Association of dopamine transporter gene variants with childhood ADHD features in bipolar disorder.

Bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD) exhibit remarkably high rates of comorbidity, as well as patterns of familial co-segregation. Epidemiological data suggests that these disorders either share a common genetic architecture or that ADHD features in BD may represent an etiologically distinct subtype. We previously used the Wender Utah Rating Scale (WURS) to assess ADHD features in BD families and identified three heritable factors relating to impulsivity, mood instability, and inattention. Linkage analysis revealed a LOD score of 1.33 for the inattention factor on 5p15.3 near the dopamine transporter gene (DAT1), which has been associated with both BD and ADHD. Pharmacological evidence also suggests a role for DAT in both disorders. We have now evaluated the association of ten DAT1 variants for the WURS total score and factors in an overlapping sample of 87 BD families. Significant associations for three SNPs were observed across the WURS measures, notably for a SNP in intron 8 with the WURS total score (P = 0.007) and for variants in introns 9 and 13 with mood instability (P = 0.009 and 0.004, respectively). Analysis of an independent sample of 52 BD cases and 46 healthy controls further supported association of the intron 8 variant with mood instability (P = 0.005), and a combined analysis confirmed the associations of this SNP with WURS total score. Impulsivity and mood instability (P = 0.002, 0.007, and 8 × 10(-4), respectively). These data suggest that variants within DAT1 may predispose to a subtype of BD characterized by early prodromal features that include attentional deficits.

Further evidence for linkage of bipolar disorder to chromosomes 6 and 17 in a new independent pedigree series.

OBJECTIVES: We have previously reported the results of a linkage analysis of bipolar disorder in an initial set of 20 pedigrees ascertained through collaboration among three sites. We now report the results of our genome-wide linkage analysis in an independent sample of 34 pedigrees segregating bipolar disorder. METHODS: Families were ascertained through a bipolar I or II disorder proband for the presence of bipolar I disorder, bipolar II disorder, or recurrent major depression in at least two other family members. A total of 440 markers at an average spacing of 8 cM were genotyped in 229 family members using fluorescent methods. RESULTS: Initial nonparametric analyses of chromosomes 6 and 17 provided evidence for a modest replication of linkage to these chromosomes previously reported in other studies. Additional analyses using multipoint parametric methods provided further evidence to support the 6q25 region with a heterogeneity logarithm of odds score of 3.28. Evidence from two-point parametric analyses also provides a modest replication of our previous findings of linkage to the 23 cM region of chromosome 22q13 in our original University of California, San Diego sample of 20 families and 57 families from the National Institute of Mental Health bipolar disorder sample. CONCLUSIONS: Our results suggest replication of some reported linkage peaks, such as 6q25 and 17p12; however, other peaks from our own previous study, such as 5p15, 13q32, and 22q13, were either not replicated or were only modestly replicated in these analyses.

Suggestive evidence for linkage of ADHD features in bipolar disorder to chromosome 10p14.

Higher rates of bipolar disorder amongst the first-degree relatives of probands with ADHD, and increased rates of ADHD in the relatives of bipolar probands have been reported in many studies. This suggests some commonality in the genetic basis for bipolar disorder and ADHD. We hypothesized that ADHD symptoms in bipolar disorder may access a quantitative subphenotype that is genetically less complex and therefore advantageous for mapping studies. The Wender Utah Rating Scale (WURS) was used to quantify ADHD features in 57 bipolar families collected for linkage studies. The factor structure of the WURS was first examined, and heritability was estimated. Linkage analysis was then conducted using the WURS total score and factor scores as quantitative traits. Three factors were identified: impulsivity and defiant behavior, mood instability and anxiety, and inattention. The total WURS and factor scores were each significantly heritable (0.34

Suggestive linkage of a chromosomal locus on 18p11 to cyclothymic temperament in bipolar disorder families.

