Clarifying the role of sleep in depression: A narrative review

Psychiatry Research 291 (2020) 113239 Contents lists available at ScienceDirect Psychiatry Research journal homepage: www.elsevier.com/locate/psychres Review article Clarifying the role of sleep in depression: A narrative review a,⁎ b c d Seithikurippu R. Pandi-Perumal , Jaime M. Monti , Deepa Burman , Ramanujam Karthikeyan , Ahmed S. BaHammame,f, David Warren Spenceg, Gregory M. Brownh, Meera Narashimhani,j T a Somnogen Canada, Inc., College Street, Toronto, ON, Canada Department of Pharmacology and Therapeutics, School of Medicine Clinics Hospital, University of the Republic, Montevideo 11600, Uruguay Department of Family Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Palestine, State of, United States d Department of Animal Behavior and Physiology, School of Biological Sciences, Madurai Kamaraj Univesity, Madurai 625021, Tamil Nadu, Independent Researcher, Avvai Street, Bank Colony, Narayanapuram, Madurai, India e University of Sleep Disorders Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia f The Strategic Technologies Program of the National Plan for Sciences and Technology and Innovation, Saudi Arabia g Independent Researcher, Dufferin Street, Toronto, ON, Canada h Centre for Addiction and Mental Health, University of Toronto, 250 College St, Toronto, ON, Canada i Department of Medicine, University of South Carolina, Columbia, SC, United States j Department of Neuropsychiatry and Behavioral Science, University of South Carolina School of Medicine, Columbia, SC, United States b c A R T I C LE I N FO A B S T R A C T Keywords: Circadian rhythms Depression Insomnia Melatonin Obstructive sleep apnea Sleep It has been established that 4.4 to 20% of the general population suffers from a major depressive disorder (MDD), which is frequently associated with a dysregulation of normal sleep-wake mechanisms. Disturbances of circadian rhythms are a cardinal feature of psychiatric dysfunctions, including MDD, which tends to indicate that biological clocks may play a role in their pathophysiology. Thus, episodes of depression and mania or hypomania can arise as a consequence of the disruption of zeitgebers (time cues). In addition, the habit of sleeping at a time that is out of phase with the body's other biological rhythms is a common finding in depressed patients. In this review, we have covered a vast area, emerging from human and animal studies, which supports the link between sleep and depression. In doing so, this paper covers a broad range of distinct mechanisms that may underlie the link between sleep and depression. This review further highlights the mechanisms that may underlie such link (e.g. circadian rhythm alterations, melatonin, and neuroinflammatory dysregulation), as well as evidence for a link between sleep and depression (e.g. objective findings of sleep during depressive episodes, effects of pharmacotherapy, chronotherapy, comorbidity of obstructive sleep apnea and depression), are presented. 1. Introduction In recent decades there has been increasing recognition of, and consequently of the diagnosis of, psychiatric dysfunctions, which globally affect one in every four individuals (Vigo et al., 2016). Psychological depression, which is not only a common disease in its own right but also occurs comorbidly with many other physical and mental disorders, ranks among the top ten most prevalent diseases in the world. (Vigo et al., 2016) It is estimated that 4.4 to 20% of the general population suffers from major depression. (Dowlati et al., 2010) In addition, it has been established that the presence of depressed mood is associated with the abnormal circadian activity of the hypothalamicpituitary-adrenal (HPA) axis. (Moulton et al., 2015) Presently, enough data is available to suggest that disruption of the mechanisms involved in the regulation of the sleep-wake cycle overlap with those of depression. In this review article, some of the more important of these mechanisms will be discussed. 2. Circadian abnormalities Circadian rhythms are cycles with a recurring periodicity of approximately 24 h, generated by cellular circadian genomic mechanisms and coordinated by the endogenous biological pacemaker, the hypothalamic suprachiasmatic nucleus (SCN). (Golombek and Rosenstein, 2010; Halberg, 1959) Circadian rhythm sleep disorders (CRSDs) are patterns that last for at least one month and result in sleepwake rhythm disturbances due to alterations in the circadian timing system or to a misalignment between the timing of the endogenous Abbreviations: w, stage wake; Rem, rapid eye movement; N1, stage N1; N2, stage N2; N3, stage N3 Corresponding author. E-mail address: pandiperumal2020@gmail.com (S.R. Pandi-Perumal). ⁎ https://doi.org/10.1016/j.psychres.2020.113239 Received 5 May 2019; Received in revised form 14 June 2020; Accepted 14 June 2020 Available online 