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Rimonabant is a cannabinoid type 1 receptor (CB1) antagonist formerly used to treat obesity, but which was withdrawn from the market in late 2008 because of its association with psychiatric adverse effects such as depression and anxiety. Previously, we showed that a single dose of rimonabant produced a negative bias on an emotional word memory task, in the absence of subjective mood effects. The present study investigated whether a similar effect on emotional processing could be seen after 7 days’ daily treatment with rimonabant 20 mg, using a randomized, placebo-controlled, between-subjects design in healthy volunteers (final n = 21). In comparison with placebo, rimonabant induced a negative bias on a memory recognition task without producing a change in subjective mood. This raises the possibility that the depressogenic effects of rimonabant may be linked to emotional memory biases, and that such biases may be detectable in the absence of subjective mood changes. Investigating such effects could be useful in detecting adverse psychiatric effects of novel treatments. [ABSTRACT FROM PUBLISHER]

Rationale: The psychotomimetic effects of cannabis are believed to be mediated via cannabinoid CB1 receptors. Furthermore, studies have implicated CB1 receptors in the pathophysiology of schizophrenia. Objective: These studies investigated the effects of the CB1 receptor antagonist, AVE1625, in acute pharmacological and neurodevelopmental models of schizophrenia. AVE1625 was administered to rodents alone or as a co-treatment with clinically used antipsychotic drugs (APDs). Methods: The antipsychotic potential of AVE1625 was tested using psychotomimetic-induced hyperactivity and latent inhibition (LI) deficit models. The procognitive profile was assessed using hole board, novel object recognition, auditory evoked potential, and LI techniques. In addition, the side-effect profile was established by measuring catalepsy, antipsychotic-induced weight gain, plasma levels of prolactin, and anxiogenic potential. Results: AVE1625 (1, 3, and 10 mg/kg ip), reversed abnormally persistent LI induced by MK-801 or neonatal nitric oxide synthase inhibition in rodents, and improved both working and episodic memory. AVE1625 was not active in positive symptom models but importantly, it did not diminish the efficacy of APDs. It also decreased catalepsy and weight gain induced by APDs, suggesting that it may decrease APD-induced extrapyramidal side effects (EPS) and compliance. Unlike other CB1 antagonists, AVE1625 did not produce anxiogenic-like effects. Conclusions: These preclinical data suggest that AVE1625 may be useful to treat the cognitive deficits in schizophrenia and as a co-treatment with currently available antipsychotics. In addition, an improved side-effect profile was seen, with potential to ameliorate the EPS and weight gain issues with currently available treatments. [ABSTRACT FROM AUTHOR]

Emotional processing measures are sensitive to acute administration of clinically useful antidepressant drugs. We wished to test the hypothesis that these models would also be able to detect agents likely to cause depression as an adverse effect. The anti-obesity drug and cannabinoid type 1 receptor antagonist, rimonabant, is associated with significant rates of depression and anxiety in clinical use. Thirty healthy adult volunteers were randomly assigned to receive a single dose of rimonabant (20 mg) or lactose placebo in a double-blind, between-groups design. Three hours after medication administration, subjects undertook an emotional processing test battery including facial emotion recognition, emotional word attentional dot probe, self-relevant word classification, emotional and declarative memory and the emotion-potentiated acoustic startle response. Subjective state was assessed via self-report measures. A single dose of rimonabant did not alter subjective mood. However, rimonabant selectively reduced incidental recall of positive self-relevant adjectives, an effect contrary to that seen following the administration of antidepressants. There were no effects of rimonabant on the other measures of emotional processing. These results suggest that a single dose of rimonabant decreases positive emotional memory in the absence of changes in subjective state. Further studies are required to examine whether rimonabant might produce a wider range of negative emotional biases with repeated treatment. [ABSTRACT FROM AUTHOR]