BDNF Val66Met and clinical response to antipsychotic drugs: A systematic review and meta-analysis

Cargnin, Sarah; Massarotti, Alberto; Terrazzino, Salvatore

doi:10.1016/j.eurpsy.2015.12.001

Cited by 14 publications

(9 citation statements)

References 42 publications

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“…One recent schizophrenia study utilized clinically assigned clozapine therapy as a proxy for treatment resistance (by comparing clozapine-treated patients to those who have never been prescribed clozapine) and found that PRS was significantly higher in clozapine patients than in non-clozapine patients(17), although another study failed to replicate the finding (18). However, both were cross-sectional studies that can be affected by ascertainment bias and inaccuracies of classification; for example, a similar cross-sectional study providing evidence for a pharmacogenetic role for the BDNF Val66Met variant(19) was not supported by subsequent longitudinal studies conducted in the context of clinical trials(20). Furthermore, PRS may have additional advantages in clinical prediction because it is a continuous variable that can have different cutoffs that maximize predictive power, whereas the candidate gene approach can compare only carriers to non-carriers.…”

Section: Introductionmentioning

confidence: 99%

Schizophrenia Polygenic Risk Score as a Predictor of Antipsychotic Efficacy in First-Episode Psychosis

Zhang

Robinson

et al. 2019

AJP

142

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Objective: Pharmacogenomic studies of antipsychotics have typically examined effects of individual polymorphisms; by contrast, polygenic risk scores (PRS) derived from genome-wide association studies (GWAS) can quantify the influence of thousands of common alleles of small effect in a single measure. We examined whether PRS for schizophrenia are predictive of antipsychotic efficacy in four independent cohorts of patients with first-episode psychosis (total n=510). Method: All subjects received initial treatment with antipsychotic medication for first-episode psychosis, and all were genotyped on standard SNP arrays imputed to the 1000 Genomes reference panel. PRS was computed based on the results of the large-scale schizophrenia GWAS reported by the Psychiatric Genomics Consortium. Symptoms were measured by total symptom rating scales at baseline and week 12 or at the last follow-up visit before drop-out. Results: In the discovery cohort, higher PRS significantly predicted higher symptom scores at 12-week follow-up (controlling for baseline symptoms, sex, age, and ethnicity). The PRS threshold of PT<0.01 gave the strongest result in the discovery cohort, and was used to replicate the findings in the other three cohorts. Higher PRS significantly predicted greater post-treatment symptoms in the combined replication analysis (p=.0095), and was individually significant in two of the three replication cohorts. Across the four cohorts, PRS was significantly predictive of adjusted 12-week symptom scores (pooled partial r=0.18, p=0.002, 3.24% of variance explained). Patients with low PRS were more likely to be treatment responders than those with high PRS (OR=1.91 in Caucasian samples, p<0.01). Conclusion: Patients with higher PRS for schizophrenia tended to have less improvement with antipsychotic drug treatment. PRS burden may have potential utility as a prognostic biomarker.

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Section: Introductionmentioning

confidence: 99%

Schizophrenia Polygenic Risk Score as a Predictor of Antipsychotic Efficacy in First-Episode Psychosis

Zhang

Robinson

et al. 2019

AJP

142

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“…They meta-analyzed the PGx variants in association with an antipsychotic response (11 meta-analysis studies; 20 variants across 10 genes), antipsychotic-induced weight/BMI gain (eight meta-analysis studies; 38 variants across 20 genes and four phenotypes of CYP2D6 ), metabolic syndrome (one meta-analysis study; three variants in HTR2C ), antipsychotic-related prolactin levels (two meta-analysis studies; two variants in DRD2 and four phenotypes of CYP2D6 ), antipsychotic-induced tardive dyskinesia (four meta-analysis studies; five variants across four genes), clozapine-induced agranulocytosis (one meta-analysis study; 13 PGx variants across nine genes), and plasma levels of antipsychotic drugs (three meta-analysis studies; two PGx variants in CYP1A2 , four phenotypes of CYP2D6 and three phenotypes of CYP2C19 ) ( Supplementary Tables S1 and S2 ). For treatment response, three meta-analysis studies reported in a mixed population, Caucasians and Asians separately [ 40 , 41 , 42 ]; one meta-analysis study reported in a mixed population and Caucasians [ 31 ]; six meta-analysis studies reported in mixed populations only [ 34 , 43 , 44 , 45 , 46 , 47 ]; one meta-analysis study reported in Asians [ 48 ]. For antipsychotic-induced weight/BMI gain, two meta-analysis studies reported in a mixed population, Caucasians and Asians separately [ 49 , 50 ]; two meta-analysis studies reported in a mixed population and Asians separately [ 51 , 52 ]; three meta-analysis studies reported in mixed population only [ 35 , 53 , 54 ]; one meta-analysis study did not state the ethnicity of the population [ 32 ].…”

