Clozapine is the only drug with proven efficacy in schizophrenia that does not respond to other antipsychotics. However, potentially serious side effects such as agranulocytosis have limited clozapine treatment. The specific mechanism of action responsible for its superior efficacy among antipsychotics is also still elusive. We previously found that chronic treatment with clozapine, but not risperidone, improved cognitive impairments in a mouse model of psychiatric disorders induced by early postnatal activation of the neuropeptide receptor VPAC2. Then, we have identified connective tissue growth factor (CTGF) as a candidate molecule, which is upregulated by clozapine. This study aimed to clarify the involvement of CTGF in the effects of clozapine in vivo. Chronic administration of intranasal CTGF with L-penetratin, a cell-penetrating peptide, improved cognitive impairments in the novel object recognition test. Additionally, concomitant treatment with intranasal injection of the neutralizing antibody against CTGF and L-penetratin blocked the ameliorative effects of clozapine on cognitive impairments. These results suggest that CTGF signaling pathway might be at least partly involved in the effects of clozapine and would offer new insights into an alternative therapeutic strategy for treatment resistant schizophrenia.