Bipolar Disorder: Parikh SV

Yatham LN, Kennedy SH, O'Donovan C, Parikh SV, MacQueen G, McIntyre RS, Sharma V, Beaulieu S, Anonymous00162. · Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada. · Bipolar Disord. · Pubmed #17156158 No free full text.

Abstract: In 2005, the Canadian Network for Mood and Anxiety Treatments (CANMAT) published guidelines for the management of bipolar disorder. This update reviews new evidence since the previous publication and incorporates recommendations based on the most current evidence for treatment of various phases of bipolar disorder. It is designed to be used in conjunction with the 2005 CANMAT Guidelines. The recommendations for the management of acute mania remain mostly unchanged. Lithium, valproate and several atypical antipsychotics continue to be recommended as first-line treatments for acute mania. For the management of bipolar depression, new data support quetiapine monotherapy as a first-line option. Lithium and lamotrigine monotherapy, olanzapine plus selective serotonin reuptake inhibitors (SSRI), and lithium or divalproex plus SSRI/bupropion continue to remain the other first-line options. First-line options in the maintenance treatment of bipolar disorder continue to be lithium, lamotrigine, valproate and olanzapine. There is recent evidence to support the combination of olanzapine and fluoxetine as a second-line maintenance therapy for bipolar depression. New data also support quetiapine monotherapy as a second-line option for the management of acute bipolar II depression. The importance of comorbid psychiatric and medical conditions cannot be understated, and this update provides an expanded look at the prevalence, impact and management of comorbid conditions in patients with bipolar disorder.

Zaretsky AE, Rizvi S, Parikh SV. · Department of Psychiatry, University of Toronto Medical School, Ontario. · Can J Psychiatry. · Pubmed #17444074 No free full text.

Abstract: OBJECTIVE: Although medication is the mainstay of treatment for bipolar disorder, several adjunctive psychosocial interventions have been manualized over the last decade. This paper's objective is to empirically evaluate the different treatment approaches. METHOD: We conducted a systematic review of the recent literature pertaining to psychosocial interventions in bipolar, using MEDLINE and PsycINFO. Bibliographies of papers were scrutinized for further relevant references. Articles published from 1999 up to and including 2006 were reviewed. Randomized controlled trials were emphasized. CONCLUSIONS: Although psychological models of bipolar disorder fail to inform the psychotherapy treatment to the same extent as in unipolar depression, manualized adjunctive, short-term psychotherapies have been shown to offer fairly consistent benefits to bipolar disorder patients. Cognitive-behavioural therapy, family-focused therapy, and psychoeducation offer the most robust efficacy in regard to relapse prevention, while interpersonal therapy and cognitive-behavioural therapy may offer more benefit in treating residual depressive symptoms.

Huxley NA, Parikh SV, Baldessarini RJ. · International Consortium for Bipolar Disorder Research (Drs. Huxley, Parikh, and Baldessarini). · Harv Rev Psychiatry. · Pubmed #10973937 No free full text.

Abstract: Cost-effective psychotherapeutic interventions can enhance pharmacotherapy and improve outcomes in major depression and schizophrenia, but they are rarely studied in bipolar disorder, despite its often unsatisfactory response to medication alone. Following a literature search, we compiled and evaluated research reports on psychotherapeutic interventions in bipolar disorder patients. We found 32 peer-reviewed reports involving 1052 patients-14 studies on group therapy, 13 on couples or family therapy, and five on individual psychotherapy-all supplementing standard pharmacotherapy. Methodological limitations were common in these investigations. Nevertheless, important gains were often seen, as determined by objective measures of increased clinical stability and reduced rehospitalization, as well as other functional and psychosocial benefits. The results should further encourage rising international interest in testing the clinical and cost-effectiveness of psychosocial interventions in these common, often severe and disabling disorders.

Yatham LN, Kennedy SH, Schaffer A, Parikh SV, Beaulieu S, O'Donovan C, MacQueen G, McIntyre RS, Sharma V, Ravindran A, Young LT, Young AH, Alda M, Milev R, Vieta E, Calabrese JR, Berk M, Ha K, Kapczinski F. · Department of Psychiatry, University of British Columbia,2255 Wesbrook Mall, Vancouver, BC V6T 2A1, , Canada. · Bipolar Disord. · Pubmed #19419382 No free full text.

