Tsuyoshi Kondo

Combination of dopamine D2 receptor gene polymorphisms as a possible predictor of treatment-resistance to dopamine antagonists in schizophrenic patients.

Both the A1 allele carriers of TaqI A and Del allele noncarriers of -141C Ins/Del for dopamine D(2) receptor (DRD(2)) gene polymorphisms have been reported to have a lowered DRD(2) density. The present study aimed to examine whether the combinations of these two DRD(2) gene polymorphisms predict treatment response to antidopaminergic agents in schizophrenic patients. Subjects consisted of 49 acutely exacerbated schizophrenic inpatients treated with bromperidol (30 cases, mean dose+/-S.D.: 11.4+/-4.8 mg/day) or nemonapride (19 cases, 18 mg/day). Clinical symptoms were evaluated using Brief Psychiatric Rating Scale (BPRS) before and 3 weeks after the treatment. DRD(2) genotypes were determined using a polymerase chain reaction method. The A1 noncarriers with a Del allele showed poorer percentage improvement in anxiety-depression symptom after 3-week treatment (n=9, 7.3+/-42.9%) than A1 carriers without Del alleles (n=25, 62.4+/-38.0%) or A1 noncarriers without Del alleles (n=10, 65.4+/-29.2%). However, these preliminary results should be replicated in further research with a larger number of the subjects in each haplotype subgroup.

Influence of duration of untreated psychosis on auditory P300 in drug-naive and first-episode schizophrenia

Abstractu2002 P300 amplitude reduction in schizophrenia is, according to previous studies, partially recovered by treatment with neuroleptics. However, whether this medication‐induced P300 recovery is associated with duration of untreated psychosis (DUP) remains unreported; the present study is a preliminary examination of this question. Auditory P300 was recorded from 18 drug‐naive and first‐episode schizophrenia patients, among whom 10 were identified as short DUP, and eight as long DUP. Follow‐up event‐related potential tests were carried out after treatment with haloperidol or bromperidol for approximately 2u2003months. Recovery of P300 amplitude was replicated after neuroleptic medication was administered. A significant interaction was found between DUP and the medication effect in P300 amplitude over the left temporo‐parietal area; a significant P300 recovery was seen in short DUP but not in long DUP. These results suggest that first‐episode schizophrenia patients with long DUP might have severe impairments in the left temporal structures, supporting DUP as a key variable in future neurobiological studies of first‐episode schizophrenia.

Comorbid atypical autistic traits as a potential risk factor for suicide attempts among adult depressed patients: a case–control study

BackgroundThe present study aims to examine if autism spectrum disorder (ASD) is a risk factor for suicide attempts among adult depressed patients and to elucidate the characteristics of suicide attempts in adult depressed patients with ASD.MethodsWe conducted a case–control study. Subjects consisted of 336 retrospectively recruited first-time visit patients to our outpatient clinic with a current major depressive episode; 31 of the 336 patients had attempted suicide. The demographic backgrounds (i.e., age, gender, personal/family history of suicidality); specific psychopathology like bipolarity, agitation, and psychotic features; and comorbidity such as physical diseases, alcohol abuse, cluster B personality disorder, and ASD including pervasive developmental disorder not otherwise specified (PDD-NOS) were examined as potential risk factors for suicide attempts. We compared these variables between the suicide attempters and non-attempters. In addition, we compared suicide attempters to non-attempters within the ASD group and non-ASD group. Binary logistic regression analysis was performed using the significant independent variables from the comparisons between the suicide attempters and non-attempters, and the odds ratios (OR) and 95% confidence intervals (CI) were calculated.ResultsLogistic regression analysis demonstrated that agitation during a depressive episode (OR = 7.15, 95% CI = 2.88–17.74), past suicidal behaviors (OR = 4.32, 95% CI =1.70–10.98), and comorbid PDD-NOS (OR = 4.04, 95% CI = 1.20–13.54) were significantly associated with suicide attempts. The most prevalent suicidal method was drug overdose (59.1%) among non-ASD attempters while hanging was the most prevalent (44.4%) in ASD attempters.ConclusionsDepressed adults with comorbid atypical autistic traits are at higher risk for suicide attempts and may engage in methods that are more lethal.

