Effect of sleep deprivation on brain metabolism of depressed patients.

OBJECTIVE: Sleep deprivation is a rapid, nonpharmacologic antidepressant intervention that is effective for a subset of depressed patients. The objective of this study was to identify which brain structures' activity differentiates responders from nonresponders and to study how metabolism in these brain regions changes with mood. METHOD: Regional cerebral glucose metabolism was assessed by positron emission tomography (PET) with [18F]deoxyglucose (FDG) before and after total sleep deprivation in 15 unmedicated awake patients with unipolar major depression and 15 normal control subjects, who did the continuous performance test during FDG uptake. RESULTS: After sleep deprivation, four patients showed a 40% or more improvement on the Hamilton Rating Scale for Depression. Before sleep deprivation the depressed responders had a significantly higher cingulate cortex metabolic rate than the depressed nonresponders, and this normalized after sleep deprivation. The normal control subjects and nonresponding depressed patients showed no change in cingulate metabolic rate after sleep deprivation. CONCLUSIONS: Overactivation of the limbic system as assessed by PET scans may characterize a subset of depressed patients. Normalization of activity with sleep deprivation is associated with a decrease in depression.     

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.     

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.     

Biological and behavioral effects of one night's sleep deprivation in depressed patients and normals.

Twenty-five patients with major depressive illness and 20 normal volunteers were sleep deprived for one night in order to assess mood, physiology, and biochemistry. Fifteen patients showed mild to moderate improvement in depression, normally lasting one day, while volunteers tended to experience slight increases in dysphoria following sleep deprivation (SD). Prior to SD depressed patient responders had lower baseline levels of HVA in CSF than non-responders. Following SD responders tended to have decreases in CSF calcium and MHPG and increases in serum cortisol compared to nonresponders. Nonresponders also showed a flattened diurnal temperature rhythm following SD. Alterations in central neurotransmitters, circadian rhythms, and stress activation are discussed as possible mediators of the selective mood improvement in depressed patients compared to normal volunteer controls.     

Acute mood and thyroid stimulating hormone effects of transcranial magnetic stimulation in major depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has recently been demonstrated to have antidepressant effects. Some work suggests that rTMS over prefrontal cortex administered to healthy individuals produces acute elevations of mood and serum thyroid-stimulating hormone (TSH). We sought to determine whether single rTMS sessions would produce acute mood and serum TSH elevations in subjects with major depressions. METHODS: Under double-blind conditions et al 14 medication-free subjects with major depression received individual sessions of either active or sham rTMS. rTMS was administered over the left prefrontal cortex at 10 Hz et al 100% of motor threshold, 20 trains over 10 min. Immediately before and after rTMS sessions, subjects' mood was rated with the Profile of Mood States (POMS) and the 6-Item Hamilton Depression Scale, and blood was drawn for later analysis of TSH. Subjects and raters were blind to treatment assignment. RESULTS: The group receiving active stimulation manifested significantly greater improvement on the POMS subscale of Depression (p < or = .0055) and a trend toward greater improvement on the modified Hamilton Rating (.05 < p < or =.1). No hypomania was induced. The change in TSH from pre- to post-rTMS was significantly different between active and sham sessions. CONCLUSIONS: This blinded, placebo-controlled trial documents that individual rTMS sessions can acutely elevate mood and stimulate TSH release in patients experiencing major depressive episodes.     

Prolongation of the antidepressant response to partial sleep deprivation by lithium

Depressed patients given a loading dose of lithium on the first of 2 successive days of partial sleep deprivation (PSD), and kept at maintenance levels thereafter, showed significantly greater prolongation of the antidepressant effects of PSD than patients treated with PSD and placebo, even though the acute elevation in mood derived from PSD was as great on placebo as on lithium. Depression was assessed 3 days after PSD with an augmented version of the Hamilton Rating Scale for Depression. Patients on lithium alone, without PSD, did not have the acute elevation in mood seen in the two PSD groups and had significantly less improvement in depression than those who received PSD with lithium.     

