Improvement of the sleep-wake cycle as a target for remission in depression

b y C . R . S o l d a t o s a n d C . G . T h e l e r i t i s , G r e e c e

◄ Constantin R. SOLDATOS,* MD
Christos G. THELERITIS,*† MD
*National and Kapodistrian University of
Athens, Mental Health Care Unit Evgenidion
Hospital, Athens, GREECE
†National and Kapodistrian University of
Athens, First Psychiatry Department
Eginition Hospital, Athens

Sleep disorders have been long associated with depression; they are often used to identify newly presenting depressive patients, and may be part of a more general alteration of biological rhythms. Furthermore, persistent insomnia is a common residual symptom in incompletely remitted depression. As a rule, to avoid the recurrence of depressive symptomatology, treatment of associated insomnia should be pursued in patients taking antidepressants. Combining pharmacotherapy with nonpharmacological treatments that take into account the sleep-wake cycle (sleep deprivation, light therapy) could help in the resolution of both depressive symptoms and associated sleep disorders. A novel pharmaceutical agent, agomelatine, an agonist of melatonergic MT1 and MT2 receptors, as well as an antagonist of 5-HT2C receptors, shows a unique synchronizing effect on circadian rhythms and demonstrates robust antidepressant efficacy.
Medicographia. 2009;31:140-145. (see French abstract on page 145)

Keywords: insomnia; sleep disorder; slow-wave sleep; rapid eye movement; incomplete remission; circadian rhythm; psychotherapy; pharmacotherapy

Sleep in depression

It has long been reported that sleep is disturbed in depression.1-5 Epidemiological studies have demonstrated that 50% to 90% of patients suffering from depression complain of poor sleep.6 In a large European community study, for instance, 63% of patients diagnosed with depression reported sleep problems.7 On the other hand, it has been reported that about 20% of subjects with insomnia screened in general population studies are found to be depressed.8-10 Moreover, subjective reports of sleep disturbance and objectively assessed polysomnographic abnormalities have been correlated with an increased risk of new-onset major depression,11 persistence of depressive symptomatology,12 and recur- rence of depression following successful treatment.13 Polysomnographic studies have documented several sleep disturbances in depression: difficulty in initiating and maintaining sleep, prolonged sleep onset latency, multiple awakenings during the night, early morning awakening, and decreased total sleep time.1,3,5,6 Furthermore, slow-wave sleep (SWS) and rapid eye movement (REM) sleep are often found to differ between depressed patients and healthy individuals.1,14 Abnormal sleep architecture in depressed patients is reflected in reduced SWS,15 a greater number of stage shifts, earlier onset and a higher percentage of REM sleep, especially in the early part of the night, and an increased REM density.16
It should also be noted that computerized sleep electroencephalogram (EEG) analysis of SWS frequently reveals a lower level of delta wave activity during the first non-REM period than in the second non-REM period, ie, a lower delta sleep ratio, which is contrary to what happens in normal individuals.17 However, it should be noted that no single sleep abnormality is specific for depression, because similar polysomnographic aberrations have also been reported in several other psychiatric conditions.1

