Sleep deprivation as a model experimental antidepressant treatment: findings from functional brain imaging.

This paper reviews the functional brain imaging studies in depressed patients treated with sleep deprivation. Sleep deprivation is an excellent experimental model of antidepressant treatments which offer new opportunities to understand the basic neural mechanisms. Its antidepressant effects are efficacious and rapid; sleep deprivation is easy to administer, inexpensive, and relatively safe; it can be studied in patients, normal controls, and animals; and it may lead to new treatments and new paradigms for antidepressant therapies. Seven published papers, coming from five different research centers, using either positron emission tomography (PET) with 18fluorodeoxyglucose (FDG) or single photon emission computerized tomography (SPECT) with Technetium-99-bexamethyl propyleneamine oxime (HMPAO) have relatively consistent findings. First, before sleep deprivation, responders have significantly elevated metabolism compared with non-responders, and usually the normal controls, in the orbital medial prefrontal cortex, and especially in the ventral portions of the anterior cingulate cortex. Secondly, after sleep deprivation, these hyperactive areas normalize in the responders. The magnitude of the clinical improvement was significantly correlated with decreased local glucose metabolic rate or cerebral blood flow in three studies. The results are consistent with some but not all functional brain imaging studies of antidepressant medications in depressed patients. Finally, a SPECT study using a radioactively labeled D2 receptor antagonist suggests that the antidepressant benefits of sleep deprivation are correlated with endogenous release of dopamine.

Ultradian rhythms of alternating cerebral hemispheric EEG dominance are coupled to rapid eye movement and non-rapid eye movement stage 4 sleep in humans.

Objective: To replicate the left minus right (L-R) hemisphere EEG power shifts coupled to rapid eye movement (REM) and non-rapid eye movement (NREM) sleep observed in 1972 by Goldstein (Physiol Behav (1972) 811), and to characterize the L-R EEG power spectra for total EEG, delta, theta, alpha and beta bands.Background: Ultradian alternating cerebral hemispheric dominance rhythms are observed using EEG during both waking and sleep, and with waking cognition. The question of whether this cerebral rhythm is coupled to the REM-NREM sleep cycle and the basic rest-activity cycle (BRAC) deserves attention.Methods: L-R EEG signals for ten young, normal adult males were converted to powers and the means were normalized, smoothed and subtracted. Sleep hypnograms were compared with L-R EEGs, and spectra were computed for C3, C4 and L-R EEG powers.Results: Significant peaks were found for all C3, C4 and L-R frequency bands at the 280-300, 75-125, 55-70 and 25-50 min bins, with power dominating in the 75-125 min bin. L-R EEG rhythms were observed for all bands. Greater right hemisphere EEG dominance was found during NREM stage 4 sleep, and greater left during REM for total EEG, delta and alpha bands (Chi-squares, P<0.001). Theta was similar, but not significant (P=0.163), and beta was equivocal.Conclusions: Earlier ultradian studies show that lateral EEG and L-R EEG power have a common pacemaker, or a mutually entrained pacemaker with the autonomic, cardiovascular, neuroendocrine and fuel-regulatory hormone systems. These results for L-R EEG coupling to sleep stages and multi-variate relations may present a new perspective for Kleitman's BRAC and for diagnosing variants of pathopsychophysiological states.

Sleep abnormalities during abstinence in alcohol-dependent patients. Aetiology and management.

