Nosology, Diagnostic Challenges, and Unmet Needs in Bipolar Disorder

Terence A. Ketter, MD

Bipolar Disorders Clinic, Department of Psychiatry and Behavioral Science, Stanford University School of Medicine, Stanford, California

Nosology of Bipolar Disorder

Bipolar disorders fall within the DSM-IV-TR1 category of mood disorders, which also includes depressive disorders and other mood disorders such as those due to general medical conditions and substance use. Differentiating bipolar disorder from depressive and other mood and psychiatric disorders can be challenging because of its complex presentation, which is often confounded by both psychiatric and medical comorbidities. Unipolar MDD is a key differential diagnosis, and bipolar disorder differs from MDD by the presence of a manic or hypomanic episode or significant subthresold mood elevation. The subtypes of bipolar disorder are bipolar I disorder, bipolar II disorder, cyclothymic disorder, and bipolar disorder NOS.

Bipolar I disorder. Bipolar I disorder is differentiated from other bipolar disorders by the presence of at least 1 manic or mixed episode. In a mixed episode, symptoms of both a manic episode and a major depressive episode occur nearly every day for at least 1 week.1 Although not required for the diagnosis of bipolar I disorder, major depressive episodes are seen in most patients. Bipolar I disorder affects approximately 1% of the population.2 The disorder is distributed evenly among men and women; however, the first episode in women is more often depressive than manic, while the index episode in men is more often manic than depressive. About 90% of patients diagnosed with bipolar I disorder will have recurrent episodes, and remissions commonly become briefer with increasing age and increasing number of prior episodes.1 The classic biphasic course of bipolar I disorder is illustrated in AV 1.3 Substance use disorders and anxiety disorders, and, to a lesser extent, eating disorders and ADHD, are commonly comorbid with bipolar I disorder.4

Bipolar II disorder. Bipolar II disorder is characterized by 1 or more depressive episodes lasting at least 2 weeks plus at least 1 hypomanic episode lasting at least 4 days (AV 2).1,3 Like bipolar I disorder, bipolar II disorder also affects approximately 1% of the population,2 but, unlike bipolar I disorder, appears to be more common in women than men. Among bipolar II disorder patients, men are likely to experience as many or more hypomanic episodes than depressive episodes, while women may experience more depressive or dysphoric hypomanic (concurrent depressive and hypomanic) episodes than “pure” hypomanic episodes (ie, without concurrent depression).5 On initial consideration, bipolar II disorder might be thought by some to be milder than bipolar I disorder because hypomania is not as severe as mania and psychosis is less common in bipolar II than in bipolar I disorder. Although patients with bipolar II disorder can have psychotic depressions, psychotic mood elevations would be classified as mania and, therefore, indicate bipolar I disorder. However, the severity of bipolar II disorder should not be underestimated, as the depressive episode burden in bipolar II disorder appears to be more substantial than in bipolar I disorder. The rates of suicidal ideation and suicide attempts are high in both illnesses, and, in at least some studies, are higher in bipolar II disorder than in bipolar I disorder.6 In bipolar II disorder, the depressive episodes are generally more pervasive and clinically significant than the mood elevations. Rapid cycling (an illness course defined by having at least 4 mood episodes per year that commonly involve highly recurrent, treatment-resistant depressive episodes) appears to occur more often in bipolar II disorder than in bipolar I disorder.1 Common comorbidities include substance use disorders and anxiety disorders, and, to a lesser extent, eating disorders, ADHD, premenstrual dysphoric disorder, and borderline personality disorder.1

Cyclothymic disorder. Cyclothymic disorder is characterized by a chronic pattern of recurrent hypomanic and mild depressive symptoms (AV 3).1,3 Symptoms are mild in that they are not sufficient to meet criteria for manic or major depressive episodes and are not required to meet the criteria for a hypomanic episode. However, the mood disturbance is chronic, as patients are not symptom-free for more than 2 months in a 2-year period. Mood oscillation in cyclothymia compared with bipolar I disorder and bipolar II disorder has higher frequency but lower amplitude. Cyclothymic disorder may be evenly distributed between men and women in the community, but more women than men are seen in clinical settings.1 Patients often seek treatment due to comorbid disorders such as anxiety disorders, substance use disorders, or personality disorders. Estimated lifetime prevalence rates of cyclothymic disorder range from 0.4% to 1%, and between 15% to 50% of patients diagnosed with cyclothymic disorder will progress to bipolar I disorder or bipolar II disorder (more often bipolar II disorder).

Bipolar disorder NOS. Bipolar disorder NOS is a residual category for disorders with bipolar features that do not meet the criteria for bipolar I disorder or bipolar II disorder.1 For example, patients may have hypomanic episodes without depressive episodes, or manic symptoms that rapidly alternate with depressive symptoms but do not meet the duration criteria for manic or major depressive episodes.


