Effects of bupropion SR on anterior paralimbic function during waking and REM sleep in depression: preliminary findings using.

This study sought to clarify the effects of bupropion SR on anterior paralimbic function in depressed patients by studying changes in the activation of these structures from waking to REM sleep both before and after treatment. Twelve depressed patients underwent concurrent EEG sleep studies and [18F]fluoro-2-deoxy-D-glucose ([18F]-FDG) positron emission tomography (PET) scans during waking and during their second REM period of sleep before and after treatment with bupropion SR. Nine subjects completed pre- and post-treatment waking PET studies. Five subjects completed pre- and post-treatment waking and REM sleep PET studies. Bupropion SR treatment did not suppress electrophysiologic measures of REM sleep, nor did it alter an indirect measure of global metabolism during either waking or REM sleep. Bupropion SR treatment reversed the previously observed deficit in anterior cingulate, medial prefrontal cortex and right anterior insula activation from waking to REM sleep. In secondary analyses, this effect was related to a reduction in waking relative metabolism in these structures following treatment in the absence of a significant effect on REM sleep relative metabolism. The implications of these findings for the relative importance of anterior paralimbic function in REM sleep in depression and for the differential effects of anti-depressant treatment on brain function during waking vs. REM sleep are discussed.

Bupropion SR reduces periodic limb movements associated with arousals from sleep in depressed patients with periodic limb movement disorder.

BACKGROUND: Antidepressant-induced periodic limb movement disorder (PLMD) may limit the tolerability of some antidepressant medications and interfere with treatment response. Given the role of dopamine in PLMD and the effects of bupropion sustained-release (SR) on central dopaminergic function, we hypothesized that bupropion SR would not be associated with antidepressant-induced PLMD. METHOD: In an expanded case-series design, we compared the effects of bupropion SR, after about 10 weeks of treatment, on measures of PLMD, depression, and sleep in 5 depressed (Research Diagnostic Criteria) patients who also met criteria for having pretreatment PLMD. Depression was measured using the Beck Depression Inventory and the Hamilton Rating Scale for Depression. Patients were considered to have PLMD if polysomnographic recordings showed > 5 periodic limb movements/hour of sleep that were associated with arousals from sleep. RESULTS: Bupropion SR treatment was associated with a reduction in measures of PLMD and an improvement in depression. CONCLUSION: These results show that bupropion SR is not associated with antidepressant-induced PLMD. Rather, bupropion SR treatment reduces objective measures of PLMD in depressed patients with the disorder.

Treatment of men with major depression: a comparison of sequential cohorts treated with either cognitive-behavioral therapy or newer generation antidepressants.

OBJECTIVE: This report compares response to cognitive-behavioral therapy (CBT) and pharmacotherapy in sequential cohorts of men with DSM-III-R major depression. METHOD: Patients were enrolled in consecutive standardized 16-week treatment protocols conducted in the same research clinic. The first group (N = 52) was treated with Beck's model of CBT, whereas the second group (N = 23) received randomized but open-label treatment with either fluoxetine (N = 10) or bupropion (N = 13). Crossover to the alternate medication was permitted after 8 weeks of treatment for antidepressant nonresponders. The patient groups were well matched prior to treatment. Outcomes included remission and nonresponse rates, as well as both independent clinical evaluations and self-reported measures of depressive symptoms. RESULTS: Despite limited statistical power to detect differences between treatments, depressed men treated with pharmacotherapy had significantly greater improvements on 4 of 6 continuous dependent measures and a significantly lower rate of nonresponse (i.e., 13% vs. 46%). The difference favoring pharmacotherapy was late-emerging and partially explained by crossing over nonresponders to the alternate medication. The advantage of pharmacotherapy over CBT also tended to be larger among the subgroup of patients with chronic depression. CONCLUSION: Results of prior research comparing pharmacotherapy and CBT may have been influenced by the composition of study groups, particularly the gender composition, the choice of antidepressant comparators, or an interaction of these factors. Prospective studies utilizing flexible dosing of modern antidepressants and, if necessary, sequential trials of dissimilar medications are needed to confirm these findings.

