Nalmefene for treatment of alcohol dependence

Drug Evaluation

Nalmefene for treatment of alcohol dependence Michael Soyka & Susanne R€osner† †

Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by IBI Circulation - Ashley Publications Ltd on 10/27/10 For personal use only.

University of Munich, Psychiatric Hospital, Nussbaumstr. 7, D-80336 Munich, Germany

1.

Introduction

2.

Overview of the market

3.

Introduction to the compound

4.

Preclinical evidence

5.

Clinical findings

6.

Ongoing trials

7.

Regulatory affairs

8.

Conclusion

9.

Expert opinion

Importance of the field: Alcohol use and dependence are frequent disorders. Despite numerous established psychosocial approaches, relapse to heavy drinking is common in alcohol-dependent patients after detoxification and relapse prevention remains a significant medical challenge. Areas covered in this review: The opioidergic system plays a crucial role in mediating the rewarding effects of alcohol, in part by modulating dopaminergic neurotransmission in mesolimbic brain areas. This review will discuss the neurochemical basis of alcoholism with respect to the opiodergic system. Nalmefene is an alternate opioid receptor that also targets the kappa opioid receptors and thus offers a different treatment approach. The treatment studies conducted so far are discussed. What the reader will gain: We present a comprehensive overview of the implication of the opioidergic system in mediating the rewarding effects of alcoholism and the preclinical and clinical studies conducted so far with nalmefene. Take home message: Although the number of clinical studies conducted with naltrexone by far exceeds the number conducted with nalmefene, the four studies on nalmefene published so far may indicate a role of this opioid antagonist in the treatment of alcoholism. Results of some ongoing studies on nalmefene will provide additional data on its use for this indication. Keywords: alcohol, alcoholism, nalmefene, opioid antagonists, opioid receptors, therapy Expert Opin. Investig. Drugs (2010) 19(11):1451-1459

1.

Introduction

Alcohol dependence is defined by a cluster of somatic, psychological and behavioural symptoms. Prevalence estimates range between 7 and 10% in most Western countries [1-4]. A number of psychosocial and psychotherapeutic approaches are used in alcoholism, including cognitive-behavioural therapies, motivational enhancement, 12-step therapies and family therapy, among many others [5,6]. Despite the enormous number of affected patients and the costs resulting from non-treatment of alcoholism, few pharmacotherapies have been developed to reduce relapse risk or alcohol intake in alcoholism ([6-8], for a very recent update see [9]). Among so-called anticraving drugs, the putative NMDA modulator acamprosate and the opioid antagonist naltrexone have been shown to be effective in a substantial number of clinical studies and meta-analyses [6,9,10]. Acamprosate is indicated for relapse prevention of alcoholism and available in many countries worldwide. Its precise mechanism of action is still under investigation, but current evidence suggests a multiple mediation of effects, with modulations of the NMDA receptor being considered as the primary mechanism of action [11]. The opioid antagonists naltrexone (both the oral and depot form), naloxone and nalmefene are available for various clinical indications (Box 1). Multiple lines of evidence suggest that opioid receptors are implicated in the development of alcohol use and alcoholism [12]. Altered activity of mu-opioid receptor-mediated neurotransmission has been suggested as one of the key 10.1517/13543784.2010.522990 © 2010 Informa UK, Ltd. ISSN 1354-3784 All rights reserved: reproduction in whole or in part not permitted

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Box 1. Drug summary. Nalmefene III Alcohol addiction Opioid mu receptor antagonist Opioid kappa receptor antagonist Opioid receptor antagonist Route of administration Alimentary Chemical structure Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by IBI Circulation - Ashley Publications Ltd on 10/27/10 For personal use only.

