Joyce D. Kales

Child and parent reaction to the Three Mile Island nuclear accident.

Thirty-five local children and their parents were studied 1 1/2 years after the Three Mile Island (TMI) nuclear accident. On a standardized self-report measure, the children were found to have a level of residual anxiety that was not identified by their parents. These children also consistently reported stronger and more symptomatic responses to the TMI accident for themselves than their parents did for them. Child intensity-of-reaction scores were significantly related to mother-father discordance in mood and reaction to the event. Four of the children who were psychiatrically disturbed showed significantly high or low intensity-of-reaction levels.

Hypnotic efficacy of triazolam: sleep laboratory evaluation of intermediate-term effectiveness.

Triazolam (U-33030), an investigational hypnotic drug, was evaluated in seven insomniac subjects in the sleep laboratory. The protocol consisted of 22 consecutive nights: four placebo nights for adaptation and baseline, two weeks of drug administration (0.5 mg triazolam) for short- and intermediate-term drug effectiveness, and four placebo nights for withdrawal effects. With short-term drug use, both sleep induction and sleep maintenance improved, with total wake time decreasing markedly--a 45 per cent decrease from baseline. At the end of two weeks of drug use, none of the efficacy parameters was significantly decreased from baseline; there was only a 17 per cent decrease in total wake time. Following drug withdrawal, sleep difficulty significantly increased above baseline levels. Two of the subjects experienced episodes of amnesia during the drug administration period. The per cent of REM sleep decreased significantly during both short and intermediate drug conditions. Following drug withdrawal, the per cent of REM sleep was similar to baseline. Slow-wave (stages 3 and 4) sleep was significantly decreased for both drug conditions; and following drug withdrawal, it returned completely to the baseline leve. These data indicate that triazolam is effective for short-term use, loses most of its effectiveness with intermediate-term use, and its withdrawal is followed by a significant sorsening of sleep. These findings are discussed in relation to the potential labeling and promotion of triazolam. Finally, the findings of amnesia associated with triazolam administration need to be more thoroughly evaluated.

Effectiveness of hypnotic drugs with prolonged use: flurazepam and pentobarbital.

This study represents the first attempt to rigorously evaluate the effectiveness of hypnotic drugs under conditions of prolonged use. Flurazepam, 30 mg, and pentobarbital, 100 mg, were separately evaluated in identical 47‐night sleep laboratory drug evaluation studies on insomniac subjects, which included 4 weeks of drug administration. Flurazepam was found to be effective in inducing and maintaining sleep over all treatment conditions. With long‐term use, only a slight loss of effectiveness was suggested. Flurazepam also produced a moderate decrease in REM sleep and marked decrease in eye movement density and stage 4 sleep with short‐ and intermediate‐term use. While the decreases in both REM sleep and eye movement density lessened with long‐term use, stage 4 sleep remained markedly suppressed. No rebound was noted in any of these parameters after withdrawal. Pentobarbital was found to be effective in inducing and maintaining sleep only with short‐term drug administration. This strongly suggests that it is of limited value for insomniac patients who require nightly medication beyond short‐term use. Pentobarbital caused a minimal decrease in REM sleep with short‐ and intermediate‐term administration, and slight rebound following withdrawal. Stages 3 and 4 sleep were decreased with short‐term use and increased above baseline levels after withdrawal.

Comparative Effectiveness of Nine Hypnotic Drugs: Sleep Laboratory Studies

The effectiveness of nine hypnotic drugs was compared using a standard protocol in separate sleep laboratory drug evaluation studies. All of these drugs were relatively effective in improving sleep with initial and short-term use. However, with intermediate-term use (two weeks), most of the drugs showed a marked decrease in their effectiveness. Following withdrawal, sleep was similar to baseline with most of the drugs, continued to be improved with flurazepam (Dalmane), 30 mg, and worsened beyond baseline levels with triazolam (U33030), 0.5 mg. The determination of a drugs effectiveness with continued use is most important clinically in enabling the physician to rationally and effectively use hypnotic drugs in the adjunctive treatment of insomnia.

Sleep laboratory studies of flurazepam: a model for evaluating hypnotic drugs.

The results from six separate evaluations of flurazepam 30 mg in the sleep laboratory were combined to determine the effectiveness of the drug in inducing and maintaining sleep and its effects on sleep stages in a large sample of insomniac subjects. The combined studies provide a model from which a detailed profile of the effects of a hypnotic drug over short‐, intermediate‐, and long‐term conditions can be thoroughly evaluated. Although sleep was significantly improved on the first night of flurazepam administration, peak effectiveness of the drug did not result until the second and third consecutive drug nights. Flurazepam continued to be effective in inducing and maintaining sleep with intermediate‐ and long‐term drug use with only a slight loss of effectiveness with long‐term use. Sleep was also significantly improved on the first and second nights of drug withdrawal. Carryover effectiveness of active metabolites of flurazepam from one drug night to the next drug night and to withdrawal nights is discussed. The clinical implications are discussed with regard to the time of peak effectiveness of the drug, dosage recommendations and schedule, minimizing possible effects of the drug on daytime performance, and the rationale and method for using drug holidays in the treatment regimen. With this comprehensive profile of the drugs actions, the physician is able to more rationally and effectively utilize the drug in treating the insomniac patient. With short‐term administration, flurazepam produced a slight decrease in rapid eye movement (REM) sleep and an increase in REM latency. These effects were much more pronounced with intermediate‐term drug administration, again possibly due to the accumulation of active metabolites. After withdrawal there was no rebound in REM sleep. Stages 3 and 4 sleep decreased progressively through short and intermediate drug administration. With initial withdrawal, there was a slight recovery in both sleep stages.

