Available online at www.sciencedirect.com Psychiatry Research 165 (2009) 201 – 214 www.elsevier.com/locate/psychres Review Pathophysiology of depression: Role of sleep and the melatonergic system Venkataramanujan Srinivasan a,1 , Seithikurippu R. Pandi-Perumal b,⁎, Ilya Trakht b , D.Warren Spence c , Ruediger Hardeland d , Burkhard Poeggeler d , Daniel P. Cardinali e a Department of Physiology, School of Medical Sciences, University Sains Malaysia, Kubang Kerian, Kota Bharu, Kelantan, Malaysia b Division of Clinical Pharmacology and Experimental Therapeutics, Department of Medicine, College of Physicians and Surgeons of Columbia University, 630 West 168th Street- Rm # BB813, New York, NY 10032, USA c Sleep and Alertness Clinic, 750 Dundas Street West, Toronto, Canada ON M6J-3S3 d Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of Goettingen, D-37073 Goettingen, Germany e Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155. 1121 Buenos Aires, Argentina Received 22 June 2007; received in revised form 13 September 2007; accepted 12 November 2007 Abstract Profound disturbances in sleep architecture occur in major depressive disorders (MDD) and in bipolar affective disorders. Reduction in slow wave sleep, decreased latency of rapid eye movement (REM) sleep and abnormalities in the timing of REM/non-REM sleep cycles have all been documented in patients with MDD. It is thus evident that an understanding of the basic mechanisms of sleep regulation is essential for an analysis of the pathophysiology of depressive disorders. The suprachiasmatic nucleus (SCN), which functions as the body's master circadian clock, plays a major role in the regulation of the sleep/wakefulness rhythm and interacts actively with the homeostatic processes that regulate sleep. The control of melatonin secretion by the SCN, the occurrence of high concentrations of melatonin receptors in the SCN, and the suppression of electrical activity in the SCN by melatonin all underscore the major influence which this neurohormone has in regulating the sleep/wake cycle. The transition from wakefulness to high sleep propensity is associated with the nocturnal rise of endogenous melatonin secretion. Various lines of evidence show that depressed patients exhibit disturbances in both the amplitude and shape of the melatonin secretion rhythm and that melatonin can improve the quality of sleep in these patients. The choice of a suitable antidepressant that improves sleep quality is thus important while treating a depressive disorder. The novel antidepressant agomelatine, which combines the properties of a 5-HT2C antagonist and a melatonergic MT1/MT2 receptor agonist, has been found very effective for resetting the disturbed sleep/wake cycle and in improving the clinical status of MDD. Agomelatine has also been found useful in treating sleep problems and improving the clinical status of patients suffering from seasonal affective disorder. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Depression; Sleep; Melatonin; Agomelatine; Suprachiasmatic nucleus; Chronobiotics; Seasonal affective disorder Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202 Prevalence of sleep disorders in depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 ⁎ Corresponding author. Tel: +1 917 455 7147; fax: +1 212 342 2969. E-mail address: sleepresearch@gmail.com (S.R. Pandi-Perumal). 1 Current address for V. Srinivasan is: Prof. of Physiology, SRM Medical College & Research Centre SRM University Kattankulathoor -603203 Kancheepuram District INDIA. 0165-1781/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2007.11.020 202 V. Srinivasan et al. / Psychiatry Research 165 (2009) 201–214 3. Sleep changes as markers for depression . . . . . . . . . . . . . . . . . . . . . . . . 4. Physiology of sleep regulatory mechanisms: role of the melatonergic system . . . . . 5. Regulation of melatonin secretion by the SCN . . . . . . . . . . . . . . . . . . . . . 6. Melatonin's role in the regulation of sleep . . . . . . . . . . . . . . . . . . . . . . . 7. Melatonin in MDD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Antidepressants and sleep: role of the novel melatonergic antidepressant agomelatine . 9. Agomelatine in sleep disturbances of SAD . . . . . . . . . . . . . . . . . . . . . . . 