch from depression to mania/hypomania7,93, as well as a delay in receiving approved bipolar depression treatment. 

Attention deficit hyperactivity disorder

Differentiating ADHD and bipolar disorder is complicated by similarities between the disorders including early age of onset, reciprocal comorbidity, similar psychiatric comorbidities, chronic course and persistence into adulthood; both disorders are also associated with impaired educational, occupational and interpersonal functioning, and increased morbidity and mortality in adulthood94. Clinical differentiation is most challenging when ADHD is comorbid with conduct disorder and/or oppositional defiant disorder, since the presenting symptoms (e.g. temper tantrum, aggressive behavior) can overlap with symptoms of a manic or mixed state. In uncomplicated cases, the appearance of prominent mood dysregulation, sleep irregularities and aggressive behaviors are more likely to predict a diagnosis of bipolar disorder than ADHD, especially if there is impulsive behavior associated with spending money, sex, or tobacco, alcohol or drug use94. Conversely, fidgeting, restlessness, and inefficient and disorganized behaviors arising from inattentiveness, distractibility and forgetfulness, often suggest ADHD.

Substance abuse

Clinicians treating patients for substance abuse should be aware that approximately 60% of patients with bipolar I disorder have a lifetime diagnosis of substance use disorder95. Comparatively, just one third of patients with MDD have a comorbid substance use disorder, making this a diagnostically important symptom96. Substance abuse and bipolar disorder are both associated with mood symptoms, anxiety symptoms, family history of mood/anxiety problems, disruptive behaviors and relationship problems97. Patients with bipolar disorder and comorbid substance abuse are likely to have developed substance abuse disorder before age 13; comorbid occurrence is also associated with cocaine and amphetamine use, episodic substance use, mood problems that persist without substance use, manic symptoms and a family history of bipolar disorder97. Differentially, substance abuse that occurs independently of bipolar disorder is more likely to have onset after age 13, and to be associated with multiple substances, continuous substance use, no manic/hypomanic symptoms and family history of anxiety disorders97.

Borderline personality disorder

Since emotional dysregulation and depression accompanied by negative cognitions are ubiquitous features of both borderline personality disorder and bipolar disorder98, mistaken diagnosis of these two conditions is predictable. The lifetime co-occurrence of borderline personality disorder and bipolar disorder is 27.6%99, with evidence that 15% of patients with bipolar disorder have comorbid borderline personality disorder. Having either disorder may increase the risk that the other disorder will be misdiagnosed100. To differentiate the disorders, clinicians should look for emotional shifts between depression and rage for borderline personality disorder and between depression and mania for bipolar disorder; depression and rage in borderline personality disorder can mimic a mixed bipolar episode98. In borderline personality disorder, mood shifts tend to be rapid, with changes lasting hours to days and closely linked to interpersonal events, whereas bipolar mood shifts tend to be more enduring (except in cases of rapid cycling or mixed features). Additionally, patients with borderline personality disorder tend to have more intense and severe disruptions in interpersonal relationships than do patients with bipolar disorder. A longitudinal approach to diagnosis may be best practice for a clinician since typically the onset of borderline personality is around puberty, while bipolar disorder usually appears in late adolescence or early adulthood98. Borderline personality symptoms are also likely to become less striking as the patient ages, while bipolar disorder persists and depressive symptoms may possibly become more severe and disabling with aging. To date, borderline personality disorder has not demonstrated response to pharmacological therapy, with psychological and psychosocial therapies the current mainstays of management.


The first step in treatment for bipolar disorder is confirming the diagnosis, including a history of a manic or hypomanic episode, and determining the nature of the presenting episode. Timely diagnosis is extremely important since bipolar disorder is a highly progressive illness1. In acute management, the primary goal of treatment is to stabilize presenting symptoms with minimal adverse events and ensure the patient’s safety. Although there are many first-line acute treatment options for a manic episode, including most antipsychotic agents that are approved for bipolar I disorder and mood stabilizing drugs (e.g. lithium, lamotrigine)93,101, only a few treatment options are available to treat bipolar depression. Immediate- and extended-release quetiapine, fluoxetine/olanzapine combination, cariprazine and lurasidone are the only medications currently approved by the FDA to treat bipolar depression; cariprazine and quetiapine are the only agents that are approved to treat symptoms of both mania and depression associated with bipolar I disorder. According to current treatment guidelines, antidepressants should not be used as monotherapy in patients with bipolar depression since available evidence does not support their efficacy and there are concerns about safety related to mood switching93,102,103. The limited number of approved treatments for bipolar depression is a clinical concern since not all patients respond to available treatment options and response may decrease over time. A comprehensive literature review found consistent evidence suggesting that pharmacological and psychosocial treatment in the earlier stage of illness resulted in better outcomes for response, relapse rate, time to recurrence, symptomatic recovery, remission, psychosocial functioning and employment104.

Possibly due to the long-standing, but discredited, view that bipolar II is a less severe form of bipolar disorder, its treatment has been understudied relative to bipolar.

and the evidence base for treatment is not well established93. Additionally, there are currently no approved treatments for mixed bipolar states and treatment guidelines for this symptom profile are limited82; antidepressants have been shown to be an ineffective treatment for mixed bipolar depression105.

