Chronic oral treatment with risperidone impairs recognition memory and alters brain-derived neurotrophic factor and related signaling molecules in rats.

Antipsychotic drugs (APDs) are essential for the treatment of schizophrenia and other neuropsychiatric illnesses such as bipolar disease. However, they are also extensively prescribed off-label for many other conditions, a practice that is controversial given their potential for long-term side effects. There is clinical and preclinical evidence that chronic treatment with some APDs may lead to impairments in cognition and decreases in brain volume, although the molecular mechanisms of these effects are unknown. The purpose of the rodent studies described here was to evaluate a commonly prescribed APD, risperidone, for chronic effects on recognition memory, brain-derived neurotrophic factor (BDNF), its precursor proBDNF, as well as relevant downstream signaling molecules that are known to influence neuronal plasticity and cognition. Multiple cohorts of adult rats were treated with risperidone (2.5 mg/kg/day) or vehicle (dilute acetic acid solution) in their drinking water for 30 or 90 days. Subjects were then evaluated for drug effects on recognition memory in a spontaneous novel object recognition task and protein levels of BDNF-related signaling molecules in the hippocampus and prefrontal cortex. The results indicated that depending on the treatment period, a therapeutically relevant daily dose of risperidone impaired recognition memory and increased the proBDNF/BDNF ratio in the hippocampus and prefrontal cortex. Risperidone treatment also led to a decrease in Akt and CREB phosphorylation in the prefrontal cortex. These results indicate that chronic treatment with a commonly prescribed APD, risperidone, has the potential to adversely affect recognition memory and neurotrophin-related signaling molecules that support synaptic plasticity and cognitive function.

Analysis of smoking behavior on the pharmacokinetics of antidepressants and antipsychotics: evidence for the role of alternative pathways apart from CYP1A2.

Smoking is common among psychiatric patients and has been shown to accelerate the metabolism of different drugs. We aimed to determine the effect of smoking on the serum concentrations of psychopharmacological drugs in a naturalistic clinical setting. Dose-corrected, steady-state serum concentrations of individual patients were analyzed retrospectively by linear regression including age, sex, and smoking for amitriptyline (n=503), doxepin (n=198), mirtazapine (n=572), venlafaxine (n=534), clozapine (n=106), quetiapine (n=182), and risperidone (n=136). Serum levels of amitriptyline (P=0.038), clozapine (P=0.02), and mirtazapine (P=0.002) were significantly lower in smokers compared with nonsmokers after correction for age and sex. In addition, the ratios of nortriptyline/amitriptyline (P=0.001) and nordoxepin/doxepin (P=0.014) were significantly higher in smokers compared with nonsmokers. Smoking may not only induce CYP1A2, but may possibly also affect CYP2C19. Furthermore, CYP3A4, UGT1A3, and UGT1A4 might be induced by tobacco smoke. Hence, a different dosing strategy is required among smoking and nonsmoking patients. Nevertheless, the clinical relevance of the results remained unclear.

The predictive value of ABCB1, ABCG2, CYP3A4/5 and CYP2D6 polymorphisms for risperidone and aripiprazole plasma concentrations and the occurrence of adverse drug reactions.

We investigated in ninety Caucasian pediatric patients the impact of the main polymorphisms occurring in CYP3A, CYP2D6, ABCB1 and ABCG2 genes on second-generation antipsychotics plasma concentrations, and their association with the occurrence of adverse drug reactions. Patients with the CA/AA ABCG2 genotype had a statistically significant lower risperidone plasma concentration/dose ratio (Ct/ds) (P-value: 0.007) and an higher estimated marginal probability of developing metabolism and nutrition disorders as compared to the ABCG2 c.421 non-CA/AA genotypes (P-value: 0.008). Multivariate analysis revealed that the ABCG2 c.421 CA/AA genotype was found associated to a higher hazard (P-value: 0.004) of developing adverse drug reactions classified as metabolism and nutrition disorders. The ABCB1 2677TT/3435TT genotype had a statistically significant lower aripiprazole Ct/ds if compared with patients with others ABCB1 genotypes (P-value: 0.026). Information obtained on ABCB1 and ABCG2 gene variants may result useful to tailor treatments with these drugs in Caucasian pediatric patients.