16 June 2020 0165-1781/ © 2020 Published by Elsevier B.V. Psychiatry Research 291 (2020) 113239 S.R. Pandi-Perumal, et al. A compelling body of evidence demonstrates that brain activities involving the regulation of mood behavior are comprehensively influenced by the biological clock. (Bechtel, 2015; Gold and Sylvia, 2016; Landgraf et al., 2014; McCarthy and Welsh, 2012; Schnell et al., 2014) Many physiological processes including sleep/wake activity, the timing of food intake, energy storage, and distribution, body temperature, blood pressure, carbohydrate metabolism, hormone synthesis, nerve cells cell function and synthesis and mood states are under circadian regulation. (Dibner et al., 2010; Dunlap et al., 2004; Pandi‐Perumal et al., 2006) Transmission of environmental information passes through the retinohypothalamic tract and reaches the SCN to synchronize its activity to the external world. (Dai et al., 1998; Friedman et al., 1991; Sadun et al., 1984) In response, the SCN transmits signals to different parts of the body through humoral and neural means, thus providing important cues for the initiation of critical brain processes. (Moore MD, 1997; Takahashi et al., 2008) Components of the biological clock system drive the processes occurring at central sites: these include sleep, neurotransmitter synthesis, and function, as well as various molecular activities, all of which are involved in rhythm regulation. Concerning the latter, special emphasis has been given to the role of melatonin in the regulation of essential body processes including sleep, aging, immune response, and mood. (Brzezinski, 1997; Srinivasan et al., 2006) Seasonal changes in the environment can influence the secretion of melatonin and, when these changes include the shortening of daylight hours, may contribute to the development of depressive disorders, notably seasonal affective disorder. (Hasler et al., 2010; Pandi‐Perumal et al., 2006) It has been found that since the intensity of light and its duration affects circadian clock functioning, (Roenneberg et al., 2003) those geographical regions, which have the greatest reductions in sunlight duration, generally located at higher latitudes, tend also to have an elevated incidence of depressive disorders. (Booker et al., 1991) Furthermore, increases in depressed mood are usually associated with the abnormal circadian activity, which itself may be influenced by environmental entrainers, such as the time of day. In this respect, severe deteriorative moods are more observable during morning time and correlate with the synthesis of cortisol. (Dunlap et al., 2004) Several key neurotransmitter systems provide the body with Information about the environment. (Kafka et al., 1983) Dopamine, for example, is closely involved with and provides the critical tuning of, both emotional expression and cognitive activity. (Beaulieu et al., 2004) In this respect, the concentration of dopamine influences mood oscillation. (Hampp et al., 2008) In turn, dopamine concentration, as well as that of a number of other neurotransmitters, including serotonin, GABA and glutamate, are all under the control of the circadian oscillator,(Akhisaroglu et al., 2005; Barnard and Nolan, 2008; Castaneda et al., 2004; Imbesi et al., 2009; Voderholzer et al., 2007) and are prominently influenced by the clock genes. (Hampp et al., 2008; McClung, 2007; Weber et al., 2004) As an example, Per2, a clock gene alters transactions in the dopaminergic pathway (Hampp et al., 2008) and additionally acts as a potential modulator of glutamate function. (Spanagel et al., 2005) circadian rhythm and the sleep-wake times required by school or work schedules, all of which may result in impairments in sleep and wake functioning. The actual clinical presentation of a CRSD is often influenced by a combination of physiological, behavioral, and environmental factors. (Barion and Zee, 2007) 2.1. Circadian rhythms and depression Disturbances of circadian rhythms may be caused by external abnormal schedules (such as jet lag, shift work), sleep disorders, or by several psychiatric disorders, including anxiety and depression. (Zee et al., 2013) In this respect, the decreased circadian amplitude of several rhythms, as well as phase advances or delays, have been described in affective disorders. The various therapies that are now used for affective disorders, including non-pharmacological treatments (light-therapy, sleep deprivation, rhythm therapy) and pharmacological therapies (lithium, antidepressants, agomelatine) have been shown to simultaneously influence circadian rhythms, thus indicating that biological clocks play a role in the pathophysiology of these disorders. (Schulz and Steimer, 2009) 2.2. Circadian genes and depression A series of transcription-translation feedback loops, make up the biological basis of the genomic circadian clock. These feedback loops, in