Ronald A. Remick

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, CSNK1ε, DBP, GSK3β, NPAS2, PER1, PER2, and PER3) to BPAD. Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1ε. 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.

Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder

A role for the dopamine transporter (DAT) in bipolar disorder is implicated by several lines of pharmacological evidence, as well as suggestive evidence of linkage at this locus, which we have reported previously. In an attempt to identify functional mutations within DAT contributing a susceptibility to bipolar disorder, we have screened the entire coding region, as well as significant portions of the adjacent non-coding sequence. Though we have not found a definitive functional mutation, we have identified a number of single nucleotide polymorphisms (SNPs) that span the gene from the distal promoter through exon 15. Of the 39 SNPs that are suitable for linkage disequilibrium (LD) studies, 14 have been analyzed by allele-specific PCR in a sample of 50 parent-proband triads with bipolar disorder. A haplotyped marker comprised of five SNPs, spanning the region between exon 9 and exon 15, was constructed for each individual, and transmission/disequilibrium test (TDT) analysis revealed this haplotype to be in linkage disequilibrium with bipolar disorder (allele-wise TDT p = 0.001, genotype-wise TDT p = 0.0004). These data replicate our previous finding of linkage to markers within and near DAT in a largely different family set, and provide further evidence for a role of DAT in bipolar disorder. Published 2001 Wiley-Liss. Inc.

Weight gain with antidepressants and lithium

Undesired weight gain is a common complaint of patients receiving pharmacological treatment for major affective disorders. It has been found to jeopardize patient compliance and may pose additional health hazards. A review of the literature on weight gain associated with tricyclic antidepressants, monoamine oxidase inhibitors, and lithium was carried out with the aim of deriving practical management strategies. Tricyclic antidepressants were found to stimulate appetite, carbohydrate craving, and a dose-dependent continuous weight gain of 0.57 to 1.37 kg per month of treatment. Proposed mechanisms include noradrenergic or antihistaminic inhibition of satiety and decreased metabolic rate. Novel serotonergic and dopaminergic antidepressants were found to be anorectic. Monoamine oxidase inhibitors may stimulate appetite and potentiate insulin-induced hypoglycemia. Lithium maintenance therapy stimulates weight gains of over 10 kg in 20% of patients. Documented mechanisms include insulin-like actions on carbohydrate and fat metabolism, polydipsia, and sodium retention. Recommendations regarding choice of antidepressant drug as well as dietary and behavioral strategies to prevent excessive weight gain are presented. Potential adjunctive drug approaches to severe weight gain are reviewed.

Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder

In a genome-wide linkage survey, we have previously shown evidence suggesting that the chromosome 22q12 region contains a susceptibility locus for bipolar disorder (BPD). Two independent family sets yielded lod scores suggestive of linkage at markers in this region near the gene G protein receptor kinase 3 (GRK3). GRK3 is an excellent candidate risk gene for BPD since GRK3 is expressed widely in the brain, and since GRKs play key roles in the homologous desensitization of G protein-coupled receptor signaling. We have also previously shown GRK3 expression to be induced by amphetamine in an animal model of mania using microarray-based expression profiling. To identify possible functional mutations in GRK3, we sequenced the putative promoter region, all 21 exons, and intronic sequence flanking each exon, in 14–22 individuals with BPD. We found six sequence variants in the 5′-UTR/promoter region, but no coding or obvious splice variants. Transmission disequilibrium analyses of one set of 153 families indicated that two of the 5′-UTR/promoter variants are associated with BPD in families of northern European Caucasian ancestry. A supportive trend towards association to one of these two variants (P-5) was then subsequently obtained in an independent sample of 237 families. In the combined sample, the P-5 variant had an estimated allele frequency of 3% in bipolar subjects, and displayed a transmission to non-transmission ratio of 26 : 7.7 (χ2=9.6, one-sided P value=0.0019). Altogether, these data support the hypothesis that a dysregulation in GRK3 expression alters signaling desensitization, and thereby predisposes to the development of BPD.

