Antidepressant Effects Of Sleep Deprivation Research Articles

Dopamine pathways mediating affective state transitions after sleep loss

The pathophysiology of affective disorders-particularly circuit-level mechanisms underlying bidirectional, periodic affective state transitions-remains poorly understood. In patients, disruptions of sleep and circadian rhythm can trigger transitions to manic episodes, whereas depressive states are reversed. Here, we introduce a hybrid automated sleep deprivation platform to induce transitions of affective states in mice. Acute sleep loss causes mixed behavioral states, featuring hyperactivity, elevated social and sexual behaviors, and diminished depressive-like behaviors, where transitions depend on dopamine (DA). Using DA sensor photometry and projection-targeted chemogenetics, we reveal that elevated DA release in specific brain regions mediates distinct behavioral changes in affective state transitions. Acute sleep loss induces DA-dependent enhancement in dendritic spine density and uncaging-evoked dendritic spinogenesis in the medial prefrontal cortex, whereas optically mediated disassembly of enhanced plasticity reverses the antidepressant effects of sleep deprivation on learned helplessness. These findings demonstrate that brain-wide dopaminergic pathways control sleep-loss-induced polymodal affective state transitions.

Guanine-Based Purines as an Innovative Target to Treat Major Depressive Disorder.

Guanine-Based Purines as an Innovative Target to Treat Major Depressive Disorder.

0081 Habitual Sleep Duration is Negatively Correlated with Emotional Reactivity within the Rostral Anterior Cingulate Cortex in Individuals with PTSD

Abstract Introduction Sleep difficulties, such as insomnia, are highly prevalent in individuals with Post-Traumatic Stress Disorder (PTSD). However, sleep deprivation can also increase emotional reactivity to positive (as well as negative) stimuli. While the effects of sleep loss on emotional perception healthy individuals has been documented, it remains unclear how lack of sleep in individuals with PTSD may affect their emotional reactivity to positive stimuli. We hypothesized that lower habitual sleep duration would be associated with greater functional brain activation changes in response to subliminally presented happy faces in brain areas of the reward network, such as the rostral anterior cingulate cortex (rACC). Methods Thirty-nine individuals with DSM-5 confirmed PTSD were administered the Pittsburgh Sleep Quality Index (PSQI) as a measure of their average nightly sleep duration over the past month. Participants then underwent fMRI imagining while viewing subliminal presentations of faces displaying happiness, using a backward masked facial affect paradigm to minimize conscious awareness of the expressed emotion. Brain activation to masked happy expressions was regressed against sleep duration in SPM12. Results There was a negative correlation between habitual sleep duration and activation within the rACC in response to the masked happy faces (x=14,y=40,z=0; k=102, pFWE-corr= 0.008). Conclusion Individuals with PTSD who average less sleep at night showed greater emotional reactivity, as indexed by greater functional brain activation changes within an area of the reward network, than individuals who obtained more sleep per night. Future research involving actual sleep duration manipulation will be necessary to determine whether this finding reflects the well-known antidepressant effect of sleep deprivation or a form of greater emotional expression error monitoring among traumatized patients when lacking sleep. Regardless, these findings suggest that insufficient sleep could affect unconsciously perceived emotion in faces and potentially affect social and emotional responses among individuals with PTSD. Support US Army Medical Research and Materiel Command: W81XWH-14-1-0570

Perspectives in affective disorders: Clocks and sleep.

