Beatrice Balzarro

Clozapine resistance: Augmentation strategies

BACKGROUND Clozapine (CLZ) is not effective in more than 50% of treatment-resistant schizophrenic patients. In these cases, several pharmacological strategies are used in clinical practice, with different levels of evidence for both safety and efficacy. OBJECTIVES In the present paper we critically reviewed literature data regarding the efficacy and safety of adjunctive agents in CLZ-resistant schizophrenics. The following classes of agents were considered: 1) antipsychotics, 2) antidepressants, 3) mood stabilizers, 4) other agents (e.g. fatty acid supplement and glutamatergic agents), 5) electroconvulsive therapy (ECT). For lamotrigine and risperidone sufficient data were available to perform a meta-analysis. METHODS A Medline literature search covering a 20-year period was performed. For the meta-analysis, data were entered and analyzed with the Cochrane Collaboration Review Manager Software (RevMan version 5). RESULTS 62 pertinent studies were identified, including 1556 schizophrenic or schizoaffective patients. Among treatments investigated, there is evidence for CLZ augmentation with 1) amisulpride and aripiprazole, 2) mirtazapine and 3) ethyl eicosapentaenoic acid (E-EPA). Although promising, ECT augmentation needs further validation. The meta-analyses did not support either the use of risperidone or lamotrigine as CLZ adjunct. CONCLUSION Overall, there is scarce evidence of efficacy and safety as regards adjunctive strategies for CLZ-resistant patients. However, several limitations do not allow to draw any definitive conclusion; among these we underline the small sample size of clinical trials, the variable definitions of CLZ resistance, the heterogeneity of outcome measures and methodological designs.

Case-control association study for 10 genes in patients with schizophrenia: influence of 5HTR1A variation rs10042486 on schizophrenia and response to antipsychotics.

The aim of this study is to investigate possible associations between a set of single-nucleotide polymorphisms (SNPs) within 10 genes with Schizophrenia (SCZ) and response to antipsychotics in Korean in-patients treated with antipsychotics. Two hundred and twenty-one SCZ in-patients and 170 psychiatrically healthy controls were genotyped for 42 SNPs within ABCB1, ABCB4, TAP2, CLOCK, CPLX1, CPLX2, SYN2, NRG1, 5HTR1A and GPRIN2. Baseline and final clinical measures, including the Positive and Negative Symptoms Scale (PANSS), were recorded. Rs10042486 within 5HTR1A was associated with both SCZ and clinical improvement on PANSS total scores as well as on PANSS positive and PANSS negative scores. The haplotype analyses focusing on the four, three and two blocks’ haplotypes within 5HTR1A confirmed such findings as well. We did not observe any significant association between the remaining genetic variants under investigation in this study and clinical outcomes. Our preliminary findings suggest that rs10042486 within 5HTR1A promoter region could be associated with SCZ and with clinical improvement on PANSS total, positive and negative scores in Korean patients with SCZ. However, taking into account the several limitations of our study, further research is needed to draw more definitive conclusions.

Case-control association study of 36 single-nucleotide polymorphisms within 10 candidate genes for major depression and bipolar disorder

In this study we investigated 36 single nucleotide polymorphisms within 10 genes previously associated with major depression and bipolar disorder, as well as with the response to their treatment (ABCB1, ABCB4, TAP2, CLOCK, CPLX1, CPLX2, SYN2, NRG1, 5HTR1A and GPRIN2). No association with mood disorders and clinical outcomes was observed.

Antipsychotic Response in the First Week Predicts Later Efficacy

Background and Aims: Time of onset of antipsychotic action is still a debated matter. We aimed to replicate and extend previous findings that early response can predict subsequent non-response. Methods: 86 acutely psychotic patients treated with haloperidol were studied. Results: A PANSS reduction ≤16% at 1 week predicts non-response at 3 weeks of treatment (specificity 92%, sensitivity 82%). Conversely, a PANSS reduction ≥23% at 1 week of treatment predicts response at 3 weeks, with a specificity of 84% and a sensitivity of 86%. Conclusion: Our results confirm that an early response to antipsychotic treatment accurately predicts the treatment effectiveness and extends it to a prediction performed as early as 1 week.

Possible influence of CREB1, CREBBP and CREM variants on diagnosis and treatment outcome in patients with schizophrenia

The present study explores whether some single nucleotide polymorphisms (SNPs) within CREB1 (rs2709377 and rs6740584), CREBBP (rs2239317, rs2239316, rs3025702, rs130021, rs130005, rs129974 and rs9392) and CREM (rs1148247, rs4934735, rs12775799, rs6481941 and rs16935888) could be associated with schizophrenia (SKZ) and whether they could predict clinical outcomes in Korean in-patients treated with antipsychotics. Two-hundred twenty one in-patients suffering from SKZ and 170 psychiatrically healthy controls were genotyped for 10 SNPs within CREB1, CREBBP and CREM. All patients were assessed for the severity of illness at baseline and at discharge by means of the Positive and Negative Symptoms Scale (PANSS). Our findings suggest the lack of influence of SNPs under investigation in the present study on the susceptibility to SKZ and on the response to antipsychotics. However, taking into account the several limitations of our study, further research is needed to draw more definitive conclusions.

