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Challenges in Studies of Course of First-Onset BD

There are numerous challenges in the interpretation and generalizability of studies of the course and outcome of BD specifically and severe mental disorders in general.

Diagnostic Issues

Although there tends to be high diagnostic stability of BD, misdiagnosis and diagnostic shifts from other psychiatric disorders are quite common over time.6,9,13 Characteristics ofBD that complicate evaluation of its course are its episodic nature, fluctuation across different emotional states, pervasive comorbidity with other mental disorders (particularly substance use disorders) and physical conditions, and its manifestation on a spectrum without clear boundaries for either mania or depression. The natural course of BD is characterized by a constant risk of recurrences over a patient’s life span, even 30-40 years after onset and up to 70 years of age or older, causing impairment of psychosocial functioning, despite advances in pharmacological and nonpharmacological treatments.27

Perhaps the most important challenge is the difficulty in identifying the first onset of BD, which may present as symptoms of depression, mania, or both, across a range of severity. In fact, studies of youth at high risk for BD by Duffy and colleagues44,45 suggest that anxiety may be an early manifestation of BD. Moreover, as the general consensus of the field has moved toward subthreshold characterization of both mania and major depression,23 defining the point at which first onset occurs is even more obscure. Misclassification of BD at the first or index episode is pervasive, with frequent misdiagnosis of BD as MDD or major depressive episode (MDE) because of a lack of recognition of underlying manic or hypomanic episodes.46 The extensive discussion of classification of mixed states, switching of polarity,9,29,32 and residual affective symptoms10 in clinical samples highlights the complexity of applying standardized diagnostic criteria to disorders with highly variable manifestations over time. A recent follow-up of a specialty mood disorder sample in Australia demonstrated the high rate of misdiagnosis of BD as MDD in nonspecialty treatment settings47 in which the average gap between the retrospectively reported onset of disorder and actual diagnosis of BD was 19 years.

The subthreshold concept that has evolved from the application of clinical diagnostic criteria to non-treatment-seeking community samples,1,2 particularly children and adolescents,42,48 reflects the difficulty in defining diagnostic thresholds for dimensional traits that reflect normal human mood and homeostatic function. Characterization of subthreshold symptoms has also become a critical component of studies of course.7 23 Several studies in this review have established methods to characterize both subtypes of mania and depression as well as their subthreshold manifestations.7,8

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