Psychostimulant abuse has been noted to occur commonly in the long term course of patients with schizophrenia and/or schizoaffective disorder. This is particularly unfortunate, since schizophrenic individuals are also exquisitely vulnerable to reexacerbation of their psychoses under the impact of psychostimulant substances - with all the attendant morbidity which additional recurrent episodes of psychosis may entail. Dysphoria is one factor which has been described as an important contributor to the abuse of psychostimulant substances (ie. a """"""""self-medication"""""""" hypothesis), and dysphoric states are common in patients with schizophrenia who are """"""""between"""""""" psychotic episodes. Recently it has been shown that adjunctive use of imipramine (IMI) can be useful in relieving the syndromally defined dysphoric state known as post-psychotic depression (PPD), in patients who are otherwise being maintained on neuroleptic and antiparkinsonian medications. The present proposed study is designed to test if such a trial of adjunctive imipramine would be safe and effective as a treatment for dysphoria in those schizophrenic and schizoaffective patients who have been substance abusers, whether it would reduce their use or craving for psychostimulants and whether it might be a helpful technique for interrupting a vicious cycle of dysphoria, psychostimulant abuse, and re-exacerbation of psychosis in these patients. Patients who meet Research Diagnostic Criteria for schizophrenia or schizoaffective disorder, whose psychotic symptomatology has largely abated, who are currently abusing or who have a history of abusing cocaine or cannabis, and who have a persistent syndrome of syndromally defined PPD will be stabilized on an optimal dose of fluphenazine decanoate and benztropine. Full symptom and historical profiles will be obtained. Patients will the enter a 9 week double-blind trial of adjunctive IMI vs placebo. Patients will be rated with scales for depression, psychosis, and substance abuse, as well as scales for negative symptoms, demoralization, quality of life, extrapyramidal symptoms, and global functioning. Plasma samples for IMI and desipramine will also be obtained, and urine samples will be tested for substances of abuse. Patients who had received placebo and remained symptomatic will subsequently be allowed to participate in a similar open trial of IMI. The information gained from this study will lead to more rationally targeted use of medications in dysfunctional schizophrenic patients prone to substance abuse, and develop potential heuristic insights into their disorders.
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