The effect of olanzapine on craving and alcohol consumption.

Previous studies have indicated that olanzapine decreases craving after a priming dose of alcohol, that craving after a priming dose of alcohol is greater among individuals with the seven-repeat allele of the DRD4 variable number of tandem repeats (VNTR) polymorphism, and that the effect of olanzapine (a D2/D4 antagonist) is more pronounced among individuals with this allele. The present study tested the hypothesis that olanzapine may be differentially effective at reducing cue-elicited craving and differentially effective as a treatment for alcohol dependence over the course of a 12-week, randomized, placebo-controlled trial among individuals with and without the seven-repeat allele. Participants who met DSM IV criteria for alcohol dependence were randomly assigned to receive olanzapine (5 mg) or a placebo over the course of the trial. After 2 weeks of treatment, participants completed a cue reactivity assessment. The results suggested that participants who were homozygous or heterozygous for the seven (or longer)-repeat allele of the DRD4 VNTR responded to olanzapine with reductions in cue-elicited craving as well as reductions in alcohol consumption over the course of the 12-week trial, whereas individuals with the shorter alleles did not respond favorably to olanzapine.     

DRD4 VNTR polymorphism is associated with transient fMRI-BOLD responses to smoking cues

Rationale A dopamine receptor 4 variable number tandem repeat (DRD4 VNTR) polymorphism has been related to reactivity to smoking cues among smokers, but the effect of this genetic variation on brain responses to smoking cues has not been evaluated. Objectives The present study evaluated the relationship between carrying the DRD4 VNTR 7-repeat allele and transient functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent responses to smoking cues among adult dependent cigarette smokers. Materials and methods Smokers (n = 15) underwent fMRI scanning after 2-h abstinence. During scanning, they viewed visual smoking and control cues. A blood sample was assayed for the DRD4 VNTR polymorphism, and participants were categorized based on whether they carried one or two copies of the 7-repeat allele (DRD4 L, n = 7) or not (DRD4 S, n = 8). Results Contrasts in brain cue-reactivity (smoking minus control cues) between DRD4 groups were conducted using SPM2. Smoking cues as compared to control cues elicited transient brain responses in right superior frontal gyrus (BA 8/9/10/32), left anterior cingulate gyrus (BA 32), and right cuneus (BA 19). Exposure to smoking cues resulted in greater activation of right superior frontal gyrus (BA 10) and right insula in DRD4 L compared to DRD4 S individuals. By contrast, exposure to smoking cues among DRD4 S individuals resulted in no significant increases in activation compared to DRD4 L individuals. Conclusions These brain imaging results suggest that DRD4 VNTR polymorphism is related to transient brain responses to smoking cues in regions subserving executive and somatosensory processes.     

Dopamine D4 receptor polymorphism modulates cue-elicited heroin craving in Chinese

Rationale Subjective craving, which contributes to the continuation of drug use in active abuser and the occurrence of relapse in detoxified abusers, is considered to be a central phenomenon in addiction. Dopamine pathway has been implicated in the mechanism underlying the cue-elicited craving for a variety of addictive substances.Objectives The objective of this study was to test the hypothesis that heroin addicts carrying D4 dopamine receptor gene (DRD4) variable number tandem repeat (VNTR) long type allele would have higher craving after exposure to a heroin-related cue.Materials and methods Craving was induced by a series of exposure to neutral and heroin-related cue and were assessed in a cohort of Chinese heroin abusers (n=420) recruited from the Voluntary Drug Dependence Treatment Center at Shanghai.Results Significantly stronger cue-elicited heroin craving was found in individuals carrying DRD4 VNTR long type allele than the non-carriers (F=31.040, p<0.001). As for baseline craving and mean change in craving responding to neutral stimuli, no significance was found (1.06±0.34 vs 1.07±0.36, F=0.067, p =0.797 and 0.42±0.34 vs 0.45±0.37, F=0.277, p=0.599, respectively).Conclusions The results of our study suggest that DRD4 VNTR polymorphism contributes to cue-elicited craving in heroin dependence, indicating DRD4 VNTR represents one of potential genetic risk factors for cue-induced craving.Li Jin and Min Zhao contributed to the work equally. Chunhong Shao and Yifeng Li contributed to the work equally.     

