Concetta D'Arrigo

Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: An update

BACKGROUND The second-generation antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and other compounds with different mechanisms of action. All second-generation antidepressants are metabolized in the liver by the cytochrome P450 (CYP) enzyme system. Concomitant intake of inhibitors or inducers of the CYP isozymes involved in the biotransformation of specific antidepressants may alter plasma concentrations of these agents, although this effect is unlikely to be associated with clinically relevant interactions. Rather, concern about drug interactions with second-generation antidepressants is based on their in vitro potential to inhibit > or = 1 CYP isozyme. OBJECTIVE The goal of this article was to review the current literature on clinically relevant pharmacokinetic drug interactions with second-generation antidepressants. METHODS A search of MEDLINE and EMBASE was conducted for original research and review articles published in English between January 1985 and February 2008. Among the search terms were drug interactions, second-generation antidepressants, newer antidepressants, SSRIs, SNRIs, fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, escitalopram, venlafaxine, duloxetine, mirtazapine, reboxetine, bupropion, nefazodone, pharmacokinetics, drug metabolism, and cytochrome P450. Only articles published in peer-reviewed journals were included, and meeting abstracts were excluded. The reference lists of relevant articles were hand-searched for additional publications. RESULTS Second-generation antidepressants differ in their potential for pharmacokinetic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, and nefazodone is a substantial inhibitor of CYP3A4. Therefore, clinically relevant interactions may be expected when these antidepressants are coadministered with substrates of the pertinent isozymes, particularly those with a narrow therapeutic index. Duloxetine and bupropion are moderate inhibitors of CYP2D6, and sertraline may cause significant inhibition of this isoform, but only at high doses. Citalopram, escitalopram, venlafaxine, mirtazapine, and reboxetine are weak or negligible inhibitors of CYP isozymes in vitro and are less likely than other second-generation antidepressants to interact with co-administered medications. CONCLUSIONS Second-generation antidepressants are not equivalent in their potential for pharmacokinetic drug interactions. Although interactions may be predictable in specific circumstances, use of an antidepressant with a more favorable drug-interaction profile may be justified.

Metabolic drug interactions with new psychotropic agents

New psychotropic drugs introduced in clinical practice in recent years include new antidepressants, such as selective serotonin reuptake inhibitors (SSRI) and ‘third generation’ antidepressants, and atypical antipsychotics, i.e. clozapine, risperidone, olanzapine, quetiapine, ziprasidone and amisulpride. These agents are extensively metabolized in the liver by cytochrome P450 (CYP) enzymes and are therefore susceptible to metabolically based drug interactions with other psychotropic medications or with compounds used for the treatment of concomitant somatic illnesses. New antidepressants differ in their potential for metabolic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, while nefazodone is a potent inhibitor of CYP3A4. These antidepressants may be involved in clinically significant interactions when coadministered with substrates of these isoforms, especially those with a narrow therapeutic index. Other new antidepressants including sertraline, citalopram, venlafaxine, mirtazapine and reboxetine are weak in vitro inhibitors of the different CYP isoforms and appear to have less propensity for important metabolic interactions. The new atypical antipsychotics do not affect significantly the activity of CYP isoenzymes and are not expected to impair the elimination of other medications. Conversely, coadministration of inhibitors or inducers of the CYP isoenzymes involved in metabolism of the various antipsychotic compounds may alter their plasma concentrations, possibly leading to clinically significant effects. The potential for metabolically based drug interactions of any new psychotropic agent may be anticipated on the basis of knowledge about the CYP enzymes responsible for its metabolism and about its effect on the activity of these enzymes. This information is essential for rational prescribing and may guide selection of an appropriate compound which is less likely to interact with already taken medication(s).

