Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. II. Patient acceptance, side effects, and safety.

In a multicenter placebo-controlled study, the safety, side effects, and patient acceptance of alprazolam for the treatment of panic disorder and agoraphobia were examined. A total of 525 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder were randomly assigned to receive alprazolam or placebo, which they took for eight weeks. The mean daily dose at the end of the study was 5.7 mg of alprazolam or 7.5 capsules of placebo daily. Potentially serious reactions to alprazolam occurred in ten of 263 subjects who received the drug. These included acute intoxication (three), hepatitis (two), mania (two), amnesia (one), aggressive behavior (one), and depression (one). Treatment-related side effects that were worse in patients taking alprazolam than in those taking placebo included sedation, fatigue, ataxia, slurred speech, and amnesia. Sedation was the most frequent but tended to subside with dose reduction or continued administration of the drug. Patient acceptance of alprazolam, as measured by the rate of completion for study participants, was high. Eighty-four percent of patients receiving active drug completed the study compared with 50% receiving placebo.

Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. I. Efficacy in short-term treatment.

Following promising preliminary evidence, the benzodiazepine-derivative alprazolam was studied in a large, placebo-controlled, eight-week, flexible-dose trial in patients with agoraphobia with panic attacks and panic disorder. Of 526 patients, 481 completed three weeks of treatment; however, significantly more placebo (102/234) than alprazolam (21/247) recipients subsequently dropped out of the trial, primarily citing ineffectiveness (of placebo) as the reason. Alprazolam was found to be effective and well tolerated. There were significant alprazolam-placebo differences in improvement for (1) spontaneous and situational panic attacks, (2) phobic fears, (3) avoidance behavior, (4) anxiety, and (5) secondary disability, all significant by the end of week 1. At the primary comparison point (week 4), 82% of the patients receiving alprazolam were rated moderately improved or better vs 43% of the placebo group. At that point, 50% of the alprazolam recipients vs 28% of placebo recipients were free of panic attacks.

Secondary depression in panic disorder and agoraphobia. I. Frequency, severity, and response to treatment.

Depressive symptomatology in 481 subjects with panic disorder and phobic avoidance was studied as part of an investigation of the efficacy of alprazolam in panic disorder. Subjects who had a major depressive episode (MDE) before the onset of their panic disorder were not included in the trial. With this exclusion criterion, 31% of subjects had a secondary MDE occurring after the onset of the panic disorder. The occurrence of secondary MDE was related to the length of time subjects were ill with panic disorder. Compared with the subjects without depression, those subjects with current MDE had higher scores on measures of anxiety and depression but not on the number of panic attacks per week. The presence of depression and the degree of phobic avoidance contributed independently to measures of the severity of the panic illness. Alprazolam was effective in reducing panic and depressive symptomatology in both depressed and nondepressed subjects with panic disorder. The presence of an MDE was not predictive of the outcome of treatment for the panic and phobic symptoms. Subjects with or without depression responded similarly to alprazolam.

Cigarette smoking and plasma nortriptyline levels.

Cigarette smoking was found to have no effect on the steady-state plasma levels of nortriptyline in a group of 22 smokers and 31 nonsmokers. Smokers achieved a mean steady-state nortriptyline concentration of 191.2 +/- 141.3 ng/ml; nonsmokers had a level of 169.3 +/- 92.4 ng/ml. Age, sex, and number of cigarettes smoked had no effect on the plasma concentrations achieved.

Plasma concentrations of melatonin in panic disorder.

Nocturnal plasma melatonin concentrations were measured in seven patients with panic disorder and eight healthy control subjects. The five patients who had never received psychotropic medication had significantly greater melatonin concentrations from 4:00 a.m. to 7:00 a.m. than the control subjects. In addition it is possible that a phase delay occurred in these unmedicated patients. The findings are discussed in terms of previous studies showing increased melatonin in manic patients and the effect of intense stress on melatonin synthesis. The two patients who had been medication free for only 1 week showed a decreased melatonin rhythm, which is consistent with previous findings in medicated patients.

Melatonin sensitivity to dim white light in affective disorders.

