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Effect of different antipsychotic medications on craving related brain activity in patients with schizophrenia and cannabis abuse or dependence: a randomized controlled study comparing clozapine and risperidone

Projectomschrijving

Effect van medicatie op de behoefte aan cannabis
Al sinds 1994 doet het AMC onderzoek naar de comorbiditeit, het samengaan, van schizofrenie en cannabisverslaving. Ook de invloed van medicatie op beide aandoeningen is onderzocht. Er zijn aanwijzingen dat antipsychotica invloed hebben op de hunkering naar cannabis. Zij hebben namelijk invloed op de dopaminereceptor in de hersenen, die een rol speelt bij gevoelens van alertheid en je lekker voelen. Mensen kunnen zich door een antipsychoticum vlakker en minder prettig voelen. En juist dat kan het opsteken van een joint stimuleren.

Doel
Het doel van het project is het onderzoeken van de werking van twee soorten antipsychotica en hun invloed op de hersensystemen. Hebben de antipsychotica effect op de behoefte aan cannabis? En beïnvloeden ze de activiteit van hersengebieden die zijn betrokken bij hunkering en beloning?

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Samenvatting van de aanvraag

Cannabis abuse and cannabis dependence in patients with schizophrenia occur more frequently than in the general population and are associated with the following adverse outcomes: lower treatment adherence, more severe psychotic symptoms, higher frequency of psychotic episodes, and higher hospitalization rates. Until now, effective treatment of cannabis abuse and dependence has proved to be difficult in patients with schizophrenia. In most studies, antipsychotic medications with high affinity for the dopamine D2 receptor have even been found to increase craving for cannabis. The ratio of striatal D1/D2 occupancy by antipsychotic drugs may also be relevant, since D1 receptors mediate reward function (Miller et al. 1990). Clozapine has a relatively low affinity for the dopamine D2 receptor and relatively high affinity for D1 receptors, and has been associated in some correlational studies with reduced substance use in patients with schizophrenia. However, clear evidence for clozapine’s superiority in the treatment of schizophrenia and cannabis abuse and dependence is lacking (Lange et al., 2005, Green 2005) and very little is known about possible underlying mechanisms of the positive effects found in correlational studies (Green et al. 2003). Craving is regarded to be a central phenomenon that contributes to the continuation of cannabis use and to relapse in cannabis use after a period of abstinence. Three partly overlapping craving mechanisms, associated with dopaminergic neurotransmission, have been distinguished: (1) “chronic craving or anhedonia”, referring to the relative insensitivity to non-drug rewards; (2) “attentional bias”, referring to the underlying attentional focusing on drug cues as a prerequisite for motivational behaviour; and (3) “cue elicited craving”, referring to the high motivation to use cannabis elicited by drug-related stimuli. Large scale randomized controlled trials (RCT) to study the efficacy of clozapine in reducing cannabis abuse are difficult to conduct and pharmaceutical companies do not support these studies since clozapine is long off patent. Therefore we propose to conduct a relatively small RCT comparing the effect of clozapine and risperidone (a new generation dopamine D2 antagonist with relatively high D2 receptor affinity and low affinity for D1 receptors) on functional craving pathways in cannabis abusing or dependent patients with schizophrenia. Specific cognitive tasks will be used to test the different craving pathways and the associated brain activation patterns will be assessed with functional Magnetic Resonance Imaging (fMRI). We hypothesize that cannabis craving pathways are differentially modified by clozapine and risperidone: clozapine-treatment is associated with an increase in brain activation in brain areas associated with chronic craving compared to risperidone-treatment, whereas both clozapine-treatment and risperidone-treatment have comparable favourable effects on brain activation in areas associated with attentional bias and cue elicited craving. When these hypotheses are supported by our findings, the net result of clozapine treatment may be a favourable effect on subjective craving and drug use compared to risperidone treatment, since clozapine has a superior effect on one functional craving pathway. The proposed study will provide the necessary scientific basis for a decision regarding the need for a full-scale randomized controlled trial with relapse in cannabis abuse and long-term functioning as the primary outcomes. Moreover, the proposed study will enhance our understanding of underlying mechanisms for the effect of antipsychotic treatment in the reduction of anhedonia, attentional bias and craving in cannabis abusing and dependent patients with schizophrenia and schizophrenia-like disorders.

Onderwerpen

Kenmerken

Projectnummer:
31160007
Looptijd: 100%
Looptijd: 100 %
2008
2013
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. L. de Haan
Verantwoordelijke organisatie:
Amsterdam UMC - locatie AMC