Calabrese JR, Shelton MD, Bowden CL, Rapport DJ, Suppes T, Shirley ER, Kimmel SE, Caban SJ.
Bipolar rapid cycling: focus on depression as its hallmark.
J Clin Psychiatry 2001;62 Suppl 14:34-41
"The phenomenon of frequent cycling in bipolar disorder was first recognized by Emil Kraepelin in 1913. More recently, rapid cycling has been reported to be a predictor of nonresponse to treatment. At the time of presentation, most patients with DSM-IV-defined rapid cycling appear to be in the depressed phase of their illness. Frequent and more severe episodes of depression appear to be the hallmark of rapid cycling. Reported in this article are recent preliminary data suggesting that the combination of lithium and divalproex sodium administered continuously over 6 months appears to result in marked acute and continuation antimanic efficacy in 85% of patients and marked antidepressant efficacy in 60%. However, only one half of patients experienced bimodal stabilization. Comorbid alcohol, cannabis, and/or cocaine abuse and/or dependence did not appear to directly affect the spectrum of efficacy of lithium and divalproex or response rates in compliant patients. Comorbidity appeared to alter prognosis by increasing the prevalence of poor compliance. The majority of patients receiving lithium and divalproex who required additional treatment were depressed, suggesting that the frequent recurrence of depression is the primary unmet need in patients with rapid cycling. The use of antidepressants in this population has been discouraged because of concerns about the possibility of cycle acceleration. There exists a need for a pharmacotherapy that not only possesses marked acute antidepressant properties, but that does so without inducing switching or cycle acceleration." [Abstract]

Tillman R, Geller B.
Definitions of rapid, ultrarapid, and ultradian cycling and of episode duration in pediatric and adult bipolar disorders: a proposal to distinguish episodes from cycles.
J Child Adolesc Psychopharmacol. 2003 Fall;13(3):267-71.
"OBJECTIVE: To propose terminology to distinguish cycles from episodes in children and adults with bipolar disorder (BP). METHODS: To examine current definitions of rapid cycling and episodes in both child and adult BP, an Internet search of the MEDLINE database was conducted. RESULTS: Investigations of rapid cycling in adults used the terms cycle and episode interchangeably to describe discrete periods of mood disorders. Two studies of children and one study of adults with BP, however, reported cycles occurring daily (ultradian cycling) or every few days (ultrarapid cycling). Without definitions to differentiate cycles from episodes, determining the overall duration of illness in subjects who experience ultrarapid or ultradian cycling is not possible. For example, a child cycled twice a day, every day, for 365 days (1 year). With the terminology currently in use, it is unclear whether this should be described as a single episode that had a duration of 365 days or as approximately 730 episodes (2 cycles per day x 365 days), each less than 24 hours in duration. Moreover, adults with BP may have more intermittent pathology than children (e.g., adults may cycle 4 days per week, versus children may cycle 7 days per week). CONCLUSION: The following definitions are proposed. (1) Episodes will be defined by (a) the duration from onset to offset of a period of at least 2 weeks in length during which only one mood state persists or (b) the duration from onset to offset of a period of ultrarapid or ultradian cycling for at least 2 weeks. (2) Cycles will be defined by mood switches occurring daily or every few days during an episode. Further research will be needed to elucidate potential differences between child and adult cycling patterns." [Abstract]

Koukopoulos A, Sani G, Koukopoulos AE, Minnai GP, Girardi P, Pani L, Albert MJ, Reginaldi D.
Duration and stability of the rapid-cycling course: a long-term personal follow-up of 109 patients.
J Affect Disord 2003 Jan;73(1-2):75-85
"BACKGROUND: Recognition by the DSM-IV of rapid cyclicity as a course specifier has raised the question of the stability and long-term outcome of rapid-cycling (RC) patients. Data on this topic is sparse and often inconsistent. To our knowledge, these are the first personally followed patients over the long term, dealing directly with the issue of the duration of the RC course. METHODS: We examined the evolution of the course of 109 RC patients (68 women and 41 men) followed for a minimum of 2 years and up to 36 years, beginning with the index episode when the RC course was diagnosed by the authors (A.K., G.P.M., P.G., L.P., D.R.). Patients were included in the study if they met criteria for RC as defined by>/=4 affective episodes per year (). The follow-up period varied from 2-5 years for 25 patients, 6-10 years for 24 patients, 11-15 years for 24 patients, 16-20 years for 19 patients, 21-25 years for 13 patients, 30-36 years for four patients. RESULTS: In 13 patients (12%), RC emerged spontaneously and in 96 patients (88%), it was associated with antidepressant and other treatments. In 19 women (28% of all women) RC course started in perimenopausal age (45-54 years). The mean duration of RC during the follow-up period was 7.86 years (range 1-32) and its total duration (including RC course prior to the follow-up period) was 11 years (range 1-40). The total duration of the affective disorder, from the first episode to the end of the follow-up, was 21.78 years (range 1-70). At the end of the follow-up, 36 patients (33%) had complete remission for at least the past year, 44 (40%) stayed rapid cycling with severe episodes (six of this group committed suicide), while 15 (14%) were rapid cycling but with attenuated episodes. The other 14 patients (13%) became long cyclers, eight with severe episodes and six with milder ones. The main distinguishing features between those who remitted from and those who persisted in the RC course were: (1) the initial cycle pattern: patients with Depression-Hypomania(mania)-Free interval cycles (53 patients) had a worse outcome: 26.4% remitted and 52.8% persisted in the RC course through to the end of the follow up period. The Mania/Hypomania-Depression-Free interval cycles (22 patients) had a significantly better outcome, with 50% remitted and 27.2% persisting RC; and (2) the occurrence of the switch process from depression to hypomania/mania and the occurrence of agitated depressions made the prognosis worse. Continuous treatment was more effective against mania/hypomania than against depression, yet in all persisting RC cases the mania/hypomania remitted only partially. LIMITATIONS: These data derive from clinics known for their expertise in mood disorders, and they may have attracted and retained patients with a more severe course. Treatment was uncontrolled and consisted more of lithium than divalproex, lamotrigene and olanzapine, recently shown to be beneficial in subgroups of patients with rapid-cycling. CONCLUSIONS: Our findings suggest that rapid cyclicity, spontaneous or induced, once established, becomes for many years a stable rhythm in a substantial proportion of patients, linked to endogenous and environmental factors. The suggestion is made to consider as rapid-cyclers, at least for research purposes, those patients who have had a rapid cycling course for at least 2 years, borrowing the duration criterion currently employed for other chronic disorders such as Dysthymia and Cyclothymia. That our patients had poorer prognosis than some other cohorts in the literature is probably due to the shorter duration of "rapid-cycling" at entry in the latter cohorts. A true understanding of the nature of rapid-cycling will require a rigorous definition of not only duration, but also pole-switching and course patterns at entry into study." [Abstract]

Leibenluft E, Clark CH, Myers FS.
The reproducibility of depressive and hypomanic symptoms across repeated episodes in patients with rapid-cycling bipolar disorder.
J Affect Disord 1995 Feb 21;33(2):83-8
"The purpose of this study is to determine the stability of symptoms of hypomania and depression across repeated affective episodes in patients with rapid-cycling bipolar disorder. Nine patients had a total of 30 depressive episodes and 31 hypomanic episodes during the period of observation. Standardized observer ratings indicated that the three symptoms most consistently reported during depressive episodes were fatiguability, decreased work activities and hypersomnia. These results as well as those from the standardized observer ratings of hypomania indicate that depression in this population consists of a lethargic, hypoactive state while hypomania may be a heightened state of activation. The clinical and theoretical implications of these findings are discussed." [Abstract]

Joyce PR, Fergusson DM, Woollard G, Abbott RM, Horwood LJ, Upton J.
Urinary catecholamines and plasma hormones predict mood state in rapid cycling bipolar affective disorder.
J Affect Disord 1995 Apr 4;33(4):233-43
"Over the course of 1 year, a patient with a rapid cycling bipolar affective disorder was followed at weekly intervals to examine whether plasma hormones and urinary catecholamines could predict current or future mood. Higher cortisol levels were found to predict depressed mood 3 days after blood sampling, higher urinary dopamine predicted a manic mood 3 days after blood sampling, urinary norepinephrine was associated with severity of current mood and prolactin was lower with concurrent depressed mood. In multivariate analyses of mood against cortisol, prolactin and three urinary catecholamines, > 50% of the variance in mood state in 3 days was explained by combinations of these biologic measures, especially cortisol and urinary dopamine, while all five biologic variables contributed to explaining 50% of the variance in current mood state. Based on the interrelationships between urinary dopamine, norepinephrine and mood, we postulate the existence of an overcompensating mechanism which is reflected in opposing correlations between urinary dopamine and norepinephrine with mood, despite the two urinary catecholamines being positively correlated." [Abstract]

