Bipolar disorder refers to a group of affective disorders, which together are characterised by depressive and manic or hypomanic episodes. These disorders include: bipolar disorder type I (depressive and manic episodes: this disorder can be diagnosed on the basis of one manic episode); bipolar disorder type II (depressive and hypomanic episodes); cyclothymic disorder (hypomanic and depressive symptoms that do not meet criteria for depressive episodes); and bipolar disorder not otherwise specified (depressive and hypomanic-like symptoms that do not meet the diagnostic criteria for any of the aforementioned disorders). Bipolar disorder type II is especially difficult to diagnose accurately because of the difficulty in differentiation of this disorder from recurrent unipolar depression (recurrent depressive episodes) in depressed patients. The identification of objective biomarkers that represent pathophysiologic processes that differ between bipolar disorder and unipolar depression can both inform bipolar disorder diagnosis and provide biological targets for the development of new and personalised treatments. Neuroimaging studies could help the identification of biomarkers that differentiate bipolar disorder from unipolar depression, but the problem in detection of a clear boundary between these disorders suggests that they might be better represented as a continuum of affective disorders. Innovative combinations of neuroimaging and pattern recognition approaches can identify individual patterns of neural structure and function that accurately ascertain where a patient might lie on a behavioural scale. Ultimately, an integrative approach, with several biological measurements using different scales, could yield patterns of biomarkers (biosignatures) to help identify biological targets for personalised and new treatments for all affective disorders.
Psychiatric illnesses are usually primarily diagnosed by careful assessment of behaviour combined with subjective reports of abnormal experiences to group patients into disease categories. However, these categories mask substantial heterogeneity. For example, a diagnosis of schizoaffective disorder is often given to people with episodes of both affective and psychotic symptoms, either alternating or occurring together, which casts some doubt on the traditional dichotomy delineating affective and psychotic disorders into discrete illness categories.1 In the absence of definitive and objective biomarkers of pathophysiological processes underlying behaviours associated with conventionally defined psychiatric illness categories, and because of the heterogeneity within, and considerable overlap between, these behaviours, appropriate diagnosis and treatment are difficult for many psychiatric illnesses. Bipolar disorder is an especially good example of a group of psychiatric illnesses that are difficult to diagnose accurately. For example, although this disorder, along with other psychiatric illnesses, is one of the ten most debilitating of all non-communicable diseases,2,3 misdiagnosis of the illness as recurrent unipolar depression occurs in 60% of patients seeking treatment for depression.4,5We emphasise the main reasons for the challenges in diagnosis of bipolar disorder in clinical practice, describe future clinical and biological directions for improving the accuracy of diagnosis, and discuss novel approaches that are moving towards a conceptualisation of bipolar disorder and unipolar depression along an affective disorders continuum.
Bipolar disorder definitions
The origins of the categorical approach to psychiatric illness lie in the classic work of the founders of modern psychiatry, such as Emil Kraepelin. Kraepelin proposed a dichotomy between psychiatric illnesses characterised by regularly recurring episodes of notable changes in affect; and illnesses characterised by abnormal cognitions, beliefs, and experiences (ie, psychotic symptoms), which usually manifested in early adulthood and persisted throughout life.6 Kraepelin referred to the first category as “manic—depressive psychosis”, including illnesses that we now refer to as affective disorders (eg, bipolar disorder), and the second as ”dementia praecox” (premature dementia), encompassing diseases that we now refer to as psychotic disorders (eg, schizophrenia). The term bipolar was first used in 1957 by Leonhard7 for disorders comprising both manic and depressive symptoms. In 1980, the name bipolar disorder was adopted by the Diagnostic and Statistical Manual for Mental Disorders (DSM) to replace the term manic depression.
In present classification systems, bipolar disorder now refers to a group of affective disorders in which patients experience episodes of depression, characterised by low mood and related symptoms (eg, loss of pleasure and reduced energy), and episodes of either mania, characterised by elated or irritable mood or both, and related symptoms such as increased energy and reduced need for sleep, or hypomania, whose symptoms are less severe or less protracted than are those of mania. The fourth edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)8 contains four main subtypes of bipolar disorder: bipolar disorder type I (episodes of depression and at least one episode of full-blown mania); bipolar disorder type II (several protracted episodes of depression and at least one hypomanic episode but no manic episodes); cyclothymic disorder (many periods of hypomanic and depressive symptoms, in which the depressive symptoms do not meet the criteria for depressive episodes); and bipolar disorder not otherwise specified (depressive and hypomanic-like symptoms and episodes that might alternate rapidly, but do not meet the full diagnostic criteria for any of the aforementioned illnesses; panel 1). The tenth edition of the International Classification of Diseases (ICD-10)9 does not discriminate between bipolar disorder types I and II. ICD-10 also requires two discrete mood episodes, at least one of which must be manic or hypomanic, for a bipolar disorder diagnosis. However, in DSM-IV, one episode of mania (or mixed mood), or one episode of hypomania plus one major depressive episode, is sufficient for a diagnosis.
