Shiho Sakai

HTR1A Gene Polymorphisms and 5-HT1A Receptor Partial Agonist Antipsychotics Efficacy in Schizophrenia.

Abstract Individual differences in serotonin 1A (5-HT1A) receptor may result in variable response to antipsychotics with 5-HT1A receptor partial agonism. We investigated the relationship between 5-HT1A receptor gene (HTR1A) single nucleotide polymorphisms (SNPs) and efficacy of antipsychotics with 5-HT1A receptor partial agonism in Japanese patients with schizophrenia. Perospirone or aripiprazole was administered to 100 patients with schizophrenia in a randomized controlled study. Candidate SNPs were rs6295 (which affects HTR1A expression and function), rs1364043, rs878567, and rs10042486. Efficacy at week 12 of treatment was evaluated using the Positive and Negative Syndrome Scale (PANSS) 5-factor subscales (excitement/hostility, depression/anxiety, cognition, positive, and negative). Rs1364043 T allele was correlated with the percent change in the PANSS 5-factor negative score (P < 0.01). Haplotype analysis showed that the rs10042486-rs6295-rs1364043 T-C-G haplotype was correlated with worse negative score improvement (haplotype frequency, 0.675; P = 0.014), and the relatively rare T-G-T haplotype correlated with better efficacy (haplotype frequency, 0.05; P = 0.031). This is the first study to show that rs10042486-rs6295-rs1364043 HTR1A variants may be correlated with the improvement of the PANSS 5-factor negative score during treatment with 5-HT1A partial agonist antipsychotics. Studies with larger sample sizes and in different ethnic groups are warranted.

A 12-week randomized, open-label study of perospirone versus aripiprazole in the treatment of Japanese schizophrenia patients

OBJECT To evaluate the efficacy and safety of aripiprazole and perospirone in Japanese patients with schizophrenia. METHODS In this 12-week, randomized, flexible-dose, open-label study, patients diagnosed with schizophrenia were randomized to receive aripiprazole (3-30 mg/day, n=49) or perospirone (8-48 mg/day, n=51). Efficacy and safety were evaluated using the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity Scale (CGI-S), the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) and the Barnes Akathisia Rating Scale (BAS) before treatment and every 4 weeks after the initiation of treatment. RESULTS Fifty-eight patients completed this study (aripiprazole, n=31; perospirone, n=27). No significant differences in gender, episode, age, schizophrenia type, weight, previous treatment and PANSS score were observed between the two groups at baseline. Both groups showed significant improvements during the study, with reductions in the total PANSS scores (Repeated measure analysis of variance, both p<0.0001). There were no significant differences in the PANSS change scores, CGI-S change scores, DIEPSS total score, BAS total score or over time between groups. The most common adverse event was insomnia in both groups. CONCLUSIONS In Japanese schizophrenia patients, aripiprazole and perospirone showed equal efficacy, tolerability and patient compliance. Both drugs showed good efficacy for treating schizophrenia. This paper is the first randomized study to evaluate the comparative efficacy and safety of aripiprazole and perospirone in the treatment of patients with schizophrenia.

The relationship between circulating mitochondrial DNA and inflammatory cytokines in patients with major depression

BACKGROUND Although inflammatory cytokines are established biomarkers of mood disorders, their molecular mechanism is not known. We hypothesized that circulating mitochondrial DNA (mtDNA) contributes to inflammation and could be used as biomarkers. We investigated if circulating mtDNA level is associated with inflammatory cytokines and can be used as a biomarker of mood disorders. METHODS Plasma mtDNA concentration was measured with real-time quantitative PCR targeting two regions of the mtDNA and plasma levels of four cytokines (GM-CSF, IL-2, IL-4, and IL-6) were measured with a multiplex immunoassay method in 109 patients with major depressive disorder (MDD). The most significantly correlated cytokine was verified with an enzyme-linked immunosorbent assay (ELISA). The data from 28 patients with bipolar disorder (BD), 17 patients with schizophrenia (SZ), and 29 healthy controls were compared. RESULTS MtDNA levels showed a nominal positive correlation with GM-CSF, IL-2 and IL-4 in patients with MDD. The most significant correlation with IL-4 (ρ = 0.38, P < 0.00005) was verified with an ELISA (ρ = 0.19, P = 0.049). Unexpectedly, patients with MDD and BD showed significantly lower plasma mtDNA levels than controls. MtDNA levels were lower in the depressive state than in the euthymic state in patients with MDD. Patients with depression, bipolar disorder, and schizophrenia did not show significantly higher levels of these four cytokines than controls. LIMITATIONS There is a possibility that the patients in this study are different from previous studies in which increased cytokine levels were reported. MtDNA levels should be measured in patients showing elevated plasma cytokine levels. A larger sample is required to generalize the results. CONCLUSIONS The present findings coincide with our hypothesis that circulating mtDNA contributes to the inflammation in MDD. Further studies are needed to conclude whether plasma mtDNA would be a biomarker of mood disorders.

