Bipolar Disorders: Mixed States, Rapid-Cycling, and Atypical Forms

62 O. Elhaj and J. R. CalabreseFamily geneticsIn the above-mentioned paper (Calabrese et al., 2000a), the following was reportedconcerning family history and genetics: family studies of rapid-cycling bipolardisorder show no difference in family loading for bipolar disorder as comparedwith non-rapid-cycling patients, nor does rapid cycling cluster in families of rapidcyclers. Nurnberg et al. (1988) first evaluated the inheritance of rapid cycling.Twenty-nine of 195 bipolar/episodic schizoaffective patients were judged to berapid cyclers (15%). The age-corrected risk of major affective disorder was 23.5%in 179 relatives of rapid cyclers and 31% in 189 relatives of matched non-rapidcyclers, suggesting that rapid cycling is not genetic and does not aggregate withinfamilies. This result was replicated by Coryell et al. (1992) andLishet al. (1993).Coryell et al. collected information through family history and family study methodsfor 268 relatives of 45 rapid cyclers and 1273 relatives of bipolar non-rapid cyclers.More extensive data were obtained for 111 relatives of rapid cyclers and 397 relativesof non-rapid cyclers who were also re-evaluated prospectively and at 6 years aftertheir initial interview. Neither data set revealed evidence suggesting that rapid cyclinghad bred true in their cohort. Lish et al. (1993) used the Family History ResearchDiagnostic Criteria to interview 165 rapid cyclers, non-rapid cyclers, or individualswith recurrent unipolar depressive disorder about the psychiatric history of 812 adultfirst-degree relatives. Rapid cyclers were younger and more likely to be female thannon-rapid cyclers, but the relatives of rapid cyclers did not differ significantly fromthose of non-rapid cyclers in the prevalence of bipolar disorder, unipolar disorder,rapid-cycling bipolar disorder, or substance abuse. However, there was a nonsignificanttrend for the relatives of rapid-cycling bipolar patients to have moresubstance abuse than relatives of non-rapid-cycling patients. These three studiesappear to argue convincingly against any specific inheritance of rapid cycling as adiscrete course modifier. However, it remains a possibility that early-onset rapidcycling, as opposed to late-onset, might be discretely inherited.Only very recently have genetic abnormalities begun to be examined in rapidcycling. One anecdotal report has noted the presence of the same chromosomalaberration, a pericentric inversion of chromosome 9, in a bipolar II fatherand daughter (McCandless et al., 1998). The same group of investigators firstdemonstrated an association between ultradian rapid cycling and low activity ofcatechol-O-methyltransferase (COMT), and extended this finding to bipolar patientswith either a current or a lifetime history of rapid cycling (Kirov et al., 1998). Theyhypothesized that variation in the COMT gene modifies episode frequency.Concurrently, Veit et al. (1998) presented new data suggesting that COMT activityis subject to variability in humans, that this activity is associated with episodefrequency, and that low activity is primarily due to a G–A transition at codon 158.