Attempts to identify bipolar disorder (BP) genes have only enjoyed limited success. One potential cause for this problem is that the traditional categorical BP phenotypes currently used in genetic linkage studies are not the most informative, efficient, or biologically relevant. An alternative to these strict categorical BP phenotypes is quantitative BP phenotypes. By isolating one aspect of a complex trait such as BP into a simple, intermediate, quantitative trait, genes that contribute to the larger complex trait can be more readily identified. Along these lines, we utilized a temperament-based measure (cyclothymic temperament) as a quantitative, intermediate BP phenotype in linkage analyses and hypothesized that this measure might more efficiently detect loci for BP or temperamental traits that predispose to BP. A total of 158 individuals with temperament data from 28 BP families were used in the linkage analyses. All pedigrees had a proband diagnosed with BPI or BPII and at least two other family members with a mood disorder diagnosis. An 8 cM genome scan was performed and analyzed using MERLIN nonparametric multipoint regression linkage for a cyclothymic temperament trait. The highest overall LOD score was on chromosome 18 (LOD = 2.71, P = 0.0002). Other linkage peaks which may indicate potential regions of interest were found on chromosomes 3 and 7. The temperament-based cyclothymic trait yielded a higher peak LOD score and a lower P-value than analyses using traditional, categorical phenotypes in a separate analysis including these same families.

Examination of the clock gene Cryptochrome 1 in bipolar disorder: mutational analysis and absence of evidence for linkage or association.

Bipolar disorder is associated with malfunctions of the circadian system, which regulates individual circadian rhythms and which enables the adaptation to a daily 24-h cycle and seasonal change. One of the human circadian clock genes, cryptochrome 1 (Cry1) (located on 12q23-q24.1) was analyzed because of its close correspondence to a linkage hotspot for bipolar disorder. We found no evidence for linkage of 52 bipolar families to two Cry1 flanking microsatellites under several parametric and non-parametric models. In order to employ association for a more sensitive test, 25 affected subjects selected from families with positive LOD scores were screened for mutations by sequencing 9.5% of the Cry1 gene. A total of 16 single nucleotide polymorphisms (SNPs) and a 3 base pair insertion were identified. However, no mutations with probable functional impact were found. These novel SNPs and data on allele frequency and linkage disequilibrium structure will be useful for future association analyses. Nine SNPs have been analyzed in a set of 159 parent proband triads. Linkage disequilibrium analyses using single SNPs and haplotypes showed no association to bipolar disease.Additional, more powerful, studies involving Cry1 and other circadian clock genes need to be tested before an association of circadian abnormalities with bipolar disorder can be excluded.

Familiality of temperament in bipolar disorder: support for a genetic spectrum.

BACKGROUND: The array of different diagnoses and clinical presentations seen in the family members of bipolar probands suggests a quantitative or spectrum phenotype. Consistent with this idea, it has been proposed that an underlying quantitative variation in temperament may be the primary phenotype that is genetically transmitted and that it in turn predisposes to bipolar disorder (BP). Choosing the appropriate phenotypic model for BP is crucial for success in genetic mapping studies. To test this theory, various measures of temperament were examined in the family members of bipolar probands. We predicted that a gradient of scores would be observed from those with BP to those with major depression to unaffected relatives to controls. METHODS: Members of 85 bipolar families and 63 control subjects were administered clinical interviews for diagnosis (SCID) and two temperament assessments, the TEMPS-A and TCI-125. Subjects with BP, major depressive disorder, unaffected relatives, and controls were compared on each temperament scale and on eight factors extracted from a joint factor analysis of the TEMPS-A and TCI-125. RESULTS: The four groups were found to be significantly different and with the expected order of average group scores for four of the TEMPS-A scales, three of the TCI-125 scales, and one of the extracted factors. On the fifth TEMPS-A scale, hyperthymic, controls scored higher than the other three subject groups contrary to expectations. Significant differences were seen between unaffected relatives and controls on the hyperthymic scale and on the first extracted factor, anxious/reactive. LIMITATIONS: Controls were mainly recruited through advertisements, which may have introduced an ascertainment bias. It is also possible that mood state at the time of completing the questionnaire influenced subject's rating of their temperament. Additionally, bipolar I and bipolar II subjects were placed in the same group even though they had some differing clinical features. CONCLUSIONS: Our data support the theory that some dimensions of temperament are transmitted in families as quantitative traits that are part of a broader bipolar spectrum. In particular, the hyperthymic scale of the TEMPS-A and the anxious/reactive extracted factor distinguished unaffected relatives from controls. The hyperthymic scale yielded results opposite to expectation with controls higher than any family group. This may be an artifact of the self-rated form of the questionnaire, a consequence of our grouping bipolar I and II subjects together, or the result of a "protective" factor and bears further study. Nevertheless, both of these scales may be useful quantitative traits for genetic mapping studies.

