The Effect of Fluoxetine on the Pharmacokinetics and Safety of Risperidone in Psychotic Patients

• Introduction
• Materials and Methods
• Subjects
• Procedures
• Data analysis
• Results
• Pharmacokinetics
• Efficacy, tolerance and safety
• Discussion
• References

In this open, 30-day trial, the pharmacokinetics, safety and tolerability of a combination therapy of risperidone (4 or 6 mg/day) and fluoxetine (20 mg/day from day 6) were evaluated in 11 psychotic inpatients. CYP2D6 genotyping revealed that 3 and 8 patients were poor metabolizers (PMs) and extensive metabolizers (EMs) of debrisoquine, respectively. The mean (± SD) AUC of risperidone increased from 83.1 ± 46.8 ng.h/ml and 398.3 ± 33.2 ng.h/ml (monotherapy) to 345.1 ± 158.0 ng.h/ml (p < 0.05) and 514.0 ± 144.2 ng.h/ml (p < 0.001) when coadministered with fluoxetine in EMs and PMs, respectively. The AUC of the active moiety (risperidone plus 9-hydroxy-risperidone) increased from 470.0 ± 170.0 ng.h/ml to 663.0 ± 243.3 ng.h/ml (p < 0.05) and from 576.3 ± 19.6 ng.h/ml to 788.0 ± 89.1 ng.h/ml (ns) in EMs and PMs, respectively. In EMs, the AUC of 9-hydroxy-risperidone remained similar (monotherapy vs. combination therapy: 386.8 ± 153.0 ng.h/ml vs. 317.7 ± 125.2 ng.h/ml, ns), whereas it increased in PMs (178.3 ± 23.5 ng.h/ml vs. 274.0 ± 55.1 ng.h/ml (p < 0.05)). Ten of the 11 patients showed a clinical improvement (reduction of 20 % or more in total PANSS score and 70 % on the mean MADRS score compared to baseline). The severity and incidence of extrapyramidal symptoms and adverse events did not significantly increase when fluoxetine was added.

Introduction

Several independent factor analyses show that schizophrenia is characterized by multiple dimensions of symptoms [25]. In addition to positive and negative symptoms, affective symptoms in particular are common during the course of the illness.

Fluoxetine and other selective serotonin reuptake inhibitors (SSRI) are widely used to manage depressive symptoms in patients with a range of diagnoses, including schizophrenia. Moreover, studies on SSRI augmentation of neuroleptic medication reveal some evidence for increased efficacy of conventional antipsychotics in negative symptoms after addition of SSRIs [22] [39] [42]. A pilot study showed that fluoxetine added to neuroleptics improves both positive and negative symptoms in treatment-resistant schizophrenic patients [13]. Several clinical reports have dealt with the combination of risperidone and fluoxetine [29] [31] [35], but no data are available on the pharmacokinetic consequences.

The main metabolite of fluoxetine, norfluoxetine, has similar pharmacodynamic properties as fluoxetine. They are, in vivo, potent inhibitors of CYP2D6 [4] [8], but also inhibit CYP2C19 and, regarding norfluoxetine, CYP3A4 [21] [33] [40]. Consequently, fluoxetine tends to elevate the plasma concentrations of co-administered tricyclic antidepressants and neuroleptics, most of which are metabolized by one or several of these isozymes of cytochrome P-450. They may also aggravate extrapyramidal symptoms (EPS) induced by the latter [10] [14].

Risperidone is a widely used atypical antipsychotic agent with potent serotonin 5-HT2 and dopamine D2 antagonist properties. It reduces psychotic symptoms with minimal EPS production at clinically efficacious doses [5] [24]. It is extensively metabolized, and its major metabolite, 9-hydroxy-risperidone, shows similar pharmacological activity to the parent drug. It is considered that the therapeutically active moiety is essentially represented by the sum of risperidone plus 9-hydroxy-risperidone [17]. The formation of 9-hydroxy-risperidone is subjected to genetic polymorphism of the debrisoquine-type mediated by CYP2D6 [19]. Recent studies have suggested that the pharmacokinetics of the active moiety (risperidone plus 9-OH-risperidone), D2- and 5-HT2-receptor occupancy as well as safety are not affected by the genetic CYP2D6 polymorphism (Janssen, data on file). However, recent case studies have suggested that patients who are genotypically CYP2D6 deficient and patients who are taking drugs that inhibit the CYP2D6 enzyme may present a higher risk for adverse effects during risperidone treatment [6].

As fluoxetine and other serotonin re-uptake inhibitors are partly also potent inhibitors of CYP isoenzymes, they are likely to be used in combination with risperidone in psychotic patients. Therefore, their possible effect on risperidone needs to be examined. The current study was undertaken to assess the effects of fluoxetine on the pharmacokinetics of risperidone in steady state conditions, and the safety and tolerability of the combination of risperidone and fluoxetine in adult psychotic patients. In addition, the efficacy of such a combination therapy on negative symptoms and/or depressive symptoms was documented during the trial.

Materials and Methods

Subjects

Between December 1996 and June 1997, we conducted an open-label, multicenter study (three psychiatric hospitals in Switzerland) with 13 psychotic inpatients who were on risperidone medication (2 or 3 mg twice daily) at least one week prior to the start of the trial. Patients continued their pre-trial risperidone therapy at the same dosage during the 30-day study period. Risperidone was given from day 0 to day 5. Fluoxetine (20 mg) was added from day 6 to day 30.