Mood disorders are often characterised by alterations in circadian rhythms, sleep disturbances and seasonal exacerbation. Conversely, chronobiological treatments utilise zeitgebers for circadian rhythms such as light to improve mood and stabilise sleep, and manipulations of sleep timing and duration as rapid antidepressant modalities. Although sleep deprivation ("wake therapy") can act within hours, and its mood-elevating effects be maintained by regular morning light administration/medication/earlier sleep, it has not entered the regular guidelines for treating affective disorders as a first-line treatment. The hindrances to using chronotherapeutics may lie in their lack of patentability, few sponsors to carry out large multi-centre trials, non-reimbursement by medical insurance and their perceived difficulty or exotic "alternative" nature. Future use can be promoted by new technology (single-sample phase measurements, phone apps, movement and sleep trackers) that provides ambulatory documentation over long periods and feedback to therapist and patient. Light combinations with cognitive behavioural therapy and sleep hygiene practice may speed up and also maintain response. The urgent need for new antidepressants should hopefully lead to reconsideration and implementation of these non-pharmacological methods, as well as further clinical trials. We review the putative neurochemical mechanisms underlying the antidepressant effect of sleep deprivation and light therapy, and current knowledge linking clocks and sleep with affective disorders: neurotransmitter switching, stress and cortico-limbic reactivity, clock genes, cortical neuroplasticity, connectomics and neuroinflammation. Despite the complexity of multi-system mechanisms, more insight will lead to fine tuning and better application of circadian and sleep-related treatments of depression.

Meta-Analysis of the Antidepressant Effects of Acute Sleep Deprivation.

To provide a quantitative meta-analysis of the antidepressant effects of sleep deprivation to complement qualitative reviews addressing response rates. English-language studies from 1974 to 2016 using the keywords sleep deprivation and depression searched through PubMed and PsycINFO databases. A total of 66 independent studies met criteria for inclusion: conducted experimental sleep deprivation, reported the percentage of the sample that responded to sleep deprivation, provided a priori definition of antidepressant response, and did not seamlessly combine sleep deprivation with other therapies (eg, chronotherapeutics, repetitive transcranial magnetic stimulation). Data extracted included percentage of responders, type of sample (eg, bipolar, unipolar), type of sleep deprivation (eg, total, partial), demographics, medication use, type of outcome measure used, and definition of response (eg, 30% reduction in depression ratings). Data were analyzed with meta-analysis of proportions and a Poisson mixed-effects regression model. The overall response rate to sleep deprivation was 45% among studies that utilized a randomized control group and 50% among studies that did not. The response to sleep deprivation was not affected significantly by the type of sleep deprivation performed, the nature of the clinical sample, medication status, the definition of response used, or age and gender of the sample. These findings support a significant effect of sleep deprivation and suggest the need for future studies on the phenotypic nature of the antidepressant response to sleep deprivation, on the neurobiological mechanisms of action, and on moderators of the sleep deprivation treatment response in depression.

The two-process model of sleep regulation: a reappraisal.

In the last three decades the two-process model of sleep regulation has served as a major conceptual framework in sleep research. It has been applied widely in studies on fatigue and performance and to dissect individual differences in sleep regulation. The model posits that a homeostatic process (Process S) interacts with a process controlled by the circadian pacemaker (Process C), with time-courses derived from physiological and behavioural variables. The model simulates successfully the timing and intensity of sleep in diverse experimental protocols. Electrophysiological recordings from the suprachiasmatic nuclei (SCN) suggest that S and C interact continuously. Oscillators outside the SCN that are linked to energy metabolism are evident in SCN-lesioned arrhythmic animals subjected to restricted feeding or methamphetamine administration, as well as in human subjects during internal desynchronization. In intact animals these peripheral oscillators may dissociate from the central pacemaker rhythm. A sleep/fast and wake/feed phase segregate antagonistic anabolic and catabolic metabolic processes in peripheral tissues. A deficiency of Process S was proposed to account for both depressive sleep disturbances and the antidepressant effect of sleep deprivation. The model supported the development of novel non-pharmacological treatment paradigms in psychiatry, based on manipulating circadian phase, sleep and light exposure. In conclusion, the model remains conceptually useful for promoting the integration of sleep and circadian rhythm research. Sleep appears to have not only a short-term, use-dependent function; it also serves to enforce rest and fasting, thereby supporting the optimization of metabolic processes at the appropriate phase of the 24-h cycle.

A systematic review for the antidepressant effects of sleep deprivation with repetitive transcranial magnetic stimulation.

