The Effects of the Monoamine Stabilizer (-)-OSU6162 on Craving in Alcohol Dependent Individuals: A Human Laboratory Study (2015)

Khemiri, Lotfi et al. European Neuropsychopharmacology

Lotfi Khemiri, Pia Steensland, Joar Guterstam, Olof Beck, Arvid Carlsson, Johan Franck, Nitya Jayaram-Lindström

DOI: http://dx.doi.org/10.1016/j.euroneuro.2015.09.018

Article Outline

  1. 1. Introduction
  2. 2. Experimental Procedures
    1. 2.1. Participants
    2. 2.2. Study Design
    3. 2.3. Alcohol Craving Test Sessions
    4. 2.4. Clinical measures
    5. 2.5. Behavioral task of impulsivity
    6. 2.6. Statistical Analysis
  3. 3. Results
  4. 3.1. Participants
  5. 3.2. OSU6162 did not attenuate subjective ratings of cue-induced craving
  6. 3.3. OSU6162 attenuated subjective ratings of priming-induced craving
  7. 3.4. The ability of OSU6162 to attenuate alcohol craving was driven by individuals with high baseline impulsivity
  8. 3.5. OSU6162 had no significant effect on drinking, craving or mood during treatment
  9. 3.6. Side effects
  10. 4. Discussion
  11. Funding and Disclosure
  12. Contributors
  13. Funding source
  14. Appendix A. Supplementary material
  15. References

Abstract

Alcohol dependence is associated with a dysregulated dopamine system modulating reward, craving and cognition. The monoamine stabilizer (-)-OSU6162 (OSU6162) can counteract both hyper- and hypo-dopaminergic states and we recently demonstrated that it attenuates alcohol-mediated behaviors in long-term drinking rats. The present Phase II exploratory human laboratory study investigated to our knowledge for the first time the effects of OSU6162 on cue- and priming-induced craving in alcohol dependent individuals.

Fifty-six alcohol dependent individuals were randomized to a 14-day-treatment period of OSU6162 or placebo after their baseline impulsivity levels had been determined using the Stop Signal Task. On Day 15, participants were subjected to a laboratory alcohol craving test comprised of craving sessions induced by: i) active – alcohol specific cues, ii) neutral stimuli and iii) priming – intake of an alcoholic beverage (0.20 g ethanol/kg bodyweight).

Subjective ratings of alcohol craving were assessed using the shortened version of the Desire for Alcohol Questionnaire and visual analogue scales (VAS). OSU6162-treatment had no significant effect on cue-induced alcohol craving, but significantly attenuated priming-induced craving. Exploratory analysis revealed that this effect was driven by the individuals with high baseline impulsivity. In addition, OSU6162 significantly blunted the subjective liking of the consumed alcohol (VAS). Although the present 14-day-treatment period, showed that OSU6162 was safe and well tolerated, this exploratory human laboratory study was not designed to evaluate the efficacy of OSU6162 to affect alcohol consumption. Thus a larger placebo-controlled efficacy clinical trial is needed to further investigate the potential of OSU6162 as a novel medication for alcohol dependence.

Keywords:

Alcohol, Addiction, Craving, Impulsivity, Dopamine stabilizer, OSU6162

1. Introduction

The mesolimbic dopamine system is a well-studied neurobiological system in the development and maintenance of drug and alcohol dependence. The acute reinforcing effects of addictive drugs, including alcohol, is mediated in part by increased dopamine release in the nucleus accumbens (Boileau et al., 2003, Di Chiara and Imperato, 1988, Imperato and Di Chiara, 1986), activating dopamine D2 receptors (Nowak et al., 2000). In alcohol dependent individuals, brain-imaging studies using positron emission tomography (PET) have revealed a reduction of availability of dopamine D2 receptors suggested to reflect a compensatory down-regulation induced by chronic alcohol intake which has also been associated with a subsequent risk for relapse (Heinz et al., 2009, Heinz et al., 2005, Volkow et al., 1996). In addition the dopamine dysfunction observed in the human studies was correlated with the severity of alcohol craving as well as an increased activation in brain striatal regions when exposed to alcohol-related cues, reflecting an attentional bias to the specific cues and risk for relapse (Heinz et al., 2004). Furthermore, it was recently demonstrated that alcohol dependent individuals have decreased dopamine levels also in the prefrontal cortex (Narendran et al., 2014), suggesting that cortical dopamine deficits may contribute to the cognitive impairments (e.g. reduced impulse control and attention) seen in alcohol dependent individuals (Goldstein and Volkow, 2011, Stavro et al., 2012). In fact, recent studies have investigated the implications of the neural links relating to the change in the dopamine system and impulsive behaviours, to understand their putative relevance in alcohol dependence. The results indicate an association between alcohol use, increased impulsivity, an elevated subjective response to alcohol (Leeman et al., 2014) and increased dopamine levels (Boileau et al., 2003), suggesting that impulsivity (Dick et al., 2010) and the subjective response to alcohol (Crabbe et al., 2010) are risk factors for alcohol dependence.