Mechanisms for sleep changes in depression

Sleep mechanisms and the pathophysiology of depression are closely interrelated. Monoaminergic and cholinergic neurotransmission are heavily involved in both.18 Therefore, it is not surprising that depression is almost invariably associated with sleep abnormalities. Several hypotheses have been proposed to explain their occurrence. The first hypothesis suggests that an imbalance between the monoaminergic and cholinergic systems in the central nervous system could be responsible for both the pathophysiology of depression and the observed sleep aberrations.18-20 According to another hypothesis, increased pressure of REM sleep might be responsible18,21; however, a number of medications (bupropion, nefazodone, and trazodone) with welldocumented antidepressant efficacy do not suppress REM sleep, which suggests that REM sleep suppression might not be necessary for an antidepressant treatment response.22 The third hypothesis proposes an hypothalamic-pituitary-adrenal axis dysregulation.23
The last hypothesis suggests that a deficiency in the mechanism responsible for non-REM sleep, as explained by the two-process model of sleep regulation, may be implicated. According to Borbély,24 the interaction of two processes is responsible for sleep regulation: a homeostatic process (process S), with an increase of EEG slow waves during waking and an exponential decline during sleep, interacts with a circadian process (process C)—an internal clock—so that the timing and architecture of sleep is determined. It was proposed that process S is deficient in patients with depression. In fact, the clinical sleep disturbance of early morning awakening could be attributed to an impaired functioning of process S during waking or an earlier timing of process C. The fast antidepressant effect gained from sleep deprivation might arise from an increase in process S to normal levels.24 By contrast, the slow antidepressant effect of a phase advance of the sleepwake cycle might be related to gradual shifts of process S toward a correct phase relationship with regard to process C. However, it should be noted that the antidepressant effect of phase advance has not been confirmed in all studies.25 Moreover, decline of either process S during sleep or of the phase and amplitude of process C are other possible abnormalities that might be involved in sleep disturbances.26

Circadian rhythms in depression

The biological clock in the suprachiasmatic nucleus (SCN), a master pacemaker driving circadian rhythms in the brain and body, is synchronized to the external light-dark cycle via retinal light input. Nocturnal synthesis of the pineal hormone melatonin is driven by the SCN. Yet, circadian oscillators are found in every organ,27 and each organ has its own appropriate synchronizer. Although light is the major synchronizer for the SCN, it does not affect clocks in the liver; the synchronizer for the latter is food, but food is not a synchronizer for the SCN.27
Individuals have different preferences for timing their sleep28; some like to go to sleep early and wake up early in the morning, while others go to sleep late and wake up late. In addition, individual genetic characteristics of the molecular mechanisms of the biological clock might determine features of mood disorders, including age at onset,29 recurrence, 30 symptoms of insomnia and response to its treatment,31,32 and response to sleep deprivation.29 Furthermore, it has been proposed that there is an intimate relationship between the neurotransmitter systems targeted by drugs and the circadian rhythms targeted by chronotherapeutics.33 These genetic factors may actually provide a chronobiological vulnerability for depression; in this case, a “double desynchronization” may occur—“internal desynchronization” between different clocks in the body and brain, and “external desynchronization” between the timing of body rhythms with respect to the light-dark cycle.33
Stable internal and external phase relationships appear to be crucial for a stable mood state (ie, the timing between cortisol and temperature body rhythms as well as the timing of sleep with respect to the day-night cycle).34 Any desynchronization might cause mood disturbances, particularly in vulnerable individuals. Certain synchronizers have been used to stabilize phase, with light and melatonin being the most important, but also sleep deprivation having been successfully applied in everyday practice.35,36

Treatment considerations

Nonpharmacological interventions on circadian rhythms
Manipulations of the sleep-wake cycle, whether its duration (total or partial sleep deprivation) or its timing (partial sleep deprivation, phase advance), have profound and rapid effects on depressed mood in 60% of all diagnostic subgroups of affective disorders.37 The therapeutic effect of sleep deprivation is postulated to be linked to an increase in homeostatic sleep pressure; additionally, sleep deprivation– induced sleepiness may counteract the hyperarousal state that is often present in depression.26
Though sleep deprivation may have a transient effect on mood, it should always be considered as an option, since it might be the most rapid antidepressant therapeutic solution35,36; however, most patients tend to relapse soon after recovery of sleep. The combination of sleep deprivation with lithium (with or without light therapy)38-40 or pindolol41 may prevent relapse.
Light therapy was specifically developed as a synchronizer in the treatment of patients with seasonal affective disorders42; however, it has also shown efficacy in nonseasonal depression,43,44 and it can prevent relapse after sleep deprivation.45 Bright light has three major effects on the circadian system: it increases circadian amplitude, shifts circadian phase (depending on the time of its application), and thereby modifies the phase relationships between the internal clock and sleep, and the external lightdark cycle.26 As mentioned, it has been reported that bright light can prevent relapse after sleep depriva- tion; it was also recently demonstrated that light therapy combined with a selective serotonin reuptake inhibitor (SSRI) leads to more rapid and more profound improvement in patients with nonseasonal major depression,45,46 suggesting an advantage of using combined approaches.

