In a 6-week study, alprazolam was compared to imipramine and placebo in 723 patients with moderate to severe depression and associated anxiety symptoms (6). Alprazolam effectively reduced the symptoms of anxiety and depression, was comparable to imipramine, and, at the doses used, showed a faster onset of activity. For patients who completed the study, the mean final daily dose of alprazolam was 2.9 mg compared with 131.8 mg of imipramine. This study employed both the Hamilton Psychiatric Rating Scale for Depres­sion (HAM-D) (7) and the HARS. An overall view of the results on both of these scales is provided (Figs. 1 and 2). Both active drugs were clearly more effective than placebo on all measurements. The HAM-D rated alprazolam as effective as imipramine at each of four eval­uation points. In addition, on the HAM-D total score, patients receiving alpra­zolam had a lower mean score at week 1 than did those taking imipramine (p < 0.001) (Fig. 1). This difference is reflected in the mean scores of several of the symptoms clusters from the same scale (Table 1). Similarly, patients treated with alprazolam showed a significantly greater re -
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Three clinical research studies using alprazolam for the treatment of a spectrum of anxiety/depression disorders have been described. Experience indicates that a substantial number of patients suffer from combined syndromes of anxiety and depression, and the results of these studies show that alprazolam was clinically effective across the spectrum of anxious depression disorders.

This 28-day study (3) compared alprazolam and placebo in 462 clinically anxious patients whose depressed mood indicated at least moderate severity in the Hamilton Anxiety Rating Scale (HARS). The patients ranged in age from 18 to 70 years. Patients with obvious sociopathy or psychosis, primary affective disorder, or alcoholism, and those requiring medication other than the study drugs were excluded, as were patients who were known to be sensitive to ben­zodiazepines or who had serious liver, kidney, cardiovascular, or pulmonary disease. After a 4- to 7-day washout and screening period, the patients were randomly assigned to alprazolam (242) or placebo (220) regimens within a dosage range of 2 to 12 capsules per day (0.25-mg alprazolam capsules). The patients’ anxiety symptoms were assessed at the beginning of the treatment period and after 1, 2, and 4 weeks of medication on the HARS, a 35-item Self-Rating Symptom Scale (SRSS), a Target Symptoms Record, and the Patient’s and Physician’s Global Impressions scales. Side effects, or treatment-emergent symptoms, were recorded on a symptom and side effects checklist initially and at weeks 1, 2, and 4; symp­toms that appeared or worsened during treatment were considered side effects. Alprazolam was more effective than placebo in relieving anxiety associated with depressed mood on every efficacy measurement of each assessment period. By the fourth week, the difference between the two treatment groups was sig­nificant (p < 0.012) on almost every item of both the HARS and the SRSS (2,3). According to the Patient’s Global Impressions of how much change had oc­curred and the Physician’s Global Impressions of therapeutic effect, more than 75% of the patients given alprazolam responded favorably, whereas less than one-third of patients given placebo responded to treatment. The treatment-emergent symptom reported most often was drowsiness, which did not differ significantly in frequency between the groups. No other treatment-emergent symptom was reported by a significant number of patients in either group. Side effects caused four patients on placebo but no patients on alprazolam to drop out of the study.

The DSM-HI, published in 1980, provides 25 different diagnostic labels for patients with anxiety; because some anxiety disorders may coexist, a total of 138 different diagnostic combinations is possible. This multiplicity of disorders to­gether with a host of new medications, many of which have "crossover" ability, have served to confuse rather than to clarify treatment protocol for the primary care physician. Some of the confusion may be alleviated by differentiating anxiety or depressive disorders as exogenous or endogenous. Exogenous refers to a normal response to threat, and it usually can be treated successfully with behavior therapy. Only failures in this group need pharmacotherapy. Endogenous disorders, which are metabolic in nature, are both more intense and pervasive and also more physically and psychologically disruptive. Therapeutic intervention is indicated in the ma­jority of such cases. Alprazolam, even within the family of benzodiazepines, is not the only effective pharmacological agent in the treatment of anxiety or anxious depression. And although the benzodiazepines are not the sole family of compounds available to the clinician for these indications, some authorities (8) believe that they are the treatment of first choice. Widespread clinical acceptance has consequently re­sulted in a high comparative scrutiny with other compounds in the treatment of anxiety disorders, mixed anxiety and depressive disorders, and some subtypes of pure depressive disorders. Seldom can one attend a discussion on the phar­macologic treatment of these disorders without some reference to alprazolam’s relative efficacy and side effects. The pharmacokinetic (1) and psychodynamic properties (5) of alprazolam have been extensively studied and reviewed elsewhere. In this chapter, three clinical studies using alprazolam in outpatients that were conducted in whole or part by our organization, a private psychiatric clinic in San Diego, California, will be reviewed.