BackgroundSleep deprivation (SD) and repetitive transcranial magnetic stimulation (rTMS) have been commonly used to treat depression. Recent studies suggest that co-therapy with rTMS and SD may produce better therapeutic effects than either therapy alone. Therefore, this study was to review the current findings to determine if rTMS can augment the therapeutic effects of SD on depression.MethodsEmbase, JSTOR, Medline, PubMed, ScienceDirect, and the Cochrane Central Register of Controlled Trials were searched for clinical studies published between January 1985 and March 2015 using the search term “rTMS/repetitive transcranial magnetic stimulation AND sleep deprivation AND depress*”. Only randomized and sham-controlled trials (RCTs) involving the combined use of rTMS and SD in depression patients were included in this systematic review. The scores of the Hamilton Rating Scale for Depression were extracted as primary outcome measures.ResultsThree RCTs with 72 patients that met the inclusion criteria were included for the systematic review. One of the trials reported skewed data and was described alone. The other two studies, which involved 30 patients in the experimental group (SD + active rTMS) and 22 patients in the control group (SD + sham rTMS), reported normally distributed data. The primary outcome measures showed different results among the three publications: two of which showed great difference between the experimental and the control subjects, and the other one showed non-significant antidepressant effect of rTMS on SD. In addition, two of the included studies reported secondary outcome measures with Clinical Global Impression Rating Scale and a self-reported well-being scale which presented good improvement for the depressive patients in the experiment group when compared with the control. The follow-up assessments in two studies indicated maintained results with the immediate measurements.ConclusionsFrom this study, an overview of the publications concerning the combined use of rTMS and SD is presented, which provides a direction for future research of therapies for depression. More studies are needed to confirm whether there is an augmentative antidepressant effect of rTMS on SD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-015-0674-8) contains supplementary material, which is available to authorized users.

Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depressive-like Behavior via Induction of Homer1a

Major depressive disorder is among the most commonly diagnosed disabling mental diseases. Several non-pharmacological treatments of depression upregulate adenosine concentration and/or adenosine A1 receptors (A1R) in the brain. To test whether enhanced A1R signaling mediates antidepressant effects, we generated a transgenic mouse with enhanced doxycycline-regulated A1R expression, specifically in forebrain neurons. Upregulating A1R led to pronounced acute and chronic resiliencetoward depressive-like behavior in various tests. Conversely, A1R knockout mice displayed an increased depressive-like behavior and were resistant to the antidepressant effects of sleep deprivation (SD). Various antidepressant treatments increase homer1a expression in medial prefrontal cortex (mPFC). Specific siRNA knockdown of homer1a in mPFC enhanced depressive-like behavior and prevented the antidepressant effects of A1R upregulation, SD, imipramine, and ketamine treatment. In contrast, viral overexpression of homer1a in the mPFC had antidepressant effects. Thus, increased expression of homer1a is a final common pathway mediating the antidepressant effects of different antidepressant treatments.

Adenosine-based antidepressants?

The antidepressant effect of a night without sleep is a well-known but poorly understood phenomenon. The authors showed that 12-hour sleep deprivation increased hippocampal extracellular adenosine levels and adenosine receptor A1 (A1R) signalling in mice. Conversely, impairing gliotransmission in astrocytes reduced the antidepressant-like effects of 12-hour sleep deprivation. Moreover, sleep deprivation had no effects in mice lacking A1Rs and central administration of an A1R agonist mimicked the antidepressant effect of sleep deprivation. These data point to astrocytic adenosine signalling as a possible therapeutic target for a novel class of antidepressants.

Antidepressant effects of sleep deprivation require astrocyte-dependent adenosine mediated signaling

Major depressive disorder is a debilitating condition with a lifetime risk of ten percent. Most treatments take several weeks to achieve clinical efficacy, limiting the ability to bring instant relief needed in psychiatric emergencies. One intervention that rapidly alleviates depressive symptoms is sleep deprivation; however, its mechanism of action is unknown. Astrocytes regulate responses to sleep deprivation, raising the possibility that glial signaling mediates antidepressive-like actions of sleep deprivation. Here, we found that astrocytic signaling to adenosine (A1) receptors was required for the robust reduction of depressive-like behaviors following 12 hours of sleep deprivation. As sleep deprivation activates synaptic A1 receptors, we mimicked the effect of sleep deprivation on depression phenotypes by administration of the A1 agonist CCPA. These results provide the first mechanistic insight into how sleep deprivation impacts mood, and provide a novel pathway for rapid antidepressant development by modulation of glial signaling in the brain.