Abstract: The Canadian Network for Mood and Anxiety Treatments (CANMAT) published guidelines for the management of bipolar disorder in 2005, with a 2007 update. This second update, in conjunction with the International Society for Bipolar Disorders (ISBD), reviews new evidence and is designed to be used in conjunction with the previous publications. The recommendations for the management of acute mania remain mostly unchanged. Lithium, valproate, and several atypical antipsychotics continue to be first-line treatments for acute mania. Tamoxifen is now suggested as a third-line augmentation option. The combination of olanzapine and carbamazepine is not recommended. For the management of bipolar depression, lithium, lamotrigine, and quetiapine monotherapy, olanzapine plus selective serotonin reuptake inhibitor (SSRI), and lithium or divalproex plus SSRI/bupropion remain first-line options. New data support the use of adjunctive modafinil as a second-line option, but also indicate that aripiprazole should not be used as monotherapy for bipolar depression. Lithium, lamotrigine, valproate, and olanzapine continue to be first-line options for maintenance treatment of bipolar disorder. New data support the use of quetiapine monotherapy and adjunctive therapy for the prevention of manic and depressive events, aripiprazole monotherapy for the prevention of manic events, and risperidone long-acting injection monotherapy and adjunctive therapy, and adjunctive ziprasidone for the prevention of mood events. Bipolar II disorder is frequently overlooked in treatment guidelines, but has an important clinical impact on patients' lives. This update provides an expanded look at bipolar II disorder.

Mundo E, Zai G, Lee L, Parikh SV, Kennedy JL. · Neurogenetics Section, Centre for Addiction and Mental Health, Clarke Site, University of Toronto, ON, Toronto, Canada. · Neuropsychopharmacology. · Pubmed #11557174 links to  free full text

Abstract: The serotonin (5HT) receptor genes are considered good candidates for Major Depression (MD), Bipolar Disorder (BP), and Obsessive-Compulsive Disorder (OCD). The 5HT1Dbeta receptor gene has at least three polymorphisms known: G861C, T-261G, and the functional T371G (Phe-124-Cys). The aim of this study was to investigate for the presence of linkage disequilibrium between the 5HT1Dbeta receptor gene and BP. Two hundred and ninety probands with DSM-IV BPI, BPII, or Schizoaffective Disorder (Bipolar type) with their living parents were recruited. Genotyping data for the G861C and T371G polymorphisms were analyzed using the Transmission Disequilibrium Test (TDT). One hundred and sixty triads were informative for the TDT on the G861C polymorphism, which showed no preferential transmission of either allele (chi-square = 0.438, df = 1, p =.508). Only four triads were suitable for the analysis on the T371G variant, with the T allele transmitted once and the G allele transmitted four times to the affected. These findings validate further the results of pharmacological studies excluding a direct involvement of the 5HT1Dbeta receptor in the pathogenesis of BP. Further investigations combining genetic and pharmacological strategies are warranted.

Xu C, Li PP, Cooke RG, Parikh SV, Wang K, Kennedy JL, Warsh JJ. · Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada. · Bipolar Disord. · Pubmed #19133961 No free full text.

Abstract: OBJECTIVE: Recent case-control studies implicate the transient receptor potential melastatin 2 (TRPM2) channel in conferring risk for bipolar disorder (BD), though the risk variants differed. As confounding effects of population structure could not be unequivocally ruled out as the basis for the discordance, we tested the association of TRPM2 with BD in a family design, which is immune to population stratification, for those TRPM2 single nucleotide polymorphisms (SNPs) previously reported as associated with BD. METHODS: The exon 11 SNP (rs1556314) and four informative intronic SNPs (rs1785437, rs1618355, rs933151, and rs749909) were genotyped in 300 BD families by TaqMan allelic discrimination and results were analyzed using chi(2) test, transmission disequilibrium test, and pedigree-based association. SNP rs1556314 was also genotyped in our case-control sample set comprised of 184 BD and 195 healthy Caucasian subjects. RESULTS: The SNP rs1556314 in exon 11 was significantly associated with bipolar disorder type I (BD-I) (p = 0.011, p(permutation) = 0.015) in the case-control dataset and in the family design (p = 0.018, p(permutation) = 0.052, TDTPHASE). Interestingly, the C-T-A haplotype of SNPs rs1618355, rs933151, and rs749909 was significantly associated with early age at onset in BD-I families. CONCLUSION: Significant association of TRPM2 genetic variants with BD in case-control and family datasets further supports a role for TRPM2 in the pathogenesis of this disorder. Overtransmission of the G allele of rs1556314 at exon 11 of TRPM2 in BD-I but not bipolar disorder type II (BD-II) further supports different genetic contributions to the pathogenesis of these bipolar phenotypes.

Zaretsky A, Lancee W, Miller C, Harris A, Parikh SV. · Mood Disorder Clinic, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario. · Can J Psychiatry. · Pubmed #18674402 No free full text.