Cytochrome P450-mediated interaction between perazine and risperidone: implications for antipsychotic polypharmacy.

BACKGROUND: Although clinically widespread, scientific evidence for antipsychotic polypharmacy is still limited. Combining different drugs increases the potential for drug-drug interactions, enhancing the risk of adverse drug reactions. We aimed to unravel the potential pharmacokinetic interactions between risperidone (RIS) and perazine. METHODS: Using a therapeutic drug monitoring database containing plasma concentrations of RIS and its active metabolite [9-hydroxyrisperidone (9-OH-RIS)], we considered two groups: a group of patients under antipsychotic monotherapy with RIS (n = 40) and a group of patients that was comedicated with perazine (n = 16). Groups were matched for demographic characteristics and daily dosage of RIS. Plasma concentrations, concentrations corrected for the dose (C/D) of RIS, 9-OH-RIS and the active moiety (RIS + 9-OH-RIS), as well as the metabolic ratios of concentrations of 9-OH-RIS/RIS, were compared using nonparametric tests. RESULTS: All parameters other than plasma concentrations and the C/D ratio of 9-OH-RIS differed between groups. Median values for plasma concentrations of the active moiety and C/D of the active moiety were higher in the perazine group (P < 0.001 and P < 0.001, respectively). Differences were driven by variations in the plasma concentrations and C/D of RIS, which were higher in the perazine group (P < 0.001 and P < 0.001, respectively). Metabolic ratios were lower in the perazine group (P = 0.003). DISCUSSION: The coadministration of perazine in RIS-medicated patients leads to significantly higher plasma concentrations and C/D values of RIS and its active moiety, and a lower metabolic ratio, reflecting the cytochrome P450 (CYP) 2D6 phenotype. We suggest that the mechanism underlying the effect of perazine on RIS metabolism is based on an inhibition of CYP2D6 and CYP3A4 activity.

Effect of smoking on risperidone pharmacokinetics - A multifactorial approach to better predict the influence on drug metabolism.

PURPOSE: To disentangle an association between tobacco smoking, smoking habits and pharmacokinetic patterns such as plasma concentrations of risperidone (RIS), its active metabolite 9-hydroxyrisperidone (9-OH-RIS) and the active moiety, AM, (RIS+9-OH-RIS) in a naturalistic sample. METHODS: Plasma concentrations, dose adjusted plasma concentrations (C/D) of RIS, 9-OH-RIS and AM in patients out of a therapeutic drug monitoring (TDM) database were compared between smokers (n=401) and non-smokers (n=292). RESULTS: Daily dosage of risperidone differed significantly with smokers receiving higher doses than patients in the control group (p=0.001). No differences were detected in plasma concentrations of the active moiety, RIS and 9-OH-RIS (p=0.8 for AM, p=0.646 for RIS and p=0.538 for 9-OH-RIS). However, dose corrected concentrations (C/D) of metabolite (C/D 9-OH-RIS) and active moiety (C/D AM) differed between significantly between groups (p=0.002 and p=0.007). After stratifying smokers to a group of moderate smokers (<20cigarettes/day) (RS1, n=109) and a group of heavy smokers (≥20cigarettes/day) (RS2, n=135), the comparison between non-smokers and both groups only showed lower values of C/D for 9-OH-RIS (p=0.011) for the group of moderate smokers while other pharmacokinetic parameters did not differ. CONCLUSIONS: Apart from the well-known induction of CYP1A2 activity by polycyclic aromatic hydrocarbons, smoking might exert an effect on other CYP isoenzymes as well. A possible interpretation proposes a slight inducing effect of smoking on risperidone metabolism most likely via CYP3A4.