Drug name Phase Indication Pharmacology description

H N

O

O

Pivotal trial(s)

O

[68,80,81,85]

Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).

mechanisms underlying the reinforcement of alcohol consumption and development of alcoholism [13-17]. Three major classes of opioid receptors have been characterized: mu (µ), kappa (k) and delta (d) opioid receptors [14]. Mu and kappa receptors are located in the grey matter of the spinal cord, limbic system, thalamus, ventral striatum and brainstem. Delta receptors are located throughout the grey matter of the telencephalon. Beta-endorphins are endogenous ligands for the mu and delta receptors, enkephalins for the delta receptors and dynorphins predominantly for the kappa receptors [18]. Mu receptors play an essential role in mediating the analgetic and euphoric effects of opioids as well as in respiratory depression, and very probably also in physical dependence. There are at least two subtypes of mu receptors (µ1 and µ2). The µ1 receptor subtype is linked to analgesia and euphoria, the µ2 subtype to respiratory depression [18]. Some 100 variants of the mu opioid receptor gene have been identified, with more than 20 producing amino acid changes and having polymorphic frequencies of more than 1% [19,20]. The most common SNP is A118G, which results in an amino acid exchange at position 40 from asparagine to aspartate [21]. Differences in opioid neurotransmission may influence the abuse liability to drugs of abuse. Results of studies in alcoholism are conflicting concerning the relevance of the functional variant 118G allele in exon 1 of the OPRM1 gene l, and most studies indicate that an association is not likely [22-27]. An association of the kappa-opioid system with alcohol dependence has been described [28]. More of clinical 1452

relevance, the polymorphisms of the OPRM1 gene may also moderate the effects of opioid antagonists on alcohol cue reactivity and response to treatment with opioid antagonists such as naltrexone [24,29-33]. Acute alcohol ingestion affects various transmitter systems in the brain. Besides its effects on the glutamatergic, the GABA and the dopaminergic system, alcohol stimulates the release of beta-endorphin, enkephalins and dynorphin in animal models and in humans [34-39]. Opioids in the paraventricular nucleus stimulate alcohol intake, as demonstrated by Barson et al. [40] in an animal model. Blockade of the opioid receptor has been shown to decrease alcohol intake [15,17,41,42]. Reinforcing effects of alcohol are mediated by the opioidergic system [43-45]. Betaendorphins and enkephalins, both endogenous ligands, were found to support self-administration [46,47]. Alcohol increases the release of dynorphin peptide in the ventral tegmental area and the amygdala [37] and of endorphin, which is linked to the rewarding effects of alcohol [37,48]. Alcohol-induced changes in the opioid system also have a modulatory influence on the mesocorticolimbic dopamine system [49]. Midbrain dopamine neurons in the ventral tegmental area and their projections to the nucleus accumbens in the ventral striatum are thought to support reward anticipation, reinforcement and motivational processes in general [50], effects mediated by endogenous opioid peptides. Alcohol induces the release of endogenous opioids, which are in part responsible for the positively reinforcing effects of alcohol [14]. The binding of endorphins to opioid receptors in the brain is assumed to be responsible for mediating pleasant and euphoric effects [51]. Thus the reinforcing effects of alcohol are in part attributed to interactions between opioid and dopaminergic signalling pathways, although the intercellular mediators of these interactions are poorly understood [52-54]. While the acute effects of alcohol on the opioidergic system appear quite clear, the long-term effects and changes are less well understood. The opioidergic system has been seen as a ‘hedonic’ system. Long-term changes may involve peptides [55], receptor densities and effector systems [56,57] and modifications of mRNA coding for both receptors and peptides [58-60]. Functional changes in the opioid system in chronic alcoholics have also been demonstrated in positron emission tomography (PET) studies which indicate a negative correlation between mu-opioid receptor binding and alcohol craving in recently abstinent alcohol-dependent people [61]. In addition findings by Heinz et al. [62] suggest that an increase of mu-opioid receptors in different regions of the brain, including the nucleus accumbens, correlates with the severity of alcohol craving [62], indicating a special role of mu-opioid receptors in the development of alcohol dependence. 2.

Overview of the market

Even though alcohol dependence is a frequent disorder with lifetime prevalence estimates of 7 -- 12.5% in Western

Expert Opin. Investig. Drugs (2010) 19(11)


€ sner Soyka & Ro

countries [1,3,4,63], very few medications are available to treat alcohol dependence. Thus, currently only a very small group of patients are treated with drugs for relapse prevention. There is no developed market for drug treatment of alcohol dependence. From various pharmacological agents that have been examined for their potential to support alcohol dependent patients in achieving abstinence or cutting down their alcohol consumption, only three substances were repeatedly shown to be effective: the glutamate antagonist acamprosate and the opioid antagonists naltrexone and nalmefene. Several meta-analyses have indicated that naltrexone decreases alcohol consumption [10], particularly in people with the Asp40 allele of the mu-opioid receptor [32,64]. Key problems with naltrexone are the relatively poor compliance of patients and the adverse events experienced [65-67]. 3.

