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Ultra-ultra rapid cycling bipolar disorder is associated with the low activity cate-cholamine-O-methyltransferase allele [In Process Citation]
Abstract
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.
... The Met (low activity) allele of cathecol-O-methyltransferase (COMT) gene has been more frequently found in rapid-cycling bipolar disorder patients than in bipolar subjects without rapid-cycling (Kirov et al., 1998). These findings were partially confirmed by another study that reported higher frequency of low-activity allele of COMT gene in ultra-ultra rapid-cycling bipolar patients, defined as patients with shifts of mood occurring within a 24-48 h period, than in rapid-cycling bipolar subjects (Papolos et al., 1998). In contrast, a subsequent research did not find a statistically significant difference in the frequency of lowactivity monoamine oxidase A alleles between ultra-rapid cyclers, defined as those having at least 8 mood episodes/year for 2 years, and non-rapid cyclers (Kirov et al., 1999). ...
... Topic Global Rating Wehr et al. (1988) Genetics (Family Study) 3 Coryell et al. (1992) Genetics (Family Study) 3 Lish et al. (1993) Genetics (Family Study) 3 Bauer et al. (1994) Genetics (Family Study) 3 Kirov et al. (1998) Genetics 2 Papolos et al. (1998) Genetics 2 Avasthi et al. (1999) Genetics (Family Study) 3 Kirov et al. (1999) Genetics 2 Note: ...
Rapid-cycling bipolar disorder represents a frequent severe subtype of illness which has been associated with poor response to pharmacological treatment. Aim of the present article is to provide an updated review of biological markers associated with rapid-cycling bipolar disorder. A research in the main database sources has been conducted to identify relevant papers about the topic. Rapid-cycling bipolar disorder patients seem to have a more frequent family history for bipolar spectrum disorders (d range: 0.44-0.74) as well as an increased susceptibility to DNA damage or mRNA hypo-transcription (d range: 0.78-1.67) than non rapid-cycling ones. A susceptibility to hypothyroidism, which is exacerbated by treatment with lithium, is possible in rapid-cycling bipolar disorder, but further studies are needed to draw definitive conclusions. Rapid-cycling bipolar patients might have more insuline resistance as well as more severe brain changes in frontal areas (d range: 0.82-0.94) than non rapid-cycling ones. Many questions are still open about this topic. The first is whether the rapid-cycling is inheritable or is more generally the manifestation of a severe form of bipolar disorder. The second is whether some endocrine dysfunctions (diabetes and hypothyroidism) predispose to rapid-cycling or rapid-cycling is the consequence of drug treatment or medical comorbidities (e.g. obesity).
... Studies have indicated that the Met 158 COMT allele influences pre-frontal cortex and limbic activity in response to aversive or emotionally-negative stimuli and to the endocrine response to stress [35,36]. A large number of evidence suggests that this polymorphism is associated with major depressive disorder (MDD) and bipolar depression [37][38][39][40][41][42][43][44][45] (Table 1). ...
... The low activity Met 158 allele of COMT has also been associated with an increased risk of breast cancer in postmenopausal women [78], but the role of the high and low activity COMT alleles in breast carcinogenesis may vary by menopausal status [79]. The COMT low activity Met 158 variant has been proposed as a risk factor for moderate, major and bipolar depression [26,37,39,40,44,45]. However, several case-control association studies of COMT alleles were negative [38,41,42] or distribution of the high activity Val 158 variant was significantly increased in MDD [43] (Table 1). ...
Objective:
The aim of the study was assessment of a possible relationship between the polymorphisms of the candidate genes participating in the etiology of some neurological and psychiatric disorders and the risk of depression in perimenopausal and postmenopausal women.
Methods:
A total of 167 (54 perimenopausal and 113 postmenopausal) Caucasian women from western Poland, aged 42-67, were recruited as the patient group in the study because of depressive symptoms, and another 321 healthy women (102 perimenopausal and 219 postmenopausal) served as the controls. All study participants were evaluated for climacteric and depressive disorders according to the Kupperman index and Hamilton rating scale for depression (HRSD), respectively. The following candidate genes were selected for the study: 5HTR2A, 5HTR1B, 5HTR2C, TPH1, TPH2, MAOA, COMT, NET, GABRB1, ESR1, MTHFR, MTR and MTHFD1. In each group the frequencies of the polymorphisms were determined using PCR-RFLP analysis.
Results:
After correcting for Bonferroni multiple tests, we found associations between the MAOA c.1460C>T (SNP 1137070), COMT c.472G>A (SNP 4680), MTHFR c.677C>T (SNP 1801133) and ESR1 454(-351) A>G (SNP 9340799) polymorphisms to mild and moderate depressive symptoms in menopausal women. In the perimenopausal and postmenopausal women, genotype association of the MAOA c.1460 CT and c.1460 CT+TT (OR=1.83; pcorr=0.009 and OR=1.85; pcorr=0.003, resp.), and of the MTHFR c.677 TT and c.677 CT+TT (OR=3.52; pcorr=0.00009 and OR=2.06; pcorr=0.0006, resp.), as well as of the COMT c.472 GA and COMT c.472 GA+AA genotypes (OR=2.23; pcorr=0.03 and OR=2.17; pcorr=0.027, resp.) in the postmenopausal women revealed significantly higher frequencies of these variants in depressed female patients than in controls, whereas the ESR1 454(-351) AG and 454(-351) AG+GG genotypes were associated with lower risk of depression in postmenopausal women (OR=0.48; pcorr=0.012, and OR=0.52; pcorr=0.015, resp.).
Conclusions:
Our study substantiates the involvement of the MAOA and MTHFR polymorphisms in climacteric depression and offers evidence that the COMT and ESR1 genes may also play a role in the susceptibility to depressive mood in postmenopausal women.
... del that typically spans~3 Mb; the DGCR8 gene maps to the deleted region [25][26][27][28][29][30][31]. In addition to SZ, many patients meet criteria for schizoaffective disorder (SAD), ASD, obsessive compulsive disorder (OCD), Tourette Syndrome, depression, anxiety disorder, and rapid cycling BD [32][33][34][35][36][37][38][39][40]. Conversely, 22q11.2 ...
... In addition, other neuropsychiatric disorders previously reported in patients with 22q11.2 del were also among the top diseases, including BD, Tourette Syndrome and SAD, as well as cleft palate, one of the most common physical anomalies associated with VCFS [32][33][34]36,109,110]. Interestingly, target genes involved in type 2 diabetes were also somewhat enriched. ...
We are using induced pluripotent stem cell (iPSC) technology to study neuropsychiatric disorders associated with 22q11.2 microdeletions (del), the most common known schizophrenia (SZ)-associated genetic factor. Several genes in the region have been implicated; a promising candidate is DGCR8, which codes for a protein involved in microRNA (miRNA) biogenesis. We carried out miRNA expression profiling (miRNA-seq) on neurons generated from iPSCs derived from controls and SZ patients with 22q11.2 del. Using thresholds of p<0.01 for nominal significance and 1.5-fold differences in expression, 45 differentially expressed miRNAs were detected (13 lower in SZ and 32 higher). Of these, 6 were significantly down-regulated in patients after correcting for genome wide significance (FDR<0.05), including 4 miRNAs that map to the 22q11.2 del region. In addition, a nominally significant increase in the expression of several miRNAs was found in the 22q11.2 neurons that were previously found to be differentially expressed in autopsy samples and peripheral blood in SZ and autism spectrum disorders (e.g., miR-34, miR-4449, miR-146b-3p, and miR-23a-5p). Pathway and function analysis of predicted mRNA targets of the differentially expressed miRNAs showed enrichment for genes involved in neurological disease and psychological disorders for both up and down regulated miRNAs. Our findings suggest that: i. neurons with 22q11.2 del recapitulate the miRNA expression patterns expected of 22q11.2 haploinsufficiency, ii. differentially expressed miRNAs previously identified using autopsy samples and peripheral cells, both of which have significant methodological problems, are indeed disrupted in neuropsychiatric disorders and likely have an underlying genetic basis.
... Cyclothymic subjects have continuous and irregular mood 'highs' and 'lows' for extended periods of time; mood switches are often abrupt, while interposed periods of mood stability are infrequent (Akiskal et al., 2006a;Birmaher et al., 2014;Hantouche and Akiskal, 2006;Van Meter, 2013); in some cases major mood episodes of both polarities may appear (Akiskal et al., 1977;Perugi et al., 2012;van Valkenburg et al., 2006). Patients with frequent and abrupt switches of mood associated with short but definite depressive and hypomanic episodes have been considered as ultra-rapid or ultradian cyclers (Mackinnon and Pies, 2006;Papolos et al., 1998). The intensity, rapidity and unpredictability of mood swings are a major cause of distress, and produce a considerable degree of instability in terms of self-esteem, vocation and interpersonal relationships. ...
... These findings are consistent with reports in children and adolescents with BD, where an association has been observed between high familial loading, comorbidity with multiple anxiety disorders and rapid circadian switches (Masi et al., 2007). Rapid switches and comorbidity with panic disorder seem to define a particular familial subtype of BD distinguished by early onset and cyclothymic instability (MacKinnon et al., 2002;Masi et al., 2007;Papolos et al., 1998). ...