Post RM, Stoddard FJ, Gillin JC, Buchsbaum MS, Runkle DC, Black KE, Bunney WE Jr.
Alterations in motor activity, sleep, and biochemistry in a cycling manic-depressive patient.
Arch Gen Psychiatry 1977 Apr;34(4):470-7
"Biochemical and electrophysiological factors were studied longitudinally in a rapidly cycling manic-depressive patient. Slow changes in mood, motor activity, sleep, and urinary norepinephrine levels during the course of each depressed and manic episode are reported, as well as rapid alterations in many variables at the time of mood switch. Urinary concentrations of norepinephrine and its metabolite, 3-methoxy-4-hydroxyphenyl glycol (MHPG) were significantly lower in depression than in mania; norepinephrine but not MHPG excretion increased prior to the switch. We postulate that the slow behavioral and biological changes preceding switches in this patient are an important manifestation of the cyclic process in manic-depressive illness." [Abstract]

Juckel G, Hegerl U, Mavrogiorgou P, Gallinat J, Mager T, Tigges P, Dresel S, Schroter A, Stotz G, Meller I, Greil W, Moller HJ.
Clinical and biological findings in a case with 48-hour bipolar ultrarapid cycling before and during valproate treatment.
J Clin Psychiatry 2000 Aug;61(8):585-93
"BACKGROUND: The rare cases of patients with 48-hour ultrarapid cycling allow close investigation of mood cycles in affective disorders, because rhythmic changes in psychopathologic state and biological parameters happen very precisely. METHOD: A 67-year-old white man who had experienced bipolar 48-hour ultrarapid cycling (DSM-IV 296.80) for several years was studied without any medication and then again studied 4 weeks later during treatment with valproate (1800 mg/day). RESULTS: Objective and self ratings revealed pronounced manic states 1 day and depressed states the following day, which were found to be accompanied by rhythmic fluctuations in behavior and electroencephalographic parameters, blood cortisol and growth hormone levels (both elevated on depressive days), and urinary metanephrine (dopamine metabolite) and norepinephrine levels (both elevated on manic days). Using single photon emission computed tomography, regional blood flow in the left thalamus was lower than in the right thalamus on the manic day, while symmetric perfusion of the thalamus was found on the depressive day. Under valproate treatment, the patient remitted completely, and significant rhythmic changes in most of the biological parameters were no longer detectable. CONCLUSION: The biological findings in this patient with bipolar 48-hour ultrarapid cycling, which correspond to those in other types of affective disorders, suggest that disturbances in the diencephalon-pituitary axis may be especially correlated to pathologic changes of mood." [Abstract]

Ostrow D, Halaris A, Dysken M, DeMet E, Harrow M, Davis J.
State dependence of noradrenergic activity in a rapidly cycling bipolar patient.
J Clin Psychiatry 1984 Jul;45(7):306-9
"Plasma levels of the major norepinephrine (NE) metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), were measured in a rapidly cycling bipolar patient and her first-degree relatives. The mood state dependence and the reciprocal relationship between noradrenergic and cholinergic activity were investigated by assessing mood, thought disorder, and plasma MHPG following the infusion of physostigmine. A correlation was found between plasma MHPG and mood states, with exceedingly high levels during mania and hypomania. Levels were significantly decreased by ECT or combined lithium and chlorpromazine administration. A pathologic diurnal MHPG pattern was detected during periods of abnormal mood changes. Infusion of physostigmine led to a prompt reduction in MHPG release and a marked decline in mood-state measurements and the overall level of thought disorder. Muscarinic receptors exerting negative feedback control over the synthesis and/or release of NE may have become supersensitive as a consequence of alpha 2-adrenoceptor densensitization." [Abstract]

Wu LH, Dunner DL.
Suicide attempts in rapid cycling bipolar disorder patients.
J Affect Disord 1993 Sep;29(1):57-61
"We studied 100 rapid cycling patients (33% of whom had truncated episodes), and 120 non-rapid cycling bipolar patients for history of suicide attempts. In contrast to our hypothesis, no significant differences were found when comparing suicide attempt histories for these two groups." [Abstract]

Shelton MD, Calabrese JR.
Current concepts in rapid cycling bipolar disorder.
Curr Psychiatry Rep 2000 Aug;2(4):310-5
"The rapid-cycling variant of bipolar disorder (RCBD) has been variably defined, with episode frequencies ranging from several per day to a minimum of four per year. It is diagnosed disproportionately in women with bipolar II disorder. Its time of onset may be in childhood, adolescence, or adulthood. It appears to be treatment refractory, but controlled trials are lacking." [Abstract]

Kilzieh N, Akiskal HS.
Rapid-cycling bipolar disorder. An overview of research and clinical experience.
Psychiatr Clin North Am 1999 Sep;22(3):585-607
"Although many studies of RCBD have been reported over the last 2 decades, knowledge remains limited. Higher incidence in women is the sole clearly replicated finding in most studies. This finding might be mediated by cyclothymia, a temperament that is of higher prevalence in women and that might be considered as a normal variant of RC. Many questions remain unanswered. Review of putative risk factors, such as hypothyroidism and treatment with antidepressants, provides no conclusive answers. There is clinical evidence to implicate both factors. In principle, the thyroid connection can be approached rationally, yet there seems to be no relationship between thyroid status and response to thyroid augmentation. For this reason and given the potential risks of long-term thyroid use, this strategy should not be the first one to be tried in RC. Cumulatively, naturalistic studies over the past 30 years have strongly implicated antidepressants in switching and cycle acceleration, yet the double-blind, controlled, prospective studies that are needed to provide definitive answers are unlikely to be conducted for ethical reasons discussed in this article. Bipolar family history of RC probands appears indistinguishable from non-RC probands, indicating that most likely RCBD does not breed true. Although RC seems to be more lithium resistant with less likelihood of being symptom-free after 2 to 5 years of follow-up, many of these patients nonetheless have resolution of the RC course. There is no marked difference in suicide rates. An association of RC with bipolar type II, D-M-I pattern and those who switch into mania or hypomania on antidepressants is a provocative possibility: Antidepressants might introduce RC by first inducing a switch during a depressive episode, creating a D-M-I pattern, a pattern that is poorly responsive to lithium, which eventually degenerates into RC. Again, this sequence might be mediated by the high prevalence of cyclothymia in bipolar II patients. Thus, data from phenomenology, family history, and long-term outcome do not support RC as a separate entity. RC appears to be a temporary complicated phase in the illness, not a stable feature. This was noted by Kraepelin: I think I am convinced that that kind of classification must of necessity wreck on the irregularity of the disease. The kind and duration of the attacks and the intervals by no means remain the same in the individual case but may frequently change, so that the case must be reckoned always to new forms. Data by Gottschalk et al testify to the chaotic mood swings of contemporary bipolar disorder. Moreover RC is seen in other medical diseases, such as epilepsy, in which patients have phases of increase in frequency of episodes (seizures) that become refractory to treatment. Further longitudinal prospective studies are required to understand the complexity of this intriguing phenomenon and to provide better treatments. Algorithms deriving from tertiary research or university-based clinical experience may not generalize to RC or otherwise treatment-resistant bipolar patients seen in more routine practice. Illness severity in RCBD generally precludes double-blind controlled investigations. Meanwhile, clinicians may rely on discontinuing antidepressants, maintaining patients on combined mood stabilizers--of which valproate is probably the most useful--and making judicious use of atypical neuroleptics. Benzodiazepines and alcohol (which produce withdrawal), caffeine, stimulants, exposure to bright light, and sleep deprivation during excited phases should be avoided. Thyroid and nimodipine augmentation can be considered in those with the most malignant course. These are patients who need the maximal support that their psychiatrist can provide them. Office visits must be arranged as the last appointment of the day." [Abstract]

Ashman SB, Monk TH, Kupfer DJ, Clark CH, Myers FS, Frank E, Leibenluft.
Relationship between social rhythms and mood in patients with rapid cycling bipolar disorder.
Psychiatry Res 1999 Apr 19;86(1):1-8
"Disruptions in the sleep-wake cycle frequently characterize affective illness and have led to a number of theories linking sleep-wake and/or circadian rhythm disturbance to affective illness. Recently, researchers have expanded these chronobiological theories to include the role of lifestyle regularity, or daily social rhythms. In this study, the Social Rhythm Metric (SRM) was used to explore the relationship between social rhythms and mood in patients with rapid cycling bipolar disorder and to compare the social rhythms of patients with those of healthy control subjects. Patients' SRM scores and activity level indices were significantly lower than those of control subjects. In addition, the timing of five, mostly morning, activities was phase delayed in patients compared to control subjects. Patients also demonstrated a phase delay in the timing of morning activities during depression compared to hypomania or euthymia. The phase changes in the timing of morning activities are consistent with other data implicating morning zeitgebers in the pathophysiology of rapid cycling bipolar disorder." [Abstract]