The dopamine system has previously been evaluated as a potential treatment target for alcohol dependence, however, studies with traditional dopamine antagonists and agonists have been discouraging (Swift, 2010). The use of dopamine antagonists (i.e. neuroleptics) is further limited by severe side effects including anhedonia and extrapyramidal reactions resulting from excessive dopaminergic inhibition. However, recently modafinil (a dopamine transporter modulator) and aripiprazole (a commercial compound conceptually developed from the partial D2-agonist (-)-3PPP (Carlsson and Carlsson, 2006) has been shown to decrease alcohol intake and craving in alcohol dependent individuals (Joos et al., 2013, Martinotti et al., 2009, Martinotti et al., 2007, Myrick et al., 2010, Schmaal et al., 2013, Voronin et al., 2008). These results indicate that dopamine agents without complete antagonism or agonism hold promise for efficacious treatment of alcohol dependence.

The monoamine stabilizer (-)-OSU6162 (OSU6162) (Carlsson et al., 2004, Sonesson et al., 1994), is a further development from (-)-3PPP with the ability to stimulate, suppress or show no effect on the dopamine activity depending on the prevailing dopaminergic tone. This concept was postulated based on a PET study in rhesus monkeys where OSU6162-infusions induced a dopaminergic tone-dependent effect with a reduction in the striatal L-[11C]DOPA influx rate in monkeys with high baseline values and an increased striatal L-[11C]DOPA influx rate in animals with low baseline values (Tedroff et al., 1998). The mechanism of action is however not completely understood, and although in vitro studies indicate that OSU6162, like aripiprazole, acts as a partial agonist at D2-receptors (Kara et al., 2010, Seeman and Guan, 2007), behavioral studies have failed to demonstrate any intrinsic activity of the compound (Natesan et al., 2006, Sonesson et al., 1994). Instead it has been suggested that OSU6162 produces functionally opposite effects by acting as an antagonist at both presynaptic autoreceptors and postsynaptic D2 receptors (Carlsson et al., 2004, Lahti et al., 2007, Rung et al., 2008, Sonesson et al., 1994) OSU6162 appears to be clinically safe with side effects of mild severity in healthy volunteers (Rodríguez et al., 2004) and patients with e.g. Huntingtons disease and mental fatigue following stroke and brain trauma (Johansson et al., 2012, Kloberg et al., 2014, Tedroff et al., 1999). Thus an advantage of OSU6162 compared to traditional D2 antagonists, might be the lack of extrapyramidal reactions (Carlsson and Carlsson, 2006).

We recently identified OSU612 as a potential novel medication by showing that it attenuates voluntary alcohol consumption, alcohol seeking, withdrawal and cue/priming-induced reinstatement of alcohol seeking in long-term drinking rats (Steensland et al., 2012). Furthermore, OSU6162’s potential to target the dopamine system in brain regions relevant for alcohol dependence is supported by a recent human PET study showing that OSU6162 preferentially binds to D2/D3-receptors in the striatum (Tolboom et al., 2014) and our recent microdialysis study showing that the compound can counteract a hypodopaminergic state in long-term drinking rats (Feltmann, et al., Addiction Biology, 2015). Based on these results, the present study evaluated the effects of OSU6162 on cue- and priming-induced craving in alcohol dependent individuals in a Phase II placebo-controlled human laboratory study. Based on the growing body of research indicating a significant neurobiological overlap between impulsivity and alcohol dependence (Dick et al., 2010, Lejuez et al., 2010) and the knowledge that impulsivity is an important predictor of treatment outcome (Joos et al., 2013, Schmaal et al., 2013, Voronin et al., 2008) we also investigated whether baseline impulsivity predicted cue reativity and treatment response to OSU6162.

2. Experimental Procedures

2.1. Participants

Fifty-six treatment-seeking alcohol dependent individuals were recruited through public advertisements. The study physician provided verbal and written information about the procedures, before seeking participants’ written informed consent. Individuals who completed the study and the follow up visit were compensated with 1500 Swedish Crowns (approximately 180 USD). The study was approved by the regional ethical review board in Stockholm and the Swedish Medical Products Agency, registered in the European Clinical Trials Database (EudraCT;2011-003133-34), monitored by Karolinska Trial Alliance and conducted in accordance with Good Clinical Practice and the Declaration of Helsinki.

After a brief telephone interview, potential participants were invited to the Stockholm Centre for Dependency Disorders outpatient research clinic, Karolinska University Hospital (KUH) for a screening visit consisting of physical examination, psychiatric evaluation, blood samples, breathalyzer, urine test and electrocardiogram (ECG, Mortara Instrument ELI150c). In brief, included individuals were between 20 and 55 years old, fulfilling the DSM-IV criteria for alcohol dependence, had at least 45 heavy drinking days (HDD; defined as a day with consumption of at least 5 or 4 standard drinks (defined as 12 g alcohol per drink) for men and women, respectively) within the last 90 calendar days from inclusion and had not consumed alcohol for a minimum of four, and a maximum of 14 days before inclusion, confirmed by Time Line Follow Back (TLFB) interview ((Sobell and Sobell, 1992) and breathalyzer. In brief, exclusion criteria’s were fulfilment of DSM-IV criteria for any other type of substance use disorder (except nicotine), DSM-IV criteria for schizophrenia, bipolar disorder, major depression or presence of any previous heart disease of clinically significant ECG abnormalities. The complete inclusion and exclusion criteria are provided in supplementary information (SI)).