turn, are derived from both positive and negative elements formed from proteins that are encoded by clock genes, as well as from output signals from the circadian system. (Ko and Takahashi, 2006) Mutations of clock genes can affect most parameters of the circadian rhythms, including their amplitude, period and phase. In extreme cases, these mutations can render the system completely arrhythmic. As a result, profound effects on sleep and other forms of cyclical behavior can take place. (Pandi-Perumal et al., 2008) Moreover, when the natural organization of biological rhythms is disturbed beyond its limits of adaptability, as this may occur in protracted shift work or sustained jetlag conditions. Vulnerable individuals may manifest physical debilitation similar to that seen in endogenous depression, with associated symptoms of weight loss, anergia, and irritability. (Healy, 1987) From a psychological point of view, alteration in time sense may contribute causally to depression, or at least to its continuation. In addition to standard pharmacological therapies, clinical treatments for depression may involve changing a patient´s “cognitive timer” or “internal clock”. The social zeitgeber theory postulates that episodes of depression and mania or hypomania arise as a consequence of life events which disrupt environmental “zeitgebers” or timekeepers, with further effects on circadian regulation. This theory proposes that interference with events such as mealtimes, bedtimes, or scheduled social interactions may trigger a relapse into a depressed mood state. (Salvatore et al., 2012) Many individuals at risk for mental disorders live in environments prone to disrupted circadian rhythmicity, including irregular sleep schedules, meal times, or other temporal constraints. The internal coincidence model proposes that depressed patients sleep at the wrong biological clock time because of the misalignment of the phase angle between the biological clock and the sleep-wake cycle, and that, over time, this lack of synchronicity results in depressive disorders. (Wehr and Wirz-Justice, 1980) Genetic factors involved in the functioning of the biological clock contribute importantly to mood disorders, including the patient's age at the time of symptom onset,(Benedetti et al., 2005) the recurrence of symptoms,(Benedetti et al., 2003) the occurrence of insomnia (Serretti et al., 2005), and the patient's response to sleep deprivation. (Benedetti et al., 2005) The recognition of the important role played by sleep problems in the development of mood disorders has in recent years led to an increasing focus on the use of sleep manipulation as a key chronotherapeutic technique for treating depression. (WirzJustice, 2009) 2.3. Chronotherapy, sleep, and depression Chronotherapeutics is a relatively new branch of therapy and refers to a range of treatments that are used for a number of both physical and mental disorders. This treatment system is based on the principles of circadian rhythm organization and sleep physiology, and recognizes that the effectiveness of a therapy is critically influenced by the time at which it is administered. (Benedetti et al., 2007; Golombek et al., 2015) The findings of a number of studies of the clinical effectiveness of chronotherapy methods have been paralleled by basic research, which, in the last decade, has substantially improved our knowledge of the molecular machinery of the master clock. (Dibner et al., 2010) This 2 Psychiatry Research 291 (2020) 113239 S.R. Pandi-Perumal, et al. most commonly occurring of disturbances in REM, sleep regulation is decreased in REM sleep onset latency (REMSOL) and increases in total REM sleep time and REM density (REMD). (Cartwright et al., 2003; Pillai et al., 2011) The alterations of REM sleep often persist beyond the clinical episode and thus are supposed to increase the vulnerability to relapse or recurrence, and in general may decrease the effectiveness of treatment. (Clark et al., 2000; Giles et al., 1987; Mendlewicz, 2009) More specifically, it has been found that the persistence of shortened REM sleep latency during remission is associated with an increased risk of relapse. In spite of that, longitudinal studies have shown REM sleep latency to be stable in depressed individuals over time regardless of clinical state. (Rush et al., 1986) Several theories had been proposed to explain REM sleep abnormalities in patients with depression, including circadian rhythm abnormalities, whether related to time-keeping, (Van Cauter and Turek, 1986) or genetic factors. (Serretti et al., 2010) The finding that selective REM sleep deprivation (by externally forced awakenings) produces an antidepressant effect illustrates the close association which exists between mechanisms of REM sleep regulation and processes involved in the pathophysiology of depressive disorders. (Berger and Riemann, 1993) Based