Symptoms of stress and depression as correlates of sleep in primary insomnia.

OBJECTIVE: Previous studies have not evaluated the clinical correlates of the electroencephalographic spectral profile in patients with insomnia. In the preliminary study described here, we evaluated the extent to which symptoms of stress and depression are associated with subjective sleep complaints and quantitative measures of sleep in individuals with chronic insomnia. METHODS: Subjects were 14 healthy adults who met criteria for primary insomnia as specified in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. Measures of stress, depression, and subjective sleep quality were collected before subjects participated in a two-night laboratory sleep series. We hypothesized that elevated symptoms of stress and depression would be associated with subjective sleep complaints and electroencephalographic evidence of hyperarousal during sleep. Hyperarousal during sleep was defined as decreases in delta power and elevations in alpha and beta power throughout non-rapid eye movement sleep, and symptoms of stress were defined as the tendency to experience stress-related intrusive thoughts and the interaction between intrusion tendency and the number of recent stressful events (subjective stress burden). RESULTS: A stronger tendency to experience stress-related intrusive thoughts was associated with greater sleep complaints and a trend toward higher beta power, whereas increases in subjective stress burden were associated with decreases in delta power. In addition, elevations in subclinical symptoms of depression were associated with greater sleep complaints and elevations in alpha power. CONCLUSIONS: Observed relationships among symptoms of stress, depression, subjective sleep complaints, and electroencephalographic power may be relevant to the discrepancy between subjective and objective measures of sleep in patients with insomnia and may be more broadly applicable to sleep complaints in association with stressful life events and major depression.

Towards a neurobiology of dysfunctional arousal in depression: the relationship between beta EEG power and regional cerebral glucose metabolism during NREM sleep.

This study sought to clarify the neurobiological basis of variations in one aspect of central nervous system 'arousal' in depression by characterizing the functional neuroanatomic correlates of beta electroencephalographic (EEG) power density during non-rapid eye movement (NREM) sleep. First, nine healthy (n=9) subjects underwent concurrent EEG sleep studies and [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography (PET) scans during their first NREM period of sleep in order to generate hypotheses about specific brain structures that show a relationship between increased beta power and increased relative glucose metabolism. Second, brain structures identified in the healthy subjects were then used as a priori regions of interest in similar analyses from identical studies in 12 depressed subjects. Statistical parametric mapping was used to identify the relationship between beta power and relative regional cerebral glucose metabolism (rCMRglu) during NREM sleep. Regions that demonstrated significant correlations between beta power and relative cerebral glucose metabolism in both the healthy and depressed subjects included the ventromedial prefrontal cortex and the right lateral inferior occipital cortex. During a baseline night of sleep, depressed patients demonstrated a trend toward greater beta power in relation to a separate age- and gender-matched healthy control group. In both healthy and depressed subjects, beta power negatively correlated with subjective sleep quality. Finally, in the depressed group, there was a trend for beta power to correlate with an indirect measure of absolute whole brain metabolism during NREM sleep. This study demonstrates a similar relationship between electrophysiological arousal and glucose metabolism in the ventromedial prefrontal cortex in depressed and healthy subjects. Given the increased electrophysiological arousal in some depressed patients and the known anatomical relations between the ventromedial prefrontal cortex and brain activating structures, this study raises the possibility that the ventromedial prefrontal cortex plays a significant role in mediating one aspect of dysfunctional arousal found in more severely aroused depressed patients.

Changes in forebrain function from waking to REM sleep in depression: preliminary analyses of [18F]FDG PET studies.