Psychotherapeutic and psychosocial interventions
There is evidence from studies of primary insomnia that cognitive behavioral therapy (CBT) results in improvements that are as substantial as those of pharmacotherapy with sedative-hypnotics.47 The greatest advantage of CBT is that its effectiveness is more durable than that of pharmacotherapy and the benefits persist after therapy is terminated.48 CBT has also been reported to be efficient in the management of depression.49 Further research, however, is needed regarding the efficacy of CBT—in combination with antidepressant therapy—for insomniac patients with major depressive disorder.50
Behavioral modification of social rhythms may help in the treatment of depression. Frank and colleagues developed the Interpersonal and Social Rhythm Therapy (IPSRT) Intervention Program in order to establish regular social rhythm regularity (having regular bed, wake, and meal times, switching to a more regular work schedule, and incorporate a regular daily exercise session). IPSRT reduces the risk of recurrence in bipolar patients, regularizes social rhythms, accelerates remission in depressed patients, and lowers relapse rates; these effects are comparable with those of intensive pharmacotherapy.51 Further studies should determine whether IPSRT should be used alone or as an adjunctive treatment in major depression.52

Psychopharmacological treatment approaches
Melatonin, exogenously administered, acts as a synchronizer of circadian rhythms and sleep (eg, in blind persons) but does not appear to have any major effects on mood.53 Antidepressants alleviate symptoms of depression by altering the levels of various central nervous system neurotransmitters that are also involved in sleep regulation, and may have a considerable impact on sleep patterns. In general, the majority of antidepressant drugs suppress REM sleep and increase REM latency, although this is not always the case. As far as sleep efficiency and total sleep time are concerned, antidepressants can be distinguished as being either sedative or energizing.54 Currently-available antidepressants have notable limitations in terms of their only moderate efficacy compared with placebo, relatively slow onset of action, possible withdrawal symptoms, and problems of compliance. Sleep disturbances are often used to identify newly presenting depressive patients, and may be part of a more general alteration of bodily rhythms.55 Persistent insomnia is one of the most common residual symptoms in incompletely remitted depression.56
Residual depressive symptoms are one of the predictors of subsequent relapse risk,57,58 and of persistent functional disability. Complete relief of associated insomnia should be pursued in patients under treatment with antidepressants to avoid the recurrence of depressive symptomatology.59 In general, the sleep disturbances associated with depression improve as depressive symptom severity lessens with treatment, but different antidepressants have characteristic effects on sleep, particularly in the early stages of treatment.
On short-term administration, most tricyclic antidepressants (TCAs) promote sleep by increasing total sleep time and SWS. Furthermore, REM sleep suppression is reported with all TCAs except trimipramine.60,61 More specifically, amitriptyline, trimipramine, nortriptyline, dothiepin, and doxepin have all been associated with sedation (although imipramine62 and desipramine63 are less likely to be linked with sedation and have been associated with insomnia instead). Because of their sedative properties, these agents are often used as hypnotics in depressed patients suffering from insomnia.64-68 However, daytime drowsiness and poor functioning during the next day may be an untoward side effect of sedative TCAs, in particular amitriptyline and doxepin. It should also be noted that TCAs may cause insomnia by inducing or worsening periodic limb movement disorder, and that their use is often associated with nightmares.69