on that, some investigators proposed that REM suppression is a plausible explanation for the antidepressant treatment. However, this proposal is not supported by recent literature. Moreover, the effect of bupropion (an antidepressant) on REM sleep does not support this view. An earlier study compared the effect of bupropion, fluoxetine, and cognitive behavioral therapy on EEG changes during sleep in depressed men. (Nofzinger et al., 1995) The study revealed that bupropion resulted in a reduction in REM sleep latency and an increase in REM sleep percentage and REM sleep duration. (Nofzinger et al., 1995) These findings contrasted with the effects of fluoxetine and cognitive behavior therapy. A subsequent study assessed the effects of sustained-release bupropion (for 8 weeks) on sleep architecture in 20 patients with unipolar major depressive disorder. (Ott et al., 2004) Compared to baseline, treatment with bupropion significantly increased REM activity and density during the first REM period, and increased total REM density. (Ott et al., 2004) Therefore, REM suppression is not the primary mechanism responsible for the antidepressant effects of antidepressant medications. The possibility that genetic influences are involved in the REM sleep changes that occur in depression is likely. In this respect, genes that may be related to both depression and REM sleep regulation include cholinergic receptor genes, circadian clock genes, and orexinergic mechanisms. (Sehgal and Mignot, 2011) knowledge has now been combined with our understanding of the neurotransmitter systems involved in mood regulation that are targeted by antidepressant drugs and has led to new therapeutic strategies which emphasize the importance of the timing of the administration of these drugs. (McClung, 2011) 2.3.1. Sleep dysregulation in depression Mood disorders are among the most prevalent forms of mental illness. In the United States alone, about 2–5% of the population suffers from severe depression and up to 20% suffer from milder forms of the psychiatric disease. (Nestler et al., 2002) Depression is a complex, heterogeneous disorder in which several neurotransmitter and neurohumoral pathways are implicated. However, the mechanisms underlying the pathogenesis of depression are not well understood. (Nestler et al., 2002; Vaidya and Duman, 2001) Epidemiological surveys have repeatedly confirmed the association between insomnia and depressive episodes, which are frequently reported to co-occur in a majority of patients. (Ohayon et al., 1998) In this respect, more than 90% of patients with major depression have been found to suffer from sleep problems. (Buysse et al., 1994) Depression is also common in patients with an insomnia disorder. Thus, approximately 20% of patients with initial insomnia, sleep maintenance difficulties, non-refreshing sleep and early morning awakenings also show symptoms of depression. (Mellinger et al., 1985) Neuroimaging studies have revealed that, among depressed patients, numerous changes occur in limbic and paralimbic functioning during the transition from waking to REM sleep that differs significantly from the changes seen in normal patients. (Nofzinger et al., 1999) 2.3.2. Sleep architecture in depression In psychiatric disorders, both sleep disturbances and problems with sleep architecture affect the course of the illness. (Krystal et al., 2008) (Fig. 1). In patients with depressive illness, polysomnographic measures of sleep have shown that alterations in sleep architecture frequently include impaired sleep efficiency and continuity, reductions in slow wave sleep (SWS), and disinhibition of REM sleep (Fig. 2). During REM sleep, in particular, depressed patients frequently show short REM sleep latency, prolongation of the first REM period, and an increased number of rapid eye movements (increased REM density). (Tsuno et al., 2005) Elevated REM density is found so consistently in depressed patients that it is regarded as an endophenotype in family studies of depression (Fig. 3). In contrast, REM sleep suppression during the initial two nights of tricyclic antidepressant treatment has been found to be predictive of therapeutic efficacy in a few studies. (Gillin et al., 1978; Kupfer et al., 1976, 1981) Objective methods to investigate extended nocturnal sleep and excessive daytime somnolence in mood disorders have been tried in some studies, but all reported no difference in mean sleep latency or sleep duration when patients with mood disorders were compared to healthy controls. (Dauvilliers et al., 2013) Indeed, no objective hypersomnia has been recorded consequent to mood disorders. Finally, chronobiological disruption in depression can have a significant influence on the architecture of the sleep/wake cycle, food intake, attentional deficits, learning and memory dysfunction, mood, psychomotor functioning, and psychological stress. (Kondratova