Introduction to the compound

Nalmefene is an opioid receptor antagonist indicated in the management of known or suspected opioid overdose for the complete or partial reversal of opioid drug effects, including respiratory depression, induced by either natural or synthetic opioids. The drug is used in other indications, including opioid dependence, pathological gambling and alcoholism, but is currently without FDA approval for treatment of alcohol dependence. Chemistry and pharmacology Nalmefene is an antagonist at the mu- and delta-opioid receptor and a partial agonist at the kappa receptor (BioTie Therapies) and has been studied for use in substance use disorders, especially alcoholism, since the 1990s. Nalmefene has a similar chemical structure to naltrexone but was proposed to offer a number of potential advantages relative to naltrexone [68], including a more effective binding to central opioid receptors [69,70], a higher bioavailability [71,72] and the absence of a dose-dependent association with liver toxicity [68]. There is no evidence of significant activity at any other receptor type. Nalmefene is a potent antagonist at the opioid receptor [69,73]. Nalmefene and naltrexone have similar molecular weights and pharmacokinetic profiles but differing specificities for the three opioid receptor subtypes at low doses. Naltrexone is primarily selective for the mu-opioid receptor subtype while nalmefene is primarily selective for the muand kappa-opioid receptor subtypes [74,75]. Nalmefene is an antagonist at the mu- and at the kappa-opioid receptor. The kappa-opioid system has a role in mediating motivational aspects in alcohol dependence. Preclinical data indicate that kappa-opioid receptor antagonism decreases dependence-induced alcohol self-administration [76]. In alcohol-dependent rats nalmefene was found to be significantly more effective in suppressing alcohol intake than naltrexone [76]. The results were suggestive of the kappa-opioid receptor antagonism selectively decreasing alcohol self-administration. The effect of nalmefene on kappa 3.1

receptors is not fully understood: nalmefene induced an elevation in serum prolactin in healthy volunteers, while binding assays confirmed nalmefene’s affinity for kappa-opioid receptors [74]. The elevation in serum prolactin was interpreted as a partial agonist effect at kappa-opioid receptors [70]. Recent data from an animal model (mice) indicate that the in vivo pharmacology of nalmefene is similar to that of naloxone and naltrexone [77]. Nalemefene was found to have a slower onset and longer duration of action than naltrexone. Pharmacokinetics and metabolism Ingman et al. [70] used PET with the opioid receptor ligand (11C) carfentail to study the pharmacokinetics of a clinically effective dose of nalmefene (20 mg) after single and 7-day repeated dosing in 12 healthy volunteers. Ventral muopioid receptor occupancy was measured 2, 26, 50 and 74 h after completion of each dosing schedule. The results indicated that nalmefene was rapidly absorbed in all subjects. Mean half-life was 13.4 h after single and repeated dosing. Nalmefene thus has linear pharmacokinetics. Receptor occupancy was high (87 -- 100%) 2 h after both dosing schedules and also after 26 h (83 -- 100%). After 50 h receptor occupancy was still 48.4 -- 72.0% while nalmefene plasma concentration was very low. These results suggest a slow dissociation of the drug from the mu-opioid receptor. Previously, a clearance half-life of 28.7 ± 5.9 h has been reported for central opioid receptors and a plasma elimination half-life of 8.30 ± 0.34 h [78]. Oral nalmefene may block receptors for longer and have a longer half-life over 24 h than naltrexone [70-72,79]. Tolerance of single doses of 20 -- 300 mg daily or 10 -- 40 mg twice daily are usually well tolerated [71,80]. There is no evidence of any serious adverse drug reactions in hepatic or other body systems. Nalmefene is rapidly absorbed [76]. 3.2

Dosing issues The studies discussed below used very different dosages of nalmefene (see Table 1). Anton et al. [81] studied 5, 20 and 40 mg in a double-blind comparison with placebo over a 12-week treatment period in 270 recently abstinent alcoholdependent outpatients. Although more subjects in the nalmefene groups terminated the trial early secondary to adverse events, the rates did not differ significantly from those for placebo. The 20 mg group experienced more insomnia, dizziness and confusion, while the 5 mg group also showed more dizziness and the 40 mg group more nausea than the placebo group. Most symptoms were mild and improved over time. Outcome parameters concerning alcohol intake did not differ between groups. Anton et al. [81] concluded that nalmefene was “reasonably well tolerated” in recently abstinent alcoholics. 3.3

4.

