Rapid and sustained antidepressant response with sleep deprivation and chronotherapy in bipolar disorder.

BACKGROUND: The development of a rapid-acting and sustainable treatment for bipolar disorder (BPD) depression has been a goal for decades. The most widely documented rapid-onset antidepressant therapy is sleep deprivation (SD), which acts within 24-48 hours in 40%-60% of depressed patients. Conventional antidepressants usually require 2-8 weeks to meet response criteria. The delay, which may prolong suffering and increase suicidal risk, underlines the urgency of alternative treatment strategies. This study evaluates the combined efficacy of three established circadian-related treatments (SD, bright light [BL]), sleep phase advance [SPA]) as adjunctive treatment to lithium and antidepressants. METHODS: Forty-nine BPD patients were randomly assigned to a chronotherapeutic augmentation (CAT; SD+ BL+ SPA) or to a medication-only (MED) group. Clinical outcome was assessed using the Hamilton Rating Scale for Depression. RESULTS: Significant decreases in depression in the CAT versus MED patients were seen within 48 hours of SD and were sustained over a 7-week period. CONCLUSIONS: This is the first study to demonstrate the benefit of adding three noninvasive circadian-related interventions to SD in medicated patients to accelerate and sustain antidepressant responses and provides a strategy for the safe, fast-acting, and sustainable treatment of BPD.

Sleep deprivation PET correlations of Hamilton symptom improvement ratings with changes in relative glucose metabolism in patients with depression.

BACKGROUND: This PET study is a continuing investigation of the effects of antidepressant medication and one night of total sleep deprivation on cerebral metabolism in depressed patients. This study was undertaken to confirm previous correlations between symptom improvement ratings and regional changes in glucose metabolism, using a higher resolution scanner than in previous investigations. In addition, we also studied the effect of concomitant antidepressant medication in conjunction with sleep depression. METHOD: Six depressed patients were administered the selective serotonin reuptake inhibitor sertraline for a week and then underwent positron emission tomography (FDG PET) before and after sleep deprivation. Changes in relative glucose metabolism were correlated with symptom improvement ratings in Hamilton Depression Rating Scale scores. RESULTS: Positive correlations (defined as reduced HDRS scores associated with areas having reduced relative cerebral glucose metabolism after TSD) were found in the inferior frontal gyrus and inferior frontal/orbital frontal cortex. Negative correlations (defined as reduced HDRS scores associated with areas of increased relative cerebral glucose metabolism after TSD) were found in the dorsolateral prefrontal cortex. LIMITATIONS: Limitations of this study are that the number of subjects was small (n=6) and they were scanned at a 7.6 mm resolution. CONCLUSIONS: The results of this study support previous findings on the effects of sleep deprivation and antidepressant medications in the treatment of unipolar and bipolar depression, with an emphasis on the significance of cerebral glucose metabolic changes in the ventral and DLPF cortex in mood regulation.

Frontal lobe metabolic decreases with sleep deprivation not totally reversed by recovery sleep.

We studied the effects of total sleep deprivation and recovery sleep in normal subjects using position emission tomography with 18F-deoxyglycose. Sleep deprivation resulted in a significant decrease in relative metabolism of the frontal cortex, thalamus, and striatum. Recovery sleep was found to have only a partial restorative effect on frontal lobe function with minimal reversal of subcortical deficits. Sleep may be especially important for maintenance of frontal lobe activity.

Improved anatomic delineation of the antidepressant response to partial sleep deprivation in medial frontal cortex using perfusion-weighted functional MRI.