and Kondratov, 2012; Pandi-Perumal et al., 2009) 2.3.4. Insomnia, depression, and suicide Suicide is one of the major causes of death. Relevant to this point, around one million people die each year worldwide from suicide. (Agargun and Beşiroğlu, 2005) The vast majority of people who kill themselves have been shown to be suffering from depression or substance use disorders, often in combination with other mental health disorders. (Mościcki, 2001) There is evidence that insomnia is a significant risk factor for the development of and/or maintenance of an MDD. Sleep problems are strongly linked to risk factors for suicidal thoughts, behaviors and suicide-related outcomes. In one study the electroencephalographic (EEG) sleep records of patients with major depression with and without a history of suicidal behavior were compared to normal controls. It was found that, compared to controls, the recordings of those attempting suicide exhibited longer sleep latencies, lower sleep efficiency, and fewer late-night delta wave counts. (Sabo et al., 1991) A meta-analysis in 2012 also found that sleep disorders, including insomnia, nightmares and other sleep disturbances, are significantly associated with suicidal ideation, suicide attempts, and suicide completion. (Pigeon et al., 2012) 2.3.3. REM sleep in depression Since the 1960s sleep research based on polysomnography has demonstrated that in addition to disturbances in sleep continuity, depression is associated with altered sleep architecture. These abnormalities have included decreases in SWS production (Palagini et al., 2013b) as well as disturbances in REM sleep regulation. Among the 2.3.5. Melatonin and depression Melatonin regulates a number of neuroendocrine and physiological 3 Psychiatry Research 291 (2020) 113239 S.R. Pandi-Perumal, et al. Fig 1. A schematic sleep hypnogram of normal vs depressed individual It shows two hypnograms of healthy sleep (A), and sleep in a depressed patient (B). The hypnogram shows sleep stages (W, REM, N1, N2, and N3) across the time during nocturnal sleep. The schematic figure shows overnight hypnogram of a normal individual (top panel) and a person with depression (bottom panel). As you can see from this illustration, a typical polysomnographic characteristics of depression include, a. Increased sleep onset latency (SOL); b. Shortened REM sleep onset latency (REMOL) or presence of sleep onset REM period (SOREMP; REM latency 0–20 min); c. Increased REM; d. Deficit in Slow Wave Sleep (SWS), Slow wave Activity (SWA), and Stage N2 sleep; e. Sleep continuity disruption (excessive intermittent awakenings / excess of WASO); f. reversal of 1st and 2nd REM sleep episode (i.e. prolonged first REM period); g. Increased REM density (a measure of the amount of REM); and h. early morning awakening. and seasonal affective disorder (SAD)(Kripke et al., 1978) The reason for this is that the neurochemical processes which maintain the body's natural rhythms interact closely with those that affect mood states. Depressed unipolar and bipolar patients show low overall melatonin levels. (Lam et al., 1990) The melatonin-related circadian hypothesis and the HPA axis dysregulation hypothesis of depression are also closely related because melatonin and cortisol are interacting hormones, and when secretions which regulate circadian rhythms are blunted, those which elevate mood are similarly affected, thus producing a depressed emotional state. (Lanfumey et al., 2013) processes, including circadian rhythms(Pandi‐Perumal et al., 2006) It is synthesized and secreted in a cyclic manner, with the highest levels occurring at night. Melatonin has a well-established hypnotic action and plays a key role in triggering sleep. Its antioxidant actions are demonstrable even at physiological concentrations. (Hardeland et al., 2015; Pandi-Perumal et al., 2013; Reiter et al., 2005) Inasmuch as melatonin is a rhythmic-regulating factor, and thus a hormone that is critically involved in maintaining sleep/wake rhythms, it has been suggested that it also plays an important role in the pathogenesis of mood disorders including MDD, bipolar disorder (BPD) 4 Psychiatry Research 291 (2020) 113239 S.R. Pandi-Perumal, et al. Fig 2. Early REM onset without SWS. 5 Psychiatry Research 291 (2020) 113239 S.R. Pandi-Perumal, et al. Fig 3. EEG tracing shows REM density. depression. For example, brain-derived neurotrophic factor (BDNF), which is decreased in depression,(Devita et al., 2017) is also deficient in OSA patients, when compared to healthy subjects. Emotional behaviors are controlled by the amygdala, locus coeruleus, and prefrontal cortex. (Goldstein and Walker, 2014) Normal sleep is essential for regulating the amygdala response to various emotional stimuli. Obtaining normal REM sleep, with regards to duration, circadian, and neurochemical changes are important for the regulation of emotions. (Goldstein