Data emerging from both academic centers and from public and private outpatient facilities indicate that from 20% to 50% of all subjects that seek help for mood, anxiety, impulsive and addictive disorders turn out, after careful screening, to be affected by cyclothymia. The proportion of patients who can be classified as cyclothymic rises significantly if the diagnostic rules proposed by the DSM-5 are reconsidered and a broader approach is adopted. Unlike the DSM-5 definition based on the recurrence of low-grade hypomanic and depressive symptoms, cyclothymia is best identified as an exaggeration of cyclothymic temperament (basic mood and emotional instability) with early onset and extreme mood reactivity linked with interpersonal and separation sensitivity, frequent mixed features during depressive states, the dark side of hypomanic symptoms, multiple comorbidities, and a high risk of impulsive and suicidal behavior. Epidemiological and clinical research have shown the high prevalence of cyclothymia and the validity of the concept that it should be seen as a distinct form of bipolarity, not simply as a softer form. Misdiagnosis and consequent mistreatment are associated with a high risk of transforming cyclothymia into severe complex borderline-like bipolarity, especially with chronic and repetitive exposure to antidepressants and sedatives. The early detection and treatment of cyclothymia can guarantee a significant change in the long-term prognosis, when appropriate mood-stabilizing pharmacotherapy and specific psychological approaches and psychoeducation are adopted. The authors present and discuss clinical research in the field and their own expertise in the understanding and medical management of cyclothymia and its complex comorbidities.
Copyright © 2015 Elsevier B.V. All rights reserved.
... Several studies have shown that the functional Val158Met variant is part of a vulnerable genetic background shared across a range of internalizing disorders, including MDD, BD, anxiety and panic disorder (Antypa et al., 2013;Craddock and Sklar, 2013). Current evidence confirms an association of the COMT G (Val) allele with MDD, although controversial results have been reported (Burdick et al., 2007;Funke et al., 2005;Massat et al., 2005Massat et al., , 2011Papolos et al., 1998;Schosser et al., 2012;Serretti et al., 2006;Shifman et al., 2004). However, it has been reported that other polymorphisms in the COMT locus, such as rs4633 (C/T, synonymous) and rs4818 (C1886G, Leu136Leu, synonymous) in the coding regions, interact in a complex way to reduce COMT enzyme activity, due to a reduced amount of translated protein resulting from alterations in mRNA secondary structure (Nackley et al., 2009). ...
... Interestingly, the Val158Met functional variant has been associated with both MDD and BD, although conflicting results have been reported (Antypa et al., 2013;Craddock and Sklar, 2013). Most of the available case-control studies employed a genotyping approach merely based on the characterization of the Val158Met COMT variant (Burdick et al., 2007;Chen et al., 2004;Funke et al., 2005;Massat et al., 2005Massat et al., , 2011Papolos et al., 1998;Schosser et al., 2012;Serretti et al., 2006;Shifman et al., 2004). However, Nackley et al. (2006) suggested that several COMT haplotypes (combinations of SNPs) modulate protein expression and activity by altering mRNA secondary structure. ...
... 18 Imbalance of dopamine is thought to be key for the pathogenesis of psychosis, 5,17 COMT gene is located in the region on chromosome 22q11 commonly deleted in velo-cardio-facial/DiGeorge syndrome (VCFS/DGS) whose phenotypic spectrum includes severe psychiatric disease described as schizophrenia by some 4,30,36 and BD by others. 31 Genetic variation in COMT has been implicated in prefrontal cortical function 10,28 which is commonly impaired in both disorders. 38 Therefore, the largest body of works exists for schizophrenia and BD. ...
... 8,9,14,18,21 In the studies investigating of association between BD and COMT gene H/L polymorphism; it has been showed that H allele 15 or L allele 23,26,27,32 might increase susceptibility to the illness, and L allele might be a course modifier for the rapid cycling form of BD. 23,26 However, L allele has also been suggested to predict ultra-ultra rapid (ultradian) cycling but not for classical rapid cycling. 31 Interestingly, in a study, it has been suggested that there might be sexual difference as a tendency for L allele amongst female patients. 29 A significant association has been found between BD and the other polymorphism in COMT (SNP rs737865) especially among females, but significant association has not been found with H/L (Val/ Met) polymorphism in the same study. ...
... With significant main effect of the Val homozygotes of the BDNF Val66Met polymorphism and the Val/Met genotype of COMT Val158Met gene in BP-II without AD, our findings demonstrated that odds for BP-II without AD were lower for those with both the BDNF Val66Met Val/Val genotype and either the COMT Val158Met Met/Met or Val/Met genotypes (odds ratio = 0.46, 0.31 respectively ). The Met homozygotes and heterozygotes of the COMT Val158Met polymorphism is less enzymatically active compared to the Val homozygotes in the degradation pathways for dopamine, which may increase catecholamine neurotransmission and, consequently , the propensity for mood swings [65,66]. Compared to the Val homozygotes, the Met heterozygotes and homozygotes of the BDNF Val66Met polymorphism seems to have impairments in intracellular trafficking and activity-dependent secretion of BDNF in neurons [51,65]. ...
... Furthermore, our positive association was with the more homogeneous BP-II without AD group only, which may explain past inconsistencies about the influence of this polymorphism on broadly defined bipolar disorder. However, verifying the association between the COMT Val158Met polymorphism and rapid cycling BP as reported by Papolos et al. may require additional characterization and phenotyping of BP [66]. In current study, we found the Val/Val genotype of the BDNF Val66Met polymorphism was associated with BP-II without AD after controlling for age and gender. ...
Bipolar disorder (BP), especially bipolar II disorder (BP-II), is highly comorbid with anxiety disorder (AD). Monoaminergic dysfunction has been implicated in the pathogenesis of BP, it may be important to investigate genes such as the catechol-O-methyltransferase (COMT), involved in monoamine metabolism and brain-derived neurotrophic factor (BDNF) genes, modulating the monoamine system. We therefore examined the association of the COMT Val158Met and BDNF Val66Met polymorphisms with BP-II with and without comorbidity of AD, and possible interactions between these genes. Seven hundred and seventy-one participants were recruited: 314 with bipolar-II without AD, 117 with bipolar-II with AD, and 340 healthy controls. The genotypes of the COMT and BDNF polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Logistic regression analysis showed a significant effect of the COMT and the BDNF polymorphisms, and a significant interaction effect for the Val/Val genotypes of the BDNF Val66Met polymorphism and the COMsT Val158Met Val/Met and Met/Met genotypes (P=0.007, 0.048) discriminated between BP-II without AD patients and controls. Our findings provide initial evidence that the COMT and BDNF genes interact in bipolar-II without AD. Our findings suggest the involvement of dopaminergic pathway in the pathogenesis of bipolar-II.
... For COMT, a common functional polymorphism has been found in which a valine residue is substituted by methionine at amino acid 158, causing a lower activity of the COMT enzyme [Strous et al., 1997]. An association of the low-activity variant with severe affective disorders was reported by Li et al. [1997], Mynett-Johnson et al. [1998], Papolos et al., [1998], Kirov et al. [1998], andOhara et al. [1998a] but no association was found by the Biomedical European Bipolar Collaborative Group [1997], Gutierrez et al. [1997], Kunugi et al. [1997. Vandenbergh et al. [1997] found an association with polysubstance abuse, and Karayiorgou et al. [1997] with obsessive compulsive disorder. ...
In a community sample of 2,327 Caucasians, we tested the hypotheses that polymorphisms in the COMT and DRD3 genes are associated with personality traits conferring vulnerability to anxiety, depression, or alcohol misuse, or with current symptoms of these; and that the association is stronger in persons who also have been exposed to stressor experiences. To conserve resources and to allow replication, the genetic analysis was undertaken in two stages. For the COMT polymorphism, no statistically significant associations were found in the first sample of 862 persons. The remainder of the sample was therefore not analysed for that gene. For the DRD3 polymorphism, those in the first sample with at least one of the Ser⁹ alleles had significantly higher scores in neuroticism (p=0.006) and behavioral inhibition (p=0.003). There was a trend, failing to meet the 1% significance criterion, for those with this genotype also to have higher depression and anxiety. The groups did not differ in alcohol use. In persons with the Ser⁹ allele who were also exposed to stressors, there was a higher level of depression at the 5% level; and the depression level was higher in homozygotes. But when the remainder of the sample (1,465) was analysed, none of the associations reached statistical significance. We conclude that neither the COMT nor DRD3 polymorphisms are associated with anxiety, depression, or alcohol abuse. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:102–107, 2000 © 2000 Wiley-Liss, Inc.
... Associations with Novelty Seeking have been confined to females, suggesting a gender specific effect for the COMT gene (Enoch et al., 2003;Gogos et al., 1998). However, when COMT has been associated with severe affective disorders (Kirov et al., 1998;Li et al., 1997;Mynett-Johnson et al., 1998;Ohara et al., 1998;Papolos et al., 1998), as well as anxiety disorders (Ohara et al., 1998), the findings are mixed. Several studies have failed to replicate the association (Gutierrez et al., 1997;Kunugi et al., 1997;Lachman et al., 1997), and typically large studies find no relationship (n=2327), not even when environmental risk factors that increase the possibility that individuals with a risk allele develop such behaviors is taken into account (Henderson et al., 2000;Kunugi et al., 1997). ...
... This corresponds well to reports about a very close relationship between an 'ultrarapid cycling bipolar disorder' clinical phenotype and distinct genetic polymorphisms. 16 At present, only one case of developing unipolar ultra-rapid cycling after dibenzepine use is reported in the literature. 17 The switch between affective states in ultra-rapid cycling occurs especially at night, presumably between 01:00 and 03:00. ...
