Ziprasidone (ZPD) is an atypical antipsychotic drug (APD) that has been shown to fully substitute in C57BL/6 mice for the discriminative stimulus properties of the atypical APD clozapine (CLZ). In rats, however, it has failed to substitute for either 1.25 mg/kg or 5.0 mg/kg training doses of CLZ. Here the discriminative stimulus properties of ZPD were examined by training 19 adult male Sprague-Dawley rats to discriminate 2.0 mg/kg ZPD from vehicle in a two-lever drug discrimination procedure (ED50 = 0.07 mg/kg). The atypical APD CLZ produced full substitution (ED50 =0.76 mg/kg), as did the atypical APDs zotepine (ED50 = 0.63 mg/kg), olanzapine (ED50 = 0.25 mg/kg), quetiapine (ED50 = 0.93 mg/kg), and risperidone (ED50 = 0.09 mg/kg). The 5-HT2A antagonist ritanserin also fully substituted for ZPD (ED50 = 1.27 mg/kg). Partial substitution (2A/B/C receptors play an important role in the discriminative stimulus properties of ZPD and perhaps the ratio of binding to 5-HT2A/B/C and D2 receptors. While it will be necessary to test additional APDs, these initial findings suggest that ZPD drug discrimination may be a useful model to differentiate atypical from typical APDs.

No / Rationale: Weight gain caused by some antipsychotics is not only confined to adults but can also adversely affect both children and adolescents. Indeed, olanzapine and risperidone have been associated with extreme weight gain in adolescents even greater than that reported in adults. We have recently shown substantial weight gain in adult female rats following treatment with olanzapine and risperidone but not ziprasidone. Objectives: The aim of the present study was to compare the effects of several antipsychotics on weight gain and reproductive function in juvenile (aged 7 weeks) female hooded Lister rats. Methods: Olanzapine (4 mg/kg), risperidone (0.5 mg/kg), ziprasidone (2.5 mg/kg), sulpiride (10 mg/kg), haloperidol (0.5 mg/kg) or vehicle was administered i.p. once per day for 21 days. Body weight, food and water intake were measured daily, in addition to the determination of stage of the oestrous cycle. Results: Sub-chronic administration of olanzapine, risperidone, sulpiride and haloperidol, but not ziprasidone, significantly increased body weight compared to vehicle-treated animals during weeks 1-3. Sulpiride significantly increased food and water intake. Significantly increased percentage intra-abdominal fat weight was observed in olanzapine, risperidone, sulpiride and haloperidol, but not ziprasidone-treated animals. Marked disruption of the oestrous cycle was observed in all but the ziprasidone-treated group, which continued to have regular 4-day oestrous cycles. Conclusions: Weight gain observed in these juvenile animals was 1.5-2 times greater than that previously observed in adult rats. These findings have important implications for the use of antipsychotics in children and adolescent patients.

