- Email: [email protected]
New findings concerning naltrexone treatment of alcoholism
s150
X08 Validation of animal models in schizophrenia
with treatment outcome. The most common new-onset adverse clinical events were diarrhea, headache, pruritus, gastroinestinal side effects and impairment of libido. Acamprosate was discontinued in 10 (2.3%) of patients because of adverse events, mainly diarrhea. 1 death occured during the study (status asthmaticus). Findings from a linear regression analysis conIirmed no significant effect of age, sex, level of education, marital status, living alone or not, a family history of alcoholism, the duration of alcoholism, and a baseline GGT value on the main criteria. The severity of alcohol dependence according to DSM-111-t’criteria was found to be associated with duration of abstinence (p = 0.003). Some variables of the NEO-FFI scales were found to be possibly associated with treatment outcome. Conclusions: The efficacy of acamprosate in reducing relapse rates in recently detoxified alcoholics has been demonstrated in a number of placebo-controlled double-blind studies. Alcohol research currently tries to link patient characteristics to treatment outcome. The “matching hypothesis” states that clients who are appropriately matched to treatments will show better outcomes. As in the Project Match study on different kinds of psychotherapy (The Project Match Research Group 1997a, b) no relevant differences concerning abstinence could be demonstrated for the different treatment groups. It seems noteworthy that the least intensive and structured (‘brief’) intervention in combination with pharmacotherapy also resulted in a favorable treatment outcome. This tinding suggests that at least a subgroup of alcohol dependent patients clearly benefits from a combination of phannacotherapy and brief intervention therapy. Alcohol history, severity of dependence and certain personality traits may be predictive of treatment outcome. References [l] al Quatari M, Bouchenafa 0, Littleton J. Mechanisms of action of acamprosate.
[2]
[3] [4]
[5]
Part II. Ethanol dependence modifies effects of acamprosate on NMDA receptor binding in membranes from rat cerebral cortex. Alcohol Clin Exp Res 1998; 22: 81&814 Project Match Research Group. Matching Alcoholism Treatments to Client Heterogeneity: Project MATCh Posttreatment Drinking Outcomes. J Stud Alcohol 1997a; 58: 7-29 Project Match Research Group. Project MATCH secondary a priori hypotheses. Addition 1997b; 92: 1671-1698 Sass H., Soyka M., Mann K., Zieglgiinsberger W. Relapse prevention by acamprosate: results from a placebo controlled study in alcohol dependence. Arch Gen Psychiatry 1996; 53: 673480 Soyka M. Relapse Prevention in Alcoholism: Recent Advances and Future Possibilities. CNS Drugs 1997; 7: 3 13-327
[s.o7.05]
New findings concerning alcoholism
naltrexone
treatment
of
M. Berghmd. Department of Clinical Alcohol Research, Lund University, Malmoe University Hospital, Malmoe, Sweden
Naltrexone treatment of substance use disorders has been increasingly used during the 90ies both in alcohol use disorders and in opiate disorders. The tirst part of the paper concerns treatment of opiate use disorders. Six randomized controlled studies have reported the effect of naltrexone maintenance therapy in opiate use disorders. The studies have in general reported positive effects. In addition, naltrexone has been used in two randomized controlled studies during rapid detox and two during ultrarapid detox of opiate dependence. The reported change of craving during naltrexone treatment in these studies is summarized. The second part of the paper presents data from previous naltrexone studies in alcohol use disorders. The early studies by Volpicelli et al. 1992 and by O’Malley et al. 1992 both reported impressive effect sizes around 30% fewer abusing alcoholics on active drug. Several new US studies support this tinding, while the results of two European studies have shown less convincing results. In these two studies psychosocial treatment “as usual” was used contrary to the US studies, in which cognitive behavior therapy, CBT, was used as one of the treatment alternatives. Prediction of positive effects has been presented in the early US studies including high level of craving and signs of cognitive dysfunction.
In the Swedish Naltrexone Study (Balldin, Berglund, Borg, Mansson et al., 1998) a design with randomization for naltrexone/placebo as well as for coping skill educational program (manual baaed)/treatment as usual was used. 120 alcoholics, 102 men and 18 women, attended the study. The treatment period was 6 months. The attrition rate was 23%. The percentage of heavy drinking days was lower in the CBT group versus the treatment as usual group (21 f 21% vs. 30 -f 7; p < 0.05). The percentage of days with heavy drinking in the placebo/CBT group was 25 f 22% and in the naltrexone/CBT group 16 f 20% (p < 0.05). In the treatment as usual group there was no difference between naltrexone and placebo. Reported craving was significantly lower in the Naltrexone CBT group compared with the other groups. The result of the Swedish Naltrexone Study was similar to the O’Malley study concerning alcoholics sampling alcohol. In a one-year follow-up the outcome was stable contrary to the O’Malley study supporting the importance of a six months treatment period. New positive findings concerning naltrexone treatment in the Swedish study is presented and compared with previous findings in Naltrexone studies both in opiate dependence and in alcohol dependence.