... Although family studies have produced inconclusive results regarding the familiality of rapid cycling, 104-106 recent candidate gene association studies suggest that the low activity allele at a common polymorphism within the catechol-o-methyl transferase (COMT) gene may be associated with increased susceptibility to rapid cycling within bipolar patients. [107][108][109] This observation has biological consistency with the observed tendency for antidepressants to induce rapid cycling in that both increase availability of catecholamines at neuronal synapses. However, this genetic finding requires confirmation in large independent samples and, even if confirmed, makes only a modest contribution to rapid cycling. ...
Bipolar disorder (also known as manic depressive illness) is a complex genetic disorder in which the core feature is pathological disturbance in mood (affect) ranging from extreme elation, or mania, to severe depression usually accompanied by disturbances in thinking and behaviour. The lifetime prevalence of 1% is similar in males and females and family, twin, and adoption studies provide robust evidence for a major genetic contribution to risk. There are methodological impediments to precise quantification, but the approximate lifetime risk of bipolar disorder in relatives of a bipolar proband are: monozygotic co-twin 40-70%; first degree relative 5-10%; unrelated person 0.5-1.5%. Occasional families may exist in which a single gene plays the major role in determining susceptibility, but the majority of bipolar disorder involves the interaction of multiple genes (epistasis) or more complex genetic mechanisms (such as dynamic mutation or imprinting). Molecular genetic positional and candidate gene approaches are being used for the genetic dissection of bipolar disorder. No gene has yet been identified but promising findings are emerging. Regions of interest identified in linkage studies include 4p16, 12q23-q24, 16p13, 21q22, and Xq24-q26. Chromosome 18 is also of interest but the findings are confusing with up to three possible regions implicated. To date most candidate gene studies have focused on neurotransmitter systems influenced by medication used in clinical management of the disorder but no robust positive findings have yet emerged. It is, however, almost certain that over the next few years bipolar susceptibility genes will be identified. This will have a major impact on our understanding of disease pathophysiology and will provide important opportunities to investigate the interaction between genetic and environmental factors involved in pathogenesis. This is likely to lead to major improvements in treatment and patient care but will also raise important ethical issues that will need to be addressed.
... Associations with Novelty Seeking have been confined to females, suggesting a gender specific effect for the COMT gene (Enoch et al., 2003;Gogos et al., 1998). However, when COMT has been associated with severe affective disorders (Kirov et al., 1998;Li et al., 1997;Mynett-Johnson et al., 1998;Ohara et al., 1998;Papolos et al., 1998), as well as anxiety disorders (Ohara et al., 1998), the findings are mixed. Several studies have failed to replicate the association (Gutierrez et al., 1997;Kunugi et al., 1997;Lachman et al., 1997), and typically large studies find no relationship (n=2327), not even when environmental risk factors that increase the possibility that individuals with a risk allele develop such behaviors is taken into account (Henderson et al., 2000;Kunugi et al., 1997). ...
This dissertation explains why behavioral genetic research can be better informed by
using characteristics in the human iris as biomarkers for personality, and is divided into
five parts. Part I gives an introduction to the classical twin method and an overview of
the findings that have led most developmental researchers to recognize that the normal
variation of personality depends on a complex interplay between genetic and
environmental factors. Part II highlights empirical findings that, during the last twenty
years, have gradually moved genetic and environmental theory and research to evolve
toward one another, and also presents the theory of genetics and experience that
currently is used to explain how the interplay between genes and the environment
works. Part III explains why, from a developmental perspective, it is of interest to
identify candidate genes for personality, and gives a brief overview of genes that have
been associated with personality. Problems associated with genetic research on the
molecular level and how these apply to personality are also highlighted. Part IV
examines molecular research on the iris and the brain, which suggests that genes
expressed in the iris may be associated with personality, and explains how the use of
iris characteristics and a person-oriented methodology can increase power to test
candidate genes for personality by taking advantage of the self-organizing properties of
the nervous system. The empirical foundation for the questions posed in this
dissertation and also the empirical results are presented here. Part V discusses the
associations found between iris characteristics and personality, and exemplifies how
iris characteristics can be used within the theoretical frameworks presented in parts I,
II, III and IV. In other words, Part V explains how iris characteristics and a personoriented
methodology – as well as identifying, and increasing power to test candidate
genes for personality - can be used to investigate how people’s experiences in
themselves are influenced by genetic factors.
... El polimorfisme Val 158 Met de la COMT també ha estat relacionat amb altres patologies com el trastorn obsessiu-compulsiu (Karayiorgou et al., 1999), la depressió (Ohara et al., 1998a), el trastorn de pànic (Woo et al., 2004;Rothe et al., 2006), el trastorn bipolar (Papolos et al., 1998;Rotondo et al., 2002) Waldman et al., 1998;Yang et al., 2007). Alguns estudis apunten a que l'al·lel de 10 repeticions està associat a una major expressió del transportador de dopamina Cheon et al., 2005;VanNess et al., 2005), cosa que seria compatible amb la hipòtesi d'un excés de recaptació de dopamina en els pacients amb TDAH. ...
... 289per year(Papolos et al., 1998;Tillman and Geller, 2003). Neuroimaging studies show a290 degree of uncoupling between the neuronal networks involved in emotion regulation in this 291 more pathological variant of the disorder (Anand et al., 2009; Cerullo et al., 2012; Chai et al., 292 2011; Chen et al., 2011; Chepenik et al., 2010). ...
Bipolar disorder is characterized by repeated erratic episodes of mania and depression, which can be understood as pathological complex system behavior involving cognitive, affective and psychomotor disturbance. In order to illuminate dynamical aspects of the longitudinal course of the illness, we propose here a novel complex model based on the notion of competition between recurrent maps, which mathematically represent the dynamics of activation in excitatory (Glutamatergic) and inhibitory (GABAergic) pathways. We assume that manic and depressive states can be considered stable sub attractors of a dynamical system through which the mood trajectory moves. The model provides a theoretical framework which can account for a number of complex phenomena of bipolar disorder, including intermittent transition between the two poles of the disorder, rapid and ultra-rapid cycling of episodes and manicogenic effects of antidepressants.
Copyright © 2015. Published by Elsevier Ltd.
... Following this discovery, we postulated that hemizygosity for the low activity variant (158met) might account for the psychi atric manifestations of VCFS and that homozygosity for the low activity variant may be a factor in the development of psychiatric problems occurring in the general population. We obtained some evidence that the low activity allele may be associated with ultra-ultra rapid cycling BPD that is found in the general population and in a subgroup of patients with VCFS (Lachman et a/., 1997b;Papolos et a/., 1998). The finding was subsequently replicated by another group (Kirov et al., 1998). ...
Bipolar disorder (BPD) is a highly heritable psychiatric illness that is characterized by severe extremes of mood. It is found in approximately 1% of the population and often leads to a lifetime of disability. Although it has been very difficult to map BPD susceptibi. lity genes by classi cal linkage analysis, investigators have recently mapped several chromosomal loci by using model-free, non parametric methods of linkage. Evidence for BPD sus ceptibility genes on 4p, 18p, 18q, 21 q and 22q has been obtained. Following the completion of the human genome project, the combination of linkage data and sequencing information should lead to the identification of the genes responsible for this enigmatic condition sometime in the next few years.
... and attention deficit hyperactivity disorder, panic disorder and Parkinson's disease (Woo et al. 2002, Eisenberg et al. 1999, Frisch et al. 2001, Papolos et al. 1998, Lachman et al. 1996a, Vandenbergh et al. 1997, Strous et al. 1997, Tiihonen et al. 1999, Ohmori et al. 1998; for reviews see Craddock et al. 2006, Hosak 2007) have lead to a myriad of replication attempts with controversial results. Moreover, a hallmark study of Egan et al. (2001) associated the Val158Met Val allele with worse cognitive performance, prefrontal function and schizophrenia. ...
... PRODH maps to the 22q11.2 region deleted in velocardiofacial syndrome (VCFS), a haploinsufficiency disorder that leads to a variety of physical and psychiatric problems, including SZ and ASD, and IFITM1 has been found to be differentially expressed in the brains of patients with SZ and ASD [133][134][135][136][137][138][139][140][141]. In addition, another member of the interferoninducible family, IFITM3, along with the HS genes HSPA6, HSPB8 and SERPINH1, has been found to be differentially expressed in the brains of patients with ASD [29,75]. ...
Schizophrenia (SZ) and autism spectrum disorders (ASD) are highly heritable neuropsychiatric disorders, although environmental factors, such as maternal immune activation (MIA), play a role as well. Cytokines mediate the effects of MIA on neurogenesis and behavior in animal models. However, MIA stimulators can also induce a febrile reaction, which could have independent effects on neurogenesis through heat shock (HS)-regulated cellular stress pathways. However, this has not been well-studied. To help understand the role of fever in MIA, we used a recently described model of human brain development in which induced pluripotent stem cells (iPSCs) differentiate into 3-dimensional neuronal aggregates that resemble a first trimester telencephalon. RNA-seq was carried out on aggregates that were heat shocked at 39°C for 24 hours, along with their control partners maintained at 37°C. 186 genes showed significant differences in expression following HS (p<0.05), including known HS-inducible genes, as expected, as well as those coding for NGFR and a number of SZ and ASD candidates, including SMARCA2, DPP10, ARNT2, AHI1 and ZNF804A. The degree to which the expression of these genes decrease or increase during HS is similar to that found in copy loss and copy gain copy number variants (CNVs), although the effects of HS are likely to be transient. The dramatic effect on the expression of some SZ and ASD genes places HS, and perhaps other cellular stressors, into a common conceptual framework with disease-causing genetic variants. The findings also suggest that some candidate genes that are assumed to have a relatively limited impact on SZ and ASD pathogenesis based on a small number of positive genetic findings, such as SMARCA2 and ARNT2, may in fact have a much more substantial role in these disorders - as targets of common environmental stressors.