Olanzapine reduces urge to drink after drinking cues and a priming dose of alcohol

RATIONALE: Haloperidol, a D2 antagonist, has been shown to moderate the effects of alcohol consumption on craving. OBJECTIVE: The present study was designed to determine whether a single 5-mg dose of olanzapine (a D2/5-HT2 antagonist) would influence responses to alcohol cues or an alcohol challenge. It was hypothesized that olanzapine would attenuate cue-elicited urge to drink, attenuate the effects of alcohol consumption on urge to drink, and reduce the rewarding effects of alcohol. METHODS: To test these hypotheses, 26 heavy social drinkers were randomized to receive either 5 mg olanzapine or placebo approximately 8 h before each of two experimental sessions. Participants consumed a moderate dose of alcohol in one experimental session and a non-alcohol control beverage in another session. RESULTS: Results indicated that mere exposure to alcohol cues and consumption of alcohol increased urge to drink and that olanzapine attenuated these effects. Results also indicated that alcohol increased subjective stimulation and high while olanzapine did not moderate these effects. CONCLUSIONS: These results suggest that olanzapine did not influence the rewarding effects of alcohol but did attenuate the effects of alcohol cues and an alcohol challenge on urge to drink.     

Olanzapine attenuates cue-elicited craving for tobacco

Rationale Recent biological conceptualizations of craving and addiction have implicated mesolimbic dopamine activity as a central feature of the process of addiction. Imaging, and pharmacological studies have supported a role for dopaminergic structures in cue-elicited craving for tobacco.Objective If mesolimbic dopamine activity is associated with cue-elicited craving for tobacco, a dopamine antagonist should attenuate cue-elicited craving for tobacco. Thus, the aim of the present study was to determine whether an atypical antipsychotic (olanzapine, 5 mg) decreased cue-elicited craving for tobacco.Method Participants were randomly assigned to 5 days of pretreatment with olanzapine (5 mg; n=31) or were randomly assigned to 5 days of a matching placebo (n=28). Approximately 8 h after the last dose, participants were exposed to a control cue (pencil) followed by exposure to smoking cues. Participants subsequently smoked either nicotine cigarettes or de-nicotinized cigarettes.Results Olanzapine attenuated cue-elicited craving for tobacco but did not moderate the subjective effects of smoking.Discussion This study represents one of the first investigations of the effect of atypical antipsychotics on cue-elicited craving for tobacco. The results suggest that medications with similar profiles may reduce cue-elicited craving, which in turn, may partially explain recent observations that atypical antipsychotics may reduce substance use.     

Genetic influences on craving for alcohol

Introduction

Craving is being considered for inclusion in the Diagnostic and Statistical Manual (DSM) DSM-5. However, little is known of its genetic underpinnings — specifically, whether genetic influences on craving are distinct from those influencing DSM-IV alcohol dependence.

Method

Analyses were conducted in a sample of unrelated adults ascertained for alcohol dependence (N = 3976). Factor analysis was performed to examine how alcohol craving loaded with the existing DSM-IV alcohol dependence criteria. For genetic analyses, we first examined whether genes in the dopamine pathway, including dopamine receptor genes (DRD1, DRD2, DRD3, DRD4) and the dopamine transporter gene (SLC6A3), which have been implicated in neurobiological studies of craving, as well as alpha-synuclein (SNCA), which has been previously found to be associated with craving, were associated with alcohol craving in this sample. Second, in an effort to identify novel genetic variants associated with craving, we conducted a genomewide association study (GWAS). For variants that were implicated in the primary analysis of craving, we conducted additional comparisons — to determine if these variants were uniquely associated with alcohol craving as compared with alcohol dependence. We contrasted our results to those obtained for DSM-IV alcohol dependence, and also compared alcohol dependent individuals without craving to non-dependent individuals who also did not crave alcohol.

