Fluvoxamine versus imipramine and placebo: a double-blind comparison in depressed patients.

Approximately 20 million patients suffer from major depressive disorder each year, indicating a need for antidepressant agents that are synonymous with effectiveness, tolerability and patient compliance. The authors examined the effects of fluvoxamine, a selective serotonin reuptake inhibitor, in the treatment of outpatients meeting DSM-III-R criteria for major depressive disorder. A randomized, double-blind, parallel group, placebo- and imipramine-controlled single center study was conducted in 150 outpatients. Patients were randomized to receive up to 150 mg/day of fluvoxamine as a single bedtime dose, 240 mg/day of imipramine on a twice-daily (BID) schedule, or placebo for six weeks. Efficacy measurements included HAM-D, MADRS, CGI, Raskin-Covi and SCL-56 scales. The HAM-D total score indicated that both active treatment groups showed significantly (p < or = 0.05) greater therapeutic benefit than did placebo. Severely depressed patients (HAM-D > or = 30) responded better to fluvoxamine in five of six measures. Side-effects from fluvoxamine were similar to those reported for other selective serotonin reuptake inhibitors (nausea, somnolence) and were well tolerated. Imipramine was associated with anticholinergic effects such as dry mouth and dizziness. The pharmacokinetic properties of fluvoxamine which allow the drug to be administered as a single daily dose should aid in the maintenance of patient compliance, while offering significant clinical benefit in the improvement of depressive symptoms.

Early human trials in the assessment of cognition activators.

The assessment of cognition enhancers in the clinic is a broad topic that can be addressed from both academic/theoretical and therapeutic/drug development perspectives. The most important first step is to decide which perspective one is employing and to clearly specify, a priori, the goal of any intended study. Since the therapeutic benefit of cognition enhancers is not apparent until after many weeks of exposure, it is virtually impossible to demonstrate efficacy in early, short-duration Phase 2 trials. It is possible, however, to gain some knowledge of the doses that effect CNS, rCBF, PET etc. in either normal volunteers or the population of interest. However, these results should not be interpreted as evidence for, or lack of, efficacy. Recently, there has been growing interest in the reversal of scopolamine- or benzodiazepine-induced memory deficits in humans. A major problem is the potential for overinterpretation of the results of such studies. From a drug development approach, it is necessary to utilize larger numbers of subjects and longer-term studies. Specification of the indication should be as precise as possible and the outcome measures should accurately reflect both the current state of the patient and the course of the disease. The absence of normative and longitudinal data on such measures is a hurdle that is only now being overcome. Such data provide a scientific basis for the determination of the types of design and sample sizes that give adequate power to thoroughly assess new cognition enhancers.

Use of carbamazepine in psychiatric disorders.

Use of carbamazepine for the treatment of psychiatric disorders is reviewed. Carbamazepine's mechanism of action may be related to inhibition of kindling (repeated subtherapeutic electrical stimulation) in the temporal lobe and limbic system. In most published studies, carbamazepine was useful in affective disorders, especially in patients with bipolar manic disorders. In controlled, double-blind studies in patients with primary affective or schizoaffective disorders, carbamazepine significantly decreased manic symptoms and showed some antidepressant effect. Synergistic effects have been observed when carbamazepine is used with lithium. Carbamazepine has been reported to decrease symptoms in patients with aggression, dyscontrol syndromes, schizophrenia, and alcohol withdrawal syndrome, but few of these studies have been controlled, comparative trials; carbamazepine may be useful in patients with these disorders who do not respond to conventional therapies. Beneficial effects of carbamazepine in psychiatric disorders are usually observed with doses of 400-1600 mg/day and serum concentrations of 8-12 micrograms/mL. Carbamazepine is useful alone or in combination with other agents for bipolar affective disorders, especially in patients who are intolerant of or unresponsive to lithium. Serum carbamazepine concentration, hematological profile, and serum electrolytes should be monitored carefully to minimize the risk of toxicity.

The neuroleptic malignant syndrome: presentation and treatment.

The neuroleptic malignant syndrome is a potentially lethal reaction following the use of antipsychotic medications. The four cardinal signs are hyperthermia, muscular rigidity, autonomic dysfunction, and altered consciousness. The differential diagnosis of the syndrome includes malignant hyperthermia of anesthesia, heat stroke, and acute lethal catatonia. Treatment consists of prompt recognition of the syndrome and initiation of intense supportive measures to manage the hyperthermia and prevent secondary complications. Clinical reports describing beneficial results from use of anticholinergic agents, amantadine, bromocriptine, and dantrolene are reviewed.

Mechanism and management of important psychotherapeutic drug interactions.

Interactions between drugs can result in unintended changes in desired pharmacologic effects. Because psychotherapeutic drugs represent the most widely used class of pharmacologic agents, physicians must anticipate possible consequences of their interactions. An overview of drug interaction reports reveals that they can be usefully divided into those with either a pharmacokinetic or pharmacodynamic mechanism. We review the most important of these interactions and present methods to avoid or minimize their untoward effects.