Abstract: OBJECTIVE: Psychosocial research in bipolar disorder (BD) has not yet assessed the relative benefits of a short course of psychoeducation (PE), compared with a longer course of cognitive-behavioural therapy (CBT) containing psychoeducational principles. This pilot study evaluated the efficacy and added benefit of adding a course of CBT to a standard course of brief PE, as maintenance therapy for BD. METHOD: Seventy-nine consenting adult men and women with BD on stable medication regimens, who were in full or partial remission from an index episode (BD I = 52; BD II = 27), were randomized to receive either 7 sessions of individual PE, or 7 sessions of PE followed by 13 additional individual sessions of CBT. Weekly mood and medication adherence was rated using the National Institute of Mental Health's Life Chart Method, while psychosocial functioning and mental health use were assessed monthly. RESULTS: Forty-six participants completed the entire study. Participants who received CBT in addition to PE experienced 50% fewer days of depressed mood over the course of one year. Participants who received PE alone had more antidepressant increases compared with those who received CBT. There were no group differences in hospitalization rates, medication adherence, psychosocial functioning, or mental health use. CONCLUSIONS: Pilot data from this real-world study suggest that even after medication treatment has been optimized, a longer course of adjunctive CBT may offer some additional benefits over a shorter course of PE alone for the maintenance treatment of BD. Larger randomized controlled trials with equal treatment lengths are indicated.

Xu C, Li PP, Kennedy JL, Green M, Hughes B, Cooke RG, Parikh SV, Warsh JJ. · Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. · Bipolar Disord. · Pubmed #18199248 No free full text.

Abstract: BACKGROUND: The nuclear-encoded mitochondrial complex I subunit gene, NDUFV2, has been implicated in the pathogenesis of bipolar disorder (BD) in Japanese by virtue of association of variants in its promoter with BD and decreased NDUFV2 messenger ribonucleic acid (mRNA) levels in B lymphoblasts (BLCL) in BD patients compared to controls. We sought to determine if these same changes occur in non-Japanese populations and, if so, their relationship to altered basal intracellular Ca(2+) ([Ca(2+)](B)) in BLCL from BD patients. METHODS: Bipolar disorder patients and healthy subjects included 298 subjects of European Caucasian descent. The 5'-nuclease allelic discrimination TaqMan assay was used to detect selected single nucleotide polymorphisms (SNPs) in promoter, introns and 3'UTR regions, spanning the NDUFV2 gene. NDUFV2 mRNA levels and [Ca(2+)](B) in BLCLs were determined. RESULTS: The A allele of the NDUFV2 SNP rs1156044 was significantly associated (Bonferroni-corrected) with BD (p = 0.013) but differed in allele (rs1156044 G allele) from that previously reported as associated with BD. There was a trend for elevated BLCL [Ca(2+)](B) associated with SNP rs977581 in BD patients, but NDUFV2 mRNA levels in BLCLs did not differ between patients and controls, nor represented genotypes. CONCLUSIONS: While genetic variants of NDUFV2 may increase risk for BD, the role of its altered expression and the link to intracellular Ca(2+) abnormalities in BD remains equivocal.

Parikh SV, Velyvis V, Yatham L, Beaulieu S, Cervantes P, Macqueen G, Siotis I, Streiner D, Zaretsky A. · Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. · Bipolar Disord. · Pubmed #17845273 No free full text.

Abstract: OBJECTIVES: Psychological studies have identified that different coping strategies affect outcome in bipolar disorder (BD), with the possibility of preventing mania by effective coping with prodromes. This study seeks to examine coping mechanisms using a recently developed scale to clarify the relationship of coping styles to clinical and demographic characteristics, and to identify coping differences between bipolar I and II subjects. METHODS: The Coping Inventory for Prodromes of Mania (CIPM) was completed by 203 bipolar patients, along with other diagnostic and clinical measures. The CIPM is organized into four factors of coping including: stimulation reduction (SR), problem-oriented coping (PR), seeking professional help (SPH), denial and blame (DB). CIPM psychometric properties and its relationship to demographic and clinical factors, dysfunctional attitudes, and mood symptoms were examined. Coping profiles were generated by BD subtype (I versus II). RESULTS: The CIPM displayed psychometric properties consistent with the single previous study with this instrument. Neither demographic/clinical characteristics nor mood symptoms showed any particular relationship with the CIPM. Clear differences in coping also emerged between BD I and BD II subjects. BD I tended to use a wider range of coping strategies and scored highly on the SPH factor as compared to BD II subjects. BD II participants preferred to use DB and PR, but were less likely to use SPH and SR. CONCLUSIONS: The CIPM appears to be a valid measure of coping. Coping style preferences appear to differ according to bipolar subtype.

Goldstein BI, Velyvis VP, Parikh SV. · Department of Psychiatry, University of Toronto, Sunnybrook and Women's College Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. · J Clin Psychiatry. · Pubmed #16426095 No free full text.