Both dim and bright light has been shown to suppress the nocturnal secretion of the pineal hormone melatonin. Early reports suggests that an abnormal response to light occurs in patients with bipolar affective disorder, where as patients with major depressive disorder respond similarly to controls. It has been suggested that this abnormal sensitivity of the melatonin response to light could be a trait marker of bipolar affective disorder. However reports lack consistency. Hence, we investigated the melatonin suppression by dim light (200 lux) in patients with bipolar affective disorder, seasonal affective disorder and major depressive disorder. Results suggest that a supersensitive melatonin suppression to light in bipolar affective disorder (p < .005), and seasonal affective disorder (p < .05), whereas patients with major depressive disorder display similar suppression to controls. The supersensitivity may be a mechanism where by phase-delayed rhythms, are resynchronised to a new circadian position. Conversely, an abnormality may exist in the pathway from the retina to the suprachiamatic nucleus.

Renal function related changes in lithium kinetics.

The renal clearance of lithium will decrease, and hence the risk of acute lithium toxicity will increase, in any situation leading to dehydration and sodium depletion. Patients on long term lithium therapy with progressively declining urinary concentrating ability may be at special risk in this regard. Chronic histological changes in the kidney attributed to lithium therapy correlate with age rather than with the duration of lithium therapy. Age-related renal histological changes are associated with decreased glomerular filtration rate and therefore reduced renal lithium clearance. Thus, the dose of lithium should be reduced with advancing age.

Clinical pharmacokinetics of dothiepin. Single-dose kinetics in patients and prediction of steady-state concentrations.

The pharmacokinetics of dothiepin were evaluated in 9 depressed patients following a single oral dose of 75 mg. Blood and plasma concentrations of dothiepin and 2 major metabolites, northiaden and dothiepin S-oxide, were measured by gas chromatography/mass fragmentography. The mean (+/-SD) peak plasma concentrations of dothiepin were 49 +/- 27 micrograms/L at 3 +/- 1.2h. Mean (+/-SD) estimates of other parameters were as follows: absorption half-life 1.1 +/- 1.1h; distribution half-life 2.2 +/- 0.8 h; elimination half-life 25 +/- 7h; apparent volume of distribution 70 +/- 62 L/kg; and oral clearance 2.1 +/- 1.6 L/kg/h. The mean (+/-SD) peak plasma concentration of dothiepin S-oxide was 125 +/- 43 micrograms/L at 3.5 +/- 1.3h with an elimination half-life of 22 +/- 12 h. The mean peak plasma concentration of northiaden was 6 +/- 3 micrograms/L at 4.5 +/- 1.1h, with an elimination half-life of 31 +/- 12 h. No significant differences were found in pharmacokinetic parameters compared with a previous study in 7 healthy volunteers. When data for the patients and healthy volunteers were combined (n = 16), pharmacokinetic parameters were not found to be affected by age. However, a significant difference was found between males and females for the elimination half-lives of dothiepin and northiaden, and for the apparent volume of distribution of dothiepin. The 24-hour blood/plasma concentrations of dothiepin and dothiepin S-oxide accurately predicted the steady-state concentrations obtained following 4 weeks' treatment with dothiepin 150 mg nocte.

Effect of the menstrual cycle stage on the melatonin suppression by dim white light.

Patients with bipolar disorder have been shown to have a supersensitive melatonin suppression to dim white light (200 and 500 lux) compared to normal healthy subjects. Previous studies suggest menstrual cycle dependent changes in the melatonin rhythm, but it is not known if the melatonin sensitivity to light changes during the menstrual cycle. The present study investigated the melatonin suppression to dim white light (200 lux) in different stages of the menstrual cycle. No significant differences in the percent suppression of melatonin were found across the stages of the menstrual cycle (p = .97). Our findings suggest that the menstrual cycle hormonal changes do not affect the melatonin sensitivity to dim light in healthy controls.

Prolactin response to dl-fenfluramine in panic disorder.

The objective of this study was to test the hypothesis that serotonin receptors are hypersensitive in patients with panic disorder. Eleven patients and 12 controls received a single PO dose of 60 mg of dl-fenfluramine at 0900h on a single occasion. Blood samples were collected with an indwelling intravenous catheter at 30-min intervals from 0930h to 1530h and prolactin determined by radioimmunoassay. In both groups, fenfluramine induced a rise in the plasma prolactin concentration from baseline. The patients showed a greater increase in prolactin response than the normal controls. This result is consistent with the hypothesis of increased serotonin receptor function in patients with panic disorder.

Human melatonin response to light at different times of the night.