This study used functional magnetic resonance imaging (fMRI) to clarify the sites of brain activity associated with the antidepressant effects of sleep deprivation (SD). We hypothesized: 1) depressed responders' baseline ventral anterior cingulate (AC) perfusion will be greater than that of nonresponders and controls; 2) following partial sleep deprivation (PSD), ventral AC perfusion will significantly decrease in responders only. Seventeen unmedicated outpatients with current major depression and eight controls received perfusion-weighted fMRI and structural MRI at baseline and following 1 night of late-night PSD. Talairach-transformed gray matter masks were merged with Talairach Daemon-based region of interest (ROI) templates. Baseline left ventral AC (LVAC) perfusion was greater in responders than nonresponders. There was no difference involving the medial frontal cortex. Responders' LVAC perfusion dropped from baseline to PSD scans compared with nonresponders and controls, as did perfusion in the right dorsal AC. In the patient group as a whole, decrease in LVAC perfusion from baseline to PSD scans correlated directly with the decrease in the modified 17-item Hamilton Depression Rating Scale (HDRS17) between baseline and PSD conditions. These data--the first using fMRI--show greater anatomic specificity than previous findings of SD and depression in linking decreased brain activity in this area with clinical improvement.

Does amygdalar perfusion correlate with antidepressant response to partial sleep deprivation in major depression?

This study used functional MRI (fMRI) to clarify the sites of brain activity associated with the antidepressant effects of sleep deprivation (SD). We hypothesized: (1) baseline perfusion in right and left amygdalae will be greater in responders than in nonresponders; (2) following partial sleep deprivation (PSD), perfusion in responders' right and left amygdalae would decrease. Seventeen unmedicated outpatients with current major depression and eight controls received perfusion-weighted fMRI and structural MRI at baseline and following 1 night of late-night PSD. Baseline bilateral amygdalar perfusion was greater in responders than nonresponders. Clusters involving both amygdalae decreased from baseline to PSD specifically in responders. Right amygdalar perfusion diverged with PSD, increasing in nonresponders and decreasing in responders. These novel amygdalar findings are consistent with the overarousal hypothesis of SD as well as other functional imaging studies showing increased baseline amygdalar activity in depression and decreased amygdalar activity with remission or antidepressant medications.

Similar sleep EEG topography in middle-aged depressed patients and healthy controls.

OBJECTIVES: One of the early hypotheses relating sleep disturbances in depression to a model of sleep regulation is the S-deficiency hypothesis. It is postulated that, in depressed patients, sleep propensity during wakefulness does not rise to the level attained by nondepressed subjects, resulting in altered sleep structure or changes in the electroencephalogram during sleep. We aimed to test this hypothesis by assessing topographic changes in the sleep electroencephalogram associated with depression. DESIGN: Cross-sectional clinical study. SETTING: Mental Health Clinical Research Center. PARTICIPANTS: Sixteen unmedicated depressed outpatients (mean age: 41.2 years) and 16 pair-matched healthy controls (mean age: 41.1 years). INTERVENTIONS: None. MEASUREMENTS: Baseline sleep electroencephalogram recordings were obtained from a central referential electrode and from 3 bipolar derivations (frontocentral, centroparietal, parietooccipital) along the anteroposterior axis. RESULTS: Symptoms of depression at the time of sleep recordings were moderate (24-item Hamilton Rating Scale of Depression range: 16-31). No differences between patients and controls were found in sleep variables and all-night electroencephalogram spectra in non-rapid-eye-movement and rapid-eye-movement sleep. The ultradian modulation of slow-wave activity (power within 0.75-4.5 Hz), as well as the exponential decline of slow-wave activity, during sleep did not differ between the groups. The statistical analyses of electroencephalogram power gradients between adjacent derivations revealed no Group x Derivation interactions. An anterior dominance in non-rapid-eye-movement sleep power was present in the 0.75- to 2-Hz range, which diminished throughout the night. CONCLUSIONS: These findings in moderately depressed patients do not support the existence of an S-deficiency during sleep. Because the build up of sleep propensity during waking can be dissociated from its decline, future studies need to investigate the waking electroencephalogram spectra in depression.

TEMPS-A: validation of a short version of a self-rated instrument designed to measure variations in temperament.