Abstract: OBJECTIVE: To examine the association of alcohol consumption with symptoms, illness course, and health care utilization among non-alcoholic patients with bipolar disorder. METHOD: Subjects were 148 patients with bipolar I or II disorder enrolled in a longitudinal study of cognitive-behavioral therapy versus psychoeducation. Subjects were 18 to 60 years old, in full or partial remission, and non-heavy drinkers with no history of substance use disorders. At least 4 weeks of consistent naturalistic treatment with mood stabilizer was required for enrollment. Measures included the Structured Clinical Interview for DSM-IV, the Hamilton Rating Scale for Depression, the Clinician-Administered Rating Scale for Mania, and the Khavari Alcohol Test. Data were gathered from July 2002 to December 2004. RESULTS: Mean weekly alcoholic beverage consumption was minimal among both men (3.8 standard drinks, SD = 8.9) and women (1.2 standard drinks, SD = 1.9). Nonetheless, total alcohol consumption among men was associated with lifetime manic episodes (F = 10.2, df = 1, p = .003) and emergency department visits (F = 4.3, df = 1, p = .046). Spirits consumption among men was strongly associated with lifetime manic episodes (F = 81.8, df = 1, p < .001) and emergency department visits (F = 14.0, df = 1, p < .001). Among women, the frequency of alcohol consumption was associated with lifetime episodes of depression (F = 15.5, df = 1, p < .001) and hypomania (F = 4.8, df = 1, p < .03). Wine consumption among women was associated with lifetime hypomanic episodes (F = 13.6, df = 1, p < .001) and current manic symptoms (F = 4.0, df = 1, p < .05). CONCLUSION: Despite low volumes of consumption, alcohol was associated with measures of illness severity in bipolar disorder among both men and women. The adverse effects of alcohol on bipolar disorder may occur over a range of consumption, rather than being confined to heavy drinkers.

Xu C, Macciardi F, Li PP, Yoon IS, Cooke RG, Hughes B, Parikh SV, McIntyre RS, Kennedy JL, Warsh JJ. · Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, University of Toronto, 150 College Street, Toronto, Ontario, Canada M5T 1R8. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #16252251 No free full text.

Abstract: Disturbed intracellular calcium (Ca(2+)) homeostasis has been implicated in bipolar disorder (BD). Reduced mRNA levels of the transient receptor potential Ca(2+) permeable channel melastatin type 2, TRPM2, in B lymphoblast cell lines (BLCL) from bipolar I disorder (BD-I) patients showing elevated basal intracellular Ca(2+) ([Ca(2+)](B)), an index of altered intracellular Ca(2+) homeostasis, along with its location within a putative BD susceptibility locus (21q22.3), implicates the involvement of this gene in the Ca(2+) abnormalities and the genetic diathesis to BD. We tested this hypothesis by examining the association of selected single nucleotide polymorphisms (SNPs) and their haplotypes, spanning the TRPM2 gene, with BD and BLCL [Ca(2+)](B), in a case control design. The 5' TaqMan SNP assay was used to detect selected SNPs. BLCL [Ca(2+)](B) was determined by ratiometric fluorometry. SNP rs1618355 in intron 18 was significantly associated with BD as a whole (P < 7.0 x 10(-5); odds ratio (OR) = 2.60), and when stratified into BD-I (P < 7.0 x 10(-5), OR = 2.48) and BD-II (P = 7.0 x 10(-5), OR = 2.88) subgroups. In addition, the alleles of the individual SNPs forming a seven marker at-risk haplotype were in excess in BD (12.0% in BD vs. 0.9% in controls; P = 2.3 x 10(-12)). A weak relationship was also detected between BLCL [Ca(2+)](B) and TRPM2 SNP rs1612472 in intron 19. These findings suggest genetic variants of the TRPM2 gene increase risk for BD and support the notion that TRPM2 may be involved in the pathophysiology of BD.

Wasserman MJ, Corson TW, Sibony D, Cooke RG, Parikh SV, Pennefather PS, Li PP, Warsh JJ. · Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada. · Neuropsychopharmacology. · Pubmed #14970832 links to  free full text

Abstract: Elevated basal intracellular calcium (Ca(2+)) levels ([Ca(2+)](B)) in B lymphoblast cell lines (BLCLs) from bipolar I disorder (BD-I) patients implicate altered Ca(2+) homeostasis in this illness. Chronic lithium treatment affects key proteins modulating intracellular Ca(2+) signaling. Thus, we sought to determine if chronic exposure to therapeutic lithium concentrations also modifies intracellular Ca(2+) homeostasis in this surrogate cellular model of signal transduction disturbances in BD. BLCLs from BD-I (N=26) and healthy subjects (N=17) were regrown from frozen stock and incubated with 0.75 mM lithium or vehicle for 24 h (acute) or 7 days (chronic). [Ca(2+)](B), lysophosphatidic acid (LPA)-stimulated Ca(2+) mobilization ([Ca(2+)](S)), and thapsigargin-induced store-operated Ca(2+) entry (SOCE) were determined using ratiometric fluorometry with Fura-2. Compared with vehicle, chronic lithium exposure resulted in significantly higher [Ca(2+)](B) (F=8.47; p=0.006) in BLCLs from BD-I and healthy subjects. However, peak LPA-stimulated [Ca(2+)](S) and SOCE were significantly reduced (F=11.1, p=0.002 and F=8.36, p=0.007, respectively). Acute lithium exposure did not significantly affect measured parameters. In summary, the effect of chronic lithium to elevate [Ca(2+)](B) in BLCLs while attenuating both receptor-stimulated and SOCE components of intracellular Ca(2+) mobilization in BLCLs suggests that modulation of intracellular Ca(2+) homeostasis may be important to the therapeutic action of lithium.