and Walker, 2014) Disturbances in sleep architecture, such as a reduction in slow wave sleep (SWS) and REM sleep, may initiate the appearance of psychiatric disorders. OSA produces significant disruptions in sleep architecture, with notable reductions in SWS, sleep spindles, and REM sleep. (Bardwell et al., 2000) The evidence that has so far been provided suggests that REMpredominant OSA may play a previously unrecognized role in the development of mood disorders, although at this point much of the consideration of this association remains speculative. Nevertheless, there are some studies that are relevant to this suggestion. An American study of patients with OSA revealed that patients with REM-predominant OSA have more depressive symptoms compared to OSA patients with nonstage specific OSA. (Conwell et al., 2012) A more recent Korean study demonstrated that REM-predominant OSA was significantly associated with a higher level of depressive symptoms, but only in men (Lee et al., 2016). REM-predominant OSA is characterized by the occurrence of the obstructive respiratory events predominantly during REM sleep, (Almeneessier et al., 2017) which result in selective disruption and deprivation of REM sleep. (Haba-Rubio et al., 2005) Therefore, it seems that REM-predominant OSA could have a stronger association with depression than non-stage specific OSA. The exact mechanism involved in this association remains unknown. However, it is known that major depression is associated with exaggerated REM sleep, including shorter latency to REM sleep, longer duration of REM sleep periods and increased intensity of REM sleep. (Palagini et al., 2013a) Agomelatine is a naphthalene bioisostere of melatonin, which behaves as an agonist of MT1 and MT2 melatonergic receptors located in the SCN. It is also an antagonist of serotonin 5-HT2C receptors located in the frontal cortex, amygdala, hippocampus and cortico-limbic structures involved in the regulation of mood and cognition. (PandiPerumal et al., 2009) The agent has been shown to be beneficial in the treatment of MDD, BPD, and SAD. In addition, some studies have shown rapid and beneficial effects on the regulation of sleep continuity and quality. (Catena-Dell'Osso et al., 2012) Agomelatine may also exert beneficial neuroimmunomodulatory and pro-neuroplastic effects. (Min et al., 2012) However, inferences regarding its therapeutic efficacy need to be confirmed with additional clinical trials involving patients with MDD. (Srinivasan et al., 2012) 2.3.6. Depression and OSA In general, patients with OSA have a higher rate of mood disorders, anxiety disorders, PTSD, and psychotic disorders, compared with nonOSA patients. (BaHammam et al., 2016; Sharafkhaneh et al., 2005) Due to the under-recognition of the coexistence OSA with these comorbid conditions, (Young et al., 2004; Zinchuk et al., 2017) patients with OSA can be misdiagnosed as a psychiatric disorder. The recurrent intermittent hypoxemia and re-oxygenation that occurs in patients with OSA during sleep may lead to ischemic reperfusion and neuroinflammatory injuries. Although some areas of the brain will be resilient to changes in blood oxygen levels, when these episodes of desaturation are too severe, frequent, or have a long duration, brain infarcts may follow, even in young patients. (Devita et al., 2017; Rosenzweig et al., 2013) Several brain regions are at risk during desaturation in patients with OSA; however, regions involved in the regulation of cognition and emotion such as the prefrontal cortex, hippocampus, and amygdala are particularly worth noting. (Goldstein and Walker, 2014) The prefrontal regions of the cortex are the master of the “executive system”, and its malfunction in OSA patients may result in behavioral inhibition, attentional deficits, emotional lability, poor impulse control, and impairments to working memory and contextual memory. (Glasser, 2016) The conditions of memory dysfunction, affective disorders, and breathing disorders, which are common in patients with OSA, have been attributed to hippocampal dysfunction. (Devita et al., 2017; Gao et al., 2017) Moreover, several markers of brain injury have been reported in both OSA and 2.3.7. Impact of OSA treatment on depression If a causal relationship exists between OSA and depression, then depression would be expected to improve with effective OSA therapy. A few studies have assessed the effects of CPAP therapy on depression in patients with OSA. A 2006 Cochrane meta-analysis, which included data from five clinical trials comparing CPAP with placebo and assessed 6 7 ↓ ↔ ↓ ↑ bupropion nefazodone ↑ ↑ or ↔ ↓ or ↔ ↑ Inhibition of NE or 5-HT/NEreuptake Melatonin M1 and M2 receptor agonist and 5-HT2C receptor antagonist NE and DA reuptake inhibitor 5-HT2 receptor antagonist; mild 5-HT and NE reuptake inhibitor ↓ ↑ ↑ ↔ ↓or ↔ ↑ ↓ ↔ Inhibition of 5-HT and NE reuptake; HA