OBJECTIVE: To validate a short English-language version of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A), a self-report questionnaire designed to measure temperamental variations in psychiatric patients and healthy volunteers. Its constituent subscales and items were formulated on the basis of the diagnostic criteria for affective temperaments (cyclothymic, dysthymic, irritable, hyperthymic, and anxious), originally developed by the first author and his former collaborators. Further item wording and selection were achieved at a later stage through an iterative process that incorporated feedback from clinicians, researchers, and research volunteers. METHOD: A total of 510 volunteers (284 patients with mood disorders, 131 relatives of bipolar probands, and 95 normal controls) were recruited by advertisement in the newspapers, announcements on radio and television, flyers and newsletters, and word of mouth. All participants were interviewed using the Structured Clinical Interview for DSM-III-R, and completed the 110-item TEMPS-A and the Temperament and Character Inventory (TCI-125). The factorial structure, the alpha coefficients, and the item-total correlations coefficients of the TEMPS-A and the correlation coefficients between the dimensions of the TCI and the TEMPS-A subscales were then determined. RESULTS: A principal components analysis with a Varimax rotation found that 39 out of the 110 original items of the TEMPS-A loaded on five factors that were interpreted as representing the cyclothymic, depressive, irritable, hyperthymic, and anxious factors. Coefficients alpha for internal consistency were 0.91 (cyclothymic), 0.81 (depressive), 0.77 (irritable), 0.76 (hyperthymic), and 0.67 (anxious) subscales. We found statistically significant positive correlations between all-but the hyperthymic-subscales and harm avoidance. Positive correlations with the hyperthymic and cyclothymic, and novelty seeking and negative correlations with the remaining subscales were also recorded. Other major findings included positive correlations between the hyperthymic and reward dependence, persistence and self-directedness; positive correlation between the self-transcendence and the cyclothymic, hyperthymic and the anxious; and negative correlations between the depressive, cyclothymic, irritable, anxious and cooperativeness. LIMITATION: As the full-scale anxious temperament was added after the four scales of the TEMPS-A were developed, it has only been evaluated in 345 subjects. CONCLUSIONS: These data indicate that the TEMPS-A in its shortened version is a psychometrically valid scale with good internal consistency. The proposed five subscale structure is upheld. Concurrent validity against the TCI is shown. Most importantly, for each of the temperaments, we were able to show positive attributes which are meaningful in an evolutionary context, along with traits which make a person vulnerable to mood shifts. This hypothesized dual nature of temperament, which is upheld by our data, is a desirable characteristic for a putative behavioral endophenotype in an oligogenic model of inheritance for bipolar disorder.

Temperament in the clinical differentiation of depressed bipolar and unipolar major depressive patients.

OBJECTIVE: To examine differences in temperament profiles between patients with recurrent unipolar and bipolar depression. METHOD: Depressed individuals with recurrent major depressive disorder (MDD) (n = 94) and those with bipolar (n = 59) disorders (about equally divided between types I and II) were recruited by newspaper advertisement, radio and television announcements, flyers and newsletters, and word of mouth. All patients were interviewed using the Structured Clinical Interview for DSM III-R (SCID) and had the severity of their depressive episode assessed by means of the 17-item Hamilton Rating Scale for Depression. All patients filled out the TEMPS-A, a validated instrument. RESULTS: Temperament differences between bipolar and MDD patients were examined using MANCOVA. Overall significant effect of the fixed factor (bipolar vs. unipolar) was noted for the temperament scores [Hotelling's F((5,142)) = 2.47, p < 0.05]. Overall effects were found for age [F((5,142)) = 2.40, p < 0.05], but not for gender and severity of depression [F((5,142)) = 1.65, p = 0.15 and F((5,142)) = 0.66, p = 0.66, respectively]. Dependent variables included the five subscales of the TEMPS-A, but only the cyclothymic temperament scores showed significant between-group differences. LIMITATION: Small bipolar subsample cell sizes did not permit to test the specificity of the findings for bipolar II vs. bipolar I patients. CONCLUSION: The finding that the clyclothymic subscale is significantly elevated in the bipolar vs. the unipolar depressive group supports the theoretical assumptions upon which the scale is based, and suggests that it might become a useful tool for clinical and research purposes.