For study inclusion, participants had to be aged between 18 and 65 years, had to have been diagnosed as having schizophrenia according to DSM IV (295.10; 295.20; 295.30; 295.60; 295.90), schizophreniform disorder (295.40), schizoaffective disorder (295.70), brief psychotic disorder (298.8) or psychotic disorder not otherwise specified (298.9). They were found to be physically healthy based on the doctor’s consultation, physical examination, ECG, hematology and biochemical analysis and could benefit from the combination therapy of risperidone and fluoxetine for their negative and/or depressive symptomatology.

Women of reproductive age who were not using adequate contraception, pregnant or lactating women, patients with epilepsy or other substantial neurological disease, clinically relevant abnormal ECGs or abnormal laboratory tests were excluded from the study. Patients who were on medication known to be hepatic enzyme inducers or inhibitors two weeks prior to the first dose of the trial, patients who had been in trials with investigational drugs during the preceding 4 weeks or had donated blood within 60 days preceding the first visit were also excluded.

Each patient or his or her legal guardian gave written informed consent to participate in the trial. The investigators obtained approval for the study from their respective local ethics committees.

Procedures

At the screening visit (day 0), all entry criteria were checked, a physical and neurological examination was performed, and patients were evaluated using the Positive and Negative Syndrome Scale (PANSS) for schizophrenia [20] and the Montgomery and Asberg Depression Scale (MADRS) [27]. The severity of the extrapyramidal symptoms was assessed by means of the Extrapyramidal Symptom Rating Scale [9]. The effects of other adverse events were evaluated by means of an abbreviated version of the UKU Side Effect Rating Scale [26]. Since psychiatric items were rated in the PANSS and extrapyramidal symptoms were rated in the ESRS, the corresponding questions were omitted in the UKU Side Effect Rating Scale, which was reduced to 39 items from then on. Psychometric and side-effect evaluations were repeated on days 6, 13, 20 and 29. A physical examination and an ECG were repeated on day 30, and a laboratory test was performed on days 0, 13 and 30. Any serious adverse event was reported separately.

At the endpoint (day 30), patients were judged clinically improved if they had a reduction of 20 % or more in the total Positive and Negative Syndrome Scale score from baseline.

Treatment consisted of the administration of 2 mg tablets of risperidone twice daily (one patient received 3 mg twice daily) from days 1 to 30, with a 12-hour interval between the two daily doses. The drug was administered 1 hour before or after breakfast or the evening meal. From day 6 onwards, 20 mg of fluoxetine were added to the morning administration. The exact time of drug intake was reported.

Twenty-two venous blood samples were taken during the trial (8 ml each, except for days 6, 13, 20, and 29, where 12 ml samples were taken) for the determination of drug (risperidone, 9-OH-risperidone and fluoxetine, norfluoxetine) concentrations in plasma. Blood samples were taken before drug administration on days 4, 5, 6, 13, 20, 27, 29 and 30 in order to measure the plasma drug concentrations of risperidone, 9-OH-risperidone and the active moiety. After the blood sampling, the patient was administered risperidone with 150 ml of water. The exact time of the drug intake was recorded as t₀. To ensure compliance, additional 4 ml of blood were obtained for the measurement of the plasma concentrations of fluoxetine and norfluoxetine by gas chromatography on days 6, 13, 20 and 29 (Janssen, data on file).

Additional blood samples were taken on days 5 and 30, on which the 12-hour pharmacokinetic studies were performed. On the morning of the kinetic session, an intravenous cannula was placed in the patient’s forearm, and one blood sample (8 ml) was taken as trough concentration (C_oh). The patient’s heart rate and arterial blood pressure were then measured with the patient lying down; these measures were repeated 1, 2 and 12 hours after the administration of the medication. During these two sessions, the patients received medication with 150 ml of water after overnight fasting and were kept fasting for 2 hours after taking the drug. Sequential blood sampling took place at predefined times - 1, 2, 3, 4, 6, 8 and 12 hours. For each blood sample, 8 ml of blood was collected in heparinized tubes through a venous cannula. The tubes were centrifuged at 2000 g within an hour; plasma was transferred to a 5 ml tube and stored at -20 °C until analysis.

At the screening visit (day 0), a 10 ml blood sample was taken for CYP2D6 genotyping - detection of the inactivating alleles (CYP2D6*3, CYP2D6*4, CYP2D6*6) was performed by polymerase chain reaction as previously described [15] [16].

Concomitant medication included benzodiazepines, antiparkinsonian agents, and contraceptives in females. No additional treatment or rescue medications were allowed. If the patient had to take any drug or had inadvertently taken one, the name, dosage and date of intake had to be duly reported.

Total active moiety and risperidone were measured in plasma by means of a standardized radioimmunoassay method (RIA) with scintigraph detection after extraction from plasma; the concentration of 9-OH-risperidone was calculated as the difference between the two measured values (27 and Janssen, data on file). This explains why negative values are sometimes observed. The LOQ was 0.1 ng/ml and 2.2 ng/ml for risperidone and the “active moiety,” respectively.

Data analysis

The primary variables to be compared before and 24 days after coadministration of fluoxetine were the area under the plasma concentration-time curve, from time 0 through 12 h (AUC_{0 - 12h}), the mean plasma concentration during 12 hours, (C_avg,) the peak plasma concentration, (C_max), and time to peak concentration (T_max ). Secondary variables to be compared were trough levels (C_0h) and levels after 12 h(C_12h) before and during coadministration of fluoxetine; clinical ratings about efficacy (PANSS, MADRS) and safety (ESRS, UKU).