Kirov G, Murphy KC, Arranz MJ, Jones I, McCandles F, Kunugi H, Murray RM, McGuffin P, Collier DA, Owen MJ, Craddock N.
Low activity allele of catechol-O-methyltransferase gene associated with rapid cycling bipolar disorder.
Mol Psychiatry 1998 Jul;3(4):342-5
"Catechol-O-methyltransferase (COMT) plays a major role in the breakdown of catecholamines. An amino acid polymorphism (val-108-met) determines high and low activity of the enzyme. A recent study in a small sample of patients with velo-cardio-facial syndrome who had bipolar affective disorder suggested that the Met (low activity) COMT allele might be associated with rapid-cycling in this population. We therefore tested the hypothesis that the Met allele might be associated with rapid cycling bipolar disorder in the wider population. We studied a sample of British Caucasian DSM-IV bipolar patients, of whom 55 met criteria for rapid cycling at some time during the illness and 110 met stringent criteria for a definite non-rapid cycling course. The COMT genotype was determined using a PCR assay. The low activity allele was more frequent in the group of rapid cyclers: 0.55 vs 0.42 (one-tailed chi 2 = 5.12, d.f. = 1, P = 0.012), and bearers of low activity alleles showed a dose-dependent increased risk of lifetime occurrence of rapid cycling: chi 2 test of linear association = 4.84, d.f. = 1, P = 0.014. Our data support the hypothesis that variation in the COMT gene modifies the course of bipolar disorder." [Abstract]

Papolos DF, Veit S, Faedda GL, Saito T, Lachman HM.
Ultra-ultra rapid cycling bipolar disorder is associated with the low activity catecholamine-O-methyltransferase allele.
Mol Psychiatry 1998 Jul;3(4):346-9 [Abstract]

OMIM - Online Mendelian Inheritance in Man: COMT
[Catechol-O-methyltransferase has been located at 22q11.2]

Rotondo, Alessandro, Mazzanti, Chiara, Dell'Osso, Liliana, Rucci, Paola, Sullivan, Patrick, Bouanani, Siham, Gonnelli, Chiara, Goldman, David, Cassano, Giovanni B.
Catechol O-Methyltransferase, Serotonin Transporter, and Tryptophan Hydroxylase Gene Polymorphisms in Bipolar Disorder Patients With and Without Comorbid Panic Disorder
Am J Psychiatry 2002 159: 23-29
"OBJECTIVE: Genetic epidemiologic and clinical data suggest that comorbid panic disorder may define a subtype of bipolar disorder. Comorbid panic disorder might thereby influence the strength of association between bipolar disorder and genes that have been implicated in bipolar disorder on the basis of their function in monoamine neurotransmission and previously reported linkage results. Polymorphic markers at catechol O-methyltransferase (COMT), serotonin transporter (5-HTT), and tryptophan hydroxylase (TPH) genes were analyzed in a case-control association study of bipolar disorder patients with or without lifetime panic disorder. METHOD: Unrelated subjects of Italian descent meeting DSM-III-R criteria for lifetime bipolar disorder (N=111), with (N=49) or without (N=62) comorbid lifetime panic disorder, were compared to 127 healthy subjects. DNA was extracted from blood leukocytes. The frequencies of COMT Val158Met, 5-HTTLPR, and TPH IVS7+218C>A polymorphisms were determined. Genotype and allele frequency comparisons between affected (bipolar disorder, bipolar disorder without panic disorder, or bipolar disorder with panic disorder) and unaffected individuals were carried out with chi-square tests or Fisher’s exact tests. RESULTS: Relative to the comparison subjects, subjects with bipolar disorder without panic disorder, but not those with comorbid bipolar disorder and panic disorder, showed significantly higher frequencies of the COMT Met158 and the short 5-HTTLPR alleles and genotypes. The differences in the frequencies of the TPH IVS7+218A alleles and genotypes approached statistical significance. CONCLUSIONS: The findings support the hypothesis that comorbid panic disorder identifies a genetic subtype of bipolar disorder and suggest a role for COMT and 5-HTT in vulnerability to these disorders." [Abstract]

MacKinnon DF, Zandi PP, Gershon ES, Nurnberger JI Jr, DePaulo JR Jr.
Association of rapid mood switching with panic disorder and familial panic risk in familial bipolar disorder.
Am J Psychiatry. 2003 Sep;160(9):1696-8.
"OBJECTIVE: Comorbid bipolar and panic disorders aggregate in families. A phenotypic trait shared by both disorders is the sudden shift in affect observed in panic attacks and some rapid cycling states. The authors investigated whether comorbidity of bipolar disorder and panic disorder is associated with rapid mood switching in families with a high rate of bipolar disorder. METHOD: Six hundred six subjects with bipolar disorder from the NIMH Bipolar Disorder Genetics Initiative were included in the study. Logistic regression analysis was used to analyze rapid mood switching as a function of panic disorder diagnosis, sex, and familial risk for panic. RESULTS: Familial panic and the diagnosis of panic disorder in an individual subject increased the odds for rapid mood switching. The familial effect persisted when individuals with panic disorder were excluded from the analysis. CONCLUSIONS: Panic and rapid mood switching occurring together in familial bipolar disorder may define a useful subphenotype for future studies." [Abstract]

Cusin C, Serretti A, Lattuada E, Lilli R, Lorenzi C, Mandelli L, Pisati E, Smeraldi E.
Influence of 5-HTTLPR and TPH variants on illness time course in mood disorders.
J Psychiatr Res 2001 Jul-Aug;35(4):217-23
"The aim of our study was to investigate gene variants in the long-term outcome of mood disorders. We retrospectively studied a sample of inpatients affected by recurrent and rapid cycling mood disorders. The serotonin transporter gene-linked functional polymorphic region (5-HTTLPR) and the A218C tryptophan hydroxylase (TPH) gene variant were determined using a PCR-based technique. For 5-HTTLPR polymorphism we genotyped 435 inpatients affected by major depressive (n=153), bipolar (n=213) and rapid cycling (n=69) mood disorders and 456 controls; for TPH we genotyped 399 inpatients (MD, n=132; BP, n=203; rapid cycling n=64) and 259 controls. Random Regression Model analysis was used to investigate the longitudinal time course of the illness. 5-HTTLPR and TPH polymorphisms were not associated with mood disorders time course. However we observed an excess of 5-HTTLPR*long alleles among rapid cycling subjects compared to both controls (P=0.018) and remitting mood disorders (P=0.006). TPH frequencies did not differ between mood disorders subtypes. Our results suggest that 5-HTTLPR variants may confer a susceptibility toward rapid cycling mood disorders." [Abstract]

Rousseva A, Henry C, Van Den Bulke D, Fournier G, Laplanche JL, Leboyer M, Bellivier F, Aubry JM, Baud P, Boucherie M, Buresi C, Ferrero F, Malafosse A.
Antidepressant-induced mania, rapid cycling and the serotonin transporter gene polymorphism.
Pharmacogenomics J 2003;3(2):101-4
"The genes involved in the serotonin system are major candidates in association studies on affective disorders and responses to antidepressants. We studied a functional polymorphism of the serotonin transporter (5-HTT) gene (a 44 bp insertion/deletion in the 5-HTT-linked polymorphic region (5-HTTLPR)) and lifetime history of antidepressant-induced mania (AIM) in a population of 305 patients with bipolar affective disorder. AIM was defined using a broad definition and a restrictive definition. No association was found between the 's' allele of the 5-HTTLPR and AIM for either definition. However, we found an association between the 5-HTTLPR and lifetime history of rapid cycling in a subsample of patients (for allele and genotype distributions: exact probability, p=0.0009 and chi(2)=9.4; df=1; p=0.002, respectively). These results may help to explain the conflicting association results obtained with the 5-HTT gene polymorphism, in particular with AIM. Indeed, the precise phenotype associated with the 5-HTT gene is unclear. The association between the 's' allele and rapid cycling may provide further evidence for an association between the 5-HTTLPR 's' allele and a pattern of affective instability." [Abstract]

Mannisto, Pekka T., Kaakkola, Seppo
Catechol-O-methyltransferase (COMT): Biochemistry, Molecular Biology, Pharmacology, and Clinical Efficacy of the New Selective COMT Inhibitors
Pharmacol Rev 1999 51: 593-628 [Full Text]

Graf WD, Unis AS, Yates CM, Sulzbacher S, Dinulos MB, Jack RM, Dugaw KA, Paddock MN, Parson WW.
Catecholamines in patients with 22q11.2 deletion syndrome and the low-activity COMT polymorphism.
Neurology 2001 Aug 14;57(3):410-6
"In patients with the 22q11.2 deletion syndrome and low-activity COMT, controlled studies of pharmacologic agents that decrease catecholamine production, block presynaptic catecholamine storage, or enhance S-adenosylmethionine, the cosubstrate of COMT, are warranted." [Abstract]