Risperidone and total 9-hydroxyrisperidone in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 2002-2010.

BACKGROUND: Information on the plasma risperidone and total 9-hydroxyrisperidone concentrations ('total risperidone') attained in clinical practice is scant. The aim of this work was to gather such information to better inform the interpretation of results. METHOD: This involved the audit of plasma total risperidone data from a risperidone therapeutic drug monitoring service 2002-2010. RESULTS: There were 586 samples from 411 patients [289 (70%) males aged at the time of the first sample (median, range) 37 (7-83) years and 121 females aged 42 (10-91) years]. In patients aged 18 years and over, the mode of risperidone administration was oral: 242 samples (163 patients), risperidone long-acting injection (RLAI): 42 samples (39 patients), both oral and RLAI: 18 samples (12 patients), no information: 266 samples (211 patients). No risperidone/9-hydroxyrisperidone was detected in 10% of the samples, including 5 samples from patients prescribed RLAI. In the remainder, the mean (SD) total plasma total risperidone was all samples 35 (36), oral only 33 (29), RLAI only 23 (16), oral and RLAI 50 (21) µg/L. Overall, only 45% of the samples had plasma total risperidone within the range 20-59 mcg/L. Multiple linear regression analysis (95 samples) revealed that sex, smoking habit, and dose explained 21% of the variation in plasma total risperidone after oral dosage (dose alone only explained 11% of the variation). There was no discernable influence of age, body weight, and the plasma risperidone:total 9-hydroxyrisperidone ratio on plasma total risperidone. CONCLUSIONS: Risperidone therapeutic drug monitoring can help assess adherence and guide dosage even after RLAI.

A stability indicating HPLC method for the determination of electrochemically controlled release of risperidone.

A rapid stability indicating reversed-phase high-performance liquid chromatography (HPLC) method is developed for the determination of the electrochemically controlled risperidone release from a novel drug delivery system, based on the intrinsically conducting polymer (ICP), polypyrrole. The chromatographic separation was carried out on a C(18) column using acetonitrile-potassium dihydrogen phosphate (45:55, v/v, pH 6.5; 0.05 M) as the mobile phase. The isocratic flow is at 1.0 mL/min, with a runtime of 6 min, and the UV detection is at 237 nm. This provided a calibration curve linear over the range of 1-100 µg/mL. Intra-day and inter-day accuracy range between 98.4% and 102.6%, and the RSD for precision is <1.43%. The limit of detection and quantitation were determined to be 0.001 µg/mL and 0.01 µg/mL, respectively. The analytical method confirmed risperidone is stable for the oxidizing electric potential and the acidic environment involved during the manufacture and operation of the novel drug delivery system. The rate of risperidone release from polypyrrole depended on electrical stimulation applied to the polymer. This HPLC method is significantly faster than previously published methods and is the first to investigate the effect of an oxidizing potential on risperidone stability, which is essential for the evaluation of controlled delivery from an ICP-based system.

Predictors of risperidone and 9-hydroxyrisperidone serum concentration in children and adolescents.

INTRODUCTION: Little is known about risperidone metabolism in a clinical sample, where polypharmacy is common. Such knowledge is important since several of its side effects are dose dependent. METHODS: Medically healthy patients aged 7 to 17 years old treated with risperidone for at least 6 months were enrolled. Trough serum risperidone and 9-hydroxyrisperidone concentrations were measured. RESULTS: One hundred seven participants (92% males) were recruited, representing a heterogenous clinical group with attention-deficit/hyperactivity disorder, disruptive behavior disorders, pervasive developmental disorders, anxiety disorders, mood disorders, tic disorders, or psychotic disorders. Risperidone had been used at a mean dose of 0.03 mg/kg, for a mean 2.5 years, predominantly to treat irritability and aggression. Cytochrome CYP2D6 inhibitors were divided into prominent (fluoxetine, bupropion, and lamotrigine), intermediate (sertraline), and weak inhibition groups (citalopram or escitalopram). The concentrations of risperidone and its metabolite were strongly associated with the dose of risperidone and time since the last dose and, to a lesser extent, with male sex. In addition, risperidone concentration increased with pubertal stage (p < 0.05), while body mass index z-score (p = 0.001) predicted a higher 9-hydroxyrisperidone concentration. The use of CYP2D6 inhibitors was much more strongly associated with risperidone concentration (p < 0.0001) than with its metabolite's (p = 0.06). CONCLUSIONS: In chronically treated youths, the metabolism of risperidone depends on the stage of sexual development, whereas that of 9-hydroxyrisperidone varies with body fat. Moreover, CYP2D6 inhibitors more strongly affect risperidone metabolism than that of its metabolite. The clinical implications of these findings, in relation to efficacy and tolerability, deserve further investigation.