Exercise as medicine-the use of group medical visits to promote physical activity and treat chronic moderate depression: a preliminary 14-week pre-post study.

OBJECTIVE: The evidence that regular physical activity can treat depressive disorders is increasingly robust. However, motivating patients with depression to engage in physical activity can be challenging. Interdisciplinary group medical visits (GMVs) with an integrated physical activity component may be a novel means to support patients in becoming more active. METHODS: We conducted a 'pre-post' pilot study within a primary care setting. Participants were adults (≥18 years) with a chronic major depressive disorder or a bipolar 2 disorder (depression; chronic). A psychiatrist and exercise therapist co-led a series of 14 weekly 2 h GMVs. Each group visit combined specific medical advice, physical activity, patient discussions and a targeted educational component. Participants also attended 11 weekly hatha yoga classes. Primary outcome was 'steps' as measured by accelerometer (SenseWear) as well as depression (Patient Health Questionnaire, PHQ-9) and anxiety (Generalised Anxiety Disorder, GAD-7) ratings. RESULTS: 14 of 15 participants (93.3%) completed the 14-week programme. After 3 months postintervention, median depression scales (PHQ-9) decreased 38% from 16 to 10 (p<0.01; IQR pre/post 8/12); and median anxiety scales (GAD-7) decreased 50% from 13 to 6.5 (p<0.05; IQR 8.5/9). Median daily 'steps' increased 71% from 3366 to 5746 (IQR 2610/6237), though this was not significant (p>0.10). CONCLUSIONS: While other studies have examined the efficacy of GMVs in addressing chronic illnesses and the promotion of lifestyle changes, none to our knowledge have embedded physical activity within the actual patient visits. Interdisciplinary GMVs (eg, psychiatrist/exercise professional) may be a means to decrease depression and anxiety ratings within clinical care while improving physical activity.

A linkage disequilibrium study of bipolar disorder and microsatellite markers on 22q13.

Bipolar disorder is a major psychiatric disorder characterized by extreme mood states that alternate between mania and depression. Family, twin, and adoption studies indicate a genetic component to the disease, but the etiology is suspected to be complex, with multiple genes contributing to an increased susceptibility to the disorder. We have previously reported a genome scan in which a genome-wide maximum LOD score indicated evidence of linkage at the marker D22S278 at 22q13. This area is of particular interest since it is also implicated in schizophrenia, and thus may harbor a susceptibility gene common to both disorders. In our further efforts to fine map this region, we examined 10 microsatellite markers spanning an interval of 2.3 MB in a set of 142 parent-proband triads. Linkage disequilibrium to illness was tested using the Transmission Disequilibrium Test. Haplotypes were determined and marker-to-marker linkage disequilibrium across the region was examined. D22S281 and D22S685 yielded suggestive evidence of linkage disequilibrium to bipolar disorder (empirical values of 0.023 and 0.036, respectively), but a marker-to-marker analysis indicates that a higher density screen is needed to adequately analyze this region.

Do patients really prefer individual outpatient follow-up visits, compared with group medical visits?

OBJECTIVE: Access to outpatient psychiatric care remains problematic in Canada. We have been using group medical visits (GMV) to treat psychiatric outpatients with mood and anxiety disorders. Our study aimed to show that patients are similarly satisfied with GMV and individual psychiatric treatment, hence the concern that patients truly prefer individual treatment may be unfounded. METHOD: Our study compared patient satisfaction in people who have had previous individual psychiatric care and are now receiving GMV to determine whether there is a treatment preference. RESULTS: Questionnaire data were analyzed using repeated measures ANOVA. The ANOVAs showed no differences in patients' experiences with individual treatment, compared with GMV. In addition, we found when asked directly, most patients preferred GMV or had no treatment preference. CONCLUSIONS: These findings indicate that patients' perspectives of individual psychiatric treatment and GMV are roughly equal. This suggests that the method of GMV deserves further study and comparison with other clinical models of psychiatric outpatient treatment.