Section: Resultsmentioning

confidence: 99%

The Progress and Pitfalls of Pharmacogenetics-Based Precision Medicine in Schizophrenia Spectrum Disorders: A Systematic Review and Meta-Analysis

Teng

Sandhu

Liemburg

et al. 2023

JPM

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The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report the evidence for associations between pharmacogenetic (PGx) variants and antipsychotics outcomes, including antipsychotic response, antipsychotic-induced weight/BMI gain, metabolic syndrome, antipsychotic-related prolactin levels, antipsychotic-induced tardive dyskinesia (TD), clozapine-induced agranulocytosis (CLA), and drug concentration level (pharmacokinetics) in SSD patients. Through an in-depth systematic search in 2010–2022, we identified 501 records. We included 29 meta-analyses constituting pooled data from 298 original studies over 69 PGx variants across 39 genes, 4 metabolizing phenotypes of CYP2D9, and 3 of CYP2C19. We observed weak unadjusted nominal significant (p < 0.05) additive effects of PGx variants of DRD1, DRD2, DRD3, HTR1A, HTR2A, HTR3A, and COMT (10 variants) on antipsychotic response; DRD2, HTR2C, BDNF, ADRA2A, ADRB3, GNB3, INSIG2, LEP, MC4R, and SNAP25 (14 variants) on weight gain; HTR2C (one variant) on metabolic syndrome; DRD2 (one variant) on prolactin levels; COMT and BDNF (two variants) on TD; HLA-DRB1 (one variant) on CLA; CYP2D6 (four phenotypes) and CYP2C19 (two phenotypes) on antipsychotics plasma levels. In the future, well-designed longitudinal naturalistic multi-center PGx studies are needed to validate the effectiveness of PGx variants in antipsychotic outcomes before establishing any reproducible PGx passport in clinical practice.

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“…Earlier findings attributed the response to antipsychotics to the presence of the BDNF Val66Met polymorphism (Nikolac Perkovic et al 2014). However, this relationship was questioned in a recent meta-analysis (Cargnin et al 2016). Nevertheless, although no n−3 PUFA supplementation studies assessing neurotrophin profile have been conducted in schizophrenia patients, the animal studies described strongly support the results of the present study, which indicate increases in BDNF peripheral levels after n−3 PUFA supplementation in first-episode schizophrenia patients.…”

Section: Discussionmentioning

confidence: 99%

An increase in plasma brain derived neurotrophic factor levels is related to n-3 polyunsaturated fatty acid efficacy in first episode schizophrenia: secondary outcome analysis of the OFFER randomized clinical trial

et al. 2019

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Rationale N−3 polyunsaturated fatty acids (n−3 PUFA) influence multiple biochemical mechanisms postulated in the pathogenesis of schizophrenia that may influence BDNF synthesis. Objectives A randomized placebo-controlled study was designed to compare the efficacy of a 26-week intervention composed of either 2.2 g/day of n−3 PUFA or olive oil placebo, with regard to symptom severity in first-episode schizophrenia patients. The secondary outcome measure of the study was to describe the association between n−3 PUFA clinical effect and changes in peripheral BDNF levels. Methods Seventy-one patients aged 16–35 were enrolled in the study and randomly assigned to the following study arms: 36 to the EPA + DHA group and 35 to the placebo group. Plasma BDNF levels were assessed three times, at baseline and at weeks 8 and 26 of the intervention. BDNF levels were determined in plasma samples using Quantikine Human BDNF ELISA kit. Plasma BDNF level changes were further correlated with changes in the severity of symptoms in different clinical domains. Results A significantly greater increase in plasma BDNF levels was observed in the intervention compared to the placebo group (Cohen’s d = 1.54). Changes of BDNF levels inversely correlated with change in depressive symptoms assessed using the Calgary Depression Rating Scale in Schizophrenia (Pearson’s r = − 0.195; p = 0.018). Conclusions The efficacy of a six-month intervention with n−3 PUFA observed in first-episode schizophrenia may be related to an increase in BDNF levels, which may be triggered by the activation of intracellular signaling pathways including transcription factors such as cAMP-reactive element binding protein.

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BDNF Val66Met and clinical response to antipsychotic drugs: A systematic review and meta-analysis

Cited by 14 publications

References 42 publications

Schizophrenia Polygenic Risk Score as a Predictor of Antipsychotic Efficacy in First-Episode Psychosis

Schizophrenia Polygenic Risk Score as a Predictor of Antipsychotic Efficacy in First-Episode Psychosis

The Progress and Pitfalls of Pharmacogenetics-Based Precision Medicine in Schizophrenia Spectrum Disorders: A Systematic Review and Meta-Analysis

An increase in plasma brain derived neurotrophic factor levels is related to n-3 polyunsaturated fatty acid efficacy in first episode schizophrenia: secondary outcome analysis of the OFFER randomized clinical trial

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