The reversible monoamine oxidase inhibitor moclobemide is associated with less REM sleep suppression and appears not to affect sleep notably.70 SSRIs are considered to be more energizing agents than other antidepressants. Although SSRIs are commonly associated with insomnia, sedation and daytime sleepiness have been occasionally reported with high doses of these drugs. Fluvoxamine and paroxetine have been reported as being more sedating than other SSRIs.22,26,67,69 Objective polysomnographic findings on the effects of SSRIs on sleep show prolongation of sleep onset latency, increased wakefulness, decreased sleep efficiency, increased number of arousals during the night, increased REM latency, and decreased total REM sleep, when compared with placebo and sedative TCAs.64-67,69 Furthermore, SSRIs can exacerbate periodic limb movement disorder and can cause nightmares. However, patients’ subjective sleep ratings whilst taking SSRIs are frequently positive. The same is also true in terms of clinicians’ ratings of sleep items on the Hamilton Rating Scale for Depression in clinical trials that investigated citalopram, sertraline, fluoxetine, fluvoxamine, and paroxetine. However, it is unlikely that a depressed patient with a history of severe sleep disturbance will benefit more from SSRI treatment than from the administration of more sedative antidepressants.
Venlafaxine,70,71 a serotonin and norepinephrine reuptake inhibitor (SNRI), decreases total sleep time and may cause insomnia in 4% to 18% of depressed patients. Also, its administration has been associated with REM sleep behavior disorder. Venlafaxine and duloxetine72 (another SNRI), as well as reboxetine, a norepinephrine reuptake inhibitor, appear to have a similar profile to SSRIs regarding their influence on REM sleep and overall sleep architecture. Another antidepressant that may cause insomnia is bupropion, a dopamine and norepinephrine and lengthens REM latency.
Trazodone, a serotonin, á1-adrenergic, and histamine receptor blocker, increases total sleep time, enhances SWS, and may cause excessive daytime sleepiness. Trazodone does not suppress REM sleep.5 It is a very sedative antidepressant and has often been used for the management of severe insomnia in depression. A number of trials have shown that trazodone is more effective than the TCAs and equally as effective as a hypnotic agent, zolpidem, in improving sleep.64-67,69 Nefazodone, a compound closely related to trazodone, is a potent antagonist of postsynaptic 5-HT2 receptors, but with a less potent á1-adrenoreceptor–blocking activity and no affinity for histamine receptors. It promotes sleep without suppressing REM sleep.5 Its pharmacological profile makes it one of the best antidepressants to relieve insomnia in the context of depression, and it is widely used as an adjunct to SSRIs and SNRIs.5 Also, maprotiline, which acts by inhibiting reuptake of norepinephine and blocking the histamine receptor, causes sedation and suppresses REM sleep. Similarly, amoxapine, which blocks the serotonin and histamine receptors and inhibits the uptake of norepinephrine, is another antidepressant that causes sedation. Tianeptine, a glutamate modulator,73 enhances sleep continuity and ameliorates subjective sleep quality without significantly modifying REM sleep parameters.54
Mirtazapine is a selective serotonin and á2- adrenoreceptor blocker, which also blocks histamine receptors (noradrenergic and specific serotonergic antidepressant). Potent antagonism of H1 receptors causes immediate, nonspecific sedative effects upon administration. Mirtazapine increases total sleep time and suppresses REM sleep. It is frequently used when sleep complaints are a major concern in depression and its efficacy is comparable to that of sedative TCAs.64-67,69
Agomelatine, an agonist of melatonergic MT1 and MT2 receptors, as well as an antagonist of 5-HT2C receptors, uniquely combines circadian synchronizing effects with selective norepinephrine and dopamine augmentation properties in the prefrontal cortex, and demonstrates robust antidepressant efficacy.74-76 When administered in the evening, it advances circadian phase and directly increases sleepiness through thermoregulatory mechanisms.77,78 This promotes a rapid sleep onset, but is without any after-effects the following day. The drug does not raise extracellular serotonin levels, and that is why it does not produce any of the side effects (diarrhea, nausea, sexual dysfunction, insomnia) usually observed with SSRIs. Furthermore, agomelatine does not block histaminergic, á1-adrenergic, and muscarinic receptors, and as a result does not share the side effects of TCAs.79

