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Articles by R. H Perlis
Total Records ( 7 ) for R. H Perlis
  R. H Perlis , J. W Smoller , M. A.R Ferreira , A McQuillin , N Bass , J Lawrence , G. S Sachs , V Nimgaonkar , E. M Scolnick , H Gurling , P Sklar and S. Purcell
 

OBJECTIVE: Lithium remains a first-line treatment for bipolar disorder, but the mechanisms by which it prevents the recurrence of mood episodes are not known. The authors utilized data from a genomewide association study to examine associations between single nucleotide polymorphisms (SNPs) and the outcome of lithium treatment in two cohorts of patients with bipolar I disorder or bipolar II disorder. METHOD: The hazard for mood episode recurrence was examined among 1,177 patients with bipolar I disorder or bipolar II disorder, including 458 individuals treated with lithium carbonate or citrate, who were participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) cohort. SNPs showing the greatest evidence of association in Cox regression models were then examined for association with positive lithium response among 359 bipolar I or II disorder patients treated with lithium carbonate or citrate in a second cohort from the University College London. RESULTS: The strongest association in the STEP-BD cohort (minimum p=5.5x10–7) was identified for a region on chromosome 10p15 (rs10795189). Of the regions showing suggestive evidence (p<5x 10–4) of association with lithium response, five were further associated with positive lithium response in the University College London cohort, including SNPs in a region on chromosome 4q32 spanning a gene coding for the glutamate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) receptor GRIA2. CONCLUSIONS: Multiple novel loci merit further examination for association with lithium response in bipolar disorder patients, including one region that spans the GRIA2 gene, for which expression has been shown to be regulated by lithium treatment.

  M. J Ostacher , R. H Perlis , A. A Nierenberg , J Calabrese , J. P Stange , I Salloum , R. D Weiss , G. S Sachs and for STEP BD Investigators
  Objective

Bipolar disorder is highly comorbid with substance use disorders, and this comorbidity may be associated with a more severe course of illness, but the impact of comorbid substance abuse on recovery from major depressive episodes in these patients has not been adequately examined. The authors hypothesized that comorbid drug and alcohol use disorders would be associated with longer time to recovery in patients with bipolar disorder.

Method

Subjects (N=3,750) with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were followed prospectively for up to 2 years. Prospectively observed depressive episodes were identified for this analysis. Subjects with a past or current drug or alcohol use disorder were compared with those with no history of drug or alcohol use disorders on time to recovery from depression and time until switch to a manic, hypomanic, or mixed episode.

Results

During follow up, 2,154 subjects developed a new-onset major depressive episode; of these, 457 subjects switched to a manic, hypomanic, or mixed episode prior to recovery. Past or current substance use disorder did not predict time to recovery from a depressive episode relative to no substance use comorbidity. However, those with current or past substance use disorder were more likely to experience switch from depression directly to a manic, hypomanic, or mixed state.

Conclusions

Current or past substance use disorders were not associated with longer time to recovery from depression but may contribute to greater risk of switch into manic, mixed, or hypomanic states. The mechanism conferring this increased risk merits further study.

  R. H Perlis , J. W Smoller , J Mysore , M Sun , T Gillis , S Purcell , M Rietschel , M. M Nothen , S Witt , W Maier , D. V Iosifescu , P Sullivan , A. J Rush , M Fava , H Breiter , M Macdonald and J. Gusella
  Objective

Presymptomatic individuals with the Huntingtin (HTT) CAG expansion mutation that causes Huntington's disease may have higher levels of depressive symptoms than healthy comparison populations. However, the prevalence of HTT CAG repeat expansions among individuals diagnosed with major depressive disorder has not been established.

Method

This was a case-control genetic association study of HTT CAG allele size in two discovery cohorts of individuals with major depressive disorder and comparison subjects without major depression as well as a replication cohort of individuals with major depression and comparison subjects without major depression.

Results

CAG repeat lengths of 36 or greater were observed in six of 3,054 chromosomes from individuals with major depression, compared with none of 4,155 chromosomes from comparison subjects. In a third cohort, one expanded allele was observed among 1,202 chromosomes in the major depression group, compared with none of 2,678 chromosomes in comparison subjects. No clear pattern of clinical features was shared among individuals with the expanded repeats.

Conclusions

In clinical populations of individuals diagnosed with major depression, approximately 3 in 1,000 carried expanded HTT CAG alleles.