Analysis of variance (ANOVA) was performed to compare the dose-normalized plasma concentrations and pharmacokinetic values of risperidone and 9-hydroxy-risperidone (AUC_{0 - 12h}, C_avg, C_max, T_max) between day 5 (monotherapy) and day 30 (combined therapy). A general linear model which included factors of gender, subject (nested within gender) and treatment was used. Both original and log-transformed data were analyzed (the later only shown when they provide additional information). Where indicated, including the clinical variables, the Wilcoxon matched-pairs signed-rank test was used (Wilcoxon MPSRT). All tests were two-tailed and considered significant where &#945; < 0.05. For calculations, SAS statistical software was used.

Results

Two of the 13 patients were excluded from the study before day 5 (one patient because he withdrew his study participation consent, the other one because of major problems in drawing blood samples). Eleven patients were considered as the study sample. Eight male and three female patients (mean age ± SD: 43 ± 14 y (range 18 - 63 y)) with the DSM IV diagnosis of psychotic disorder not otherwise specified for two of them and of schizophrenia for 9 of them (disorganized type: n = 1, paranoid type: n = 6, residual type: n = 1, undifferentiated type: n = 1). Two patients raised special issues. One patient received 1 mg risperidone b. i. d. instead of 2 mg from day 20 to day 30 due to moderate somnolence. Data were normalized on a 2 × 2 mg/day dose. Another patient received 3 mg of risperidone b. i. d. for the whole study period - for calculations, his plasma levels were normalized as 2/3 of the measured value. The mean duration of the risperidone treatment at start of the fluoxetine coadministration was 5.5 days. Clinical and pharmacokinetic data were available from 11 patients, including incomplete pharmacokinetic data from one patient.

Five patients received benzodiazepines before and during the trial, two patients continued their antiparkinsonian medication - one of them also treated with fenofibrate - and one patient continued treatment with captopril. During the study, one patient took paracetamol on three occasions and another used a laxative once.

Pharmacokinetics

The results of the pharmacokinetic variables of risperidone before and after coadministration of fluoxetine are summarized in Table [1]. Three and eight patients were found to be poor (PMs) and extensive metabolizers (EMs), respectively. They differed clearly in many pharmacokinetic variables. At baseline (day 5), before administration of fluoxetine, some values of risperidone are significantly higher in PMs than in EMs (C_0h, C_12h, C_max, AUC_{0 - 12h}), while some corresponding values for 9-OH-risperidone are significantly higher in EMs (C_12h, AUC_12h). As an example, maximal concentrations of risperidone were 3 times higher in PMs than in EMs. On day 5, the risperidone/9-OH-risperidone trough level (C_min) ratios were 0.11 ± 0.10 and 1.40 ± 0.36 in EMs and PMs, respectively (p < 0.001). On day 30, the corresponding figure in EMs (0.91 ± 0.56) was significantly higher than that measured on day 5 (p = 0.005). No significant differences were observed between EMs and PMs when taking account of the ‘active moiety,’ that is, the sum of risperidone + 9-OH-risperidone. On day 30, no statistically significant differences between EMs and PMs were calculated in the patients comedicated with fluoxetine with regard to the pharmacokinetic parameters of risperidone.

For risperidone and for the ‘active moiety,’ in contrast to 9-OH-risperidone, fluoxetine treatment lead to a significant increase of some parameters (C_0h, C_12h, C_max, AUC_{1 - 12h}) (Table [1]) in EMs. The time until peak concentrations (T_max) showed no differences between EMs and PMs, and they were not influenced by fluoxetine treatment in EMs.

The individual values of AUC_{0 - 12 h}of risperidone, 9-hydroxy-risperidone and active moiety as measured on days 5 and 30 are shown in Fig. [1] a-c (the data of both drugs were available for 2 PMs and 7 EMs). The data of the 2 PMs show that risperidone plasma levels are higher than those in EMs before coadministration of fluoxetine, and that the AUCs of day 30 in EMs tend to approach those in PMs (Fig. [1 ]). There is a high interindividual variability in the ‘active moiety,’ but no apparent difference between EMs and PMs (Fig. [1 c]). In the EMs, the 9-hydroxy-risperidone AUC remained similar (monotherapy vs. combination therapy: 386.8 ± 153.0 ng.h/ml vs. 317.7 ± 125.2 ng.h/ml, ns), but there was a significant (p < 0.05) increase of the ‘active moiety’ from day 5 to day 30 (Table [1], Fig. [1 b] and 1 c).

The median plasma concentrations of fluoxetine and norfluoxetine on day 30 during the first 12 hours post-dose ranged between 55.2 and 87.2 ng/ml and 61.2 and 107 ng/ml, respectively. This demonstrates patient compliance.

Fig. [2] describes trough plasma concentrations of risperidone, 9-OH-risperidone and ‘active moiety’ on 8 different days before and after coadministration with fluoxetine. After addition of the antidepressant, the mean trough concentrations of the ‘active moiety’ in EMs tend to be similar to those measured in the 2 PMs, as a consequence of the pronounced increase of risperidone and the relative stability of 9-OH-risperidone.

This observation is confirmed by the comprehensive kinetic data presented in Fig. [3], which show the evolution of risperidone and 9-OH-risperidone concentrations over the 12 hperiod after administration of risperidone, before and after fluoxetine comedication (days 5 and 30, respectively). At any time point, risperidone concentrations in EMs are considerably higher after fluoxetine comedication and they are quite similar to those observed in PMs. 9-OH-risperidone concentrations under risperidone monotherapy are higher than those measured when risperidone is combined with fluoxetine.

