Studies of acamprosate for the treatment of alcohol dependence

Abstract: Alcohol dependence is a widespread psychiatric disorder with a prevalence of 4-6% in the adult population in western countries. Acamprosate (Calcium acetyl homotaurinate) is approved in many countries as a medication for the treatment of alcohol dependence. It is assumed that acamprosate modulates glutamate neurotransmission within the central nervous system (CNS). However, there are still uncertainties concerning some aspects of acamprosate treatment. The aim of this thesis was therefore to investigate the effect of acamprosate on certain correlates of alcohol dependence. In one experiment, 56 patients were treated for 21 days with acamprosate vs. placebo. A test battery was then administered by which subjective and physiological responses were measured following presentation of alcohol related stimuli (cue-induced craving) and/or following consumption of a small amount of alcohol (priming-induced craving) in alcohol dependent patients. The results showed that acamprosate attenuated priming-induced craving. Furthermore, acamprosate reduced the priming-induced elevation in plasma cortisol levels. There was also a negative correlation between acamprosate plasma levels and alcohol craving following a priming drink. No effect of acamprosate on cueinduced craving was observed. General craving responses and the correlation to alcohol consumption were also examined, together with neuroendocrine responses. The results showed that acamprosate attenuated general craving responses, and a strong correlation was found between craving and alcohol consumption. No treatment effects on neuroendocrine responses were found. A newly developed liquid chromatography mass spectrometry (LC MS) method was used to evaluate the pharmacokinetics of acamprosate in humans. The aim was to verify earlier pharmacokinetic data in addition to investigate the presence of acamprosate in the CNS. In a 21 days open label study, 13 healthy subjects provided plasma samples regularly and on the last day of treatment also a sample of cerebrospinal fluid (CSF). The results showed that steady state plasma levels of acamprosate was achieved within 5 days following start of treatment and remained above level of quantification for 3 days following termination of treatment. Acamprosate levels in the CSF were between 9 33 ng/mL, which is suggested to represent a pharmacologically relevant concentration. The efficacy of combining acamprosate with psychosocial intervention was investigated in alcohol dependent patients, using an extended psychosocial intervention (EPI) compared to a minimal psychosocial intervention (MPI) for 24 weeks in addition to acamprosate treatment. The results showed no differences between MPI and EPI on any drinking related measure. In conclusion, a potential mechanism by which acamprosate mediates its therapeutic effect may be by attenuating the urge to drink following an alcohol slip, and this effect may be dose-dependent. In addition, it was found that acamprosate modulates the hypothalamic pituitary adrenocortical (HPA) axis response and crosses the blood-brain barrier in humans. Finally, the results suggest that the addition of an intensive psychosocial treatment to concomitant acamprosate treatment does not add to treatment efficacy.