Normal control subjects were examined on three separate occasions with light of sufficient intensity to suppress nocturnal plasma melatonin concentrations. One hour of light was given at each of the following times: (a) 2100-2200h; (b) midnight to 0100h; (c) 0400-0500h. Melatonin synthesis was just becoming apparent at 2100h. There was significant suppression of melatonin by light when given at midnight-0100h and 0400-0500h, but not when light was given at 2100-2200h. In each case following light, melatonin synthesis was shown to resume, even after light applied in the second half of the dark period (0400-0500h). A second experiment was undertaken to examine a possible "rebound" in melatonin levels following light given at 2100-2200h. Six further control subjects were exposed to light at this time, and plasma melatonin levels were measured until 0400h. No rebound in melatonin concentrations was observed. These results are compared with other studies of melatonin response to evening light exposure.

Melatonin, cortisol and prolactin response to acute nocturnal light exposure in healthy volunteers.

An investigation of the cortisol and prolactin responses accompanying acute melatonin suppression by light (600 lux) in humans is described. Light given from midnight to 0300h suppressed nocturnal plasma melatonin concentrations by 65%. Despite this significant suppression of melatonin, no significant effect on plasma cortisol or prolactin concentrations was observed. These data support recent studies which argue that, if there is a relationship between melatonin, the hypothalamo-pituitary, and the hypothalamo-pituitary-adrenal axis in humans, it is neither direct nor simple.

Managing long-term therapy for panic disorder.

Diagnostic criteria for panic disorder have been well defined; but treatment modalities, less so. Combined psychotherapy and pharmacotherapy is the most effective treatment for these disorders. Benzodiazepines, tricyclic antidepressants, monoamine oxidase inhibitors, and other medications have been found effective in clinical studies. Alprazolam, a triazolo analog of the 1,4 benzodiazepine class, recently was proved effective in a cross-national study involving approximately 1700 patients, with minimal side effects. Therapy with the medication is advised for at least 6 months. Medications should be tapered over a prolonged period, at least 8 weeks, especially where high doses are employed.

Long-term clinical management of depressive disorders.

The author provides evidence that depression is an often chronic and recurrent illness. He then provides World Health Organization (WHO) and other well-established recommendations for acute treatment of depression and describes maintenance treatment, which usually lasts 3 to 6 months. He lists WHO recommendations for prophylaxis, which should probably be continued for 2 or more years in patients with chronic depression, and reviews the following problems commonly associated with continued antidepressant treatment: cardiac toxicity, drug overdose, suicide/parasuicide, drug toxicity, drug interactions, and noncompliance. Finally, the author discusses discontinuation, which should always be accomplished according to a tapered, individualized schedule with the patient as an active partner in the process. Despite this knowledge, researchers must look for additional therapies for the one third of depressed patients who are not helped by currently available measures.

Panic disorder: a treatment update.

Panic disorder is characterized by unexpected, unprovoked attacks of cognitive symptoms (e.g., dread, fear) and physical symptoms (e.g., palpitations, trembling, shortness of breath). It is the most common anxiety disorder seen in clinical practice. Pharmacotherapy has been shown to be effective in controlling symptoms of panic disorder, although potential disadvantages (e.g., adverse drug reactions, withdrawal syndrome, dependency) must be carefully assessed and balanced against the advantages. Current data indicate that for panic disorder, benzodiazepines prescribed for more than a 6-month period are as effective as other forms of pharmacotherapy, i.e., monoamine oxidase inhibitors and tricyclic antidepressants. Generally, doses of benzodiazepines used for the treatment of panic are higher compared to those used for generalized anxiety disorder.

Antidepressant efficacy and tolerability of the selective norepinephrine reuptake inhibitor reboxetine: a review.

Reboxetine is a unique selective norepinephrine reuptake inhibitor (NRI) with proven antidepressant efficacy in pharmacologic and biochemical tests predictive of antidepressant properties. Comprehensive clinical trials, including 8 placebo-controlled and/or active treatment-controlled studies, plus 4 open studies, have assessed the short-term and long-term efficacy and tolerability of reboxetine in patients with major depressive disorders and dysthymia. Results from a total of 690 patients who entered 5 open or placebo-controlled studies are summarized in this paper. Four hundred forty-nine patients with a diagnosis of either major depressive disorder or dysthymia were treated with reboxetine in these clinical studies of 4 weeks' to 12 months' duration. In a 6-week placebo-controlled study, clinically significant improvement (> or = 50% reduction in Hamilton Rating Scale for Depression total score) was observed at last assessment in 74% of reboxetine-treated patients compared with 20% of patients in the placebo group. Similar results were observed in the 6-week run-in phases of the 3 long-term studies, where the efficacy of reboxetine was maintained over the 12-month study period. Reboxetine was well tolerated; adverse events reported were mainly mild to moderate in severity, and there were no clinically significant changes in vital signs or laboratory parameters. The first in its class, reboxetine, a selective NRI, will provide a valuable addition to the existing armamentarium of agents used in the treatment of depression.