Kunugi H, Vallada HP, Sham PC, Hoda F, Arranz MJ, Li T, Nanko S, Murray RM, McGuffin P, Owen M, Gill M, Collier DA.
Catechol-O-methyltransferase polymorphisms and schizophrenia: a transmission disequilibrium study in multiply affected families.
Psychiatr Genet 1997 Autumn;7(3):97-101
"Catechol-O-methyltransferase (COMT) metabolizes catecholamines such as dopamines, noradrenaline and adrenaline. It exists as common high and low activity alleles in the population (determined by a valine 158 methionine polymorphisms), and high red blood cell activity of COMT has previously been associated with schizophrenia. To examine the relationship between COMT and schizophrenia genetically, the transmission disequilibrium test was performed on 22 multiply affected Caucasian and Japanese families genotyped for val158met and a second, silent, polymorphism (C256G), using PCR based assays. The high activity val158 allele was transmitted from parents to the affected individuals more frequently than the low activity met158 allele, although this was not statistically significant. Combining this data with a previous study using Chinese family trios with schizophrenia (Li et al., 1996) gave a highly significant result (p = 0.0015). The G256 allele was also transmitted preferentially to the affected offspring, and this was statistically significant when schizophrenia, schizoaffective disorder and unspecified functional psychosis were included in the definition of the affected phenotype (p = 0.03). Overall, these findings may indicate an effect of COMT alleles on susceptibility to schizophrenia, or reflect linkage disequilibrium with a different causative polymorphism in the vicinity. Other reported associations of COMT with obsessive compulsive and rapid cycling bipolar disorder indicate that the COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders." [Abstract]

Lachman HM, Morrow B, Shprintzen R, Veit S, Parsia SS, Faedda G, Goldberg R, Kucherlapati R, Papolos DF.
Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome.
Am J Med Genet 1996 Sep 20;67(5):468-72
"Velo-cardio-facial-syndrome (VCFS) is a common congenital disorder associated with typical facial appearance, cleft palate, cardiac defects, and learning disabilities. The majority of patients have an interstitial deletion on chromosome 22q11. In addition to physical abnormalities, a variety of psychiatric illnesses have been reported in patients with VCFS, including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. The psychiatric manifestations of VCFS could be due to haploin-sufficiency of a gene(s) within 22q11. One candidate that has been mapped to this region is catechol-O-methyltransferase (COMT). We recently identified a polymorphism in the COMT gene that leads to a valine-->methionine substitution at amino acid 158 of the membrane-bound form of the enzyme. Homozygosity for COMT158met leads to a 3-4-fold reduction in enzymatic activity, compared with homozygotes for COMT158val. We now report that in a population of patients with VCFS, there is an apparent association between the low-activity allele, COMT158met, and the development of bipolar spectrum disorder, and in particular, a rapid-cycling form." [Abstract]

Mannisto, Pekka T., Kaakkola, Seppo
Catechol-O-methyltransferase (COMT): Biochemistry, Molecular Biology, Pharmacology, and Clinical Efficacy of the New Selective COMT Inhibitors
Pharmacol Rev 1999 51: 593-628 [Full Text]

Huotari M, Gogos JA, Karayiorgou M, Koponen O, Forsberg M, Raasmaja A, Hyttinen J, Mannisto PT.
Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice.
Eur J Neurosci 2002 Jan;15(2):246-56
"Catechol-O-methyltransferase (COMT) catalyses the O-methylation of compounds having a catechol structure and its main function involves the elimination of biologically active or toxic catechols and their metabolites. By means of homologous recombination in embryonic stem cells, a strain of mice has been produced in which the gene encoding the COMT enzyme is disrupted. We report here the levels of catecholamines and their metabolites in striatal extracellular fluid in these mice as well as in homogenates from different parts of the brain, under normal conditions and after acute levodopa administration. In immunoblotting studies, COMT-knockout mice had no COMT protein in brain or kidney tissues but the amounts of catecholamine synthesizing and other metabolizing enzyme proteins were normal. Under normal conditions, COMT deficiency does not appear to affect significantly brain dopamine and noradrenaline levels in spite of relevant changes in their metabolites. This finding is consistent with previous pharmacological studies with COMT inhibitors and confirms the pivotal role of synaptic reuptake processes and monoamine oxidase-dependent metabolism in terminating the actions of catecholamines at nerve terminals. In contrast, when COMT-deficient mice are challenged with l-dihydroxyphenylalanine, they show an extensive accumulation of 3,4-dihydroxyphenylacetic acid and dihydroxyphenylglycol and even dopamine, revealing an important role for COMT under such situations. Notably, in some cases these changes appear to be Comt gene dosage-dependent, brain-region specific and sexually dimorphic. Our results may have implications for improving the treatment of Parkinson's disease and for understanding the contribution of the natural variation in COMT activity to psychiatric phenotypes." [Abstract]

Karhunen T, Tilgmann C, Ulmanen I, Panula P.
Neuronal and non-neuronal catechol-O-methyltransferase in primary cultures of rat brain cells.
Int J Dev Neurosci 1995 Dec;13(8):825-34
"Previous biochemical and histochemical studies have suggested that catechol-O-methyltransferase (COMT) is a predominantly glial enzyme in the brain. The aim of this work was to study its localization and molecular forms in primary cultures, where cell types can be easily distinguished with specific markers, COMT immunoreactivity was studied in primary astrocytic cultures from newborn rat cerebral cortex, and in neuronal cultures from rat brain from 18-day-old rat embryos using antisera against rat recombinant COMT made in guinea pig. Double-staining studies with specific cell markers to distinguish astrocytes, neurons and oligodendrocytes were performed. COMT immunoreactivity colocalized with a specific oligodendrocyte marker galactocerebroside in cells displaying oligodendrocyte morphology, flat cells displaying type-1 astrocyte morphology and glial fibrillary acidic protein, in branched cells displaying type-2 astrocyte morphology and in cell bodies of neurons, the processes of which displayed neurofilament immunoreactivity. Western blots detected both soluble 24 kDa and membrane-bound 28-kDa COMT proteins in neuronal and astrocyte cultures. The results suggest that COMT is synthesized by cultured astrocytes, oligodendrocytes and neurons." [Abstract]

Khromova I, Voronina T, Kraineva VA, Zolotov N, Mannisto PT.
Effects of selective catechol-O-methyltransferase inhibitors on single-trial passive avoidance retention in male rats.
Behav Brain Res 1997 Jun;86(1):49-57
"The effects of new selective catechol-O-methyltransferase (COMT) inhibitors entacapone (mainly peripheral effect) and tolcapone (acting also in the brain) on normal and impaired cognitive functions were studied in aversively motivated inhibitory avoidance using a single-trial passive avoidance paradigm in young adult rats. Passive avoidance retention latency was shortened by either scopolamine (1.0 mg/kg) or bilateral lesions to nucleus basalis magnocellularis (NBM) caused by infusions of ethylcholine aziridinium (AF64A). Entacapone (30 mg/kg) administered once before training or before the retention test, 24 h after training, prevented the effect of scopolamine but did not alter extinction in these rats. However, entacapone (30 mg/kg) prolonged lag time when given during the extinction process to intact rats after training. Tolcapone administered once before training (10 mg/kg) counteracted the effect of scopolamine. It prolonged retention latency of the intact rats when given after training (10 mg/kg). Tolcapone (3 mg/kg) also prolonged lag time when given during extinction to rats bearing NBM lesions. The effect of scopolamine on extinction and retrieval was not prevented by tolcapone. Only entacapone improved memory storage. Collectively, the present results indicate that COMT inhibitors prolong retention latencies in a single-trial passive avoidance test assessed at several memory phases." [Abstract]

Joseph A. Gogos, Maria Morgan, Victoria Luine, Miklos Santha, Sonoko Ogawa, Donald Pfaff, and Maria Karayiorgou
Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior
PNAS 95: 9991-9996, 1998.
"Catechol-O-methyltransferase (COMT) is one of the major mammalian enzymes involved in the metabolic degradation of catecholamines and is considered a candidate for several psychiatric disorders and symptoms, including the psychopathology associated with the 22q11 microdeletion syndrome. By means of homologous recombination in embryonic stem cells, a strain of mice in which the gene encoding the COMT enzyme has been disrupted was produced. The basal concentrations of brain catecholamines were measured in the striatum, frontal cortex, and hypothalamus of adult male and female mutants. Locomotor activity, anxiety-like behaviors, sensorimotor gating, and aggressive behavior also were analyzed. Mutant mice demonstrated sexually dimorphic and region-specific changes of dopamine levels, notably in the frontal cortex. In addition, homozygous COMT-deficient female (but not male) mice displayed impairment in emotional reactivity in the dark/light exploratory model of anxiety. Furthermore, heterozygous COMT-deficient male mice exhibited increased aggressive behavior. Our results provide conclusive evidence for an important sex- and region-specific contribution of COMT in the maintenance of steady-state levels of catecholamines in the brain and suggest a role for COMT in some aspects of emotional and social behavior in mice." [Full Text]