Virtually every type of sleep problem occurs in alcohol-dependent patients. Typically, these individuals take a longer time to fall asleep and show decreased sleep efficiency, shorter sleep duration and reduced amounts of slow wave sleep when compared with healthy controls. Their sleep patterns are fragmented, and the typical time course of electroencephalogram (EEG) delta wave activity is severely disrupted. The amount of rapid eye movement (REM) sleep may be reduced or increased. Sleep changes can persist during months or years of abstinence, and recent studies indicate that certain alterations in sleep architecture, as well as subjective sleep complaints, predict relapse to alcoholism. The mechanisms of action of short and long term alcohol administration on sleep are incompletely understood. They may arise from an interaction with gamma-aminobutyric acid (GABA), serotonin (5-hydroxytryptamine; 5-HT), adenosine or other neurotransmitter systems. While only a few pharmacological and nonpharmacological strategies to improve or normalise disturbed sleep in individuals who have recovered from alcoholism have been studied, the use of benzodiazepines, other hypnosedatives or selective serotonin reuptake inhibitors is not recommended. Therapies include sleep hygiene, bright light therapy, meditation, relaxation methods, and other nonpharmacological approaches. Further studies are needed to clarify the relationship between sleep, sleep abnormalities and alcoholism, and to establish new approaches to improve sleep in alcohol-dependent patients and to prevent withdrawal reactions that affect sleep during abstinence.

Relationship of mood disturbance to cigarette smoking status among 252 patients with a current mood disorder.

BACKGROUND: The relationship between cigarette smoking and mood has received increasing attention. This retrospective study evaluated the relationship between mood disturbance and cigarette smoking status among patients with a current mood disorder. The association between level of nicotine dependence and severity of mood disturbance was also evaluated among current smokers. METHOD: Retrospective data for 252 patients (63.5% male, 85.0% white) admitted for treatment of a mood disorder at the San Diego Veteran Affairs Mental Health Clinical Research Center between November 1988 and June 1997 were studied. All current cigarette smokers at admission (N = 126) were matched with nonsmokers (N = 126) on the primary DSM-IV Axis I mood disorder diagnosis, admission status (inpatient or outpatient), gender, age (+/- 5 years), and ethnicity. The Hamilton Rating Scale for Depression (HAM-D), the Beck Depression Inventory, and the Profile of Mood States (POMS) were administered to patients on admission. Conditional logistic regression analysis for matched sets with a backward elimination was used to identify factors independently predictive of current smoking status. RESULTS: A greater number of cups of coffee consumed per day (p = .002), a history of alcoholism (p = .004), and higher POMS fatigue subscale scores (p = .007) were predictive of current smoking status. Among current smokers, the HAM-D terminal insomnia item was positively associated with mean number of cigarettes smoked per day (p = .012). CONCLUSION: Cigarette smoking should be addressed in the treatment of patients with a current mood disorder. Smokers experience greater levels of fatigue than nonsmokers. In addition, higher cigarette consumption levels are associated with mild-to-severe symptoms of terminal insomnia.

Increased cerebral response during a divided attention task following sleep deprivation.

We recently reported that the brain showed greater responsiveness to some cognitive demands following total sleep deprivation (TSD). Specifically, verbal learning led to increased cerebral activation following TSD while arithmetic resulted in decreased activation. Here we report data from a divided attention task that combined verbal learning and arithmetic. Thirteen normal control subjects performed the task while undergoing functional magnetic resonance imaging (FMRI) scans after a normal night of sleep and following 35 h TSD. Behaviourally, subjects showed only modest impairments following TSD. With respect to cerebral activation, the results showed (a) increased activation in the prefrontal cortex and parietal lobes, particularly in the right hemisphere, following TSD, (b) activation in left inferior frontal gyrus correlated with increased subjective sleepiness after TSD, and (c) activation in bilateral parietal lobes correlated with the extent of intact memory performance after TSD. Many of the brain regions showing a greater response after TSD compared with normal sleep are thought to be involved in control of attention. These data imply that the divided attention task required more attentional resources (specifically, performance monitoring and sustained attention) following TSD than after normal sleep. Other neuroimaging results may relate to the verbal learning and/or arithmetic demands of the task. This is the first study to examine divided attention performance after TSD with neuroimaging and supports our previous suggestion that the brain may be more plastic during cognitive performance following TSD than previously thought.

Health-related quality-of-life measure enhances acute treatment response prediction in depressed inpatients.

