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.     

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.     

Antidepressant response to partial sleep deprivation in unipolar depression is not related to state anxiety

One night of total or partial sleep deprivation (SD) produces a temporary remission in up to 60% of patients with major depression, yet mechanisms remain unclear. We investigated whether the antidepressant effects of SD are caused, even partially, by an improvement in anxiety. As part of a functional magnetic resonance imaging study, 19 unmedicated major depression patients and eight controls completed the Spielberger State/Trait Anxiety Inventory (STAI) (state version) at baseline and sleep-deprived scanning sessions. We found (1) greater anxiety in patients than controls; (2) no baseline or SD STAI difference between responders and nonresponders; (3) no STAI change with SD in any subject group; and (4) no significant correlation between any STAI and Hamilton Depression Rating Scale measures. Our findings did not provide support for an anxiolytic process associated with the antidepressant effects of SD.     

Effects of partial sleep deprivation on the diurnal variation of mood and motor activity in major depression.

Partial sleep deprivation (PSD), keeping a subject awake from 2 AM to 9 PM produces an acute mood improvement in 60% of patients with major depression. We sought to characterize the timing, subcomponent mood, and motor activity changes of this response. Thirty-seven subjects with major depression were rated with the 6-item Hamilton Depression Scale (HAM-6) at 1 PM and completed the Profile of Mood States (POMS) every 2 hr on the day before and day of PSD. Locomotor activity was monitored continuously during the trial with an automated device. Bipolar I patients responded more frequently than other groups. Positive mood responders had greater improvement than nonresponders in POMS subscales of depression, tension, confusion, and anger. The mood improvement increased steadily during the day, peaked in late afternoon, and declined thereafter. Responders showed significantly higher levels of locomotor activity on the baseline pre-PSD day than did nonresponders. All subjects increased motor activity following sleep deprivation, however.     

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.     

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.     

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.     

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.     

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.     

Therapeutic use of sleep deprivation in depression

Total sleep deprivation (TSD) for one whole night improves depressive symptoms in 40-60% of treatments. The degree of clinical change spans a continuum from complete remission to worsening (in 2-7%). Other side effects are sleepiness and (hypo-) mania. Sleep deprivation (SD) response shows up in the SD night or on the following day. Ten to 15% of patients respond after recovery sleep only. After recovery sleep 50-80% of day 1 responders suffer a complete or partial relapse; but improvement can last for weeks. Sleep seems to lead to relapse although this is not necessarily the case. Treatment effects may be stabilised by antidepressant drugs, lithium, shifting of sleep time or light therapy. The best predictor of a therapeutic effect is a large variability of mood. Current opinion is that partial sleep deprivation (PSD) in the second half of the night is equally effective as TSD. There are, however, indications that TSD is superior. Early PSD (i.e. sleeping between 3:00 and 6:00) has the same effect as late PSD given equal sleep duration. New data cast doubt on the time-honoured conviction that REM sleep deprivation is more effective than non-REM SD. Both may work by reducing total sleep time. SD is an unspecific therapy. The main indication is the depressive syndrome. Some studies show positive effects in Parkinson's disease. It is still unknown how sleep deprivation works.     

Thyroid function and response to 48-hour sleep deprivation in treatment-resistant depressed patients.

BACKGROUND: Clinical depression is associated with abnormalities of the hypothalamic-pituitary-thyroid axis. Changes in thyroid function during sleep deprivation may be related to its antidepressant effects. METHODS: Levels of thyroid-stimulating hormone, tri-iodothyronine, tri-iodothyronine uptake, thyroxine, and free thyroxine were measured before, during, and after a 48-hour sleep deprivation in nine treatment-resistant depressed patients. Clinical state was assessed every 4 hours. A retrospective study of 26 similar patients was added for cross-validation. RESULTS: Significant increases in thyroid-stimulating hormone and tri-iodothyronine during sleep deprivation were not correlated with clinical improvement. Sleep deprivation responders had lower tri-iodothyronine uptake levels than nonresponders in both the prospective (p <.02) and the retrospective (p <.03) samples. CONCLUSIONS: The lower tri-iodothyronine uptake values in responders may identify a subgroup of depressed patients who respond to sleep deprivation by virtue of some abnormality of the hypothalamic-pituitary-thyroid axis that is temporarily corrected by sleep deprivation.     

