Gaku Okugawa

Diffusion tensor magnetic resonance imaging of disruption of regional white matter in schizophrenia.

Diffusion tensor imaging provides a new approach for quantifying anisotropic diffusion of white matter in vivo. We used this technique to investigate subtle disruption of regional white matter in schizophrenia. Twelve patients with schizophrenia were compared with 11 healthy controls. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale. A significant fractional anisotropy (FA) reduction was found in all white matter regions bilaterally in schizophrenic patients. Higher FA of left frontal white matter correlated significantly with higher dosage of antipsychotic medication. These findings support the view that the pathological process is a distortion of the central nervous system myelination affecting the whole white matter. Our findings also show the effects of antipsychotics on the white matter in the left frontal region in schizophrenia.

ABCB1 (MDR1) gene polymorphisms are associated with the clinical response to paroxetine in patients with major depressive disorder.

Variability in antidepressant response is due to genetic and environmental factors. Among genetic factors, the ones controlling for availability of the drug at the target site are interesting candidates. Multidrug resistance 1 (ABCB1, MDR1) gene encodes a blood-brain barrier transporter P-glycoprotein that plays an important role in controlling the passage of substances between the blood and brain. In the present study, we therefore examined the possible association of 3 functional ABCB1 polymorphisms (C3435T: rs1045642, G2677T/A: rs2032582 and C1236T: rs1128503) with response to paroxetine in a Japanese major depression sample followed for 6 weeks. Analysis of covariance at week 6 with baseline scores included in the model as covariate showed significant association of the non-synonymous SNP G2677T/A with treatment response to paroxetine (p=0.011). Furthermore, the wild variants haplotype (3435C-2677G-1236T) resulted associated with poor response (p=0.006). To our best knowledge, this study is the first suggestion of a possible association of ABCB1 variants with SSRIs response.

Effects of the serotonin type 2A, 3A and 3B receptor and the serotonin transporter genes on paroxetine and fluvoxamine efficacy and adverse drug reactions in depressed Japanese patients.

In this study, we tested the influence of the serotonin type 2A, 3A and 3B receptor genes (HTR2A, HTR3A, HTR3B) in addition to a polymorphism in the promoter region of the serotonin transporter (SERTPR), and investigated the different characteristics of clinical responses to paroxetine and fluvoxamine. A total of 100 Japanese patients affected by major recurrent depression were enrolled in a randomized 6-week study. The clinical response was evaluated using the Hamilton Rating Scale for Depression (HAM-D), and adverse drug reactions were assessed at each visit. Patients with the l allele of SERTPR showed a better response to SSRIs than s/s genotype carriers (p = 0.015–0.042), more significantly to fluvoxamine. The –1438G/G genotype of HTR2A was associated with a good response to SSRIs (p = 0.010–0.039), especially to fluvoxamine, and significantly with severe nausea in paroxetine-treated patients (p = 0.013). The 178C/C genotype of the HTR3A was associated with an antidepressant response (p = 0.022–0.042), and more significantly in paroxetine-treated patients (p = 0.002–0.042). These effects were independent of one another. We replicated the finding that the SERPTR polymorphism was associated with a response to SSRIs. We additionally found that HTR2A and HTR3A polymorphisms are associated with the efficacy, and the HTR2A polymorphism is also associated with adverse drug reactions. Furthermore, the effects of these polymorphisms varied from one SSRI to another and thus may depend on the characteristics of each SSRI.

Subtle Disruption of the Middle Cerebellar Peduncles in Patients with Schizophrenia

Diffusion tensor imaging (DTI) was used to investigate subtle disruption in the middle cerebellar peduncles in patients with schizophrenia. Fractional anisotropy (FA) was measured in 25 patients with schizophrenia and 21 healthy subjects using DTI. The FA of the right and left middle cerebellar peduncles was significantly lower in the schizophrenic patients compared to healthy subjects. FA in the left middle cerebellar peduncles was significantly correlated with the dosage of neuroleptics in patients with schizophrenia. There were no significant differences of mean diffusivity in the right and left middle cerebellar peduncles between patients with schizophrenia and healthy subjects. The findings of the study suggest that antipsychotics may improve the subtle disruption in the middle cerebellar peduncles in patients with schizophrenia.

Effect of 5‐HT1A gene polymorphisms on antidepressant response in major depressive disorder

Variability in antidepressant response is due to genetic and environmental factors. Among genetic factors, the ones controlling for availability of the drug at the target site are interesting candidates. Rs6295C/G SNP in the 5‐HT1A gene (HTR1A) has been found to affect the expression and function of HTR1A. In fact rs6295C/G is in strong linkage disequilibrium with other polymorphisms of HTR1A suggesting that those functional effects could be associated with polymorphisms other than or together with the synonymous rs6295C/G. In the present study we examined the possible association of a panel of markers in strong linkage disequilibrium of the HTR1A with SSRI/SNRI response in 137 Japanese major depression subjects followed for 6 weeks. We observed a significant association of better response to antidepressant in rs10042486C/C (P < 0.0001), rs6295G/G (P < 0.0001) and rs1364043T/T (P = 0.018) genotype carriers (minor allele homozygotes), independently from clinical variables. Furthermore minor allele homozygous carriers in all these three SNPs were associated with treatment response by various assessment such as HAM‐D score change over time (P = 0.001), week 2 (P < 0.0001), 4 (P = 0.007), and 6 (P = 0.048) as well as response rate (P = 0.0005) and remission rate (P = 0.004). We also pointed out the genotyping mis‐definition of rs6295C/G in the previous four articles. In conclusion, this is the first study that reports a significant association of antidepressant response with rs10042486C/T and rs1364043T/G variants of HTR1A and also with rs10042486–rs6295–rs1364043 combination. This finding adds an important information for the pathway of detecting the genetics of antidepressant response even if results must be verified on larger samples.