Based on recent functional brain imaging studies of healthy human REM sleep, we hypothesized that alterations in REM sleep in mood disorder patients reflect a functional dysregulation within limbic and paralimbic forebrain structures during that sleep state. Six unipolar depressed subjects and eight healthy subjects underwent separate [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) PET scans during waking and during their first REM period of sleep. Statistical parametric mapping contrasts were performed to detect changes in relative regional cerebral glucose metabolism (rCMRglu) from waking to REM sleep in each group as well as interactions in patterns of change between groups. Clinical and EEG sleep comparisons from an undisturbed night of sleep were also performed. In contrast to healthy control subjects, depressed patients did not show increases in rCMRglu in anterior paralimbic structures in REM sleep compared to waking. Depressed subjects showed greater increases from waking to REM sleep in rCMRglu in the tectal area and a series of left hemispheric areas including sensorimotor cortex, inferior temporal cortex, uncal gyrus-amygdala, and subicular complex than did the control subjects. These observations indicate that changes in limbic and paralimbic function from waking to REM sleep differ significantly from normal in depressed patients.

A method for the assessment of the functional neuroanatomy of human sleep using FDG PET.

Although sleep is characterized by relative behavioral inactivity, cortical activity is known to cycle in well-defined periods across this state. Cognitive function during sleep has been difficult to define, although disturbances in sleep are known to result from, and to cause, various human pathologies, including neuropsychiatric disorders. Assessment of brain function in humans (related to cognitive operations) during sleep has been limited, until recently, to surface electrophysiologic recordings that limit analysis of regional function, particularly in deep structures. The current report describes one method of assessing human forebrain activation during sleep using the [18F]2-fluoro-2-deoxy-d-glucose ([18F]FDG) method and positron emission tomography (PET) measures of regional cerebral glucose utilization. In comparison with other functional brain imaging techniques (e.g., assessment of blood flow or functional magnetic resonance imaging), this method offers the advantage of a more naturalistic study of sleep since subjects do not have to sleep in a scanning device. This leads to a higher rate of successful completion of studies. The primary disadvantage of this method is the decreased temporal resolution necessitating assessments of global sleep states (e.g., REM or NREM) as opposed to assessing events within a sleep state (e.g., sleep spindles or rapid eye movements).

Forebrain activation in REM sleep: an FDG PET study.

Rapid eye movement (REM) sleep is a behavioral state characterized by cerebral cortical activation with dreaming as an associated behavior. The brainstem mechanisms involved in the generation of REM sleep are well-known, but the forebrain mechanisms that might distinguish it from waking are not well understood. We report here a positron emission tomography (PET) study of regional cerebral glucose utilization in the human forebrain during REM sleep in comparison to waking in six healthy adult females using the 18F-deoxyglucose method. In REM sleep, there is relative activation, shown by increased glucose utilization, in phylogenetically old limbic and paralimbic regions which include the lateral hypothalamic area, amygdaloid complex, septal-ventral striatal areas, and infralimbic, prelimbic, orbitofrontal, cingulate, entorhinal and insular cortices. The largest area of activation is a bilateral, confluent paramedian zone which extends from the septal area into ventral striatum, infralimbic, prelimbic, orbitofrontal and anterior cingulate cortex. There are only small and scattered areas of apparent deactivation. These data suggest that an important function of REM sleep is the integration of neocortical function with basal forebrain-hypothalamic motivational and reward mechanisms. This is in accordance with views that alterations in REM sleep in psychiatric disorders, such as depression, may reflect dysregulation in limbic and paralimbic structures.

Homicidal behavior and sleep apnea: a case report and medicolegal discussion.

This case report documents the use of sleep apnea as a criminal defense for a man who fatally shot his wife during his usual sleeping hours. The defendant, who had severe sleep apnea as determined by a clinical evaluation and a polysomnographic study, admitted to shooting his wife but claimed that he was asleep at the time. Two physicians testified for the defense that the sleep apnea was of sufficient severity that the defendant may have had a confusional arousal related to the sleep apnea in which he could have shot his wife accidentally. Another physician, testifying for the prosecution, found no evidence to support this defense after a review of the patient's history and polysomnographic records and a review of relevant literature which may have linked sleep apnea with sleep-related violence. In this case, there was substantial apparent motive for the murder, including a past history of spousal and child abuse and a note written by the victim around the time of the shooting describing her intention to take the children and leave the suspect. The jury rejected the sleep apnea defense, handing down a first-degree murder verdict. In the discussion, we briefly review medicolegal issues related to the case as well as prospective guidelines for the medicolegal assessment of future cases.