Objectif : L'accès aux soins psychiatriques ambulatoires demeure problématique au Canada. Nous avons eu recours aux visites médicales en groupe (VMG) pour traiter les patients externes psychiatriques souffrant de troubles de l'humeur et d'anxiété. Notre étude visait à démontrer que les patients sont semblablement satisfaits des VMG et du traitement individuel psychiatrique. C'est pourquoi il n'est peut-être pas fondé d'affirmer que les patients préfèrent vraiment le traitement individuel. Méthode : Notre étude comparait la satisfaction de patients qui avaient auparavant reçu des soins psychiatriques individuels et qui avaient maintenant droit à des VMG afin de déterminer s'il existe une préférence de traitement. Résultats : Les données d'un questionnaire ont été analysées à l'aide de mesures répétées de l'analyse de variance. Les analyses de variance n'indiquaient aucune différence dans les expériences des patients en traitement individuel, comparé aux VMG. En outre, quand nous l'avons demandé directement, nous avons constaté que la plupart des patients préféraient la VMG ou n'avaient aucune préférence de traitement. Conclusions : Ces résultats indiquent que les points de vue des patients sur le traitement psychiatrique individuel et les VMG sont à peu près égaux, ce qui suggère que la méthode des VMG mérite une étude approfondie et une comparaison avec d'autres modèles cliniques de traitement psychiatrique ambulatoire.

The mood disorders association of british columbia psychiatric urgent care program: a preliminary evaluation of a suggested alternative model of outpatient psychiatric care.

OBJECTIVE: To describe an alternative model of psychiatric outpatient care for patients with mood and anxiety disorders (the Mood Disorders Association of British Columbia Psychiatric Urgent Care Program or the MDA Program) using group medical visits (GMV) and (or) email communications in lieu of individual follow-up appointments. METHOD: Annual costs of the MDA Program were compared with average costs of private psychiatrists offering outpatient care and patients being treated in a mental health centre. In addition, questionnaires as to patient satisfaction with the MDA Program intake, GMV experience, and family physician satisfaction with the MDA Program were administered. RESULTS: The MDA Program model of care is significantly more cost effective than individual psychiatric outpatient care or health authority mental health centre care for patients with moderate or severe illness. Patients and family physicians were very satisfied with the model of care and GMVs offered. CONCLUSIONS: The MDA Program model of care appears to be efficient and cost-effective, and patients and referring physicians appear satisfied with the care offered in this program.

Heritability and linkage analysis of personality in bipolar disorder.

BACKGROUND: The many attempts that have been made to identify genes for bipolar disorder (BD) have met with limited success, which may reflect an inadequacy of diagnosis as an informative and biologically relevant phenotype for genetic studies. Here we have explored aspects of personality as quantitative phenotypes for bipolar disorder through the use of the Temperament and Character Inventory (TCI), which assesses personality in seven dimensions. Four temperament dimensions are assessed: novelty seeking (NS), harm avoidance (HA), reward dependence (RD), and persistence (PS). Three character dimensions are also included: self-directedness (SD), cooperativeness (CO), and self-transcendence (ST). METHODS: We compared personality scores between diagnostic groups and assessed heritability in a sample of 101 families collected for genetic studies of BD. A genome-wide SNP linkage analysis was then performed in the subset of 51 families for which genetic data was available. RESULTS: Significant group differences were observed between BD subjects, their first-degree relatives, and independent controls for all but RD and PS, and all but HA and RD were found to be significantly heritable in this sample. Linkage analysis of the heritable dimensions produced several suggestive linkage peaks for NS (chromosomes 7q21 and 10p15), PS (chromosomes 6q16, 12p13, and 19p13), and SD (chromosomes 4q35, 8q24, and 18q12). LIMITATIONS: The relatively small size of our linkage sample likely limited our ability to reach genome-wide significance in this study. CONCLUSIONS: While not genome-wide significant, these results suggest that aspects of personality may prove useful in the identification of genes underlying BD susceptibility.