Affective state and EEG sleep profile in response to rapid tryptophan depletion in recently recovered nonmedicated depressed individuals.

BACKGROUND: The current study examines whether a tryptophan-free amino acid drink (TFD) causes a transient mood relapse in unmedicated patients recently recovered from major depression. TFD is thought to reduce cerebral serotonin, a neurotransmitter implicated in depression. Some studies report that TFD reverses the antidepressant and REM-suppression effects of selective serotonin reuptake inhibitors (SSRIs). METHODS: Following an average of 10 weeks of Cognitive Behavioral Therapy (CBT), 13 recovered patients who achieved 50% or greater reduction on the initial Hamilton Rating Scale of Depression (HRSD) underwent a double-blind challenge with the TFD and a control drink. In order to demonstrate the central physiological effects of the TFD on REM sleep in these patients, all night polygraphic sleep recordings were obtained before and after the TFD and control drink. RESULTS: Relative to the control drink, TFD decreased REM latency and plasma concentrations of tryptophan but had no statistically significant effect on mood symptoms as measured by the HRSD, Beck Depression Inventory (BDI), and Profile of Mood States (POMS). LIMITATIONS: High participant attrition, a physiologically active control drink, physical side effects in response to both drinks, and low statistical power may be methodological considerations that limit interpretation of findings. CONCLUSIONS: The failure to find a transient mood relapse after the TFD may suggest that: (a) nonpharmacological recovery from depression does not occur via serotonergic mechanisms, (b) participant variables may be operating, or (c) CBT alters psychological responses to unfavorable biological states.

Increasing task difficulty facilitates the cerebral compensatory response to total sleep deprivation.

STUDY OBJECTIVES: To test the role of task difficulty in the cerebral compensatory response after total sleep deprivation (TSD). DESIGN: Subjects performed a modified version of Baddeley's logical reasoning task while undergoing functional magnetic resonance imaging twice: once after normal sleep and once following 35 hours of TSD. The task was modified to parametrically manipulate task difficulty. SETTING: Inpatient General Clinical Research Center and outpatient functional magnetic resonance imaging center. PATIENTS OR PARTICIPANTS: 16 young adults (7 women; mean age, 27.6 +/- 6.1 years; education, 15.4 +/- 1.8 years) were included in the final analyses. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Behaviorally, subjects performed the same after TSD as while well rested. Neuroimaging data revealed a linear increase in cerebral response with a linear increase in task demands in several brain regions after normal sleep. Even stronger linear responses were found after TSD in several brain regions, including bilateral inferior parietal lobes, bilateral temporal cortex, and left inferior and dorsolateral prefrontal cortex. CONCLUSIONS: Task difficulty facilitates the cerebral compensatory response observed following TSD. Compensation manifests as both new regions that did not show significant responses to task demands in the well-rested condition, as well as stronger responses within regions typically underlying task performance. The possible significance of these 2 types of responses should be explored further, as should the importance of the parietal lobes for cognitive performance after TSD.

A quantitative neuromotor predictor of antidepressant non-response in patients with major depression.