REM sleep enhancement by bupropion in depressed men.

OBJECTIVE: The authors compared the effects of bupropion, fluoxetine, and cognitive behavior therapy on EEG sleep in depressed subjects. METHOD: All-night sleep EEG studies were performed before treatment and after partial or full remission on 18 men with depression diagnosed according to Research Diagnostic Criteria and randomly assigned to treatment with either bupropion (N = 7) or fluoxetine (N = 11). Response to these drugs was measured by changes in Hamilton Depression Rating Scale scores. Pre- and posttreatment EEG sleep study results before and after treatment with cognitive behavior therapy were also available for 18 men matched in age and severity of Hamilton depression scale score, and one-time EEG sleep measures were available for 36 men who were not depressed. RESULTS: REM latency was reduced and REM sleep percent and REM time increased after treatment in the depressed men given bupropion. These effects contrasted with the effects of fluoxetine and cognitive behavior therapy. CONCLUSIONS: This study represents the first report of an antidepressant medication that shortens REM latency and increases REM sleep. If confirmed, this finding may require a revision of our current understanding of the relation among depression, REM sleep, and anti-depressant mechanisms.

Affect intensity and phasic REM sleep in depressed men before and after treatment with cognitive-behavioral therapy.

This article explored the relationship between daytime affect and REM sleep in 45 depressed men before and after treatment with cognitive-behavioral therapy and in a control group of 43 healthy subjects. The intensity of daytime affect (as measured by the sum of positive and negative affects) in depressed men correlated significantly and positively with phasic REM sleep measures at both pre- and posttreatment. This relationship was not found in healthy control subjects. In depressed men, both affect intensity and phasic REM sleep measures decreased over the course of treatment. The results suggest a relationship between phasic REM sleep and intensity of affect reported by depressed men. On the basis of this preliminary observation, it was hypothesized that abnormalities in phasic REM sleep in depressed patients are related, in part, to fundamental alterations in the intensity of their affective experience.

Correlation of nocturnal penile tumescence and daytime affect intensity in depressed men.

Although depressed patients have been shown to have diminished nocturnal penile tumescence (NPT), there remains considerable variability of NPT in depression. We hypothesized that affective experience during the day accounts for some of this variability. Forty-five depressed men had assessments of affect intensity and affect balance, NPT, and daytime sexual function, both before and after treatment with Beck's cognitive behavior therapy (CBT). Forty-three normal control subjects were studied for comparison. Daytime affect intensity in depressed men, but not in control subjects, correlated significantly and positively with measures of NPT duration and rigidity both before and after treatment, regardless of the adequacy of daytime sexual function. When the effect of daytime affect on REM activity was controlled, the observed correlations became nonsignificant at pretreatment, but remained significant at posttreatment. Neuropharmacologically mediated changes in arousal responsivity associated with depression may underlie the observed relation between daytime affect intensity, rapid eye movement activity, and NPT.

Sleep disorders related to another mental disorder (nonsubstance/primary): a DSM-IV literature review.

BACKGROUND: Disturbances of the sleep/wake cycle are fundamental clinical symptoms for patients with many of the mental disorders. This review of the literature on research in sleep and mental disorders from 1966 to 1991 highlights the major developments and findings that are central to the development of a DSM-IV diagnosis of sleep disorders related to another mental disorder (nonsubstance/primary). METHOD: As a framework, the review discusses the classification criteria listed in the International Classification of Sleep Disorders (ICSD, 1990) for sleep disorders associated with mental disorders. Research relevant to the classification system is reviewed and the merits of modifying the DSM-III-R criteria based on the accumulated research are discussed. RESULTS: Overall, the review supports the notion of consistent biological alterations in the sleep/wake cycle for patients with many of the mental disorders. CONCLUSION: On the basis of this evidence, sleep disorders related to another mental disorder warrant separate diagnostic classification within a nosology for sleep disorders. The review also reveals the historical development of sleep research as a tool within the field of psychiatry for characterizing the biological bases of mental disorders.

