We now recognize that bipolar disorder is often accompanied by anxiety, eating, and substance use disorders (1) and high rates of medical illness, especially cardiovascular, cerebrovascular, and metabolic diseases (2). Individuals with bipolar disorder also suffer from a marked disruption in sleep rhythms and social relations. Rather than defining bipolar disorder solely as one of episodic mood disturbances, we should consider defining it as a multisystem disorder involving disturbances in all of the above-mentioned domains. By employing a symptom-based rather than an etiologically based approach, DSM-IV fails to reflect the multisystem presentation of bipolar disorder.

Increasingly sophisticated neuroimaging and genetic research have deepened our understanding of the neurobiology of bipolar disorder as one involving complex disturbances in relationships, linking environment, genes, neural systems, and behavior. This approach supports the research agenda for DSM-V, emphasizing the need to translate basic and clinical neuroscience research findings into a new classification system for psychiatric disorders (3). Although the understanding of the pathophysiology of bipolar disorder remains limited, preliminary findings from recent neuroimaging studies have indicated persistent dysfunctions specific to bipolar disorder within neural systems underlying mood and cognition (4, 5) that are also found in healthy first-degree relatives as endophenotypes of the disorder (6). Specific genetic variables contributing to normal functional variation may further affect dysfunctions within these systems (7).

How can DSM-V reflect the clinical complexity and pathophysiology of bipolar disorder? An immediate first step is initiating large-scale studies to identify the specific clinical spectrum, neurocognitive, and neuroimaging measures that best distinguish individuals with bipolar disorder from those with other mood and psychotic disorders and incorporating these as supplementary diagnostic criteria into DSM-V. The future challenge will be to test the construct validity of these new measures versus conventional criteria in longitudinal studies examining clinical outcome and treatment response, leading ultimately to an etiologically and pathophysiologically based classification system for bipolar disorder.