CYP1A2*F Polymorphism contributes at least partially to the Variability of Plasma Levels of Dehydroaripiprazole, an active Metabolite of Aripiprazole, in Schizophrenic Patients.

AIM: The relationship between CYP1A2 polymorphisms and the steady-state plasma levels of aripiprazole and its active metabolite, dehydroaripiprazole, were investigated in Japanese schizophrenic patients. BACKGROUND: It has been implied that cytochrome P450 (CYP) 1A2 may play a role in the metabolism of aripiprazole. Genetic variations in the CYP1A2 gene have been reported. OBJECTIVE: The authors investigated the relationship between 2 CYP1A2 polymorphisms, CYP1A2*C (-3860G>A) and CYP1A2*F (-163C>A), and the steady-state plasma levels/dose (C/D) ratios of aripiprazole and dehydroaripiprazole in Japanese schizophrenic patients. METHODS: All 89 subjects (46 males and 43 females) had been receiving 2 fixed daily doses of aripiprazole (24 mg; n=56 and 12 mg: n=33) for more than 2 weeks. No other drugs were used except flunitrazepam and biperiden. The plasma drug levels were determined by LC/MS/MS. These CYP1A2 polymorphisms were detected using polymerase chain reaction analysis. RESULTS: The mean C/D ratios of dehydroaripiprazole were significantly (P < 0.05) lower in patients with the A/A allele of CYP1A2*F than in those without the allele. No differences were found in the values of aripiprazole and the combination of aripiprazole and dehydroaripiprazole among the CYP1A2*F genotype. There were no differences in the values of aripiprazole, dehydroaripiprazole, or the combination of the 2 compounds among the CYP1A2*C genotype. The absence of the A allele of CYP1A2*F was correlated with the mean C/D ratios of dehydroaripiprazole (standardized partial correlation coefficient = 0.276, P < 0.01) by multiple regression analysis. CONCLUSION: The findings of this study suggest that the CYP1A2*F polymorphism contributes at least partially to the variability in the steady-state plasma levels of dehydroaripiprazole.

A High Plasma Lamotrigine Concentration at Week 2 as a Risk Factor for Lamotrigine-Related Rash.

BACKGROUND: Reportedly, a high plasma concentration of lamotrigine plays a role in the development of lamotrigine-related rash. The relationship between plasma concentrations of lamotrigine at week 2 and the lamotrigine-related rash was prospectively studied in 84 patients (22 males and 62 females) with treatment-resistant depressive disorder during an 8-week treatment of lamotrigine augmentation. METHODS: Eighty-four depressed patients with an insufficient response to at least 3 psychotropics, including antidepressants, mood stabilizers, and atypical antipsychotics, were included. The diagnoses were major depressive disorder (n = 39), bipolar I disorder (n = 10), and bipolar II disorder (n = 35). The final doses of lamotrigine were 100 mg/d for 57 subjects who were not taking valproate and 75 mg/d for 27 subjects taking valproate. Blood sampling was performed at week 2. Lamotrigine plasma concentrations were measured using high-performance liquid chromatography. The development of lamotrigine-related rash was assessed during the 8-week treatment. RESULTS: Six females developed lamotrigine-related rash. The mean plasma lamotrigine concentrations at week 2 were significantly (P = 0.009) higher in the rash group (4.81 ± 1.23 µmol/L) than in the nonrash group (3.35 ± 1.39 µmol/L). Receiver-operating characteristic analysis indicated that a plasma lamotrigine concentration of 4.38 µmol/L or greater at week 2 was significantly (P < 0.0001) predictive of lamotrigine-related rash. The proportion of patients with a lamotrigine concentration of 4.38 µmol/L or greater was significantly divided by the cutoff point into the rash group and the nonrash group (5/1 versus 13/65, P = 0.001). CONCLUSIONS: This study suggests that a high plasma lamotrigine concentration during week 2 is a risk factor for lamotrigine-related rash and a plasma lamotrigine concentration of 4.38 µmol/L may be a considered a threshold for rash in treatment-resistant depressive disorder.

Relationship Between UGT1A4 and UGT2B7 Polymorphisms and the Steady-State Plasma Concentrations of Lamotrigine in Patients With Treatment-Resistant Depressive Disorder Receiving Lamotrigine as Augmentation Therapy.