  J Huang , R. H Perlis , P. H Lee , A. J Rush , M Fava , G. S Sachs , J Lieberman , S. P Hamilton , P Sullivan , P Sklar , S Purcell and J. W. Smoller
  Objective:

Family and twin studies indicate substantial overlap of genetic influences on psychotic and mood disorders. Linkage and candidate gene studies have also suggested overlap across schizophrenia, bipolar disorder, and major depressive disorder. The purpose of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders.

Method:

The authors combined GWAS data from three large effectiveness studies of schizophrenia (CATIE, genotyped: N=741), bipolar disorder (STEP-BD, geno-typed: N=1,575), and major depressive disorder (STAR*D, genotyped: N=1,938) as well as from psychiatrically screened control subjects (NIMH-Genetics Repository: N=1,204). A two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups was applied, followed by a model selection step to identify the best-fitting model of allelic effects across disorders.

Results:

The strongest result was seen for a single nucleotide polymorphism near the adrenomedullin (ADM) gene (rs6484218), with the best-fitting model indicating that the effect was specific to bipolar II disorder. Findings also revealed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries, including variants in NPAS3 that showed pleiotropic effects across schizophrenia, bipolar disorder, and major depressive disorder.

Conclusions:

This study provides the first genomewide significant evidence implicating variants near the ADM gene on chromosome 11p15 in psychopathology, with effects that appear to be specific to bipolar II disorder. Although genomewide signifi-cant evidence of cross-disorder effects was not detected, the results provide evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrate an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future large-scale cross-disorder GWAS analyses.

  R. H Perlis , J Huang , S Purcell , M Fava , A. J Rush , P. F Sullivan , S. P Hamilton , F. J McMahon , T Schulze , J. B Potash , P. P Zandi , V. L Willour , B. W Penninx , D. I Boomsma , N Vogelzangs , C. M Middeldorp , M Rietschel , M Nothen , S Cichon , H Gurling , N Bass , A McQuillin , M Hamshere , Craddock Wellcome Trust Case Control Consortium Bipolar Disorder Group , P Sklar and J. W. Smoller
  Objective:

Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts.

Method:

The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort.

Results:

Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety.

Conclusions:

The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation.

  J. W Smoller , M Allison , B. B Cochrane , J. D Curb , R. H Perlis , J. G Robinson , M. C Rosal , N. K Wenger and S. Wassertheil Smoller
 

Background  Antidepressants are commonly prescribed medications, but their effect on cardiovascular morbidity and mortality remains unclear.

Methods  Prospective cohort study of 136 293 community-dwelling postmenopausal women in the Women's Health Initiative (WHI). Women taking no antidepressants at study entry and who had at least 1 follow-up visit were included. Cardiovascular morbidity and all-cause mortality for women with new antidepressant use at follow-up (n = 5496) were compared with those characteristics for women taking no antidepressants at follow-up (mean follow-up, 5.9 years).

Results  Antidepressant use was not associated with coronary heart disease (CHD). Selective serotonin reuptake inhibitor (SSRI) use was associated with increased stroke risk (hazard ratio [HR],1.45, [95% CI, 1.08-1.97]) and all-cause mortality (HR,1.32 [95% CI, 1.10-1.59]). Annualized rates per 1000 person-years of stroke with no antidepressant use and SSRI use were 2.99 and 4.16, respectively, and death rates were 7.79 and 12.77. Tricyclic antidepressant (TCA) use was associated with increased risk of all-cause mortality (HR,1.67 [95% CI, 1.33-2.09]; annualized rate, 14.14 deaths per 1000 person-years). There were no significant differences between SSRI and TCA use in risk of any outcomes. In analyses by stroke type, SSRI use was associated with incident hemorrhagic stroke (HR, 2.12 [95% CI, 1.10-4.07]) and fatal stroke (HR, 2.10 [95% CI, 1.15-3.81]).

Conclusions  In postmenopausal women, there were no significant differences between SSRI and TCA use in risk of CHD, stroke, or mortality. Antidepressants were not associated with risk of CHD. Tricyclic antidepressants and SSRIs may be associated with increased risk of mortality, and SSRIs with increased risk of hemorrhagic and fatal stroke, although absolute event risks are low. These findings must be weighed against quality of life and established risks of cardiovascular disease and mortality associated with untreated depression.

 
 
 
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