Predicting response to antidepressant medication has been a challenge to clinicians and researchers for decades. Attention has been paid to the role of motor retardation as a putative indicator of treatment response, yet previous findings have been mixed. One reason for this inconsistency may be related to the subjective nature of motor retardation and how it is assessed. In the present study, we adopted a measure of motor programming previously shown to characterize parkinsonian bradykinesia to test whether neuromotor function could predict response to antidepressant treatment. Twenty-eight patients (14 males and 14 females with a mean age of 42.0 years) meeting DSM-IV criteria for a depressive disorder were randomized to receive 8 weeks of treatment with one of three antidepressant medications (sertraline, phenelzine, or bupropion). Treatment outcomes were assessed using the 17-item version of the Hamilton Rating Scale for Depression (HRSD). Patients were considered asymptomatic if their post-treatment HRSD total score was equal to or less than 7. Treatment responders (n=15) had significantly less baseline impairment (P=0.01) on the neuromotor measure than non-responders (n=13). There was a significant relationship between amount of improvement on the HRSD and severity of baseline neuromotor function (r=-0.51; P=0.006). No significant group effects were found for baseline psychomotor slowing or clinical ratings of motor retardation. These results demonstrate that a quantitative measure of motor programming may be a useful predictor of antidepressant non-response.

Rapid tryptophan depletion reverses phenelzine-induced suppression of REM sleep.

Treatment with the monoamine oxidase inhibitor phenelzine completely suppressed rapid eye movement (REM) sleep in five depressed patients. Hypothesizing that increased serotonergic neurotransmission eliminated REM sleep, we administered a tryptophan-free amino acid drink (TFD) known to reduce plasma tryptophan and brain levels of serotonin. The TFD reversed the REM sleep suppression, while the control drink (TFD plus tryptophan) had virtually no effect on sleep. Neither TFD nor control drink affected mood, total sleep time, sleep efficiency or the all-night electroencephalogram power spectra in non-rapid eye movement (NREM) sleep. We report the first non-disruptive, double-blind method for studying human subjects overnight with and without REM sleep. It opens up a novel strategy for investigating the functions of REM sleep, and the roles of serotonin and REM sleep in the regulation of NREM sleep and mood.

Effects of rapid tryptophan depletion on sleep electroencephalogram and mood in subjects with partially remitted depression on bupropion.

Serotonin has been implicated in both sleep and mood regulation. When central serotonin was depleted with a tryptophan-free amino acid drink (TFD), some studies have reported that the antidepressant benefits were reversed in partially remitted patients treated with SSRIs. Other studies showed that the TFD increased rapid eye movement (REM) sleep in both normal males and in remitted depression patients on selective serotonin reuptake inhibitors (SSRIs) without affecting mood. In this study, we administered a TFD to patients with remitted depression who were being treated with bupropion, an antidepressant whose mechanism of action apparently does not affect the serotonin system. We hypothesized that the TFD would increase the propensity for REM sleep without affecting depression ratings. Eight partially remitted depression subjects on bupropion were administered a TFD and a control drink containing tryptophan in double-blind, random order on separate days. The effects of these drinks were monitored with sleep electroencephalograms, mood ratings, and plasma tryptophan measures comparing baseline, TFD, and control nights. The TFDs reduced REM latency and stage 2 percent and increased REM time and percent. Subjective measures of elation, vigor, and friendliness significantly decreased on both TFD and control drinks but depression ratings did not. Plasma levels of tryptophan decreased with the TFD. Although the TFD altered REM sleep, certain mood measures, and plasma tryptophan levels, no relapses into depression were seen with our subjects. Bupropion alone did not affect sleep measures.

Different effects of phenelzine treatment on EEG topography in waking and sleep in depressed patients.

A novel approach to investigate the relationship between depression and changes in sleep-wake regulatory mechanisms used the monoamine oxidase inhibitor (MAOI) phenelzine that is known to suppress rapid-eye-movement (REM) sleep. Sleep architecture and EEG topography during wakefulness and sleep were studied in eight depressed patients before and after five weeks of treatment with phenelzine (30-90 mg/day), which induced a significant alleviation of depressive symptoms. Theta power (4.75-7.5 Hz) during a 5-min wake EEG prior to sleep increased two-fold during administration of phenelzine. REM sleep was almost completely eliminated. This latter effect was compensated by increased duration of stage 2, whereas total sleep time was not shortened. In non-REM sleep (stages 2, 3, and 4), treatment slightly reduced EEG power between 2.0-6.25 Hz and 8.5-13.75 Hz; power in the 16.75-25.0 Hz band increased. Activity in the delta band (2.0-3.25 Hz) tended to be reduced in the fronto-central derivation, but not in centro-parietal and parieto-occipital derivations. However, the Treatment X Derivation interaction was not significant. These data indicate that in contrast to wakefulness the effects of phenelzine treatment on the EEG in non-REM sleep were small. Rank correlation analyses revealed no association between the antidepressant treatment response and the changes in sleep and EEG power spectra during administration of phenelzine.