Can repetitive transcranial magnetic stimulation prolong the antidepressant effects of sleep deprivation?

Repetitive transcranial magnetic stimulation (rTMS) has been proposed for stabilizing the antidepressant effect of sleep deprivation (SD) by preventing the relapse after a night of recovery sleep. In this study, we aimed to replicate these data coming from a small pilot study in a larger patient sample. Thirty-seven patients were randomly assigned to receive either active or sham rTMS on four consecutive days after one night of SD. The majority of the participants had experienced an antidepressant effect of SD in the past. At each rTMS session 1000 stimuli were applied over the left dorsolateral prefrontal cortex at 10 Hz with an intensity of 110% resting motor threshold. For sham stimulation, a sham-coil system was used. Treatment effects were assessed with a modified version of the Hamilton Depression Rating Scale and a self-report well-being scale (BfS) before SD, after SD, during rTMS and 3 days after rTMS. SD led to a highly significant reduction of depressive symptoms in the whole group as reflected by a mean Hamilton Depression Rating Scales score reduction of 56% (with omission of sleep items). In both the active and the sham-stimulated group, the symptom reduction remained stable for the whole observation period. No difference between active and sham rTMS was observed. SD is capable of inducing pronounced antidepressant effects. In contrast to a previous study, active rTMS was not superior to sham rTMS in stabilizing the antidepressant effects of SD, which was mainly due to a pronounced effect in the sham group in this study population.

Antidepressant effects of selective slow wave sleep deprivation in major depression: A high-density EEG investigation

Sleep deprivation can acutely reverse depressive symptoms in some patients with major depression. Because abnormalities in slow wave sleep are one of the most consistent biological markers of depression, it is plausible that the antidepressant effects of sleep deprivation are due to the effects on slow wave homeostasis. This study tested the prediction that selectively reducing slow waves during sleep (slow wave deprivation; SWD), without disrupting total sleep time, will lead to an acute reduction in depressive symptomatology. As part of a multi-night, cross-over design study, participants with major depression (non-medicated; n = 17) underwent baseline, SWD, and recovery sleep sessions, and were recorded with high-density EEG (hdEEG). During SWD, acoustic stimuli were played to suppress subsequent slow waves, without waking up the participant. The effects of SWD on depressive symptoms were assessed with both self-rated and researcher-administered scales. Participants experienced a significant decrease in depressive symptoms according to both self-rated (p = .007) and researcher-administered (p = .010) scales, while vigilance was unaffected. The reduction in depressive symptoms correlated with the overnight dissipation of fronto-central slow wave activity (SWA) on baseline sleep, the rebound in right frontal all-night SWA on recovery sleep, and the amount of REM sleep on the SWD night. In addition to highlighting the benefits of hdEEG in detecting regional changes in brain activity, these findings suggest that SWD may help to better understand the pathophysiology of depression and may be a useful tool for the neuromodulatory reversal of depressive symptomatology.

Reduced intra-cortical inhibition after sleep deprivation: A transcranial magnetic stimulation study

Sleep deprivation has multiple effects on brain function. It increases the risk for epileptic seizures both in healthy individuals and in patients with epilepsy. Furthermore it represents an effective antidepressive intervention with rapid onset. However, the mechanisms underlying these effects are still largely unknown [2]. Transcranial magnetic stimulation (TMS) can be used as a non-invasive method for the measurement of motor cortex excitability. Here we used TMS for assessing sleep deprivation effects on cortical excitability in healthy individuals. Before and after 24 h of sleep deprivation, parameters of cortical excitability (resting motor threshold, short intracortical inhibition, intracortical facilitation, cortical silent period) were measured in a sample of 15 healthy volunteers (11 women, 4 men, aged between 21 and 30 years with a mean of 24.3 ± 2.7 years). We detected a significant ( p = 0.042) reduction of short intracortical inhibition (SICI) after sleep deprivation. Motor threshold, intracortical facilitation and contralateral silent period remained unchanged. Our results confirm previous studies which have demonstrated changes of SICI after sleep deprivation. Our findings further suggest that the increased risk for epileptic seizures after sleep deprivation is mediated by a reduction of intracortical inhibition. Whether this mechanism is also involved in mediating the antidepressant effect of sleep deprivation has to be addressed by further studies in depressive patients.