Efficacy, tolerance and safety

Ten of the 11 patients showed a clinical improvement, with a reduction of 20 % or more in total PANSS score and 70 % on the mean MADRS score compared to baseline. The evolution of clinical ratings for efficacy is presented in Table [2]. The mean total ESRS-score was relatively low at admission (mean: 3.7 (range: 0 - 12)) and was somewhat lower at the end point (mean decrease -0.9 (- 8 to + 6), not significant). Most ESRS symptoms belonged to the parkinsonism cluster (mean: 3.6 (range 0 - 12), which showed a reduction until the end of the treatment by - 1.8 points (p = 0.07; Wilcoxon MPSR test). Three patients had an ESRS score of zero on admission and during the trial. During the comedication period, four patients showed an increase (+ 3 to + 12) and four showed a decrease (-2 to -8) on the ESRS total score. None of the patients required an introduction of the antiparkinsonian medication for emerging EPS - the two patients receiving antiparkinsonian drugs at admission continued taking them unchanged throughout the study period.

As measured on the UKU-scale, there were only 2 patients with a moderate or marked increase in symptom severity on day 29 compared to day 6 or baseline. The three PMs (patients A, B, C) received risperidone at 2 mg b. i. d. Patients A (who was on antiparkinsonian medication) and B were clinically responders, and did not show any relevant adverse effects. At day 30, their risperidone and 9-OH-risperidone plasma concentrations were 25.3 ng/ml and 31.2 ng/ml (patient A) and 46.2 ng/ml and 12.4 ng/ml (patient B). Patient C dropped out due to a marked somnolence and extrapyramidal symptoms (akathisia, slowness, parkinsonism), which were corrected through a reduction in the risperidone dose to 1 mg b. i. d. from days 20 - 30, as reported above. However, at day 20, before the posology reduction, his risperidone and 9-OH-risperidone plasma levels were 28.2 ng/ml and 13.0 ng/ml, respectively, indicating no clear relationship between plasma levels and side effects. Overall, there were no statistically significant differences between PMs and EMs comparing the total mean scores of each visit of the ESRS, MADRS and PANSS scales.

Another patient reported EPS of moderate severity after the end of the study, from days 55 to 70. This patient recovered after an adjustment of the risperidone dose.

There were no consistent or clinically relevant changes in blood pressure or heart rate, with the sole exception of two patients with orthostatic hypotension and consequent reflex tachycardia one and two hours after dosing on day 5 (that is, risperidone monotherapy). Eight patients had paired ECG data, that is, both at baseline and at least one during or at the end of treatment. Four patients had some moderate abnormalities at admission but there were no abnormalities recorded at the end of the study.

Discussion

In the general Caucasian population, about 5 - 10 % of the subjects have a genetic deficiency of CYP2D6 [7]. Therefore, the presence of 3 PMs in the present study is unexpectedly high, but their number is nevertheless too low for extensive statistical comparisons. The finding that risperidone plasma concentrations (e. g. day 5, C_0h) and risperidone/9-OH-risperidone ratios are significantly higher in PMs than in EMs confirms previous findings that support the hypothesis that CYP2D6 controls the hydroxylation of risperidone in vivo and in vitro. However, CYP3A4 (and CYP3A5) also seem to be involved [12] [19] [36].

The steady-state concentrations of risperidone, 9-OH-risperidone and the ‘active moiety’ in patients are within the range of those measured by other authors [2] [11] [17] [23] [30]; but apparently, CYP2D6 genotype or phenotype was not determined in their subjects. The coadministration of fluoxetine induced a major (7-fold) increase in risperidone plasma concentrations in EMs (Table [1]), but the increase in the active moiety was only about 1.5-fold, mimicking the situation seen in poor metabolizers. The effect on risperidone was most prominent in extensive metabolizers and less in poor metabolizers. This is in line with the CYP2D6 and CYP3A4-inhibiting potency of fluoxetine and norfluoxetine. A positron emission tomographic study has shown that D2-occupancy in the brain of psychiatric patients reaches 60 - 80 % at ‘active moiety’ plasma levels of 10 - 25 ng/ml [34]. These concentrations were measured in steady-state conditions in patients treated with 2, 4 or 6 mg/day risperidone. In addition, D2 - and 5-HT2-receptor occupancy is similar in the poor metabolizers compared to extensive metabolizers [28]. These findings support the view that the active 9-hydroxy metabolite of risperidone contributes to the clinical effects of risperidone, and thus partly counterbalances the marked variability in the concentrations of risperidone [28]. These findings are consistent with the positive clinical response observed in this study after risperidone-fluoxetine combination treatment and the absence of a significant increase in prevalence or severity of EPS or adverse events. However, other authors have described an increased risk of adverse effects in poor metabolizers in a case series with risperidone-treated patients [6], but in this latter study, most patients were treated with higher doses - 6 - 16 mg/day - than in our study. Similar interaction studies showed that amitriptyline [37] did not affect the mean plasma concentrations or pharmacokinetics of risperidone in schizophrenic patients or influence the antipsychotic fraction (the total concentration of risperidone and 9-hydroxyrisperidone) and that venlafaxine only moderately influences the pharmacokinetics of risperidone [1]. These observations are in line with the in vitro observation that fluoxetine and norfluoxetine are strong CYP2D6 inhibitors in human liver microsomes in contrast to amitriptyline, nortriptyline and venlafaxine [3] [18] [32] [38].