Results

Twenty-one percent of the full sample reported craving alcohol. Of those reporting craving, 97.3% met criteria for DSM-IV alcohol dependence with 48% endorsing all 7 dependence criteria. Factor analysis found a high factor loading (0.89) for alcohol craving. When examining genes in the dopamine pathway, single nucleotide polymorphisms (SNPs) in DRD3 and SNCA were associated with craving (p < 0.05). There was evidence for association of these SNPs with DSM-IV alcohol dependence (p < 0.05) but less evidence for dependence without craving (p > 0.05), suggesting that the association was due in part to craving. In the GWAS, the greatest evidence of association with craving was for a SNP in the integrin alpha D (ITGAD) gene on chromosome 7 (rs2454908; p = 1.8 × 10^− 6). The corresponding p-value for this SNP with DSM-IV alcohol dependence was similar (p = 4.0 × 10^− 5) but was far less with dependence without craving (p = 0.02), again suggesting the association was due to alcohol craving. Adjusting for dependence severity (number of endorsed criteria) attenuated p-values but did not eliminate association.

Conclusions

Craving is frequently reported by those who report multiple other alcohol dependence symptoms. We found that genes providing evidence of association with craving were also associated with alcohol dependence; however, these same SNPs were not associated with alcohol dependence in the absence of alcohol craving. These results suggest that there may be unique genetic factors affecting craving among those with alcohol dependence.     

Naltrexone decreases craving and alcohol self-administration in alcohol-dependent subjects and activates the hypothalamo–pituitary–adrenocortical axis

BACKGROUND: This laboratory study investigated the mechanisms by which the opioid antagonist, naltrexone, reduces the risk of relapse to heavy drinking in individuals with alcohol dependence. METHODS: Eighteen alcohol-dependent, non-treatment-seeking volunteers were randomized to 50 mg naltrexone or placebo for 6 days and participated in an alcohol self-administration experiment on the sixth day. Following baseline assessments of craving and endocrine levels, subjects were first administered a priming drink designed to raise blood alcohol levels to 0.03 g/dl and then had the opportunity to drink up to eight additional drinks or to receive US $3 for each drink not consumed over a 2-h period. Each additional drink was designed to raise blood alcohol levels by 0.015 g/dl. RESULTS: At baseline, naltrexone treatment resulted in higher cortisol levels and lower levels of craving than placebo treatment. Although there were no significant differences in response to the priming dose, naltrexone-treated subjects drank fewer drinks, consumed them more slowly, and reported lower levels of alcohol craving during the alcohol self-administration portion of the experiment. Naltrexone also resulted in higher levels of adrenocorticotropic hormone and cortisol than placebo treatment, and levels of cortisol were negatively correlated with intensity of alcohol craving. The number of drinks chosen was positively correlated with level of alcohol craving. Ratings of nausea were low and did not differ between the naltrexone and placebo groups at any point in the study. CONCLUSIONS: These results confirm the hypothesis that naltrexone reduces desire to drink and the amount of alcohol consumed in alcohol-dependent subjects. It is hypothesized that naltrexone may reduce drinking via suppressing craving for alcohol and that this effect may be related in part to naltrexone's ability to activate the hypothalamo-pituitary-adrenocortical axis.     

Investigation of target plasma concentration-effect relationships for olanzapine in schizophrenia

Olanzapine is an atypical antipsychotic effective in the treatment of schizophrenia. The present study has examined the potential use of target concentration monitoring of olanzapine in plasma as a marker of clinical response and an aid in patient management. Fifty-three patients (mean age 32 years; 40 M, 13 F) with a DSM-IVR diagnosis of schizophrenia completed a 6-week trial of oral olanzapine. Participants received once-daily olanzapine, and their psychotic symptoms were measured with the PANSS (Positive and Negative Symptom Scale) on admission and again after 6 weeks. Responders were classified as having a >/=20% decrease in PANSS scores. Plasma olanzapine was quantified by high-performance liquid chromatography. Receiver operator characteristic (ROC) curve analysis was used to identify a break point in plasma olanzapine that might serve as a surrogate for PANSS classification, and the two methods were compared using the McNemar chi2 test. After 6 weeks the median olanzapine dose was 15 mg/d (range 5-30 mg/d), and the mean plasma olanzapine was 32 micrograms/L at a mean of 13.5 hours after dose. With the PANSS (total), there were 42 responders and 11 nonresponders. ROC curve analysis for total PANSS identified a break point at 23 micrograms/L plasma olanzapine, with the proportions of responders and nonresponders identified by PANSS and the plasma break point being similar. Similar break points were found for the positive, negative, and global PANSS subscores. Nevertheless, these relationships were very modest, and at best the target plasma olanzapine concentration identified only 20% more responders than nonresponders. We suggest that plasma olanzapine monitoring can be used for dose-response optimization, but only to complement the normal clinical evaluation process.     

