Acute antipyschotic efficacy and side effects in schizophrenia: Association with serotonin transporter promoter genotypes
The serotonin transporter (5-HTT) plays an important role in serotonergic neurotransmission. In the present study, we investigated the effects of the 44 bp insertion/deletion polymorphism in the promoter region of 5-HTT gene (5-HTTLPR) on symptomatology of psychosis and clinical response to antipsychotic drugs.
In total 56 patients acutely treated with haloperidol or risperidone either for the first episode of schizophrenia, schizophreniform or schizoaffective disorders, or for the relapse of these psychotic disorders after tapering their maintenance treatment, were genotyped for the 5-HTTLPR L and S alleles and for the new A/G functional variant within the L alelle (La/g). Psychopathological symptoms were assessed with the Brief Psychiatric Rating Scale (BPRS) and with Clinical Global Impression (CGI) twice: at 8-12 days after the first dose of antipsychotic and after 4 weeks. Extrapyramidal side effects were assessed with the Simpson-Angus Extrapyramidal Side Effects Scale (EPS), the Barnes Akathisia Scale (BARS) and the Abnormal Involuntary Movement Scale (AIMS).
Age, body mass index (BMI), illness duration, drug type and dosage were considered as covariates when analysing association with genetic variants as they were associated with baseline or final BPRS and CGI scores and/or extrapyramidal side effects. 5-HTTLPR was not associated with baseline and final BPRS and CGI scores or with the CGI% reduction. However, the 5-HTTLPR S allele was associated with a lower improvement in BPRS scores (P=0.022) and this effect was even stronger after pooling subjects with S or Lg containing alleles (P=0.006). We did not observe any effect of 5-HTTLPR on acute antipsychotics side effects.
Present result supports a contribution of serotonin system to neuroleptics efficacy for the treatment of schizophrenia. The analysis of the La/g functional variant may significantly improve the predictive power of 5-HTTLPR genotyping and represent a step further towards the development of the personalized antipsychotic treatment.
Available from: Martin Schaefer
- "Different study designs and medications could be at the basis of this lack of replication. We could not find a genetic association between the short/long promoter variation in the serotonin trasnporter and antipsychotic induced motoric side effects, but the study was exploratory with a small sample (47 subjects) to hold enough power to detect minor genetic effects . The serotoninergic system was nevertheless proved to hold a potential for being a mediator of motoric effects induced by antipsyhotics. "
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ABSTRACT: We previously investigated a sample of patients during an active phase of psychosis in the search for genetic predictors of haloperidol induced side effects. In the present work we extend the genetic association analysis to a wider panel of genetic variations, including 508 variations located in 96 genes. The original sample included 96 patients. An independent group of 357 patients from the CATIE study served as a replication sample. Outcomes in the investigation sample were the variation through time of: 1) the ESRS and UKU total scores 2) ESRS and UKU subscales (neurologic and psychic were included) related to tremors and 3) ESRS and UKU subscales that do not relate to tremors. Outcome in the replication sample was the presence vs absence of motoric side effects from baseline to visit 1 (∼ one month of treatment) as assessed by the AIMS scale test. Rs2242480 located in the CYP3A4 was associated with a different distribution of the UKU neurologic scores through time (permutated p = 0.047) along with a trend for a different haloperidol plasma levels (lower in CC subjects). This finding was not replicated in the CATIE sample. In conclusion, we did not find conclusive evidence for a major association between the investigated variations and haloperidol induced motoric side effects.
Available from: Richard Musil
- "Especially studies on never-treated first-episode patients are important in this context for antipsychotic treatment has been found to change, e.g., receptor physiology27) or brain morphology.28) Amongst others, polymorphisms in the serotonin 2A receptor or the serotonin transporter promoter gene have been associated with the clinical effect of the applied antipsychotic drugs.29,30) In a pharmacogenetic study evaluating 30 variants of dopamine and serotonin candidate genes in 120 FES neuroleptic-naïve patients receiving risperidone monotherapy for 8 weeks, two SNPs in the dopamine D2 receptor and AKT1 were significant predictors of treatment response to risperidone (response defined as PANSS improvement).31) "
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ABSTRACT: First episode schizophrenia (FES) patients tend to be more responsive to treatment. An adequate response has been associated with a favourable long-term course in FES patients. Yet, despite the generally very favourable response profile around one quarter of the patients shows persisting symptoms of psychosis. To improve the outcome and course of psychosis great effort has emerged in identifying biological and clinical variables associated with non-response in order to identify non-responders as early as possible and adopt specific treatment strategies improving illness outcome. Different antipsychotic treatment regimens have been evaluated in terms of their efficacy in reducing symptoms of FES with psychological interventions gaining increasing importance in the treatment concept of patients suffering from their first illness episode. Therefore, aim of this review is to summarize current evidence on the response patterns, the most important predictors of response/non-response as well as on effective treatment interventions in FES patients.
Available from: Lynette C Daws
- "Selective 5-HT reuptake inhibitors (SSRIs) such as fluoxetine (Prozac) improve symptoms for some autistic patients, but they have limited effectiveness as a comprehensive ASD therapeutic, and their use in juveniles is controversial (West et al. 2009; Kirsch et al. 2008; Henry et al. 2009; Daws 2009; Richardson-Jones et al. 2010). Risperidone, a D 2 /5-HT 2 antagonist, is often used to control aggression and self-injury in ASD, but it is less efficacious in some patient groups and does not enhance sociability (West et al. 2009; Marek et al., 2003; Dolzan et al. 2008). Buspirone, an anxiolytic 5-HT 1A partial agonist is reported to enhance rodent social interaction at low doses (File and Seth, 2003). "
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ABSTRACT: J. Neurochem. (2011) 116, 291–303.
BTBR mice are potentially useful tools for autism research because their behavior parallels core social interaction impairments and restricted-repetitive behaviors. Altered regulation of central serotonin (5-HT) neurotransmission may underlie such behavioral deficits. To test this, we compared 5-HT transporter (SERT), 5-HT1A and 5-HT2A receptor densities among BTBR and C57 strains. Autoradiographic [3H] cyanoimipramine (1nM) binding to SERT was 20–30% lower throughout the adult BTBR brain as compared to C57BL/10J mice. In hippocampal membrane homogenates, [3H] citalopram maximal binding (Bmax) to SERT was 95 ± 13 fmol/mg protein in BTBR and 171 ± 20 fmol/mg protein in C57BL/6J mice, and the BTBR dissociation constant (KD) was 2.0 ± 0.3 nM versus 1.1 ± 0.2 in C57BL/6J mice. Hippocampal 5-HT1A and 5-HT2A receptor binding was similar among strains. However, 8-OH-DPAT-stimulated [35S] GTPγS binding in the BTBR hippocampal CA1 region was 28% higher, indicating elevated 5-HT1A capacity to activate G-proteins. In BTBR mice, the SERT blocker, fluoxetine (10 mg/kg) and the 5-HT1A receptor partial-agonist, buspirone (2 mg/kg) enhanced social interactions. The D2/5-HT2 receptor antagonist, risperidone (0.1 mg/kg) reduced marble burying, but failed to improve sociability. Overall, altered SERT and/or 5-HT1A functionality in hippocampus could contribute to the relatively low sociability of BTBR mice.
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