BACKGROUND: Many nonbiological variables are reported to predict treatment response for major depression; however, there is little agreement about which variables are most predictive. METHOD: Inpatient subjects (N = 59) diagnosed with current DSM-IV major depressive disorder completed weekly depressive symptom ratings with the Hamilton Rating Scale for Depression (HAM-D-17) and Beck Depression Inventory (BDI), and weekly health-related quality-of-life (HRQL) ratings with the Quality of Well-Being Scale (QWB). Acute responders were identified by a 50% decrease in HAM-D-17 score from baseline within 4 weeks of medication treatment. Predictor variables were initially chosen from a literature review and then tested for their association with acute treatment response. RESULTS: An initial predictive model including age at first depression, admission BDI score, and melancholia predicted acute treatment response with 69% accuracy and was designated as the benchmark model. Adding the admission QWB index score to the benchmark model did not improve the prediction rate; however, adding the admission QWB subscales for physical and social activity to the benchmark model significantly improved acute treatment response prediction to 86% accuracy (p = .001). CONCLUSION: In addition to being designed for use in cost-effectiveness analyses, the QWB subscales appear to be useful HRQL variables for predicting acute inpatient depression treatment response.

Sleep and sleep electroencephalogram in depressed patients treated with phenelzine.

BACKGROUND: The beneficial effect of antidepressant interventions has been proposed to depend on suppression of rapid eye movement (REM) sleep or inhibition of electroencephalographic (EEG) slow-wave activity (SWA) in non-REM sleep. Use of the monoamine oxidase inhibitor phenelzine sulfate can eliminate REM sleep. We studied the relation between REM sleep suppression and antidepressant response and the effect of phenelzine therapy on sleep EEG power spectra. METHODS: Open-labeled prescriptions of 30 to 90 mg of phenelzine were given to 11 patients with major depressive disorder (6 men and 5 women; mean age, 41.4 years); all were physically healthy. Mood, dream recall, sleep, sleep EEG, and ocular and muscular activity during sleep were studied before treatment and during the third and fifth weeks of pharmacotherapy. RESULTS: Six patients remitted from depression, 2 responded partially, and 3 showed no antidepressant response. Independent from clinical response, REM sleep was dramatically suppressed. On average, only 4.9 minutes of REM sleep was observed in treatment week 5, and it was completely absent in 6 patients. This effect was compensated for by increased stage 2 sleep. In non-REM sleep, EEG power was higher than at baseline between 16.25 and 25 Hz. Slow-wave activity (power within 0.75-4.5 Hz) and the exponential decline of SWA during sleep were not affected. CONCLUSIONS: Antidepressant response to phenelzine treatment does not depend on elimination of REM sleep or inhibition of SWA in non-REM sleep. In depressed patients, REM sleep is regulated independently from non-REM sleep and can be manipulated without altering the dynamics of SWA.

The effects of transdermal nicotine therapy for smoking cessation on depressive symptoms in patients with major depression.

This study examines the effects of transdermal nicotine patches for smoking cessation on depressive and withdrawal symptoms among 38 non-medicated subjects with Major Depressive Disorder. The study was conducted over a 29-day period, which included a 7 day baseline phase, a 14 day treatment phase, and an 8 day placebo phase. During the treatment phase subjects received either active nicotine patches (N = 18) or placebo patches (N = 20) that were administered in a randomized, double-blind fashion. The target quit date (TQD) was day 8. Significantly, more subjects in the placebo group than in the nicotine group resumed smoking following the TQD (50% vs. 22%). There was little evidence for effects of active nicotine patches on measures of mood (HRSD, BDI, POMS) or withdrawal symptoms among subjects that remained abstinent throughout the study (N = 24). Those who resumed smoking had more severe withdrawal symptoms than those who remained abstinent. One patient in the placebo group (n = 20) became more depressed after 2 weeks of abstinence. None of the patients in the nicotine group (n = 18) became more depressed.