Daily ratings measures of alcohol craving during an inpatient stay define subtypes of alcohol addiction that predict subsequent risk for resumption of drinking

Background

Both depressive symptoms and alcohol craving have been postulated as important predictors of relapse in patients with addictive disorders. The purpose of this study was to examine the course of affective symptoms and cravings for alcohol use during the initial 25 days of residential treatment for middle aged and older adults addicted to alcohol and the relationship between these symptoms and recovery outcomes.

Methods

95 alcohol-dependent subjects were enrolled in this observational study. Participants completed a daily diary of alcohol craving, positive affect, and negative affect during residential treatment. Participants were interviewed 1 and 6 months after discharge to assess clinical symptoms of relapse and functioning.

Results

Latent class analysis identified three groups of individuals for each of the three daily measures. For alcohol craving, 17 subjects reported elevated cravings during the entire treatment stay, 37 subjects reported initially elevated but then a slight improvement in craving, and 41 subjects reported relatively low craving from the time of admission to the end of residential treatment. Alcohol craving class was associated with negative affect but not positive affect. Alcohol craving class but not affective class was predictive of time to relapse to any drinking in the 6 months after residential treatment (p < 0.05).

Conclusion

Results suggest that non-cue induced alcohol craving may define a subtype of alcohol dependence that is less responsive to treatment and may explain heterogeneity in treatment outcomes. These results also may suggest a role for differential treatment programming to address high states of craving for alcohol.     

The priming effect of alcohol pre-load on attentional bias to alcohol-related stimuli

Background Previous research has shown attentional bias toward alcohol-related stimuli in non-dependent social drinkers. The aim of this study was to investigate whether attentional bias towards alcohol-related stimuli would increase after priming with either one of two doses of alcohol (0.3 or 0.6 g/kg) or placebo.Methods Questionnaires were used to measure alcohol use, mood states, craving for alcohol and alcohol outcome expectancies. Attentional bias was assessed using a dot-probe detection task and a modified Stroop task.Results Mood ratings showed dose dependent increases in positive mood after the alcohol pre-load. In the dot-probe task, all subjects showed an attentional bias towards the alcohol-related stimuli over neutral stationery-related items, although the attentional bias was significantly positive only at the low alcohol dose. In addition, a negative correlation was found between the attentional bias under the high alcohol dose and the alcohol use questionnaire score. In the Stroop task, a dose related effect of alcohol was found, with subjects making more errors for alcohol-related words under the high alcohol dose.Conclusions These data support ideas derived from the incentive learning theories of drug addiction. Furthermore, these data suggest that history of alcohol exposure may influence the priming effects of an alcohol pre-load on attentional bias.     

DRD2 Taq1A polymorphism modulates prolactin secretion induced by atypical antipsychotics in healthy volunteers

Hyperprolactinemia mediated by antagonism of dopaminergic neurotransmission in the pituitary gland is a common adverse effect of antipsychotics. Recent studies have suggested that polymorphisms of dopamine receptors can affect the therapeutic response to antipsychotics. Thus, our aim was to evaluate whether 2 such polymorphisms (DRD2 Taq1A and DRD3 Ser9Gly) modulate prolactin release in healthy volunteers (n = 119) receiving a single dose of quetiapine (25 mg, n = 26), olanzapine (5 mg, n = 57), or risperidone (1 mg, n = 36). The increases in maximum concentration and in area under the curve were calculated from plasma prolactin levels after subtraction of pretreatment levels. Multiple regression analyses revealed that prolactin increases in maximum concentration and in area under the curve depended on drug (quetiapine < olanzapine < risperidone; P < 0.001), sex (women > men; P < 0.001), and Taq1A polymorphism (A1? > A2/A2; P < 0.05). Analysis of the individual drugs revealed that prolactin secretion was modulated by sex and Taq1A polymorphism in olanzapine and risperidone (P < 0.05); however, these factors were not linked to prolactin secretion in quetiapine.     