Abelson Helper Integration Site-1 Gene Variants on Major Depressive Disorder and Bipolar Disorder

Objective The present study aimed to explore whether 4 single nucleotide polymorphisms (SNPs) within the AHI1 gene could be associated with major depressive disorder (MD) and bipolar disorder (BD), and whether they could predict clinical outcomes in mood disorders. Methods One hundred and eighty-four (184) patients with MD, 170 patients with BD and 170 healthy controls were genotyped for 4 AHI1 SNPs (rs11154801, rs7750586, rs9647635 and rs9321501). Baseline and final clinical measures for MD patients were assessed through the Hamilton Rating Scale for Depression (HAM-D). Allelic and genotypic frequencies in MD and BD subjects were compared with those of each disorder and healthy group using the χ2 statistics. Repeated measures ANOVA was used to test possible influences of SNPs on treatment efficacy. Results The rs9647635 A/A was more represented in subjects with BD as compared with MD and healthy subjects together. The rs9647635 A/A was also more presented in patients with MD than in healthy subjects. With regard to the allelic analysis, rs9647635 A allele was more represented in subjects with BD compared with healthy subjects, while it was not observed between patients with MD and healthy subjects. Conclusion Our findings provide potential evidence of an association between some variants of AHI1 and mood disorders susceptibility but not with clinical outcomes. However, we will need to do more adequately-powered and advanced association studies to draw any conclusion due to clear limitations.

The Influence of AHI1 Variants on the Diagnosis and Treatment Outcome in Schizophrenia

The present study aimed to explore whether four single nucleotide polymorphisms (SNPs) within the AHI1 gene could be associated with schizophrenia (SCZ) and whether they could predict the clinical outcomes in SCZ patients treated with antipsychotics. Four hundred twenty-six (426) in-patients with SCZ and 345 controls were genotyped for four AHI1 SNPs (rs11154801, rs7750586, rs9647635 and rs9321501). Baseline and clinical measures for SCZ patients were assessed through the Positive and Negative Syndrome Scale (PANSS). Allelic and genotypic frequencies in SCZ subjects were compared with those of controls using the χ2 statistics. The repeated-measure ANOVA was used for the assessment of treatment outcomes measured by PANSS changes. The case-control analysis did not show any difference in the genotypic distribution of the SNPs, while in the allelic analysis, a weak association was found between the rs9647635 A allele and SCZ. Furthermore, in the haplotype analysis, three haplotypes resulted in being associated with SCZ. On the other hand, two SNPs (rs7750586 and rs9647635) were associated with clinical improvement of negative symptoms in the allelic analysis, although in the genotypic analysis, only trends of association were found for the same SNPs. Our findings suggest a possible influence of AHI1 variants on SCZ susceptibility and antipsychotic response, particularly concerning negative symptomatology. Subsequent well-designed studies would be mandatory to confirm our results due to the methodological shortcomings of the present study.

Generalized tonic–clonic seizure secondary to duloxetine poisoning: A short report with favorable out come

Duloxetine is a potent and selective inhibitor of serotonin and norepinephrine reuptake (SNRI) with a weak activity over dopamine reuptake used in the treatment of major depressive disorder. Daily doses of 60 mg are effective in treatment of major depression. There are few cases of isolated duloxetine overdose in humans. We think this is the first report of a generalized tonic-clonic seizure following isolated duloxetine poisoning with a very high dosage.

Case–control association study of GRIA1, GRIA2 and GRIA4 polymorphisms in bipolar disorder

Abstract Objective. The present study aimed to investigate whether some single nucleotide polymorphisms (SNPs) within GRIA1, GRIA2 and GRIA4 could be associated with bipolar disorder (BD) and they could predict clinical outcomes in in-patients with BD treated with mood stabilizers. Methods. One hundred and thirty-two (132) patients with BD and 170 healthy controls were genotyped for 17 SNPs within GRIA1, GRIA2 and GRIA4. Baseline and final clinical measures including Young Mania Rating Scale for patients with BD were recorded. Statistical significance was set at the 0.005 level in order to reduce the likelihood of false positive results. Results. We failed to show an evidence for a possible association of GRIA1, GRIA2 and GRIA4 with BD patients, in terms of influences on diagnosis and treatment outcomes, although this was the first study to explore the influence of such genes for bipolar disorder. Conclusion. Our results suggest that 17 SNPs within GRIA1, GRIA2 and GRIA4 may not be associated with the development and treatment outcomes in BD. However, taking into account that the several limitations of our study including the moderately small sample size of our study, our findings should be considered with caution and further research is needed to draw more definitive conclusions.

PDE7B, NMBR and EPM2A Variants and Schizophrenia: A Case-Control and Pharmacogenetics Study

Background: We investigated phosphodiesterase 7B (PDE7B), neuromedin B receptor (NMBR) and epilepsy progressive myoclonus type 2A (EPM2A) genes in schizophrenia (SCZ). To the best of our knowledge, these genes have been poorly investigated in studies of SCZ. Methods: Five hundred and seventy-three SCZ inpatients of Korean ethnicity and 560 healthy controls were genotyped for 2 PDE7B, 3 NMBR and 3 EPM2A polymorphisms. Differences in the allelic and genetic frequencies among healthy subjects and patients were calculated using the χ2 statistics. Repeated-measure ANOVA was used to test possible influences of single-nucleotide polymorphisms on treatment efficacy. In case of positive findings, clinical and demographic variables were added as covariates, in order to investigate possible stratification bias. Results: The rs2717 and rs6926279 within the NMBR gene and rs702304 and rs2235481 within the EPM2A gene were associated with SCZ liability. rs1415744 was also associated with Positive and Negative Symptom Scale negative clinical improvement. The results remained the same after inclusion of the covariates and were partially confirmed in the allelic and haplotype analyses. Conclusion: Our preliminary findings suggest a possible role of NMBR and EPM2A genes in SCZ susceptibility and, for the second one, also in antipsychotic pharmacogenetics. Nonetheless, further research is needed to confirm our findings.