Bien que les troubles cognitifs soient un aspect essentiel de la schizophrénie, le dysfonctionnement des systèmes émotionnels y est également considéré comme un élément très important de cette maladie d’autant plus que plusieurs régions du cerveau sont concernées par la régulation émotionnelle. Le principal objectif du présent travail était d’explorer, en imagerie par résonnance magnétique fonctionnelle (IRMf), l’effet de la ziprasidone sur les différentes réponses neuronales à l’affichage de stimuli émotionnels au niveau de la région préfrontale,particulièrement dans le cortex cingulaire antérieur [CCA], le cortex orbito-frontal [COF] et le cortex préfrontal dorso-latéral [CPFDL]. Nous avons examiné les activations cérébrales, chez des patients souffrants de schizophrénie avant et après médication à la ziprasidone, en leur présentant des séries d’images émotionnellement chargées (négatives, neutres et positives) associées à différentes instructions quand aux types d’images qu’ils devaient sélectionner (négatives,neutres et positives). Nous avons analysé les différents changements d’activation (avant et après médication) essentiellement pour les valences extrêmes des stimuli (positives et négatives), ensuite nous avons regardé l’effet du type d’instruction sur ces changements. L’échantillon comprenait 13 patients atteints de schizophrénie et 15 témoins sains. Nous avons également effectué une évaluation clinique des symptômes dépressifs, positifs et négatifs de la maladie ainsi que des mesures biochimiques et de poids avant et après 16 semaines de médication. Malgré l’absence de changement significatif sur les mesures cliniques (PANSS et Dépression) avant et après une moyenne de 14.3 semaines de médication à la ziprasidone, plusieurs régions préfrontales (CCA, COF, CPDL) ont sensiblement accru leur réponse aux stimuli positifs par rapport aux stimuli négatifs. En outre, dans les régions habituellement impliquées dans le contrôle cognitif (CCA et CPFDL), cette tendance s'est accentuée lorsque les patients ont été invités à ne sélectionner que les stimuli négatifs (effet du type d’instruction). Nous avons également trouvé plusieurs similitudes dans le fonctionnement préfrontal (à la fois dans le volume et la force d'activation) entre les contrôles sains et les patients après médication en tenant compte du type d’instruction plus que de la valence émotionnelle des images. Pour conclure, les résultats de la présente étude suggèrent que le traitement antipsychotique avec la ziprasidone améliore le fonctionnement cognitif lié au traitement de l'information émotionnelle dans le cortex préfrontal chez les patients souffrant de schizophrénie. Étant donné le mécanisme d'action neuro-pharmacologique de la ziprasidone (plus d'affinité pour la sérotonine que pour les récepteurs de la dopamine dans le cortex préfrontal), nous pensons que nos résultats démontrent que le contrôle cognitif et la régulation des réactions face à des stimuli émotionnellement chargés dans la schizophrénie sont liés à une plus forte concentration de dopamine dans les voies préfrontales. / Objective We assessed psychological and neuronal manifestations associated with cognitive processing of emotional visual stimuli among schizophrenic patients after 16 weeks of antipsychotic medication with ziprasidone (daily average dose of 108 mg). We were especially interested in evaluating to what extent the restoration of emotional regulation involved the prefrontal cortex. Methods Thirteen schizophrenic patients (assessed using DSM-IV criteria) were clinically evaluated (using Positive and Negative Syndrome Scale - PANSS, Calgary Depression Scale - CDS)and were scanned using functional magnetic resonance imaging (fMRI), before starting and at the end of 16 weeks of ziprasidone treatment. Their results were compared with those of 15 healthy subjects. In each neuroimaging session, participants watched 14 blocks of emotionally laden images taken from the standardized sets developed by International Affective Picture System [NIMH Center for Emotion and Attention (CSEA) at the University of Florida]. In each block, one type of image (e.g. positive, negative) predominated and subjects were instructed to select all images of a given type, which could be either concordant (e.g. select all positive images in a block with a majority of positive images) or non-concordant (e.g. select all positive images in a block with a majority of negative images). The blood oxygenation level dependent (BOLD) signal in response to emotional stimuli was used as dependent measure for the brain activity. Results Despite observing no significant changes on clinical measures (PANSS and CDS) before and after 16 weeks of ziprasidone treatment, several prefrontal regions (i.e. anterior cingulate - ACC, orbitofrontal – OFC, and dorsolateral prefrontal – DLPFC cortices) increased significantly their response to positive than to negative stimuli. Moreover, in the regions typically involved in cognitive control (ACC and DLPFC), this pattern was accentuated whenever patients were instructed to select only the negative stimuli. Among the healthy controls, we found that prefrontal activity was more sensitive to the type of instruction, than to the type of image in a block; specifically, the prefrontal areas had a higher BOLD signal whenever subjects had to select the negative, than the positive images. We also found more similarities in prefrontal functioning (both in the volume and the strength of activation) between patients and controls after the treatment, when taking into account the instruction type (select negative versus positive stimuli), than when comparing the emotional valence of images. Conclusion The results of the present study suggest that antipsychotic treatment with ziprasidone restores the cognitive functioning related to the processing of emotional information in prefrontal cortex in patients with schizophrenia. Given the neuro-pharmacological action mechanism of ziprasidone (more affinity for serotonin than dopamine receptors in prefrontal cortex), we believe that our findings demonstrate that cognitive control and regulation of reactions when facing emotionally laden stimuli in schizophrenia is related to a higher concentration of dopamine in prefrontal pathways.

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