A study is proposed to assess the relative effectiveness of a non-benzodiazepine anxiolytic (buspirone) and a tricyclic antidepressant with possible effectiveness in anxiety and panic (imipramine) in the treatment of those long-term users of benzodiazepines (BZ) who, after withdrawal from the BZ, exhibit symptoms of anxiety, depression, or panic of sufficient severity to warrant further psychotropic drug treatment. A minimum of 184 patients will participate. They will have taken one of the following 4 BZ's: Clorazepate, diazepam, alprazolam, lorazepam. After a 1 to 2 week period of dose stabilization and dosage increase in initially low dose, symptomatic patients with daily patient ratings of overall symptom severity, a 4 to 8 week period of gradual withdrawal will be instituted. Those patients who are successfully withdrawn and who, post-withdrawal, are diagnosable a Major or Minor Depressive Disorder, Generalized or Atypical Anxiety Disorder, or Panic Disorder, or who have at least anxiety and/or depression of prescribed minimal severity as evaluated by standard rating instruments, will enter an 8 week double-blind trial of imipramine or buspirone. Trial visits will be at weeks 0, 1, 2, 4, 6, and 8, and will be followed by a 2 week period of placebo treatment. Unimproved patients will leave the study and be treated by doctor choice. One year follow-up will be conducted for all patients. An effort will be made to determine the proportion of initially low dose symptomatic patients whose discomfort had been caused by persisting or recurring withdrawal and the proportion who had been symptomatic because of under-treatment. Length of BZ half-life, length of continuous BZ use, daily BZ dosage, and content and severity of several psychopathology dimensions will be examined as potential predictors of the patient's response to gradual BZ withdrawal. Further goals of the study include: a) clinical determination of the most effective approach to gradual withdrawal; b) an examination of the impact of long-term BZ use upon psychomotor and cognitive functioning; and c) obtaining further information concerning the proportion of patients who may be successfully withdrawn from BZ's of long-term use, of patients who after withdrawal remain symptomatic and in need of further treatment, of patients who may be successfully treated with a non-BZ, and of patients for whom return to BZ treatment is appropriate.

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National Institute of Mental Health (NIMH)
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University of Pennsylvania
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Rickels, Karl; Garcia-Espana, Felipe; Mandos, Laura A et al. (2008) Physician Withdrawal Checklist (PWC-20). J Clin Psychopharmacol 28:447-51
Schweizer, E; Rickels, K; Weiss, S et al. (1993) Maintenance drug treatment of panic disorder. I. Results of a prospective, placebo-controlled comparison of alprazolam and imipramine. Arch Gen Psychiatry 50:51-60
Rickels, K; Schweizer, E; Weiss, S et al. (1993) Maintenance drug treatment for panic disorder. II. Short- and long-term outcome after drug taper. Arch Gen Psychiatry 50:61-8
Schweizer, E; Rickels, K; Case, W G et al. (1991) Carbamazepine treatment in patients discontinuing long-term benzodiazepine therapy. Effects on withdrawal severity and outcome. Arch Gen Psychiatry 48:448-52
Schweizer, E; Rickels, K; Case, W G et al. (1990) Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper. Arch Gen Psychiatry 47:908-15
Rickels, K; Schweizer, E; Case, W G et al. (1990) Long-term therapeutic use of benzodiazepines. I. Effects of abrupt discontinuation. Arch Gen Psychiatry 47:899-907
Rickels, K; Case, W G; Schweizer, E et al. (1990) Benzodiazepine dependence: management of discontinuation. Psychopharmacol Bull 26:63-8
Rickels, K (1990) Evaluating antidepressants and anxiolytics. Psychopharmacol Ser 8:3-25
Schweizer, E; Case, W G; Rickels, K (1989) Benzodiazepine dependence and withdrawal in elderly patients. Am J Psychiatry 146:529-31
Rickels, K; Fox, I L; Greenblatt, D J et al. (1988) Clorazepate and lorazepam: clinical improvement and rebound anxiety. Am J Psychiatry 145:312-7

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