Clinical effects of serotonin reuptake inhibitors in the treatment of depressive illness.

The serotonergic hypothesis of depression has stimulated the development of a range of chemically diverse compounds that have an exclusive effect on this neurotransmitter for potential use as antidepressant drugs. The group of serotonin reuptake inhibitors are at various stages of clinical development. The authors review the efficacy, side effect profiles, and toxicity of zimelidine, fluvoxamine, and citalopram in detail and ifoxetine, fluoxetine, indalpine, paroxetine, and sertraline in brief. Evidence suggests that, compared with tricyclic antidepressants, these drugs may cause fewer anticholinergic effects and lower cardiotoxicity in the treatment of major depressive disorders. These advantages need to be weighed against an emerging pattern of gastrointestinal complaints, insomnia, and akathisia. The place of serotonin reuptake inhibitors in therapy can be fully evaluated only after further studies, particularly those involving long-term use. The adverse experience associated with zimelidine suggests that caution and vigilance should be exercised in future studies of agents in this class. These drugs will undoubtedly provide important insights into depressive illness and some anxiety disorders and may fulfill their initial promise.

Diazepam versus alprazolam for the treatment of panic disorder.

BACKGROUND: Alprazolam has proven efficacy as a treatment for panic disorder, but the place of other benzodiazepines is less well established. METHOD: To compare the efficacy and tolerability of diazepam and alprazolam for the disorder, a placebo-controlled, double-blind trial was undertaken in two sites. Two hundred forty-one subjects with panic disorder or agoraphobia with panic attacks were randomly assigned to flexible doses of diazepam, alprazolam, or placebo for 8 weeks. RESULTS: At the end of the trial, over 60% of subjects taking either diazepam or alprazolam were at least moderately improved compared with less than 30% of those taking placebo. On all measures of efficacy, subjects taking diazepam and alprazolam showed an equally favorable response. Despite some sedation early in the trial, both drugs were tolerated well. More severely ill subjects responded less well to either benzodiazepine. CONCLUSION: The results indicate that diazepam is an effective alternative to alprazolam for the treatment of panic disorder.

A placebo controlled trial of diazepam and oxprenolol for anxiety.

Sixty-two patients with moderately severe anxiety symptoms were treated in a double bline 3-week trial with either oxprenolol, diazepam or placebo. The Hamilton Anxiety Scale and a Target symptom improvement score were the main measures of change used. All treatment groups significantly improved in the three weeks of the trial. However in the third week of treatment improvement was greater in the diazepam and oxprenolol groups. Observer preferences significantly favoured the diazepam group. The implications of the study were discussed.

Differential effects of the D1-DA receptor antagonist SCH39166 on positive and negative symptoms of schizophrenia.

In the present open study the effects of the D1-dopamine antagonist SCH 39166 on positive and negative symptoms of schizophrenia (DSM-IIIR) were investigated. SCH 39166 was given orally according to a fixed dosage schedule (day 1: 25 mg b.i.d; day 4: 50 mg b.i.d.; day 7: 100 mg b.i.d.; day 18: 200 mg b.i.d.; day 21: 225 mg b.i.d.). Seven patients completed 2 weeks, and five patients completed the study. The reason for premature withdrawal was lack of efficacy or refusal to take SCH 39166. In none of the patients a reduction of the BPRS or CGI score was found. As measured with the PANSS, a significant reduction was observed in the score of the negative subscale, whereas the positive symptoms scale and general psychopathology score remained unaffected. Akathisia, rigidity and hypokinesia were reported occasionally, although only mild in severity. The results of the present study do not support the hypothesis that D1-dopamine antagonists are clinically effective antipsychotics in schizophrenia, considering the fact that SCH 39166 had no effect on positive symptoms. The present study provides circumstantial evidence for an effect of SCH 39166 on negative symptoms.