MacKinnon DF, Zandi PP, Gershon E, Nurnberger JI Jr, Reich T, DePaulo JR.
Rapid switching of mood in families with multiple cases of bipolar disorder.
Arch Gen Psychiatry. 2003 Sep;60(9):921-8.
"BACKGROUND: Heterogeneity within the diagnostic construct of bipolar disorder is most likely an obstacle to discovering its causes. Phenomena in the bipolar spectrum, including rapid cycling, cyclothymia, and affective instability of borderline personality, may be important markers of etiologic heterogeneity. Rapid switching of mood may be central to these phenomena. METHODS: We performed a case-control study, using diagnostic data from a multisite bipolar disorder linkage study, to explore clinical and demographic factors potentially related to rapid switching in bipolar disorder. Participants were 18 years or older and members of a family in which 2 or more first-degree relatives had bipolar disorder. Of 718 individuals interviewed and diagnosed as having bipolar disorder, 603 gave sufficient information about rapid switching and thus constituted the study group (60% female; mean age, 41 years; and mean education level, 13.8 years). RESULTS: Rapid switching of mood was reported by 44% of interviewees and was associated with early age at onset of bipolar disorder, higher risk of anxiety and substance abuse or dependence comorbidity, suicide attempts, antidepressant drug use, and having a relative with rapid switching. CONCLUSIONS: Rapid switching is associated with a complex clinical course of bipolar disorder. These results extend previous associations among rapid switching, anxiety, substance abuse, and early onset of bipolar disorder to a family study population. Rapid switching of mood seems to be the core phenomenon behind several variants of non-DSM-IV rapid cycling, DSM-III-R mixed states, and borderline personality disorder and the link connecting comorbidity, suicide, and early onset of bipolar disorder. Further biological investigation of the rapid-switching phenomenon is justified on epidemiologic grounds." [Abstract]

Dittmann S, Biedermann NC, Grunze H, Hummel B, Scharer LO, Kleindienst N, Forsthoff A, Matzner N, Walser S, Walden J.
The Stanley Foundation Bipolar Network: results of the naturalistic follow-up study after 2.5 years of follow-up in the German centres.
Neuropsychobiology. 2002;46 Suppl 1:2-9.
"The Stanley Foundation Bipolar Network (SFBN) is an international, multisite network investigating the characteristics and course of bipolar disorder. Methods (history, ratings and longitudinal follow-up) are standardized and equally applied in all 7 centres. This article describes demographics and illness characteristics of the first 152 German patients enrolled in the SFBN as well as the results of 2.5 years of follow-up. Patients in Germany were usually enrolled after hospitalisation. More than 72% of the study population suffered from bipolar I disorder and 25% from bipolar II disorder. The mean +/- SD age of the study participants was 42.08 +/- 13.5 years, and the mean +/- SD age of onset 24.44 +/- 10.9 years. More than 40% of the sample reported a rapid-cycling course in history, and even more a cycle acceleration over time. 37% attempted suicide at least once. 36% had an additional Axis I disorder, with alcohol abuse being the most common one, followed by anxiety disorders. During the follow-up period, only 27% remained stable, 56% had a recurrence, 12.8% perceived subsyndromal symptoms despite treatment and regular visits. 27% suffered from a rapid-cycling course during the follow-up period. Recurrences were significantly associated with bipolar I disorder, an additional comorbid Axis I disorder, rapid cycling in history, a higher number of mood stabilizers and the long-term use of typical antipsychotics. Rapid cycling during follow-up was only associated with a rapid-cycling course in history, a higher number of mood stabilizers and at least one suicide attempt in history." [Abstract]

Tondo L, Hennen J, Baldessarini RJ.
Rapid-cycling bipolar disorder: effects of long-term treatments.
Acta Psychiatr Scand. 2003 Jul;108(1):4-14.
"OBJECTIVE: To compare responses to long-term treatment of rapid-cycling (RC) vs. non-RC bipolar disorder patients and assess relative effectiveness of specific agents in RC patients. METHOD: Studies identified by literature searching were analyzed for effects of RC status and treatment-type on clinical outcome (recurrence or non-improvement per exposure-time), using random-effects methods to estimate pooled rates and their 95% CI for quantitative meta-analytic modeling. RESULTS: Data were obtained from 16 reports with 25 trial-arms involving 1856 (905 RC and 951 non-RC) patients treated with carbamazepine, lamotrigine, lithium, topiramate, or valproate, alone or with other agents over an average of 47.5 months (7347 total patient-years). Estimated RC prevalence was 15.4%. Crude rates (%/month) of recurrence (2.31/1.20) and clinical non-improvement (1.93/0.49) averaged 2.9-fold greater in RC vs. non-RC subjects. The pooled RC/non-RC risk ratio (RR) for inferior treatment-response (in 13 direct comparisons) was 1.40 (CI 1.26-1.56; P < 0.0001). Pooled crude recurrence and non-improvement rates suggested no clear advantage for any treatment, nor superiority for anticonvulsants over lithium. However, only lithium vs. carbamazepine could be directly compared (in four treatment-arms) meta-analytically in RC patients (RR = 0.93, CI 0.74-1.18, indicating no difference in effectiveness). CONCLUSION: As expected, RC was associated with lower effectiveness of all treatments evaluated. Direct comparisons of specific treatment alternatives for RC patients were rare, and provided no secure evidence of superiority of any treatment. Additional long-term studies comparing RC/non-RC patients randomized to specific treatments are required." [Abstract]

Feldman-Naim S, Turner EH, Leibenluft E.
Diurnal variation in the direction of mood switches in patients with rapid-cycling bipolar disorder.
J Clin Psychiatry 1997 Feb;58(2):79-84
"BACKGROUND: We assessed diurnal variation in the direction of mood switches in a sample of outpatients with rapid-cycling bipolar disorder who were on stable medication regimens. We predicted that patients would be more likely to switch from depression into mania or hypomania during the daytime hours and from mania/hypomania into depression overnight. METHOD: Fifteen patients with rapid-cycling bipolar disorder completed self-rated mood scales twice a day: once shortly after awakening and once at bedtime. Using 3 months of data for each patient, we performed categorical analyses (McNemar chi-square) to study the direction of mood switches between each day's morning and evening rating and between each evening rating and the subsequent morning rating. RESULTS: As predicted, switches that occurred between the morning and evening ratings were more likely to be from depression into mania/ hypomania or euthymia (64.3%) than in the opposite direction (35.6%; p < .0001). Similarly, switches that occurred between the evening rating and the next morning's ratings were more likely to be from mania/hypomania or euthymia into depression (64.8%) than in the opposite direction (35.2%; p < .0001). CONCLUSION: Extended wakefulness, exposure to light, increased activity, and/or endogenous rhythms could contribute to the elevation of mood during the course of the day. Sleep, darkness, reduced activity, and/or endogenous rhythms could contribute to the tendency to switch into depression overnight. Clinicians should attend to the time of day that clinical assessments are performed in patients with rapid-cycling bipolar disorder. Potential therapeutic implications include the use of light or activity during depression and use of induced sleep or exposure to darkness during mania/hypomania." [Abstract]

Calabrese JR, Shelton MD, Rapport DJ, Kujawa M, Kimmel SE, Caban S.
Current research on rapid cycling bipolar disorder and its treatment.
J Affect Disord 2001 Dec;67(1-3):241-55
"Rapid cycling is a pattern of presentation of bipolar disorder that specifies the course of the illness and is associated with a greater morbidity. The validity of rapid cycling as a distinct course modifier for bipolar disorder has been demonstrated and the term has been incorporated into the DSM-IV. The phenomenon of rapid cycling tends to appear late in the course of the disorder, occurs more frequently among females, and is more frequently seen in patients with bipolar type II disorder. Stimulants such as cocaine may also play some role in rapid-cycling. It is generally accepted that a recent history of rapid cycling predicts non-response to monotherapy with lithium and probably carbamazepine as well; however it is also possible that concurrent use of antidepressants may play a role in destabilizing the illness course under these agents. Thus, clinical considerations suggest that discontinuing antidepressants may facilitate the recovery process. Among clinically available monotherapies, valproate and lamotrigine appear to be the most useful clinically. However, other treatments such as lithium, carbamazepine, the atypical antipsychotic agents, thyroid hormone, and bupropion are frequently needed augmentation strategies. Electroconvulsive therapy may also prove efficacious in selected cases. The present paper provides a critical review of the evidence for the foregoing clinical issues in rapid cycling." [Abstract]