Fluvoxamine dose-dependent interaction with haloperidol and the effects on negative symptoms in schizophrenia

Augmentation with low-dose fluvoxamine (50–100xa0mg/day) to antipsychotic treatment may improve the negative symptoms in schizophrenic patients, but involves a risk of drug-drug interaction. We studied the effects of fluvoxamine on plasma concentrations of haloperidol and reduced haloperidol, and their clinical symptoms, in haloperidol treated patients. Twelve schizophrenic inpatients with prevailingly negative symptoms receiving haloperidol 6xa0mg/day were additionally treated with incremental doses of fluvoxamine for 6 weeks (25, 75 and 150xa0mg/day for 2 weeks each). Plasma drug concentrations were monitored together with clinical assessments before and after each phase of the three fluvoxamine doses. Geometric mean of haloperidol concentrations during coadministration of fluvoxamine 25, 75 and 150xa0mg/day were 120% (95%CI; 114–127%), 139% (95%CI; 130–149%), and 160% (95%CI; 142–178%) of those before fluvoxamine coadministration, respectively. We found positive correlations between increase in plasma haloperidol concentrations and plasma fluvoxamine concentrations. Scores in negative symptoms were significantly reduced after fluvoxamine coadministration, whereas no changes were observed in the other psychiatric symptoms or any subgrouped side effects. Therefore, this study indicates that fluvoxamine increases plasma haloperidol concentrations in a dose-dependent manner. However, relatively small elevations in haloperidol concentration did not lead to the development of extrapyramidal symptoms under the conditions of this study.

Effects of genetic polymorphisms of CYP2D6, CYP3A5, and ABCB1 on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in Japanese patients with schizophrenia.

Background: We studied the effects of various factors, including genetic polymorphisms of the cytochrome P450 (CYP) 2D6, CYP3A5, and ABCB1, age, gender, and smoking habit on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in 89 patients with schizophrenia (46 males, 43 females). Methods: All patients had been receiving fixed doses of aripiprazole for at least 2 weeks. The daily doses were 24 mg (n = 56) and 12 mg (n = 33). No other drugs except biperiden and flunitrazepam were coadministered. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass-spectrometric detection. The CYP2D6 (CYP2D6*5, CYP2D6*10, and CYP2D6*14), CYP3A5 (CYP3A5*3), and ABCB1 (C3435T and G2677T/A) genotypes were identified by PCR analyses. Results: The mean concentration/dose ratios of aripiprazole and the sum of aripiprazole and dehydroaripiprazole were significantly higher in patients with 1 (P < 0.01 and P < 0.01) or 2 (P < 0.001 and P < 0.05) mutated alleles for CYP2D6 than in those without mutated alleles. No differences were found in the values of dehydroaripiprazole among CYP2D6 genotypes. There were no differences in the values of aripiprazole, dehydroaripiprazole, and the sum of the 2 compounds among CYP3A5 or the 2 ABCB1 variants. Multiple regression analyses including these polymorphisms, age, gender, and smoking habit showed that only the number of mutated alleles for CYP2D6 was correlated with mean concentration/dose ratios of aripiprazole [standardized partial correlation coefficients (beta) = 0.420, P < 0.001] and the sum of the 2 compounds (standardized beta = 0.335, P < 0.01). Conclusions: The findings of this study suggest that CYP2D6 genotypes play an important role in controlling steady-state plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole in Asian subjects, whereas CYP3A5 and ABCB1 genotypes seemed unlikely to have an impact.

Longitudinal Predictions of the Brooding and Reflection Subscales of the Japanese Ruminative Responses Scale for Depression

The Ruminative Responses Scale (RRS) is a measure of depressive rumination which has two subscales: Brooding and Reflection. This article examines the longitudinal predictions for depression and the test-retest reliability of the Brooding and Reflection of the Japanese RRS. Japanese university students (N = 378) completed the RRS, the Center for Epidemiologic Studies Depression Scale (CES-D), and the Inventory to Diagnose Depression, Lifetime Version (IDDL) which was modified to assess symptoms experienced in the 8-wk. follow-up period. The standardized betas of the initial Brooding and Reflection subscales for the IDDL scores were significant and positive after controlling for baseline CES-D scores, but those for the CES-D scores at Time 2 were not significant. Longitudinal predictions of Brooding were partially consistent with those of other language versions (significant in almost all studies); however, longitudinal predictions of Reflection were not consistent with those of other language versions (negative in previous studies). The test-retest correlations of both subscales were similar to those obtained in Western countries.

