Neuropsychopharmacology (2006) 31, 1310–1317 The Effect of Olanzapine on Craving and AlcoholConsumption Kent E Hutchison*,1, Lara Ray1, Erica Sandman1, Marie-Christine Rutter1, Annie Peters1, Dena Davidson2 1Department of Psychology, University of Colorado at Boulder, Boulder, CO, USA; 2Institute of Psychiatric Research, Indiana University University of Indianapolis, Indianapolis, IN, USA; 3Providence Veteran Affairs Medical Center and Center for Alcohol and Addiction Studies at 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.
Neuropsychopharmacology (2006) 31, 1310–1317. doi:10.1038/sj.npp.1300917; published online 12 October 2005 Keywords: alcohol; craving; olanzapine; gene; DRD4 time, target individuals who are vulnerable on these specificmechanisms. Based on this notion, it is imperative to begin Previous studies have suggested that currently accepted thinking about how best to test and develop treatments that pharmacotherapies (ie naltrexone, disulfram, and acampro- target specific mechanisms that play an important role in sate) as well as medications currently under development the etiology of alcohol dependence and relapse. Likewise, it (eg ondansetron, topiramate, and aripiprazole) for alcohol is equally important to describe individual differences in dependence are modestly effective. Perhaps more impor- these mechanisms that are likely to predict the treatment tantly, it is becoming increasingly clear that these pharma- cotherapies are more effective for some individuals than The action of alcohol and other drugs on the mesolimbic others. For example, preliminary work has suggested that dopamine pathways is thought to be an important naltrexone is more effective for individuals with a genetic mechanism in the etiology of alcohol and drug dependence, variant that changes the binding profile of the m-opioid and, more specifically, the development of intense craving receptor (eg Oslin et al, 2003). These findings have led and loss of control (Berridge and Robinson, 1998; Robinson many to the conclusion that it is unlikely that we will have and Berridge, 1993; Wise, 1988). While both the animal and one pharmacotherapy that is effective for the majority of human literature suggests that mesolimbic and prefrontal alcohol-dependent individuals. Instead, it is likely that a brain structures with dopaminergic connections are im- variety of pharmacotherapies will be developed, each of portant, the role of specific dopamine receptor subtypes which may target different mechanisms, and, at the same remains unclear. However, recent studies have indicatedthat the D2 family of dopamine receptors (D2, D3, and D4) *Correspondence: Dr KE Hutchison, Department of Psychology, may play a critical role in incentive sensitization. For University of Colorado, Muenzinger Psychology Building D-244, example, D4 receptors are localized to the same structures Campus Box 345, Boulder, CO 80309-0345, USA, Tel: + 1 303 492 (eg orbitofrontal cortex, amygdala, and hippocampus) that 3298, Fax: + 1 303 492 2967, E-mail: [email protected] have been implicated in both animal and human models Received 14 February 2005; revised 2 August 2005; accepted 15August 2005 of addiction and appetitive motivation (Oak et al, 2000; Online publication: 1 September 2005 at Asghari et al, 1995; Van Tol et al, 1991). In addition, selective D4 receptor antagonists block the sensitization of Olanzapine and the DRD4 VNTRKE Hutchison et al these dopamine pathways, suggesting that the D4 receptor is drowsiness as a causal agent). It is important to note that important to the process of sensitization (Feldpausch et al, there are very few published studies that have used such a 1998). D4 receptors that are localized in the shell of the stringent experimental control in a test of a pharmacolo- nucleus accumbens may modulate excitatory transmission gical agent that targets alcohol craving. In this study, (Svingos et al, 2000). This research suggests that the D4 olanzapine was found to be much more effective at receptor may be central to the development of incentive attenuating craving among individuals with the seven- sensitization and craving, and that the D4 receptor may be repeat allele (Hutchison et al, 2003).
generally involved in both the acquisition and expression of None of the aforementioned studies examined the effect of olanzapine on drinking behavior in an alcohol-dependent With respect to clinical research, previous studies have population. A recent report suggested that olanzapine did indicated that craving for alcohol is diminished by not attenuate drinking in an alcohol-dependent population dopamine antagonists (Modell et al, 1993), and that alcohol (Guardia et al, 2004). However, the investigators did not and alcohol cues increase activation in the same neuronal stratify subjects by the DRD4 genotype and they used doses substrates that serve the process of incentive sensitization in of olanzapine that were two to three times greater than the humans (Modell and Mountz, 1995). Thus, the effect of doses shown to attenuate craving in our previous studies.
