Dennis J. Munjack

Demonstration of the Efficacy and Safety of a Novel Substance P (NK1) Receptor Antagonist in Major Depression

The efficacy and safety of a selective NK1 antagonist, L-759274, was investigated in outpatients with diagnosis of major depressive disorder with melancholic features, following evidence obtained with the novel compound aprepitant that Substance P (NK1) antagonists may provide a unique mechanism of antidepressant activity. A randomized, double-blind placebo-controlled study was carried out. Patients, male or female, aged 18–60, scoring ⩾25 points on total of first 17 items of 21-item Hamilton Depression Scale (HAMD), and scoring ⩾4 (moderately ill) on Clinical Global Impressions-Severity Scale were randomized to oral L-759274 40 mg daily (n=66) or placebo (n=62) for 6 weeks. For patients receiving L-759274, improvement (mean decrease from baseline) in HAMD-17 total score was 10.7 points, compared with a mean 7.8 point improvement in patients receiving placebo (p<0.009). Mean scores for item 1 of HAMD-17 (depressed mood) also improved to a greater extent in the active group compared with the placebo group (0.3 points, p<0.058). Compared with placebo, mean scores on Clinical Global Impressions-Improvement Scale improved significantly by the end of the trial (p=0.009). L-759274 was generally safe and well-tolerated. The incidence of sexual side effects was on par with that observed in patients receiving placebo, and the incidences of gastrointestinal effects were low. Antidepressant actions have now been observed with two different highly selective NK1 antagonists (aprepitant and L-759274). NK1 antagonism is a replicated and generally well-tolerated antidepressant mechanism.

Alprazolam, propranolol, and placebo in the treatment of panic disorder and agoraphobia with panic attacks

Fifty-five patients completed a 5-week double-blind study comparing alprazolam, propranolol, and placebo in the treatment of panic disorder and agoraphobia with panic attacks. There was no concomitant behavioral treatment. Patient and therapist rating scales included Sheehans Panic and Anxiety Attack Scales, the Marks-Sheehan Phobia Scale, the Hamilton Anxiety Scale, the Hamilton Depression Scale, and the Side Effects Checklist. The results generally support the efficacy of alprazolam, but not propranolol, in the treatment of panic disorder and agoraphobia with panic attacks. The significance of the results are discussed, as well as a number of the unique aspects of our procedures and patient population.

Placebo-controlled, multicenter study of sertraline treatment for obsessive-compulsive disorder

The safety and efficacy of sertraline versus placebo were examined in a group of nondepressed outpatients with obsessive-compulsive disorder (OCD). Patients with moderate-to-severe OCD were recruited at 10 sites. After a 1-week placebo lead-in, patients were treated in a double-blind fashion for 12 weeks with sertraline or placebo. Sertraline was administered at a starting dose of 50 mg/day, with flexible titration up to 200 mg/day. The efficacy measures were the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the National Institute of Mental Health Global Obsessive Compulsive Scale (NIMH), and the Clinical Global Impression Scale (CGI) Severity of Illness and Improvement subscales. One hundred sixty-seven patients were randomly assigned and received at least one dose of double-blind medication: 86 received sertraline and 81 received placebo. All efficacy measures showed significantly greater improvement in the sertraline group from the end of week 8 until the end of week 12. Significantly greater improvement (p < 0.05) in the sertraline group first became apparent by the end of week 3 on the Y-BOCS and the CGI Improvement scale, and by the end of weeks 6 and 8, respectively, on the NIMH and CGI Severity scale. Sertraline was well tolerated, without serious adverse effects. In conclusion, sertraline was safe and effective in the treatment of patients with OCD.

A double-blind, placebo-controlled, multicenter study with alprazolam and extended-release alprazolam in the treatment of panic disorder.

This is a double-blind, placebo-controlled, flexible-dose, multicenter, 6-week study comparing regular alprazolam (compressed tablet, CT), given four times per day, and extended release alprazolam (XR), given once in the morning. The aim of the XR preparation is to offer less frequent dosing and to reduce interdose anxiety. Of the intent-to-treat group of 209 patients, 184 completed 3 weeks of medication and were evaluated according to protocol. There was a completer rate for the 6 weeks of 94% (CT), 97% (XR), and 87% (placebo). On global measures, Hamilton Rating Scale for Anxiety, phobia rating, and work disability measures, both active treatment groups were equally effective and significantly more efficacious than the placebo cell on endpoint MANOVA analysis. On analysis of the panic factor with endpoint data, both active treatment groups were equally effective throughout the 6-week trial and significantly more efficacious than the placebo group. Drowsiness occurred more frequently with CT alprazolam (86% of patients) than with the XR preparation (79%) or placebo (49%).

ALPRAZOLAM LEVELS AND RESPONSE IN PANIC DISORDER : PRELIMINARY RESULTS

Fifty-five young adult patients completed a study comparing alprazolam, propranolol, and placebo in the treatment of panic disorder and agoraphobia with panic attacks. Twenty completed 5 weeks of treatment with alprazolam. No concomitant psychological treatment was administered. Plasma alprazolam levels were determined at baseline and at the end of the trial by means of automated gas chromatography. These levels were significantly correlated with dose (p = 0.001). Dividing the data into quartiles based on alprazolam concentration, no direct, linear relationship was found between alprazolam levels and response (as defined by a criterion of zero panic attacks). However, analysis of the combined middle two quartiles versus the combined upper and lower quartiles showed a positive trend toward a curvilinear relationship; i.e., there was a greater response rate within the 18-62 ng/ml concentration range than in the combined 0-17 plus 63-107 ng/ml range, (chi 2 = 2.4; p = 0.12). The findings are very preliminary in nature. It remains to be seen if the results will reach significance with a large sample size and a more tightly controlled study design.