S.08 Validation of animal models in schizophrenia Js.08.011
Pharmacological models predicting antlpsychotic actions - what is their future use?
SO. Ggren. Department of Neuroscience, Karolinska Institute, Stockholm, Sweden Drug development during the past decade has been directed towards compounds (like clozapine) that are effectivs antipsychotic drugs with a low propensity to cause EPS including tardive dyskinesia and with efficacy in treatment resistant patients, e.g. atypical antipsychotic drugs. A combination of various experimental models has been used to characterize “atypical” antipsychotic properties in the rat (see bgren, 1996). A blockade of locomotor hyperactivity elicited by small doses of “DA agonists” such as d-amphetamine or apomorphine has been employed as an animal model for investigations of limbic DA functions and, thus, as a measure of therapeutic efficacy. This model is based on the hypothesis that stimulation of DA receptors within parts of the mesolimbic DA system, e.g. the nucleus accumbens, is at least partly responsible for the locomotor response. Other measures predictive of “antipsychotic” effects include inhibition of apomorphine-induced climbing, inhibition of the conditioned avoidance response (CAR) or a differential action in the paw test. Measures for the potential of inducing EPS have varied. The ability to induce catalepsy in relationship to potency in the “antipsychotic” test has_become a useful measure for assessment of the potential for EPS (Ogren 1996; Amt et al., 1997). Inhibition of oral stereotypies, e.g. gnawing, elicited by high doses of DA agonists such as apomorphine, although earlier used as a measure for antipsychotic effects, is today seen as an indicator of later motor side effects. The relevance of the use of direct or indirect DA agonists such as d-amphetamine as a behavioural model for the acute phase of schizophrenia, e.g. positive or paranoid forms has been extensively documented with classical and novel antipsychotic drugs. The neuropharmacological profile of novel antipsycotic compounds is summarized in Table I. Thus, both DA D2 antagonists such as remoxipride, sulpiride and amisulpiride as well as compounds with multitransmitter interactions such as quietipine, risperidone, sertindole, ziprasidone as well as clozapine and olanzapine are active in these behavioural model. Unlike haloperidol, the novel antipsychotic” drugs preferentially block behaviours associated with the mesolimbic DA system, e.g. locomotion over those associated with the nigrostriatal DA system, e.g. catalepsy. Thus, there exists a clear difference between the doses required to block DA agonist-induced hyperactivity and the doses causing catalepsy or the doses required to block stereotypies (bgren 1996; Amt et al., 1997). The inhibition of DA agonist-induced locomotion suggest a preferential blockade of limbic
X08 Validation of animal models in schizophrenia
with treatment outcome. The most common new-onset adverse clinical events were diarrhea, headache, pruritus, gastroinestinal side effects and impairment of libido. Acamprosate was discontinued in 10 (2.3%) of patients because of adverse events, mainly diarrhea. 1 death occured during the study (status asthmaticus). Findings from a linear regression analysis conIirmed no significant effect of age, sex, level of education, marital status, living alone or not, a family history of alcoholism, the duration of alcoholism, and a baseline GGT value on the main criteria. The severity of alcohol dependence according to DSM-111-t’criteria was found to be associated with duration of abstinence (p = 0.003). Some variables of the NEO-FFI scales were found to be possibly associated with treatment outcome. Conclusions: The efficacy of acamprosate in reducing relapse rates in recently detoxified alcoholics has been demonstrated in a number of placebo-controlled double-blind studies. Alcohol research currently tries to link patient characteristics to treatment outcome. The “matching hypothesis” states that clients who are appropriately matched to treatments will show better outcomes. As in the Project Match study on different kinds of psychotherapy (The Project Match Research Group 1997a, b) no relevant differences concerning abstinence could be demonstrated for the different treatment groups. It seems noteworthy that the least intensive and structured (‘brief’) intervention in combination with pharmacotherapy also resulted in a favorable treatment outcome. This tinding suggests that at least a subgroup of alcohol dependent patients clearly benefits from a combination of phannacotherapy and brief intervention therapy. Alcohol history, severity of dependence and certain personality traits may be predictive of treatment outcome. References [l] al Quatari M, Bouchenafa 0, Littleton J. Mechanisms of action of acamprosate.