Effects of Electroconvulsive Therapy on Frontal White Matter in Late-Life Depression: A Diffusion Tensor Imaging Study

This study was conducted to elucidate the effects of electroconvulsive therapy (ECT) on frontal white matter in late-life depressed patients. Diffusion tensor imaging was performed on 8 late-life depressed patients and 12 healthy age-matched controls. The patients were scanned before and after a course of ECT. Fractional anisotropy (FA) was determined in the frontal and temporal regions and the corpus callosum. A significant white matter FA reduction was found in widespread frontal and temporal brain regions in patients with depression before ECT treatment compared with controls. A significant increase in frontal white matter FA was seen following ECT treatment. A course of bilateral ECT ameliorated white matter integrity in frontal brain regions. This suggests a strong relationship with the antidepressant action of ECT.

Controlled clinical comparison of paroxetine and fluvoxamine considering the serotonin transporter promoter polymorphism

The present study aimed to compare the effects of two currently used selective serotonin reuptake inhibitors (SSRIs) in Japan taking the individual background in 5-HTT gene-linked polymorphic region (5HTTLPR) genotype into account. Clinical responses to paroxetine and fluvoxamine were evaluated by total and cluster depressive symptoms for 81 Japanese patients who were diagnosed with major depression. Patients with the l allele had a greater percentage reduction on the total score (P=0.059) and somatic anxiety items (P=0.026) of the 21-item Hamilton Depression Rating Scale (HAM-D) score compared to s/s genotype carriers. Paroxetine was significantly more effective than fluvoxamine in the s/s carriers, as evaluated on the percentage reduction in total score (P=0.012) and core (P=0.049) HAM-D after 4 weeks of medication, but not in the l/s carriers. These findings suggest that the genetic test may be useful in investigating the efficacy of the two SSRIs, and that normalization by the 5HTTLPR genotypes may lead to improvement of the precision of comparative analysis.

Selective reduction of the posterior superior vermis in men with chronic schizophrenia

Cerebellar structures were measured in 30 chronic schizophrenic men and 18 healthy men using high resolution MRI. The volume of the posterior superior vermis was found to be significantly smaller in the schizophrenic men, but there was no difference in other cerebellar regions or the intracranial volume. The findings support the view that within the cerebellum the posterior superior vermis may be selectively reduced in men with chronic schizophrenia.

Corpus Callosum in Patients with Obsessive-Compulsive Disorder: Diffusion-Tensor Imaging Study

PURPOSE To prospectively examine microstructural white matter abnormalities in the corpus callosum (CC) of patients with obsessive-compulsive disorder (OCD), as compared with control subjects, and to investigate the relationship between diffusion-tensor (DT) imaging measures of the CC region and clinical symptoms of OCD. MATERIALS AND METHODS Institutional review board approval was obtained, and each participant--or the participants parent(s)--provided written informed consent. Sixteen patients with OCD (seven male, nine female; mean age, 28.7 years +/- 9.8 [standard deviation]) and 16 matched healthy volunteers (control subjects) (seven male, nine female; mean age, 29.9 years +/- 9.0) were examined. Mean diffusivity and fractional anisotropy (FA) were measured in five subdivisions of the CC. The paired t test was performed to compare the mean diffusivity or the FA in CC regions between the patients with OCD and the control subjects. RESULTS There were no significant differences (rostrum, P = .15; genu, P = .88; rostral body, P = .12; isthmus, P = .77; splenium, P = .88) in mean diffusivity between the patients with OCD and the healthy volunteers. A significant reduction in FA was observed in the rostrum of the CC in patients with OCD compared with the rostral FA in the control subjects (P < .001). Higher FA in only the rostrum correlated significantly with lower Yale-Brown obsessive-compulsive scale score (r = -0.72, P = .002). CONCLUSION Study results support the widely held view that the orbital prefrontal region is involved in the pathophysiology of OCD and indicate that the orbitofrontal circuit influences symptom severity in patients with OCD.

Reduced grey and white matter volumes in the temporal lobe of male patients with chronic schizophrenia

Magnetic resonance imaging (MRI) and tissue segmentation were used to quantify grey matter, white matter and cerebrospinal fluid (CSF) volumes in the brains of 32 males with chronic schizophrenia and 32 healthy males. Tissue volumes in the frontal, temporal, parietal, and occipital regions were measured separately. Males with schizophrenia had significant reductions of grey and white matter volumes in the temporal regions compared with controls. Patients also had significantly smaller white matter volumes in the cerebrum and increased CSF volumes in the frontal and the temporal regions as well as the cerebrum.The findings of the present study suggest that volumes of grey and white matter are reduced in the temporal region of males with chronic schizophrenia. The volume of white matter in the whole brain also appears to be reduced. Among the different brains regions, grey matter reduction was significant only in the temporal region.