An open-label, 12-week clinical and sleep EEG study of nefazodone in chronic combat-related posttraumatic stress disorder.

BACKGROUND: We examined the effects of nefazodone on polysomnographic sleep measures and subjective reports of sleep quality and nightmares. as well as other symptoms, in patients with chronic combat-related posttraumatic stress disorder (PTSD) during a 12-week, open-label clinical trial. To our knowledge, this is the first polysomnographic study of treatment in patients with PTSD. METHOD: The subjects were 12 male veterans (mean age = 54 years) who met DSM-IV diagnostic criteria for PTSD (mean duration = 30 years). All but I patient also met DSM-IV criteria for major depressive disorder. Patients were evaluated weekly with clinical ratings in an open-label clinical trial. Polysomnographic recordings for 2 consecutive nights were obtained before treatment and at 2, 4, 8, and 12 weeks. The dose of nefazodone was adjusted according to individual clinical needs. Final mean daily dose was 441 mg. RESULTS: The patients reported significantly fewer nightmares and sleep problems during treatment. Nevertheless, contrary to studies in depressed patients, nefazodone did not significantly affect polysomnographic sleep measures compared with baseline. In addition, the patients showed significant improvement in the Clinical Global Impressions of PTSD symptoms (global score, hyperarousals and intrusions subscales), the Clinician-Administered PTSD Scale (global, hyperarousal, and intrusions subscales), the Hamilton Rating Scale for Depression (HAM-D). and the Beck Depression Inventory (BDI). CONCLUSION: These patients with chronic, treatment-resistant, combat-related PTSD showed significant improvement of subjective symptoms of nightmares and sleep disturbance, as well as depression and PTSD symptoms. in this 12-week open-label clinical trial. Nevertheless, objective polysomnographic sleep measures did not change. Further studies, including double-blind. placebo-controlled trials, are needed to extend these findings and to understand the relationships between the physiology of sleep and symptoms of poor sleep and nightmares.

Effects of sleep and sleep deprivation on interleukin-6, growth hormone, cortisol, and melatonin levels in humans.

The objective of this study was to evaluate the effects of nocturnal sleep, partial night sleep deprivation, and sleep stages on circulating concentrations of interleukin-6 (IL-6) in relation to the secretory profiles of GH, cortisol, and melatonin. In 31 healthy male volunteers, blood samples were obtained every 30 min during 2 nights: uninterrupted, baseline sleep and partial sleep deprivation-early night (awake until 0300 h). Sleep was measured by electroencephalogram polysomnography. Sleep onset was associated with an increase in serum levels of IL-6 (P < 0.05) during baseline sleep. During PSD-E, the nocturnal increase in IL-6 was delayed until sleep at 0300 h. Sleep stage analyses indicated that the nocturnal increase in IL-6 occurred in association with stage 1-2 sleep and rapid eye movement sleep, but levels during slow wave sleep were not different from those while awake. The profile of GH across the 2 nights was similar to that of IL-6, whereas the circadian-driven hormones cortisol and melatonin showed no concordance with sleep. Loss of sleep may serve to decrease nocturnal IL-6 levels, with effects on the integrity of immune system functioning. Alternatively, given the association between sleep stages and IL-6 levels, depressed or aged populations who show increased amounts of REM sleep and a relative loss of slow wave sleep may have elevated nocturnal concentrations of IL-6 with implications for inflammatory disease risk.

Can critically timed sleep deprivation be useful in pregnancy and postpartum depressions?