H1 receptor blockade Inhibition of 5-HT and NE reuptake Reversible or irreversible inhibition of monoamine oxidase enzyme Inhibition of 5-HT reuptake ↑ ↓ ↑ or ↓ ↓ ↓ ↓ ↓ or ↔ ↓ ↑ ↑ ↑ or ↑ ↑ ↑ ↓ ↓ or ↔ ↑ or ↔ Sedative tricyclic amitriptyline trimipramine nortriptyline doxepin Activating tricyclic imipramine desipramine Monoamine oxidase inhibitors moclobemide(a) phenelzine(b) tranylcypromine(b) Selective serotonin reuptake inhibitors fluoxetine fluvoxamine citalopram escitalopram paroxetine sertraline Norepinephrine or serotonin and norepinephrine reuptake inhibitors duloxetine venlafaxine reboxetine Other antidepre-ssants agomelatine 2.3.9. Sleep deprivation as a therapy for depression Pflug and Tolle were the first to propose that sleep deprivation therapy or “wake therapy” be used as a non-invasive antidepressant treatment. (Pflug and Tolle, 1971) Therapeutic sleep deprivation (SD) is a rapid-acting treatment for MDD and within hours leads to a dramatic decrease in depressive symptoms in 50–60% of patients with MDD. SWS Table 1 Effect of antidepressant drugs on sleep. 2.3.8. Effects of antidepressant therapies on sleep architecture With the exception of antihyperlipidemic agents and analgesics, antidepressants are the most prescribed drugs in the United States. (Statistics, 2011) In view of the importance of pharmaceutical therapy in managing depression, various studies have used polysomnography to measure objectively the physiological effects of antidepressants. Table 1 presents a summary of the effect of antidepressant drugs on sleep. (Monti et al., 1990; Pandi-Perumal et al.; Staner et al., 1990; Wichniak et al., 2012, 2017; Winokur et al., 2001) As discussed above, the reduction of REMOL is one of the most robust and cardinal features of sleep in depressed patients and is thus considered a trait marker of depression. Patients taking antidepressant medications show prolonged REM sleep onset latency and a reduction in the amount of REM sleep. In addition, they have a greater amount of REM sleep without atonia (RSWA), compared to subjects who are not taking antidepressant medications, but lower RSWA than those with clinical RBD. (McCarter et al., 2015; Postuma et al., 2013) Most tricyclic antidepressants improve sleep quality, increase total sleep time and decrease wake time after sleep onset, while many selective serotonin reuptake inhibitors (SSRIs) have the opposite effect. In patients with depression and reduced REM sleep latency, amitriptylineinduced REM sleep suppression during the first two treatment nights was found to correlate with a good clinical response. (Gillin et al., 1978; Kupfer et al., 1976) This finding, however, was not consistently confirmed. (Bielski and Friedel, 1977) Drug class REMS latency REM sleep Sleep continuity Mechanism of action depression, revealed that the pooled fixed effects significantly favored a beneficial effect of CPAP therapy. However, the beneficial effect of CPAP treatment disappeared after the application of random effects modeling. (Giles et al., 2006) Three randomized trials reported no significant difference in the change in the depression between the control and CPAP therapy arms. (Bardwell et al., 2007; Haensel et al., 2007; Henke et al., 2001) However, the above-mentioned studies were short-term studies with follow-up periods ranging from 2 to 4 weeks of CPAP use. This short follow-up is unlikely to show a significant response to treatment. (Povitz et al., 2014) A recent multicenter observational longitudinal study that followed patients for at least 1-year and included 300 patients with OSA and depressive symptoms (measured by the 13-item, self-rated Pichot depression scale [QD2A] ≥ 7) at diagnosis demonstrated a significant improvement in depression scores in response to CPAP therapy. (Gagnadoux et al., 2014) Nevertheless, depressive symptoms persisted in 42% of the patients after 1 year of CPAP therapy. Predictors of persistence of depressive symptoms included persistent excessive daytime sleepiness (OR, 2.72), comorbid cardiovascular disease (OR, 1.76), and female sex (OR, 1.53). (Gagnadoux et al., 2014) A recent systematic review and meta-analysis evaluated the efficacy of CPAP or mandibular advancement devices (MAD) in treating depression in patients with OSA. CPAP treatment resulted in significant improvement in depression compared with control groups (Q statistic, p<0.001; I2 = 71.3%, 95% CI: 54%, 82%). (2014) Additionally, treatment with a MAD was also significantly beneficial for depressive symptoms. In summary, treatment of OSA results in a reduction of depressive symptoms in some patients with OSA; however, depression may persist in other patients, despite good adherence to CPAP therapy. Current evidence indicates that patients with OSA with persistent daytime sleepiness, despite good adherence CPAP treatment, are at a higher risk for the persistence of depressive