Preclinical evidence

Nalmefene was found to reduce alcohol consumption in animal models [12,82]. Walker and Koob [76] studied the effects


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Table 1. Design and outcomes of randomised clinical trials on nalmefene for drinking problems. Ref.

Country

N

Dosing (mg/day)

Treatment (weeks)

Reduction of heavy drinking

Reduction of number of drinking days

Reduction in number of drinks per drinking day

[80]

USA

21

0, 10, 40

12

n.s.

n.s.

[68] [81] [84]

USA USA Finland

105 270 403

0, 20, 80 0, 5, 20, 40 0, 10 -- 40

12 12 28

p £ 0.05 (40 mg group only) p £ 0.05 n.s. p £ 0.01

n.s.

n.s.

p £ 0.05

p £ 0.05

n.s.: Not significant (p > 0.05).

of naltrexone, nalmefene and nor-binaltorphimine on alcohol consumption in nondependent and dependent rats and showed that nalmefene was significantly more effective at suppressing ethanol intake than naltrexone in ethanoldependent animals, while in a human study, nalmefene was equally effective as naltrexone in reducing subjective responses to alcohol in non-treatment-seeking alcoholics [83]. The effects of nalmefene on craving and further subjective responses to alcohol-related cues were assessed in a clinical laboratory study [83,84]. Non-treatment-seeking alcoholics (n = 125) and social drinkers (n = 90) were randomly assigned to receive nalmefene (titrated to 40 mg per day), naltrexone (titrated to 50 mg per day) or placebo for 7 days before they attended an alcohol challenge clinical laboratory session in which an alcoholic drink was provided in a bar-like setting. Effects on subjective responses were measured before subjects had free access to alcohol. It was shown that social drinkers consumed less alcohol than alcohol-dependent subjects during the laboratory choice consumption paradigm and attained lower blood alcohol levels than the alcohol-dependent group following the priming drink. Both nalmefene and naltrexone reduced craving, drinking amounts and frequency to a similar extent among the alcohol-dependent group, while no effects were observed in the social drinker group, relative to placebo. The findings of this laboratory trial indicate that nalmefene is as effective as naltrexone in diminishing drinking-associated reactions in people dependent on alcohol. 5.

Clinical findings

To date, four randomised controlled trials have been published that evaluated the effectiveness and safety of oral nalmefene for the treatment of alcohol dependence and heavy drinking [68,80,81,85]. In a first pilot study with a small sample size [80], 21 alcohol-dependent subjects were randomly assigned to 12 weeks of double-blind treatment with 40 mg nalmefene, 10 mg nalmefene or placebo (seven patients per treatment group). Concurrently, patients were referred to Alcoholics Anonymous (AA) support groups and encouraged to attend psychosocial therapies, while no such treatment was provided in the study. Compared with placebo, nalmefene significantly decreased the number of drinks per drinking day in both dosing groups (p £ 0.05). An additional effect on 1454

heavy drinking--defined as drinking more than 5 standard units (SU) of alcohol per day for men and 4 for women--was observed in the higher (40 mg) dosing group (p £ 0.05), while there was a trend towards a higher proportion of abstinent days in the nalmefene groups (p = 0.09). The opioid antagonist was well tolerated, and no serious adverse drug reactions occurred. The promising results from the first pilot study were confirmed by a further single-centre trial by the same research group [68]. After a 2-week, single-blind run-in period and a 1-week dose titration period, starting with an initial dose of 0.5 mg per day, 105 patients were enrolled to receive 80 mg of nalmefene (n = 35), 20 mg of nalmefene (n = 35) or placebo (n = 35). During the 12-week treatment with nalmefene, weekly cognitive behavioural therapy was additionally provided. In this trial, significant effects on rates of heavy drinking were shown in both dosing groups (p = 0.23). Heavy drinking rates were also found to be significantly reduced (p £ 0.05) when the analysis was limited to the sampler subgroup, indicating that non-abstinent patients (who had at least one drink during the trial) also benefit from treatment to a similar degree. Differences in other outcomes, such as percentage of abstinent days (p = 0.48) and the number of drinks consumed per drinking day (p = 0.06), were not statistically significant. There was no evidence of hepatotoxic side effects or serious adverse drug experiences, and the occurrence of specific adverse drug experiences did not differ between the 20 mg and 80 mg nalmefene groups. The authors concluded that the comparatively high patient drop-out rate in the 80 mg dosing group indicates that a lower dosing of 20 to 40 mg per day may be preferable. Furthermore, the absence of dose-dependent differences in efficacy might indicate ceiling effects [68]. The results of a first multicentre trial on nalmefene [81] did not find significant effects for nalmefene on drinking outcomes. The trial evaluated three doses of nalmefene (5, 20 and 40 mg) in a double-blind comparison with placebo over a 12-week treatment period in 270 recently detoxified alcohol-dependent subjects. Motivational enhancement therapy with individualized treatment goals of total abstinence or drinking reduction was provided twice during the first several weeks of treatment, then again at weeks 6 and 12 of the trial. Although all subjects--irrespective of group