Risperidone Treatment of Children with Autistic Disorder: Effectiveness, Tolerability, and Pharmacokinetic Implications

BACKGROUND Recent evidence indicates that atypical antipsychotics represent a promising option for the treatment of autistic disorder. In particular, risperidone appears to be effective in treating aggressiveness, hyperactivity, irritability, stereotypies, social withdrawal, and lack of interests. OBJECTIVE The aim of the present study was to evaluate the effectiveness and tolerability of risperidone in children with autistic disorder and to examine the correlation between plasma levels of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) and the clinical response. METHODS The effect of treatment with risperidone (0.75-2 mg/day; mean +/- SD dose = 1.26 +/- 0.42 mg/day) was studied for 24 weeks in 20 children (14 boys, 6 girls) ages 3 to 10 years (mean age 6.0 +/- 2.4 years), diagnosed with autistic disorder. Fourteen items selected from the Childrens Psychiatric Rating Scale (CPRS-14) and Clinical Global Impression (CGI) were used for behavioral evaluation. Patients were classified as responders if they showed a 25% or greater decrease on CPRS-14 total score at final evaluation compared with baseline and a final CGI rating of 1 or 2. Patients were rated for extrapyramidal side effects on the Abnormal Involuntary Movement Scale (AIMS). Other side effects, including the expected side effects of atypical antipsychotics drugs, were assessed by a checklist. Blood samples for determination of risperidone and its active metabolite 9-OH-risperidone were obtained after 12 weeks, and serum prolactin levels were measured on admission and at weeks 12 and 24. RESULTS The psychopathological state, as assessed by CPRS, improved significantly over the duration of treatment. The mean CPRS-14 scores decreased significantly from 63.7 +/- 10.0 at baseline to 52.9 +/- 14.3 at week 12 (p < 0.01). At the end of 12 weeks of treatment, 8 patients were considered responders, and 10 patients reached a minimal improvement. No further improvement was observed in the following 12 weeks. In all children, serum prolactin levels increased significantly (p < 0.001) from 166 +/- 88 UI/mL at baseline to 504 +/- 207 UI/mL at week 12 of risperidone treatment. Weight gain and increased appetite were the most common unwanted effects. A mean increase of 3.7 +/- 1.7 kg in body weight was observed at final evaluation as compared with baseline. There was no significant correlation between percent improvement in total CPRS score and the plasma level of risperidones active fractions (the sum of the risperidone and 9-OH-risperidone plasma concentration). CONCLUSIONS This study provides further evidence of the beneficial effects of risperidone in children diagnosed with autistic disorder. However, the potential advantages of risperidone should be weighed against the risk of unwanted effects, such as an increase in serum prolactin levels and weight gain. No relation was observed between total plasma risperidone and 9-OH-risperidone concentrations and clinical response.

Olanzapine augmentation of paroxetine-refractory obsessive-compulsive disorder

The aim of the present study was to investigate the effect of adjunctive olanzapine in patients with obsessive-compulsive disorder (OCD) refractory to paroxetine. Twenty-one patients unresponsive to treatment with paroxetine, administered for at least 12 weeks at the dose of 60 mg/day, participated to a 12-week open-label, add-on trial with olanzapine (10 mg/day). The psychopathological state was evaluated by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and by Clinical Global Impression (CGI). Three patients did not complete the 12-week adjunctive treatment with olanzapine. In the 18 completers, the mean Y-BOCS score decreased significantly from 27.1+/-4.0 at baseline to 20.1+/-3.9 at final evaluation (P<.001). Seven patients (38.9%) were rated as responders at final evaluation. Steady-state plasma concentrations of paroxetine were not modified during olanzapine coadministration. The drug combination was generally well tolerated and initial sedation and weight gain were the most frequent unwanted effects. Our findings confirm the results of previous studies and indicate that the addition of olanzapine to ongoing treatment with serotonin reuptake inhibitors (SRI) may be beneficial in some patients unresponsive to SRI monotherapy.

Determination of olanzapine in human plasma by reversed-phase high-performance liquid chromatography with ultraviolet detection.

A sensitive high-performance liquid chromatographic method with ultraviolet absorbance detection for the determination of olanzapine in human plasma is described. Clozapine was used as internal standard. Analytes were concentrated from alkaline plasma by liquid-liquid extraction with n-hexane-isoamyl alcohol (90:10, vol/vol). The organic phase was back-extracted with 150 μL phosphate buffer (KH2PO4 with 25% H3PO4) 0.1 mol/L pH 2.2. The chromatographic separation required 6 minutes at a flow-rate of 1.0 mL/min and was carried out on a Water Spherisorb S5 C6 analytical column (250 mm×4.6 mm ID) with a mobile phase water-acetonitrile 55:45 vol/vol containing 0.009 moL/L eptansulfonic acid sodium salt and 0.06 mol/L potassium phosphate monobasic pH 2.7. The peaks were detected at 254 nm. Mean recoveries for olanzapine and internal standard were 89.4±3.3% and 90.4±1.0%, respectively. Coefficient of variation value for intraday was 5.0% at concentrations of 10, 50, and 100 ng/mL and for interday was 4.0% at concentrations of 5 and 25 ng/mL. Accuracy, expressed as percent error, ranged from −8.00% to 1.24%. Limit of detection and limit of quantification for olanzapine were 2 and 5 ng/mL, respectively. The method is suitable for pharmacokinetic studies and therapeutic drug monitoring.