Although antipsychotics and mood stabilizers are the foundation of treatment in bipolar disorder, it is estimated that between 40% and 50% of patients are nonadherent or only partially adherent to their treatment106. Several studies have reported that specific demographic and illness characteristics, including younger age, male sex, being unmarried, minority ethnicity, comorbid substance abuse, illness severity, inadequate social support and poor insight, may be associated with nonadherence106. Negative patient attitudes are of further importance since fear of adverse events, denial of illness severity and the need for treatment, perceived medication ineffectiveness, fears of medication dependence, and the stigma of being on medication are cited as additional contributing factors. The consequences of nonadherence can be serious and patients may experience poor outcomes, worse quality of life, functional impairment, and increased risks of relapse, rehospitalization and suicidality106. Although manic symptoms have been particularly noted in association with treatment nonadherence in bipolar disorder, bipolar depression may contribute to social isolation or a lack of engagement in self-care that may precipitate or worsen nonadherence107.

All effective treatments for bipolar disorder have potential side effects that need to be acceptable to patients to maximize treatment adherence and favorable outcomes; monitoring for common adverse effects should be common practice for clinicians. Although individual antipsychotic agents are associated with different propensities for causing specific adverse events, common effects associated with atypical antipsychotics include weight gain, extrapyramidal symptoms, sedation and metabolic dysfunction93. Similarly, mood stabilizers used to treat bipolar disorder, including lithium, divalproex, carbamazepine and lamotrigine, have a variety of adverse effects including weight gain, gastrointestinal symptoms, renal toxicity, cardiovascular effects, tremor, sedation and hypothyroidism93. Patients on lithium, divalproex or carbamazepine need to have their serum medication levels monitored regularly to ensure that that they are in a therapeutic range to avoid toxicity.

The potential for drug–drug interactions is a particular concern for patients with bipolar disorder, who tend to have complex and varied treatment regimens108. Given the long-term, chronic, progressive nature of bipolar disorder and the level of associated impairment, a strategy that combines pharmacological treatment, psychosocial intervention and lifestyle approaches is recommended beginning at the first episode. Psychosocial interventions that have shown efficacy include cognitive behavioral therapy, psychoeducation, interpersonal and family psychotherapy, and functional remediation1. Awareness of the increased risk of cardiovascular disease and metabolic abnormalities in patients with bipolar depression should also prompt clinicians to perform physical examinations to assess risk factors. Additionally, healthy behaviors, such as smoking cessation, exercise and weight control, should be encouraged and patients should be monitored for treatment-related issues and suicidality.

Unmet needs

Given the large amount of time spent unwell as a result of mood episodes and subsyndromal symptoms, as well as considerable levels of associated impairment and disability, it is not surprising that there are significant unmet needs in bipolar disorder and bipolar depression. Studies of treated patients with bipolar I disorder have found residual morbidity in 40% of patients during the follow-up period, with approximately three quarters of it related to depressive or dysthymic symptoms30,109,110. Unresolved depressive morbidity is likely an important contributor to substance abuse, functional disability and excess mortality in bipolar disorder111.

Unmet needs in bipolar disorder may differ considerably when comparing the viewpoints of the patient, provider and caregivers; current research suggests that patient-centric outcomes should be recognized as important factors in the assessment and treatment of bipolar depression112. From the patient perspective, unmet needs are generally associated with treatment satisfaction, quality of life, level of functioning and general health (Figure 4)102,113.

Figure 4. Unmet patient needs in bipolar disorder.Display full size

Medication side effects and concerns about the return of symptoms were reported by patients with bipolar depression to be the leading factors related to decisions about changing a treatment or trying a new one114. Intolerable adverse events are a frequent cause of treatment nonadherence, although events that are often thought of as mild and/or transient by clinicians (e.g. gastrointestinal issues, dry mouth) were reported as the reason for treatment discontinuation for 20–30% of patients who were surveyed by the Depression and Bipolar Support Alliance115. Weight gain was reported as the treatment-emergent event most commonly related to medication discontinuation in real-world treatment; lethargy, anxiety, shaking/trembling and suicidal thoughts were also highly associated with treatment discontinuation. Circadian rhythm disturbance, as shown by sleep alterations during and between episodes of bipolar depression, is another unmet patient need that may represent a risk factor for relapse/recurrence and comorbidity, making it a frequent target of treatment116.

From a clinician’s perspective, better patient education and support, referral to specialist care as necessary, improved treatment effectiveness, and better medication adherence have been identified as pressing clinical needs102. Since bipolar illness is increasingly recognized as an illness that is treated in primary care, complex factors such as diagnosis, psychiatric comorbidities, greater suicide risk and confusion about appropriate treatment may become impediments to treatment success117. Knowing the specific symptoms that differentiate bipolar and unipolar depression, using screening tools to aid diagnosis and using evidence-based treatment guidelines, which recommend ongoing symptom/side-effect monitoring, psychosocial interventions, medication monitoring, and dose adjustment or switching to a different oral antipsychotic, may help improve treatment adherence for patients in clinical practice and ease some burdens for primary care providers117,118.

Caregivers also experience considerable burdens (e.g. depression, work disruption) that adversely affect patient recovery and the home environment102, highlighting the need for a strong alliance among the patient, the family and the mental health provider113. To meet patient and caregiver needs, clinicians should rely on evidence-based practices in the clinic and seek out education pertaining to accurate diagnosis and appropriate treatment102.

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