€ sner Soyka & Ro

allocation--showed a reduction in heavy drinking days, craving and gamma-glutamyl transferase and carbohydratedeficient transferrin concentrations over the course of the trial, there were no significant effects for nalmefene compared with placebo at any tested dose or for any of the outcome measures. While the time to the first heavy drinking days more than doubled in the pooled nalmefene dosing groups (median: 9 days) compared with placebo (median: 4 days), this effect did not reach statistical significance (p = 0.28). The rate of treatment adherence (90%) and adverse event reporting indicated that nalmefene was reasonably well tolerated. Although there were more symptoms of mild-tomoderate nausea, insomnia and dizziness in the nalmefene groups than in the placebo group, these adverse experiences did not result in excessive trial termination. In contrast to the multicentre trial described above, in a multicentre randomised, controlled trial performed at 15 specialized alcohol treatment centres and private general practices in Finland targeted nalmefene was shown to have significant effects on various drinking outcomes in a sample of heavy drinkers [85]. A total of 403 subjects were enrolled in the trial and instructed to take between 10 mg and 40 mg of nalmefene (n = 242) or placebo (n = 161) during the 28-week treatment period when they considered drinking to be imminent. Concomitant psychosocial intervention was minimal and no treatment goals were imposed. The trial subjects were regular or heavy drinkers, the majority drinking heavily (‡ 5 SU for men, ‡ 4 SU for women) on more than 70% of days, with 93% of the subjects meeting the Diagnostic and Statistical Manual (DSM)-IV criteria for alcohol dependence. During the treatment period, alcohol consumption decreased considerably in the nalmefene and control groups, the reduction was significantly greater in the former. Significant effects were shown for the risk of heavy drinking (p < 0.01) and the levels of serum alanine aminotransferase (p < 0.01) and gammaglutamyl transferase (p < 0.01). The most common adverse events associated with nalmefene were nausea, insomnia, fatigue, dizziness and alcoholic hangover. A post hoc analysis of this trial [86] was performed with the aim to assess the influence of opioid receptor gene polymorphisms (OPRM1, OPRD1, OPRK1) on the therapeutic response of heavy drinkers to nalmefene. The analysis did not identify main or moderating effects of the genotypes on drinking outcomes, in contrast to the results from naltrexone studies in which the Asn40Asp polymorphism in OPRM1 was shown to significantly determine the treatment response of alcohol-dependent patients [31,32]. Nalmefene has also been studied in pathological gambling. In a 16-week, dose-ranging, multicentre trial [87], 207 subjects with a DSM-IV diagnosis of pathological gambling were randomly assigned to receive nalmefene (25 mg, 50 mg or 100 mg per day) or placebo. Of the subjects who received 25 mg of nalmefene, 59.2% were rated as ‘much improved’ or ‘very much improved’ at the last evaluation, compared with 34.0% of those who received placebo. Low-dose

nalmefene was associated with few adverse events, while doses of 50 mg or more resulted in intolerable side effects including nausea, dizziness and insomnia. 6.