Interactions between Antiepileptics and Second-Generation Antipsychotics

Introduction: Pharmacokinetic and pharmacodynamic drug interactions (DIs) can occur between antiepileptics (AEDs) and second-generation antipsychotics (SGAPs). Some AED and SGAP pharmacodynamic mechanisms are poorly understood. AED–SGAP combinations are used for treating comorbid illnesses or increasing efficacy, particularly in bipolar disorder. Areas covered: This article provides a comprehensive review of the interactions between antiepileptics and second-generation antipsychotics. The authors cover pharmacokinetic AED–SGAP DI studies, the newest drug pharmacokinetics in addition to the limited pharmacodynamic DI studies. Expert opinion: Dosing correction factors and measuring SGAP levels can help to compensate for the inductive properties of carbamazepine, phenytoin, phenobarbital and primidone. Further studies are needed to establish the clinical relevance of combining: i) AED strong inducers with amisulpride, asenapine, iloperidone, lurasidone and paliperidone; ii) valproate with aripiprazole, asenapine, clozapine and olanzapine; iii) high doses of oxcarbazepine (≥ 1500 mg/day) or topiramate (≥ 400 mg/day) with aripiprazole, lurasidone, quetiapine, risperidone, asenapine and olanzapine. Two pharmacodynamic DIs are beneficial: i) valproate–SGAP combinations may have additive effects in bipolar disorder, ii) combining topiramate or zonisamide with SGAPs may decrease weight gain. Three pharmacodynamic DIs contributing to decreased safety are common: sedation, weight gain and swallowing disturbances. A few AED–SGAP combinations may increase risk for osteoporosis or nausea. Three potentially lethal but rare pharmacodynamic DIs include pancreatitis, agranulocytosis/leukopenia and heat stroke. The authors believe that collaboration is needed from drug agencies and pharmaceutical companies, the clinicians using these combinations, researchers with expertise in meta-analyses, grant agencies, pharmacoepidemiologists and DI pharmacologists for future progression in this field.

Lack of a pharmacokinetic interaction between mirtazapine and the newer antipsychotics clozapine, risperidone and olanzapine in patients with chronic schizophrenia

The effect of mirtazapine on steady-state plasma concentrations of the newer atypical antipsychotics clozapine, risperidone and olanzapine was investigated in 24 patients with chronic schizophrenia. In order to treat residual negative symptoms, additional mirtazapine (30 mg per day) was administered for six consecutive weeks to nine patients stabilized on clozapine therapy (200-650 mg per day), eight on risperidone (3-8 mg per day) and seven on olanzapine (10-20mg per day). There were only minimal and statistically insignificant changes in mean plasma concentrations of clozapine and its metabolite norclozapine, risperidone and its metabolite 9-hydroxyrisperidone, and olanzapine during the study period. Mirtazapine co-administration with either clozapine, risperidone or olanzapine was well tolerated. In the overall sample, a slight improvement in negative symptomatology, as assessed by the Scale for Assessment of Negative Symptoms, was observed at final evaluation (P<0.01) and six patients (two in each treatment group) were classified as responders. While double-blind, controlled studies are needed to evaluate the potential clinical benefits of mirtazapine in chronic schizophrenia, our findings indicate that mirtazapine has a negligible effect on the metabolism of clozapine, risperidone and olanzapine and can be added safely to an existing treatment with these antipsychotics.

Effect of adjunctive lamotrigine treatment on the plasma concentrations of clozapine, risperidone and olanzapine in patients with schizophrenia or bipolar disorder.