Effects of brief naps on mood and sleep in sleep-deprived depressed patients

To determine the effects of brief naps on mood and electroencephalographic (EEG) sleep in sleep-deprived depressed patients, data from 19 hospitalized patients with depression were analyzed; all were kept awake from 0700h until the following day, when they were allowed 10-min naps at either 0830h or 1500h. Six of the patients showed a clinically significant improvement (greater than 40% change) on the Hamilton Rating Scale for Depression (HRSD) before the nap after all-night sleep deprivation, and the group as a whole showed a significant improvement on the HRSD, the Profile of Mood States, and the Brief Psychiatric Rating Scale subscale for depression. Naps did not alter mood in the responders, but did improve measured depression on the HRSD in the non-responders. Morning and afternoon naps did not differ significantly in their effects on mood or nap sleep. On the recovery sleep, patients who were classified as responders after the nap showed a significantly greater increase in delta (Stage 3 + 4) sleep compared with baseline than nonresponders.     

No Influence of a functional polymorphism within the serotonin transporter gene on partial sleep deprivation in major depression.

Sleep deprivation exerts transient antidepressant efficacy. As a potential mechanism of action an enhancement of serotonergic and dopaminergic neurotransmission within the CNS is discussed. Because genetic variations influencing neurotransmission could have an impact on therapeutic outcome and stability of improvement, we investigated the functional polymorphism of the serotonin transporter (5-HTT) gene, the 5-HTT-linked polymorphic region (5-HTTLPR), to examine the serotonergic pathway. We included 56 patients with major depression (DSM-IV). Psychiatric ratings including the HAM-D21 and HAM-D6 scale were assessed on the day prior to partial sleep deprivation (PSD) and on day 1 and 2 after PSD and related to the different genotypes. The 5-HTTLPR variants were determined following PCR amplification using genomic DNA. 58.1% of the patients were responders to PSD. A significant overall reduction in depression scores could be observed on day 1. Subdivision according 5-HTTLPR gene variants showed no differences in clinical outcome on day 1. As expected the therapeutical effect of PSD was only transient and most patients experienced an exacerbation of depressive symptoms on day 2. 5-HTTLPR variants had no influence on reduction of depressive symptoms on day 2 or relapse on day 3. Thus, the previously reported influence of the serotonin transporter gene on PSD outcome in bipolar depression could not be confirmed in unipolar depressed patients.     

Serum thyrotropin concentrations and bioactivity during sleep deprivation in depression

BACKGROUND: One night of sleep deprivation induces a brief remission in about half of depressed patients. Subclinical hypothyroidism may be associated with depression, and changes in hypothalamic-pituitary-thyroid function may affect the mood response to sleep deprivation. We wished to define precisely the status of the hypothalamic-pituitary-thyroid axis of depressed patients during sleep deprivation and the possible relationship of hypothalamic-pituitary-thyroid function to the mood response. METHODS: We studied 18 patients with major depressive disorder and 10 normal volunteers. We assessed mood before and after sleep. We measured serum thyrotropin every 15 minutes during the night of sleep deprivation, thyrotropin bioactivity, the thyrotropin response to protirelin the next afternoon, and other indexes of hypothalamic-pituitary-thyroid function. To determine if the changes were limited to the hypothalamic-pituitary-thyroid axis, we measured serum cortisol, which also has a circadian secretory pattern. RESULTS: Nocturnal serum thyrotropin concentrations were consistently higher in responders, entirely because of elevated levels in the women reponders. Responders had exaggerated responses to protirelin the next afternoon. The bioactivity of thyrotropin in nonresponders was significantly greater than in responders (F(1,8. 99) = 7.52; P =.02). Other thyroid indexes and serum cortisol concentrations were similar among groups. CONCLUSIONS: Depressed patients have mild compensated thyroid resistance to thyrotropin action, not subclinical autoimmune primary hypothyroidism. Sleep deprivation responders compensate by secreting more thyrotropin with normal bioactivity; nonresponders compensate by secreting thyrotropin with increased bioactivity.     

全部睡眠剥夺对健康男性青年情绪的影响

目的 探讨长时间睡眠剥夺（SD）对情绪的影响。方法 挑选身体健康男性青年志愿者30名,剥夺全部睡眠52h。采用情绪状态问卷、贝克焦虑问卷、考虑自评量表、状态焦虑问卷和自评抑郁量表,分别在SD前（基础值）、SD期间（1次／6h,共8次）及一夜恢复性睡眠后评定受试者的情绪状态。结果 与基础值比较,随SD时间的延长,疲惫－惰性、焦虑、抑郁、困惑-迷茫等消极情绪的因子分逐渐增加（P＜0．05－0．001）,并与SD时间呈正相关;而有力－好动积极情绪因子分逐渐下降（P＜0．001）,与SD时间呈负相关（r＝－0．846,P＜0．001）。一夜恢复性睡眠后,疲惫－惰性和有力－好动因子分与基础值的差异仍有显著性（P＜0．05－0．01）,余均恢复到基础水平。结论 长时间的SD可导致情绪逐渐恶化。;一夜的恢复性睡眠对情绪的改善有一定效果。     