... In fact, rapid cycling may describe a distinct phenotype with biologically different properties driving both the mood and sleep disturbance. For example, rapid cycling has been linked to panic disorder in familial and genetic studies (MacKinnon and Zamoiski 2006;MacKinnon et al. 2003a, b) and has also been linked to low-activity risk alleles of the catechol-Omethyl transferase gene (Papolos et al. 1998;Kirov et al. 1998;Joyce et al. 1995) as well as abnormalities in the hypothalamic-pituitary-thyroid axis (Chakrabarti 2011). ...
Background
Poor sleep quality is known to precede the onset of mood episodes and to be associated with poor treatment outcomes in bipolar disorder (BD). We sought to identify modifiable factors that correlate with poor sleep quality in BD independent of residual mood symptoms.
Methods
A retrospective analysis was conducted to assess the association between the Pittsburgh Sleep Quality Index and clinical variables of interest in euthymic patients with DSM-IV BD (n = 119) and healthy controls (HC; n = 136) participating in the Prechter Longitudinal Study of Bipolar Disorder. Multivariable linear regression models were constructed to investigate the relationship between sleep quality and demographic and clinical variables in BD and HC participants. A unified model determined independent predictors of sleep quality.
Results and discussion
Euthymic participants with BD and HC differed in all domains. The best fitting unified multivariable model of poor sleep quality in euthymic participants with BD included rapid cycling (β = .20, p = .03), neuroticism (β = .28, p = 2 × 10−3), and stressful life events (β = .20, p = .02). Poor sleep quality often persists during euthymia and can be a target for treatment. Clinicians should remain vigilant for treating subjective sleep complaints independent of residual mood symptoms in those sensitive to poor sleep quality, including individuals with high neuroticism, rapid cycling, and recent stressful life events. Modifiable factors associated with sleep quality should be targeted directly with psychosocial or somatic treatment. Sleep quality may be a useful outcome measure in BD treatment studies.
... In a number of studies, COMT has been associated with cognitive impairment in several psychiatric disorders, and also in the general population [4] . In several independent studies, Damino acid oxidase activator (DAOA) and Catechol-O-methyltransferase (COMT) have been found to be associated with bipolar disorder [5,6,7,8,9,10,11,12,13]. The DAOA gene acts through the N-methyl-D-aspartate (NMDA) receptors [14] that have a central role in memory function and synaptic plasticity [15] and have been shown to be modified in bipolar disorder [16,17] . ...
Bipolar disorder is characterized by severe mood symptoms including major depressive and manic episodes. During manic episodes, many patients show cognitive dysfunction. Dopamine and glutamate are important for cognitive processing, thus the COMT and DAOA genes that modulate the expression of these neurotransmitters are of interest for studies of cognitive function.
Focusing on the most severe episode of mania, a factor was found with the combined symptoms of talkativeness, distractibility, and thought disorder, considered a cognitive manic symptoms (CMS) factor. 488 patients were genotyped, out of which 373 (76%) had talkativeness, 269 (55%) distractibility, and 372 (76%) thought disorder. 215 (44%) patients were positive for all three symptoms, thus showing CMS (Table 1). As population controls, 1,044 anonymous blood donors (ABD) were used. Case-case and case-control design models were used to investigate genetic associations between cognitive manic symptoms in bipolar 1 disorder and SNPs in the COMT and DAOA genes. [Table: see text].
The finding of this study was that cognitive manic symptoms in patients with bipolar 1 disorder was associated with genetic variants in the DAOA and COMT genes. Nominal association for DAOA SNPs and COMT SNPs to cognitive symptoms factor in bipolar 1 disorder was found in both allelic (Table 2) and haplotypic (Table 3) analyses. Genotypic association analyses also supported our findings. However, only one association, when CMS patients were compared to ABD controls, survived correction for multiple testing by max (T) permutation. Data also suggested interaction between SNPs rs2391191 in DAOA and rs5993883 in COMT in the case-control model. [Table: see text] [Table: see text].
Identifying genes associated with cognitive functioning has clinical implications for assessment of prognosis and progression. Our finding are consistent with other studies showing genetic associations between the COMT and DAOA genes and impaired cognition both in psychiatric disorders and in the general population.
... A relatively frequent val-158-met polymorphism (a methionine to valine substitution at codon 158) results in lower levels of COMT enzymatic activity in the synaptic cleft compared with the val polymorphism [28]. The met-allele has been associated with the enhanced vulnerability to anxiety [15], panic disorder [13,53], as well as bipolar affective disorder [36,38]. While links between COMT and major depressive disorder (MDD) are not universally recognized [32], an interaction between COMT and 5-HTTLPR genotypes has been shown to predispose individuals with a history of stressful life events to MDD [33]. ...
Background:
Investigating genetic modulation of emotion processing may contribute to the understanding of heritable mechanisms of emotional disorders. The aim of the present study was to test the effects of catechol-O-methyltransferase (COMT) val158met and serotonin-transporter-linked promoter region (5-HTTLPR) polymorphisms on facial emotion processing in healthy individuals.
Methods:
Two hundred and seventy five (167 female) participants were asked to complete a computerized facial affect recognition task, which involved four experimental conditions, each containing one type of emotional face (fearful, angry, sad or happy) intermixed with neutral faces. Participants were asked to indicate whether the face displayed an emotion or was neutral. The COMT-val158met and 5-HTTLPR polymorphisms were genotyped.
Results:
Met homozygotes (COMT) showed a stronger bias to perceive neutral faces as expressions of anger, compared with val homozygotes. However, the S-homozygotes (5-HTTLPR) showed a reduced bias to perceive neutral faces as expressions of happiness, compared to L-homozygotes. No interaction between 5-HTTLPR and COMT was found.
Conclusions:
These results add to the knowledge of individual differences in social cognition that are modulated via serotonergic and dopaminergic systems. This potentially could contribute to the understanding of the mechanisms of susceptibility to emotional disorders.
... Therefore, altered catecholamine metabolism due to presence of different COMT alleles may lead to neuropsychiatric disorders. 6 The COMT gene has long been implicated to be involved in the pathogenesis of obsessive-compulsive disorder, 9 aggressive and antisocial behaviour, 8 schizophrenia, 15,16 bipolar affective disorder, 17,18 suicidal risk 19 and Parkinson disease. 5 On the other hand, it was also suggested that COMT polymorphism is not associated with anxiety, depression, or alcohol abuse. ...
The objective was to investigate possible association of the catechol o-methyl transferase (COMT) gene polymorphisms with myofacial pain syndrome (MFPS). The polymorphism of the COMT gene was compared between 49 patients with MFPS and 113 control subjects. Relationship between COMT polymorphism and psychiatric status of the patients was also assessed using SCL-90-R, BDS, and STAI-I and II tests. A PCR-based restriction fragment length polymorphism assay was used to detect G ? A transition at position 1947 in COMT. There was no relationship between MFPS and COMT polymorphism (p > 0.05). The patients who had MFPS without any temporomandibular joint problem had significantly higher expression of LL genotype when compared to those with joint problems (p < 0.05). There was no relationship between nocturnal bruxism and COMT polymorphism (p > 0.05). In conclusion, MFPS is not related to COMT polymorphism. COMT polymorphism is not associated with the psychiatric status of the patients. COMT polymorphism may be important for dose adjustment when the use of catechol drugs is anticipated.
Mood disorders such as depression and bipolar disorder are common mental illnesses, affecting millions of patients worldwide. The application of newly available brain imaging methods to the study of mood disorders holds substantial promise in uncovering the brain mechanisms affected in these illnesses. This comprehensive and authoritative text features contributions from leading international experts, providing easily accessible information on the study of the brain mechanisms involved in the causation of mood disorders and the available treatments. Topics covered include the potential of magnetoencephalography (MEG), neuroimaging brain inflammation in depression, electrophysiology studies in mood disorders, and the applications of machine learning, filling an important gap in available neuropsychiatric literature and highlighting new developments. An invaluable resource for practitioners in the fields of psychiatry, neurology, primary care medicine, and related mental health professions, as well as researchers, students, graduate and post-graduate trainees.