BACKGROUND: In a previous study, the authors had shown that in treatment-resistant depressive disorder, an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentrations. Lamotrigine is mainly metabolized by UGT1A4 and UGT2B7, and polymorphisms of said UGTs that affect enzyme activities have been reported. This study investigated the effect of these polymorphisms on the steady-state plasma concentrations (Css) of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy. METHODS: The subjects were 103 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 = 46), bipolar II disorder (n = 44), and bipolar I disorder (n = 13). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 67 subjects who were not taking valproate and 75 mg/d for 36 subjects taking valproate, respectively. Blood sampling was performed at the 8th week. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. The genotypes of UGT1A4 142T>G, UGT2B7 -161C>T, and UGT2B7 372A>G were identified by polymerase chain reaction analyses. RESULTS: There were no significant relationships between these polymorphisms and the Css of lamotrigine in the subjects regardless of valproate comedication. CONCLUSIONS: This study suggests that these genetic polymorphisms do not affect the Css of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy.

A Partial Response at Week 4 Can Predict Subsequent Outcome during Lamotrigine Augmentation Therapy in Treatment-Resistant Depressive Disorder: A Preliminary Study.

BACKGROUND/AIMS: The present study prospectively examined whether or not a partial response at week 4 predicts subsequent response at week 8 during lamotrigine augmentation therapy in 51 (16 males and 35 females) inpatients with treatment-resistant depressive disorder using an open-study design. METHODS: The subjects were 51 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 = 19), bipolar I disorder (n = 9), and bipolar II disorder (n = 23). The final doses of lamotrigine were 100 mg/day for 29 subjects who were not taking valproate and 75 mg/day for 22 subjects taking valproate. Depressive symptoms were evaluated by the Montgomery-Åsberg Depression Rating Scale (MADRS) before the start of lamotrigine and then at week 4, and finally after the 8th week of treatment. RESULTS: A significant linear relationship was found between percent improvements in MADRS scores at weeks 4 and 8 (r = 0.492, y = 0.438x + 30.223, R2 = 0.226, p < 0.001). The receiver operating characteristics analysis indicated that a percent improvement of 16% or greater at week 4 was significantly (p < 0.01) predictive of response (50% or more reduction in the MADRS score). The patients were significantly divided by the cut-off point into the responders and the nonresponders (18/26 vs. 1/25, p < 0.001). CONCLUSION: The present study suggests that a partial response at week 4 can predict subsequent outcome at week 8 during lamotrigine augmentation therapy in patients with treatment-resistant depressive disorder, and that the absence of a partial improvement at week 4 is highly predictive of nonresponse.

Prediction of an Optimal Dose of Aripiprazole in the Treatment of Schizophrenia From Plasma Concentrations of Aripiprazole Plus Its Active Metabolite Dehydroaripiprazole at Week 1.

BACKGROUND: It has been suggested that a plasma trough concentration of aripiprazole plus its active metabolite, dehydroaripiprazole of 225 ng/mL is a threshold for a good therapeutic response in the treatment of acutely exacerbated patients with schizophrenia. The present study investigated whether or not an optimal dose of aripiprazole could be predicted from these concentrations at week 1. METHODS: The subjects were 26 inpatients with schizophrenia, who received aripiprazole once a day for 3 weeks. The daily doses were 12 mg for the first week and 24 mg for the next 2 weeks. No other drugs except biperiden and flunitrazepam were coadministered. Blood samples were taken at weeks 1 and 3 after the treatment. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass-spectrometric detection. RESULTS: There was a significant linear relationship between the plasma concentrations of aripiprazole plus dehydroaripiprazole at weeks 1 (x) and 3 (y) (P < 0.001). Regression equation was y = 2.580x + 34.86 (R = 0.698). Based on the equation, a nomogram to estimate an optimal dose of aripiprazole could be constructed. CONCLUSIONS: The present study suggests that an optimal dose of aripiprazole for the treatment of patients with schizophrenia can be predicted from the plasma concentrations of the sum of the 2 compounds at week 1.

Both Serum Brain-Derived Neurotrophic Factor and Interleukin-6 Levels Are Not Associated with Therapeutic Response to Lamotrigine Augmentation Therapy in Treatment-Resistant Depressive Disorder.