Heritability and genome-wide SNP linkage analysis of temperament in bipolar disorder.

BACKGROUND: The many attempts to identify genes for bipolar disorder (BD) have met with limited success, which has generally been attributed to genetic heterogeneity and small gene effects. However, it is also possible that the categorical phenotypes used in genetic studies of BD are not the most informative or biologically relevant. We have explored aspects of temperament as quantitative phenotypes for BD through the use of the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Auto-questionnaire (TEMPS-A), which is designed to assess lifelong, milder aspects of bipolar symptomatology and defines five temperaments: hyperthymic, dysthymic, cyclothymic, irritable, and anxious. METHODS: We compared temperament scores between diagnostic groups and assessed heritability in a sample of 101 families collected for genetic studies of BD. A genome-wide SNP linkage study was then performed in the subset of 51 families for which genetic data was available. RESULTS: Significant group differences were observed between BD subjects, their first-degree relatives, and independent controls, and all five temperaments were found to be significantly heritable, with heritabilities ranging from 21% for the hyperthymic to 52% for the irritable temperaments. Suggestive evidence for linkage was observed for the hyperthymic (chromosomes 1q44, 2p16, 6q16, and 14q23), dysthymic (chromosomes 3p21 and 13q34), and irritable (chromosome 6q24) temperaments. LIMITATIONS: The relatively small size of our linkage sample likely limited our ability to reach genome-wide significance in this study. CONCLUSIONS: While not genome-wide significant, these results suggest that aspects of temperament may prove useful in the identification of genes underlying BD susceptibility.

Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder.

Bipolar affective disorder (BPAD) is suspected to arise in part from malfunctions of the circadian system, a system that enables adaptation to a daily and seasonally cycling environment. Genetic variations altering functions of genes involved with the input to the circadian clock, in the molecular feedback loops constituting the circadian oscillatory mechanism itself, or in the regulatory output systems could influence BPAD as a result. Several human circadian system genes have been identified and localized recently, and a comparison with linkage hotspots for BPAD has revealed some correspondences. We have assessed evidence for linkage and association involving polymorphisms in 10 circadian clock genes (ARNTL, CLOCK, CRY2, CSNK1epsilon, DBP, GSK3beta, NPAS2, PER1, PER2, and PER3) to BPAD. Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1epsilon. This finding was not substantiated in the association study. Fifty-two SNPs in 10 clock genes were genotyped in 185 parent proband triads. Single SNP TDT analyses showed no evidence for association to BPAD. However, more powerful haplotype analyses suggest two candidates deserving further studies. Haplotypes in ARNTL and PER3 were found to be significantly associated with BPAD via single-gene permutation tests (PG = 0.025 and 0.008, respectively). The most suggestive haplotypes in PER3 showed a Bonferroni-corrected P-value of PGC = 0.07. These two genes have previously been implicated in circadian rhythm sleep disorders and affective disorders. With correction for the number of genes considered and tests conducted, these data do not provide statistically significant evidence for association. However, the trends for ARNTL and PER3 are suggestive of their involvement in bipolar disorder and warrant further study in a larger sample.

Diagnosis and management of depression in primary care: a clinical update and review.

THERE HAS BEEN SIGNIFICANT PROGRESS in the area of mood disorders over the last 2 decades, encompassing advances in our knowledge of epidemiology, diagnosis, pathogenesis and treatment. This article presents a clinically oriented update and review on the diagnosis and management of major depressive disorder.

Monoamine Oxidase Inhibitors in General Anesthesia: A Reevaluation.

A controlled study on the cardiovascular safety of monoamine oxidase inhibitors (MAOI) during general anesthesia for electroconvulsive therapy (ECT) was completed. No serious changes in blood pressure, heart rate, or ectopic beats were noted in either the MAOI or control groups during ECT. Based on pharmacological data, a review of the literature, and these preliminary results, the recommended 2-week discontinuation of MAOI before ECT appears unwarranted. Clinical guidelines for the concomitant use of MAOI and general anesthesia are offered.