Electroencephalographic sleep studies in depressed outpatients treated with interpersonal psychotherapy: I. Baseline studies in responders and nonresponders.

Electroencephalographic (EEG) sleep measures have been examined as predictors of therapeutic response in patients with major depression. Although some studies have reported that EEG sleep measures are predictive of a favorable outcome with medications, two recent studies found no differences in the baseline sleep characteristics of responders and nonresponders to psychotherapy. To clarify this issue, we compared baseline EEG sleep in a group of patients with recurrent depression who responded to interpersonal psychotherapy (n = 19) and a comparable group who did not respond (n = 18). Baseline ratings of depression severity did not differ in the groups, but some differences in baseline sleep were noted. Psychotherapy nonresponders had longer sleep latencies, lower sleep efficiency, and increased automated measures of phasic rapid eye movement (REM) activity. In addition, the two groups had different EEG sleep adaptation patterns for REM latency and phasic REM density measures across the two study nights. These preliminary results suggest that baseline EEG sleep patterns, as well as the pattern of laboratory adaptation, may differ for depressed patients who respond to psychotherapy and those who do not.     

Baseline cerebral hypermetabolism associated with carbamazepine response, and hypometabolism with nimodipine response in mood disorders.

BACKGROUND: Positron emission tomography (PET) studies have reported baseline (medication free) differences between mood disorder patients and healthy control subjects, but relatively little is known about relationships between baseline PET scans and treatment responses. Carbamazepine (CBZ) and to a more limited extent nimodipine (NIMO) seem useful in mood disorders. We explored whether baseline regional cerebral glucose metabolism (rCMRglu) could discriminate CBZ and NIMO responders from nonresponders and healthy control subjects. METHODS: In refractory mood disorder patients, we examined relationships between responses to these drugs, assessed by Clinical Global Impression-Improvement scores, and baseline rCMRglu, determined with fluorine-18 deoxy-glucose and PET. RESULTS: CBZ responders had baseline left insular hyper-metabolism compared to healthy control subjects and nonresponders, whereas nonresponders had widespread (including left insular) hypometabolism. Degree of CBZ response correlated with baseline paralimbic (including insula) and prefrontal hypermetabolism. In responders but not nonresponders, CBZ decreased widespread metabolism, with the degree of decrease in left insula correlating with response. In contrast, NIMO responders but not nonresponders had baseline widespread (including left insular) hypometabolism. Left prefrontal and left insular baseline hypometabolism, but not metabolic changes with treatment correlated with degree of NIMO response. CONCLUSIONS: These data suggest that baseline anterior paralimbic and prefrontal hypermetabolism may be associated with CBZ response, and hypometabolism with NIMO response. Based on these preliminary data, further exploration of relationships between baseline PET scans and treatment responses is indicated.     

Correlates of therapeutic response in panic disorder presenting with palpitations: heart rate variability, sleep, and placebo effect.

OBJECTIVE: To examine the correlates of therapeutic response of patients with panic disorder presenting with palpitations, we hypothesized that therapeutic response would correlate with heart rate variability (HRV) and sleep measures. METHODS: After a 1-week placebo washout, 27 patients free of structural heart disease and not on cardioactive drugs were randomized in a double-blinded fashion to 4 weeks of treatment with clonazepam (a known antipanic agent) or placebo. We performed standard sleep measures and recorded HRV from 24-hour Holter acquisitions at baseline and end of study. We defined response to therapy as a 50% improvement in the Hamilton Anxiety Rating Scale (HARS) score, confirmed by questionnaires and reaction to sodium lactate infusion. RESULTS: There were 12 responders and 15 nonresponders. Normalization of sleep pattern (including less stage 1 and rapid eye movement [REM] sleep) was observed in both drug and placebo responders (P = 0.011 and P = 0.05, respectively) and in placebo responders alone, compared with nonresponders (P = 0.006 and P = 0.013, respectively). Placebo responders were more likely to show less depression, but even after we controlled for depression, main sleep effects remained. None of the HRV measures correlated with response, but compared with placebo, clonazepam led to a decrease in all the time and frequency domain measures of HRV (all P < 0.05). CONCLUSIONS: Central mechanisms are related to the therapeutic response of patients with panic disorder presenting with palpitations, but this does not directly correlate with HRV. Larger and longer studies may allow objective explanations of placebo response in panic disorder.     