BACKGROUND/AIMS: Serum levels of brain-derived neurotrophic factor (BDNF) and interleukin-6 (IL-6) were prospectively monitored in relation with therapeutic response to lamotrigine augmentation therapy in 46 (15 males and 31 females) inpatients with treatment-resistant depressive disorder during an 8-week treatment with lamotrigine using an open-study design. METHODS: The subjects were 46 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 = 19), bipolar I disorder (n = 6), and bipolar II disorder (n = 22). The final doses of lamotrigine were 100 mg/day for 26 subjects who were not taking valproate and 75 mg/day for 20 subjects taking valproate, respectively. Depressive symptoms were evaluated by the Montgomery-Åsberg Depression Rating Scale (MADRS) before and after the 8-week treatment. Blood sampling was performed before the start of lamotrigine treatment and at week 8. Serum BDNF and IL-6 levels were measured using quantitative sandwich enzyme immunoassays. RESULTS: No significant changes in serum BDNF or IL-6 levels during the 8-week lamotrigine treatment were observed in the total of subjects, responders or nonresponders. There was no significant correlation between the changes in serum BDNF or IL-6 levels and the percent improvement in MADRS scores in the overall subjects. CONCLUSION: The present study suggests that the acute effect of lamotrigine augmentation therapy for a major depressive episode is not related to either BDNF or IL-6, at least in patients with treatment-resistant depressive disorder.

Prediction of an Optimal Dose of Lamotrigine for Augmentation Therapy in Treatment-Resistant Depressive Disorder From Plasma Lamotrigine Concentration at Week 2.

BACKGROUND: The authors have previously shown that an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentration and that a plasma lamotrigine concentration of 12.7 µmol/L may be a threshold for a good therapeutic response in treatment-resistant depressive disorder. The present study investigated whether or not an optimal dose of lamotrigine could be predicted from plasma lamotrigine concentration at week 2. METHODS: The subjects were 37 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 = 15), bipolar I disorder (n = 6), and bipolar II disorder (n = 16). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 16 subjects who were not taking valproate and 75 mg/d for 21 subjects taking valproate, respectively. Blood sampling was performed at weeks 2 and 8. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. RESULTS: There were significant linear relationships between the plasma lamotrigine concentrations at week 2 (x) and those at week 8 (y) for subjects who were not taking valproate (P < 0.01) and those taking valproate (P < 0.01). Regression equations were y = 2.032x + 2.549 for the former and y = 3.599x + 5.752 for the latter, respectively. Based on the equations, a nomogram to estimate an optimal dose of lamotrigine could be calculated. CONCLUSIONS: The present study suggests that an optimal dose of lamotrigine for augmentation therapy in treatment-resistant depressive disorder can be predicted from a plasma lamotrigine concentration at week 2.

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 µmol/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 µmol/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 µmol/L may be a threshold for a good therapeutic response in treatment-resistant depressive disorder.

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.

Lack of correlation between the steady-state plasma concentrations of aripiprazole and haloperidol in Japanese patients with schizophrenia.

BACKGROUND: Both aripiprazole and haloperidol have been used in the treatment of schizophrenia, and are metabolized by the cytochrome P450 (CYP) 2D6 and CYP3A4. The authors studied the correlations between the steady-state plasma concentrations (Css) of aripiprazole and its active metabolite, dehydroaripiprazole, and those of haloperidol in 19 Japanese patients with schizophrenia, together with the effects of CYP2D6 genotypes on the steady-state kinetics of these compounds. METHODS: All the patients received first 24 mg/d of aripiprazole for 3 weeks and later received 6 mg/d of haloperidol for 2 weeks. Blood samplings were performed at least 2 weeks after the initiation of each treatment. The Css values of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection, and those of haloperidol were measured by using an enzyme immunoassay. CYP2D6 genotypes were determined by using polymerase chain reaction analysis. RESULTS: None of the correlations between the Css of aripiprazole (r = 0.286) or the sum of aripiprazole plus dehydroaripiprazole (r = 0.344) and those of haloperidol were significant. The mean Css of aripiprazole was significantly higher (P < 0.05) in the subjects with 1 *10 allele of CYP2D6 (n = 6) than in those with no mutated alleles (n = 13), whereas there were no significant differences in those of haloperidol between the 2 groups. CONCLUSIONS: This study suggests that the Css of aripiprazole and that of aripiprazole plus dehydroaripiprazole do not correlate with that of haloperidol in the same individual, because of the greater involvement of CYP2D6 in the metabolism of aripiprazole than in that of haloperidol.

