ORIGINAL INVESTIGATION The drug-induced helplessness test: an animal assay for assessing behavioral despair in response to neuroleptic treatment Michael E. Ballard & Ana M. Basso & Kelly B. Gallagher & Kaitlin E. Browman & Gerard B. Fox & Karla U. Drescher & Gerhard Gross & Michael W. Decker & Lynne E. Rueter & Min Zhang Received: 6 December 2005 / Accepted: 21 August 2006 / Published online: 9 November 2006 # Springer-Verlag 2006 Abstract Rationale Neuroleptic dysphoria encompasses a range of unpleasant subjective responses and, as a result, is difficult to study in preclinical animal models. Objective Based on the learned helplessness model of depression, increases in escape failures (EFs) in the drug- induced helplessness test (DH) are proposed to reflect drug- induced depressive-like state, a contributing factor to neuroleptic dysphoria in humans. Materials and methods Effects of the typical antipsychotic haloperidol and the atypical antipsychotics risperidone, olanzapine, aripiprazole, quetiapine, and clozapine were investigated in the DH test. We further characterized this test by examining compounds affecting motor function, cognition, anxiety, and those with antidepressant activity. Results The antipsychotics haloperidol, risperidone, aripi- prazole, and olanzapine, all increased EFs, while quetiapine had no effect, and clozapine reduced EFs. Amphetamine, diazepam, and ciproxifan, had no effect on EFs. Scopol- amine significantly reduced EFs and MK-801 showed a trend toward reducing EFs at doses not significantly sti mulating locomotor activity. Subchronic, but not acute, imipramine and subchronic fluoxetine significantly re- duced EFs at doses significantly suppressing locomotor activity. Dissociation appears to exist between perfor- mance in the DH test and compound effects on catalepsy or locomotor activity. Conclusions After discussing potential alternative interpre- tations of the drug-induced changes of EFs, we propose the DH test as a useful test for assessing a drug-induced, depressive-like state that may contribute to neuroleptic dysphoria. Keywords Antipsychotic . Dysphoria . Depression . Secondary negative symptoms . Dopamine Introduction Schizophrenia is a debilitating mental illness afflicting nearly 1% of the population. Patients with schizophrenia also frequently suffer from mood disorders. For example, nearly 60% of schizophrenics experience depression at some point during their illness (Bartels and Drake 1988) and 25–30% are depressed on a regular basis (Elk et al. 1986; Siris et al. 2001). In addition to nonmedicated schizophrenics with intrinsic mood disorders, antipsy- chotics can induce “neuroleptic dysphoria” in both schizo- phrenic (Gerlach and Larsen 1999; Harrow et al. 1994; Singh 1976) and healthy people (Belmaker and Wald 1977). Neuroleptic dysphoria is described by Voruganti and Awad (2004a) as a “global, nonspecific descriptive term that represents a mixture of unpleasant emotions” in response to antipsychotic treatment. As a result of inherent depression and neuroleptic dysphoria, schizophrenics ex- hibit a remarkably high risk of suicide, with 50% of them Psychopharmacology (2007) 190:1–11 DOI 10.1007/s00213-006-0577-y M. E. Ballard : A. M. Basso : K. B. Gallagher : K. E. Browman : G. B. Fox : M. W. Decker : L. E. Rueter : M. Zhang (*) Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA e-mail: Min.Zhang@abbott.com K. U. Drescher : G. Gross Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Ludwigshafen, Germany