2.2. Study Design

In this double blind, placebo-controlled study, participants were randomized to receive OSU6162 or matched placebo tablets (Galenica AB, Malmö, Sweden) during a 14-day-treatment-period and were instructed to take medication according to the following schedule: Day 1–5:10 mg×2; Day 6–10:15 mg×2; Day 11–14:30 mg×2. The length of the treatment period was based on a recommendation from Swedish Medical Products Agency as the present study was the first to evaluate OSU6162 in an alcohol dependent population. The randomization procedure (see SI for details) was done by the Karolinska Trial Alliance, without the involvement of the research staff and the medication was dispensed to the research clinic by the KUH pharmacy. The study comprised three follow-up visits during the 14-day-treatment-period and a laboratory based alcohol craving test session on day 15 (Test day). The follow-up visits included ECG, blood and urine sample collection, medication dispensing, breathalyzer test and reporting of drinking, mood, and adverse events. Participants were instructed to refrain from drinking during the treatment period, although drinking was not ground for exclusion. However, alcohol intake the day before and on the Test day (confirmed via TLFB and breathalyzer) resulted in exclusion from the craving test session to prevent bias in the subjective craving experience.

On the Test day participants arrived at the research clinic in the morning, and took the final dose of study medication in the presence of a research staff. Nicotine and caffeine was allowed before arrival, but not during the course of the Test day. After completion of the craving experimental sessions, participants received lunch and debriefing and stayed in the research clinic until they were sober. All participants were offered referral for treatment within the Stockholm Centre for Dependency Disorders.

2.3. Alcohol Craving Test Sessions

The human laboratory test sessions are modified from (Hammarberg et al., 2009), and the procedures are described in detail in SI. In brief, the test comprised three craving sessions induced by: i) active – alcohol specific cues, ii) neutral stimuli and iii) priming – intake of an alcoholic beverage (0.20 g ethanol/kg bodyweight).

The order of the cue-sessions (active cue and neutral stimuli) was randomized and counter-balanced between participants, within each treatment group. During each session, subjective ratings of alcohol craving were collected before, immediately after and at 5 and 10 minutes post cue presentation (the mean of the two latter time-points was defined as “post-cue” measurements). Craving was assessed using the shortened Swedish version of the Desire for Alcohol Questionnaire (Short-DAQ) (Love et al., 1998) consisting of eight items (Table S1) scored on a seven-point Likert scale where 1 and 7 indicated “Do not agree at all” and “Fully agree”, respectively, as well as a single-item Visual Analogue Scale (VAS, ranging from 0 to 100) measuring “How much craving for alcohol do you experience right now?”.

Post the cue sessions, the priming session was conducted during which each participant first took one sip of their preferred alcoholic beverage before finishing the drink. Subjective craving ratings were collected: before, immediately after, as well as 5, 10, 25 and 40 minutes after finishing the alcoholic beverage (the mean of the four latter time-points were defined as “post drink” measurements) and assessed with Short-DAQ and VAS as described above. To capture subjective effects immediately after the first sip of alcohol, VAS items of “craving”, “anxiety” and “arousal” were collected. In addition, a VAS item of “liking” was included as an amendment to the protocol after the first 15 participants.

2.4. Clinical measures

Psychiatric evaluation was done at screening using the Structured Clinical Interview for DSM-IV (American Psychiatric Association, 2000). Mood and craving during treatment were assessed using the Montgomery-Åsberg Depression Self Rating Scale (MADRS-S) (Svanborg and Asberg, 2001) and the Penn Alcohol Craving Scale (PACS) (Flannery et al., 1999), respectively. Alcohol consumption was quantified as change between inclusion and Test day in percent HDD (TLFB self-report) and phosphatidylethanol (S-PEth) serum levels (analyzed by the clinical chemistry laboratory, KUH). Presence of illicit drugs e.g., amphetamine, cocaine, cannabis (THC) or opiates was evaluated on weekly follow-up visits using urine dipsticks. Verification of positive samples was conducted at the aforementioned laboratory. OSU6162 compliance was measured by plasma concentrations (analysis methodology in SI) on second follow-up visit and Test Day, and pill counts on every visit. ECG was recorded and evaluated by a cardiologist as a safety measure at the second follow-up visit and Test day.

2.5. Behavioral task of impulsivity

During the inclusion visit (before intake of study medication), participants performed the Stop Signal Task (SST, see SI for methodological details), a computerized neuropsychological test widely used as a measure of impulsivity (Aron et al., 2003, DeVito et al., 2009). The outcome of interest was the stop signal reaction time (SSRT)-a measure of the participants’ ability to inhibit a prepotent response. Each participant was defined as being high or low impulsive, based on the median split of the SSRT scores in accordance with previous studies in alcohol dependent individuals (Joos et al., 2013, Schmaal et al., 2013).