alcohol and alcohol cues on the activation of these The objective of the present study was to extend our dopamine pathways represents a target that may prove to previous results by testing the effects of olanzapine in an be useful in terms of pharmacotherapy development, and alcohol-dependent population over the course of a 12-week genetic variants that alter the functioning of these pathways trial. More specifically, the present study utilized the dose of may prove to be important in terms of predicting the olanzapine that was supported in our previous studies (ie success of such a pharmacotherapy. Other research has 5 mg) and stratified patients by DRD4 genotype. The effect suggested that clozapine, a D4 receptor antagonist that is of olanzapine on cue-elicited craving was assessed after 2 somewhat similar to olanzapine, reduced substance abuse weeks of treatment, while the effect of olanzapine on among patients with comorbid substance abuse/dependence drinking behavior was assessed after 4, 8, and 12 weeks of (Green et al, 1999) and, specifically, alcohol use (Drake et al, treatment. Consistent with our preliminary work, it was 2000). Thus, clinical research also supports an important hypothesized that olanzapine would decrease cue-elicited role for the D2 family of receptors, and specifically the D4 craving and reduce drinking among the DRD4 L indivi- Given the potential importance of the dopamine path- ways, and specifically the D4 receptor, a series of studieswere conducted to examine whether a second-generation D2/D4 antagonist (eg olanzapine) reduced craving for alcohol and whether a functional variable number oftandem repeats (VNTR) polymorphism in the D4 receptor The present study was approved by the University of gene (DRD4) might moderate these effects. The D4 Colorado Human Research Committee, and all subjects dopamine receptor gene (DRD4) has a VNTR polymorph- provided written informed consent after receiving a full ism in exon 3, with common variants of two, four, and seven explanation of the study. Participants were recruited by repeats (Van Tol et al, 1992). Previous work has suggested newspaper or radio advertisements. All female subjects that the seven-repeat allele either alters intracellular tested negative for pregnancy prior to participation, all function (Asghari et al, 1995; Oak et al, 2000) and/or subjects were required to have a blood alcohol concentra- suppresses expression by altering mRNA stability or tion of zero before each session, and all subjects were translational efficiency (Schoots and Van Tol, 2003). The required to be in excellent health, as indicated by a first study found that olanzapine reduced craving after thorough medical screening designed to ensure that there exposure to the sight and smell of alcohol, as well as were no contraindications for the use of the study consumption of small doses of alcohol (Hutchison et al, medication. Subjects were also excluded if they met the 2001). A subsequent investigation found that the DRD4 criteria for specific psychiatric diagnoses (ie bipolar VNTR polymorphism moderated the effects of alcohol on disorder, schizophrenia, bulimia, or anorexia nervosa), craving and other variables such that individuals with the reported a psychological disorder requiring pharmacother- seven-repeat allele demonstrated significantly higher crav- apy, endorsed current use of illicit drugs other than ing after consumption of alcohol as compared to the control marijuana, or tested positive for the use of illicit drugs beverage, while individuals with the short-repeat alleles did other than marijuana. Subjects were only included if they met DSM IV criteria for alcohol dependence. Furthermore, To replicate and extend the results with olanzapine and there was a minimum drinking requirement of 14 drinks the DRD4 VNTR, a third study was designed to examine (females) or 21 drinks (males) on average per week for four whether olanzapine (5 mg) reduced craving as compared to consecutive weeks. Participants also had to be within 21 cyproheptadine (4 mg), which was conceptualized as an days of their last drink to be included in the study.
active control medication. Olanzapine is a potent D4, D2, 5- Research participants were screened medically at the HT2, and H1 antagonist that may cause drowsiness, whereas University of Colorado at Boulder General Clinical Research cyproheptadine is also a powerful 5-HT2 and H1 antagonist Center (GCRC). To be included in the trial, patients needed that may cause drowsiness. Thus, cyproheptadine repre- a normal medical exam, CBC, EKG, urine toxicology screen, sents an active control that can be used to better isolate the and liver function tests that were within 3 Â the normal effect of olanzapine and exclude alternative explanations (eg limit. A total of 154 subjects were assessed for eligibility, 78 of whom met the full criteria for participation in the study.
alcohol-related cue (eg the preferred alcoholic beverage).
