Charles S. Wilcox

Double-blind, placebo-substitution study of nefazodone in the prevention of relapse during continuation treatment of outpatients with major depression.

The efficacy of nefazodone in prevention of relapse of depression was evaluated in a 36-week double-blind, placebo-substitution, continuation treatment trial. After 16 weeks of acute, single-blind treatment with nefazodone, 131 patients responding to treatment and in stable remission were randomized in a 36-week double-blind trial to either nefazodone (n = 65) or placebo (n = 66). Patients were defined as having relapsed if they had a total score > or = 18 on the 17-item Hamilton Depression Scale on two consecutive visits or if they discontinued treatment for lack of efficacy. Relapse rates were significantly lower for patients randomized to continued nefazodone treatment than for patients switched to placebo. Kaplan-Meier estimates of relapse rates 9 months (36 weeks) after the end of acute treatment were 1.8% for nefazodone versus 18.3% for placebo (P = 0.009) by the Hamilton Depression Scale and 17.3% versus 32.8% (P = 0.028) by discontinuation for lack of efficacy. The mean modal dose of nefazodone was 412 mg/day at study endpoint. These results demonstrate the clinical effectiveness of up to 1 years treatment (16 weeks acute and 36 weeks continuation) with nefazodone in depressed patients. Long-term efficacy of nefazodone was accompanied by a good safety profile without any weight gain and with minimal symptoms of withdrawal upon abrupt discontinuation of treatment.

The Oral Dose-Effect Relationship for Fluvoxamine: a Fixed-Dose Comparison Against Placebo in Depressed Outpatients

This 7- to 8-week, multicenter, randomized, double-blind, placebo-controlled study was performed to determine the dose-effect relationship and minimum effective dose for fluvoxamine maleate in a titrated fixed-dose study of major depressive disorder. Gradual titration over 2 weeks to fixed maintenance doses was employed to minimize dropout due to initial side effects. The study enrolled 600 outpatients, male and female, age 18-65, meeting DSM-III-R criteria for major depressive disorder. A 13-item subscore of the standard 21-Item Hamilton Depression Scale was used to minimize the possible contribution of known side effects from serotonin reuptake inhibitors to the overall HAM-D score. Secondary efficacy assessments included the HAM-D retardation factor, HAM-D depressed mood item, CGI-severity of illness item, and SCL depression factor. Fluvoxamine (50-150 mg/day) was therapeutically effective and well tolerated during 6 weeks of therapy. Based on the HAM-D depressed mood item, efficacy was dose dependent. The minimum effective dose was 50 mg/day. Fluvoxamine maleate shows dose-related effectiveness in the acute treatment of major depressive disorder.

Serotonin 5-HT1a Receptor Agonists as Antidepressants

Although typically considered anxiolytics, for 20 years serotonin 5-HT1A receptor agonists have been evaluated for effectiveness in treating depressive disorders and depressive symptoms occurring in a range of diagnostic categories, including major and minor depression, mixed states of anxiety and depression, and mixed syndromes of depression and alcohol dependence. 5-HT1A agonists have also been studied as adjuncts to standard antidepressant therapy. Most of the work has been done with the widely marketed azapirone, buspirone. A limited amount has been done with other, unmarketed azapirones, including gepirone, ipsapirone, tandospirone and zalospirone. Nonazapirone 5-HT1A receptor agonists have also been studied, and one, flesinoxan, is continuing in clinical trials for the treatment of depression and anxiety.As a whole, the results have shown antidepressant effects for all compounds, though neither consistently nor robustly. The compounds appear to be well tolerated but adverse effects such as dizziness and nausea are common, and the short half-life of these drugs makes twice or 3 times daily administration necessary. Tolerability and adverse effect problems have been attributed to a metabolite of the azapirones, 1-pyrimidinyl-piperazine (1-PP), which is not a metabolite of the nonazapirone flesinoxan. The short half-life issue has been addressed by extended release oral preparations and transdermal administration via a once-daily skin patch. One study was of 6 months’ duration; the remaining studies have lasted 10 weeks or less. We cannot recommend buspirone, the only currently marketed 5-HT1A receptor agonist, as a first-line treatment for depression, but it is reasonable to consider its use as an adjunct to standard antidepressant drug therapy or in mixed states of anxiety and depression.The combined results have greatly contributed to our understanding of the role of the 5-HT1A receptor in a range of clinical forms of depression. They have also been useful in understanding the mechanisms of actions of other antidepressants and have guided the development of new medications.

Long-Term Comparison of Alprazolam, Lorazepam and Placebo in Patients with an Anxiety Disorder

In a double‐blind, placebo‐controlled study of 200 patients with moderate to moderately severe anxiety we compared the anxiolytic efficacy and safety of alprazolam and lorazepam. Dosing was flexible and ranged from 1 to 4.5 mg/day of alprazolam and from 2 to 9 mg/day of lorazepam. The mean daily dose at the end of the 16 week study was alprazolam 3.3 mg and lorazepam 5.1 mg. Both active drugs were significantly more effective than placebo in relieving the symptoms of anxiety on the Hamilton Anxiety Rating Scale, with a trend toward more improvement in the alprazolam group in the later weeks of the study. Target Symptoms, Physicians and Patients Global Impressions and the Self Rating Symptom Scale indicate that alprazolam and lorazepam were superior to placebo. The major side effects were sedation and drowsiness; the frequency was similar for alprazolam and lorazepam and twice as high for active drug as placebo. An overall rating of side effect severity was not significantly different among the three groups.