Electroencephalographic sleep in clinically stable schizophrenic patients: two-weeks versus six-weeks neuroleptic-free.

EEG sleep studies in schizophrenic patients are influenced by alterations in clinical state and medication status. The current study defines longitudinal alterations in electroencephalographic (EEG) sleep for 10 healthy men who were schizophrenic patients who remained relatively clinically stable during a double-blind neuroleptic withdrawal study. Clinical assessments and EEG sleep studies were performed at baseline on haloperidol, and then at 2-week and 6-week drug-free periods. Sleep continuity and rapid eye movement (REM) sleep measures declined not only between the haloperidol baseline and 2-week drug-free conditions, but continued to decline from 2-week to 6-weeks neuroleptic-free. Alterations in EEG sleep from the 2-week to 6-week haloperidol-free assessments did not correlate with changes in clinical symptoms suggesting effects related to drug-withdrawal or subclinical state changes. These results show that despite relative clinical stability over time, the EEG sleep of schizophrenic patients continues to change following withdrawal of a neuroleptic and is dependent on the duration of the drug-free interval.

Are buckling force measurements reliable in nocturnal penile tumescence studies?

The study of nocturnal penile tumescence (NPT) is frequently used to evaluate male erectile dysfunction. Buckling force, a measure of rigidity, is an important part of this evaluation, but its reliability is unknown. Accordingly, we studied the reliability of buckling force measurement and the stability of "maximum buckling force" between consecutive NPT series repeated in the same subject. For individual subjects, we correlated buckling forces for separate episodes of sleep-related tumescence that were of comparable fullness (0-100%) as rated by a technician's visual estimates. For healthy control subjects, test-retest correlations were > 0.8 both within-night and across study series separated by an average of 70 weeks. In depressed men, correlations within nights were > 0.9, but fell to 0.64 across study series separated by an average of 21 weeks. Despite the high reliability of buckling force measurement, we found little stability of "maximum buckling force" between NPT series for individual subjects. Considerable variability in the maximum degree of penile rigidity was seen over time despite a constant level of reported daytime erectile function. We conclude that although penile rigidity is one of the more important variables in the assessment of male erectile dysfunction and can be measured reliably, the instability of maximum rigidity during sleep-related erections suggests that it is, at best, an imprecise correlate of daytime erectile function.

Sexual function in depressed men. Assessment by self-report, behavioral, and nocturnal penile tumescence measures before and after treatment with cognitive behavior therapy.

Clinicians have long associated depression with alterations in sexual function, predominantly loss of sexual interest. In a longitudinal study measuring self-report, behavioral, and nocturnal penile tumescence variables before and after treatment with cognitive behavior therapy in an unmedicated sample of 40 outpatient depressed men, we found, contrary to expectation, that sexual activity per se was not reduced during the depressed state. Rather, loss of sexual interest appeared to be related to the cognitive set of depression, ie, loss of sexual satisfaction that then improved with remission from depression. Depressed men were heterogeneous, however, with respect to sexual behavior, eg, an anxious and more chronically depressed subgroup of men who did not have remissions with cognitive behavior therapy reported increased sexual interest and sexual activity. Also, contrary to expectation, nocturnal penile tumescence abnormalities in depressed men did not reverse when measured in early remission, nor did nocturnal penile tumescence measures correlate significantly with behavioral measures of sexual function. Nocturnal penile tumescence alterations in depression may thus be similar to other persistent electroencephalographic sleep abnormalities seen in depressed patients in remission, in being more trait-like than statelike.