Associations of the dopamine D4 receptor gene VNTR polymorphism with drug use in adolescent psychiatric inpatients

BACKGROUND: The VNTR polymorphism in the Dopamine D4 receptor gene (DRD4) has been associated with differential urge for substances across multiple methodologies ranging from neuroimaging to assessment in the natural environment. It is unclear whether the DRD4 gene is a marker for an underlying propensity for greater urge or whether the DRD4 gene differentially moderates the neuroadaptive effects of extended substance use on urge. Examination of the DRD4 in an adolescent sample may provide evidence of a mechanism of this putative relationship. METHOD: Data from a subset of 77 participants in a larger assessment study characterized adolescents for substance-related behaviors by DRD4 genotype. The psychiatrically admitted adolescents were genotyped for the variable number of tandem repeats polymorphism in the DRD4 gene (L>or=7 [n=25], S=or<7 [n=52]). Associations of the DRD4 with scores on the SASSI, and ADI were examined as well as selected individual items thought to be most related to the intermediate phenotype of urge. RESULTS: The DRD4 gene was not associated with any DSM-IV substance misuse diagnostic classification. Individual items related to urge were also nonsignificantly related to DRD4 status. Carriers of the long variant of the DRD4 polymorphism were more likely to have used hard drugs within the previous 6 months and scored higher on the self-medication subscale of the ADI compared to short variant homozygotes. DISCUSSION: Preliminary results provide little evidence for the DRD4 VNTR polymorphism to be related to urge-related phenomena in hospitalized adolescents on a psychiatric inpatient unit. The association of the DRD4 gene with hard drug use may support literature linking this gene to impulsivity. Subscale findings may suggest a role of negative affect in previous DRD4 urge findings.     

Alcohol drinking of alcohol-preferring AA rats is differentially affected by clozapine and olanzapine

Clinical evidence suggests that atypical antipsychotic drugs might reduce alcohol drinking and help to maintain abstinence. This study aimed to compare the effects of two widely used atypical antipsychotic drugs clozapine and olanzapine on alcohol intake in alcohol-preferring AA (Alko, Alcohol) rats that were taught to drink 10% alcohol in a 4 h limited access paradigm. Effects of acute clozapine (0, 0.3, 1.0 and 5.0 mg/kg) and olanzapine (0, 0.1, 0.5 and 1.25 mg/kg) treatments on the limited access alcohol drinking were studied. In repeated treatment experiment, clozapine (1.0 mg/kg) or olanzapine (0.5 mg/kg) was administered once daily, before limited access alcohol drinking session, over 5 successive days. To reveal any effect of the drugs selective for alcohol drinking, alcohol was exchanged with 0.1% saccharin solution for the 4 h limited access, and acute treatments were repeated. Effects of the drugs on ambulatory locomotor activity were tested with doses that were used in the acute experiments. Acute clozapine treatment had no effect on either alcohol or saccharin drinking, but olanzapine significantly reduced 4 h alcohol drinking. Repeated olanzapine treatment significantly reduced 4 h alcohol drinking when compared with vehicle or clozapine, but a tolerance developed to this effect. Repeated clozapine treatment produced no significant effect compared with vehicle. Both drugs significantly reduced locomotor activity. In conclusion, the atypical antipsychotic olanzapine non-selectively reduced alcohol drinking, while clozapine failed to do so, even if both were administered at pharmacologically effective doses.     

Parental alcoholism and the effects of alcohol on mediated semantic priming.

In this study, researchers tested the effects of a moderate dose of alcohol on the spread of activation of associated information in memory using a mediated semantic priming task in which target words are preceded by primes that are either unrelated or indirectly related to the target. Male and female participants with or without a parental history (PH+ and PH-, respectively) of alcoholism were administered the priming task after consuming alcohol or a placebo beverage. Among PH- individuals, alcohol constrained the spread of activation of associated information, as manifested by a reduced priming effect. In contrast, alcohol enhanced priming effects among PH+ participants, though this latter effect appears to be due to a particularly slow response among these individuals to unprimed words. Results are discussed with regard to theories of alcohol's effects on cognitive processes.     