Of these 78, 13 did not start the trial within 21 days of their For the purposes of this study, Gatorade was used as the last drink and were not included in the analyses.
control cue, whereas the individuals’ favorite alcoholicbeverage served as the alcohol cue. During the control cue exposure, participants were asked to lift and sniff theGatorade, but were not allowed to taste the Gatorade for a Prior to medication randomization, all participants were period of 3 min. Participants completed measures of mood instructed to remain abstinent from alcohol for a minimum and craving (see below) before and after exposure to the of 4 days. Participants were randomized to olanzapine control cues. After a 5-min relaxation period, participants or placebo. Participants were instructed to take 2.5 mg repeated the cue exposure with their preferred alcohol of the study medication (either olanzapine or a matching beverage and subsequently completed the same measures of placebo) for the first 5 days of treatment. On the sixth craving and mood. At the end of the cue exposure session, day, participants increased to 5 mg per day dose for the participants met with a therapist to process their reactivity remainder of the 12 weeks. Participants were also instructed to the cues, to discuss urge coping strategies, and to follow- to take the medication 3 h prior to going to bed in order to diminish the impact of any drowsiness experienced as a Participants were also assessed for outcome and side result of the olanzapine. The participants were instructed to effects during treatment on weeks 4, 8, and 12. Lastly, report any side effects to the study physician or nurse at the medication compliance was checked through a urine screen GCRC. At the discretion of the medical staff at the GCRC, at the beginning of session 2 and at each assessment visit.
participants were instructed to decrease their dose back to2.5 mg to alleviate side effects or discontinue the study medication. Over the course of the study, eight participantsin the olanzapine condition were reduced from the 5 mg All participants receive two sessions of a brief structured dose to the 2.5 mg dose, while two participants in the psychosocial intervention. These sessions took place at the placebo dose were reduced from 5 to 2.5 mg.
end of the baseline session (session 1) and the cue reactivity In order to confirm that participants took the medication, session (session 2). The sessions consisted of providing the medications were packed into an opaque capsule with feedback on clients’ drinking behavior (measured by study 50 mg of riboflavin. A urine sample was collected on the questionnaires), eliciting pros and cons about drinking morning of the experimental session. The urine sample was alcohol, setting treatment goals, and eliciting strategies for tested for riboflavin content by examining it under an achieving treatment goals. The therapists in the study were ultraviolet light, a procedure that makes the riboflavin three female doctoral students in clinical psychology at the detectable (Del Boca et al, 1996). None of the samples tested University of Colorado at Boulder. Individual therapists were crossed with treatment condition such that eachtherapist worked with equal numbers of participants in eachof the medication conditions.
Individuals interested in the study called the laboratory and completed a telephone screening assessment. Eligibleparticipants were then invited to a secondary screening During the first experimental session, participants com- visit, which consisted of a structured clinical interview pleted a battery of individual difference measures that (Structured Clinical Interview for DSM IVFSCID Clinician included demographics, drinking behavior, personality Version) assessing for alcohol dependence and concurrent dimensions, and motivation for change. Participants psychiatric diagnoses. In addition to the clinical interview, also completed a series of outcome measures, including participants completed the medical screening visit at the medication side effects, starting 2 weeks after medication GCRC during this initial appointment. As stated above, the randomization. In addition, measures of urge to drink medical visit was designed to ensure that there were no and affect were included to the cue-exposure paradigm, contraindications to the use of study medications.
conducted during the second experimental session. The Eligible participants were invited back to the laboratory following measures were utilized in this study: for a baseline session (session 1), during which participantscompleted measures of demographics, personality, alcohol Stages of change readiness and treatment eagerness scale use, alcohol-related problems, and motivation for change.
