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while patients maintain their daily BZ intake of either diazepam, lorazepam, or alprazolam, patients will be gradually withdrawn from their BZ (3/8 first week, 1/4 second and third week, 1/8 fourth week), to be followed by 3 placebo weeks, while still under the protective umbrella of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.
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