Approximately 45 million people worldwide are diagnosed with bipolar disorder (BD). While there are many known risk factors and models of the pathologic processes influencing BD, the exact neurologic underpinnings of BD are unknown. We attempt to integrate the existing literature and create a unifying hypothesis regarding the pathophysiology of BD with the hope that a concrete model may potentially facilitate more specific diagnosis, prevention, and treatment of BD in the future. We hypothesize that dysfunctional signaling from the parvocellular neurons of the paraventricular hypothalamic nucleus (PVN) results in the clinical presentation of BD. Functional damage to this nucleus and its signaling pathways may be mediated by myriad factors (e.g. immune dysregulation and auto-immune processes, polygenetic variation, dysfunctional interhemispheric connections, and impaired or overactivated hypothalamic axes) which could help explain the wide variety of clinical presentations along the BD spectrum. The neurons of the PVN regulate ultradian rhythms, which are observed in cyclic variations in healthy individuals, and mediate changes in functional hemispheric lateralization. Theoretically, dysfunctional PVN signaling results in prolonged functional hemispheric dominance. In this model, prolonged right hemispheric dominance leads to depressive symptoms, whereas left hemispheric dominance correlated to the clinical picture of mania. Subsequently, physiologic processes that increase signaling through the PVN (hypothalamic-pituitaryadrenal axis, hypothalamic- pituitary-gonadal axis, and hypothalamic-pituitary-thyroid axis activity, suprachiasmatic nucleus pathways) as well as, neuro-endocrine induced excito-toxicity, auto-immune and inflammatory flairs may induce mood episodes in susceptible individuals. Potentially, ultradian rhythms slowing with age, in combination with changes in hypothalamic axes and maturation of neural circuitry, accounts for BD clinically presenting more frequently in young adulthood than later in life.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
This book was originally published in 2004 and concerns developmental neurobiology. In the decade preceding publication, developmental neurobiology made important strides towards elucidating the pathophysiology of psychiatric disorders. Nowhere has this link between basic science and clinical insights become clearer than in the field of schizophrenia research. Each contributor to this volume provides a fresh overview of the relevant research, including directions for further investigation. The book begins with a section on advances in developmental neurobiology. This is followed by sections on etiological and pathophysiological developments, and models that integrate this knowledge. The final section addresses the clinical insights that emerge from the developmental models. This book will be valuable to researchers in psychiatry and neurobiology, students in psychology, and all mental health practitioners.
Objective:
To reveal psychopathological characteristics and core dynamic patterns of continuous cycling bipolar affective disorders in youth.
Material and methods:
One hundred and seven patients (62 men and 45 women), including 59 patients of the clinical group and 48 of the follow-up group, were examined.
Results and conclusion:
Three types of continuous cycling bipolar affective disorders in youth are described: rhythmic, dysrhythmic and pseudorhythmic. A correlation between the dynamics of affective disorders in youth and the nosological affiliation of each of the identified types of continuous cycling course was found. The results may be useful for solving differential/diagnostic, prognostic and therapeutic tasks.
The catecholamine (CA) hypothesis of bipolar disorder (BD)-a deficiency of CA in depression and excess in mania-was proposed nearly three decades ago. CA abnormalities remain the most replicated finding in the pathophysiology of BD. However, the role of CA abnormalities in the pathophysiology of BD still remains unclear. For example, it is unclear whether changes in CAs seen in manic and depressed states are secondary to the mood state or primary, and it remains to be clarified whether abnormalities in the CA system are presynaptic or postsynaptic. Rapid advances in the field of neuroscience in the last three decades have increased our knowledge of the role of CAs in the working of the nervous system and provided new tools to explore CA abnormalities. Clinical research in CA abnormalities in BD has evolved from measurement of changes in CAs in bodily fiuids and peripheral tissue to neuroendocrine challenge studies to molecular analysis of postmortem tissue and direct visualization of CA system with brain imaging methods such as single photon emission computed tomography (SPECT) and positron emission tomography (PET).
Over the past two decades, driven by the enormous public health importance of bipolar disorder, research initiatives have begun to elucidate the pathophysiology of this prevalent and debilitating condition. These research initiatives have led to breakthroughs in our understanding of causation, and now promise to foster the development of novel treatments. This new edition presents contributions from the leaders at the forefront of these areas of research, and includes chapters on the groundbreaking advances in the fields of genetics, neuroimaging, neuropsychopharmacology, oxidative stress and neuronal resilience, inflammatory mechanisms, psychosocial factors, childhood onset and late-life bipolar disorder, and many other important areas. Throughout, the therapeutic implications and potential of this new understanding are emphasized. This will be essential reading for those interested in the neurobiology of mental illness, and will be of interest to mental health practitioners more generally.
Catechol-O-methyltransferase (COMT) inactivates catecholamines, Val/Val genotype was associated to an increased amygdala (Amy) response to negative stimuli and can influence the symptoms severity and the outcome of bipolar disorder, probably mediated by the COMT polymorphism (rs4680) interaction between cortical and subcortical dopaminergic neurotransmission. The aim of this study is to explore how rs4680 and implicit emotional processing of negative emotional stimuli could interact in affecting the Amy connectivity in bipolar depression. Forty-five BD patients (34 Met carriers vs. 11 Val/Val) underwent fMRI scanning during implicit processing of fearful and angry faces. We explore the effect of rs4680 on the strength of functional connectivity from the amygdalae to whole brain. Val/Val and Met carriers significantly differed for the connectivity between Amy and dorsolateral prefrontal cortex (DLPFC) and supramarginal gyrus. Val/Val patients showed a significant positive connectivity for all of these areas, where Met carriers presented a significant negative one for the connection between DLPFC and Amy. Our findings reveal a COMT genotype-dependent difference in corticolimbic connectivity during affective regulation, possibly identifying a neurobiological underpinning of clinical and prognostic outcome of BD. Specifically, a worse antidepressant recovery and clinical outcome previously detected in Val/Val patients could be associated to a specific increased sensitivity to negative emotional stimuli.
Historically, the first note on polarity was made in the early 1960s when Leonhard reported that 17.9 % of patients had a manic and 25.6 % had a depressive predominant polarity, while the rest of the patients had similar occurrence of the two poles. However, the concept was formulated by Jules Angst.
Objectives:
The pathophysiology of migraine headaches is not clearly understood yet. The dopaminergic system has been hypothesized to be involved in migraine pathogenesis. The aim of this study was to investigate catechol-O-methyltransferase (COMT) polymorphisms and chronic headaches. We analyzed five single nucleotide polymorphisms (SNPs) in COMT.
Materials & methods:
The study population consisted of 71 patients with migraine with aura, 152 patients with migraine without aura, 86 patients with tension-type headache, and 191 healthy controls. The selected polymorphic markers included one causing His62His (rs4633) and two non-synonymous SNPs, Ala72Ser and Val158Met (rs6267, rs4680 respectively). Two other non-polymorphic SNPs (rs6270, rs740602) were examined.
Results:
We found no significant differences in any genotypes, allele frequencies, or haplotypes among the patient groups and controls.
Conclusions:
Our results indicate that the five polymorphisms in COMT have no association with migraineurs in Western Japan. The possibility that segments elsewhere in the gene may contain a mutation responsible for modifying the expression of COMT or the activity of the enzyme is important. We cannot conclusively exclude the entire COMT gene from being involved in migraine pathogenesis.
Background and Objective: Catechol methyl-O-transferase (COMT) is an enzyme that has a role in the metabolism of medicine including 'catecholamine'. COMT enzyme is coded a gene localized in 22q11.2 of human. A functional polymorphism on COMT gene results in an alteration of the COMT gene activity. For COMT gene, as a result of (Guanin-Adenin) G-A and valin-methionine alteration in 108/158 codon, three genothype having H (high activity) and L (low activity) alleles (HH,HL,LL) have been described. It has been known to be effective on pathogenesis of neuropsychiatric disorders, schizophrenia, bipolar affective disorder, Parkinson's disease, obsessive compulsive disorder, migraine, and agressive - antisocial behavior. In addition It has been known to have role on the metabolism of 'catechol' including medicine that has been used in the treatment of illness as, asthma, and Parkinson's disease. The functional polymorphism of COMT gene is important as it guides to diagnosis and treatment of disorders due to neurotransmitter dysfunction. In this study, we aimed to elucidate allelic distribution of the COMT gene in a healthy people Turkish sample. Method: This functional polymorphism has been determined in 182 healthy Turkish people having no relationship with each other by using polymerase-chain-reactions (PCR) and Restriction Fragment Lenght Polymorphism (RFLP) methods. Results: The frequency of H and L alleles of COMT gene are established as 0.58 and 0.42. The allelic distribution of the COMT gene polymorphism here was in Hardy-Weinberg equilibrium. Conclusion: Knowing the COMT gene polymorphism may contribute to understanding of the ethiology of some psychiatric disorders and may help to individualization of the treatment.
The recent advances of molecular genetics in basic science, the number of genetic studies in the psychiatric field has been increasing in the last years. Clinical genetic studies revealed that not only schizophrenia and mood disorders but also some of the neurotic disorders such as anxiety disorders have a genetic component. Genetic knowledge obtained by genetic research must be applicable in clinical practice. Molecular genetic positional and candidate gene approaches are being used for the genetic dissection of schizophrenia and bipolar disorder. This will have a major impact on our understanding of disease pathophysiology and will provide important opportunities to investigate the interaction between genetic and environmental factors involved in pathogenesis. The genetic mutations and chromosomal regions related to schizophrenia and bipolar disorder have been evaluated in this review.
Definition of mood disorders, impact on a global scale and unmet needsCauses and associations in mood disorders: genetics and pharmacogeneticsPathogenesis of mood disordersConcluding remarks
Bipolar disorder is an episodic affective illness, once believed to involve complete inter-episode remission. More recent data have highlighted the presence of persistent symptoms during purported periods of Wellness, including subsyndromal affective symptoms and neurocognitive impairment. These unremitting symptoms are of extreme clinical importance, as they are directly related to a worsening of clinical course, functional impairments and psychosocial difficulties in patients with bipolar disorder. Although there is now substantial evidence demonstrating the prevalence of neurocognitive impairment during euthymia, there have been few studies, to date, targeting this disabling aspect of the illness using pharmacological strategies.
While treatment approaches have previously focused on primary affective and psychotic symptoms of the disease, it is important to consider the debilitating impact that impaired cognition has on patients with bipolar disorder. A recent focus has been placed on the significant need for large-scale clinical trials designed to specifically target cognitive impairment in patients with schizophrenia, with a parallel need existing in the field of bipolar research.