A third study compared the efficacy and side effects of alprazolam, diazepam, and placebo in patients with anxiety (4). Of the 235 patients who participated in the 28-day study, 78 were given alprazolam, 85 were given diazepam, and 72 were given placebo. Two-thirds of the patients were diagnosed as having anxiety, one-third as having anxiety with depressive mood, and one patient as having obsessive-compulsive neuroses, according to the DSM-III classifications. Al­though patients had to be at least moderately anxious to be included in the study, the majority were diagnosed as being markedly, severely, or extremely anxious. At the end of the study, 80.3% of the alprazolam-treated patients and 60% of the diazepam-treated patients showed a moderate or marked improvement ac­cording to the Physician’s Global Impressions, whereas 62.2% of the patients who had received placebo showed no improvement or their condition worsened. The results of the other four evaluation scales, including the HARS, substantiated the effectiveness of alprazolam at an average daily dose of 1.5 mg and diazepam at an average daily dose of 18.6 mg. Side effects experienced by patients taking alprazolam were fewer and less
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The author acknowledges the technical and editorial assistance over the years provided by The Upjohn Company biomedical staff, especially Sally Boukma. Study 2 was done in collaboration with J. P. Feighner, M.D.; L. F. Fabre, M.D.; K. Rickels, M.D.; and W. T. Smith, M.D. Study 3 assistance was provided by S. G. Thein, Jr., Ph.D. Parts of the text describing Study 2 were reproduced with permission from JAMA, June 10, 1983, vol. 249, pp. 3059-3063, © 1983, American Medical Association.
REFERENCES (more…)

San Diego Neuropsychiatric Medical Clinic and Human Relations Center, Inc., San Diego, California 92103
In 1955, Goodman and Gilman in their textbook, The Pharmacologic Basis of Therapeutics, devoted only two chapters to psychopharmacology. The first chapter focused on barbiturates and the second on bromides, chloral hydrate, paraldehyde, and cannabis. Since then, the field of psychopharmacology has become much more sophisticated and, to be accepted, new pharmacologic treat­ments have had to conform to increasingly stringent scientific criteria, namely, prospective, double-blind, placebo-controlled studies. The understanding of anxiety and depression has grown considerably during this time, although it is still often difficult to separate the two in clinical practice. In addition, options for the management of these disorders have become more complex. Neuroleptics and antidepressants, including monoamine oxidase (MAO) in­hibitors and tricyclics, were introduced in the late 1950s, as were the antianxiety agents, benzodiazepines. However, chlordiazepoxide was viewed with skepticism, and in 1965, diazepam was endorsed in a lukewarm fashion. As newer anxiolytic and antidepressant treatments were investigated, some (e.g., subcoma insulin, atropine coma therapy, and hypnotherapy) were never incorporated as standards because of lack of efficacy or because of failure to compare favorably with more acceptable modes of therapy. Others (e.g., electroconvulsive therapy) were used only for the treatment of the most severe complications of these disorders, such as depression unresponsive to pharmacotherapy. In some cases, treatments have withstood the test of time. These include thioridazine for the treatment of anxiety associated with allergic bronchial asthma and combined neuroleptic-antide­pressant therapy for some phobic disorders associated with paranoid ideation and depression that preceded or were associated with anxiety. (more…)