Sleep EEG and amitryptiline treatment in depressed inpatients

We studied the baseline sleep electroencephalogram (EEG) variables and treatment-related sleep changes after 35-46 days of amitryptiline treatment (AMI) in a group of 18 depressed inpatients, mostly suffering from a major depressive disorder endogenous subtype (according to the Research Diagnostic Criteria, RDC), with a short rapid eye movement (REM) latency. The aim of the study was to identify potential sleep "predictors" of clinical response to AMI as well as short-term sleep changes associated with alleviation of depression. Clinical response to the drug was defined as a reduction of more than 50% of the Hamilton Rating Score for Depression (HRSD). Eleven men and 7 women, 25-68 years old, were included in the study. Their sleep was recorded at baseline and after an average of 39 +/- 4 days of AMI treatment, at a mean daily dose of 165 +/- 35 mg. The comparison of responders (n = 9) and nonresponders (n = 9) with Wilcoxon's test showed that responders (1) were more severely depressed at baseline, and (2) had less stage 4 sleep. A discriminant function using baseline HRSD, stage 4 and the number of stage shifts allowed for discrimination between responders and nonresponders with a 100% hit rate. Antidepressant treatment had, however, no differential effect on sleep parameters in the two response groups.     

Sleep deprivation as a predictor of response to light therapy in major depression

Light therapy (LT) is regarded as the treatment of choice for seasonal affective disorder (SAD). In nonseasonal depression the results of light therapy are nonconclusive. Sleep deprivation (SD), however, is effective in 50-60% of the patients with major depression. The predictive value of Total Sleep Deprivation (TSD) for the treatment outcome of antidepressiva has been already examined. Purpose of the present study was to test whether light therapy is more beneficial in TSD responders than in TSD nonresponders. 40 inpatients with major depressive disorder completed one night of TSD. Twenty TSD responders and 20 TSD nonresponders were randomly assigned to 14 days of bright light therapy (2500 lux, 7-9 a.m.) or 14 days of dim light therapy (red light 50 lux, 7-9 a.m.). Manova with repeated measurements revealed a significant difference in the course of depression over the time between TSD responders and nonresponders, but no significant difference between bright and dim light. Questions of placebo effect, of SAD and of personality variables as predictors of response to SD and LT are being discussed.     

Increased limbic blood flow and total sleep deprivation in major depression with melancholia

Single photon emission computed tomography (SPECT) with technetium-99m-d,l-hexamethyl-propylene amine oxime (99Tcm-HMPAO) was carried out in 20 melancholic patients before and after total sleep deprivation. Findings in 11 responders to total sleep deprivation (defined by > or = 40% improvement on the Hamilton Rating Scale for Depression) were compared with findings in nine nonresponders. On the basis of a semiquantitative evaluation of SPECT findings, responders showed relative hyperperfusion before sleep deprivation in the right anterior cingulate cortex and in the right and left fronto-orbital cortex and basal cingulate gyrus. Responders who showed > or = 50% improvement also showed hippocampal overactivation before sleep deprivation. It is possible that limbic overactivation may characterize depressed responders to total sleep deprivation as a distinct subtype. Another possibility is that the pattern of limbic hyperactivation reflects the increased number of bipolar patients in the responder group, with response to total sleep deprivation being only a covariate of this bipolar-unipolar distinction.     