10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction According to the World Health Organization, depression affects nearly 121 million people worldwide. It is also one of the top 10 causes of morbidity and mortality (Rosenzweig-Lipson et al., 2007). Depression is a heterogeneous syndrome rather than a single disease, and has been characterized as a collection of “physiological, neuroendocrine, behavioral and psychological symptoms” (Nestler et al., 2002; Fuchs et al., 2006). Due to its complexity, many gaps remain in our understanding of the etiology and pathophysiology of depression. However, an increasing amount of evidence is now pointing to the possibility that chronobiological difficulties may underlie or at least accompany the condition. Numerous studies undertaken in depressive patients have suggested that a common comorbidity of depression is a dysregulation of the circadian timing system. This seems to occur in various types of depression, but is particularly evident in bipolar affective disorder (Bunney et al., 1970; Sitaram et al., 1978; Wehr and Goodwin, 1979). In nearly 80% of depressed patients, including those with major depressive disorders (MDD) or bipolar affective disorder, profound disturbances in sleep architecture have been documented (Wehr and Goodwin, 1979; Reynolds and Kupler, 1988; Armitage and Hoffmann, 2001). It should be stressed that a marked overlap exists in the neuronal pathways regulating the sleep/wake cycle and those presumably altered in depressive illness (Lustberg and Reynolds, 2000). A particular feature of MDD is the abnormality in the timing and distribution of rapid eye movement (REM) and nonREM (NREM) sleep stages that can be regarded as a primary characteristic of the disease (Armitage, 2007). Studies of sleep in depressive and affective disorders have been useful in supporting theoretical considerations about their pathophysiology (Srinivasan et al., 2006). The introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors in the 1960s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 204 205 205 206 206 209 209 210 210 prompted a host of studies on the possible neurotransmitter abnormalities in depressed patients. Those studies demonstrated that functional alterations in brainstem noradrenergic or serotonergic systems were involved in both the regulation of mood and affective behaviors and in the regulation of the sleep/wake cycle. Various imaging studies (Drevets, 2001; Mayberg, 2003; Berton and Nestler, 2006) have now shown that several brain areas such as the prefrontal cortex, cingulate cortex, hippocampus, striatum, amygdala and thalamus are active during the experience of sleep disorders (insomnia, fatigue) as well as of disorders of mood (including depressed mood, feelings of worthlessness, diminished ability to concentrate, recurrent thoughts of death or suicide, as well as other symptoms as per the DSM-IV criteria for depressive disorders (American Psychiatric Association, 1994). Other studies have shown that an increased incidence of depressive symptoms correlates with poor sleep quality or chronic insomnia, disturbances which appear to be major risk factors for depression (Lustberg and Reynolds, 2000). Hence, an understanding of the physiological mechanisms of sleep regulation, and especially of the sequellae of their breakdown can assist in unraveling the complexities of the pathophysiology of depressive disorders. Of particular importance in sleep regulation is the activity of the hypothalamic suprachiasmatic nucleus (SCN). The SCN determines the sleep/wake rhythm, consisting in the timing of sleep propensity and wakefulness, and, further, it helps to consolidate both states (Borbely, 1982; Edgar et al., 1993; Klerman et al., 1999; Zee and Manthena, 2007). Inasmuch as neurons of the SCN express high levels of MT1 and MT2 melatonin receptors (Dubocovich and Markowska, 2005), and, further, since exogenous melatonin has been shown to depress SCN neuronal activity (Liu et al., 1997) and to phase-shift the neuronal firing rate (McArthur et al., 1997), melatonin is assumed to be a key regulator of the sleep/wakefulness rhythm. V. Srinivasan et al. / Psychiatry Research 165 (2009) 201–214 203 Fig. 1. The two polysomnograms show the characteristics of healthy sleep (a) in comparison with sleep in a depressed patient (b). (1) In depression, the period between sleep onset and the first occurrence of REM sleep, shown in gray, is markedly reduced (reduced REM latency). (2) The depressed patient spend less time in sleep stages 3 and 4 (reduced NREM