[2]
[3] [4]
[5]
Part II. Ethanol dependence modifies effects of acamprosate on NMDA receptor binding in membranes from rat cerebral cortex. Alcohol Clin Exp Res 1998; 22: 81&814 Project Match Research Group. Matching Alcoholism Treatments to Client Heterogeneity: Project MATCh Posttreatment Drinking Outcomes. J Stud Alcohol 1997a; 58: 7-29 Project Match Research Group. Project MATCH secondary a priori hypotheses. Addition 1997b; 92: 1671-1698 Sass H., Soyka M., Mann K., Zieglgiinsberger W. Relapse prevention by acamprosate: results from a placebo controlled study in alcohol dependence. Arch Gen Psychiatry 1996; 53: 673480 Soyka M. Relapse Prevention in Alcoholism: Recent Advances and Future Possibilities. CNS Drugs 1997; 7: 3 13-327
[s.o7.05]
New findings concerning alcoholism
naltrexone
treatment
of
M. Berghmd. Department of Clinical Alcohol Research, Lund University, Malmoe University Hospital, Malmoe, Sweden
Naltrexone treatment of substance use disorders has been increasingly used during the 90ies both in alcohol use disorders and in opiate disorders. The tirst part of the paper concerns treatment of opiate use disorders. Six randomized controlled studies have reported the effect of naltrexone maintenance therapy in opiate use disorders. The studies have in general reported positive effects. In addition, naltrexone has been used in two randomized controlled studies during rapid detox and two during ultrarapid detox of opiate dependence. The reported change of craving during naltrexone treatment in these studies is summarized. The second part of the paper presents data from previous naltrexone studies in alcohol use disorders. The early studies by Volpicelli et al. 1992 and by O’Malley et al. 1992 both reported impressive effect sizes around 30% fewer abusing alcoholics on active drug. Several new US studies support this tinding, while the results of two European studies have shown less convincing results. In these two studies psychosocial treatment “as usual” was used contrary to the US studies, in which cognitive behavior therapy, CBT, was used as one of the treatment alternatives. Prediction of positive effects has been presented in the early US studies including high level of craving and signs of cognitive dysfunction.
In the Swedish Naltrexone Study (Balldin, Berglund, Borg, Mansson et al., 1998) a design with randomization for naltrexone/placebo as well as for coping skill educational program (manual baaed)/treatment as usual was used. 120 alcoholics, 102 men and 18 women, attended the study. The treatment period was 6 months. The attrition rate was 23%. The percentage of heavy drinking days was lower in the CBT group versus the treatment as usual group (21 f 21% vs. 30 -f 7; p < 0.05). The percentage of days with heavy drinking in the placebo/CBT group was 25 f 22% and in the naltrexone/CBT group 16 f 20% (p < 0.05). In the treatment as usual group there was no difference between naltrexone and placebo. Reported craving was significantly lower in the Naltrexone CBT group compared with the other groups. The result of the Swedish Naltrexone Study was similar to the O’Malley study concerning alcoholics sampling alcohol. In a one-year follow-up the outcome was stable contrary to the O’Malley study supporting the importance of a six months treatment period. New positive findings concerning naltrexone treatment in the Swedish study is presented and compared with previous findings in Naltrexone studies both in opiate dependence and in alcohol dependence.
S.08 Validation of animal models in schizophrenia Js.08.011
Pharmacological models predicting antlpsychotic actions - what is their future use?
SO. Ggren. Department of Neuroscience, Karolinska Institute, Stockholm, Sweden Drug development during the past decade has been directed towards compounds (like clozapine) that are effectivs antipsychotic drugs with a low propensity to cause EPS including tardive dyskinesia and with efficacy in treatment resistant patients, e.g. atypical antipsychotic drugs. A combination of various experimental models has been used to characterize “atypical” antipsychotic properties in the rat (see bgren, 1996). A blockade of locomotor hyperactivity elicited by small doses of “DA agonists” such as d-amphetamine or apomorphine has been employed as an animal model for investigations of limbic DA functions and, thus, as a measure of therapeutic efficacy. This model is based on the hypothesis that stimulation of DA receptors within parts of the mesolimbic DA system, e.g. the nucleus accumbens, is at least partly responsible for the locomotor response. Other measures predictive of “antipsychotic” effects include inhibition of apomorphine-induced climbing, inhibition of the conditioned avoidance response (CAR) or a differential action in the paw test. Measures for the potential of inducing EPS have varied. The ability to induce catalepsy in relationship to potency in the “antipsychotic” test has_become a useful measure for assessment of the potential for EPS (Ogren 1996; Amt et al., 1997). Inhibition of oral stereotypies, e.g. gnawing, elicited by high doses of DA agonists such as apomorphine, although earlier used as a measure for antipsychotic effects, is today seen as an indicator of later motor side effects. The relevance of the use of direct or indirect DA agonists such as d-amphetamine as a behavioural model for the acute phase of schizophrenia, e.g. positive or paranoid forms has been extensively documented with classical and novel antipsychotic drugs. The neuropharmacological profile of novel antipsycotic compounds is summarized in Table I. Thus, both DA D2 antagonists such as remoxipride, sulpiride and amisulpiride as well as compounds with multitransmitter interactions such as quietipine, risperidone, sertindole, ziprasidone as well as clozapine and olanzapine are active in these behavioural model. Unlike haloperidol, the novel antipsychotic” drugs preferentially block behaviours associated with the mesolimbic DA system, e.g. locomotion over those associated with the nigrostriatal DA system, e.g. catalepsy. Thus, there exists a clear difference between the doses required to block DA agonist-induced hyperactivity and the doses causing catalepsy or the doses required to block stereotypies (bgren 1996; Amt et al., 1997). The inhibition of DA agonist-induced locomotion suggest a preferential blockade of limbic