(SOCRATES). This is a 19-item measure of motivational At this time, participants also met with a therapist for the processes associated with the stages of change model.
psychosocial and medication management component of Specifically, the SOCRATES consists of three subscales this trial (described in detail below). At the end of session 1, assessing recognition of alcohol-related problems (Recogni- participants were randomized to receive either olanzapine tion subscale), uncertainty about drinking (Ambivalence subscale), and taking action to change drinking behavior The cue reactivity session (session 2) took place 2 weeks (Taking Steps subscale). The SOCRATES has been shown to after session 1. Following standardized procedures pre- be a valid and reliable measure of motivation for change viously reported in the literature (eg Rohsenow et al, 2000), participants took part in a cue-exposure paradigm. Ingeneral, this procedure involves comparing reactivity A 30-day time-line follow-back procedure (TLFB; Sobell between control cues (eg a nonalcoholic beverage) vs an and Sobell, 1980). This measure was used to assess the Olanzapine and the DRD4 VNTRKE Hutchison et al quantity and frequency of drinking in the 30 days prior to Table 1 DRD4 VNTR Allele and Genotype Frequencies the experiment. Consistent with previous outcome studies(eg Project MATCH Research Group, 1998; Monti et al, 2001; Killeen et al, 2004), the primary outcome variableswere drinks per drinking day, total number of drinks, and Years of sustained drinking. This variable was assessed by the item, ‘How many years have you been drinking the quantity of alcohol per week that you are drinking now?’ Side-effect checklist. The short form of the Systematic Assessment for Treatment Emergent Events (SAFTEE) wasutilized at each time point in the trial. This measure is recommended for use in clinical trials (Levine and Schooler, 1986; Jacobson et al, 1986) and consists of a survey of 24 common drug side effects (scored as present or absent).
Check on blind. Participants indicated which of the medications that they believed they received at thebeginning of the cue-reactivity session.
Alcohol urge questionnaire (AUQ). The AUQ was used to assess urge to drink. The AUQ consists of eight items related to urge to drink that are rated on a 7-point Likert scale, with the extremes anchored by ‘Strongly Disagree’ and ‘Strong Agree’. The AUQ has demonstrated high Profile of mood states (POMS). The POMS is a 40-item questionnaire assessing for multiple mood dimensions (McNair et al, 1971). The POMS has been used extensively in laboratory studies of the effects of alcohol and wasutilized in this study to measure changes in mood duringthe cue-exposure paradigm.
Genomic DNA was isolated from buccal cells using published procedures (Lench et al, 1988). The 48-bp VNTR A series of analyses were conducted to determine whether in the third exon of the DRD4 was assayed using previously the medication  DRD4 groups differed on drinking and reported methods (Sander et al, 1997). The primer demographic variables (see Table 2 for the means and sequences were forward, 50-AGGACCCTCATGGCCTTG-30 standard deviations for the medication  DRD4 groups).
Analyses of the baseline data suggested that the groups did TGGTCTACTCG-30 (Lichter et al, 1993). PCR conditions not differ on these variables including ethnic background.
were as follows: 200 mM of each of the four dNTPs, 2.5 mM Thus, it is highly unlikely that population stratification, MgCl2, 200 nM forward primer (fluorescently labeled), gender, or other variables measured at baseline confounded 200 nM reverse primer, 40 ng of genomic DNA, 1 U of AmpliTaq Gold polymerase (ABI), and 1 Â PCR II buffer(ABI) in a total volume of 20 ml. Amplification wasperformed with the following conditions: 951C for 10 min Cue-Elicited Craving and Drinking Behavior (to activate the Gold polymerase); 35 cycles of 941C for 30 s,551C for 30 s, and 721C for 60 s; and a final elongation at Analyses were then conducted to determine whether the 721C for 30 min. PCR products were electrophoresed in groups differed in terms of cue-elicited craving after 2 4.25% polyacrylamide under denaturing conditions with weeks of treatment and in terms of drinking behavior over Applied Biosystems 3100. Participants were classified as the 12-week trial. These analyses utilized an ‘intent-to-treat’ DRD4 L (ie homozygous or heterozygous for an allele X7 approach such that all individuals who returned for the repeats; S/L or L/L), or were classified as DRD4 S (ie both cue reactivity assessment at 2 weeks were included in alleles o7 repeats; S/S). Table 1 provides the allele and the analyses, even if they dropped out of the trial.
Six individuals in the olanzapine group and seven in the Table 2 Pretest Differences between the Medication Groups aStandard deviations appear in parentheses below the means of continuous variables.
placebo group dropped out of the study after the cue DRD4 S Individuals
reactivity assessment, and were included in the analyses.
For these individuals the last observation was carried forward in the analyses, following an intent-to-treatapproach.
