To characterize the effects of antidepressant drugs in agoraphobia two complementary approaches, both of which are adaptations of pharmacological dissections, are proposed. The major study is a double-blind placebo controlled, multiple dose trial with imipramine in 80 agoraphobic patients. Only patients without significant depression/dysphoria will participate in this study and encouragement or instructions to enter phobic situations will not be provided concurrently with imipramine in order to assess the extent of specific antipanic and antiphobic effects of imipramine with as little contamination as possible. The major aims of this study include: 1) to delineate and stratify dose-response relationships for central agoraphobic symptoms, e.g., panic, phobia, avoidance behavior which would indicate specific, and possibly differential, imipramine effects, with concurrent investigation of plasma imipramine and desipramine levels and 2) to determine optimum dose ranges of imipramine in the treatment of agoraphobia and panic attacks. The second study is a pilot, open trial with imipramine and two structurally different new antidepressants in a total of thirty agoraphobic patients with associated depression/dysphoria. This is a neurochemically based pharmacological dissection of imipramine's mixed neurochemical and clinical effects using fluvoxamine and oxaprotiline which have selective serotonergic and noradrenergic effects, respectively. The primary aim of this pilot investigation is to explore the relationship of the antidepressant, antipanic and antiphobic effects of antidepressant drugs and to assess the possibility of differential neurobiochemical mediation of their effects in agoraphobic patients. The identification of optimum imipramine dosages for targeted agoraphobic symptoms and the possibility of identifying newer effective agents which may be better tolerated and thus more accessible to a greater number of agoraphobic patients have important clinical-practical implications. The proposed studies also promise to shed light on the relationship of the antipanic, antiphobic and antidepressant effects of antidepressant drugs, clarify the indications and expectations for their use in agoraphobia and finally begin to provide a biochemical basis and rationale for the treatment of agoraphobia and panic attacks with antidepressants.
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