Sleep deprivation and hypothalamic-pituitary-adrenal (HPA) axis activity in depressed patients

In the present study we investigated HPA axis activity in depressed patients treated with partial sleep deprivation (PSD) in order to identify endocrinological characteristics related to PSD responsiveness. Thirty-three drug-free patients (14 men, 19 women) suffering from major depression according to DSM-IV criteria were treated with PSD. Response to PSD was defined as a reduction of at least 30% according to the 6-item version of the Hamilton Depression Scale (6-HAMD). Subsequently, the combined dexamethasone-suppression/CRH-stimulation test (DEX/CRH test) was performed. Patients were pretreated with 1.5 mg dexamethasone (DEX) at 23:00 h and challenged with 100 microg corticotropin-releasing hormone (CRH) the following day. Postdexamethasone cortisol concentrations (before CRH administration) served as parameters for the DST status (dexamethasone suppression test). The cortisol stimulation after CRH was used as measurement for the DEX/CRH test status. Of the depressive patients, 54.5% (18 out of 33) responded to PSD. DST suppressors (postdexamethasone cortisol levels < 15 ng/ml) showed a significantly greater reduction in 6-HAMD scores after PSD than DST nonsuppressors. Furthermore, a significant negative correlation between postdexamethasone cortisol levels and reduction in 6-HAMD scores after PSD could be established. However, there was no relationship between the cortisol stimulation following CRH challenge and response to PSD. Although the combined DEX/CRH challenge test is a more sensitive marker for HPA axis dysregulation in depression than the standard DST, the negative feedback of the HPA system reflected by the DST status is apparently more closely associated with response to partial sleep deprivation in major depressive disorder.     

Effect of flumazenil-augmentation on microsleep and mood in depressed patients during partial sleep deprivation

The antidepressive effect of sleep deprivation (SD) in depressed patients disappears after sleep of the recovery night and after early morning naps. Both can provoke a rapid relapse into depression in SD-responders. In addition, the occurrence of short episodes of sleep (termed microsleep, MS) during partial SD (PSD) is associated with SD-nonresponse, suggesting that MS during the time awake may be related to relapse or PSD-nonresponse. The GABA-benzodiazepine receptor antagonist flumazenil augments vigilance and reduces NonREM-sleep pressure in early morning recovery sleep in volunteers after SD. Therefore, in this study 27 patients with major depression were subjected to a PSD. In a double blind randomized design either flumazenil or placebo was orally applied during PSD in order to examine whether the application of flumazenil reduces sleep propensity and thus, increases antidepressant efficacy of PSD. EEG was registered continuously for 60h by a portable device for the assessment of microsleep episodes at baseline and during PSD. Flumazenil application significantly suppressed frequency and total amount of MS. While the antidepressant efficacy of PSD was not different between flumazenil and placebo during PSD, the subjective mood improved after the recovery night in patients treated with flumazenil. It is concluded that GABAergic mechanisms are involved in the regulation of MS during PSD, which may be related to a mood stabilizing effect after the recovery night. However, the mechanisms underlying the association between the occurrence of MS during PSD and mood variation have to be further clarified.     

Motor activity in depressed patients during therapeutic sleep deprivation

ProblemBoth sleep and motor activity have a bidirectional relationship with depression. The existing literature on motor activity during therapeutic sleep deprivation in depressed patients is inconsistent and fragmentary. In the present study we measured motor activity continuously during 40 hours of sleep deprivation in depressed patients.MethodThirty-four inpatients suffering from a major depression (DSM-IV) underwent sleep deprivation with a continuous waking period of 40 hours. Motor activity of the patients was continuously recorded using an actigraph on the non-dominant wrist. The effect of sleep deprivation was assessed by the Hamilton Depression Scale (six-item version), thus separating the group into responders and non-responders to sleep deprivation.ResultsWe found no significant differences in motor activity between responders and non-responders on the day before sleep deprivation. During the night, responders to sleep deprivation exhibited a higher motor activity and less periods of rest. On the day after sleep deprivation, responders exhibited a higher activity, too.ConclusionsMotor activity levels differ between the two groups, thus giving more insight into possible mechanisms of action of the therapeutic sleep deprivation. We suggest that higher motor activity during the night prevents naps and leads to better response to sleep deprivation.     