2.6. Statistical Analysis

The primary outcomes were (i) total Short-DAQ and (ii) VAS scores, respectively, for craving during the laboratory test sessions. Data were analyzed using mixed ANOVAs with Treatment (OSU6162 or placebo) as between-subject factor. Within-subject factors were Condition (active, neutral) and Time (before, immediately after and post-cue) for the cue-induced sessions and Time (before, immediately after and post-drink) for the priming-induced session. Significant main effect of Treatment or Condition and interactions were further analyzed using Student’s unpaired or paired t-tests, where appropriate. Data from the VAS items after the first alcohol sip (priming-session) were analyzed by separate Student’s unpaired t-tests, comparing scores between treatment groups.

In a priori determined exploratory analyses, separate ANOVAs were performed to evaluate the potential influence of baseline impulsivity (i.e. high or low impulsive based on median split of the SSRT (Joos et al., 2013; Schmaal et al., 2013)), on the outcome from the cue- and priming-induced craving test sessions, respectively. Difference in alcohol consumption (HDD and Peth), craving (PACS) and mood (MADRS-S) between inclusion and Test day were compared between treatment groups using Student’s unpaired t-tests.

This human laboratory study is to our knowledge the first exploratory study evaluating the effects of OSU6162 in alcohol dependent patients, using two different but highly dependent measurements of subjective craving. Thus, the risk of type 1 error was deemed less troublesome than type 2 errors, and the alpha-level was set to 0.05, two-tailed, uncorrected. Data was assessed for normality by ocular inspection together with Shapiro Wilks normality test and analyzed using IBM SPSS statistics (version 21.0, SPSS inc., Chicago, Illinois). If equality of variances was violated (assessed by Levenes test), the results of the Welch t-test were reported. Greenhouse-Geisser corrections were applied if the sphericity assumption was violated (evaluated using Mauchlys test). Missing values were not replaced. If not stated otherwise, mean values±standard deviations are reported.

3. Results

3.1. Participants

Study recruitment began in September 2012, and the last participant visit was in December 2013. The two treatment groups were homogeneous at inclusion with regards to sociodemographic background, alcohol consumption patterns, craving and mood (Table 1). Of the 56 randomized, one participant in the placebo group dropped out after a severe relapse on Day 1. Thus, 55 participants completed the 14day-treatment-period and provided data regarding alcohol use, craving, mood and side effects. Seven participants were excluded from the alcohol craving test sessions because of: alcohol consumption the day before (n=3), not complying with study procedures during Test day (n=1) or presenting urine sample positive for opiates (n=2) or THC (n=1). In the priming session, three participants did not comply with study procedures after taking the first sip of alcohol, and thus only provided data for the baseline and first sip time-points. In the OSU6162 group, analyzed blood samples had detectable OSU6162 plasma levels on Day 7 (38.9±24.7 ng/mL) and the Test day (105.0±73.8 ng/mL). No OSU6162 was detected at any time-point in any blood samples from the placebo group.

Table 1Participant characteristics at inclusion. There were no significant differences between the OSU6162- or placebo-treated groups for any of the outcomes. Continuous variables are presented as mean (standard deviation). Abbreviations: MADRS-S-Montgomery-Åsberg Depression Self Rating Scale; PACS-Penn Alcohol Craving Scale.

 

OSU6162 (n=28)

PLACEBO (n=28)

Significance

Males / Females

14 / 14 16/12 p=0.60

Age

47.3 (6.5) 45.3 (7.7) p=0.30

Education years

13.3 (2.5) 14.1 (2.8) p=0.26

Married / Partner

54% 54% P=1.0

Full time employment

78.6% 71.4% P=0.54

Part time employment

7.1% 17.9% P=0.23

Unemployed

14.3% 7.1% P=0.39

Sick leave/retired

0% 3.6% P=0.31

Daily nicotine use (%)

68% 64% P=1.0

DSM-IV criteria for alcohol dependence

5.2 (1.1) 5.1 (1.4) P=0.62

Heavy drinking last 90 days (%)

73% 68% P=0.29

Drinks per day last 90 days

5.8 (2.2) 5.7 (2.4) P=0.88

MADRS-S score

9.2 (6.8) 7.9 (6.7) P=0.46

PACS craving score

11.1 (6.5) 10.4 (6.0) P=0.70

3.2. OSU6162 did not attenuate subjective ratings of cue-induced craving

In the cue-induced craving sessions (Short-DAQ; Fig. 1), there was a significant main effect of Condition (F(1,45)=76.5;p<0.001) and Time (F(2,90)=21.1;p<0.001) but no significant main effect of Treatment (F(1,45)=2.1;p=0.154). In addition, there was a significant Timelow asteriskCondition interaction (F(1.7,76.2)=22.5;p<0.001) but no significant Treatmentlow asteriskCondition (F(1,45)=1.3;p=0.262) or Timelow asteriskConditionlow asteriskTreatment interaction (F(2,90)=1.1;p=0.320). Thus, based on the lack of significant treatment effects, post hoc analyses were conducted to evaluate differences between the active and neutral sessions regardless of treatment. There was a significantly higher level of subjective craving immediately after presentation of the active cue (24.0±8.6) compared to the neutral stimuli (17.3±8.9;t(46)=−8.0;p<0.001) as well as compared to before (18.9±9.2;t(46)=−6.0;p<0.001) and post presentation of the active cue (19.8±9.3;t(46)=5.7;p<0.001). Within the neutral condition, there was no significant difference in the level of subjective craving between any of the measured time-points (Before:17.8±8.8; Immediately after:17.3±8.9 and Post:17.1±8.8). The VAS craving data yielded significant effects on cue-craving (Fig. S1) similar to the Short-DAQ results (see SI for full analysis).

