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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. 1-3 In addition to regular circannual episodes, 4 a spectrum of cycle frequencies has been observed, from the classical rapid cycling (RC) pattern of four or more episodes per year, 5,6 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. 7-10 RC has a female preponderance, and occurs with greater frequency premenstrually, at the puerperium and at menopause. 11,12 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. [13][14][15] 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). 16,17 Between 85-90% of VCFS patients are hemizygous for COMT. 18 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). 19,20 There is nearly an equal distribution of L and H alleles in Caucasians. 21 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.The study included eight patients diagnosed with BPD I, 17 with BPD II, and three co-morbid with obsessive-compulsive disorder (OCD). Childhood or adolescent onset of illness was reported in all 25 of the patients, 17 (83%) began before puberty. Of six UURC patients, five had childhood onsets with 'de novo' ultra-ultra rapid cycling (ie, not antidepressantinduced). This form of cycling has recently been reported to be common in childhood-onset BPD. 22 A sizable majority, 23/25 (92%) of the patients reported having had cycle acceleration when treated with antidepressants (Table 1).COMT genotype was determined in 24 women and one man diagnosed as rapid-cyclers by DSM-IV criteria. Of six patients found to have UURC, five were women. We and others have found that there is no association between COMT genotype and patients with BPD when patients are not selected for cycle frequency. 23,24 Similarly, there was no difference when the frequency of the COMT polymorphism in this group...

The analysis of submicroscopic copy number variations (CNVs), also known as copy number polymorphisms (CNPs), is emerging as a new tool for understanding the genetic basis of cancer, developmental disorders, and complex traits. One area where this may be particularly useful is in the identification of genetic variants underlying schizophrenia (SZ) and bipolar disorder (BD). Linkage analysis and pharmacological studies carried out over the past decade have implicated a number of positional and physiological candidate genes. Yet, despite extensive analysis, the underlying allelic variants responsible for disease susceptibility have remained, largely, elusive. Although the borders of most CNV have not been precisely mapped, it appears that a considerable number of SZ and BD candidate genes have their coding elements disrupted by polymorphic CNVs, suggesting that these would be good variants to consider for underlying disease susceptibility. One such gene is GSK3beta, which codes for glycogen synthase kinase, a key component of the Wnt signaling pathway and a target of lithium salts. A CNV in the GSK3beta locus at chromosome 3q13.3 appears to disrupt the gene's 3'-coding elements. The CNV also affects two other annotated genes. We now report that patients with BD have an increased frequency of this CNV-primarily the duplication variant-compared with controls (P = 0.002). The finding suggests that GSK3beta may be involved in BD susceptibility in some individuals and that CNVs in this and other candidate genes for psychiatric disorders should be analyzed as causative functional genetic variants.