sleep). (3) In depression, the number of awakenings and arousals is increased and the patient awakens early in the morning (disturbed sleep continuity). The sleep stages (REM, S1–4, sleep stages 1–4) are given across the time. BM, body movement; EM, eye movement (reproduced with permission from Nissen, C., Nofzinger, E.A., 2007. Sleep and depression: a functional neuroimaging perspective, In: Pandi-Perumal, S.R., Ruoti, R.R., Kramer, M. (Eds.), Sleep and Psychosomatic Medicine, Informa Healthcare, London, figure 5.1, pp. xxiii (color plate). Moreover, the close association between sleep and mood disorders suggests that melatonin may also be important in the regulation of mood (Srinivasan et al., 2006). 2. Prevalence of sleep disorders in depression Chronic insomnia is considered to be one of the most frequent and prominent factors that trigger depression and is often viewed as a predictor of a depressive disorder. In one study self-reported sleep disturbance was a major prodromal symptom 5 weeks prior to the recurrence of a depressive episode (Perlis et al., 1997). Depressed patients often complain of difficulties in falling asleep, frequent nocturnal awakenings and early morning wakefulness. Further, more than 90% of depressed patients suffer from impairment of sleep quality (Mendelson et al., 1987). Sleep disturbances in depressed patients have been analyzed by polysomnography (PSG) (Fig. 1). A reduction in slow wave sleep, shortening of REM onset latency (REMOL), increased REM sleep, and sleep continuity disturbances were among the symptoms found in an assessment of untreated depressed patients (Kupfer et al., 1981). Indeed, REM sleep abnormalities are considered specific for MDD although there are some controversies on this issue. In a retrospective study of 67 male depressive patients and 67 carefully age-matched male healthy control subjects Hubain et al. (2006) found that the influence of age, severity, adaptation and gender were strongly associated with depressive symptoms. (Hubain et al., 2006). In contrast to most studies in this area, REM sleep was found to be reduced. Further, aging was found to influence most sleep variables, but not the order of their association with depression. One of the main markers of depression was the absence of sleep, a finding 204 V. Srinivasan et al. / Psychiatry Research 165 (2009) 201–214 that was interpreted to support the authors' conclusion that a possible linkage between hyperarousal and stress underlies its physiopathology (Hubain et al., 2006). It is interesting to note that although unipolar and bipolar types of depression can be clearly distinguished, no significant differences between the two groups of patients are observed in terms of nocturnal sleep patterns (Duncan et al., 1979; Berger et al., 1982; Feinberg et al., 1982; Lauer et al., 1992). Further, the sleep abnormalities exhibited by manic patients are similar to those found in unipolar and bipolar depressed individuals (Hudson et al., 1992; Riemann et al., 2001). However, patients with seasonal affective disorder (SAD) do not show the sleep patterns seen in MDD (Anderson et al., 1994). 3. Sleep changes as markers for depression Both epidemiological and electroencephalographic studies implicate sleep disturbance in the pathogenesis of depression (Lustberg and Reynolds, 2000). PSG studies in depressed patients show a reduction in the absolute number of delta waves during the first NREM sleep period and a general decrease in delta activity throughout the night (Fig. 1). Additionally, an alteration in the temporal distribution of REM sleep with impairment of the timing of the REM/NREM sleep cycle was documented (Buysse et al., 1997). It has been suggested that patients with decreased REMOL prior to treatment are prone of developing subsequent episodes of depression and experiencing rapid relapses after remission (Rush et al., 1989). The presence of sleep abnormalities in the first degree relatives of depressed patients (even those who never experienced the illness) suggests that these sleep changes can be viewed as “markers” of depression (Giles et al., 1990; Lustberg and Reynolds, 2000). The decrease in slow wave activity during the first NREM period and the increase of REM sleep occur more frequently in early depression although the significance of this is not clear (Kupfer and Ehlers, 1989). Functional neuroimaging studies using positron emission tomography