Fig. 1 Opens large image

Fig. 1

The monoamine stabilizer OSU6162 did not attenuate subjective ratings of cue-induced craving in alcohol dependent patients. Mean craving total scores on the shortened version of the Desire for Alcohol Questionnaire (Short-DAQ) during the (A) neutral and (B) active cue-induced craving session. There was no statistically significant difference in craving between the OSU6162- and placebo-treated groups during the neutral or active cue sessions, respectively. Data was collected at the following time-points: before, immediately after and at 5 and 10 minutes post cue presentation (the mean of the two latter time-points were defined as “post-cue” measurements). Values are presented as mean±s.e.m.

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3.3. OSU6162 attenuated subjective ratings of priming-induced craving

During the priming-induced craving session, the mean time to finish the alcoholic beverage was 8.6 minutes (ranging from three to 18 minutes between subjects) with no significant difference between treatment groups (t(42)=−0.09;p=0.927). When analysing the Short DAQ data there was a significant main effect of Time (F(1.5,63.6)=13.7;p<0.001) and Treatment (F(1,43)=4.1;p=0.050) but no significant Timelow asteriskTreatment interaction (F(1.5,63.6)=1.4;p=0.255). Post hoc analysis revealed that the OSU6162-treated individuals had significantly lower levels of subjective craving compared to placebo immediately after finishing the alcoholic drink (on average it took 9 minutes to finish the drink). However, no significant difference was found between the different treatment groups before or post finishing the drink (mean of time-points 5, 10, 25 and 40 minutes; Fig. 2A). For the VAS data (Fig. 2B) there was a significant main effect of Time (F(1.6,70,2)=29,2;p<0.001) and a trend toward significance for Treatment (F(1,43)=3.3;p=0.075) but no significant Timelow asteriskTreatment interaction (F(1.6, 70,2)=0.85;p=0.412).

Fig. 2 Opens large image

Fig. 2

The monoamine stabilizer OSU6162 attenuated subjective ratings of priming-induced craving in alcohol dependent patients. Mean total scores on (A) the shortened version of the Desire for Alcohol Questionnaire (Short-DAQ) and (B) VAS craving item during the priming-induced craving session as well as (C) VAS-items of “craving”, “liking”, “anxiety” and “arousal” after the first sip of alcohol. The OSU6162-treated group rated significantly lower craving (Short-DAQ) immediately after finishing the alcoholic drink compared to the placebo-treated group (A) and there was a trend towards decreased craving in the OSU6162- compared to the placebo-treated group using the VAS at the same time-point (B). The OSU6162 group further rated significantly lower subjective liking, and a trend toward lower craving, after the first sip of alcohol (C). Data was collected at the following time-points: before drink, after the first sip, immediately after finishing the alcoholic beverage, as well as 5, 10, 25 and 40 minutes post consumption of the alcoholic beverage (the mean of the four latter time-points were defined as “post drink” measurements). Values are presented as mean±s.e.m; *p<0.05 compared to corresponding placebo.

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After the first sip from the alcoholic beverage (Fig. 2C), OSU6162 treated individuals reported significantly lower subjective liking of the alcohol (t(31)=−2.27;p=0.031) and a trend toward lower craving (t(46)=−1.88;p=0.066) compared to placebo, while there was no significant difference between treatment groups regarding arousal (t(46)=−1.29;p=0.205) or anxiety (t(46)=−0.24;p=0.814).

3.4. The ability of OSU6162 to attenuate alcohol craving was driven by individuals with high baseline impulsivity

In individuals with high baseline impulsivity, the analysis of the Short-DAQ data from the cue-induced craving sessions revealed a significant main effect of Treatment (F(1,22)=4.5;p=0.044), but no significant Treatmentlow asteriskCondition interaction (F(1,22)=1.4;p=0.248) or Timelow asteriskConditionlow asteriskTreatment interaction (F(1.5,32.2)=0.93;p=0.377). Post hoc analysis revealed that the high impulsive OSU6162-treated individuals rated significantly lower subjective craving immediately after, and post (mean of the 5 and 10 minutes time-points) the presentation of the neutral cue compared to placebo-treated individuals (Fig. 3A, left panel). In the active cue session, there was a significant decrease in subjective craving in the OSU6162-, compared to placebo-treated individuals only post presentation of the active cue (Fig. 3A, right panel). In individuals with low baseline impulsivity, however, there was no significant main effect of Treatment (F(1,21)=0.16;p=0.695), and no significant Treatmentlow asteriskCondition (F(1,21)=0.152;p=0.701) or Timelow asteriskConditionlow asteriskTreatment (F(2,42)=0.275;p=0.761) interactions (Fig. 3B). The VAS data yielded significant effects on cue-induced craving in high and low impulsive individuals similar to the Short-DAQ results (see details in SI; Fig. S2).

