Clozapine generates obsessive compulsive disorder-like behavior in mice

Area of Science:

• Neuroscience
• Pharmacology
• Behavioral Science

Background:

• Clozapine is associated with obsessive-compulsive symptoms (OCS) in schizophrenia patients.
• Establishing a causal link is difficult due to OCS comorbidity with schizophrenia.
• The potential for clozapine to induce OCS de novo remains unclear.

Purpose of the Study:

• To investigate if chronic clozapine treatment induces obsessive-compulsive disorder (OCD)-like behavior in mice.
• To explore potential gene-environment interactions between clozapine and OCD models.
• To assess the efficacy of fluoxetine in mitigating clozapine-induced behaviors.

Main Methods:

• Mice received long-term clozapine treatment via sustained-release pellets.
• Obsessive-compulsive disorder (OCD)-like behaviors, specifically grooming, were monitored up to 40 weeks.
• Experiments included wild-type and Sapap3 knockout mice, with and without clozapine, and fluoxetine treatment.

Main Results:

• Chronic clozapine administration significantly increased grooming behavior in mice starting at 30 weeks.
• Clozapine exacerbated grooming behavior earlier in Sapap3 heterozygous knockout mice, indicating a gene-drug interaction.
• Fluoxetine treatment effectively reduced clozapine-induced grooming behavior.

Conclusions:

• Chronic clozapine treatment can induce de novo OCD-like behaviors in a mouse model.
• These findings support the hypothesis that clozapine may cause OCS independently of schizophrenia.
• The study highlights a potential clozapine-OCD gene interaction and the therapeutic potential of fluoxetine.