Hypnotic Efficacy of Estazolam Compared with Flurazepam in Outpatients with Insomnia

Eslazolam is a new benzodiazepine hypnotic agent with an intermediate half‐life of 12 to 15 hours. The authors designed an investigation to compare its hypnotic efficacy to that of flurazepam, generally considered the reference standard. The hypnotic efficacy of estazolam at two doses (1 mg and 2 mg) was compared with that of flurazepam (30 mg) in a double‐blind, placebo‐controlled, multicenter, 7‐night study that involved 223 outpatients with insomnia. On subjective assessments of the patients, no differences were noted between estazolam 2 mg and flurazepam 30 mg on any of six sleep parameters. Patients who were receiving estazolam 1 mg rated their sleep significantly better than did patients who were receiving placebo on all parameters except sleep latency. Global evaluation of the physicians indicated significant improvement in quality of sleep, sleep depth, sleep duration, and nocturnal awakenings in all three active treatment groups; estazolam 2 mg and flurazepam also decreased sleep latency significantly. The percentage of patients who reported any adverse experience was 68% for flurazepam, 58% for estazolam 2 mg, and 54% for estazolam 1 mg; the incidence of adverse events in the placebo group was 43%. In conclusion, estazolam 2 mg was found to be as effective a hypnotic as flurazepam 30 mg. Estazolam 1 mg is also effective in the treatment of outpatients with insomnia, but to a lesser degree.

Neuroendocrine effects of buspirone in patients with generalized anxiety disorder

This study investigated a therapeutic regimen of buspirone, a new anxioselective drug, in patients with generalized anxiety disorder. The single-blind study, conducted in 23 outpatients, consisted of 28 days of buspirone treatment followed by four days of placebo treatment. Patients received a single 10-mg dose of buspirone on study day one, which was titrated to 10 mg three times daily by study day seven and which remained at 10 mg three times daily through study day 28. Blood samples were drawn on days one, 14, 28, and 32 for determination of plasma levels of prolactin, growth hormone, and cortisol. The therapeutic effect of buspirone was assessed by standard psychometric rating scales. When titrated to a total daily dose of 30 mg per day (10 mg three times daily), buspirone provided effective antianxiety therapy and had no significant effect on plasma levels of prolactin, growth hormone, or cortisol.

Development of an early detection battery for dementia of the Alzheimer type

1. To develop a diagnostic battery sensitive to and specific for the early detection of Alzheimer disease (AD) dementia, the authors reviewed over 400 journal articles dealing with the diagnosis of A.D. or senile dementia and cognitive assessment in organic brain dysfunction and closed head injury. 2. We culled those studies that met our criteria for solid, reliable and statistically significant results and recommend the testing paradigms that most often produced good discrimination of mild AD dementia from normal senescence. 3. These include tests of language, verbal and non-verbal memory, perception, praxis, attention and reasoning. 4. The battery we assembled takes less than 1 hour to administer, requires no special equipment, and was designed as an early screen for use by psychologists, psychiatrists and other trained health care professionals; it is not intended for repeated administration, as in pharmacological or longitudinal studies.

Efficacy and safety of pentoxifylline in geriatric patients with intermittent claudication

The effects of pentoxifylline on intermittent claudication were evaluated at a dose of 1200 mg/day in an open-label twelve-week study on geriatric patients with chronic occlusive arterial disease (COAD). Standardized treadmill testing and clinical signs and symptoms of COAD were followed up before and during drug administration. Twenty-four subjects with a mean age of 73.5 years, capa ble of walking between 20 and 200 meters on the treadmill, were entered into the trial; 22 participated for eight weeks and 19 completed the study in terms of treadmill walking distance measurements at 12 weeks. The mean walking dis tance for all patients was increased 111% over baseline at week 12. Thirteen subjects were considered drug responders ( ≥ 50% increase in treadmill walking distance) and 9 were considered nonresponders (<50% increase). Improve ments in clinical signs and symptoms of COAD were noted. Decreases in ele vated systemic systolic pressures (but not diastolic) were unexpectedly observed in many drug responders. Seven of 19 males reported sexual function improve ments while receiving pentoxifylline. Fourteen (58%) of the 24 subjects reported mild side effects of dyspepsia, nausea, vomiting, dizziness, headache, or insom nia; no subjects were withdrawn from the study because of side effects. In sum mary, pentoxifylline improved function and symptoms in 13 of 22 geriatric patients with intermittent claudication; the drug was safe and well tolerated at the usual dosage in this geriatric patient population.