Linkage studies suggest a possible locus for bipolar disorder near the velo-cardio-facial syndrome region on chromosome 22

Velo-cardio-facial syndrome (VCFS) is a congenital anomaly characterized by multiple dysmorphisms, cleft palate, cardiac anomalies, and learning disabilities, that results from a microdeletion of chromosome 22q11. An increased prevalence of psychiatric illness has been observed, with both schizophrenia and bipolar disorder commonly being diagnosed. For these reasons, the VCFS region is an interesting candidate region for bipolar disorder. We examined this region in 17 bipolar families from three populations: 13 families from the general North American population (University of California, San Diego/University of British Columbia, UCSD/UBC), three larger families from New York, and a portion of Old Order Amish pedigree 110. Three microsatellite markers spanning 13 cM around the VCFS region were genotyped in all the families. A maximum lod score of 2.51 was obtained in the UCSD/UBC families under a dominant model at D22S303. In the combined family set, maximum lod scores of 1.68 and 1.28 were obtained at this marker under dominant and recessive models, respectively. Four additional markers were subsequently typed in selected positive families, and yielded positive lods at 6 of 7 markers spanning 18 cM in this region. Nonparametric, multipoint analyses using the affected pedigree member (APM) method also yielded suggestive evidence for linkage in both the UCSD/UBC family set (P = 0.0024) and in the combined families (P = 0.017). Affected sibpair analyses were similarly positive in the UCSD/UBC families (P = 0.017), and in the combined families (P = 0.004). These results are suggestive of a possible locus for bipolar disorder near the VCFS region on chromosome 22.

Shape- and weight-based self-esteem and the eating disorders

OBJECTIVES To determine the psychometric properties of the Shape- and Weight-Based Self-Esteem (SAWBS) Inventory in women with eating disorders, and to compare SAWBS scores in women who have eating disorders with women from psychiatric and normal control groups. METHOD Women with eating disorders (n = 48), women with other psychiatric disorders (n = 44), and undergraduate control women (n = 82) completed the SAWBS Inventory and measures of depression, self-esteem, and eating disorder symptomatology. Twenty women from the eating disorder group completed the SAWBS Inventory a second time 1 week later. RESULTS Similar to previous work in undergraduate samples, SAWBS scores were stable over 1 week, and demonstrated concurrent and discriminant validity in women with eating disorders. In between-group comparisons, SAWBS scores were higher among women with eating disorders than in either control group, even after controlling for age, socioeconomic status, body mass index, and self-esteem. A differing relationship between depression and SAWBS emerged as a function of group; SAWBS scores differed significantly among depressed, but not nondepressed women from the three groups. CONCLUSION The psychometric properties of the SAWBS Inventory were established in women with eating disorders. As expected, SAWBS scores were higher in women with eating disorders than in the control groups. Clinical implications of these findings are discussed.

A Canadian multicenter, double-blind study of paroxetine and fluoxetine in major depressive disorder