Changes in QEEG prefrontal cordance as a predictor of response to antidepressants in patients with treatment resistant depressive disorder: a pilot study

INTRODUCTION: Previous studies of patients with unipolar depression have shown that early decreases of EEG cordance (a new quantitative EEG method) can predict clinical response. We examined whether early QEEG decrease represents a phenomenon associated with response to treatment with different antidepressants in patients with treatment resistant depression. METHOD: The subjects were 17 inpatients with treatment resistant depression. EEG data and response to treatment were monitored at baseline and after 1 and 4 weeks on an antidepressant treatment. QEEG cordance was computed at three frontal electrodes in theta frequency band. The prefrontal cordance combines complementary information from absolute and relative power of EEG spectra. Recent studies have shown that cordance correlates with cortical perfusion. Depressive symptoms were assessed using Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: All 17 patients completed the 4-week study. All five responders showed decreases in prefrontal cordance after the first week of treatment. Only 2 of the 12 nonresponders showed early prefrontal cordance decrease. The decrease of prefrontal QEEG cordance after week 1 in responders as well as the increase in nonresponders were both statistically significant (p-value 0.03 and 0.01, respectively) and the changes of prefrontal cordance values were different between both groups (p-value 0.001). CONCLUSION: Our results suggest that decrease in prefrontal cordance may indicate early changes of prefrontal activity in responders to antidepressants. QEEG cordance may become a useful tool in the prediction of response to antidepressants.     

Modafinil reduces microsleep during partial sleep deprivation in depressed patients

Objective

Sleep deprivation (SD) can induce a prompt decrease in depressive symptoms within 24 h. Following the recovery night, however, a relapse into depression occurs in most patients. Recovery sleep, naps and even very short episodes of sleep (microsleep; MS) during SD have been shown to provoke a rapid relapse into depression. This study tested the hypothesis that modafinil reduces MS during SD and stabilizes the treatment response to PSD compared to placebo.

Methods

A total of 28 patients (13 men, 15 women; age 45.1 ± 12.1 years) with a major depressive episode and a cumulative daytime microsleep of five or more minutes were investigated using a double-blind placebo-controlled study design. All patients were treated with a stable mirtazapine monotherapy. A partial SD (PSD) was performed after one week. Additional morning treatment with modafinil vs. placebo started during PSD and was maintained over two weeks. Sleep-EEG and MS episodes were recorded with a portable EEG. Depression severity was assessed using the Hamilton Depression Rating Scale before, during and after PSD and at follow-ups after one and two weeks.

Results

Patients treated with modafinil showed significantly reduced microsleep during PSD (11.63 ± 15.99 min) compared to the placebo group (47.77 ± 65.31 min). This suppression of MS was not associated with the antidepressive effect of PSD.

Conclusions

Compared to placebo, modafinil was efficient in reducing daytime microsleep following partial sleep deprivation but did not enhance the antidepressive effects of PSD and did not stabilize antidepressive effects over two weeks.     

Neuroendocrinological investigations during sleep deprivation in depression. II. Longitudinal measurement of thyrotropin, TH, cortisol, prolactin, GH, and LH during sleep and sleep deprivation

Thyrotropin (TSH), thyroxin (T4), triiodothyronine (T3), free T3 (fT3), cortisol, prolactin, and human growth hormone (HGH) were measured every 2 hr during a night of sleep, the following day, and a night of sleep deprivation (SD) in 14 patients with major depressive disorder. In subgroups fT4 (n = 5), reverse T3 (rT3), and luteinizing hormone (LH) (n = 6) were also investigated. Significant increases in TSH, T4, fT4, T3, fT3, rT3, and cortisol and decreases in prolactin levels occurred during the night of SD, compared to the pattern during the night of sleep. The pre-SD T4 and T3 levels of the responders to SD were already higher than in the nonresponders, and increased less during SD. The cortisol and HGH concentrations of the responders rose higher during SD than those of the nonresponders. Changes in TSH and prolactin were not correlated to clinical response. Analysis of possible neurochemical mechanisms underlying this "pattern" of changes in different endocrine profiles suggests that enhanced noradrenergic activity might play a role in the changes in TSH, cortisol, thyroid hormones, and possibly HGH secretion during SD, and increased dopaminergic tone probably induced the decline in prolactin levels. Additional effects of the serotonergic system cannot be excluded at present. In conclusion, the data suggest that enhanced noradrenergic activity of the locus coeruleus stimulates alpha and/or beta adrenergic receptors in depressed patients during SD. This mechanism could well be involved in the antidepressant effect of this therapy.