Effects of sleep deprivation on mood and central amine metabolism in depressed patients.

Nineteen patients, each hospitalized with a major depressive episode, were deprived of sleep for one night. Ten patients responded with clear improvement in depressive symptoms; the substantial clinical change was transient, usually lasting one day. Those who responded had significantly higher initial depression ratings (P less than .01) and tended to be older than nonresponders who experienced mild increases in irritability, fatigue, and discomfort following sleep deprivation. Amine metabolites, 5-hydroxyindoleacetic acid (5HIAA), and homovanillic acid (HVA) were not substantially affected by sleep deprivation, although there was a significant interaction of clinical response and direction of 3-methoxy-4-hydroxyphenylglycol (MHPG) change. Sleep deprivation thus produces acute, but only transient improvement in a selected group of severely depressed patients; it appears to be an important tool in the study of the affective disorders.     

Risperidone in the treatment of psychotic depression

In the preset study, the authors investigated that effects of the antipsychotic drug risperidone on psychotic depression and examined the mechanism of risperidone to ameliorate psychotic depression. Fifteen patients met the DSM-IV criteria for major depressive disorder with psychotic features and the remaining five patients met those for bipolar I disorder (most recent episode depressed) with psychotic features (M/F: 8/12, age: 54+/-18). All patients were evaluated regarding their clinical improvement using the Hamilton Rating Scale for Depression (Ham-D), and Positive and Negative Syndrome Scale (PANSS). In addition, plasma concentrations of HVA and MHPG were analyzed by HPLC. Patients with a 50% or more improvement in Ham-D score were defined as responders. Three were prescribed risperidone alone, and the other 17 were administered risperidone as an addition to preexisting antidepressants or mood stabilizers. The preexisting antidepressants or mood stabilizers were as follows: paroxetine (6), lithium (3), valproic acid (3), clomipramine (2), fluvoxamine (1), amitriptyline (1), amoxapine (1). The average dose of risperidone was 1.8+/-0.5 mg/day. Eleven of twenty patients (55%) turned out to be responders 4 weeks after initiation of risperidone administration. No differences were observed between responders and nonresponders with respect to age, sex, Ham-D score before risperidone treatment, dose and plasma level of risperidone or its active metabolite, 9-hydroxyrisperidone. Plasma HVA levels before risperidone administration in responders were significantly higher than those in nonresponders. In addition, a significant correlation was observed between changes in plasma HVA level and the percentage improvement on Ham-D score. These results indicate that treatment with risperidone is effective to ameliorate psychotic depression, and the influence of risperidone on dopaminergic activity is associated with its efficacy.     

Diurnal variation of mood and the cortisol rhythm in depression and normal states of mind

Summary A large scale chronobiological investigation was undertaken in 20 drug-free psychiatric inpatients displaying RDC major depression (endogenous subtype) in comparison to 10 healthy control subjects and 10 of the patients after clinical recovery. A series of measurements was taken 6 times a day and, in 8 of a total of 14 variables, also once a night over a period of 10 to 14 days. The following variables were assessed: mood (three different scales), performance (two tests), motor activity (three measures), salivary flow, urinary excretion of water, sodium, potassium, and free cortisol (UFC), and rectal temperature. A phase chart of the acrophases of the 8 variables with measurements taken during day and night revealed two clusters in the depressives and three in the non-depressed subjects. In the depressives, the acrophases of the mood scales clustered around the time of awakening in the morning, together with the acrophase of UFC, whereas all other acrophases clustered in the afternoon. In the non-depressed subjects, however, the mood scales reached their circadian maxima in the middle of the night around the time when sleep was interrupted to take measurements. All other acrophases corresponded roughly with those found in the depressives. The coincidence of the time course of depressed mood and cortisol excretion in the patients was interpreted as reflecting a temporal relationship between diurnal mood swings in depression and the cortisol rhythm. This interpretation was supported by the significant correlation between the acrophases of the two respective rhythms in patients showing a significant diurnal variation in mood. The mood curves of non-depressed subjects seemed unrelated to the cortisol rhythm. Probably, they mirror diurnal fluctuations of vigilance rather than fluctuations of mood. According to the literature, this rhythm is temporally related to the rhythm of melatonin secretion.     