Effectiveness of temazepam with short-intermediate-, and long-term use: sleep laboratory evaluation.

The effectiveness of 30 mg temazepam (SaH 47-603) for inducing and maintaining sleep was evaluated in the sleep laboratory in six insomniac subjects under conditions of short-, intermediate-, and long-term drug administration. Administration of temazepam had no effect on sleep induction. In addition, effectiveness was not demonstrated for sleep maintenance: wake time after sleep onset was not significantly decreased on any of the three drug conditions, while the number of nightly awakenings was significantly decreased on all three drug conditions. Total wake time was decreased only slightly with short-term drug administration and was similar to baseline with intermediate- and long-term use. The percent REM sleep was essentially unchanged throughout the drug administration period. On the initial set of withdrawal nights, the per cent REM sleep was slightly but no significantly increased over baseline. The per cent slow wave sleep decreased significantly with short-, intermediate-, and long-term drug administration. After withdrawal, the percent slow wave sleep returned to baseline values.

Flunitrazepam, an Investigational Hypnotic Drug: Sleep Laboratory Evaluations

It is an analogue of nitrazepam (Mogadon*+), a hypnotic drug which has been widely used in Europe since 1965 but not available for clinical use in the United States. In a preliminary study of the effectiveness of flunitrazepam, our results suggested that the drug was effective in doses of 0.25, 1, and 2 mg.2 In this study, three separate sleep laboratory evaluations of flunitrazepam are described. The primary

Hypnotic Effectiveness of Sodium Salicylamide with Short-Term Use: Sleep Laboratory Studies

Sodium salicylamide in doses of 650 and 1,300 mg was evaluated in two separate sleep laboratory drug evaluation studies of insomniac patients. Each study utilized a standard protocol of 10 consecutive laboratory nights consisting of four placebo nights for adaptation and baseline, three drug nights for short-term drug administration and three placebo nights for evaluating withdrawal. Neither dose had a clear-cut hypnotic effect in inducing or maintaining sleep. Sleep stages were not effected by drug administration or drug withdrawal. Both the objective findings and subjective estimates suggest that the 1,300-mg dose may have a slight sedative effect. However, when salicylamide is used as an ingredient in over-the-counter preparations, the usual dose is only 200-400 mg.

Nocturnal Psychophysiological Correlates of Somatic Conditions and Sleep Disorders

Modern sleep research studies have provided the practicing physician with considerable new information concerning the basic psychophysiology of sleep, the effects of medical conditions on sleep and the role of maturational and emotional factors in producing certain sleep disorders. Medical and psychiatric disorders, sleep disorders and drug-induced sleep stage alterations are studied in the sleep laboratory using the same techniques developed to analyze sleep patterns in normal subjects. After initial sleep laboratory adaptation, a profile of the sleep characteristics of various clinical conditions is obtained. This profile can be compared to sleep profiles of normal subjects as well as to the effects on sleep of subsequent experimental or therapeutic procedures. Various studies have shown that coronary artery, duodenal ulcer and nocturnal headache patients experience angina, increased gastric acid secretion and migraine or cluster headaches, respectively during REM sleep. Adult nocturnal asthmatic episodes occur out of all sleep stages while attacks of dyspnea in asthmatic children occur in all stages except stage 4 sleep. Hypothyroid patients show decreases in stages 3 and 4 sleep, while in hyperthyroid patients the percentage of time spent in stages 3 and 4 sleep is markedly increased. Enuretic episodes occur predominantly in non-rapid eye movement (NREM) sleep. Sleepwalking and night terror episodes occur exclusively out of NREM sleep, particularly from stages 3 and 4 sleep. Most child somnambulists and children with night terrors “outgrow” this disorder, suggesting a delayed maturation of the central nervous system. Stimulant drugs are effective in the treatment of the sleep attacks of narcolepsy and in treating certain cases of hypersomnia, while imipramine is an effective treatment for the auxiliary symptoms of narcolepsy. Psychological disturbances are frequent in adult somnambulism and night terrors as well as in hypersomnia and insomnia. Proper pharmacologic treatment to provide symptomatic relief for insomnia is recommended to enhance the psychotherapeutic process.

Schizophrenia: Historical Perspectives

Whereas mental aberrations have been described throughout history, and even inferred in prehistoric times, psychiatry as a distinct medical discipline and the birth of the nosological concepts of schizophrenia are both only about two centuries old. However, before these relatively recent systematic and scientific efforts to study mental disorders, one can find references and descriptions pertaining to mentally ill individuals that date back to early civilizations.1–10 An understanding of diseases of the mind seems to have rested in general on prevailing religious, social, and philosophical views of behavior, reason, and human volition. Nonetheless, there were numerous efforts to classify descriptively symptoms and syndromes and to propose hypotheses concerning causation that provide interesting historical links to our contemporary systems of classification and theories of etiology.2