Srinivasan J, Cohen NL, Parikh SV. · Depression Clinic, Centre for Addiction and Mental Health, Toronto, Ontario. · Can J Psychiatry. · Pubmed #12971021 No free full text.

Abstract: OBJECTIVE: Patient attitudes toward mental illness are an important determinant of treatment compliance and treatment outcome. A patient's age, sex, style of thinking, lifestyle, and beliefs all may influence perceptions. This study aimed to determine patient attitudes. METHOD: Patients with a depressive disorder (n = 102) who were referred for psychiatric consultation and treatment to a community general hospitial psychiatric outpatient clinic completed a 9-item self-report questionnaire to determine their perceptions of the biological, psychological, cognitive, and spiritual causes of their depressive disorder. RESULTS: Women were more likely to endorse their depressive disorder as related to a biological abnormality. With respect to age, older individuals were less likely to identify cognitive factors and loss of spirituality as causal factors in their depression. CONCLUSIONS: A relation exists between demographic variables, including sex and age, and beliefs about causes of depression and related disorders. These findings have implications for refining patient psychoeducation.

Carter TD, Mundo E, Parikh SV, Kennedy JL. · Neurogenetics Section, R-31, Centre for Addiction and Mental Health, Dept. of Psychiatry, University of Toronto, 250 College Street, Toronto, ON, Canada M5T 1R8. · J Psychiatr Res. · Pubmed #12765852 No free full text.

Abstract: The primary aim of our study was to investigate the effect of the age at onset (AAO) of Bipolar Disorder (BP) on the clinical course of the illness. We studied 320 subjects with a diagnosis of BP I or BP II who had been previously recruited for a genetic research protocol. All subjects gave their informed consent to participate in the study. Each subject was interviewed using the SCID I. The main clinical variables were compared between subjects with early (</=18 years) and later (>/=18 years) age at onset of BP (chi square tests and t-tests for independent samples). In addition, a logistic regression analysis was applied to the variables that were significantly related to earlier onset of BP in the exploratory analyses. We found a significantly earlier AAO in subjects with anxiety disorders (t=2.44, P=0.015) and rapid cycling course (t=3.16, P=0.002). When we compared a number of clinical characteristics between early and later onset of BP, subjects with early AAO had more frequent suicidal ideation/attempts (chi(2)=12.12, P=0.002), Axis I comorbidity (chi(2)=8.12, P=0.004), substance use disorders (chi(2)=5.45, P=0.019) and rapid cycling course (chi(2)=9.87, P=0.002). The Odds Ratios associated with these variables were: 1.407 (suicide ideation), 1.646 (Axis I comorbidity), 1.468 (substance abuse), and 2.082 (rapid cycling course). Overall, these results suggest a role of early AAO as a significant predictor of poor outcome in BP and, if replicated, they may have important clinical implications.

Dalton EJ, Cate-Carter TD, Mundo E, Parikh SV, Kennedy JL. · Neurogenetics Section, Center for Addiction and Mental Health, University of Toronoto, Ontario, Canada. · Bipolar Disord. · Pubmed #12656940 No free full text.

Abstract: OBJECTIVE: Bipolar disorder is associated with a high frequency of both completed suicides and suicide attempts. The primary aim of this study was to identify clinical predictors of suicide attempts in subjects with bipolar disorder. METHODS: We studied 336 subjects with a diagnosis of bipolar I, bipolar II, or schizoaffective disorder (bipolar type). The Structured Clinical Interview for DSM-IV (SCID-I) was administered and subsequently two expert psychiatrists established a diagnosis. Predictors of suicide attempts were examined in attempters and non-attempters. RESULTS: The lifetime rate of suicide attempts for the entire sample was 25.6%. A lifetime co-morbid substance use disorder was a significant predictor of suicide attempts: bipolar subjects with co-morbid substance use disorders (SUD) had a 39.5% lifetime rate of attempted suicide, while those without had a 23.8% rate (odds ratio = 2.09, 95% CI = 1.03-4.21, chi2 = 4.33, df = 1, p = 0.037). CONCLUSIONS: Lifetime co-morbid SUD were associated with a higher rate of suicide attempts in patients with bipolar disorder. This relationship may have a genetic origin and/or be explained by severity of illness and trait impulsivity.