Fig. 3 Opens large image

Fig. 3

The monoamine stabilizer OSU6162 attenuated cue-induced craving in alcohol dependent individuals with high baseline impulsivity. Mean craving total scores on the shortened version of the Desire for Alcohol Questionnaire (Short-DAQ) in (A) high and (B) low impulsive alcohol dependent individuals during cue-induced craving sessions. (A) OSU6162 significantly reduced craving in the high impulsive alcohol dependent individuals compared to placebo immediately after, and post presentation of the neutral cue, as well as post presentation of the alcoholic cue presentation. (B) No difference in craving was found between OSU6162 and placebo group in the low impulsive alcohol dependent individuals. Data was collected at the following time-points: before, immediately after and at 5 and 10 minutes post cue presentation (the mean of the two latter time-points were defined as “post-cue” measurements). Values are presented as mean±s.e.m; *p<0.05 compared to corresponding placebo.

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In the priming-induced craving session, analysis of the Short-DAQ data from individuals with high baseline impulsivity showed a significant main effect of Treatment (F(1,20)=9.8;p=0.005) and Time (F(1.3,26.0)=8.8;p=0.004) but no significant Timelow asteriskTreatment interaction (F(1.3,26.0)=2.5;p=0.116). Post hoc analysis revealed that the OSU6162 group had significantly lower subjective craving than the placebo group at all measured time-points (Fig. 4A, left panel). In contrast, in individuals with low baseline impulsivity (Fig. 4B, left panel), there was a main effect of Time (F(2,42)=4.3;p=0.021) but no significant main effect of Treatment (F(1,21)=0.12;p=0.731) or Timelow asteriskTreatment interaction (F(2,42)=0.428;p=0.639). The VAS data yielded significant effects on priming-induced craving in high and low impulsive individuals similar to the Short-DAQ results (Fig. 4A and B, middle panels; See SI for full statistical analysis).

Fig. 4 Opens large image

Fig. 4

The monoamine stabilizer OSU6162’s ability to attenuate priming-induced craving in alcohol dependent individuals was driven by the individuals with high baseline impulsivity. Mean craving total score on the shortened version of the Desire for Alcohol Questionnaire (short-DAQ) and VAS craving item in (A) high and (B) low impulsive alcohol dependent individuals during the priming-induced craving session. (A) OSU6162 significantly reduced craving in the high impulsive alcohol dependent individuals compared to placebo during the priming-induced craving session, including craving after the first sip of alcohol (right panel). (B) No significant difference in craving was found at any time-point between the OSU6162- and placebo-treated group in the low impulsive alcohol dependent individuals. Data was collected at the following time-points: before drink, after the first sip, immediately after finishing the alcoholic beverage, as well as 5, 10, 25 and 40 minutes post consumption of the alcoholic beverage (the mean of the four latter time-points were defined as “post drink” measurements).Values are presented as mean±s.e.m; *p<0.05 and **p<0.01 compared to corresponding placebo.

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After the first sip of alcohol, the OSU6162-treated individuals with high, but not low, baseline impulsivity rated significantly lower on the VAS craving item compared to placebo (High:t(22)=2.9, Fig. 4A, right panel; Low:t(22)=−0.45, Fig. 4B, right panel). There was no significant difference between the treatment groups in any of the other VAS item assessed after the first sip of alcohol in neither the high nor the low impulsive individuals (Fig. 4A and B, right panels).

3.5. OSU6162 had no significant effect on drinking, craving or mood during treatment

During the 14- day-treatment-period, the OSU6162 group significantly reduced their drinking from 73 to 19 percent HDD (t(27)=9.9;p<0.001) paralleled by a significant reduction in serum PEth levels from 0.83 to 0.60 (t(27)=2.7;p=0.012). The placebo group significant reduced their drinking from 68 to 10 percent HDD (t(26)=15.9;p<0.001) and from 0.69 to 0.54 in serum PEth levels (t(26)=2.5;p=0.020). However, there were no statistically significant difference between treatment groups regarding change in percent HDD (OSU6162:−54.6±0.29; Placebo:−57.6±0.19; t(46.4)=−0.45;p=0.658), serum PEth levels (OSU6162:−0.23±0.45; Placebo:−0.15±0.31; t(48.4)=−0.77;p=0.447), PACS score (OSU6162:−4.9; Placebo:−4.2; t(53)=−0.541;p=0.591) or MADRS-S score (OSU6162:−3.6; Placebo:−2.9; t(53)=−0.641;p=0.524) during the treatment period. Finally, there were no significant treatment effects on any drinking, craving or mood outcomes during the treatment period when the participants were divided into high- and low-impulsive individuals (See SI for statistical details).