There is now early evidence for the presence of neurocognitive deficits in patients with bipolar disorder and a relationship between these impairments and functional disability, making this a symptom domain that requires immediate clinical attention. Convergent data indicate a compelling need for formal assessment of cognition in patients with bipolar disorder, and for researchers and clinicans alike to consider the necessity for treatment specific to cognition in this population. Although limited data exist from cognitive enhancement trials in this population, there are a number of potential pharmacotherapy targets based on evidence from neuroimaging, molecular genetic, pharmacological and animal studies related to the pathophysiology of bipolar disorder. Future directions for potential cognitive enhancement strategies in bipolar disorder may include medications that influence dopaminergic or glutamatergic neurotransmission; however, urther work is needed to adequately assess the safety and effectiveness of these agents in bipolar patients. Finally, psychosocial intervention and/or cognitive remediation should be considered as alternatives to medications, although these techniques will also require additional systematic study.
Objective:
THE long-term course of bipolar disorder is typified by recurring mood episodes of opposite polarity as well as mixed states. Rapid-cycling bipolar disorder refers to the presence of at least 4 mood episodes in the previous 12 months that meet the criteria for manic, hypomanic, or major depressive episode. The purpose of this study was to synthesize data regarding prevalence, clinical correlates, and familial/genetic aspects related to rapid cycling in bipolar disorder.
Datasources:
we searched the MEDLINE database through September 7, 2013 for articles regarding rapid cycling in bipolar disorder. Searches were performed using the keywords rapid cycling or rapid-cycling. The search strategy was augmented through the inspection of reference lists of relevant review articles. Eligible articles included original studies in English on rapid-cycling bipolar patients according to the criteria defined by the Diagnostic and Statistical Manual of Mental Disorders.
Study selection:
This study followed the recommendations of the Preferred Items for Reporting of Systematic Reviews and Meta-Analyses statement. The initial search returned 2,715 articles; 2,594 were excluded for several reasons (not aligned with objectives, pertaining to bipolar disorder but not focusing on rapid cycling, case reports, and case series). The final review included 119 articles.
Data extraction:
Two investigators (K.N.F. and D.D.) independently reviewed articles for eligibility. Final decisions regarding eligibility were made by consensus following the full-text review.
Results:
The literature suggests that rapid cycling affects a significant proportion of bipolar patients and is related to a longer course of illness, an earlier age at onset, and more illegal drug and alcohol abuse and increased suicidality. Year prevalence of rapid cycling among all bipolar patients ranges between 5%-33.3%, while lifetime prevalence ranges between 25.8%-43%.The etiology remains unclear, although a causal or triggering role for the use of antidepressants and hypothyroidism is implicated. Rapid cycling seems to represent a transitory phenomenon rather than a stable pattern that characterizes the individual patient and probably is related to a worse outcome.
Conclusions:
Rapid cycling is a frequent, although underrecognized, condition in bipolar disorder, and it constitutes a worsening of the primary disorder. There is no good evidence that rapid cycling represents a discrete subtype. Early recognition of this pattern can lead to better treatment strategy and improvement of the long-term course. Conceptualizing rapid cycling according to Research Domain Criteria will be an important advance.
Aim: To determine if the functional Val108/158Met polymorphism causes a tendency toward alcohol addiction in Turkish cases. This polymorphism of the catechol-O-methyltransferase (COMT) gene has been associated with many psychiatric disorders, as well as with alcoholism. Materials and methods: The allele and genotype associations of the Val108/158Met polymorphism in 110 Turkish alcoholics and 330 healthy subjects were investigated, constituting our study and control groups, by polymerase chain reaction-restriction fragment length polymorphism. Results: Distribution of the Met/Met genotype was 16.4% to 20.6% and frequency of the Met allele was 36.8% to 39.5% in the study group compared to the control group. The results did not show any significant differences in the genotype distribution and allele frequencies of the polymorphism, neither between the study and the control groups (c 2 = 0.985, P = 0.611 and c 2 = 0.517, P = 0.472) nor between female (c 2 = 0.247, P = 0.884 and c 2 = 0.115, P = 0.735, respectively) and male (c 2 = 0.728, P = 0.695 and c 2 = 0.485, P = 0.486, respectively) alcoholics. The power of the study for genotype analysis was set at 79.1%. Conclusion: The present study shows that the polymorphic Met allele of the COMT polymorphism is not associated with alcoholism in Turkish cases; however, due to the lack of statistical power, this research should be evaluated again with an enlarged study group to confirm the possible association between the polymorphism and alcoholism.
Nach den derzeit gültigen diagnostischen Leitlinien des ICD-10 finden Subtypen des bipolaren Spektrums syndromorientiert und in Bezug auf den Verlauf nur randständig Berücksichtigung. Im Gegensatz dazu hat im amerikanischen DSM-IV eine Unterteilung von Bipolar-I-Störung (ausgeprägte manische und depressive Episoden) und Bipolar-II-Störung (hypomanische und depressive Episoden) bereits 1994 Eingang gefunden. Auch wird eine differenzielle Verlaufsbeobachtung der Erkrankung mit klinischer Relevanz, wie das Rapid Cycling (RC), mit einbezogen. Dabei handelt es sich um einen Verlauf einer bipolaren Erkrankung mit mindestens 4 affektiven Episoden in einem Jahr. Für diesen wird ebenso wie bei gemischten Episoden und einem atypischen Beginn (initiale Depression) bei Patienten mit einer bipolaren Erkrankung ein schlechteres Ansprechen auf die Standardtherapie Lithium postuliert. Aufgrund dessen sind medikamentöse Alternativen und zusätzliche Therapieansätze hinsichtlich einer Phasenprophylaxe aus klinischer Sicht dringend notwendig; diese werden im Beitrag auf aktuellem Stand dargestellt und diskutiert. Ebenso werden mit RC assoziierte Parameter wie gehäuftes Auftreten bei Frauen, hypothyreote Stoffwechsellage, bipolarer Subtyp, COMT-Allel, Einfluss durch Schlaf und Induktion durch Antidepressiva dargestellt.
A high-performance liquid chromatography with electrochemical detection (HPLC-ECD) method was developed to determine the activity of S-catechol-O-methyltransferase (COMT) in rat tissues including the liver, kidney, lung ,spleen and brain. The 3,4-dihydroxybenzoic acid was used as the substrate for S-COMT in rat tissues. After incubated with different tissues, the product 4-hydroxy-3-methoxybenzoic acid was formed from the substrate and separated to measure the COMT activity. The analysis was performed on a Agilent C8 column (5 mum, 150>
Introduction:
Bipolar Disorder (BD) is a serious mood disorder, the aetiology of which is still unclear. The disorder is characterised by extreme mood variability in which patients fluctuate between markedly euphoric, irritable, and elevated states to periods of severe depression. The current research literature shows that BD patients demonstrate compromised neurocognitive ability in addition to these mood symptoms. Viable candidate genes implicated in neurocognitive and socioemotional processes may explain the development of these core emotion abnormalities. Additionally, links between faulty neurocognition and impaired socioemotional ability complement genetic explanations of BD pathogenesis. This review examines associations between cognition indexing prefrontal neural regions and socioemotional impairments including emotion processing and regulation. A review of the effect of COMT and TPH2 on these functions is also explored.
Methods:
Major computer databases including PsycINFO, Google Scholar, and Medline were consulted in order to conduct a comprehensive review of the genetic and cognitive literature in BD.
Results:
This review determines that COMT and TPH2 genetic variants contribute susceptibility to abnormal prefrontal neurocognitive function which oversees the processing and regulation of emotion. This provides for greater understanding of some of the emotional and cognitive symptoms in BD.
Conclusions:
Current findings in this direction show promise, although the literature is still in its infancy and further empirical research is required to investigate these links explicitly.
Velocardiofacial syndrome (VCFS) is a genetic disability syndrome that is caused, in most cases, by a de-novo 3 Mb microdeletion at chromosome region 22q11.2. The behavioral phenotype includes characteristic developmental, cognitive, and linguistic deficits, and psychiatric disorders, including childhood abnormalities of attention, mood, and anxiety. Recently, it was established that approximately 30% of people with VCFS develop schizophrenia, establishing VCFS as the first known genetic cause of schizophrenia. There has been recent progress in describing the molecular biology of the deletion site, characterizing the behavioral phenotype, and in defining the structural brain abnormalities in VCFS. However, numerous knowledge gaps remain in tracing the pathways from gene expression to brain structure, and to cognitive and psychiatric symptoms.
Catechol O-methyltransferase (COMT) is an enzyme that inactivates catecholamines. Two common COMT alleles determine high and low activity of the enzyme. Previous studies using biochemical methods found lower enzyme activity in patients with major depression and bipolar disorder in comparison with control values, suggesting that a dysfunction in catecholamine metabolism may be related to the etiology of depression.
The authors studied two recently described DNA polymorphisms at the COMT gene (a silent C256G mutation and a structural mutation, Val-108-Met) in 88 patients with bipolar disorder and in 113 healthy comparison subjects, all of Spanish origin.
The frequency of the C256 allele was 0.58 in the patients and 0.54 in the comparison subjects. The frequency of the Val108 variant was 0.57 for both the patients and the comparison subjects. No allelic or genotypic associations were observed.
The lack of association suggests that the COMT gene is not a major risk factor for bipolar disorder.