Benazzi F.
Is 4 days the minimum duration of hypomania in bipolar II disorder?
Eur Arch Psychiatry Clin Neurosci 2001;251(1):32-4
"DSM-IV requires that bipolar II disorder has hypomania with a minimum duration of 4 days, a cutoff not based on data. The study aim was to test if hypomania lasting 2 to 3 days could identify a group of bipolar II with typical clinical features of bipolar disorders. Consecutively, 65 unipolar and 103 bipolar II major depressive episode (MDE) outpatients were interviewed with the Structured Clinical Interview for DSM-IV. Almost all had had 2 to 3 days of hypomania, and all had had more than one hypomania. Typical clinical variables distinguishing bipolar from unipolar disorders (age at onset, atypical features, and recurrences) were compared. Bipolar II had significantly lower age at onset, more recurrences, and more atypical features. Findings suggest that hypomania lasting 2 to 3 days may identify a bipolar II group having typical features of bipolar disorders." [Abstract]

Dubovsky SL.
Rapid cycling bipolar disease: new concepts and treatments.
Curr Psychiatry Rep 2001 Dec;3(6):451-62
"Having been recognized by Kraeplin at the beginning of the 20th century, rapid cycling was first described as a specific entity by Dunner et al. in 1974. The prevalence of rapid cycling ranges from 12% to 20% in patients with bipolar disorder who are not selected for a high rate of cycling." [Abstract]

Serretti A, Mandelli L, Lattuada E, Smeraldi E.
Rapid cycling mood disorder: Clinical and demographic features.
Compr Psychiatry 2002 Sep-Oct;43(5):336-43
"Rapid cycling bipolar disorder is defined as four or more illness episodes per year. We compared demographic, clinical, and symptomatological features of subjects with rapid cycling bipolar disorder (RC) and those with non-rapid-cycling bipolar disorder (NR). Five hundred ninety-five subjects (RC = 275, NR = 320), were included in the study. Subjects were assessed using the Operational Criteria for Psychotic Illness checklist (OPCRIT, n = 496), the Hamilton Rating Scale for Depression (HAMD, n = 47), the Social Adjustment Scale (SAS, n = 160), and the Self-Esteem Scale (SES, n = 160). RC were older at the time of assessment and with more medical illnesses. RC showed a lower risk for psychotic and disorganised features, particularly within bipolar I disorder. Finally, bipolar I RC showed a lower risk for violent suicide attempt. Our findings suggest that rapid cycling bipolar disorder is a condition chacterized by less severe psychotic and suicidal features, particularly within bipolar I disorder. Copyright 2002, Elsevier Science (USA). All rights reserved." [Abstract]

Amann B, Stampfer R, Schmidt F, Mikhaiel P, Hummel B, Sterr A, Schafer M, Grunze H.
[Clinical relevance and treatment possibilities of rapid cycling in patients with bipolar disorder]
Fortschr Neurol Psychiatr 2001 Dec;69(12):569-80
"In the actual version of the WHO diagnostic guidelines, the ICD-10, subtypes of bipolar disorder are not specified, in contrast to the American DSM-IV, where bipolar disorder has already been differentiated in bipolar I (severe manic and depressive episodes) and bipolar II disorder (depressive and hypomanic episodes). Furthermore, aspects of the longitudinal course of the illness, like rapid cycling (RC), are reflected as well. Rapid cycling is defined as four or more affective episodes within one year of the illness. It has been postulated that rapid cycling is related with a poor response to lithium, to the same extent as mixed episodes or an atypical onset (depressive episode first) of the disease. Here, the current status of alternative pharmacological and supportive therapy of rapid cycling is presented and discussed. Furthermore, the article also displays biological parameters associated with rapid cycling like higher prevalence in women, hypothyreoidism, subtype of bipolar disorder, COMT-allele, influence of sleep or risk of antidepressant induced cycling." [Abstract]

Avasthi A, Sharma A, Malhotra S, Gupta N, Kulhara P, Malhotra S.
Rapid cycling affective disorder: a descriptive study from North India.
J Affect Disord 1999 Jul;54(1-2):67-73
"A series of 33 (4.29%) cases of rapid cycling affective disorder (RCAD ICD-10-DCR) out of a pool of 770 consecutive cases of ICD-10 affective disorder (AD) was collected over a period of 5 years. All cases of RCAD belonged to bipolar affective disorder. RCAD when compared with non-rapid cycling bipolar affective disorder (BPAD) revealed a significantly longer mean duration of illness, greater number of total episodes, greater number of hospitalizations and stronger family loading of bipolar affective disorder. These findings implicate RCAD as a severe form of bipolar affective disorder." [Abstract]

Ketter TA, Kimbrell TA, George MS, Dunn RT, Speer AM, Benson BE, Willis MW, Danielson A, Frye MA, Herscovitch P, Post RM.
Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder.
Biol Psychiatry 2001 Jan 15;49(2):97-109
"BACKGROUND: Functional brain imaging studies in unipolar and secondary depression have generally found decreased prefrontal cortical activity, but in bipolar disorders findings have been more variable. METHODS: Forty-three medication-free, treatment-resistant, predominantly rapid-cycling bipolar disorder patients and 43 age- and gender-matched healthy control subjects had cerebral glucose metabolism assessed using positron emission tomography and fluorine-18-deoxyglucose. RESULTS: Depressed bipolar disorder patients compared to control subjects had decreased global, absolute prefrontal and anterior paralimbic cortical, and increased normalized subcortical (ventral striatum, thalamus, right amygdala) metabolism. Degree of depression correlated negatively with absolute prefrontal and paralimbic cortical, and positively with normalized anterior paralimbic subcortical metabolism. Increased normalized cerebello-posterior cortical metabolism was seen in all patient subgroups compared to control subjects, independent of mood state, disorder subtype, or cycle frequency. CONCLUSIONS: In bipolar depression, we observed a pattern of prefrontal hypometabolism, consistent with observations in primary unipolar and secondary depression, suggesting this is part of a common neural substrate for depression independent of etiology. In contrast, the cerebello-posterior cortical normalized hypermetabolism seen in all bipolar subgroups (including euthymic) suggests a possible congenital or acquired trait abnormality. The degree to which these findings in treatment-resistant, predominantly rapid-cycling patients pertain to community samples remains to be established." [Abstract]

Gyulai L, Alavi A, Broich K, Reilley J, Ball WB, Whybrow PC.
I-123 iofetamine single-photon computed emission tomography in rapid cycling bipolar disorder: a clinical study.
Biol Psychiatry 1997 Jan 15;41(2):152-61
"The regional distribution of I-123 iofetamine (IMP) in the brain of 12 patients with rapid cycling bipolar disorder was studied by single-photon computed emission tomography imaging. Patients who were either medication free (n = 4) or on lithium monotherapy (n = 8) were assessed serially in depressed/dysphoric, manic/hypomanic, or euthymic states. In 23 imaging studies, IMP images of the brain were taken on a GE Starcam system 20 min after injection of 3-4 mCi of I-123 labeled IMP. The I-123 IMP distribution in the anterior part of the temporal lobes was asymmetric in both depression/dysphoria and mania/hypomania but not in euthymia. Images taken sequentially on the same patient showed temporal lobe asymmetry in the pathological mood states that diminished or disappeared in the euthymic state. The observed changes most likely reflect an altered cerebral blood flow and changes in high-affinity IMP binding to amine receptors in the temporal lobes. This pilot study suggests the presence of a state-dependent temporal dysfunction in bipolar disorder." [Abstract]

Baldessarini RJ, Tondo L, Floris G, Hennen J.
Effects of rapid cycling on response to lithium maintenance treatment in 360 bipolar I and II disorder patients.
J Affect Disord 2000 Dec;61(1-2):13-22
"INTRODUCTION: Rapid cycling (RC) in bipolar disorders is widely believed to predict future morbidity and poor treatment response, although empirical testing of its predictive utility remains limited. METHODS: In 360 DSM-IV bipolar I (N=218) and II (N=142) disorder subjects (64% women) followed over an average of 13.3 years, we evaluated factors associated with RC status with bivariate and multivariate techniques, and response to lithium maintenance treatment (recurrence rates, time ill, survival analysis of time to recurrence on lithium). RESULTS: RC risk (15.6% of cases) was 5. 1-times greater in bipolar II vs. I subjects (30.3%/6.0%), in minor excess in women vs. men (17.9%/11.5%), and associated with premorbid cyclothymia, depressive first episodes, older onset age, and being employed or married. Before lithium, RC vs. non-RC cases had more mean total (3.9/1.2), manic, and depressive episodes/year, and greater percent time ill (60%/38%). During treatment, prior RC status was unrelated to time to first recurrence and other measures of morbidity and improvement including percent time ill, although depressive episodes were 2.7-times more frequent, and there was 13.7% less chance of full protection from all recurrences in RC cases. Limitations: The study is naturalistic, without random assignment or blind assessment. CONCLUSIONS: The RC bipolar subtype was strongly associated with type II diagnosis, higher average prelithium episode frequency and percent time ill, and weakly with female sex, but not with greater overall morbidity during treatment." [Abstract]