3.6. Side effects

The OSU6162 treatment was generally well tolerated without any reports of serious side effects and no significant difference in the frequency of side effect reports (e.g. headaches, gastrointestinal symptoms, fatigue and vertigo) compared to the placebo group (Table S2). Comparison of ECG at screening compared to test day showed that the OSU6162 group had significantly greater decrease in heart rate compared to the placebo group (OSU6162:−7.6; Placebo:−0.15; t(52)=−2.6; p=0.013). No significant difference in QTc changes was found between the treatment groups (OSU6162:−1.8 ms; Placebo:−3.9 ms; t(48)=0.32; p=0.752).

4. Discussion

The present human laboratory study is, to our knowledge, the first evaluation of the monoamine stabilizer OSU6162’s effect on clinically relevant alcohol use outcomes, such as craving, in alcohol dependent individuals. The main findings were that OSU6162, compared to placebo, significantly attenuated subjective ‘liking’ of the consumed alcohol and priming-induced craving, an effect driven by individuals with high levels of baseline impulsivity. Together with our previous results showing that OSU6162 attenuates alcohol-mediated behaviors in long-term drinking rats (Steensland et al., 2012), the present results indicate that pharmacological stabilization of the dopamine system might prove useful in modulating some of the reward driven behaviors in alcohol dependence and that OSU6162 might have potential as a novel medication for alcohol dependence.

OSU6162 had no significant effect on cue-induced alcohol craving, but significantly blunted priming-induced craving in dependent individuals. The lack of treatment effect on cue-induced craving could possibly be explained by the methodological challenges that subjective cue-craving response for alcohol is less robust than for other drugs of abuse (Lingford-Hughes et al., 2006). A significant decrease in subjective priming-induced craving as assessed by Short-DAQ was indeed observed following OSU6162 treatment compared to placebo, immediately after the participants had finished the alcoholic beverage. However, it should be noted that when the craving was assessed using a VAS, there was no significant effect (although a trend). The findings that OSU6162 blunted priming-induced craving as well as the liking of alcohol indicate that the dopamine stabilizing properties of this agent are evident when alcohol is consumed.

The mechanism behind OSU6162’s ability to attenuate alcohol-mediated behaviors in rodents (Steensland et al., 2012) and alcohol dependent individuals as presented in the current study is at present, not fully understood. It is possible that OSU6162 caused a general emotional blunting in a nonspecific manner. However, this is unlikely since OSU6162 had no significant effect on anxiety or arousal. Our previous microdialysis study showed that OSU6162 blunts alcohol-induced dopamine output in the nucleus accumbens of alcohol-naïve rats (Steensland et al., 2012), indicating that OSU6162 might have the potential to attenuate the rewarding properties of alcohol. This suggestion is supported by our present findings that OSU6162 attenuated the “liking” of the consumed alcohol. However, our more recent microdialysis study in long-term drinking rats (Feltmann et al., in press), indicates that OSU6162 rather might have the ability to counteract the hypo-dopaminergic state in the striatum associated with alcohol dependence (Narendran et al., 2014, Tupala et al., 2001, Volkow et al., 2007, Volkow et al., 1996). The different effects of OSU6162 treatment on the dopamine output in response to an alcohol-challenge in alcohol-naïve (Steensland et al., 2012) vs long-term drinking rats with an established hypo-dopaminergic state (Feltmann et al., in press), highlights OSU6162’s ability to stimulate or attenuate dopamine depending on the prevailing tone. OSU6162’s ability to stabilize dopamine activity is further supported by a PET study in Rhesus monkeys (Tedroff et al., 1998). Although, OSU6162’s stabilizing ability remains to be shown in humans, it is tempting to speculate that an OSU6162-induced normalization of an dopamine deficiency could possibly explain the present results showing that OSU6162 blunted priming-induced alcohol craving in dependent individuals, as dopamine deficiency has been suggested to drive craving and contribute to relapse (Koob, 2013).

In the present study we found that OSU6162’s ability to blunt priming-induced alcohol craving was found only in individuals with high baseline level of impulsivity. A neurobiological overlap between impulsivity and alcohol dependence has been suggested (Dick et al., 2010, Lejuez et al., 2010) and cortical dopamine deficits potentially related to long-term alcohol use, contributes to impaired impulse control in alcohol dependent individuals (Goldstein and Volkow, 2011, Stavro et al., 2012). Furthermore, the finding that both impulsivity trait and impaired response inhibition predict higher cue-induced alcohol craving (Papachristou et al., 2013) is supported by the present study showing that placebo-treated high impulsive participants, had a consistently higher rating of their baseline subjective craving (i.e. before being subjected to the cue- or priming-exposures), than the low impulsive. Thus, given the role of dopamine in regulating impulsive behavior and OSU6162’s unique pharmacological profile to regulate the dopamine activity based on the prevailing dopaminergic tone (Carlsson et al., 2004, Sonesson et al., 1994, Tedroff et al., 1998), it is possible that OSU6162’s more beneficial effects on craving in the high impulsive alcohol dependent individuals is explained by the function of a potential hypodopaminergic state in this specific group on individuals. This hypothesis is further supported by the findings that the OSU6162-treated high impulsive participants had a significantly lower rating of subjective craving compared to the placebo-treated also at baseline, i.e. before the start of the priming-session. The present results further suggest that alcohol dependent individuals with low dopamine levels are likely to experience greater impairments in impulse control and thus are more likely to benefit from a dopaminergic agent such as OSU6162. Although, the ability of OSU6162 to affect impulsivity per se needs to be investigated, previous studies show that modafinil improves neuropsychological task performance including stop signal reaction time task in health volunteers (Turner et al., 2003) as well as response inhibition (Schmaal et al., 2013), and prolonging time to relapse (Joos et al., 2013) in alcohol dependent individuals with high, but not low, baseline impulsivity (SSRT). Collectively, these results highlight the potential benefits of targeting the dopamine system in relation to impulsive behavior as well as indicate that impulsivity represents a clinically important phenotype in alcohol dependence, and needs to be taken into account when evaluating dopaminergic agents in this patient population.

