Expanding the bipolar construct while preserving its diagnostic integrity: are we keeping the baby or the bathwater?

Strakowski et al provide a thought-provoking discussion of the clinical and scientific merits, and shortcomings, of adopting a broadened nosologic construct of bipolar disorder, extending beyond the categorical limits of bipolar I and II disorder. Perhaps the most scientifically compelling argument for such a conceptualization involves the realization that bipolar disorder encompasses varied dimensions of psychopathology that entail more than mood disturbances, including cognitive dysfunction, chronobiological disruptions, psychosis, interpersonal conflict, and behavioral activation. Unlike Mendelian diseases, complex traits such as bipolar disorder – though robustly heritable – are believed to involve multiple genes that collectively exert small effects. In that sense, casting a wider phenotypic “net” could potentially enhance the yield for detecting signals that are true phenotypes, or more probably, non-obvious endophenotypes. Furthermore, variable expressivity of putative risk alleles can readily account for form fruste clinical presentations of affective illness that defy categorical distinction. On the other hand, efforts to discern links between suspected genotypes and presumptive disease entities suffer when phenotypes are poorly defined or unrefined. The dilemma at hand fundamentally involves the limits with which descriptive psychopathology can be expected to shed light on biological disease states. Strakowski et al point out the arbitrary and incomplete nature of current diagnostic descriptors, but one must ask whether additional phenomenologic descriptors would be any less arbitrary. Clearly the features that now define bipolar I or II disorder fail to capture many variations of complex mood disorder; and similarly, the designation of unipolar depression alone often inadequately describes cases with poor treatment responses or levels of functional impairment that are not commensurate with the prognosis of uncomplicated major depression. Polarity is only one of many dimensions of mood disorder complexity, alongside psychosis, agitation, anxiety, acuity, chronicity, comorbidity, and melancholia. One wonders how broadened phenomenology would clarify polarity as a central organizing principle for mood disorder nosology. One must equally consider the hazards of extracting symptoms from other known disorders and refitting them as bipolar equivalents – such as the impulsivity or affective instability of borderline personality disorder, the distractibility and hyperactivity of attention-deficit/hyperactivity disorder, or the autonomic hyperarousal and psychomotor acceleration of severe anxiety disorders – when doing so compromises the diagnostic integrity of other disorders. Without prior knowledge about disease etiology, phenomenologic expansion may lead researchers and clinicians toward altogether wrong conceptual frameworks. Imagine reformulating pulmonary emboli, costochondritis and peptic ulcer disease as collectively falling within the angina spectrum based solely on the presence of chest pain (and proposing lytic therapy for all such presentations); or deciding that pregnancy, anasarca, and obesity plausibly have common etiologies based on shared disturbances of abdominal girth. Since DSM-III, psychiatric nosology has made no pretense that descriptive diagnoses impart information about etiology. Until novel external validators of disease states are established, expanded phenomenology seems inescapably arbitrary. From a practical standpoint, the greatest clinical peril in prematurely broadening the bipolar construct likely concerns recommendations about best treatments for difficult mood disorders. Strakowski et al suggest that patients with “bipolar-like symptoms” might benefit from the same drugs used to treat bipolar I disorder, arguing that mood stabilizers “are thought to be relatively specific for bipolar disorder”. Yet, one might challenge the diagnostic specificity of virtually any psychotropic drug, and there is little basis for inferring diagnosis from clinical response elsewhere in medicine. Consider, for example, that successful diuresis with furosemide does not establish a cardiogenic versus peripheral etiology for edema; nor does an anti-inflammatory response to corticosteroids point to an autoimmune versus infectious etiology for joint pain. Moreover, as intriguing as the hypothesis may be that mood stabilizers could have value for complex forms of non-bipolar I or II “spectrum” disorders, it must be acknowledged that no controlled studies exist to determine the efficacy of mood stabilizing drugs for “expanded bipolar spectrum” patients. Extrapolation about possible treatment outcomes from studies of mood stabilizers for treatment-resistant or highly recurrent unipolar depression is less than encouraging. For example, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) comprised a study group with highly recurrent unipolar depression – a designation some authorities would construe as tantamount to Kraepelinian manic-depressive illness – yet adjunctive lithium yielded only a 15.9% response rate 1, despite earlier promising results with much smaller samples in highly recurrent unipolar depression 2. Similarly, despite encouraging preliminary open label data, three placebo-controlled studies have failed to demonstrate efficacy for adjunctive lamotrigine in treatment-resistant unipolar depression 3,4,5. No randomized studies exist with divalproex or carbamazepine for complex unipolar depression, although efficacy with either of these mood stabilizers is more robust for mania than depression in bipolar I disorder. Strakowski et al preface their discussion of a possible expanded role for mood stabilizers by pointing out unresolved controversies regarding the safety and efficacy of antidepressants in bipolar depression. Strikingly, though, randomized trials indicate that antidepressant safety and efficacy appear more substantial in bipolar II than bipolar I disorders 6,7 – and perhaps even superior to lithium for relapse prevention – suggesting that “soft” spectrum bipolar disorders may in fact be the most hospitable niche for antidepressant use, in contrast to bipolar I disorder. As hypotheses about an expanded bipolar spectrum await empirical study, several points merit consideration for future clinical and research efforts: • There is a need to empirically determine inclusion and exclusion criteria for candidate entities within the bipolar “spectrum”. With no proposed exclusion criteria, risks for diagnostic incoherence run high. • Endophenotypic approaches, particularly focusing on clinically unaffected first-degree relatives of bipolar I or II probands, may be especially useful to discern observable characteristics that reflect the expression of bipolar risk alleles, and help to parse true phenotypes from phenocopies. • Meaningful clinical trials of mood stabilizers are needed for non-bipolar I or II spectrum disorders in order to base treatment recommendations on empirical observation and replace speculation and opinion with factual outcome data.