Mundo E, Tharmalingham S, Neves-Pereira M, Dalton EJ, Macciardi F, Parikh SV, Bolonna A, Kerwin RW, Arranz MJ, Makoff AJ, Kennedy JL. · Neurogenetics Section, Centre for Addiction and Mental Health (CAMH), Department of Psychiatry, University of Toronto, Clarke Site R-31, Toronto, Ontario, Canada M5T 1R8. · Mol Psychiatry. · Pubmed #12610658 No free full text.

Abstract: There is evidence for the involvement of glutamatergic transmission in the pathogenesis of major psychoses. The two most commonly used mood stabilizers (ie lithium and valproate) have been found to act via the N-methyl-D-aspartate receptor (NMDAR), suggesting a specific role of NMDAR in the pathogenesis of bipolar disorder (BP). The key subunit of the NMDAR, named NMDA-1 receptor, is coded by a gene located on chromosome 9q34.3 (GRIN1). We tested for the presence of linkage disequilibrium between the GRIN1 (1001-G/C, 1970-A/G, and 6608-G/C polymorphisms) and BP. A total of 288 DSM-IV Bipolar I, Bipolar II, or schizoaffective disorder, manic type, probands with their living parents were studied. In all, 73 triads had heterozygous parents for the 1001-G/C polymorphism, 174 for the 1970-A/G, and 48 for the 6608-G/C. These triads were suitable for the final analyses, that is, the transmission disequilibrium test (TDT) and the haplotype-TDT. For the 1001-G/C and the 6608-G/C polymorphisms, we found a preferential transmission of the G allele to the affected individuals (chi(2)=4.765, df=1, P=0.030 and chi(2)= 8.395, df=1, P=0.004, respectively). The 1001G-1970A-6608A and the 1001G-1970A-6608G haplotypes showed the strongest association with BP (global chi(2)=14.12, df=4, P=0.007). If these results are replicated there could be important implications for the involvement of the GRIN1 in the pathogenesis of BP. The role of the gene variants in predicting the response to mood stabilizers in BP should also be investigated.

Yoon IS, Li PP, Siu KP, Kennedy JL, Macciardi F, Cooke RG, Parikh SV, Warsh JJ. · Section of Biochemical Psychiatry, Centre for Addiction and Mental Health-Clarke Site, Toronto, Ontario, Canada. · Biol Psychiatry. · Pubmed #11690598 No free full text.

Abstract: BACKGROUND: As altered storage-operated calcium (Ca(2+)) entry (SOCE) may affect Ca(2+) homeostasis in bipolar disorder (BD), we determined whether changes occur in the expression of TRPC7 and SERCA2s, proteins implicated or known to be involved in SOCE, in B lymphoblast cell lines (BLCLs) from BD-I patients and comparison subjects. METHODS: mRNA levels were determined in BLCL lysates from BD-I, BD-II, and major depressive disorder patients, and healthy subjects by comparative reverse transcriptase-polymerase chain reaction, and BLCL basal intracellular Ca(2+) concentration ([Ca(2+)]B) was determined by ratiometric spectrophotometry using Fura-2, in aliquots of the same cell lines, at 13-16 passages in culture. RESULTS: TRPC7 mRNA levels were significantly lower in BLCLs from BD-I patients with high BLCL [Ca(2+)]B compared with those showing normal [Ca(2+)]B (-33%, p =.017) and with BD-II patients (-48%, p =.003), major depressive disorder patients (-47%, p =.049) and healthy subjects (-33%, p =.038). [Ca(2+)]B also correlated inversely with TRPC7 mRNA levels in BLCLs from the BD-I group as a whole (r = -.35, p =.027). CONCLUSIONS: Reduced TRPC7 gene expression may be a trait associated with pathophysiological disturbances of Ca(2+) homeostasis in a subgroup of BD-I patients.

Yoon IS, Li PP, Siu KP, Kennedy JL, Cooke RG, Parikh SV, Warsh JJ. · Section of Biochemical Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, Canada, M5T 1R8. · Mol Psychiatry. · Pubmed #11673796 links to  free full text