Impact of multiple inhibitors or substrates of cytochrome P450 2D6 on plasma risperidone levels in patients on polypharmacy.

Studies that focus on multidrug interactions in natural settings are sparse. In this investigation, data from therapeutic drug monitoring (TDM) were used to study the impact of multiple cytochrome P450 enzyme (CYP) 2D6 substrates and inhibitors on plasma risperidone levels. CYP2D6 catalyzes the conversion of risperidone to the active metabolite 9-OH-risperidone. The question whether CYP2D6 activity is important for the level of the "active moiety" (ie, the sum of risperidone and 9-OH-risperidone) is controversial. Concentration-to-dose (C:D) ratios of risperidone and 9-OH-risperidone in 218 patients were associated with the number of concomitantly used substrates or inhibitors of CYP2D6. The C:D ratios of risperidone in patients with 0, 1, and >1 numbers of CYP2D6 inhibitors were 2.6, 8.5, and 17 nmol L mg, respectively. Differences between the groups were highly significant (P < 0.001). All patients with >1 CYP2D6 inhibitors were administered at least 1 potent CYP2D6 inhibitor, that is fluoxetine, paroxetine, thioridazine, and/or levomepromazine. The C:D ratios of the active moiety (risperidone + 9-OH-risperidone) in patients with 0, 1, and >1 numbers of concomitant CYP2D6 inhibitors were 17, 24, and 30 nmol L mg, respectively (P = 0.001), which was explained by higher levels of risperidone without any change in the levels of 9-OH-risperidone. Concomitant use of 1 or several drugs recognized as substrates for CYP2D6, without any proven inhibitory effect, had no apparent influence on the levels of risperidone or 9-OH-risperidone, suggesting that the risk of drug-drug interactions between different substrates of CYP2D6 is low when used in therapeutic doses. In conclusion, the results suggest that an increase in the number of concomitant inhibitors may be associated with a lower CYP2D6 activity, although the type of inhibitor is probably more important. Drug-dependent inhibition of CYP2D6 increases the active moiety of risperidone. An indication for risperidone TDM should therefore include concomitant medication with established CYP inhibitors.

Age and gender effects on olanzapine and risperidone plasma concentrations in children and adolescents.

BACKGROUND: Risperidone and olanzapine are second-generation antipsychotics that are increasingly used in child and adolescent psychiatry. So far, little is known about plasma concentrations and concentration-to-dose (C/D) ratios of these agents in children and adolescents compared to adults. METHOD: This study investigated whether age and gender influence risperidone and olanzapine plasma concentration by determining risperidone and olanzapine plasma levels by tandem mass spectrometry in 162 Caucasian patients (98 risperidone and 64 olanzapine). RESULTS: For risperidone and 9-hydroxyrisperidone, the C(total)/D ratio was almost identical in both age groups (10-18 and 19-45 years, respectively). In the younger age group, females exhibited significantly higher total plasma levels than males while receiving similar doses of risperidone. For olanzapine, in adolescents significantly higher C/D ratios were detected by an average of 43% (after adjustment for weight: 34%) compared to adults. CONCLUSION: This study demonstrates an age effect for olanzapine but not for risperidone resulting in higher olanzapine plasma levels in younger patients. For risperidone, we found a gender effect as female adolescent patients had significantly higher risperidone plasma concentrations than male adolescent patients. Future prospective studies are necessary to clarify whether the prescribed dosage should be different in young and older patients.