Bipolar disorder subtypes
Diagnostic and Statistical Manual for Mental Disorders fourth edition (DSM-IV) criteria
- Bipolar disorder type I
- At least one episode of full-blown mania or mixed episode (manic and depressive symptoms). Usually has at least one depressive episode
- Bipolar disorder type II
- Several protracted depressive episodes and at least one hypomanic episode, but no manic episodes
- Cyclothymic disorder
- Several periods of hypomanic and depressive symptoms. Depressive symptoms do not meet criteria for depressive episodes
- Bipolar disorder not otherwise specified
- Depressive and hypomanic-like symptoms and episodes that might alternate rapidly, but do not meet the full diagnostic criteria for any of the above disorders
International Classification of Diseases 10th edition (ICD-10) criteria: differences from DSM-IV
- ICD-10 does not discriminate between bipolar disorder types I and II
- ICD-10 requires two discrete mood episodes, at least one of which must be manic, for a bipolar disorder diagnosis. In DSM-IV, one episode of mania (or mixed mood), or one episode of hypomania plus a major depressive episode, suffice for a BD diagnosis
Why is bipolar disorder so difficult to diagnose accurately?
Bipolar disorder types I and II are especially difficult to diagnose accurately in clinical practice, particularly in their early stages. Only 20% of patients with bipolar disorder who are experiencing a depressive episode are diagnosed with the disorder within the first year of seeking treatment,5and the mean delay between illness onset and diagnosis is 5–10 years.10 A major reason for the difficult diagnosis is the challenge of differentiating bipolar disorder type I or II from unipolar depression—an illness characterised by recurrent depressive episodes— especially in patients who present during a depressive episode and in those with no clear history of mania or hypomania.4,5Unipolar depression is reportedly the most frequent misdiagnosis in patients with bipolar disorder,5especially in bipolar disorder type II, because patients with this illness, by definition, never experience an episode of mania (figure 1).
Figure 1Mood changes over time in bipolar disorder type I, bipolar disorder type II, and recurrent unipolar depressive disorder
Another reason for the difficulty in distinction of bipolar disorder type I or II from unipolar depression is that the prevalence of depressive symptoms is higher than that of hypomanic or manic symptoms during the course of bipolar disorder type I or II, and these disorders often start with a depressive episode. People with bipolar disorder type II in particular spend much of their lives in a depressed state,5,11–13 and more time in depressive than hypomanic or manic episodes, which compounds the diagnostic problem.14 For ex ample, in two studies, people with bipolar disorder type I experienced hypomanic or manic symptoms only 9% of the time (9% of follow-up weeks),15and individuals with bipolar disorder type II experienced hypomanic symptoms only 1% of the time (1% of follow-up weeks).16 Patients with bipolar disorder type II seek treatment for depressive symptoms much more frequently than they do for hypomanic or manic symptoms, and often do not recognise the consequences of, and thus fail to seek help for, the latter symptoms, which makes identification and treatment of these symptoms by clinicians especially difficult.
Mixed mood episodes, which are characterised by the presence of both depressive and hypomanic or manic symptoms, or a rapid alternation of the three symptom types, are being increasingly recognised as more common in people with bipolar disorder than was previously thought.17 This idea challenges the traditional view of bipolar disorder as a group of illnesses characterised by discrete depressive, hypomanic, or manic episodes. The identification of hypomanic and manic symptoms in bipolar disorder patients with a history of mixed episodes is made even more difficult, especially for less experienced clinicians, by both the reporting bias towards depressive symptoms and the absence of discrete hypomanic or manic episodes in these patients. Furthermore, increasing evidence suggests that sub threshold symptoms of bipolar disorder (ie, depressive-like, hypomanic-like, or manic-like symptoms that do not meet diagnostic thresholds for depressive, hypomanic, manic, or mixed episodes) in patients with bipolar disorder are associated with shorter time to future relapse into full-blown illness episodes than in patients without such subthreshold symptoms.18 This finding emphasises the significance of the effects of subthreshold symptoms of bipolar disorder on the future disease course.
In parallel, increasing evidence suggests that many patients diagnosed with unipolar depression might actually have a misdiagnosed bipolar disorder subtype. For example, in patients with a unipolar depression diagnosis, the 11-year rate for conversion to bipolar disorder type II is 9%,19 and the 5-year rate for development of a manic or hypomanic episode is 20%.20 Furthermore, results from antidepressant treatment trials for patients with unipolar depression indicate that up to two-thirds of these patients do not respond to first-line antidepressants, a third do not achieve full remission from symptoms after four treatments, and the rate of depression recurrence is very high, even in those who achieve remission after treatment with antidepressants.21,22
Together, these studies suggest that the boundary between bipolar disorder, particularly type II, and unipolar depression is not clear cut (panel 2), and that many people with treatment-resistant unipolar depression could have undiagnosed bipolar disorder.23 Misdiagnosis of bipolar disorder type I or II as unipolar depression has many potentially deleterious consequences, including prescription of inappropriate drugs, such as antidepressants in the absence of a mood-stabilising drug, which might lead to switching to mania, and, ultimately, poor clinical and functional outcome and high health-care costs.24–27 Accurate diagnosis of bipolar disorder in its early stages, ideally before the first episode of hypomania or mania, or when there is no clear history of hypomania or mania, could therefore help to prevent the long-term detrimental effects of misdiagnosis.