Abstract: Reduced inositol monophosphatase (IMPase) activity and elevated basal intracellular calcium levels ([Ca(2+)](B)) have been reported in B lymphoblast cell lines (BLCLs) from bipolar I affective disorder (BD-I) patients, which may reflect cellular endophenotypes of this disorder. As the PI cycle couples to intracellular Ca(2+) mobilization, these two putative endophenotypes may be related. Using an RT-PCR assay, mRNA levels were estimated for IMPA1 and 2 genes encoding human IMPase 1 and 2, respectively, in BLCLs phenotyped on [Ca(2+)](B), from patients with a DSM-IV diagnosis of BD-I (n = 12 per phenotype) and from age- and sex-matched healthy subjects (n = 12). IMPA2 mRNA levels were significantly lower in BLCLs from male BD-I patients with high [Ca(2+)](B) (n = 6) compared with healthy male subjects (n = 5) (-52%, P = 0.013), male BD-I patients with normal BLCL [Ca(2+)](B) (n = 8) (-42%, P = 0.003) and female BD-I patients with high [Ca(2+)](B) (n = 6) (-59%, P = 0.0004). A significant negative correlation was observed between IMPA2 mRNA levels and [Ca(2+)](B) in BLCLs from male (P = 0.046), but not female BD-I patients. Sex-dependent differences were also evident in postmortem temporal cortex IMPA2 mRNA levels which, in contrast to BLCLs, were significantly higher in male BD-I subjects compared with male controls (P = 0.025, n = 4/group). Collectively, these observations suggest a potential sex-dependent link between abnormalities in IMPA2 expression and calcium homeostasis in the pathophysiology of BD.

Emamghoreishi M, Li PP, Schlichter L, Parikh SV, Cooke R, Warsh JJ. · Section of Biochemical Psychiatry, Centre for Addiction and Mental Health, Clarke Site, Toronto, Ontario, Canada. · Biol Psychiatry. · Pubmed #11032978 No free full text.

Abstract: BACKGROUND: Evidence of extensive cross-talk between calcium (Ca(2+))- and cAMP-mediated signaling systems suggests that previously reported abnormalities in Ca(2+) homeostasis in bipolar I (BP-I) patients may be linked to disturbances in the function of G proteins that mediate cAMP signaling. METHODS: To test this hypothesis, the beta-adrenergic agonist, isoproterenol, and the G protein activator, sodium fluoride (NaF), were used to stimulate cAMP production in B lymphoblasts from healthy and BP-I subjects phenotyped on basal intracellular calcium concentration ([Ca(2+)](B)). cAMP was measured by radioimmunoassay and [Ca(2+)](B) by ratiometric fluorometry with fura-2. RESULTS: Isoproterenol- (10 microM) stimulated cAMP formation was lower in intact B lymphoblasts from BP-I patients with high [Ca(2+)](B) (>/= 2 SD above the mean concentration of healthy subjects) compared with patients having normal B lymphoblast [Ca(2+)](B) and with healthy subjects. Although basal and NaF-stimulated cAMP production was greater in B lymphoblast membranes from male BP-I patients with high versus normal [Ca(2+)](B), there were no differences in the percent stimulation. This suggests the differences in NaF response resulted from higher basal adenylyl cyclase activity. CONCLUSIONS: These findings suggest that trait-dependent disturbances in processes regulating beta-adrenergic receptor sensitivity and G protein-mediated cAMP signaling occur in conjunction with altered Ca(2+) homeostasis in those BP-I patients with high B lymphoblast [Ca(2+)](B).

Vincent JB, Neves-Pereira ML, Paterson AD, Yamamoto E, Parikh SV, Macciardi F, Gurling HM, Potkin SG, Pato CN, Macedo A, Kovacs M, Davies M, Lieberman JA, Meltzer HY, Petronis A, Kennedy JL. · Department of Genetics, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. · Am J Hum Genet. · Pubmed #10712198 links to  free full text

Abstract: Larger CAG/CTG trinucleotide-repeat tracts in individuals affected with schizophrenia (SCZ) and bipolar affective disorder (BPAD) in comparison with control individuals have previously been reported, implying a possible etiological role for trinucleotide repeats in these diseases. Two unstable CAG/CTG repeats, SEF2-1B and ERDA1, have recently been cloned, and studies indicate that the majority of individuals with large repeats as detected by repeat-expansion detection (RED) have large repeat alleles at these loci. These repeats do not show association of large alleles with either BPAD or SCZ. Using RED, we have identified a BPAD individual with a very large CAG/CTG repeat that is not due to expansion at SEF2-1B or ERDA1. From this individual's DNA, we have cloned a highly polymorphic trinucleotide repeat consisting of (CTA)n (CTG)n, which is very long ( approximately 1,800 bp) in this patient. The repeat region localizes to chromosome 13q21, within 1.2 cM of fragile site FRA13C. Repeat alleles in our sample were unstable in 13 (5.6%) of 231 meioses. Large alleles (>100 repeats) were observed in 14 (1. 25%) of 1,120 patients with psychosis, borderline personality disorder, or juvenile-onset depression and in 5 (.7%) of 710 healthy controls. Very large alleles were also detected for Centre d'Etude Polymorphisme Humaine (CEPH) reference family 1334. This triplet expansion has recently been reported to be the cause of spinocerebellar ataxia type 8 (SCA8); however, none of our large alleles above the disease threshold occurred in individuals either affected by SCA or with known family history of SCA. The high frequency of large alleles at this locus is inconsistent with the much rarer occurrence of SCA8. Thus, it seems unlikely that expansion alone causes SCA8; other genetic mechanisms may be necessary to explain SCA8 etiology.

