Bipolar spectrum disorders are recurrent illnesses characterized by episodes of depression, hypomania, mania or the appearance of mixed states. Great variability is evident in the frequency of episode recurrence and duration. In addition to regular circannual episodes, a spectrum of cycle frequencies has been observed, from the classical rapid cycling (RC) pattern of four or more episodes per year, to those with distinct shifts of mood and activity occurring within a 24-48 h period, described as ultra-ultra rapid cycling (UURC) or ultradian cycling. RC has a female preponderance, and occurs with greater frequency premenstrually, at the puerperium and at menopause. Tricyclic antidepressants and MAOIs, both of which increase functional monoamines norepinephrine, dopamine and serotonin, are known to precipitate mania or rapid-cycling in an estimated 20-30% of affectively ill patients. We have recently reported a strong association between velo-cardio-facial syndrome (VCFS) patients diagnosed with rapid-cycling bipolar disorder, and an allele encoding the low enzyme activity catechol-O-methyltransferase variant (COMT L). Between 85-90% of VCFS patients are hemizygous for COMT. Homozygosity for the low activity allele (COMT LL) is associated with a 3-4 fold reduction of COMT enzyme activity compared with homozygotes for the high activity variant (COMT HH). There is nearly an equal distribution of L and H alleles in Caucasians. Individuals with COMT LL would be expected to have higher levels of transynaptic catecholamines due to a reduced COMT degradation of norepinephrine and dopamine. We therefore hypothesized that the frequency of COMT L would be greater in RC BPD ascertained from the general population. Significantly, we found that the frequency of COMT L was higher in the UURC variant of BPD than among all other groups studied (P = 0.002). These findings indicate that COMT L could represent a modifying gene that predisposes to ultra-ultra or ultradian cycling in patients with bipolar disorder.