In conclusion, in this group of patients, the short-term clinical efficacy and tolerance of the risperidone and fluoxetine association were good, despite the pharmacokinetic interaction existing between the two drugs. Nevertheless, given the moderate increase in risperidone plus 9-hydroxy-risperidone (50 %), a moderate (1/3) risperidone dose reduction may be considered when adding fluoxetine to the antipsychotic therapy in daily practice.

Acknowledgements

This study was partially supported by a grant from Janssen Research Foundation

References

• 1 Amchin J, Zarycranski W, Taylor K P, Albano D, Klockowski P M. Effect of venlafaxine on the pharmacokinetics of risperidone.  J Clin Pharmacol. 1999;  39 297-309
  PubMedSearch in Google Scholar
• 2 Aravagiri M, Marder S R, Wirshing D, Wirshing W C. Plasma concentrations of risperidone and its 9-hydroxy metabolite and their relationship to dose in schizophrenic patients: simultaneous determination by a high performance liquid chromatography with electrochemical detection.  Pharmacopsychiatry. 1998;  31 102-109
  Thieme ConnectPubMedSearch in Google Scholar
• 3 Ball S E, Ahern D, Scatina J, Kao J. Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2.  Br J Clin Pharmacol. 1997;  43 619-626
  CrossrefPubMedSearch in Google Scholar
• 4 Baumann P. Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors.  Clin Pharmacokinet. 1996;  31 444-469
  CrossrefPubMedSearch in Google Scholar
• 5 Bondolfi G, Dufour H, Patris M, May J P, Billeter U, Eap C B,. et al . Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomised double-blind study. The Risperidone Study Group.  Am J Psychiatry. 1998;  155 499-504
  PubMedSearch in Google Scholar
• 6 Bork J A, Rogers T, Wedlund P J, de Leon J. A pilot study on risperidone metabolism: the role of cytochromes P450 2D6 and 3A.  J Clin Psychiatry. 1999;  60 469-476
  CrossrefPubMedSearch in Google Scholar
• 7 Brosen K. Drug-metabolizing enzymes and therapeutic drug monitoring in psychiatry.  Ther Drug Monit. 1996;  18 393-396
  CrossrefPubMedSearch in Google Scholar
• 8 Brøsen K. The pharmacogenetics of the selective serotonin reuptake inhibitors.  Clin Investig. 1993;  71 1002-1009
  PubMedSearch in Google Scholar
• 9 Chouinard G, Ross-Chouinard A, Annabel L, Jones B. The Extrapyramidal symptom rating scale.  Can J Neurol Sci. 1980;  7 233
  PubMedSearch in Google Scholar
• 10 Ciraulo D A, Shader R I. Fluoxetine drug-drug interaction: I. Antidepressants and antipsychotics.  J Clin Psychopharmacol. 1990;  10 48-50
  PubMedSearch in Google Scholar
• 11 Darby J K, Pasta D J, Elfand L, Dabiri L, Clark L, Herbert J. Risperidone dose and blood level variability: accumulation effects and interindividual and intraindividual variability in the nonresponder patient in the clinical practice setting.  J Clin Psychopharmacol. 1997;  17 478-484
  CrossrefPubMedSearch in Google Scholar
• 12 Fang J, Bourin M, Baker G B. Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4.  Naunyn Schmiedebergs Arch Pharmacol. 1999;  359 147-151
  PubMedSearch in Google Scholar
• 13 Goff D C, Brotman A W, Waites M, McCormick S. Trial of fluoxetine added to neuroleptics for treatment-resistant schizophrenic patients.  Am J Psychiatry. 1990;  147 492-494
  PubMedSearch in Google Scholar
• 14 Goff D C, Midha K K, Brotmann A W, Waites M, Baldessarini R J. Elevation of plasma concentrations of haloperidol after the addition of fluoxetine.  Am J Psychiatry. 1991;  148 790-792
  PubMedSearch in Google Scholar
• 15 Griese E U, Zanger U M, Brudermanns U, Gaedigk A, Mikus G, Morike K ,. et al . Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population.  Pharmacogenetics. 1998;  8 15-26
  PubMedSearch in Google Scholar
• 16 Heim M, Meyer U A. Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification.  Lancet. 1990;  336 529-532
  CrossrefPubMedSearch in Google Scholar
• 17 Heykants J, Huang M L, Mannens G, Meuldermans W, Snoeck E, Van Beijsterveldt L. et al . The pharmacokinetics of risperidone in humans: a summary.  J Clin Psychiatry. 1994;  55 (Suppl 5) 13-17
  PubMedSearch in Google Scholar
• 18 Holliday S M, Benfield P. Venlafaxine: a review of its pharmacology and therapeutic potential in depression.  Drugs. 1995;  49 280-294
  CrossrefPubMedSearch in Google Scholar
• 19 Huang M L, Van Peer A, Woestenborghs R, De Coster R, Heykants J, Jansen A A. et al . Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects.  Clin Pharmacol Ther. 1993;  54 257-268
  PubMedSearch in Google Scholar
• 20 Kay S R, Fiszbein A, Opler L A. The positive and negative syndrome scale (PANSS) for schizophrenia.  Schizophr Bull. 1987;  13 261-276
  CrossrefPubMedSearch in Google Scholar
• 21 Kobayashi K, Yamamoto T, Chiba K, Tani M, Ishizaki T, Kuroiwa Y. The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4’-hydroxylase activity in human liver microsomes.  Br J Clin Pharmacol. 1995;  40 481-485
