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

Abstract

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 (1-5mg/kg) significantly reduced alcohol drinking (p<0.05) in the hamster, whereas higher doses (10-20mg/kg) did not. In addition, 5 mg/kg of iloperidone reduced alcohol drinking to the same extent as clozapine (8mg/kg), whereas haloperidol (0.2mg/kg) did not. Moreover, iloperidone's effects were enhanced via the addition of desipramine (3mg/kg), but not idazoxan (1.5/3mg/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.

Behavioral predictors of alcohol drinking in a neurodevelopmental rat model of schizophrenia and co-occurring alcohol use disorder

“…Alcohol was then reintroduced to the rats in adulthood (PND 90) in a continuous-access 2-bottle choice (water and 20% alcohol) design. The position of the two bottles were switched daily to prevent positional preference, consistent with our previous investigations (Khokhar and Green, 2016). The animals’ performance on the behavioral assay was correlated with their alcohol drinking between PND 90 and PND 150 to assess the predictive ability of these measures toward future alcohol drinking.…”

Unique Effects of Clozapine: A Pharmacological Perspective

“…In these studies, neither the desipramine, nor the low doses of paliperidone alone, were sufficient to reduce alcohol drinking significantly, but the combination of the two drugs was able to do so, suggesting that modulation through both the dopaminergic and noradrenergic mechanisms is required for this effect. Lastly, our recently published findings with iloperidone, an antipsychotic with an ɑ-2/D2 receptor antagonism ratio similar to that of clozapine (Kalkman & Loetscher, 2003), shows remarkable efficacy for reducing alcohol drinking in the hamster (almost to the same extent as clozapine), and this effect can be enhanced by the addition of desipramine, but not idazoxan (an ɑ-2 antagonist) (Khokhar & Green, 2016). The lack of additional effect of idazoxan suggests that since iloperidone acts as a potent norepinephrine ɑ-2 receptor antagonist, the further addition of another ɑ-2 antagonist does not enhance iloperidone's ability to reduce alcohol drinking.…”

Long-acting injectable paliperidone palmitate for schizophrenia and alcohol use disorder

“…Nicotine, alcohol and cannabis are the substances that are used most frequently. 1 AUD usually occurs in patients with schizophrenia, contributes greatly to their morbidity 2 and drastically increased their course. 3 There are few data available on pharmacological approaches in this population, but among antipsychotics, clozapine shows positive evidence in the literature, 4 it has been associated with a decrease in alcohol consumption in patients with schizophrenia, but its toxicity reduces its use.…”

“…Some of these studies have been carried out with risperidone, aripiprazole, paliperidone and iloperidone. 1,3,[7][8][9][10] Chau et al 8 propose the unique and broad pharmacology of clozapine profile, including its weak dopamine D 2 receptor blockade, its potent antagonism of the noradrenergic receptor alpha-2, and its ability to elevate chronically and highly. Norepinephrine may have the property of reducing alcohol abuse.…”

“…The data suggest that iloperidone, alone or in combination with desipramine, should be analyzed in patients with schizophrenia and alcohol use disorder. 1 Aripiprazole was the first antipsychotic developed to possess agonist properties at dopamine D 2 autoreceptors, a groundbreaking strategy that presented a new vista for schizophrenia drug discovery. The dopamine D 2 receptor is the crucial target of all extant antipsychotics, and all developed prior to aripiprazole were D 2 receptor antagonists.…”