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.

AIMS: 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. METHODS: The subjects were 70 inpatients with schizophrenia (36 men and 34 women), receiving fixed doses of aripiprazole (24 mg in 45 cases and 12 mg in 25 cases) for periods of between 2 and 30 weeks. Prolactin concentrations were measured by chemiluminescence immunoassay. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection. The genotypes of Taq1A, -141C Ins/Del DRD2 and CYP2D6 were detected by polymerase chain reaction methods. RESULTS: Prolactin concentrations were significantly higher in women than in men (8.9 ± 7.5 vs 3.4 ± 3.0 ng/mL, P < 0.001). No correlations were found between prolactin concentrations and plasma concentrations of aripiprazole, dehydroaripiprazole or the sum of the two compounds. Prolactin concentrations were not affected by any polymorphism. CONCLUSION: The present study suggests that only sex plays a significant role in prolactin concentrations during aripiprazole treatment.

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

BACKGROUND: The effects of paroxetine coadministration on plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, were studied in 14 Japanese patients with schizophrenia. METHODS: The patients had been treated with aripiprazole (24 mg/d in 5 cases, 12 mg/d in 5 cases, and 6 mg/d in 4 cases) for at least 2 weeks. Paroxetine 10 mg/d was coadministered during the first week, and the dose was increased to 20 mg/d during the second week. Blood samples were taken 3 times, before the start of paroxetine and then 1 and 2 weeks after paroxetine coadministration. On the same days, the severity of illness and extrapyramidal adverse effects were evaluated by the clinical global impressions and the Drug-Induced Extra-Pyramidal Symptoms Scale, respectively. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection. RESULTS: Plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole during coadministration of paroxetine 10 and 20 mg/d were significantly (P < 0.05) higher (1.5-fold and 1.7-fold; 1.4-fold and 1.5-fold) than those before paroxetine coadministration. Those values during coadministration of paroxetine 20 mg/d were also significantly (P < 0.05) higher (1.1-fold and 1.1-fold) than those during coadministration of paroxetine 10 mg/d. Plasma concentrations of dehydroaripiprazole were unchanged throughout the study period. The mean clinical global impression score was significantly (P < 0.05) higher during the paroxetine 10 mg/d than that before coadministration, whereas the Drug-Induced Extra-Pyramidal Symptoms Scale scores remained unchanged during the study. CONCLUSIONS: This study suggests that lower doses (10-20 mg/d) of paroxetine coadministration increase plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole.

Effects of the CYP2D6*10 allele on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in Japanese patients with schizophrenia.

The CYP2D6*10(*10) allele that causes decreased CYP2D6 activity is present in Asians with a high frequency of approximately 50%. We studied the effects of the *10 allele on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole. The subjects were 63 Japanese patients with schizophrenia who had only the wild-type or *10 alleles. Twenty-seven patients were homozygous for the wild-type allele, 31 were heterozygous, and five were homozygous for the *10 allele. All patients had been receiving the fixed doses of aripiprazole for at least 2 weeks. The daily doses were 24 mg (n = 40) and 12 mg (n = 23). 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 mean ± standard deviation values of concentration/dose ratios of aripiprazole in the patients with zero, one, and two *10 alleles were 9.0 ± 2.9, 12.7 ± 4.4, and 19.0 ± 6.8 ng/mL/mg, respectively, and those values for dehydroaripiprazole were 4.9 ± 1.6, 5.9 ± 1.7, and 5.9 ± 1.9 ng/mL/mg, respectively. The respective values for the sum of aripiprazole and dehydroaripiprazole were 13.9 ± 4.3, 18.6 ± 5.9, and 24.6 ± 8.5 ng/mL/mg. The mean concentration/dose ratios of aripiprazole were significantly (P < 0.01 or P < 0.001) different among the three genotype groups. The values for the sum of aripiprazole and dehydroaripiprazole were significantly higher in patients with one (P < 0.01) and two (P < 0.001) *10 alleles compared with those with zero *10 alleles. This study suggests that the *10 allele plays an important role in controlling the steady-state plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole in Asian subjects.