Plasma alprazolam concentrations. Relation to efficacy and side effects in the treatment of panic disorder
D. J. Greenblatt, J. S. Harmatz and R. I. Shader
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Mass.
A series of 237 patients with DSM-III-diagnosed panic disorder, or
agoraphobia with panic attacks, received alprazolam as part of the
placebo-controlled Cross-National Collaborative Panic Study. After a 1-week
drug-free period, alprazolam dosage was titrated upward with the objective
of reaching 6.0 mg/d in all patients. At week 3 of treatment, alprazolam
plasma levels were significantly correlated with daily dosage (regression
slope: 11.7 ng/mL per milligram per day) but with considerable individual
variation. Among patients with spontaneous panic attacks, 70% of those with
plasma alprazolam levels greater than 20 ng/mL achieved complete remission
vs 31% of those with levels less than 20 ng/mL. Situational panic attack
remission increased in frequency with increasing plasma levels, but the
relationship was not significant. Patient- and physician-rated global
improvement and Hamilton Anxiety and Depression Scale score reductions were
maximal at 20 to 39 ng/mL, with no further benefit at higher levels.
Central nervous system-depressant side effects increased in frequency with
higher plasma levels. Between weeks 3 and 8 of treatment, physicians were
permitted to adjust dosage (maximum: 10 mg/d) to optimize response. At week
8, the dose-concentration relationship was essentially identical
(regression slope: 10.8 ng/mL per milligram per day), but plasma levels
were no longer related to efficacy or side effects. Thus, monitoring of
plasma alprazolam concentrations may have a clinically useful role during
short-term treatment of panic disorder.
