The scientific and ethical basis for placebo-controlled trials in depression and schizophrenia: an FDA perspective.

There is a tension between the need for scientifically valid trials of new psychotropic drugs and concern about conducting placebo-controlled trials, the trials psychopharmacologists consider the gold standard trial, when this requires that some patients be denied existing effective therapy. This paper will review the scientific principles supporting the need for placebo-controlled trials in depression and schizophrenia, and will provide preliminary data on failure rates of placebo-controlled trials for these disorders, as illustrations of the application of these principles. Next, the ethical issues pertinent to the conduct of placebo-controlled trials for these two serious psychiatric disorders will be reviewed. Preliminary data on suicides in placebo-controlled depression and schizophrenia trials will be presented to argue for the ethical acceptability of the conduct of placebo-controlled trials in these two conditions.

Premarketing studies in the drug approval process: understanding their limitations regarding the assessment of drug safety.

This paper discusses the premarketing safety database that the US Food and Drug Administration receives from drug manufacturers. It reviews the kind of data we usually receive, what we do with the data, and how the data affect labeling. In addition, it discusses some of the limitations of that database in ensuring the safe use of medications.

Regulatory issues in pediatric psychopharmacology.

Labeling claims for the effectiveness of drugs in the treatment of psychiatric illnesses in children and adolescents must be based on data from adequate and well-controlled investigations. The preferred design for demonstrating the effectiveness of a drug in pediatric psychopharmacology is generally a placebo-controlled trial. Safety information in labeling may be derived from more diverse sources. The Food and Drug Administration (FDA) has taken several steps to encourage more informative labeling of drugs for pediatric use, including a recent labeling initiative that emphasizes the possibility of extrapolating effectiveness data from adult studies to pediatric populations under appropriate circumstances. This recently finalized regulation requires pharmaceutical sponsors to reexamine existing data for their drugs to determine whether there is a sufficient basis for modifying labeling for pediatric use. Included in this new rule is a reminder that in certain situations the FDA may require new pediatric studies, thereby signaling the FDA's determination to improve labeling for the pediatric use of drugs. Improved preclinical models for predicting drug effects on growth and development, as well as improved clinical methods for detecting such changes, need to keep pace with the expansion of research in pediatric psychopharmacology.

Serum neuroleptic levels, prolactin levels, and relapse: a two-year study of schizophrenic outpatients.

For 2 years serum neuroleptic levels, prolactin levels, and clinical states were assessed in 105 male schizophrenic outpatients every 6 months. The patients were taking a variety of neuroleptics at clinically determined fixed doses. Those who had psychotic symptoms at 50% or more of their visits attained serum levels of neuroleptics and prolactin well within or above the range observed in the remitted patients. Neuroleptic and prolactin levels did not discriminate patients who relapsed from those who did not relapse. In the remitted patients who relapsed at least once during the study period, neuroleptic and prolactin serum levels were lower before the relapse episodes than before the stable periods.

Neuroleptic bioavailability, psychosocial factors, and clinical status: a 1-year study of schizophrenic outpatients after dose reduction.

Serum neuroleptic levels, prolactin levels, and clinical state were assessed for 1 year in 29 schizophrenic outpatients whose clinically determined neuroleptic dose had been reduced by 50%. Fifty-five percent of the subjects remained stable. Neuroleptic dose did not differ between relapsed and stable patients. Serum prolactin (PRL) assessed 2 weeks after dose reduction and mean PRL after reduction were significantly lower among relapsers. Serum neuroleptic levels were significantly lower for relapsers in patients on haloperidol. Among relapsers, there were no serum PRL or neuroleptic level differences between stable periods and the relapse episode. Among patients with relatively low neuroleptic bioavailability, relapsers reported lower levels of social activity and had social networks that were less enjoyable, more aversive, and less helpful than those of stable patients.

Chronic diazepam treatment in psychiatric outpatients.