  PubMedSearch in Google Scholar
• 22 Lammers C H, Deuschle M, Weigmann H, Hartter S, Hiemke C, Heese C. et al . Coadministration of clozapine and fluvoxamine in psychotic patients: clinical experience.  Pharmacopsychiatry. 1999;  32 76-77
  PubMedSearch in Google Scholar
• 23 Lee H S, Tan C H, Khoo Y M, Chee K T, Wong K E, Chong S A. et al . Serum concentrations and clinical effects of risperidone in schizophrenic patients in Singapore-a preliminary report [letter].  Br J Clin Pharmacol. 1999;  47 460-461
  PubMedSearch in Google Scholar
• 24 Lemmens P, Brecher M, Van Baelen B. A combined analysis of double-blind studies with risperidone vs. Placebo and other antipsychotic agents: factors associated with extrapyramidal symptoms.  Acta Psychiatr Scand. 1999;  99 160-170
  PubMedSearch in Google Scholar
• 25 Lindstrom E, von Knorring L. Changes in single symptoms and separate factors of the schizophrenic syndrome after treatment with risperidone or haloperidol.  Pharmacopsychiatry. 1994;  27 108-113
  PubMedSearch in Google Scholar
• 26 Lingjaerde O, Ahlfors U G, Bech P, Dencker S J, Elgen K. The UKU side effects rating scale.  Acta Psychiatr Scand. 1987;  76 (Suppl 334) 81-94
  PubMedSearch in Google Scholar
• 27 Montgomery S A, Asberg M. A new depression scale designed to be sensitive to change.  Br J Psychiatry. 1979;  134 382-389
  CrossrefPubMedSearch in Google Scholar
• 28 Nyberg S, Dahl M L, Halldin C. A PET study of D2 and 5-HT2 receptor occupancy induced by risperidone in poor metabolisers of debrisoquin and risperidone.  Psychopharmacology. 1995;  119 345-348
  PubMedSearch in Google Scholar
• 29 O’Connor M, Silver H. Adding risperidone to selective serotonin reuptake inhibitor improves chronic depression.  J Clin Psychopharmacol. 1998;  18 89-91
  CrossrefPubMedSearch in Google Scholar
• 30 Olesen O V, Linnet K. Simplified high-performance liquid chromatographic method for determination of risperidone and 9-hydroxyrisperidone in serum from patients comedicated with other psychotropic drugs.  J Chromatogr B Biomed Appl. 1997;  698 209-216
  PubMedSearch in Google Scholar
• 31 Ostroff R B, Nelson J C. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression.  J Clin Psychiatry. 1999;  60 256-259
  CrossrefPubMedSearch in Google Scholar
• 32 Otton S V, Wu D, Joffe R T, Cheung S W, Sellers E M. Inhibition by fluoxetine of cytochrome P450 2D6 activity.  Clin Pharmacol Ther. 1993;  53 401-409
  CrossrefPubMedSearch in Google Scholar
• 33 Pelkonen O, Maenpaa J, Taavitsainen P, Rautio A, Raunio H. Inhibition and induction of human cytochrome P450 (CYP) enzymes.  Xenobiotica. 1998;  28 1203-1253
  CrossrefPubMedSearch in Google Scholar
• 34 Remington G, Kapur S, Zipursky R. The relationship between risperidone plasma levels and dopamine D₂ occupancy: a positron emission tomographic study [letter].  J Clin Psychopharmacol. 1998;  18 82-83
  CrossrefPubMedSearch in Google Scholar
• 35 Saxena S, Wang D, Bystritsky A, Baxter L R Jr. Risperidone augmentation of SRI treatment for refractory obsessive-compulsive disorder.  J Clin Psychiatry. 1996;  57 303-306
  PubMedSearch in Google Scholar
• 36 Scordo M G, Spina E, Facciola G, Avenoso A, Johansson I, Dahl M L. Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone.  Psychopharmacology. 1999;  147 300-305
  CrossrefPubMedSearch in Google Scholar
• 37 Sommers D K, Snyman J R, van Wyk M, Blom M W, Huang M L, Levron J C. Lack of effect of amitriptyline on risperidone pharmacokinetics in schizophrenic patients.  Int Clin Psychopharmacol. 1997;  12 141-145
  PubMedSearch in Google Scholar
• 38 Stevens J C, Wrighton S A. Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450.  J Pharmacol Exp Ther. 1993;  266 964-971
  PubMedSearch in Google Scholar
• 39 Szegedi A, Anghelescu I, Wiesner J, Schlegel S, Weigmann H, Hartter S,. et al . Addition of low-dose fluvoxamine to low-dose clozapine monotherapy in schizophrenia: drug monitoring and tolerability data from a prospective clinical trial.  Pharmacotherapy. 1999;  32 148-153
  PubMedSearch in Google Scholar
• 40 Vandel S, Bertschy G, Baumann P, Bouquet S, Bonin B, Francois T, . et al . Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients.  Pharmacol Res. 1995;  31 347-353
  PubMedSearch in Google Scholar
• 41 Woestenborghs R, Geuens I, Lenoir H, Janssen C, Heykants J. In E. Reid and I.D. Wilson Methodological surveys in Biochemistry and analysis, Royal Society of Chemistry. Cambridge; 1990 20: 241-246
  Search in Google Scholar
• 42 Zullino D, Bondolfi G, Baumann P. The serotonin paradox: negative symptoms and SSRI augmentation.  Int J Psychiatry Clin Pract. 1998;  2 19-26
  PubMedSearch in Google Scholar

G. Bondolfi, M.D. 

Département de psychiatrie
Hôpitaux Universitaires de Genève

Boulevard de St. Georges 16-18

CH- 1205 Geneva/Switzerland

Phone: +41 (22) 327 75 55, +41 (22) 344 40 74 (Home)