Serum Ghrelin Levels and the Effects of Antidepressants in Major Depressive Disorder and Panic Disorder

Background: Two opposing models for the action of ghrelin in the behavioral responses to stress were recently proposed. Some studies suggest that an increase in ghrelin contributes to the mechanisms responsible for the development of stress-induced depression and anxiety, while others suggest that it helps minimize what otherwise would be more severe manifestations of depression and anxiety following stress. Methods: We measured serum ghrelin levels, Profile of Mood States (POMS) scores and State-Trait Anxiety Inventory scores in nonresponders (treatment-resistant patients; 30) and responders (38) with major depressive disorder (MDD), nonresponders (29) and responders (51) with panic disorder and 97 healthy controls. Results: The ghrelin concentration in nonresponders with MDD was higher than that of responders with MDD and normal controls. The ghrelin concentration in nonresponders with panic disorder was higher than that of normal controls. POMS vigor scores in patients with MDD and panic disorder were significantly decreased compared with those in healthy controls. Other POMS scores in patients with MDD and panic disorder were significantly increased compared with those of healthy controls. Trait and state anxiety of the State-Trait Anxiety Inventory in MDD and panic disorder patients were higher than those in healthy controls. Conclusions: These results indicate that decreased serum ghrelin levels might be associated with antidepressant treatment to confer the maximum therapeutic effect in patients with MDD and panic disorder.     

Sleep deprivation effects in older endogenous depressed patients

In a drug-free group of 15 older endogenous depressed inpatients, all-night sleep deprivation (SD) was associated with a significant decrease in Hamilton depression scores and in Profile of Mood States self-ratings of depression. Six of 15 patients (40%) were responders to SD, as evidenced by greater than or equal to 30% improvement in Hamilton ratings. While symptomatic improvement was short-lived (8 of 15 patients worsened after 1 night of recovery sleep), five patients showed further improvement after 1 night of recovery sleep. The final two patients had an increase in Hamilton ratings after sleep deprivation, with a return to baseline values after 1 night of recovery sleep. Responders (but not nonresponders) showed significant improvement in sleep latency, sleep efficiency, and slow wave sleep during recovery sleep (as did controls). The SD Hamilton depression rating (at 9 a.m. after all-night sleep deprivation) showed a significant inverse correlation with the increase in slow wave sleep (SWS) minutes and in SWS % from baseline to first recovery night. Responders also had significantly larger increases in SWS minutes than did nonresponders (53.8 vs. 7 minutes). Similarly, the % change in Hamilton depression ratings was predicted by baseline Stage 4 sleep. These findings suggest that there is a mutual interaction between the process of sleep regulation and the symptoms of depression. They also confirm a prediction from the two-process model of sleep regulation--namely, that improved sleep initiation and maintenance and increased SWS, attained by SD, are associated with clinical improvement.     

Thyrotropin (TSH) and thyroid hormone concentrations during partial sleep deprivation in patients with major depressive disorder

Thyrotropin (TSH), thyroxine (T4), free T4, triiodothyronine (T3), and free T3 (fT3) concentrations were measured in 25 patients with major depressive disorder at 8 a.m. both before and after partial sleep deprivation (PSD) during the second half of the night. Significant increases in TSH and T3 levels and a corresponding trend in fT3 levels were seen. No convincing correlations occured between changes in the secretion of any of the hormones and the antidepressant effect of PSD. However, this does not rule out the possibility that the two phenomena, which occur in depression at different anatomical levels with presumably different degrees of disturbance in the respective receptor systems, have common underlying neurochemical mechanisms. Comparison of the effect of the PSD on changes in hormone secretion and mood with the corresponding effects in a sample of depressed patients who underwent total sleep deprivation showed no significant differences between the effects of these two forms of sleep deprivation on either variable.     

Does Cognitive Impairment Cause Poststroke Depression?

Studies have demonstrated that poststroke depression is associated with cognitive impairment, but have failed to show improvement in cognitive function when mood improves. A consecutive series of patients with (n=41) or without (n=135) major depression were evaluated for cognitive functioning during acute hospitalization and either 3 or 6 months later. Patients with poststroke major depression whose mood improved at follow-up had significantly greater recovery in cognitive functioning than patients whose mood did not improve. Furthermore, patients whose cognitive functioning improved at follow-up had significantly greater improvement in mood than comparable patients whose cognitive function did not improve, suggesting that poststroke major depression leads to cognitive impairment and not vice versa. The failure of previous treatment studies to show cognitive improvement in poststroke patients with depression was probably due to the inclusion of patients with minor depression (not associated with cognitive impairment) or the failure of patients with major depression to respond to treatment.