A study is proposed to assess and compare the usefulness of the tricyclic antidepressant imipramine (IMI) and the non- benzodiazepine anxiolytic buspirone (BU) with that of a placebl (P) in the management and final outcome of gradual benzodiazepine (BZ) discontinuation in 150 chronic (greater than 1 year) users. Patients will receive IMI, BU, or P for 12 weeks. After 4 weeks of pretreatment, while patients maintain their daily BZ intake of either diazepam, lorazepam, or alprazolam, patients will be gradually withdrawn from their BZ (3/8 first week, 1/4 second and third week, 1/8 fourth week), to be followed by 3 placebo weeks, while still under the protective umbrella of IMI, BU, or P. After 2 additional placebo weeks, follow-ups are conducted 3 and 12 months later. The study design is based on the rationale that: 1) reduction of psychopathology reduces severity of withdrawal and thus leads to more successful discontinuation; 2) the anxiolytic umbrella of IMI and BU should reduce withdrawal severity, even in patients with little initial pre-taper symptomatology; and 3) IMI, by down- regulating postsynaptic NE and 5-HT receptors will directly influence withdrawal severity. A second study is proposed to replicate the earlier observation made in a 6 month clorazepate/abrupt discontinuation study that discontinuous prior BZ use significantly influences withdrawal severity. If this observation is confirmed it would have important consequences for the management of chronically anxious patients. Two groups of anxious patients, one never on a BZ and one having been treated for greater than 6 months during the past 2 years but not during the past 2 months, and matched as to duration of anxiety episode, will be treated for 6 weeks with lorazepam followed by 4 weeks of placebo. It is hypothesized that prior discontinuous BZ use, similar to continuous BZ use will cause a significant worsening of withdrawal symptomatology when compared to those patients not BZ pre-treated. A small number of patients, unsuccessful in their BZ withdrawal attempts, will be offered to enter 2 pilot projects. One will assess the possible role of micronized oral progesterone (its 3- alpha-hydroxy-5-alpha-pregnane-20-one metabilite is a potent enhanced of GABA transmission), and one the role of carbamazepine in the management of BZ withdrawal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH008957-26
Application #
3486295
Study Section
Treatment Development and Assessment Research Review Committee (TDA)
Project Start
1976-06-01
Project End
1992-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
26
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Rickels, Karl; Garcia-Espana, Felipe; Mandos, Laura A et al. (2008) Physician Withdrawal Checklist (PWC-20). J Clin Psychopharmacol 28:447-51
Schweizer, E (1995) Generalized anxiety disorder. Longitudinal course and pharmacologic treatment. Psychiatr Clin North Am 18:843-57
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

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