The Comparative Effects of Risperidone Long-Acting Injection and Paliperidone Palmitate on Social Functioning in Schizophrenia: A 6-Month, Open-Label, Randomized Controlled Pilot Trial

Purpose: The aim of this study was to compare the effects of risperidone long-acting injection (RLAI) and paliperidone palmitate (PP) on non-acute-phase social functioning in patients with schizophrenia. Patients and Methods: In this 6-month pilot, open-label, randomized controlled study, 30 patients with schizophrenia who had been treated with RLAI were randomly allocated to the RLAI continuation group or switched to the PP group. Patients were evaluated at baseline and 6 months with the Social Functioning Scale (SFS) as the primary outcome variable and University of California San Diego Performance-Based Skills Assessment Brief (UPSA-B), Social Emotional Cognition Task (SECT), Positive and Negative Syndrome Scale (PANSS), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) scores as secondary outcomes. Results: At baseline, the two groups did not significantly differ in demographic or clinical features. The two groups did not differ in total score changes for the UPSA-B, the SECT, the PANSS, and the DIEPSS. However, the total scores and the two subscales of the SFS, i.e. independence-competence and independence-performance, were more improved in the PP group compared to the RLAI group (total scores, p = 0.038; competence, p = 0.001, and performance, p = 0.007, respectively). Conclusion: These results suggest that PP may improve the total social functioning, independent life competence, and performance as compared to the RLAI group. However, these results are preliminary and need independent replication in larger samples before any definitive statement can be made.

Syndrome of inappropriate secretion of anti-diuretic hormone in an elderly depressive patient receiving paroxetine: a case report

Paroxetine is a selective serotonin reuptake inhibiter (SSRI) widely used to treat depression. SSRI can also be prescribed to elderly patients with comparative safely because there are fewer serious side-effects of SSRIs compared with those of tricyclic anti-depressants. However, fatal side-effects induced by SSRIs have sometimes been observed. Jacob and Spinler (2006) reported hyponatremia associated with SSRI with an incidence varying from 0.5–32% (Jacob and Spinler, 2006). This case report describes a case of syndrome inappropriate secretion of anti-diuretic hormone (SIADH) in association with paroxetine therapy in an elderly patient. In SIADH, ADH stimulates the retention of water in the absence of appropriate physiological stimuli. The cardinal signs are as follows: (a) hyponatremia (serum sodium concentration< 135mmol/L) with corresponding hypo-osmolarity of the serum and extracellular fluid (osmolarity< 280mOsm/L); (b) if the urine is hypertonic relative to the plasma; (c) the absence of clinical evidence of fluid volume depletion; (d) normal renal function; and (e) normal adrenal function. Common symptoms include lethargy, fatigue, anorexia, sleep disturbance, muscle cramps and headaches. These symptoms may progress as the hyponatremia worsens to include nausea and vomiting, confusion, seizure, coma and ultimately death because of cerebral edema (Kirby and Ames, 2001).

Polymorphism of rs3813034 in Serotonin Transporter Gene SLC6A4 Is Associated With the Selective Serotonin and Serotonin-Norepinephrine Reuptake Inhibitor Response in Depressive Disorder: Sequencing Analysis of SLC6A4.