Changes in Nutrition-Related Behaviors in Alcohol-Dependent Patients After Outpatient Detoxification: The Role of Chocolate

Background: Previous studies have reported changes in nutrition-related behaviors in alcohol-dependent patients after alcohol detoxification, but prospective studies assessing the effects of these changes on maintaining abstinence are lacking. Objectives: To assess changes in craving and consumption of chocolate and other sweets over time up to six months after outpatient alcohol detoxification treatment and to detect differences in abstinent versus nonabstinent patients. Methods: One hundred and fifty alcohol-dependent patients were included in this prospective observational study. Participants completed self-report questionnaires on nutrition-related behaviors and craving before detoxification treatment (baseline, t1), one week (t2), one month (t3), and six months later (t4). Results: Significant changes in craving for and consumption of chocolate as well as in craving for other sweets were observed over time. Increases were most prominent within the first month. Patients who remained abstinent until t3 consumed three times more chocolate than nonabstainers. One quarter of the patients switched from being rare (t1) to frequent (t3) chocolate eaters, and 84% of these remained abstinent until t3. No significant correlations were found between craving for alcohol and craving for or consumption of chocolate or other sweets. Conclusions/Importance: In the first month after outpatient alcohol detoxification treatment, significant changes in nutrition-related behaviors were observed. These changes were not associated with alcohol craving. For a subgroup, increasing the frequency of chocolate consumption might be a temporary protective factor with respect to alcohol relapse.     

Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients

BackgroundTherapeutic effects of all clinically used antipsychotics are related to the reduction of dopaminergic transmission in the limbic system. The aim of present study was two-fold. First, efficacy of atypical drugs (ziprasidone and olanzapine) against schizophrenia symptoms was compared to that offered by a typical antipsychotic medication, perazine. Second, associations between some dopaminergic genes polymorphisms and therapeutic response to antipsychotics were assessed in the same group of schizophrenia patients.MethodsOne hundred ninety one Caucasian patients admitted with exacerbation of paranoid schizophrenia were genotyped for polymorphisms of the DRD2 [the ins/del -141C (rs1799732) and exon 8 (rs 71653615)], DRD2/ANKK1 Taq IA (rs 1800497), DAT1 (the 40 bp VNTR), COMT (rs 4680), and MAOA gene (the 30 bp VNTR in promoter). The patients were randomly assigned to the treatment with perazine, olanzapine or ziprasidone givenasmonotherapy for 3 months. Treatment efficacy was measured from baseline (T0) to T1 (14 days) and T2 (3 months). A retention rate was also assessed at T1 and T2.ResultsThe three antipsychotics did not differ in terms of reduction of the PANSS score or retention rate at the follow-up. There was no interaction between the investigated polymorphisms and response to the antipsychotic treatment.ConclusionsThe present results suggest that: i) there are no major differences in short-term efficacy or effectiveness of atypical (olanzapine, ziprasidone) and typical (perazine) antipsychotic drugs; ii) the studied polymorphisms are not primarily involved in treatment response to antipsychotics in schizophrenia patients.     

Disruption of conditioned reward association by typical and atypical antipsychotics

Antipsychotic drugs are broadly classified into typical and atypical compounds; they vary in their pharmacological profile however a common component is their antagonist effects at the D2 dopamine receptors (DRD2). Unfortunately, diminished DRD2 activation is generally thought to be associated with the severity of neuroleptic-induced anhedonia. The purpose of this study was to determine the effect of the atypical antipsychotic olanzapine and typical antipsychotic haloperidol in a paradigm that reflects the learned transfer of incentive motivational properties to previously neutral stimuli, namely autoshaping. In order to provide a dosing comparison to a therapeutically relevant endpoint, both drugs were tested against amphetamine-induced disruption of prepulse inhibition as well. In the autoshaping task, rats were exposed to repeated pairings of stimuli that were differentially predictive of reward delivery. Conditioned approach to the reward-predictive cue (sign-tracking) and to the reward (goal-tracking) increased during repeated pairings in the vehicle treated rats. Haloperidol and olanzapine completely abolished this behavior at relatively low doses (100 µg/kg). This same dose was the threshold dose for each drug to antagonize the sensorimotor gating deficits produced by amphetamine. At lower doses (3-30 µg/kg) both drugs produced a dose-dependent decrease in conditioned approach to the reward-predictive cue. There was no difference between drugs at this dose range which indicates that olanzapine disrupts autoshaping at a significantly lower proposed DRD2 receptor occupancy. Interestingly, neither drug disrupted conditioned approach to the reward at the same dose range that disrupted conditioned approach to the reward-predictive cue. Thus, haloperidol and olanzapine, at doses well below what is considered therapeutically relevant, disrupts the attribution of incentive motivational value to previously neutral cues. Drug effects on this dimension of reward processing are an important consideration in the development of future pharmacological treatments for schizophrenia.     