have indicated that MDD patients have higher rates of brain glucose metabolism during the first NREM sleep period as compared to non-depressed controls, a change associated with decreased slow wave activity (Gillin et al., 1996). Despite this associational evidence, whether sleep disturbance has a causal role on depression is still not completely resolved. However, the clinical management of depression should entail an awareness of the reciprocal relationship between insomnia and the depressive episodes (Lustberg and Reynolds, 2000). It has been suggested that the existence of abnormalities in the timing of REM/NREM sleep cycle in patients with depression is due to disturbances in the organization of pathways active in regulation of the sleep/wake cycle (Armitage, 2007). 4. Physiology of sleep regulatory mechanisms: role of the melatonergic system Two different processes participate in sleep regulation, namely, a homeostatic mechanism depending on sleep debt and the circadian system that regulates sleep induction and wakefulness (Borbely, 1982). NREM sleep and, in particular, slow wave sleep, are controlled by the homeostatic processes. In healthy young individuals, sleep progresses through four non-REM stages (stage 1 through stage 4), which take nearly 70 to 90 min (Fig. 1). Stage 1 sleep represents the transition from drowsy wakefulness to deep sleep stages and accounts for less than 5% of the total sleep at night. Stage 2 sleep is characterized by the appearance of Kcomplexes and sleep spindles. Stage 3 and stage 4 are deep stages of sleep (i.e. slow wave sleep) and display desynchronized delta waves. Thereafter, the individual enters into a REM sleep episode followed by reentry into NREM. The elapsed time from sleep onset to the beginning of the first REM period is called REMOL. Periods of NREM sleep constitute nearly 80% of the total sleep time while REM sleep accounts for 20% of the sleep time. REM sleep grows longer with each successive ultradian cycle. During each night, individuals experience approximately five cycles of NREM sleep and REM sleep that last 70 to 90 min each. This entire sequence of sleep stages throughout the night constitutes the “sleep architecture” of an individual (Fuller et al., 2006). As mentioned above, physiological regulation of sleep involves a homeostatic process (referred to as “S”, for sleep) that depends upon sleep and wakefulness period and a circadian process (“C”) that is independent of sleep and waking behaviors (Borbely, 1982; Daan et al., 1984). The S component controls NREM sleep and the C component controls REM sleep and the ratio of NREM/REM sleep. The SCN interacts with both sleep regulatory mechanisms, S and C. Indeed, it has been suggested that a functional disruption of the master clock plays a role in disorders of sleep and wakefulness (Zee and Manthena, 2007). Isolation of the SCN from other regions of the brain abolished circadian electrical activity in these brain structures without affecting the circadian electrical activity of SCN neurons (Inouye and Kawamura, 1979). Melatonin is a major neurohormone influencing the activity of SCN neurons. The effect of melatonin is V. Srinivasan et al. / Psychiatry Research 165 (2009) 201–214 exerted via two distinct melatonin receptors, MT1 and MT2 (Reppert et al., 1996; Dubocovich and Markowska, 2005). Melatonin inhibits (via MT1 receptors) as well as phase-shifts (via MT2 receptors) the electrical activity of SCN neurons (Mason and Brooks, 1988). In transgenic mice lacking MT1 receptors, melatonin does not elicit acute inhibitory responses but can still shift the phase of circadian rhythmicity in SCN firing rate (Liu et al., 1997). Therefore, MT2 receptors in the SCN are considered responsible for the phase-shifting and entrainment effects of melatonin. The firing rate of the SCN decreases in the transition from NREM to REM sleep, as shown by the simultaneous recording of electroencephalographic activity and SCN electrical activity in male Wistar rats (Deboer et al., 2003). These observations however require further confirmation in primates, since the relative amount of REM sleep in rodents is quite limited. The role of the SCN in the regulation of sleep was first studied in squirrel monkeys. In this primate species SCN lesions, on the one hand, resulted in the loss of consolidated sleep/wake periods and, on the other hand, caused a prolonged sleep compared to animals