A study of genetic (CYP2D6 and ABCB1) and environmental (drug inhibitors and inducers) variables that may influence plasma risperidone levels.

Risperidone (R) is metabolized to 9-hydroxyrisperidone (9-OHR) by cytochrome P450 2D6 (CYP2D6). The main objective of this naturalistic study was to investigate the variables associated with two plasma ratios: the plasma R:9-OHR concentration ratio and the total concentration-to-dose (C:D) ratio. These ratios were studied as continuous measures by linear regression analyses and as three dichotomous variables in logistic regression analyses: R:9-OHR ratio >1 (indicative of lack of CYP2D6 activity), C:D ratio >14 (indicative of diminished R elimination), and C:D ratio <3.5 (indicative of increased R elimination). Plasma R levels; genotypes for CYP2D6, CYP3A5; and ABCB1 genes, and co-medication, including CYP inhibitors and CYP3A inducers, were studied in 277 patients. Almost all CYP2D6 poor metabolizers (PMs) had an inverted R:9-OHR ratio (>1). Having a CYP2D6 PM phenotype was strongly associated with a C:D ratio >14 (OR=8.2; 95% confidence interval [CI]=2.0-32.7), indicating diminished R elimination. CYP2D6 ultrarapid metabolizers (UMs) did not exhibit an increased R elimination. Some ABCB1 (or MDR1) variants were significantly associated with increased R:9-OHR ratios and decreased C:D ratios, but the results were neither consistent nor robust. Taking CYP inhibitors was significantly associated with a C:D ratio >14 (OR=3.8; CI=1.7-8.7) and with an inverted R:9-OHR ratio. Taking CYP3A inducers was significantly associated with a C:D ratio <3.5 (OR=41.8; CI=12.7-138), indicating increased R elimination. Female gender and old age appeared to be associated with a lower R elimination. Our study indicated that the CYP2D6 PM phenotype may have a major role in personalizing R doses, whereas the CYP3A5 PM phenotype probably has no role. CYP inducers and inhibitors appear to be relevant to R dosing. New studies are needed, particularly to further assess the role of the CYP2D6 UM phenotype and ABCB1 variants in R pharmacokinetics.

[Anesthesia for cesarean section in a parturient taking risperidone and haloperidol].

We report a case of anesthesia for cesarean section in a schizophrenic patient. Her psychiatric symptoms were well controlled with low doses of risperidone until 35 weeks' gestation, when she suddenly developed psychotic manifestations. Risperidone 6 mg x day(-1) and haloperidol 12 mg x day(-1) PO were given for 3 weeks before delivery. Elective cesarean section was performed under spinal anesthesia at 38 weeks. The parturient showed good psychiatric condition during and after the surgery. The neonate did not show any symptoms which antipsychotics could have caused. Maternal and umbilical blood concentrations of risperidone and haloperidol are reported.

HPLC-DAD determination of plasma levels of the antipsychotic risperidone and its main metabolite for toxicological purposes.

A new, rapid analytical method, based on liquid chromatography with diode array detection, has been developed and applied to the determination of risperidone and its main active metabolite 9-hydroxyrisperidone in human plasma. The chromatographic separation was obtained on a C8 (150 x 4.6 mm, 5 microm) column, using a mobile phase composed of acetonitrile (27%) and a pH 3.0 phosphate buffer (73%). A sample clean-up procedure was carried out by using C8 cartridges and eluting the analytes with methanol. The extraction yield was highly satisfactory for both analytes, with average absolute recovery values of about 95%. The experimental conditions permitted the quantitative determination of risperidone and 9-hydroxyrisperidone with high precision (RSD < 3.6%) and satisfactory sensitivity (LOQ = 4 ng mL(-1)). The method was applied to plasma samples from a patient who had tried to poison himself with 150 mg of risperidone, and was undergoing polypharmacy.