Abstract Selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRI/SNRI) are commonly used for treating major depression. Regretfully, significant heterogeneity exists regarding the benefits of SSRI/SNRI in individual cases. We previously reported that a polymorphism located in the serotonin transporter linked promoter region (5-HTT LPR) is associated with an interindividual difference in SSRI treatment efficacy. However, this explains only a small part of the variation of this complex phenotype. Other 5-HTT variants in the coding regions, 3′ untranslated region (3′ UTR), and introns adjacent to each exon could also contribute to treatment response. Therefore, we performed a sequencing analysis of the SLC6A4 gene (coding for 5-HTT) and investigated the association between variants detected in this study and the antidepressant response to SSRI/SNRI in 201 Japanese depressive patients. Seventeen novel mutations were identified by sequencing analysis. We found that the polymorphism G2563T (rs3813034) as a tag single-nucleotide polymorphism of IVS9 A-90G (rs140701), G2356T (rs1042173), and A3641C (rs7224199) is associated with interindividual variability of SSRI/SNRI efficacy at week 6, independent from clinical variables and effect of 5-HTT LPR (P < 0.001 by multiple regression analysis). This polymorphism could help determine individualized SSRI/SNRI treatments for depressive patients in combination with 5-HTT LPR.

Olfactory reference syndrome treated by blonanserin augmentation

IN PATIENTS WITH coronary heart disease (CHD), depression following myocardial infarction (MI) is associated with a 2–2.5-fold increased risk for severe adverse cardiovascular events and we have highly effective treatments for major depressive disorder (MDD). Why have large-scale studies of patients with depression and comorbid CHD repeatedly failed to show that effective treatment of depression improves cardiac outcome? We believe that the mismatch between instruments used in depression and those used in CHD is the most likely explanation. Using the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) randomized trial as an example of this mismatch, the method used to assess depression was based on modified DSM-IV-TR criteria for either current MDD, minor depressive disorder with a history of past MDD, or dysthymia. The principle modification was that current symptoms of depression must be present for 7 days instead of 14 days to facilitate enrollment and start treatment early. A structured version of the 17-item Hamilton Depression Rating Scale (HDRS) was integrated with the National Institute of Mental Health Diagnostic Interview Scale as modified for cardiac patients to form a new instrument: the Depression Interview and Structured Hamilton (DISH). According to the ENRICHD authors, the DISH produces accurate DSM-IV diagnoses, assesses the longitudinal course of the depressive disorder, and provides a reliable HDRS. The method used to assess CHD in the ENRICHD study focused on acute MI and required a characteristic increase in creatine kinase cardiac isoenzyme above the upper limits of the reference or an increase in other biomarkers to more than twice the upper limit. When cardiac isoenzyme values were less than twice the reference range, there was a mandatory review by the onsite cardiologist. Also, at least one of the following must have been present: (i) symptoms compatible with acute MI; or (ii) characteristic evolutionary electrocardiographic ST-T wave changes or new Q waves. Thus, instruments used in depression are less rigorous than those used in CHD. Depression instruments largely employ scales of categorical variables, when most depressive symptoms/behaviors are better described on ordinal scales. During instrument development, subjects with comorbid medical illness were excluded during field-testing. Parametric statistics were often used to analyze non-Gaussian data. These factors may explain why treatment of depression has not been found to improve cardiovascular conditions. We propose using the objectivity of CHD parameters to assess the efficacy of psychiatric interventions in patients with comorbid depression and to define the link between depression and CHD. REFERENCES

Serotonin 7 Receptor Variants Are Not Associated with Response to Second-Generation Antipsychotics in Japanese Schizophrenia Patients.

Background: Individual differences in serotonin 7 receptor (5-HT7R) may result in variable response to antipsychotics with 5-HT7R antagonism. This study investigated the relationship between single nucleotide polymorphisms (SNPs) in the 5-HT7R gene (HTR7) and the efficacy of second-generation antipsychotic drugs with a high affinity for this receptor in Japanese schizophrenia. Methods: Perospirone or aripiprazole was administered to 100 patients with schizophrenia in a randomized controlled study. All patients were genotyped for three candidate SNPs (rs12412496, rs7916403, and rs1935349). Patient improvement on the Positive and Negative Syndrome Scale (PANSS) total score at 12 weeks was assessed as the primary outcome. PANSS 5-factor scores were investigated as the secondary outcome. Results: Improvement on the PANSS total score and genetic polymorphisms showed no correlation. The rs12412496-rs7916403-rs1935349 A-T-A haplotype was correlated with worse improvement in the cognition score (haplotype frequency: 0.285, p = 0.046, permuted p = 0.043). Conclusion: Our results show that HTR7 variants are not related to the overall improvement in schizophrenia symptoms.