To analyze reactivity to alcohol cues, a series of 2 Â 2 Â 2 mixed design analyses of variance (ANOVAs) were conducted, where cue (control cues vs alcohol cues) was atwo-level within-subjects factor, medication (olanzapine or placebo) was a two-level between-subjects factor, and DRD4(DRD4 L vs DRD4 S) was a two-level between-subjects factor. The craving score at baseline was used as a covariate to control for the nonspecific effects of olanzapine on DRD4 L Individuals
DRD4 Â cue interaction, F(1, 59) ¼ 6.14, po0.05, and asignificant DRD4 Â cue interaction, F(1, 59) ¼ 10.29, po0.01.
Cue-elicited craving was clearly greater among DRD4 Lindividuals and olanzapine attenuated craving specifically among these individuals (see Figure 1). There was nosignificant main effect of olanzapine on craving (p40.05).
With respect to changes in negative affect, the analysesrevealed a significant medication  DRD4  cue interaction, F(1, 59) ¼ 8.11, po0.01, a significant medication  cueinteraction, F(1, 59) ¼ 5.58, po0.05, and a significant main effect for cue, F(1, 59) ¼ 8.73, po0.01. Likewise, analyses revealed a significant medication  DRD4  cue interaction on the Tension scale, F(1, 59) ¼ 6.88, po0.05, as wellas a significant main effect for cue and F(1, 59) ¼ 7.91, Mean craving (AUQ) scores at baseline and after exposure to po0.01. These results suggested that olanzapine attenuated alcohol cues. Analyses indicated a medication  DRD4  trial interaction (po0.05) such that olanzapine significantly reduced craving at baseline andafter cue exposure among the DRD4 L individuals and reduced craving at particularly among the DRD4 L individuals (see Figures 2 baseline among the DRD4 S individuals. Olanzapine did not reduce cue- elicited craving among the DRD4 S individuals.
To analyze the effects of olanzapine on drinking behavior, a series of 2  2  2 mixed design ANOVAs were conducted,where medication (olanzapine vs placebo) was a two-level DRD4  Assessment interaction on drinks per drinking between-subjects factor, DRD4 (DRD4 L vs DRD4 S) was a day, F(3, 180) ¼ 3.02, po0.05, and a significant main effect two-level between-subjects factor, and Assessment (base- for medication, F(1, 60) ¼ 4.88, po0.05. Olanzapine signifi- line, 4, 8, and 12 weeks) was a four-level within-subjects cantly reduced drinks per drinking day among the DRD4 L factor. Analyses revealed a significant medication  individuals (see Figure 4). An analysis of total number of Olanzapine and the DRD4 VNTRKE Hutchison et al DRD4 S Individuals
POMS Tension
POMS Depression
DRD4 L Individuals
POMS Tension
POMS Depression
Mean score on the Depression subscale of the POMS and Mean score on the Tension subscale of the POMS standard errors before and after cue exposure to alcohol for the DRD4 S and standard errors before and after cue exposure to alcohol for the group and the DRD4 L group. Analyses indicated that olanzapine DRD4 S group and the DRD4 L group. Analyses indicated that olanzapine significantly reduced the negative affect during the cue-reactivity paradigm among DRD4 L individuals, but had no effect on DRD4 S participants among DRD4 L individuals, but had no effect on DRD4 S participants drinks also revealed a significant three-way interaction, glucose and GGT data revealed nonsignificant decreases F(3, 180) ¼ 5.39, po0.05, indicating that olanzapine signifi- across the 12-week trial, indicating that olanzapine did not cantly reduced the total number of drinks for DRD4 L have any deleterious effects in terms of blood glucose levels individuals. Similarly, an analysis of percent days abstinent or liver function in this sample. Finally, w2 tests were revealed a trend for a medication  DRD4 interaction, such conducted comparing the medication groups on each of 24 that DRD4 L individuals responded more favorably to items from the side effect checklist. None of these tests were All urine samples tested positive for riboflavin, suggesting that individuals were compliant with the medicationinstructions immediately prior to each appointment. In Finally, analyses were conducted to assess whether side addition, analyses of the pill count data suggested high effects differed across medication groups. ANOVAs were compliance and did not reveal any significant differences in used to examine change in weight, glucose levels, and GGT compliance across the medication  DRD4 groups. With levels before and after the 12-week trial. With respect to respect to the integrity of the medication blind, 63% of the weight gain, a significant medication  Time interaction participants in the olanzapine condition guessed correctly indicated significant weight gain among individuals treated at the beginning of the experimental session and 65% of the with olanzapine as compared to placebo, F(1, 41) ¼ 6.54, participants in the placebo condition guessed correctly.