Free and glucuronidated olanzapine serum concentrations in psychiatric patients: influence of carbamazepine comedication

The influence of carbamazepine on the glucuronidation of the antipsychotic olanzapine was studied in a group of psychiatric patients. Steady-state serum concentrations of free and glucuronidated olanzapine were measured in 31 psychiatric patients in monotherapy (dose range, 2.5-30 mg/d; median, 15 mg/d) and in 16 patients being comedicated with carbamazepine (dose range, 5-50 mg/d; median, 20 mg/d). The concentrations were determined by HPLC with and without acid hydrolysis of glucuronidated olanzapine. For the monotherapy group, the concentrations of free and glucuronidated olanzapine ranged from 0 nmol/L to 292 nmol/L (median, 94 nmol/L) and from 0 nmol/L to 180 nmol/L (median, 27 nmol/L), respectively. The serum concentrations of the carbamazepine-treated group ranged from 21 nmol/L to 310 nmol/L (median, 81 nmol/L) and from 0 to 376 nmol/L (median, 57 nmol/L) for free and glucuronidated olanzapine, respectively. Two patients with outlying values were excluded from further analysis. The median concentration-to-daily dose ratios (C/D) of free and glucuronidated olanzapine in the monotherapy group were 5.8 nmol/L/mg and 2.2 nmol/L/mg, respectively (n =30). The corresponding values for the group comedicated with carbamazepine were 3.6 and 3.1 nmol/L/mg (n =15). Thus, the median C/D of free olanzapine in the carbamazepine group was 38% lower than that of the monotherapy group (P <0.01), confirming that carbamazepine accelerates the metabolism of olanzapine. Further, for the carbamazepine group the median glucuronidated olanzapine fraction constituted 79% of the free fraction compared with 43% for the monotherapy group (P <0.01), which suggests that an increased rate of olanzapine glucuronidation contributes to the increased rate of metabolism of olanzapine induced by carbamazepine.     

Influence of ritonavir on olanzapine pharmacokinetics in healthy volunteers

HIV infection and psychotic illnesses frequently coexist. The atypical antipsychotic olanzapine is metabolized primarily by CYP1A2 and glucuronosyl transferases, both of which are induced by the HIV protease inhibitor ritonavir. The purpose of this study was to determine the effect of ritonavir on the pharmacokinetics of a single dose of olanzapine. Fourteen healthy volunteers (13 men; age range, 20-28 years) participated in this open-label study. Subjects received olanzapine 10 mg and blood samples were collected over a 120-hour post-dose period. Two weeks later, subjects took ritonavir 300 mg twice daily for 3 days, 400 mg twice daily for 4 days, and 500 mg twice daily for 4 days. The next morning, after 11 days of ritonavir, olanzapine 10 mg was administered and blood sampling was repeated. Plasma samples were analyzed for olanzapine with HPLC. We compared olanzapine noncompartmental pharmacokinetic parameter values before and after ritonavir with a paired Student t test. Ritonavir reduced the area under the plasma concentration-time curve of olanzapine from 501 ng. hr/mL (443-582) to 235 ng. hr/mL (197-294) (p < 0.001), the half-life from 32 hours (28-36) to 16 hours (14-18) (p = 0.00001), and the peak concentration from 15 ng/mL (13-19) to 9 ng/mL (8-12) (p = 0.002). Olanzapine oral clearance increased from 20 L/hr (18-23) to 43 L/hr (38-51) (p < 0.001) after ritonavir. Ritonavir significantly reduced the systemic exposure of olanzapine in volunteers. Patients receiving this combination may ultimately require higher olanzapine doses to achieve desired therapeutic effects.