Anxiety symptoms and plasma diazepam and desmethyldiazepam were assessed in 50 male outpatient veterans with primary chronic anxiety symptoms who had been taking an average of 17.7 mg of diazepam per day for a mean of 4.9 years. These subjects were moderately anxious (mean Hamilton Anxiety Scale score = 23) despite their chronic diazepam use. Although tolerance could explain this inadequate anxiolytic effect, the absence of a significant correlation between duration of use and either diazepam dose or any of the three anxiety measures argues against this hypothesis. The findings of modest diazepam dose and plasma concentration (mean=324 ng/ml) and of a trend toward a positive correlation between anxiety level and both dose and plasma level suggest inadequate dosage as a more likely explanation for the subjects' continued anxiety.

Low serum neuroleptic levels predict relapse in schizophrenic patients.

Relapse occurs in a substantial proportion of schizophrenic patients treated with neuroleptics. The determinants of relapse have been elusive. In our study, low serum neuroleptic levels identified patients who had a relapse during a six-month period. Neuroleptic levels were measured by radioreceptor assay in 61 schizophrenic men and their clinical status was assessed in the subsequent six months. Ten patients had relapses, four showing a worsening of chronic psychotic symptoms and six showing eruption of psychotic symptoms after a period of remission. These ten patients had significantly lower normalized neuroleptic levels than those whose conditions remained stable. The lowest neuroleptic levels occurred in patients who had relapses after a period of remission. Serum neuroleptic levels in drug-responsive patients appear to be a critical determinant of remission. If these observations are replicated, a rational basis may be provided for prescribing and monitoring neuroleptic treatment and perhaps for preventing relapse.

A controlled trial of diazepam withdrawal in chronically anxious outpatients.

Twenty-four middle-aged male chronically anxious outpatients who were taking diazepam at a mean dose of 17 mg/day for a mean duration of 5 years were assigned to maintenance (M), gradual withdrawal (GW) or abrupt withdrawal (AW) and followed weekly. No differences were seen in two self-report anxiety measures or in withdrawal symptoms between groups. Hamilton Anxiety Rating Scale scores were slightly elevated (F = 2.34, P less than 0.05) in the AW patients at a mean duration of 4 weeks off diazepam. Thus, withdrawal from chronic diazepam (10-30 mg/day) use produced no prominent withdrawal syndrome, but the suggestion of gradual anxiety recurrence indicates the need fro longer-term follow-up studies to adequately assess maintenance efficacy.

Tolerance to the prolactin-elevating effect of neuroleptics.

Following the rise in serum prolactin at the onset of neuroleptic treatment, patients kept on a constant dose show systematic changes in prolactin during the first 3 months. After 4 months, prolactin reaches a stable level substantially lower than that at the onset of neuroleptic treatment and not differing from that after years of treatment.

Differential effects of neuroleptic agents on the pituitary-gonadal axis in men.

Previous studies showing inconsistent effects of neuroleptic agents on the pituitary-gonadal system suggest that the drugs may differ in their effects on this system. Serum testosterone, luteinizing hormone (LH), prolactin, and neuroleptic levels were measured in 42 male schizophrenic patients during long-term treatment with thioridazine hydrochloride, trifluoperazine hydrochloride, chlorpromazine hydrochloride, and other neuroleptic agents and in six drug-free patients. Serum testosterone and LH values were significantly lower in patients taking thioridazine than in those taking other neuroleptic drugs. The relatively high serum neuroleptic levels in patients taking thioridazine may account for its differential effect on the pituitary-gonadal system.

Plasma diazepam and desmethyldiazepam concentrations during long-term diazepam therapy.

1 Factors influencing steady-state plasma concentrations of diazepam (DZ) and its major metabolite desmethyldiazepam (DMDZ) were assessed in 110 male Veterans Administration outpatient clinic patients (mean age 53 years). 2 Patients reportedly had taken DZ for 1 to 14 years (mean duration 5.1 years) at a mean daily dose of 20 mg (range 2 to 55 mg). 3 Steady-state plasma concentrations of DZ (mean 329 ng/ml) and DMDZ (mean 389 ng/ml) were highly correlated (r = 0.80), with a mean DMDZ/DZ ratio of 1.26. 4 Weight-corrected daily dose were significantly correlated with plasma level of DZ (r = 0.32), DMDZ (r = 0.38) and the sum of DZ plus DMDZ (r = 0.37), but explained a small fraction of individual variation. 5 Duration of therapy, smoking habits, alcohol consumption, and number of other drugs coingested were not significantly related to plasma level.