Kazuo Mihara

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.

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.

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.

Dopamine D2 receptor gene polymorphisms predict well the response to dopamine antagonists at therapeutic dosages in patients with schizophrenia.

Abstractu2003 Previous reports have shown that both A1 allele carriers of TaqI A and Del allele non‐carriers of −141C Ins/Del for dopamine D2 receptor (DRD2) gene polymorphisms have a better antipsychotic drug response. The present study aimed to examine the validity of a combination of these two DRD2 polymorphisms as predictors for response to DRD2 antagonists. The subjects consisted of 49 acutely exacerbated inpatients with schizophrenia treated with bromperidol (30 cases, 6–18u2003mg/day) or nemonapride (19 cases, 18u2003mg/day) for 3u2003weeks. Brief Psychiatric Rating Scale and Udvalg for Kliniske Undersøgelser side‐effects rating scale were used for clinical assessments. DRD2 genotypes were determined using a polymerase chain reaction method. In the overall 49 subjects, combined DRD2 polymorphisms weakly predicted the response to DRD2 antagonists (Fisher exact test, Pu2003=u20030.049), that is, good response in A1(+) or Del(–) subjects and poor response in A1(–) plus Del(+) subjects. In the former subjects, non‐responders with A1(+) or Del(–) showed higher scores of psychic, extrapyramidal and total side‐effects. At therapeutic doses (6–8u2003mg/day haloperidol equivalent dose) in 30 subjects, the predictability of response was greatly increased (Fisher exact test, Pu2003<u20030.0045) with higher positive and negative predictive values (78.3% and 85.7%, respectively). These findings suggest that combined DRD2 polymorphisms can be used as a pretreatment marker for response to DRD2 antagonists at therapeutic doses, and that A1(+) or Del(–) subjects are highly sensitive to DRD2 antagonists, expressed as either treatment responders or non‐responders vulnerable to extrapyramidal symptoms.

Lamotrigine augmentation therapy in a case with treatment‐resistant unipolar depression that showed insufficient response to electroconvulsive therapy

IT HAS BEEN shown that lamotrigine may be useful as augmentation of antidepressants for treatment-resistant unipolar depression. A large trial suggested a great response to lamotrigine augmentation in more severely depressed and more refractory unipolar patients. We report a case with refractory unipolar depression that had failed to sufficiently respond to several antidepressants, three augmentation strategies and electroconvulsive therapy (ECT), but that successfully achieved remission with lamotrigine augmentation of fluvoxamine. The use of lamotrigine was approved by the Ethics Committee of the University of the Ryukyus. Informed written consent and a singed release from the patient authorizing publication have been obtained. His anonymity has been preserved. The patient was a 54-year-old male office worker with recurrent major depressive disorder according to DSM-5. He had suffered his first depressive episode at the age of 38 due to work burden. Four antidepressants (paroxetine, amoxapine, trazodone, and milnacipran) and augmentation therapies with lithium, valproate, and clonazepam had showed little response. Eleven sessions of first ECT and 12 sessions of second ECT with maintenance ECT had a transient effect on him, and his depressive symptoms had relapsed on the regimen of lithium 600 mg/day (0.60 mmol/L) and valproate 600 mg/day (80 μg/mL). He had shown no (hypo)manic episodes throughout the period. His depressive symptoms were moderate with his Montgomery–Åsberg Depression Rating Scale (MADRS) score of 24 on fluvoxamine 200 mg/day, which showed partial response. Lamotrigine 25 mg/day was coadministered, and the daily dose was increased at the rate of 25 mg/2 weeks without a change in fluvoxamine dose. At the 8th week (lamotrigine 100 mg/day), his MADRS score decreased to 11 with a plasma lamotrigine concentration of 10.12 μmol/L. The dose was increased to 150 mg/day, as the concentration was under the therapeutic range (above 12.7 μmol/L) suggested by the authors. By the 10th week, his condition had remitted, with a MADRS score of 4 and a plasma lamotrigine concentration of 14.11 μmol/L. The possibility that he suffered from latent bipolar depression was not ruled out. However, the addition of lamotrigine to fluvoxamine improved his depressive symptoms, and finally led to remission. Therefore, it is suggested that lamotrigine can be a pharmacotherapeutic option for such patients. At a plasma lamotrigine concentration level below the therapeutic range, the therapeutic response was limited. Due to the increased dose of lamotrigine, the patient’s condition remitted at the therapeutic range. This result supports the notion proposed by the authors that therapeutic drug monitoring is necessary to optimize lamotrigine dose in the treatment of refractory depression.

Effects of escitalopram on plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in Japanese patients.

INTRODUCTIONnThe effects of escitalopram (10u2009mg/d) coadministration on plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, were studied in 13 Japanese psychiatric patients and compared with those of paroxetine (10u2009mg/d) coadministration.nnnMETHODSnThe patients had received 6-24u2009mg/d of aripiprazole for at least 2 weeks. Patients were randomly allocated to one of 2 treatment sequences: paroxetine-escitalopram (n=6) or escitalopram-paroxetine (n=7). Each sequence consisted of two 2-week phases. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection.nnnRESULTSnPlasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole during paroxetine coadministration were 1.7-fold (95% confidence intervals [CI], 1.3-2.1, p<0.001) and 1.5-fold (95% CI 1.2-1.9, p<0.01) higher than those values before the coadministration. These values were not influenced by escitalopram coadministration (1.3-fold, 95% CI 1.1-1.5 and 1.3-fold, 95% CI 1.0-1.5). Plasma dehydroaripiprazole concentrations remained constant during the study.nnnCONCLUSIONnThe present study suggests that low doses of escitalopram can be safely coadministered with aripiprazole, at least from a pharmacokinetic point of view.