Diagnostic Challenges of Bipolar Disorder

The diagnostic complexities of bipolar disorder make misdiagnosis common. National surveys7,8 conducted in 1992 and 2000 found similar rates of misdiagnosis: 73% versus 69%, respectively. Of those who were initially misdiagnosed, almost half experienced a delay of several months to 5 years between seeking treatment and receiving a bipolar diagnosis, and more than one-third had a 10-year or longer delay. In 2000, the most common misdiagnosis was MDD (60% of misdiagnoses); other misdiagnoses included anxiety disorders, schizophrenia, Cluster B personality disorders, and substance use disorders.8 In 2001, a nationwide US survey9 used a validated screening tool to quantify the rate of recognition of bipolar disorder in the community. Among patients who screened positive for bipolar disorder, almost 50% had never received a mood disorder diagnosis from a doctor, about 30% had been diagnosed with MDD, and only 20% had been diagnosed with bipolar disorder.

The relationship between unipolar and bipolar conditions poses a diagnostic challenge. Patients with bipolar I disorder and bipolar II disorder are symptomatic about half of the time and much more often experience depressive rather than manic or hypomanic symptoms.10,11 Therefore, a clinician evaluating a patient experiencing a first depressive episode with no history of mood elevation must determine if the patient is at risk for a bipolar condition. Several baseline markers have been identified that have potential predictive value in making this determination. One such marker appears to be early onset of depression: up to 50% of prepubertal individuals with a diagnosis of MDD may progress to a bipolar condition within 10 years.12 Severe depressive episodes (entailing hospitalization or psychosis) in late adolescence or early adulthood and a family history of bipolar illness also indicate an increased risk of eventually developing mania or hypomania.13 The greater the number of risk factors that a patient has, the greater the risk of developing mania, with as many as two-thirds of patients who have major depressive episodes and all 3 risk factors also having mania (AV 4).3,14

A "probabilistic" approach to ascertain whether a patient is more likely to ultimately have bipolar disorder versus unipolar depression has been proposed. This approach uses a number of risk factors to aid in assessing the likelihood of a bipolar outcome in patients presenting with depression.15 In addition to an earlier age at onset, psychotic features, and a family history of bipolar disorder, depressed patients at risk for a bipolar outcome are more likely than those with unipolar depression to have atypical depressive features such as hypersomnia, hyperphagia, leaden paralysis, psychomotor retardation, pathological guilt, and lability of mood. Depressed patients at risk for a bipolar outcome have more prior episodes of depression and shorter episode durations. In contrast, patients with "typical" depressive features such as insomnia, decreased appetite, physical agitation, and somatic complaints and who have a later onset of symptoms, longer depressive episodes, and no family history of bipolar disorder are more likely to have a unipolar outcome.

Unmet Needs in Bipolar Disorder

Enhanced methods of diagnosing bipolar disorder are needed, but additional treatment options are also necessary. For example, many more agents are approved for treating acute mania than for treating acute bipolar depression, despite the predominance of depressive episodes. Longer-term maintenance treatments are also somewhat limited, as most therapies are more effective in preventing mood elevation than depression and have substantive tolerability constraints. All mood stabilizers (lithium, divalproex, carbamazepine, and lamotrigine) have at least 1 boxed warning in their prescribing information, and such agents (with the exception of lamotrigine) are commonly associated with central nervous and/or gastrointestinal side effects. All first- and second-generation antipsychotics have at least 1 boxed warning as well. The second-generation antipsychotics, compared with first-generation antipsychotics, have fewer neurologic side effects, but have other substantive side effects that need to be managed, including sedation, weight gain, and metabolic disruption. There is a particular need for additional safe, tolerable, and efficacious treatment options for bipolar depression and for longer-term maintenance.

For Clinical Use


  • Use caution when diagnosing patients presenting with depression; early age at onset, family history of bipolar disorder, and history of psychosis are all predictive of a bipolar outcome, whereas later age at onset, long depressive episodes, and no family history of bipolar disorder are predictive of a unipolar outcome
  • Screen patients with depressive symptoms for any history of manic, hypomanic, or mixed episodes; atypical depressive symptoms (hypersomnia, hyperphagia, leaden paralysis, psychomotor retardation); and lability of mood, which are markers for a bipolar outcome
  • Recognize that depressive symptoms combined with insomnia, decreased appetite, physical agitation, and somatic complaints may be predictive of a unipolar condition


Drug Names

carbamazepine (Carbatrol, Tegretol, and others), divalproex (Depakote and others), lamotrigine (Lamictal and others), lithium (Eskalith, Lithobid, and others)


ADHD = attention-deficit/hyperactivity disorder
DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision
MDD = major depressive disorder
NOS = not otherwise specified

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