Although, the present exploratory human laboratory study with a 14-day-treatment period was not designed to detect OSU6162’s effect on alcohol consumption, both OSU6162 and placebo treatment induced more than 50% reduction in heavy drinking days. The lack of significant differences between the OSU6162 and placebo groups is most likely attributed to the fact that participation in a research study per se has beneficial effects on the alcohol use (Weiss et al., 2008) and that a treatment period of at least three to six months is required to reliably establish the efficacy and verify the absence of drug tolerance of potential medications (European Medicines Agency, 2010). Indeed recent findings in patients with mental fatigue indicate the treatment effect of OSU6162 is slowly titrated up during the initial weeks of treatment and does not reach a maximal effect until after several weeks of treatment (unpublished findings from co-author Dr Carlsson). Nevertheless, in line with previous studies in other patient populations (Johansson et al., 2012, Kloberg et al., 2014, Tedroff et al., 1999) OSU6162 treatment was generally well tolerated and none of the participants dropped out of the study because of intolerable side effects. Thus, the present beneficial findings of safety and effects on alcohol craving render support for a larger placebo-controlled efficacy clinical trial to evaluate OSU6162’s effect on drinking outcomes.

In summary, this early Phase II human laboratory study in alcohol dependent individuals shows that the monoamine stabilizer OSU6162 was safe and well tolerated and attenuates priming-induced alcohol craving as well as liking, in a controlled laboratory environment. OSU6162’s effects were driven by individuals with high baseline levels of impulsivity, highlighting the importance of phenotyping baseline impulsivity when evaluating dopaminergic agents in alcohol dependent individuals. A larger placebo-controlled efficacy clinical trial is needed to further investigate the potential of OSU6162 as a novel medication for alcohol dependence.

Funding and Disclosure

Dr. Carlsson is the owner of A. Carlsson Research AB and co-inventor of a use patent for (-)-OSU6162. Dr. Carlsson declares no other biomedical financial interests or conflicts of interest. Authors Khemiri, Steensland, Guterstam, Beck, Franck and Jayaram-Lindström declare no biomedical financial interests or conflicts of interest.

Contributors

Lotfi Khemiri1, Pia Steensland1, Joar Guterstam1, Olof Beck2, Arvid Carlsson3, Johan Franck1*, Nitya Jayaram-Lindström1

1Department of Clinical Neuroscience, Division of Psychiatry, Karolinska Institutet, Stockholm, Sweden

2 Department of Medicine, Division of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden

3 Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

* corresponding author:

Lotfi Khemiri, M.D.

Pia Steensland, Ph.D.

Joar Guterstam, M.D.

Olof Beck, Ph.D

Arvid Carlsson, M.D., Ph.D.

Johan Franck, M.D., Ph.D.

Nitya Jayaram-Lindström, Ph.D.

Corresponding author:

Johan Franck

Karolinska Institutet

Department of Clinical Neuroscience

Division of Psychiatry

KS, Solna, R5:01

SE-17176 Stockholm

Sweden

E-mail: [email protected]

Fax: +46-8-12349602

Funding source

The study was financially supported by Karolinska Institutet’s Research Funds, the Research Council of the Swedish Alcohol Retailing Monopoly (FO2012-0053), the Torsten Söderberg Foundation (M203/12) and the Swedish Brain Foundation (FO2011-0106, FO2012-0083 and FO2013-0042).

Acknowledgments

The study was financially supported by Karolinska Institutet’s Research Funds, the Research Council of the Swedish Alcohol Retailing Monopoly ( FO2012-0053 ), the Torsten Söderberg Foundation ( M203/12 ) and the Swedish Brain Foundation ( FO2011-0106 , FO2012-0083 and FO2013-0042 ) all to PS. We thank PhD Anders Hammarberg for his significant input on the human laboratory design, research nurses Margareta Gard-Hedander and Else-Britt Hillner, psychologist Angela Stünkel and undergraduate student Maria Östman for excellent assistance in data collection and handling of study medication.

Appendix A. Supplementary material

Supplementary material

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