Tondo L, Baldessarini RJ.
Rapid cycling in women and men with bipolar manic-depressive disorders.
Am J Psychiatry 1998 Oct;155(10):1434-6
"OBJECTIVE: This study investigated risks for rapid cycling, as defined by DSM-IV, in women and men with bipolar disorders. METHOD: The results of 10 studies with a total of 2,057 bipolar patients were meta-analyzed by pooled contingency methods. RESULTS: The proportions of women and men among rapid-cycling cases averaged 72% and 28%, respectively, but the risk of rapid cycling was inconsistently more frequent among women (29.6%) than among men (16.5%). The mean number of episodes per year was much higher in rapid-cycling patients before and during lithium treatment but was similar in rapid-cycling men and women. CONCLUSIONS: Rapid cycling was only moderately, and inconsistently, more common in bipolar women than men." [Abstract]

Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L.
Antidepressant-induced mania and cycle acceleration: a controversy revisited.
Am J Psychiatry 1995 Aug;152(8):1130-8
"OBJECTIVE: The longitudinal course of 51 patients with treatment-refractory bipolar disorder was examined to assess possible effects of heterocyclic antidepressants on occurrence of manic episodes and cycle acceleration. METHOD: Using criteria established from life charts, investigators rated the patients' episodes of mania or cycle acceleration as likely or unlikely to have been induced by antidepressant therapy. Discriminant function analyses were performed to assess predictors of vulnerability to antidepressant-induced mania or cycle acceleration. Further, the likelihood of future antidepressant-induced episodes in persons who had had one such episode was assessed. RESULTS: Thirty-five percent of the patients had a manic episode rated as likely to have been antidepressant-induced. No variable was a predictor of vulnerability to antidepressant-induced mania. Cycle acceleration was likely to be associated with antidepressant treatment in 26% of the patients assessed. Younger age at first treatment was a predictor of vulnerability to antidepressant-induced cycle acceleration. Forty-six percent of patients with antidepressant-induced mania, but only 14% of those without, also showed antidepressant-induced cycle acceleration at some point in their illness. CONCLUSIONS: Mania is likely to be antidepressant-induced and not attributable to the expected course of illness in one-third of treatment-refractory bipolar patients, and rapid cycling is induced in one-fourth. Antidepressant-induced mania may be a marker for increased vulnerability to antidepressant-induced cycle acceleration. Antidepressant-induced cycle acceleration (but not antidepressant-induced mania) is associated with younger age at first treatment and may be more likely to occur in women and in bipolar II patients." [Abstract]

Maj M, Pirozzi R, Formicola AM, Tortorella A.
Reliability and validity of four alternative definitions of rapid-cycling bipolar disorder.
Am J Psychiatry 1999 Sep;156(9):1421-4
"OBJECTIVE: This study tested the reliability and validity of four definitions of rapid cycling. METHOD: Two trained psychiatrists, using the Schedule for Affective Disorders and Schizophrenia, independently assessed 210 patients with bipolar disorder. They checked whether each patient met four definitions of rapid cycling: one consistent with DSM-IV criteria, one waiving criteria for duration of affective episodes, one waiving such criteria and requiring at least one switch from mania to depression or vice versa during the reference year, and one waiving duration criteria and requiring at least 8 weeks of fully symptomatic affective illness during the reference year. The interrater reliability was calculated by Cohen's kappa statistic. Patients who met each definition according to both psychiatrists were compared to those who did not meet any definition (nonrapid-cycling group) on demographic and clinical variables. All patients were followed up for 1 year. RESULTS: Kappa values were 0.93, 0.73, 0.75, and 0.80, respectively, for the four definitions of rapid cycling. The groups meeting the second and third definitions included significantly more female and bipolar II patients than did the nonrapid-cycling group. Those two groups also had the lowest proportion of patients with a favorable lithium prophylaxis outcome and the highest stability of the rapid-cycling pattern on follow-up. The four groups of rapid-cycling patients did not differ significantly among themselves on any of the assessed variables. CONCLUSIONS: The expression "rapid cycling" encompasses a spectrum of conditions. The DSM-IV definition, although quite reliable, covers only part of this spectrum, and the conditions that are excluded are very typical in terms of key validators and are relatively stable over time." [Abstract]

Wehr TA, Turner EH, Shimada JM, Lowe CH, Barker C, Leibenluft E.
Treatment of rapidly cycling bipolar patient by using extended bed rest and darkness to stabilize the timing and duration of sleep.
Biol Psychiatry 1998 Jun 1;43(11):822-8 [Abstract]

Leibenluft E, Albert PS, Rosenthal NE, Wehr TA.
Relationship between sleep and mood in patients with rapid-cycling bipolar disorder.
Psychiatry Res 1996 Jul 31;63(2-3):161-8
"The relationship between sleep and mood was examined in a longitudinal, naturalistic data set derived from out-patients with rapid-cycling bipolar disorder. Eleven patients completed daily self-ratings of mood and sleep logs for 18 months. Using logistic regression with autoregressive terms, we examined the effect of prior sleep (sleep duration, time of sleep onset, and time of wake onset) on the probability of being in a depressed, manic, or hypomanic episode on one or more subsequent days. Of the three sleep parameters, decreased sleep duration was the best predictor of mania or hypomania the next day, followed by wake onset time. The association between sleep duration and subsequent mood was less consistent for depression than for mania or hypomania. Four of the patients showed no relationship between mood and any of the sleep variables measured. These results reinforce the importance of monitoring, and perhaps controlling, sleep duration and wake onset time in at least some patients with rapid-cycling bipolar disorder." [Abstract]

Leibenluft E, Turner EH, Feldman-Naim S, Schwartz PJ, Wehr TA, Rosenthal NE.
Light therapy in patients with rapid cycling bipolar disorder: preliminary results.
Psychopharmacol Bull 1995;31(4):705-10
"Nine patients with rapid cycling bipolar disorder were treated with a total of 13 trials of bright light therapy in the morning (n = 5), evening (n = 3), or midday (n = 5). In each instance, the patient's mood ratings during 3 months of light therapy (added to a stable medication regimen) were compared to his or her mood ratings during 3 months on the same medication but without light treatment. Of the 3 light therapy schedules, only midday lights appeared to have beneficial clinical effects, improving mood ratings in 3 patients. In contrast, the morning light therapy trial was terminated prematurely in 3 patients because of clinical instability. Light treatment was better tolerated if patients discontinued it on days when they were hypomanic. The clinical and theoretical implications of these preliminary findings are discussed." [Abstract]

Lish JD, Gyulai L, Resnick SM, Kirtland A, Amsterdam JD, Whybrow PC, Price RA.
A family history study of rapid-cycling bipolar disorder.
Psychiatry Res 1993 Jul;48(1):37-46
"Previous studies have yielded mixed evidence as to whether rapid-cycling bipolar disorder (four or more episodes per year) is associated with a distinctive pattern of patient characteristics and familial aggregation of affective disorder. In this study, Family History Research Diagnostic Criteria (FH-RDC) were used to interview 165 patients with rapid-cycling bipolar disorder, non-rapid-cycling bipolar disorder, or recurrent unipolar depressive disorder about the psychiatric history of 812 adult first-degree relatives. In a validity study, FH-RDC diagnoses were demonstrated to agree reasonably well with best-estimate diagnoses by two psychiatrists/psychologists, based on direct interviews with the Structured Clinical Interview for DSM-III-R. Relatives of patients with recurrent unipolar depression were less likely to have bipolar disorder and more likely to have unipolar depression than were relatives of rapid-cycling or non-rapid-cycling bipolar patients. Rapid-cycling patients were younger and more likely to be female than non-rapid-cycling patients. The relatives of rapid cyclers did not differ significantly from those of non-rapid cyclers in the prevalence of bipolar disorder, unipolar disorder, rapid-cycling bipolar disorder, or substance abuse. However, there were nonsignificant trends for the relatives of rapid-cycling bipolar patients, compared with those of non-rapid-cycling bipolar patients, to have more substance abuse and less bipolar disorder given the presence of affective disorder." [Abstract]