Combination therapy
There is evidence from everyday clinical experience, and a few controlled studies as well, that combining benzodiazepine hypnotics80 or nonbenzodiazepine selective gamma aminobutyric acid (GABA) type A receptor antagonists, such as zolpidem, zopiclone, eszopiclone, and zaleplon, with antidepressants from the beginning of therapy may result in a faster relief of the concomitant sleep disturbance, and thereafter bring about a faster improvement in depressive symptoms.81 Therefore, it is common practice to use such combinations for the initial management of insomnia in the context of depression.5 Benzodiazepines commonly used for the management of insomnia are lorazepam, temazepam, alprazolam, oxazepam, triazolam, diazepam, flurazepam, and midazolam. All benzodiazepines shorten sleep onset latency, increase total sleep time and stage 2 sleep, and suppress REM sleep and SWS. Excessive daytime sleepiness is a troublesome side effect, which is more pronounced with long-acting benzodiazepines. Development of tolerance and exacerbation of insomnia with rebound of REM sleep upon withdrawal is also a major concern.82,83 Nonbenzodiazepine hypnotics have a better pharmacological profile with fewer and milder side effects than the benzodiazepines, and are currently preferred for the treatment of sleep problems in affective disorders.61,84 Recently, ramelteon, a novel selective agonist of melatonin MT1 and MT2 receptors, was approved for the treatment of primary insomnia. In comparison with the other hypnotics, it is claimed that ramelteon has the advantage of no potential for abuse. However, experience with this novel hypnotic agent in the treatment of insomnia associated with depression is still limited.5
In cases resistant to treatment, the combination of antidepressants and antipsychotics should be considered. Adding an antipsychotic to the patients’ daily regimen (ie, olanzapine) might alleviate sleep disturbances by increasing SWS.85


Sleep disturbances often occur in depressed patients, and they may be used to identify newly presenting or recurrent episodes of depression. Moreover, persistent insomnia is one of the most common residual symptoms in incompletely remitted depression. Generally, complete relief of associated insomnia should be pursued in patients under treatment with antidepressants to avoid the recurrence of depressive symptomatology. Currently-available antidepressants have notable limitations, mainly relating to their only moderate efficacy relative to placebo. A combination of nonpharmacological interventions (sleep deprivation, light therapy, CBT, IPSRT) together with pharmacotherapy could be used to improve management of sleep disturbances associated with depression. A novel antidepressant compound, agomelatine, an agonist of melatonergic MT1 and MT2 receptors as well as an antagonist of 5-HT2C receptors, has been recently introduced; it shows a synchronizing effect on circadian rhythms and demonstrates robust antidepressant efficacy, while it produces a superior and earlier improvement in the sleep-wake cycle compared with other antidepressant agents. This sleep-restorative antidepressant offers the possibility of an improved quality of remission, while minimizing relapses or recurrences of depressive episodes.

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Les troubles du sommeil sont associés depuis longtemps à la dépression ; souvent utilisés pour identifier les patients débutant une dépression, ils pourraient appartenir à une perturbation plus générale des rythmes biologiques. De plus, l’insomnie persistante est un symptôme résiduel fréquent d’une dépression incomplètement guérie. Afin d’éviter la récidive des symptômes dépressifs, il est de règle de poursuivre le traitement de l’insomnie chez les patients traités par antidépresseurs. L’association de traitements médicamenteux et non médicamenteux ciblant le cycle veille-sommeil (privation de sommeil, luminothérapie) peut contribuer à la disparition des symptômes dépressifs et des troubles du sommeil associés. L’agomélatine, une nouvelle molécule agoniste des récepteurs mélatoninergiques MT1 et MT2 et antagoniste des récepteurs 5-HT2C, possède un effet unique de synchronisation des rythmes circadiens et une bonne efficacité antidépressive.