Sleep deprivation as a probe of homeostatic sleep regulation in primary alcoholics.

BACKGROUND: Alcoholic patients show prominent disturbances of sleep electroencephalograms (EEGs) with a marked loss of slow wave sleep that is even more profound in African American alcoholics as compared to European Americans. Using partial sleep deprivation, this study examined the extent to which abnormal sleep is reversible in alcoholic subjects. METHODS: In a sample stratified on ethnicity, polysomnographic and spectral sleep EEG measures were compared in male primary alcoholic in patients (n=46) and age-matched comparison controls (n=32) at baseline-and recovery sleep following a night of partial sleep deprivation. RESULTS: As compared to controls, alcoholic patients showed a loss of slow wave sleep and more spectral power in beta frequencies. Following sleep deprivation, slow wave sleep and delta power differentially changed between the groups. European American controls showed increases of slow wave sleep that were more robust than responses found in African American controls, whereas both alcoholic groups failed to show increases of slow wave sleep from baseline to recovery. Spectral EEG analyses revealed similar results; sleep deprivation induced significant increases of delta power during NREM-1 in the controls, but not in the alcoholics. CONCLUSIONS: Alcohol dependence compromises the augmentation of slow wave sleep and delta power seen in healthy adults following sleep deprivation. The differential effect of alcoholism on sleep stage physiology suggests a defect in the regulation or plasticity of slow wave sleep with implications for theories linking sleep depth to morbidity and outcome in alcoholics.

The effects of an orally administered cholinergic agonist on REM sleep in major depression.

BACKGROUND: Centrally active cholinergic agents such as arecoline and physostigmine shorten rapid eye movement (REM) latency, reduce REM interval times, or both and do so preferentially in patients with depression. We tested an orally administered cholinergic agonist (donepezil HCL 10 mg [Aricept]) to determine whether this agent also alters REM timing in depressed patients (n = 8) compared with age- and gender-matched control subjects (n = 8). METHODS: All subjects were studied for 3 consecutive nights in the sleep laboratory. The design was a fixed-order placebo-donepezil protocol to accommodate the long half-life of donepezil. Night 1 served as an adaptation night. On night 2, placebo was administered at 8:00 PM. On night 3, donepezil was administered at 8:00 PM. RESULTS: The cholinergic challenge distinguished the groups. In depressed patients REM latency was reduced compared with baseline (47.6 vs. 64.4, p =.04) following administration of donepezil. Control subjects showed no response: REM latency after donepezil was virtually identical to baseline REM latency (71.7 vs. 69.3). CONCLUSIONS: These data indicate that donepezil is likely to be useful in testing hypotheses related to cholinergic function in mood disorders.

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.

Psychotic vs. Nonpsychotic Depression in Older Patients.

The authors analyzed data from 42 inpatients age 55 or older with major depression. Ten patients had psychotic depression, and 32 had nonpsychotic depression. There were no significant differences between the two groups in mean age at onset of depression, proportion of patients with previous episodes of depression, frequency of suicidal ideation, or number of family members with serious psychiatric illnesses. Patients with psychotic depression had greater severity of depression and more severe overall psychopathology at admission than the nonpsychotic group. Neuroleptics were used in a majority of the psychotic patients but in none of the nonpsychotic patients, whereas antidepressant use was similar. By the time of discharge, the two groups did not differ in severity of symptoms.