The effect of lamotrigine on the steady-state plasma concentrations of the atypical antipsychotics clozapine, olanzapine, and risperidone was investigated in patients with schizophrenia or bipolar disorder stabilized on chronic treatment with clozapine (200-500 mg/day; n = 11), risperidone (3-6 mg/day; n = 10) or olanzapine (10-20 mg/day; n = 14)). Lamotrigine was titrated up to a final dosage of 200 mg/day over 8 weeks, and pharmacokinetic assessments were made at baseline and during treatment weeks 6 and 10, at lamotrigine dosages of 100 and 200 mg/day respectively. The plasma concentrations of clozapine, norclozapine, risperidone, and 9-hydroxy-risperidone did not change significantly during treatment with lamotrigine. The mean plasma concentrations of olanzapine were 31 ± 7 ng/mL at baseline, 32 ± 7 ng/mL at week 6, and 36 ± 9 ng/mL at week 10, the difference between week 10 and baseline being statistically significant (P < 0.05). Adjunctive lamotrigine therapy was well tolerated in all groups. These findings indicate that lamotrigine, at the dosages recommended for use as a mood stabilizer, does not affect the plasma levels of clozapine, risperidone, and their active metabolites. The modest elevation in plasma olanzapine concentration, possibly due to inhibition of UGT1A4-mediated olanzapine glucuronidation, is unlikely to be of clinical significance.

Short- and long-term effects on prolactin of risperidone and olanzapine treatments in children and adolescents.

This study investigated prolactin levels in two groups of children and adolescents receiving risperidone (N=29) or olanzapine (N=13). It focused not only on significant differences but also on effect sizes; took into account dose effects and gender differences; used a longitudinal design (months 1, 3, 6 and 12) that helped control for individual differences; and took into account response differences due to the duration of antipsychotic treatment. Additionally, this study investigated tolerance development using statistical tests, and explored the effect of antipsychotic plasma concentrations at months 1 and 3. After adjusting for gender, treatment duration and individual effects, mean prolactin levels on risperidone were 4.9 ng/mL higher than on olanzapine (10.3 times higher after controlling for dosing potency). On risperidone treatment, the adjusted mean prolactin level at the 3rd month of treatment was significantly higher than at the 1st month; at the 12th month it was significantly lower than at the 1st month; the 1st and 6th months were not significantly different. On olanzapine treatment, adjusted mean prolactin levels at the 3rd and 6th months of treatment were significantly higher than at the 1st month; at the 12th month it was lower than at the 1st month, but the difference was not significant. In males, at the 3rd month, an increase of 1 ng/mL in plasma 9-hydroxyrisperidone concentrations raised prolactin levels significantly by 0.44 ng/mL. In females, independently of duration (1 or 3 months), an increase of 1 ng/mL in plasma olanzapine concentrations raised prolactin levels significantly by 2.1 ng/mL. After adjusting for dose and the greater potency of risperidone, the increase in prolactin levels during risperidone treatment appeared to be 10.3 times higher than that during olanzapine treatment. Our study showed a pattern consistent with the development of prolactin tolerance over time. Future prolactin studies in children and adolescents taking antipsychotics need to include larger samples with more frequent prolactin measures and long-term plasma concentrations.

Effect of Valproate on Olanzapine Plasma Concentrations in Patients With Bipolar or Schizoaffective Disorder

The effect of valproate on the steady-state plasma concentrations of olanzapine was investigated in 18 patients with bipolar or schizoaffective disorder. Additional valproate, at a dose ranging from 600 to 2000 mg/d, was administered for 4 weeks to patients stabilized on olanzapine (5-20 mg/d). During valproate coadministration, mean plasma olanzapine concentrations decreased significantly from 32.9 ± 9.7 ng/mL at baseline to 27.4 ± 9.8 ng/mL at week 2 (P = 0.02), and to 26.9 ± 9.2 ng/mL at week 4 (P = 0.001). Smoking also decreased plasma olanzapine concentrations. Valproate coadministration with olanzapine was well tolerated and no patient showed a worsening of his or her psychopathological condition. These findings indicate that valproate, at doses of up to 2000 mg/d, is associated with a minimal, presumably not clinically significant, decrease in plasma olanzapine concentrations, possibly as a result of induction of olanzapine metabolism. New studies are needed to confirm that valproate could have mild inductive effects.