BACKGROUND: The aim of this study was to test the efficacy of critically timed sleep deprivation in major mood disorders (MMD) occurring during pregnancy and postpartum. METHODS: Nine women who met DSM-IV criteria for a MMD with onset during pregnancy or within 1 year postpartum underwent a trial of either early-night sleep deprivation (ESD), in which they were sleep deprived in the early part of one night and slept from 03:00-07:00 h, or late-night sleep deprivation (LSD), in which they were deprived of sleep in the latter part of one night and slept from 21:00-01:00 h. Mood was assessed before the night of sleep deprivation, after the night of sleep deprivation, and after a night of recovery sleep (sleep 22:30-06:30 h) by trained clinicians, blind to treatment condition, using standardized scales. RESULTS: More patients responded to LSD (nine of 11 trials: 82%) compared with ESD (two of six trials: 33%) and they responded more after a night of recovery sleep (nine of 11 nights: 82%) than after a night of sleep deprivation (six of 11 nights: 55%). Pregnant women were the only responders to ESD and the only nonresponders to LSD. LIMITATIONS: The small and heterogeneous sample size prevents us from making more definitive conclusions based on statistical analyses. CONCLUSIONS: Although the findings are preliminary, the results suggest that with further study, critically timed sleep deprivation interventions may benefit women with pregnancy or postpartum major mood disorders and potentially provide a viable alternative treatment modality for those women who are not candidates for pharmacologic or psychotherapeutic interventions. Such interventions are needed to help prevent the devastating effects of depression during pregnancy and the postpartum period on the mother, infant, her family and society.

Clinical and physiological consequences of rapid tryptophan depletion.

We review here the rapid tryptophan depletion (RTD) methodology and its controversial association with depressive relapse. RTD has been used over the past decade to deplete serotonin (5-hydroxy-tryptamine, or 5-HT) in humans and to probe the role of the central serotonin system in a variety of psychiatric conditions. Its current popularity was stimulated by reports that RTD reversed the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) in remitted patients with a history of depression but not in patients treated with antidepressants which promote catecholaminergic rather than serotonergic neurotransmission (such as tricyclic antidepressants or buproprion). However, RTD has inconsistent effects in terms of full clinical relapse in depressed patients. Pooling the data from all published reports, patients who are either unmedicated and/or fully remitted are much less likely to experience relapse (7 of 61, or approximately 9%) than patients who are recently medicated and partially remitted (63 of 133, or approximately 47%; although, the numbers here may reflect patient overlap between reports). Recently remitted patients who have been treated with non-pharmacological therapies such as total sleep deprivation, electroconvulsive therapy, or bright light therapy also do not commonly show full clinical relapse with RTD. We briefly review RTD effects in other psychiatric disorders, many of which are treated with SSRIs. There is accumulating evidence to suggest that RTD affects central serotonergic neurotransmission. Nevertheless, many questions remain about the ability of RTD to reverse the beneficial effects of SSRIs or MAOIs, or to induce symptoms in unmedicated symptomatic or asymptomatic patients.

Sleep estimation from wrist activity in patients with major depression.

Actigraphy has been used to monitor individuals' sleep and wakefulness patterns without laboratory confinement. To date, its validity in monitoring sleep and wakefulness among patients with major depressive episodes has not been systematically examined. The present study investigated whether the normative criteria of the Actigraph Data Analysis Software, initially optimized for healthy individuals, could score wrist-activity data accurately in a sample of depressed patients. Application of the normative algorithm yielded a correlation coefficient of 0.85 and an average error of 35 min, comparing actigraphic and polysomnographic sleep estimates. The algorithm optimized for this sample provided a correlation coefficient of 0.81 and an error of 6 minutes. For both algorithms, agreement for individual comparisons varied substantially. These findings suggest that scoring criteria optimized on wrist-activity data of healthy young adults may not produce optimal results for patients characterized with major depressive episodes.

Polysomnographic and spectral sleep EEG in primary alcoholics: an interaction between alcohol dependence and African-American ethnicity.