PART I of the present investigation reports the behavioral analysis of a patient with regular 48-hour manic-depressive cycles. These cycles persisted with clock-like regularity over a twoyear period and afforded the researchers a unique opportunity to observe and describe manic-depressive cycles. Part 2 of this investigation will report biochemical correlates of the behavioral changes and will offer a theoretical formulation of the relationship between the observed behavior and the biochemical determinations. The intensive study of a single patient may provide information unobtainable in the study of large numbers of individuals and may help in the formulation of theoretical models which will have application beyond the single patient.
This patient in the present study who will be referred to as Mrs. J had regular 48-hour cycles of mania and depression. On the depressed day the patient was slowed down, guilty, depressed, and sad-looking, while on the
Chronic administration of lithium carbonate to bipolar manic depressive patients has been shown to prevent or reduce the frequency and severity of subsequent episodes of depression and particularly those of mania.1–4 Those patients who continue to have affective attacks in spite of lithium carbonate prophylactic treatment have been studied by our group and others in order to determine if any clinical factors might be predictive of the lithium failure group.5–6 In a prior report from our clinic we noted that a group of patients with a high frequency of affective attacks predictably had a poor prophylactic outcome with lithium treatment. These patients were termed “rapid cyclers” and were characterized by having four or more episodes of depression and/or mania per year prior to the initiation of lithium prophylactic therapy.The purpose of this paper is to describe such patients in greater clinical detail and to illustrate the effect of lithium prophylactic treatment on their clinical courses. Based on our clinical experience with such patients, an approach to the treatment of rapid cycling manic-depressive patients is presented.
Different issues pertaining to the study of Rapid Cycling Affective Disorders (RCAD) are examined. RCAD's appear to be relatively infrequent, even though their clinical characterization does not differ from the conventional affective disorders. RC can be classified as early onset and late onset, according to time of appearance; spontaneous and induced (by pharmacological or nonpharmacological agents), according to causation; and ultra-rapid (48 hours) and classical (three days to 12 weeks), according to cycle length. Case reports seem to show that the ultra-rapid cyclers may have clear differences when compared with the classical rapid cyclers: elderly male patients seem to start their affective picture with RC, whereas younger female patients are predominantly classical rapid cyclers. The inducers seem to be far less specific and the response to treatment far less consistent in the ultra-rapid cyclers. The most widely accepted etiopathogenic theory ascribes an important role to thyroid hypofunction, probably precipitated by lithium treatment. The review, however, suggests that this theory may explain only a minority of cases. Treatment approaches remain tentative, inconsistent and even conflicting with the proposed etiopathogeneses. Clearly, terminological precisions, well defined clinical samples, neurohormonal and psychophysiological tests, and epidemiological designs, can and should help elucidate the key question of whether RCAD is an autonomous clinical condition or simply one end in the spectrum of cyclicity.
The authors illustrate methods for the graphic depiction of the course of unipolar and bipolar affective illness. The utility and advantages of such an approach include 1) accurate assessment of episode patterns, 2) elucidation of relationships to environmental events, endocrine and seasonal factors, and psychosocial stressors, 3) better delineation of treatment response, 4) a greater understanding of the longitudinal and characteristic patterns of illness, and 5) the associated better patient management with psychotherapeutic and pharmacological interventions.
Using data gathered in a naturalistic study of 95 research patients at the NIMH, a retrospective method of documenting the life course of recurrent affective illness is presented, along with a partial prospective validation of this method. In these patients, the severity, frequency, and duration of manic and depressive episodes, as well as their pattern and distribution, are characterized. These variables are examined in different patients subgrouped according to gender and age of onset, polarity, and rapidity of cycling of illness. The findings are compared with data on the life course of affective illness found in studies from the pre-pharmacologic era.
A case report is presented of a patient with a psychosis of manic-depressive type. Each phase lasts for 24 hours, and is followed by the other phase. This cycle has persisted for eleven years. It is accompanied by changes of the extracellular fluid volume, of the salivation rate, and other physical factors. In addition there is an abnormally large excretion of conjugated p-tyramine and p-hydroxyphenylacetic acid. The possible significance of such findings is discussed.
The course of 434 bipolar patients (256 women, 178 men) was studied longitudinally. The prevailing patterns of the manic-depressive cycles at the end of the observation time were: mania followed by depression (usually mild), 28%; depression followed by mania (usually hypomania), 25%; and continuous circular course, with long cycles, 19%, or with short (rapid) cycles, 20%. The cycles followed an irregular pattern in 8% of the patients.
As to the intensity of the episodes, 52% of the patients had severe depressions and hypomanias; 26% had severe manias and mild depressions; and 22% had severe depressions and severe manias. No significant sex differences was found regarding the patterns of the cycles or the intensity of the episodes, except among the rapid cyclers, where women (61) outnumbered men (26).
With time the course tended to change from monopolar to bipolar, and the frequency of recurrence increased. Concurrent treatments, especially antidepressants, contributed to these changes, while female sex, middle age and menopause, along with antidepressant drugs, contributed to the establishment of rapid cyclicity. The depression-hypomania course was the one which was most prone to rapid cyclicity.
Response to lithium prophylaxis was good in the maniadepression-free interval course, in the continuous circular course with long cycles, and in the irregular course. It was less good in the depression-mania-free interval course, where it increased the frequency of recurrences, although these were shorter and milder. Response was very poor in the rapid cycling course. But rapid cyclers and patients with the depressionmania-free interval course responded well to lithium when antidepressant drugs were not administered during the depressions.
Previous studies have shown that the activity of human red cell catechol-O-methyltransferase (RBC COMT) is significantly correlated in sibs, that the population distribution is bimodal, and that RBC COMT from individuals with low activity is more thermolabile than that from individuals with high activity.
These observations and additional data from family studies are consistent with the hypothesis that RBC COMT activity is controlled by two alleles at an autosomal locus [Weinshilboum and Raymond, 1977], giving rise to genotypes with different but overlapping activity distributions.
In the present study, this hypothesis has been explored with various types of analyses. Given the assumption of Hardy-Weinberg genotype frequencies, we find that the population distribution of RBC COMT activity is explained much better by codominant or “intermediate” inheritance than by either dominant or recessive inheritance.
The intermediate genetic model has also been used to analyze the data of Scanlon et al [1979] on thermal inactivation of RBC COMT in a random sample of blood donors. Hypothesis tests based on this analysis confirm the conclusion of Scanlon et al that individuals with different COMT genotypes differ in the thermostability of their RBC COMT.
Using the RBC COMT activities of low-activity probands and their parents, we have derived the expected distribution of activity among the proband's sibs on the assumption of three genotypes in Hardy-Weinberg equilibrium in the population. The fit of this expected distribution to that observed is excellent, supporting the genetic model.
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.
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.
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.
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.
Human soluble (S) and membrane-bound (MB) catechol O-methyltransferase (COMT, EC 2.1.1.6) enzymes have been expressed at sufficiently high levels in Escherichia coli and in baculovirus-infected insect cells to allow kinetic characterization of the enzyme forms. The use of tight-binding inhibitors such as entacapone enabled the estimation of actual enzyme concentrations and, thereby, comparison of velocity parameters, substrate selectivity, and regioselectivity of the methylation of both enzyme forms. Kinetics of the methylation reaction of dopamine, (-)-noradrenaline, L-dopa, and 3,4-dihydroxybenzoic acid was studied in detail. Here, the catalytic number (Vmax) of S-COMT was somewhat higher than that of MB-COMT for all four substrates. The Km values varied considerably, depending on both substrate and enzyme form. S-COMT showed about 15 times higher Km values for catecholamines than MB-COMT. The distinctive difference between the enzyme forms was also the higher affinity of MB-COMT for the coenzyme S-adenosyl-L-methionine (AdoMet). The average dissociation constants Ks were 3.4 and 20.2 microM for MB-COMT and S-COMT, respectively. Comparison between the kinetic results and the atomic structure of S-COMT is presented, and a revised mechanism for the reaction cycle is discussed. Two recently published human COMT cDNA sequences differed in the position of S-COMT amino acid 108, the residue being either Val-108 [Lundström et al. (1991) DNA Cell. Biol. 10, 181-189] or Met-108 [Bertocci et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 1416-1420].(ABSTRACT TRUNCATED AT 250 WORDS)
Velo-cardio-facial syndrome (VCFS) is a common genetic disorder among individuals with cleft palate and is associated with hemizygous deletions in human chromosome 22q11. Toward the molecular definition of the deletions, we constructed a physical map of 22q11 in the form of overlapping YACs. The physical map covers > 9 cM of genetic distance, estimated to span 5 Mb of DNA, and contains a total of 64 markers. Eleven highly polymorphic short tandem-repeat polymorphic (STRP) markers were placed on the physical map, and 10 of these were unambiguously ordered. The 11 polymorphic markers were used to type the DNA from a total of 61 VCFS patients and 49 unaffected relatives. Comparison of levels of heterozygosity of these markers in VCFS patients and their unaffected relatives revealed that four of these markers are commonly hemizygous among VCFS patients. To confirm these results and to define further the breakpoints in VCFS patients, 15 VCFS individuals and their unaffected parents were genotyped for the 11 STRP markers. Haplotypes generated from this study revealed that 82% of the patients have deletions that can be defined by the STRP markers. The results revealed that all patients who have a deletion share a common proximal breakpoint, while there are two distinct distal breakpoints. Markers D22S941 and D22S944 appear to be consistently hemizygous in patients with deletions. Both of these markers are located on a single nonchimeric YAC that is 400 kb long. The results also show that the parental origin of the deleted chromosome does not have any effect on the phenotypic manifestation.