Prediction of response to risperidone treatment with respect to plasma concencentrations of risperidone, catecholamine metabolites, and polymorphism of cytochrome P450 2D6.

In the present study, we examined the relationships between plasma concentrations of risperidone and clinical responses, extrapyramidal symptoms, plasma levels of cotinine and caffeine, or cytochrome (cyp)2D6 genotypes. In addition, we also investigated the relationships between plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) or homovanillic (HVA) acid and clinical responses to risperidone. One hundred and 36 patients (male/female: 58/78, age 37+/-13 years) who met DSM-IV criteria for schizophrenia, schizoaffective disorder, delusional disorder and brief psychotic disorder, and who were being treated with risperidone alone, were evaluated regarding their clinical improvement and extrapyramidal symptoms using the Positive and Negative Syndrome Scale (PANSS) and Simpson and Angus (SAS), respectively, and plasma levels of cotinine, caffeine, MHPG and HVA were analysed by high-performance liquid chromatography. The cyp2D6*5 and *10 alleles were identified using the polymerase chain reaction. There was a positive correlation between plasma levels of risperidone plus 9-hydroxyrisperidone (active moiety) and SAS scores, but not the PANSS. Pretreatment HVA levels in responders were higher than those in nonresponders. In addition, there was a negative correlation between changes in HVA levels and improvement in PANSS scores. There was no association between plasma levels of risperidone and plasma levels of cotinine or caffeine. Furthermore, there were no differences in the risperidone/9-hydroxyrisperidone ratio, clinical improvements and extrapyramidal symptoms among cyp2D6 genotypes. These results indicate that pretreatment HVA levels and plasma concentrations of active moiety might play a part in predicting the clinical response and occurrence of extrapyramidal symptoms, respectively, when treating patients with risperidone.

Differential effect of HERG blocking agents on cardiac electrical alternans in the guinea pig.

Beat-to-beat alternations of the cardiac monophasic action potential, known as electrical alternans, were studied at drug concentrations that have known arrhythmogenic outcomes. Electrical alternans were elicited from the heart of anesthetized guinea pigs, both in the absence and presence of drugs that inhibit the delayed rectifier K(+) channel encoded by the human ether a-go-go related-gene (HERG), and are associated with the fatal arrhythmia, Torsade de Pointes. Two other HERG inhibiting drugs not associated with Torsade de Pointes were also studied. At concentrations known to be proarrhythmic, E-4031 and bepridil increased mean alternans 10 and 40 ms at pacing frequencies

Negative ion chemical ionization gas chromatography-mass spectrometry and atmospheric pressure chemical ionization liquid chromatography-mass spectrometry of low-dosed and/or polar drugs in plasma.

In clinical and forensic toxicology, doping control, and therapeutic drug monitoring, specific and sensitive detection and precise quantification of xenobiotics in biosamples are great challenges. Today, mass spectrometry techniques, coupled with gas chromatography or liquid chromatography, are the most powerful methods in analytic toxicology. The pros and cons of electron ionization (EI) and negative ion chemical ionization (NICI) gas chromatography-mass spectrometry (GC-MS) and of atmospheric pressure chemical ionization liquid chromatography-mass spectrometry (APCI-LC-MS) are described for determination of the low-dosed benzodiazepine flunitrazepam and its 7-amino and its nor-metabolite in plasma. In addition, application of NICI-GC-MS is described for sensitive chiral determination of amphetamine derivatives in plasma and application of APCI-LC-MS for screening, library-assisted identification, and validated quantification of oral antidiabetics and for validated quantification of the neuroleptic risperidone and its 9-hydroxy metabolite. These examples show that NICI-GC-MS and LC-MS are powerful tools for determination of low-dosed and/or rather polar drugs or poisons, thus becoming indispensable supplements to classic EI-GC-MS in clinical and forensic toxicology as well as in doping control.