Parikh SV, Vincent JB, Kennedy JL. · Bipolar Clinic, Clarke Institute of Psychiatry, University of Toronto, ON, Canada. · J Affect Disord. · Pubmed #10628891 No free full text.

Abstract: BACKGROUND: Unstable DNA has been implicated in a variety of neuropsychiatric disorders, with increasing severity of disease associated with larger DNA repeats. We examined the unstable DNA hypothesis for bipolar disorder by looking for increased severity of symptoms and earlier age of onset amongst bipolar individuals with large CAG/CTG repeats. METHODS: From a sample of 91 bipolar subjects, eight with large CAG/CTG (> or = 270bp) trinucleotide repeats were matched to eight bipolar individuals with small repeats (< or = 150bp). Medical charts were reviewed for age of onset and a number of severity indicators. Candidate CAG/CTG expansions on chromosomes 17 and 18 were also genotyped. RESULTS: No obvious differences were noted for the clinical indices, however seven out of eight individuals with large Repeat Expansion Detection (RED) products had expansions at the CTG18.1 locus, while four out of eight had large repeats at ERDA1. Both of these sites are unlikely to be related to disease. LIMITATIONS: Our total sample size is small and less than 9% have large repeats. CONCLUSIONS: The lack of increased severity or earlier age of onset amongst bipolar subjects with large CAG/CTG repeats suggests these repeats are unlikely to have a major etiological role in bipolar disorder.

Vincent JB, Petronis A, Strong E, Parikh SV, Meltzer HY, Lieberman J, Kennedy JL. · Clarke Division, Centre for Addiction and Mental Health, University of Toronto, ON, Canada. · Mol Psychiatry. · Pubmed #10395212 No free full text.

Abstract: A shift towards larger CAG/CTG triplet repeats and schizophrenia (SCZ) and bipolar affective disorder (BPAD) has been detected by several recent studies, using the Repeat Expansion Detection (RED) technique, however no specific loci have been shown to be responsible for this shift. Further analyses by our group of RED (CTG)10 ligation products amongst an extended sample of patients and comparison with controls matched for age, sex and ethnicity show no significant differences in distribution (P= 0.23, n=95; P=0.93, n=91, for SCZ and BPAD respectively). Alleles at two recently discovered unstable trinucleotide repeat loci at 18q21.1 (SEF2-1B) and 17q21.3 (ERDA1) have also been analysed in affecteds and matched controls. We observed no increase in frequency of larger alleles (>37 repeats) in affected individuals at SEF2-1B (BPAD: P=0.95, n= 100; SCZ: P=0.61, n=97) or at ERDA1 (BPAD: P= 0.4, n = 101; SCZ: P= 0.05, n = 151, with larger alleles more frequent in controls). Our findings suggest that larger CAG/CTG repeats at these loci are neither major contributory factors to the etiology of psychosis, nor in linkage disequilibrium with a gene that is. Furthermore, when the RED results were compared to allele sizes at SEF2-1B and ERDA1, it was observed that a majority of SCZ, BPAD and control individuals with large RED products had a large allele at either or both sites (78% for RED products > or =270 bp; 62% for RED products > or =180 bp).

Vincent JB, Masellis M, Lawrence J, Choi V, Gurling HM, Parikh SV, Kennedy JL. · Neurogenetics Section and the Bipolar Clinic, The Clarke Institute of Psychiatry, University of Toronto, ON, Canada. · Am J Psychiatry. · Pubmed #9892311 links to  free full text

Abstract: OBJECTIVE: This study examined the putative role of serotonin genes in the etiology of bipolar affective disorder. METHOD: Genetic association analysis was performed for individuals with bipolar affective disorder and unaffected subjects closely matched in age, sex, and ethnic background (N=103 in each group). The allele and genotype frequencies of polymorphisms at the genes for serotonin receptors HTR1A, HTR1Dalpha, HTR1Dbeta, HTR2A, HTR2C, HTR7, tryptophan hydroxylase (TPH), and the serotonin transporter (hSERT) were compared in the two groups of subjects. RESULTS: Statistically significant positive associations were found for HTR2A and hSERT polymorphisms. However, results from an independent replication group of over 100 patients with bipolar affective disorder and their matched comparison subjects failed to confirm these associations. CONCLUSIONS: These results suggest that the serotonin genes studied are not associated with bipolar affective disorder, although transmission disequilibrium studies are required in order to confirm this conclusion.

Corson TW, Li PP, Kennedy JL, Macciardi F, Cooke RG, Parikh SV, Warsh JJ. · No affiliation provided · Mol Psychiatry. · Pubmed #11317211 links to  free full text

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