Suicide-related events among child and adolescent patients during short-term antidepressant therapy

Aims:u2002 Antidepressants have been of limited use for adolescent subjects with depression because of drug‐induced suicide‐related events (SRE). Therefore, we investigated actual suicidality and its risk factors during antidepressant therapy among child and adolescent patients in clinical settings.

Relationship between plasma concentrations of lamotrigine and its early therapeutic effect of lamotrigine augmentation therapy in treatment-resistant depressive disorder.

Background: The relationship between plasma concentrations of lamotrigine and its therapeutic effects was prospectively studied on 34 (9 men and 25 women) inpatients with treatment-resistant depressive disorder during an 8-week treatment of lamotrigine augmentation using an open-study design. Methods: The subjects were depressed patients who had already shown insufficient response to at least 3 psychotropics, including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 12), bipolar I disorder (n = 7), and bipolar II disorder (n = 15). The final doses of lamotrigine were 100 mg/d for 18 subjects who were not taking valproate and 75 mg/d for 16 subjects taking valproate. Depressive symptoms were evaluated by the Montgomery Åsberg Depression Rating Scale (MADRS) before and after the 8-week treatment. Blood sampling was performed at week 8. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. Results: There was a significant linear relationship between the plasma concentrations of lamotrigine and percentage improvements at week 8 (r = 0.418, P < 0.05). A stepwise multiple regression analysis showed that plasma lamotrigine concentrations alone had a significant effect on the percentage improvements at week 8 (standardized partial correlation coefficients = 0.454, P < 0.001). The receiver operating characteristics analysis indicated that a plasma lamotrigine concentration of 12.7 &mgr;mol/L or greater was significantly (P < 0.001) predictive of response (50% or more reduction in the MADRS score). The proportion of the responders was significantly higher in the groups with a lamotrigine concentration >12.7 &mgr;mol/L (11/15 versus 4/19, P < 0.01). Conclusions: The present study suggests that an early therapeutic response to lamotrigine is dependent on its plasma concentration and that a plasma lamotrigine concentration of 12.7 &mgr;mol/L may be a threshold for a good therapeutic response in treatment-resistant depressive disorder.

Prolactin concentrations during aripiprazole treatment in relation to sex, plasma drugs concentrations and genetic polymorphisms of dopamine D2 receptor and cytochrome P450 2D6 in Japanese patients with schizophrenia

The authors investigated the correlation between prolactin concentrations during aripiprazole treatment and various factors, including age, sex, plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, and genetic polymorphisms of dopamine D2 receptor (DRD2) and cytochrome P450(CYP)2D6.

Autism spectrum disorder among first-visit depressed adult patients: diagnostic clues from backgrounds and past history

OBJECTIVEnThe present study aimed to extract discriminating indicators for diagnosis of autism spectrum disorder (ASD) from personal backgrounds and past history among depressed adult outpatients.nnnMETHODSnSubjects were 430 depressed adults, consisting of patients with ASD (n=70) and those without ASD (n=360). Group comparison and discriminant analysis was conducted with regard to backgrounds (age, gender, education, marriage, living alone, physical diseases and family history of mood disorders) and past history (school non-attendance, bullied experience, psychotic-like experiences, conduct problems, suicide-related behaviors and interpersonal friction).nnnRESULTSnSix discriminating indicators (interpersonal friction, bullied experience, psychotic-like experiences, age under 32 years, school non-attendance and university educational level) were identified by stepwise discriminant analysis (P<.001). Absence of the first 4 indicators almost excluded ASD diagnosis with the highest negative predictive value (98%) and the least negative likelihood ratio (0.11) whereas one or more out of these 4 indicators showed low positive predictive value (32%) despite high sensitivity (93%).nnnCONCLUSIONSnThe abovementioned 4 indicators may be useful clues to cover possible ASD subjects among depressed adults although further detailed ASD focused diagnostic procedure is absolutely necessary to specify true ASD subjects. Meanwhile, absence of these 4 indicators is probably helpful to rule out ASD diagnosis.