Tiihonen J, Hallikainen T, Lachman H, Saito T, Volavka J, Kauhanen J, Salonen JT, Ryynanen OP, Koulu M, Karvonen MK, Pohjalainen T, Syvalahti E, Hietala J.
Association between the functional variant of the catechol-O-methyltransferase (COMT) gene and type 1 alcoholism.
Mol Psychiatry 1999 May;4(3):286-9
"Catechol-O-methyltransferase (COMT) is an enzyme which has a crucial role in the metabolism of dopamine. It has been suggested that a common functional genetic polymorphism in the COMT gene, which results in 3 to 4-fold difference in COMT enzyme activity, may contribute to the etiology of mental disorders such as bipolar disorder and alcoholism. Since ethanol-induced euphoria is associated with the rapid release of dopamine in limbic areas, it is conceivable that subjects who inherit the allele encoding the low activity COMT variant would have a relatively low dopamine inactivation rate, and therefore would be more vulnerable to the development of ethanol dependence. The aim of this study was to test this hypothesis among type 1 (late-onset) alcoholics. The COMT polymorphism was determined in two independent male late onset (type 1) alcoholic populations in Turku (n = 67) and Kuopio (n = 56). The high (H) and low (L) activity COMT genotype and allele frequencies were compared with previously published data from 3140 Finnish blood donors (general population) and 267 race- and gender-matched controls. The frequency of low activity allele (L) was markedly higher among the patients both in Turku (P = 0.023) and in Kuopio (P = 0.005) when compared with the general population. When all patients were compared with the general population (blood donors), the difference was even more significant (P = 0.0004). When genotypes of all alcoholics (n = 123) were compared with genotypes of matched controls, the odds ratio (OR) for alcoholism for those subjects having the LL genotype vs those with HH genotype was 2.51, 95% CI 1.22-5.19, P = 0.006. Also, L allele frequency was significantly higher among alcoholics when compared with controls (P = 0.009). The estimate for population etiological (attributable) fraction for the LL genotype in alcoholism was 13.3% (95% CI 2.3-25.7%). The results indicate that the COMT polymorphism contributes significantly to the development of late-onset alcoholism." [Abstract]

Geller B, Williams M, Zimerman B, Frazier J, Beringer L, Warner KL.
Prepubertal and early adolescent bipolarity differentiate from ADHD by manic symptoms, grandiose delusions, ultra-rapid or ultradian cycling.
J Affect Disord 1998 Nov;51(2):81-91
"BACKGROUND: In contrast to differential diagnosis (ddx) of older adolescent and adult bipolarity (BP), which includes schizophrenia and substance use disorders, the main ddx of prepubertal and early adolescent BP is attention-deficit disorder with hyperactivity (ADHD). To address this ddx issue, and to provide prepubertal mania manifestations, interim baseline data are presented from the National Institute of Mental Health (NIMH)-funded study 'Phenomenology and Course of Pediatric Bipolarity'. METHODS: Data are from the first 60 BP and the first 60 ADHD cases from 270 consecutively ascertained subjects (90 BP, 90 ADHD and 90 community controls). Comprehensive assessments included the Washington University at St. Louis Kiddie and Young Adult-Schedule for Affective Disorders and Schizophrenia--Lifetime and Present Episode Version-DSM-IV (WASH-U-KSADS) blindly administered by nurses to mothers about their offspring and to children/adolescents about themselves. Caseness was established by consensus conferences that included diagnostic and impairment data, teacher and school reports, agency records, videotapes and medical charts. RESULTS: Mean baseline age of BP cases was 11.0+/-2.7 years and the mean age at onset of BP was 8.1+/-3.5 years. Elated mood, grandiosity, hypersexuality, decreased need for sleep, racing thoughts and all other mania items except hyperenergetic and distractibility were significantly and substantially more frequent among BP than ADHD cases (e.g., elation: 86.7% BP vs. 5.0% ADHD; grandiosity: 85.0% BP vs. 6.7% ADHD). In the BP group, 55.0% had grandiose delusions, 26.7% had suicidality with plan/intent and 83.3% were rapid, ultra-rapid or ultradian cyclers. LIMITATIONS: Sites for consecutive case ascertainment from the lowest socioeconomic status classes were unavailable due to current health care policies. CLINICAL RELEVANCE: Prepubertal and early adolescent BP cases differentiate from ADHD by mania-specific criteria and commonly present with ultra-rapid or ultradian cycling." [Abstract]

Geller B, Cook EH Jr.
Ultradian rapid cycling in prepubertal and early adolescent bipolarity is not in transmission disequilibrium with val/met COMT alleles.
Biol Psychiatry 2000 Apr 1;47(7):605-9
"BACKGROUND: Prepubertal children and early adolescents with bipolar disorders (PEA-BP) who participate in the ongoing study "Phenomenology and Course of Pediatric Bipolar Disorders" have a high prevalence of ultradian (within 24-hour periods) rapid cycling. Based on a case-control finding reported in bipolar (BP) adults of an association between rapid and ultradian rapid cycling with the low-activity allele of catechol-O-methyltransferase (l-COMT), study of linkage and linkage disequilibrium of l-COMT in the PEA-BP population seemed warranted. METHODS: Genotypes on a subset of the larger PEA-BP sample, for whom trio blood collection was complete (i. e., probands and both of their biological parents), were used to perform transmission disequilibrium tests (TDTs). Diagnoses were established from a comprehensive battery that included WASH-U-KSADS (Washington University Kiddie Schedule for Affective Disorders and Schizophrenia) given to both mothers and children and from consensus conferences. Probands with PEA-BP (N = 52) were 10.9 +/- 2.8 years old at index episode; had a mean age of BP onset at 8.0 +/- 3.8 years; were severely impaired, with a mean Children's Global Assessment Scale score of 44.5 +/- 8.9; and manifested the cardinal features of BP (84.6% had euphoric mood, 76.9% had grandiosity, and 57.7% had psychosis). Ultradian rapid cycling occurred in 75%. Genotyping of the single nucleotide polymorphism at COMT was performed using automated capillary electrophoresis single-strand conformational polymorphism with detection by laser-induced fluorescence. RESULTS: Transmission disequilibrium tests were not significant for preferential transmission of l-COMT for the ultradian rapid-cycling subgroup or for the entire PEA-BP sample. CONCLUSIONS: The lack of linkage disequilibrium between l-COMT and ultradian rapid cycling in the PEA-BP sample compared to reported findings of an association in case-control studies of adults is discussed in terms of age-specific developmentally relevant phenotypes, anticipatory mechanisms, and heterogeneity. Repeat TDT analyses after these PEA-BP probands reach their adult phenotypes will be informative." [Abstract]

Kramlinger KG, Post RM.
Ultra-rapid and ultradian cycling in bipolar affective illness.
Br J Psychiatry 1996 Mar;168(3):314-23
"BACKGROUND. Rapid-cycling bipolar disorder is defined as four or more affective episodes yearly. The conventionally recognised limit in episode duration is usually considered 24 hours (i.e. a cycle duration of 48 hours). We report a small series of intensively observed bipolar patients who showed much faster patterns of mood oscillation. METHODS. Detailed, systematic, longitudinal assessment of five bipolar patients during extended in-patient psychiatric evaluation were conducted, including retrospective life charting and prospective evaluation of daily mood by self and blinded observer ratings, and motor activity recording. RESULTS. Our data demonstrate a spectrum of cycling frequencies in rapid-cyclers, including distinct, clinically robust mood shifts that occur at frequencies faster than once per 24 hours. Affective oscillations spanned a range of cycling frequencies from four episodes per year (rapid cycling) to those occurring within the course of weeks to several days (ultra-rapid cycling), to distinct, abrupt mood shifts of less than 24 hours duration (ultra-ultra rapid or ultradian cycling). The time of onset and duration of these ultradian affective fluctuations are highly variable and they are observed in bipolar patients without evidence of personality disorder. CONCLUSIONS. The potential clinical and theoretical implications of these first systematic observations of ultra-rapid and ultradian cycling in the context of the evolution of otherwise classical bipolar affective illness are discussed." [Abstract]

George MS, Huggins T, McDermut W, Parekh PI, Rubinow D, Post RM.
Abnormal facial emotion recognition in depression: serial testing in an ultra-rapid-cycling patient.
Behav Modif 1998 Apr;22(2):192-204
"Normal subjects use the right insula and bilateral anterior temporal and prefrontal cortices to recognize the emotion expressed in a human face. Mood disorder subjects have a selective deficit in recognizing human facial emotion. Brain imaging studies show that they fail to activate the right insula to the same degree as controls, even when accurately assessing facial emotion. Many issues remain, however, including whether the facial emotion recognition errors in mood disorder subjects are state dependent or persist during normal mood states (and, thus, reflect a trait abnormality). To probe this issue, we repeatedly studied a male bipolar II patient's ability to recognize faces' emotional content. This patient made significantly more errors in facial emotion recognition during the depressed state. He also demonstrated a significant negative bias when he was depressed compared with nondepressed states. This case study demonstrates the state dependency of the defect in human facial emotion recognition." [Abstract]

Murai T, Fujimoto S.
Rapid cycling bipolar disorder after left temporal polar damage.
Brain Inj. 2003 Apr;17(4):355-8.
"The case of a 48-year-old woman with rapid cycling bipolar disorder subsequent to a traumatic brain injury is reported. Both depressive and manic episodes had an average duration of approximately 1 month, alternating without stable euthymic periods. Neuroradiological examinations revealed a circumscribed lesion in the left temporal pole. After 1 year without treatment, psychiatric intervention and pharmacotherapy was initiated. Her mood swings were successfully treated with the co-administration of valproate and lithium. Case reports of rapid cycling bipolar disorder after traumatic brain injury are very rare and this case supports the idea that temporal polar dysfunction is a candidate for the neurobiological basis of rapid cycling bipolar disorder." [Abstract]