Masoliver E, Menoyo A, Perez V, Volpini V, Rio ED, Perez J et al. Serotonin transporter linked promoter (polymorphism) in the serotonin transporter gene may be associated with antidepressant-induced mania in bipolar disorder. Psychiatr Genet 16: 25-29
Department of Psychiatry, Santa Creu i Sant Pau Hospital and ICO I Institut de Recerca Oncologica, Barcelona, Spain. Psychiatric Genetics
(Impact Factor: 1.94).
03/2006; 16(1):25-9. DOI: 10.1097/01.ypg.0000180684.26288.d7
Several pharmacogenetic studies suggest that response to pharmacotherapy in bipolar disorder may be mediated by genetic factors. The aim of this study was to investigate further the association of the genetic variations of the serotonin transporter (5-HTT) gene with antidepressant-induced mania, already reported in recent studies. We also studied the possible association of these genetic variants with diagnosis expression and treatment response to lithium therapy.
The sample consisted of 103 and 85 outpatients with diagnosis of bipolar and unipolar disorder, respectively, and 101 controls. Two described polymorphisms of the 5-HTT, the variable number of tandem repeat (VNTR) and serotonin transporter linked promoter (5-HTTLPR) polymorphisms, were genotyped using standard procedures.
The association analysis performed showed a significantly higher rate of homozygous s/s genotype for 5-HTTLPR among patients with a history of antidepressant-induced mania (60% patients s/s versus 40% l/l, chi, P=0.04). No significant difference in the distribution of genotypes of the two polymorphisms was observed between the three groups. We found no significant association between these polymorphisms and lithium response.
The 5-HTTLPR polymorphism could be a useful contributor, among other clinical variables, to predict the risk for manic switches when a patient with bipolar disorder is treated with antidepressant drugs. The contribution of these genetic markers in diagnosis expression and treatment response to lithium is likely to be minor.
Available from: Hitoshi Maeshima
- "Author's personal copy (Masoliver et al., 2006; Mundo et al., 2006; Rousseva et al., 2003 "
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The relationship between psychomotor agitation in unipolar depression and mood-switching from depression to manic, hypomanic and mixed states has been controversial. We investigated the future risk of initial mood-switching as a function of psychomotor agitation in unipolar depression.
We identified 189 participants diagnosed with major depressive disorder (MDD). We divided all patients with MDD into two categories (1) agitated patients (n=74), and (2) non-agitated patients (n=115). These groups were prospectively followed and compared by time to mood-switching. Kaplan–Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazard ratio estimates for a multivariate model were conducted to examine the risk of mood-switching by psychomotor agitation.
During follow-up, mood-switching occurred in 20.3% of the agitated patients and 7.0% of the non-agitated patients. In the Kaplan–Meier survival estimates for time to incidence of mood-switching with agitated or non-agitated patients, the cumulative probability of developing mood-switching for agitated patients was higher than those for non-agitated patients (log-rank test: χ2=7.148, df=1, p=0.008). Survival analysis was also performed using Cox proportional hazards regression within a multivariate model. The agitation remained significantly associated with incidence of mood-switching (HR=2.98, 95% CI: 1.18–7.51).
We did not make a clear distinction between antidepressant-induced mood-switching and spontaneous switching.
The main finding demonstrated that MDD patients with agitation were nearly threefold as likely to experience mood-switching, suggesting that psychomotor agitation in MDD may be related to an indicator of bipolarity.