BACKGROUND: Disturbances of sleep EEG are prominent in alcoholic patients, persist into recovery, and recently have been found to predict those alcoholics who are most likely to relapse. Increasing evidence indicates that there are ethnic differences in sleep EEG and that African-Americans may be at elevated risk for disordered sleep. METHODS: This study compared polysomnographic and spectral sleep EEG measures in male primary alcoholic inpatients (n = 31) and age-matched comparison controls (n = 31) stratified by African-American and Euro-American ethnicity. RESULTS: African-American alcoholic patients showed more severe sleep abnormalities than Euro-American alcoholics, and the interaction between alcohol dependence and ethnicity uniquely contributed to prolonged sleep latency (p < 0.001), loss of delta sleep (p < 0.001), and short rapid eye movement (REM) latency (p < 0.001). Spectral EEG analyses confirmed polysomnographic findings of disordered sleep architecture in alcoholics. Compared with controls, alcoholics had lower delta (0.75-4.5 Hz) activity over the whole night (p < 0.05), reductions in mean spectral power (0.75-40 Hz, p < 0.05), and decreases of delta (p < 0.01) and theta (4.5-7.5 Hz,p = 0.05) activity during the first period of non-REM sleep, with African-American alcoholics having the lowest theta of the four groups. CONCLUSIONS: In view of the possible connection between relapse and poor sleep and the role of sleep in the maintenance of health, these data have implications for treatment and morbidity outcomes in African-American alcoholics.

Depressive symptoms and cigarette smoking predict development and persistence of sleep problems in US adolescents.

OBJECTIVE: To evaluate factors related to the development and persistence of adolescent sleep problems. METHODS: In this longitudinal, population-based study, the Teenage Attitudes and Practices Survey was administered by telephone to 7960 adolescents (3921 girls and 4039 boys) 12 to 18 years old in 1989 and at follow-up in 1993. Sleep problems at both time points were assessed using a single item on the Teenage Attitudes and Practices Survey. Those who responded that they "often or sometimes" had trouble going to sleep or staying asleep during the past 12 months were categorized as reporting sleep problems, whereas those who responded "often" were categorized as having frequent sleep problems. Multiple logistic regression analyses were used to identify baseline characteristics predictive of the development and persistence of sleep problems or frequent sleep problems, respectively, from baseline to follow-up. RESULTS: Of the 4866 adolescents without sleep problems at baseline, 28% developed sleep problems by 1993, and 9% developed frequent sleep problems. Of the 3094 adolescents who reported sleep problems at baseline, 52% reported sleep problems in 1993, and 21% reported frequent sleep problems. Female sex and notable depressive symptoms were associated with the development and persistence of sleep problems and frequent sleep problems at follow-up. Cigarette smoking status showed a dose-response relationship with development of sleep problems and frequent sleep problems, and with persistence of frequent sleep problems at follow-up. CONCLUSION: The reduction of depressive symptoms and cigarette smoking among adolescents are important factors to consider in prevention and treatment efforts focused on adolescent sleep problems.

Neuropsychological sequelae in Kleine-Levin syndrome: case report.

Kleine-Levin syndrome is characterized by periodic hypersomnia, hyperphagia, sexual disinhibitions and behavioral disturbances. The prognosis is generally benign, with normal cognitive and social functions after the episodes. We describe a typical case of Kleine-Levin syndrome associated with apparent academic decline, neuropsychological sequelae and personality alterations after the second episode of the illness. Further research in the natural history of Kleine-Levin syndrome is needed, for example, to determine whether early intervention would improve long-term prognosis.

Sociodemographic predictors of temperament and character.

The Unified Biosocial Theory of Personality postulates that human personality is organized around four temperaments - Novelty Seeking, Harm Avoidance, Reward Dependence, and Persistence - and three characters - Self-Directedness, Cooperativeness, and Self-Transcendence. The objective of the present study was to investigate the influence of sociodemographic factors on temperament and character without the confounding influence of mental disorders. Volunteers (n=94) did not meet criteria for any Axis I and Axis II diagnosis, had no first-degree relatives with mental disorders, and were medically healthy. After giving written informed consent, volunteers completed the Temperament and Character Inventory. Analyses were conducted to determine the degree of association of each sociodemographic factor (i.e., age, gender, ethnicity, marital status, educational attainment, and occupational status) to personality dimension, while controlling for possible interactions with other sociodemographic factors. Partial correlation analysis showed a significant association between gender and Reward Dependence, and occupational status was significantly related to Reward Dependence, Cooperativeness, and Self-Transcendence. Stepwise regression analysis indicated that gender and occupational status were significant predictors of Reward Dependence. Occupational status was the only predictor of Cooperativeness and Self-Transcendence. These data suggest that sociodemographic factors should be considered in studies investigating temperaments and characters as defined by the Unified Biosocial Theory of Personality.