The validity of rapid cycling as a distinct course modifier for bipolar disorder was assessed by comparing patients with and without a history of rapid cycling (4 or more affective episodes in 12 months) on demographic, clinical, family history, and outcome variables. These data were also used to formulate operational criteria for the modifier.
Data on subjects with rapid-cycling (N = 120) and nonrapid-cycling (N = 119) bipolar disorder from four sites were pooled and analyzed by using case-control and historical cohort methods.
The rapid-cycling group contained more women and more subjects from higher social classes than the nonrapid-cycling group. Family history did not differ between the groups. The diagnosis had predictive validity in that the rapid-cycling patients had more episodes than the nonrapid-cycling patients during prospective follow-up. The relationship between gender and episode frequency supported the validity of the cutoff point of 4-8 episodes per year. The data regarding whether patients with rapid cycling based on truncated episodes more closely resembled rapid-cycling or nonrapid-cycling patients were equivocal. Patients whose only rapid cycling was associated with antidepressants resembled spontaneously rapid-cycling patients, while the majority of spontaneously rapid-cycling patients also had periods of antidepressant-associated rapid cycling.
The validity of rapid cycling as a distinct course modifier for bipolar disorder is supported by differences in gender, prospectively assessed outcome, and perhaps social class between rapid-cycling and nonrapid-cycling patients. The relationship of gender to episode frequency supports the cutoff of 4 or more episodes per year.
DSM-III-R criteria, applied retrospectively in a research-oriented psychiatric clinic, identified patients (N = 146) with a mood disorder and a seasonal pattern of recurrence (seasonal mood disorder). The seasonal mood disorder syndrome was not rare (10% of all mood disorders); diagnostic distribution was as follows: recurrent depression, 51%, and bipolar disorder, 49%, with 30% of the latter having mania (bipolar disorder type I) and 19% having hypomania (bipolar disorder type II). Most patients were women (71%); onset age averaged 29 years, with a mean of eight cycles in 12 years of illness; mean episode duration was 5.0 months. Mood disorder was found in a high proportion (68%) of the families. All but one patient followed one of two seasonal patterns in equal frequency: type A, fall-winter depression with or without spring-summer mania or hypomania; and type B, spring-summer depression with or without fall-winter mania or hypomania. Both types showed consistent times of onset and remission. These results emphasize that DSM-III-R seasonal mood disorder includes severe cases of recurrent depression and bipolar disorder and support a distinction between two seasonal subtypes.
The purpose of this article is to review the literature concerning gender differences in the course of bipolar illness and discuss issues relevant to the treatment of women with the illness.
The literature concerning the following topics is reviewed: gender differences in the course of bipolar illness; effects of the female reproductive cycle on the course of bipolar illness; special considerations in the treatment of bipolar women (focusing on the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-thyroid axes); and hypotheses to explain the greater prevalence of rapid cycling among bipolar women than among bipolar men.
Data clearly indicate that rapid cycling is more common among bipolar women. Data also suggest that bipolar women may have more depressive episodes (and fewer manic episodes) and may be more likely to suffer from mixed (as opposed to pure) mania than bipolar men. While it is clear that bipolar women are at high risk for postpartum episodes, the effects of other reproductive system events (i.e., puberty, menstrual cycle, pregnancy, menopause, use of oral contraceptives or hormone replacement therapy) on the course or treatment of bipolar illness have received little systematic study. It is unclear whether women are at higher risk than men for developing lithium-induced hypothyroidism. Higher rates of hypothyroidism, greater use of antidepressants, and gonadal steroid effects are possible explanations for the greater prevalence of rapid cycling among bipolar women.
Gender differences in bipolar illness and the effects of the female reproductive system on the course and treatment of the illness deserve more study. The importance of a longitudinal approach to these questions is emphasized.
Catechol-O-methyltransferase (COMT) inactivates catecholamines and catechol drugs such as L-DOPA. A common genetic polymorphism in humans is associated with a three-to-four-fold variation in COMT enzyme activity and is also associated with individual variation in COMT thermal instability. We now show that this is due to G-->A transition at codon 158 of the COMT gene that results in a valine to methionine substitution. The two alleles can be identified with a PCR-based restriction fragment length polymorphism analysis using the restriction enzyme Nla III. The identification of a gentic marker associated with significant alterations in enzyme activity will facilitate the analysis of a possible role for the COMT gene in neuropsychiatric conditions in which abnormalities in catecholamine neurotransmission are believed to occur, including mood disorders, schizophrenia, obsessive compulsive disorder, alcohol and substance abuse, and attention deficit hyperactivity disorder. In addition, this polymorphism may have pharmacogenetic significance in that it will help make it possible to identify patients who display altered metabolism of catechol drugs.
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.
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.
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.
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.
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.
The purpose of this study was to conduct a systematic assessment of psychiatric illness in patients diagnosed with velo-cardio-facial syndrome, a genetic syndrome that involves over 40 somatic anomalies, learning disabilities, and behavioral disorders and is associated with a microdeletion on chromosome 22q11.
Subjects were referred for psychiatric diagnostic evaluation without regard to age or previous psychiatric history. In order to establish DSM-III-R consensus clinical diagnoses for patients who ranged in age from 5 to 34 years, the Diagnostic Interview for Children and Adolescents--Revised or the Structured Clinical Interview for DSM-III-R (SCID) was used. A review of available medical and psychiatric records and a clinical interview performed by two research psychiatrists to validate specific symptoms and syndromes reported in the Diagnostic Interview for Children and Adolescents--Revised and the SCID were used to elucidate the chronological appearance and duration of symptoms.
Sixty-four percent (N = 16 of 25) of this unselected series of patients with velo-cardio-facial syndrome met DSM-III-R criteria for a spectrum of bipolar disorders with full syndromal onset in late childhood or early adolescence (mean age at onset = 12 years, SD = 3). In addition, 20% (N = 5) met DSM-III-R criteria for attention deficit hyperactivity disorder (ADHD), while 16% (N = 4) met criteria for attention deficit disorder without hyperactivity. In contrast to previous reports of a high prevalence of schizophrenia, none of the patients was diagnosed with schizophrenia, and only four had psychotic symptoms during a phase of their illness, all in their 20s or 30s.
Given that the prevalence of bipolar disorder in the general population is estimated to be 1.5% and that the average age at onset is 24, these findings support an unusually strong association between velo-cardio-facial syndrome and early-onset bipolar disorder and suggest that a gene deleted at the 22q11 chromosomal locus may be involved in its pathogenesis. If confirmed, these findings may provide a new and fruitful line of investigation into the molecular basis of bipolar spectrum disorders.
In the present study, we address the role of the gene for catechol-O-methyltransferase (COMT), a key modulator of dopaminergic and noradrenergic neurotransmission, in the genetic predisposition to obsessive-compulsive disorder (OCD). We show that a common functional allele of this gene, which results in a 3- to 4-fold reduction in enzyme activity, is significantly associated in a recessive manner with susceptibility to OCD, particularly in males. This association is further supported by psychiatric evaluation of patients who carry microdeletions encompassing the comt gene. The mechanism underlying this sex-selective association remains to be defined and may include a sexual dimorphism in COMT activity, although close linkage with a nearby disease susceptibility locus cannot be excluded at this point.
Abnormal catecholamine transmission has been implicated in the pathogenesis of mood disorders. Consequently, alterations in genes that are involved in catecholamine metabolism could be potential candidates for bipolar affective disorder (BPD) vulnerability. One such candidate is catechol-O-methyltransferase (COMT). A functional polymorphism has recently been characterized that is responsible for substantial variability in COMT enzymatic activity. A relatively low activity allele is associated with a methionine residue at amino acid 158 of membrane bound COMT whereas a high activity variant has a valine at this site. We have now screened 63 unrelated patients with BPD for this functional polymorphism. However, no significant association was detected. This suggests that the codon 158 COMT polymorphism is not a susceptibility gene in BPD.
To provide a review of the epidemiology, phenomenology, natural course, comorbidity, neurobiology, and treatment of child and adolescent bipolar disorder (BP) for the past 10 years. This review is provided to prepare applicants for recertification by the American Board of Psychiatry and Neurology.
Literature from Medline and other searches for the past 10 years, earlier relevant articles, and the authors' experience and ongoing National Institute of Mental Health-funded project "Phenomenology and Course of Pediatric Bipolarity" were used.
Age-specific, developmental (child, adolescent, and adult) DSM-IV criteria manifestations; comorbidity and differential diagnoses; and episode and course features are provided. Included are age-specific examples of childhood grandiosity, hypersexuality, and delusions. Differential diagnoses (e.g., specific language disorders, sexual abuse, conduct disorder [CD], schizophrenia, substance abuse), suicidality, and BP-II are discussed.
Available data strongly suggest that prepubertal-onset BP is a nonepisodic, chronic, rapid-cycling, mixed manic state that may be comorbid with attention-deficit hyperactivity disorder (ADHD) and CD or have features of ADHD and/or CD as initial manifestations. Systematic research on pediatric BP is in its infancy and will require ongoing and future studies to provide developmentally relevant diagnostic methods and treatment.
No evidence for linkage of COMT polymorphism in bipolar disorder
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19 Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM. Human catechol-O-methyltransferase pharmacogenetics. Description of a functional polymorphism and its
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48 hour sleep-wake cycles in manic-depressive illness
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