symptoms. From: Monti et al., 1990; Staner et al., 1999; Winokur et al., 2001; Pandi-Perumal et al., 2007; Wichniak et al., 2012, 2017. SWS, slow wave sleep; REMS, rapid-eye movement sleep; 5-HT, 5-hydroxytryptamine; NE, norepinephrine; HA, histamine; DA, dopamine; (a), reversible inhibitor of monoamine oxidase; (b), irreversible inhibitor of monoamine oxidase; ↑= significant increase; ↓ = significant decrease; ↔ = no significant change. Psychiatry Research 291 (2020) 113239 S.R. Pandi-Perumal, et al. Psychiatry Research 291 (2020) 113239 S.R. Pandi-Perumal, et al. financial, professional, nor any other personal interest of any nature or kind in any product or services and/or company that could be construed or considered to be a potential conflict of interest that might have influenced the views expressed in this manuscript. (Wu and Bunney, 1990) Approximately 80% of SD responders relapse into depression after the next night of sleep, and even brief daytime naps can reverse the therapeutic effect (Riemann et al., 1993). Although the procedure is safe, there is a slight risk of the occurrence hypomania/ mania; nevertheless, this risk is less than that associated with conventional antidepressants. It should be mentioned that in unmedicated depressed patients sleep deprivation accelerates the response to medication and potentiates any ongoing antidepressant drug therapy. The synaptic plasticity model proposes that a homeostatic increase in net synaptic strength with prolonged wakefulness shifts the inducibility of associative synaptic plasticity in MDD, thus improving symptoms related to its impairment. (Wolf et al., 2016) Some recent evidence has indicated that light therapy (LT) may be useful in the treatment of bipolar depression, either as monotherapy or in combination with total sleep deprivation (TSD). The degree of clinical change spans a continuum for complete remission to worsening in 2–7% of cases. Sleep deprivation is an unspecific therapy, and its exact mechanism of action remains unknown. (Giedke and Schwärzler, 2002) In this respect, well-designed controlled trials are required to investigate the optimal intensity and frequency of LT that should be used in the treatment of bipolar depression. (Tseng et al., 2016) Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.psychres.2020.113239. References Agargun, M.Y., Beşiroğlu, L., 2005. Sleep and suicidality: do sleep disturbances predict suicide risk?Oxford University Press. Akhisaroglu, M., Kurtuncu, M., Manev, H., Uz, T., 2005. Diurnal rhythms in quinpiroleinduced locomotor behaviors and striatal D2/D3 receptor levels in mice. Pharmacology Biochemistry and Behavior 80 (3), 371–377. Almeneessier, A.S., Almousa, Y., Hammad, O., Olaish, A.H., ET, A.L., BaHammam, A.S., 2017. Long-term adherence to continuous positive airway pressure in patients with rapid eye movement-only obstructive sleep apnea: a prospective cohort study. 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This review has briefly highlighted different mechanisms that may underlie this link (e.g. circadian rhythm alterations, melatonin, and neuroinflammatory dysregulation) as well as evidence for a link between sleep and depression (e.g. objective findings of sleep during depressive episodes, effects of tricyclic antidepressants, chronotherapy, comorbidity of obstructive sleep apnea and depression) are presented. Hence, this selective narrative review addresses a topic that is of high public health relevance. Due to the vastness of this topic, a review such as this one, it is impossible to review the entire literature on this topic. Both subjective and objective measures of sleep disturbance have repeatedly been shown to be elevated in depression. The co-occurrence of sleep disruption and depressed mood cause considerable impairment in the quality of life of affected patients and additionally promote significant adverse effects on brain neurotransmitter function. Various antidepressants have been shown to have a beneficial effect on sleep. The residual symptoms of insomnia are likely multifactorial reflecting functional brain abnormalities. The scientific evidence that is now available strongly supports the conclusion that therapeutic interventions for depressed patients should be focused not only on the amelioration of the psychiatric symptoms but also on disturbances in sleep, which themselves are independent contributors to depressed mood. Compliance with ethical standards This article does not contain any studies with human participants or animals performed by any of the authors. No primary data have been reported. Declaration of Competing Interests The authors have read the journal's policy and have the following potential conflicts: SRP is a stockholder and the President and Chief Executive Officer of Somnogen Canada Inc., a Canadian corporation. 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