Available from: Srinath Gopinath
- "Adolescents who have not manifested the manic component of a bipolar disorder may be particularly vulnerable to SSRI antidepressant-induced mania or hypomania (Frye et al., 2009). Although preliminary studies showed conflicting results regarding the association between 5-HTTLPR polymorphism and antidepressant-induced mania (Mundo et al., 2001; Rousseva et al., 2003; Serretti et al., 2004; Baumer et al., 2006; Masoliver et al., 2006; Ferreira Ade et al., 2009), a recent meta-analysis indicated a higher incidence of antidepressant-induced mania in patients with the “s” variant of 5-HTTLPR (Daray et al., 2010). Likelihood of SSRI monotherapy response is deemed low once failure of the “SSRI challenge” test has been observed in this category. "
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ABSTRACT: First-line treatment of major depression includes administration of a selective serotonin reuptake inhibitor (SSRI), yet studies suggest that remission rates following two trials of an SSRI are less than 50%. The authors examine the putative biological substrates underlying “Treatment Refractory Depression (TRD)” with the goal of elucidating novel rationales to treat TRD. We look at relevant articles from the preclinical and clinical literature combined with clinical exposure to TRD patients. A major focus was to outline pathophysiological mechanisms whereby the serotonin (5-HT) system becomes impervious to the desired enhancement of 5-HT neurotransmission by SSRI’s. A complementary focus was to dissect neurotransmitter systems, which serve to inhibit the dorsal raphe. We propose, based on a body of translational studies, TRD may not represent a simple 5-HT deficit state but rather an excess of midbrain peri-raphe 5-HT and subsequent deficit at key fronto-limbic projection sites, with ultimate compromise in 5-HT-mediated neuroplasticity. Glutamate, 5-HT, noradrenaline and histamine are activated by stress and exert an inhibitory effect on 5-HT outflow, in part by “flooding” 5-HT1A autoreceptors by 5-HT itself. Certain factors putatively exacerbate this scenario- presence of the short arm of the serotonin transporter gene, early life adversity and comorbid bipolar disorder- each of which has been associated with SSRI-treatment resistance. By utilizing an incremental approach, we provide a system for treating the TRD patient based on a strategy of rescuing 5-HT neurotransmission from a state of SSRI-induced dorsal raphe stasis. This calls for “stacked” interventions, with an SSRI base, targeting, if necessary, the glutamatergic, serotonergic, noradrenergic and histaminergic systems, thereby successively eliminating the inhibitory effects each are capable of exerting on 5-HT neurons. Future studies are recommended to test this biologically based approach for TRD.
Available from: Julie M Cunningham
- "It is also important to note, however, that frequency of the S allele varied widely between studies, which again underscores the importance of careful study design to avoid population stratification effects. With the exception of the studies of Mundo et al. (2001) and Masoliver et al. (2006), which also investigated the VNTR region within the second intron, the remaining studies only evaluated association of AIM with one SLC6A4 polymorphism, the 5HTTLPR long/short variant. It has been demonstrated that the intron 2 VNTR is associated with differential SLC6A4 gene expression (Lovejoy et al., 2003); the 9-copy allele appears to have a higher level of expression than the 10-or 12-copy alleles do (Lott et al., 2006). "
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ABSTRACT: Polymorphisms in SNCA, MAPT and LRRK2 genes have recently been confirmed as risk factors for Parkinson's disease (PD), although with small individual attributable risk. Here we investigated the association of PD with interactions between variants of these genes.
As part of a previous study of PD susceptibility genes 119 SNCA, MAPT, and LRRK2 haplotype tagging single nucleotide polymorphisms (SNPs) and two variable number tandem repeats (VNTRs) were genotyped in 1098 PD cases from the upper Midwest, USA and 1098 matched controls. Twenty-six of these SNPs were selected for SNP-SNP (or SNP-VNTR or VNTR-VNTR) interaction analysis (256 interaction pairs). Case-control analyses were performed to study association of pairwise SNP interactions with PD susceptibility.
Out of the 256 interaction pairs investigated, 10 had uncorrected p-values <0.05. These represented six SNCA-LRRK2 pairs, three SNCA-MAPT pairs, and one MAPT-LRRK2 pair. However, none of these pairwise interactions were significant after correction for multiple testing. Secondary analyses in strata defined by type of control (sibling or unrelated), sex, or age at onset of the case also did not reveal any significant interactions after accounting for multiple testing.
This study provides no statistically significant evidence of gene-gene interaction effects for the three confirmed genetic susceptibility loci for PD. However, this does not exclude the possibility that other genomic loci or environmental risk factors interact with these genes.
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