Ongoing trials

There are several ongoing Phase III trials to support a European centralized registration of nalmefene. The Safety of Nalmefene in Patients With Alcohol Dependence (SENSE) trial is evaluating the long-term safety and tolerability of as-needed use of 20 mg nalmefene versus placebo over 52 weeks in 677 patients with alcohol dependence (ClinicalTrials.gov identification number: NCT00811941). Patient enrolment for this trial was completed in 2009 and the estimated completion date of the trial is December 2010. The Efficacy of Nalmefene in Patients With Alcohol Dependence (ESENSE1 and ESENSE2) trials are currently being conducted to assess the efficacy and safety of as-needed use of nalmefene (20 mg) versus placebo in decreasing monthly heavy drinking days and decreasing total consumption over 24 weeks in adult patients with alcohol dependence (ClinicalTrials.gov identification numbers: NCT00812461 and NCT00811720). Atotal of 600 patients have been enrolled in the trials, and the estimated completion date of the trial is December 2010. Two further trials that evaluated the effectiveness and safety of nalmefene in smoking cessation (ClinicalTrials.gov identification number: NCT00202696) and pathological gambling (ClinicalTrials.gov identification number: NCT00132119) have recently been completed. 7.

Regulatory affairs

An EU filing is expected in 2011. A UK registration filing was withdrawn in June 2007 to enable submission of an EU filing. 8.

Conclusion

Most available evidence from clinical trials suggests that nalmefene is an effective and safe treatment strategy for reducing heavy drinking in alcohol-dependent subjects. The nonsignificance of effects found in the trial by Anton et al. [81] might be caused by between-centre variations in the multicentre design. An increase in random error due to the higher variability of treatments, patients and trial procedures in multicentre trials has already been assumed as a reason for finding smaller treatment effects in multicentre trials on naltrexone than in single-site studies [88]. A further cause for the divergence of results may be the high placebo response in the trial by Anton et al. [81], which might be attributed to either the psychosocial intervention or the selection of subjects, who were highly motivated to alter their alcohol consumption. Further research is necessary to identify patient and treatment characteristics that have a significant effect on the clinical effectiveness of nalmefene. The lower tolerability of


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nalmefene in the 80 mg nalmefene groups and the effectiveness of the drug in lower dosing groups suggest that the 20 -- 40 mg per day range may be preferable for treating alcohol dependence with nalmefene. The effectiveness of nalmefene when accompanied by minimal psychosocial support indicates that the drug is a suitable treatment option for alcohol-dependent patients with low motivation to participate in or adhere to psychosocial treatments. 9.

Expert opinion

There is a sound rationale for the use of opioid antagonists in alcoholism. Nalmefene is an interesting drug for the treatment of substance use disorders, predominantly alcoholism, since it affects not only the mu- but also the kappa-opioid receptors and thus has a different mechanism of action from the extensively studied competitor, naltrexone. The halflife and mode of application are similar to those of naltrexone. Some but not many preclinical studies have been performed and indicate a therapeutic effect of nalmefene; to date results from four randomized clinical trials on a total of some 600 patients have been published and indicate a significant effect on outcome criteria in alcohol dependence. Some clinical trials essential for the drug approval process are ongoing. These results are needed to allow definite conclusions to be

drawn about nalmefene’s efficacy in alcohol dependence. The few data on gambling are inconclusive, and gambling itself may not be a central target for novel pharmacotherapies. Still, it is interesting to study drugs like nalmefene in areas other than alcoholism. The central question is whether nalmefene has substantial advantages over naltrexone in treatment of alcohol dependence. Since no studies have directly compared the two drugs it remains unclear whether nalmefene offers advantages over naltrexone in efficacy or side-effect profile. Nevertheless, the drug is one of the very few novel developments in the pharmacotherapy of alcoholism that is likely to enter clinical use [6,9] and thus deserves much further attention.

Acknowledgements The authors thank J Klesing, ELS, for editing assistance with the manuscript.

Declaration of interest Within the previous five years, M Soyka has received research or travel grants from Sanofi Aventis, Essex Pharma, Eli Lily, Prepharm and AstraZeneca. The other author has no conflict of interest.

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Affiliation

Michael Soyka1,2 & Susanne R€osner†1 † Address for correspondence †1 University of Munich, Psychiatric Hospital, Nussbaumstr. 7, D-80336 Munich, Germany E-mail: [email protected] 2 Private Hospital Meiringen, Directorate, Willigen, Meiringen, 3860, Switzerland E-mail: [email protected]

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