Fax: +41 (22) 327 75 99

Email: guido.bondolfi@hcuge.ch

References

• 1 Amchin J, Zarycranski W, Taylor K P, Albano D, Klockowski P M. Effect of venlafaxine on the pharmacokinetics of risperidone.  J Clin Pharmacol. 1999;  39 297-309
  PubMedSearch in Google Scholar
• 2 Aravagiri M, Marder S R, Wirshing D, Wirshing W C. Plasma concentrations of risperidone and its 9-hydroxy metabolite and their relationship to dose in schizophrenic patients: simultaneous determination by a high performance liquid chromatography with electrochemical detection.  Pharmacopsychiatry. 1998;  31 102-109
  Thieme ConnectPubMedSearch in Google Scholar
• 3 Ball S E, Ahern D, Scatina J, Kao J. Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2.  Br J Clin Pharmacol. 1997;  43 619-626
  CrossrefPubMedSearch in Google Scholar
• 4 Baumann P. Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors.  Clin Pharmacokinet. 1996;  31 444-469
  CrossrefPubMedSearch in Google Scholar
• 5 Bondolfi G, Dufour H, Patris M, May J P, Billeter U, Eap C B,. et al . Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomised double-blind study. The Risperidone Study Group.  Am J Psychiatry. 1998;  155 499-504
  PubMedSearch in Google Scholar
• 6 Bork J A, Rogers T, Wedlund P J, de Leon J. A pilot study on risperidone metabolism: the role of cytochromes P450 2D6 and 3A.  J Clin Psychiatry. 1999;  60 469-476
  CrossrefPubMedSearch in Google Scholar
• 7 Brosen K. Drug-metabolizing enzymes and therapeutic drug monitoring in psychiatry.  Ther Drug Monit. 1996;  18 393-396
  CrossrefPubMedSearch in Google Scholar
• 8 Brøsen K. The pharmacogenetics of the selective serotonin reuptake inhibitors.  Clin Investig. 1993;  71 1002-1009
  PubMedSearch in Google Scholar
• 9 Chouinard G, Ross-Chouinard A, Annabel L, Jones B. The Extrapyramidal symptom rating scale.  Can J Neurol Sci. 1980;  7 233
  PubMedSearch in Google Scholar
• 10 Ciraulo D A, Shader R I. Fluoxetine drug-drug interaction: I. Antidepressants and antipsychotics.  J Clin Psychopharmacol. 1990;  10 48-50
  PubMedSearch in Google Scholar
• 11 Darby J K, Pasta D J, Elfand L, Dabiri L, Clark L, Herbert J. Risperidone dose and blood level variability: accumulation effects and interindividual and intraindividual variability in the nonresponder patient in the clinical practice setting.  J Clin Psychopharmacol. 1997;  17 478-484
  CrossrefPubMedSearch in Google Scholar
• 12 Fang J, Bourin M, Baker G B. Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4.  Naunyn Schmiedebergs Arch Pharmacol. 1999;  359 147-151
  PubMedSearch in Google Scholar
• 13 Goff D C, Brotman A W, Waites M, McCormick S. Trial of fluoxetine added to neuroleptics for treatment-resistant schizophrenic patients.  Am J Psychiatry. 1990;  147 492-494
  PubMedSearch in Google Scholar
• 14 Goff D C, Midha K K, Brotmann A W, Waites M, Baldessarini R J. Elevation of plasma concentrations of haloperidol after the addition of fluoxetine.  Am J Psychiatry. 1991;  148 790-792
  PubMedSearch in Google Scholar
• 15 Griese E U, Zanger U M, Brudermanns U, Gaedigk A, Mikus G, Morike K ,. et al . Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population.  Pharmacogenetics. 1998;  8 15-26
  PubMedSearch in Google Scholar
• 16 Heim M, Meyer U A. Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification.  Lancet. 1990;  336 529-532
  CrossrefPubMedSearch in Google Scholar
• 17 Heykants J, Huang M L, Mannens G, Meuldermans W, Snoeck E, Van Beijsterveldt L. et al . The pharmacokinetics of risperidone in humans: a summary.  J Clin Psychiatry. 1994;  55 (Suppl 5) 13-17
  PubMedSearch in Google Scholar
• 18 Holliday S M, Benfield P. Venlafaxine: a review of its pharmacology and therapeutic potential in depression.  Drugs. 1995;  49 280-294
  CrossrefPubMedSearch in Google Scholar
• 19 Huang M L, Van Peer A, Woestenborghs R, De Coster R, Heykants J, Jansen A A. et al . Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects.  Clin Pharmacol Ther. 1993;  54 257-268
  PubMedSearch in Google Scholar
• 20 Kay S R, Fiszbein A, Opler L A. The positive and negative syndrome scale (PANSS) for schizophrenia.  Schizophr Bull. 1987;  13 261-276
  CrossrefPubMedSearch in Google Scholar
• 21 Kobayashi K, Yamamoto T, Chiba K, Tani M, Ishizaki T, Kuroiwa Y. The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4’-hydroxylase activity in human liver microsomes.  Br J Clin Pharmacol. 1995;  40 481-485
  PubMedSearch in Google Scholar
• 22 Lammers C H, Deuschle M, Weigmann H, Hartter S, Hiemke C, Heese C. et al . Coadministration of clozapine and fluvoxamine in psychotic patients: clinical experience.  Pharmacopsychiatry. 1999;  32 76-77
  PubMedSearch in Google Scholar
