Effects of iloperidone, combined with desipramine, on alcohol drinking in the Syrian golden hamster

Alcohol use disorder in patients with schizophrenia dramatically worsens their clinical course, and few treatment options are available. Clozapine appears to reduce alcohol use in these patients, but its toxicity limits its use. To create a safer clozapine-like drug, we tested whether the antipsychotic iloperidone, a drug that combines a weak dopamine D2 receptor blockade and a potent norepinephrine alpha-2 receptor blockade would reduce alcohol drinking, and whether its effect on alcohol drinking could be increased if combined with an agent to facilitate norepinephrine activity. Syrian golden hamsters (useful animal model for screening drugs that reduce alcohol drinking in patients with schizophrenia) were given free access to water and alcohol (15% v/v) until stable drinking was established. Animals (n = 6-7/group), matched according to alcohol intake, were treated daily with each drug (iloperidone; clozapine; haloperidol; desipramine [norepinephrine reuptake inhibitor]; with idazoxan [norepinephrine alpha-2 receptor antagonist]) or with a two-drug (iloperidone + desipramine; iloperidone + idazoxan) combination for 14 days. Moderate doses of iloperidone (1-5 mg/kg) significantly reduced alcohol drinking (p < 0.05) in the hamster, whereas higher doses (10-20 mg/kg) did not. In addition, 5 mg/kg of iloperidone reduced alcohol drinking to the same extent as clozapine (8 mg/kg), whereas haloperidol (0.2 mg/kg) did not. Moreover, iloperidone's effects were enhanced via the addition of desipramine (3 mg/kg), but not idazoxan (1.5/3 mg/kg). In this animal model, iloperidone decreases alcohol drinking as effectively as clozapine, and desipramine appears to amplify this effect. The data suggest that iloperidone, alone or in combination with desipramine, should be tested in patients with schizophrenia and alcohol use disorder.