Preliminary evidence of an association between increased REM density and poor antidepressant response to partial sleep deprivation.

BACKGROUND: One night of total sleep deprivation or of late-night partial sleep deprivation (PSD) produces a temporary remission in approximately 40-60% of patients with major depressive disorder; however, little is known about polysomnography (PSG) characteristics of responders to these types of sleep deprivation (SD). METHODS: Twenty-three unmedicated unipolar patients (17-item Hamilton Depression Rating Scale (HDRS17) >16) and 14 normal controls underwent 1 night of late-night PSD (awake after 3 a.m.) Subjects underwent baseline PSG and received the HDRS17 at standard times before and after PSD. Clinical response was defined as a reduction of >30% in the modified HDRS17 (omitting sleep and weight loss items) following PSD. RESULTS: The 12 responders and 11 nonresponders did not differ from each other significantly on baseline HDRS17 or PSG variables. The only PSG variable correlating with percent decrease in modified HDRS17 was baseline REM density (Pearson's r=-0.52, n=23, P=0.01.) In other words, the lower the baseline REM density, the more robust the antidepressant response was. LIMITATIONS: Subject numbers are relatively small. CONCLUSIONS: Increased REM density, which reflects the number of rapid eye movements per epoch of REM sleep, may be a physiological marker for severity or poor prognosis in a variety of psychiatric disorders, including relapse in recovering alcoholics, suicidality in schizophrenia, and poor response to PSD or interpersonal psychotherapy in depression.

Nefazodone in patients with treatment-refractory posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a highly prevalent and often chronic disorder among combat veterans, persisting in as many as 15% of Vietnam veterans for at least 20 years. Treatment response in veterans with combat-related PTSD has been disappointing. Although anxiolytics, anticonvulsants, antipsychotics, and antidepressants have been tried, none has been consistently associated with improvement in all primary symptom domains (i.e., intrusive recollections, avoidance/numbing, and hyperarousal). This open-label study evaluated the use of nefazodone in a group of Vietnam veterans with chronic, treatment-refractory symptoms of PTSD. METHOD: Male outpatients with DSM-IV PTSD who had failed a minimum of 3 previous medication trials were eligible for the study. Nineteen Vietnam combat veterans entered the study and were treated with nefazodone, 100-600 mg/day, for 12 weeks. PTSD symptoms, anxiety, depression, sleep, sexual functioning, and adverse events were assessed weekly. RESULTS: Severity of depression lessened, as did PTSD symptoms of intrusive recollections, avoidance, and hyperarousal. Depressive symptom severity as measured by the Beck Depression Inventory decreased by a mean of 30%. Similarly, there was an overall drop in the intensity of PTSD symptoms as measured by the Clinician Administered PTSD Scale of 32% with a 26% improvement for symptoms of intrusion, 33% for avoidance, and 28% for arousal. In addition, improvements in sleep and sexual functioning were reported. The mean daily dose of nefazodone after 12 weeks was 430 mg (range, 200-600 mg/day). The most frequently reported side effects were headaches (53%), dry mouth (42%), and diarrhea (42%), but side effects tended to be mild and transient. CONCLUSION: In this group of Vietnam veterans with chronic treatment-refractory PTSD and multiple comorbid Axis I psychiatric disorders, nefazodone was well tolerated and effective. Larger, controlled studies are warranted.