po0.01. The average weight gain in the olanzapine group Finally, study completion status (completed vs drop-out) was 6.5 lbs at the end of the 12-week trial. There were no and the integrity of the blind (guess correctly vs did not effects for the DRD4 on weight gain. Analyses of the blood guess correctly) were entered as covariates in the analyses In the present study, it is important to note that 5 mg of olanzapine did not appear to have any beneficial effects among the DRD4 S individuals. The lack of any significanteffects of olanzapine among these individuals is consistent with a recent report that failed to find any beneficial effectsof olanzapine during the course of a 12-week trial of olanzapine in an alcohol-dependent sample (Guardia et al, 2004). Conversely, the finding that olanzapine appears toattenuate reactivity to alcohol cues as well as drinking in DRD4 L individuals is not consistent with this report. There Drinks / Drinking Day
are two important differences between the present study and the previous report, which might explain the different findings. One of the primary differences is that the study by Guardia et al (2004) did not report results by DRD4genotype, whereas genotype was considered in the present study. Second, a 10–15 mg dose of olanzapine was used in the Guardia et al study, while 2.5–5 mg was used in thepresent study. Previous work in our laboratory found that the 5 mg dose of olanzapine attenuated craving for alcohol.
Thus, the difference in findings may be explained in part by dose response differences and/or dose response by genotypedifferences.
The idea that higher doses of olanzapine may be associated with iatrogenic results is not surprising giventhat these doses are likely to produce more severe side effects, which in turn may lead to reduced compliance and/ Drinks / Drinking Day
or increased drinking as a means of coping with the side effects. While a dose of 10–20 mg may be beneficial forindividuals suffering from psychosis, these doses may not be appropriate for other disorders such as alcohol dependence. Even at 2.5–5 mg, olanzapine-treated indivi-duals experienced significant weight gain in the present Mean number of drinks per drinking occasion and standard study, and, although other side effects observed in the errors for the DRD L group and the DRD4 S group across time points in olanzapine group were not significantly different from the trial. Analyses revealed a significant genotype  medication  trial interac- side effects observed in the placebo group, a greater tion such that DRD4 L participants reported greater decreases in alcoholconsumption across levels of trial as compared to DRD4 S individuals percentage of individuals in the olanzapine condition reported drowsiness. Clearly, these side effects may bemore pronounced in a study using higher doses ofolanzapine. In addition, olanzapine targets multiple neuro- described above. The significance of the results did not transmitter systems and the exact mechanism of its effect on change, suggesting that neither of these variables biased the craving and alcohol consumption is not known, although the DRD4  olanzapine interaction is consistent with thehypothesis that the effect of olanzapine on the dopaminesystem is critical. Finally, it is possible that the DRD4 VNTR may shift the dose–response curve such that DRD4 Sindividuals might respond favorably to a different dose of The findings of the present study indicate that olanzapine reduces cue-elicited craving for alcohol and cue-elicited Given the potential importance of dosing and the changes in affect among DRD4 L individuals after 2 weeks possibility of a DRD4  dose interaction, one of the of treatment. Likewise, olanzapine appears to reduce the limitations of the present study was the lack of a formal quantity of drinking over the course of a 12-week trial examination of the dose–response curve. Higher doses may among DRD4 L individuals. The biological mechanism that produce no positive effects or even iatrogenic effects, while underlies the differences in response to olanzapine among lower doses may be beneficial. Future studies should DRD4 L and S individuals is not clear. It is possible that the examine a 2.5 mg dose as well as a 5 mg dose, and stratify size of the intracytoplasmic loop may alter G protein by genotype such that the hypothesis of a dose  genotype coupling, which in turn may alter the function of the interaction can be formally tested. It seems possible that receptor. Future research will need to explore this question.
DRD4 S individuals may respond to 2.5 mg even if they do With respect to side effects, individuals treated with not respond to 5 mg. To determine whether olanzapine will olanzapine gained approximately 6.5 lbs over the course of ultimately be useful in the treatment of alcohol dependence, the 12-week study, regardless of their DRD4 genotype.
future studies also need to examine the long-term effects However, there were no other statistically significant group of olanzapine on drinking behavior after treatment has differences with respect to side effects.
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