• 23 Lee H S, Tan C H, Khoo Y M, Chee K T, Wong K E, Chong S A. et al . Serum concentrations and clinical effects of risperidone in schizophrenic patients in Singapore-a preliminary report [letter].  Br J Clin Pharmacol. 1999;  47 460-461
  PubMedSearch in Google Scholar
• 24 Lemmens P, Brecher M, Van Baelen B. A combined analysis of double-blind studies with risperidone vs. Placebo and other antipsychotic agents: factors associated with extrapyramidal symptoms.  Acta Psychiatr Scand. 1999;  99 160-170
  PubMedSearch in Google Scholar
• 25 Lindstrom E, von Knorring L. Changes in single symptoms and separate factors of the schizophrenic syndrome after treatment with risperidone or haloperidol.  Pharmacopsychiatry. 1994;  27 108-113
  PubMedSearch in Google Scholar
• 26 Lingjaerde O, Ahlfors U G, Bech P, Dencker S J, Elgen K. The UKU side effects rating scale.  Acta Psychiatr Scand. 1987;  76 (Suppl 334) 81-94
  PubMedSearch in Google Scholar
• 27 Montgomery S A, Asberg M. A new depression scale designed to be sensitive to change.  Br J Psychiatry. 1979;  134 382-389
  CrossrefPubMedSearch in Google Scholar
• 28 Nyberg S, Dahl M L, Halldin C. A PET study of D2 and 5-HT2 receptor occupancy induced by risperidone in poor metabolisers of debrisoquin and risperidone.  Psychopharmacology. 1995;  119 345-348
  PubMedSearch in Google Scholar
• 29 O’Connor M, Silver H. Adding risperidone to selective serotonin reuptake inhibitor improves chronic depression.  J Clin Psychopharmacol. 1998;  18 89-91
  CrossrefPubMedSearch in Google Scholar
• 30 Olesen O V, Linnet K. Simplified high-performance liquid chromatographic method for determination of risperidone and 9-hydroxyrisperidone in serum from patients comedicated with other psychotropic drugs.  J Chromatogr B Biomed Appl. 1997;  698 209-216
  PubMedSearch in Google Scholar
• 31 Ostroff R B, Nelson J C. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression.  J Clin Psychiatry. 1999;  60 256-259
  CrossrefPubMedSearch in Google Scholar
• 32 Otton S V, Wu D, Joffe R T, Cheung S W, Sellers E M. Inhibition by fluoxetine of cytochrome P450 2D6 activity.  Clin Pharmacol Ther. 1993;  53 401-409
  CrossrefPubMedSearch in Google Scholar
• 33 Pelkonen O, Maenpaa J, Taavitsainen P, Rautio A, Raunio H. Inhibition and induction of human cytochrome P450 (CYP) enzymes.  Xenobiotica. 1998;  28 1203-1253
  CrossrefPubMedSearch in Google Scholar
• 34 Remington G, Kapur S, Zipursky R. The relationship between risperidone plasma levels and dopamine D₂ occupancy: a positron emission tomographic study [letter].  J Clin Psychopharmacol. 1998;  18 82-83
  CrossrefPubMedSearch in Google Scholar
• 35 Saxena S, Wang D, Bystritsky A, Baxter L R Jr. Risperidone augmentation of SRI treatment for refractory obsessive-compulsive disorder.  J Clin Psychiatry. 1996;  57 303-306
  PubMedSearch in Google Scholar
• 36 Scordo M G, Spina E, Facciola G, Avenoso A, Johansson I, Dahl M L. Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone.  Psychopharmacology. 1999;  147 300-305
  CrossrefPubMedSearch in Google Scholar
• 37 Sommers D K, Snyman J R, van Wyk M, Blom M W, Huang M L, Levron J C. Lack of effect of amitriptyline on risperidone pharmacokinetics in schizophrenic patients.  Int Clin Psychopharmacol. 1997;  12 141-145
  PubMedSearch in Google Scholar
• 38 Stevens J C, Wrighton S A. Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450.  J Pharmacol Exp Ther. 1993;  266 964-971
  PubMedSearch in Google Scholar
• 39 Szegedi A, Anghelescu I, Wiesner J, Schlegel S, Weigmann H, Hartter S,. et al . Addition of low-dose fluvoxamine to low-dose clozapine monotherapy in schizophrenia: drug monitoring and tolerability data from a prospective clinical trial.  Pharmacotherapy. 1999;  32 148-153
  PubMedSearch in Google Scholar
• 40 Vandel S, Bertschy G, Baumann P, Bouquet S, Bonin B, Francois T, . et al . Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients.  Pharmacol Res. 1995;  31 347-353
  PubMedSearch in Google Scholar
• 41 Woestenborghs R, Geuens I, Lenoir H, Janssen C, Heykants J. In E. Reid and I.D. Wilson Methodological surveys in Biochemistry and analysis, Royal Society of Chemistry. Cambridge; 1990 20: 241-246
  Search in Google Scholar
• 42 Zullino D, Bondolfi G, Baumann P. The serotonin paradox: negative symptoms and SSRI augmentation.  Int J Psychiatry Clin Pract. 1998;  2 19-26
  PubMedSearch in Google Scholar

G. Bondolfi, M.D. 

Département de psychiatrie
Hôpitaux Universitaires de Genève

Boulevard de St. Georges 16-18

CH- 1205 Geneva/Switzerland

Phone: +41 (22) 327 75 55, +41 (22) 344 40 74 (Home)

Fax: +41 (22) 327 75 99

Email: guido.bondolfi@hcuge.ch