Does caffeine change the effect of sleep deprivation on moderate to severe depressed patients?

IntroductionSleep deprivation (SD) has been used as an alternative approach to treat major depressive disorder (MDD). Caffeine, due to its stimulating effect, could be an alternative to promote sleep deprivation. However, there are no data about its potential influence on the antidepressive effect of SD. The objective of this study is to assess the effect of caffeine on SD in non-psychotic patients with moderate to severe unipolar depression. MethodsRandomized, double-blind, crossover clinical trial comparing caffeine and placebo in moderate to severe depressed patients who underwent total sleep deprivation (SD). The patients were assessed with items of the Bond–Lader scale, the 6-item Hamilton Depression Rating Scale (HAMD-6), and the Clinical Global Impression (CGI)-Severity/Improvement. ResultsTwenty patients participated in this study. The patients who consumed caffeine presented the same level of energy before and after sleep deprivation (lethargic–energetic item of the Bond–Lader scale), while the patients in the placebo group had a reduced level of energy after sleep deprivation (p=0.0045). There was no difference between the caffeine and placebo groups in the other items of the Bond–Lader scale. ConclusionThe combined use of caffeine and SD can be a useful strategy to keep the patient awake without impairing the effect of SD on depressed outpatients. However, further studies involving patients who have responded to SD are needed in order to verify if caffeine also does not interfere with the results in this group.

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.

Increased spontaneous eye blink rate following prolonged wakefulness

Sleep deprivation (SD) is a technique of sleep–wake manipulation which has been used to treat depression. Changes in neurotransmitter systems, that are also involved in the effects of the antidepressant drugs, have been suggested as the possible mechanisms of action of SD. However, the therapeutic effect of SD is acute and transient, while antidepressant effects of drug treatments are gradual and stable. SD might work throughout mechanisms that are different from those mediating drug's effects. In the present study we analyzed the role of dopamine activity in SD. Spontaneous eye blink rate provides a non invasive measure of central dopamine activity. We assessed eye blink rate across prolonged wakefulness (from 10:00 a.m. to 07:00 a.m.) in 25 young normal subjects. Eye blink rate increased at the end of the wakefulness period. Blink rates and sleepiness as assessed by Karolinska Sleepiness Scale correlated positively with time spent awake. We propose that increased blink rate might reflect a dopamine activation that counteracts sleep drive. Antidepressant effects of sleep deprivation might be related to activation of the physiological mechanisms which regulate wake maintenance.

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 60 h 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.

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.

Total sleep deprivation increases extracellular serotonin in the rat hippocampus

Sleep deprivation exerts antidepressant effects after only one night of deprivation, demonstrating that a rapid antidepressant response is possible. In this report we tested the hypothesis that total sleep deprivation induces an increase in extracellular serotonin (5-HT) levels in the hippocampus, a structure that has been proposed repeatedly to play a role in the pathophysiology of depression. Sleep deprivation was performed using the disk-over-water method. Extracellular levels of 5-HT were determined in 3 h periods with microdialysis and measured by high performance liquid chromatography coupled with electrochemical detection. Sleep deprivation induced an increase in 5-HT levels during the sleep deprivation day. During an additional sleep recovery day, 5-HT remained elevated even though rats displayed normal amounts of sleep. Stimulus control rats, which had been allowed to sleep, did not experience a significant increased in 5-HT levels, though they were exposed to a stressful situation similar to slee-deprived rats. These results are consistent with a role of 5-HT in the antidepressant effects of sleep deprivation.