BACKGROUND Recent studies have suggested clinical differences among selective serotonin reuptake inhibitors. In a 12-week randomized, multicenter, double-blind trial, the antidepressant and anxiolytic efficacy of the selective serotonin reuptake inhibitors paroxetine and fluoxetine was compared in patients with moderate to severe depression. METHODS A total of 203 patients were randomized to fixed doses (20 mg/day) of paroxetine or fluoxetine for the first six weeks of therapy. From week 7-12, dosing could be adjusted biweekly, as required (paroxetine 20-50 mg/day, and fluoxetine 20-80 mg/day). The mean prescribed doses were paroxetine 25.5 mg/day (range 20.0-40.2 mg/day), and fluoxetine 27.5 mg/day (range 20.0-59.5 mg/day). Emergence of motor nervousness or restlessness was assessed using the ESRS scale for akathisia. RESULTS Both active treatments demonstrated comparable antidepressant efficacy (HAM-D, CGI). Anxiolytic activity of the two drugs (COVI, STAI, HAM-D) was also comparable. However, paroxetine was found to be superior to fluoxetine on two subscore measures at week 1 of therapy (HAM-D Agitation item, p < 0.05; Psychic Anxiety item, p < 0.05), with no differences detected after week 2. The overall incidence of adverse effects was comparable in the two treatment groups. Constipation, dyspepsia, tremor, sweating and abnormal ejaculation were more common in paroxetine-treated subjects, whereas nausea and nervousness were more frequent in fluoxetine-treated patients. Weight loss was more common in the fluoxetine versus paroxetine group (11.88% versus 2.94%, respectively). ESRS scores for akathisia were low throughout the study and showed little change. LIMITATIONS Differences observed between the two drugs in antianxiety effects were limited to two measures of anxiety among several others. DISCUSSION The data indicate that paroxetine and fluoxetine have comparable antidepressant and anxiolytic efficacy. Paroxetine appears to produce an earlier improvement in agitation and psychic anxiety symptoms compared with fluoxetine.

Segmental linkage disequilibrium within the dopamine transporter gene.

The dopamine transporter gene (DAT) has been implicated in a variety of disorders, including bipolar disorder, attention-deficit hyperactivity disorder, cocaine-induced paranoia, Tourettes syndrome, and Parkinsons disease. As no clear functional polymorphism has been identified to date, studies rely on linkage disequilibrium (LD) to assess the possible genetic contribution of DAT to the various disorders. A better understanding of the complex structure of LD across the gene is thus critical for an accurate interpretation of the results of such studies, and may facilitate the mapping of the actual functional variants. In the process of characterizing the extent of variation within the DAT gene, we have identified a number of single nucleotide polymorphisms (SNPs) suitable for LD studies, 14 of which have been analyzed, along with a 3′ repeat polymorphism, in a sample of 120 parent-proband triads. Calculations of pairwise LD between the SNPs in the parental haplotypes revealed a high degree of LD (P < 0.00001) in the 5′ (distal promoter through intron 6) and 3′ (exon 9 through exon 15) regions of DAT. This segmental LD pattern is maintained over approximately 27 kb and 20 kb in these two regions, respectively, with very little significant LD between them, possibly due to the presence of a recombination hotspot located near the middle of the gene. These analyses of the DAT gene thus reveal a complex structure resulting from both recombination and mutation, knowledge of which may be invaluable to the design of future studies.

Psychiatric disorders associated with atypical facial pain.

Atypical facial pain (AFP) patients classically present with a chronic discomfort that is neither anatomic nor dermatomal in distribution. Neuropsychiatric assessment of 68 patients with AFP indicated that 46 (68%) had a specific psychiatric disorder by DSM-III criteria. A wide spectrum of psychiatric disorders was present. The authors emphasize that psychiatric assessment of patients with AFP should be an integral part in early assessments of this disorder, rather than relying on psychiatric opinions after extensive dental and other invasive procedures have been tried in vain and often to the detriment of the patient. Comments on the excellent prognosis in treating the psychiatric syndromes associated with AFP are made.

Ineffective dental and surgical treatment associated with atypical facial pain

Patients with atypical facial pain (AFP) are subject to ineffective dental and surgical procedures for their pain complaints. Twenty-one of fifty-eight patients (36.2 percent) with AFP had sixty-five dental and surgical treatments, with only one patient showing less pain as a result of the treatment. While the majority of patients (69 percent) with AFP suffered from a psychiatric illness, fourteen (24 percent) of the patients referred for AFP had a specific medical or dental disorder that was causal in their pain complaints. There is a trend for the AFP patient with a psychiatric diagnosis to receive more ineffective treatments than those AFP patients for whom a specific medical or dental diagnosis was made. Patients with AFP should receive conservative dental and medical treatment and a psychiatric assessment before dental and surgical procedures are contemplated.