with an intact SCN (Edgar et al., 1993). The evidence supported the conclusion that the circadian signal arising from the SCN promotes wakefulness during the day and facilitates consolidation of sleep during the subjective night. Indeed, the mechanisms by which the SCN regulates sleep appear to be complex. The primary projections from the SCN involve hypothalamic and extrahypothalamic structures (e.g., the basal forebrain or midline thalamic nuclei) that are involved in the regulation of sleep/wake cycle, autonomic regulation, psychomotor performance and melatonin secretion (Abrahamson et al., 2001; Aston-Jones, 2005; Saper et al., 2005). The main purpose of the SCN output system is to integrate environmental cues with the circadian system, thus conferring maximum flexibility to the response (Saper et al., 2005). Hence, the neural pathways from the SCN, which promote wakefulness are complemented by those involved in SCN promotion of sleep (Zee and Manthena, 2007). The sleep-promoting action of the SCN also depends upon melatonin whose circadian secretion is regulated by the SCN. Signals from the SCN have been shown to influence physiology and behavior including melatonin synthesis, temperature and sleep (Bunney and Bunney, 2000). 5. Regulation of melatonin secretion by the SCN Melatonin secretion from the pineal gland is greater at night than during the day in all animal species, irres- 205 pective of whether they are diurnal, nocturnal or crepuscular (Cardinali and Pevet, 1998; Reiter, 2003; Claustrat et al., 2005). The circadian pattern of melatonin synthesis and secretion is abolished by SCN lesions (Klein and Moore, 1979). The circadian activity of the SCN is synchronized to the environmental light/ dark cycle by light perceived in the retina. The signal from the retina is mainly transmitted to the SCN through a monosynaptic retinohypothalamic tract that originates from particular light-perceptive, melanopsin-containing retinal ganglion cells (Berson et al., 2002), plus a minor contribution given by mid-wavelength cones (Panda, 2007). Projections from the SCN pass through the paraventricular nucleus, medial forebrain bundle and reticular formation to reach the intermediolateral horn cells of the spinal cord. Fibers from these cells synapse with neurons of the sympathetic superior cervical ganglia, the source of the postganglionic sympathetic innervation of the pineal gland (Klein et al., 1971). NE released from the sympathetic nerve endings interacts with β-adrenoceptors in the pinealocyes and activates adenylate cyclase, thereby enhancing pineal melatonin synthesis and secretion. During the light phase of the daily photoperiod, when the SCN electrical activity is high, NE release is low, while during scotophase, when the SCN electrical activity is low, the increase in pineal NE release stimulates melatonin synthesis and secretion (Gerdin et al., 2004). 6. Melatonin's role in the regulation of sleep The fact that the nocturnal increase of melatonin secretion occurs approximately 2 h in advance to the individual's habitual bedtime (Tzischinsky et al., 1993; Shochat et al., 1997) and that this correlates well with the onset of evening sleepiness have prompted many investigators to suggest that melatonin is involved in the physiological regulation of sleep (Zhdanova and Tucci, 2003). The period of wakefulness immediately prior to the increase of sleep propensity (‘opening of sleep gate’) is known as the ‘forbidden zone’ for sleep (Strogatz et al., 1986; Lavie, 1986). During this time, the sleep propensity is lowest and SCN neuronal activity is very high (Buysse et al., 2004; Long et al., 2005). The transition from wakefulness/arousal to high sleep propensity coincides with the nocturnal rise of melatonin secretion (Dijk and Cajochen, 1997). Melatonin promotes sleep by inhibiting the firing of SCN neurons through activation of GABAergic mechanisms in the SCN (Niles, 1991; Golombek et al., 1996). From the studies on the effects of melatonin administration on sleep, it has been concluded that melatonin exerts both 206 V. Srinivasan et al. / Psychiatry Research 165 (2009) 201–214 direct hypnotic effects and circadian rhythm regulating effects on sleep (Rajaratnam et al., 2004). As discussed above, PSG studies of adults with major depression have consistently shown that they suffer from various sleep abnormalities such as prolonged sleep onset latency, decreased slow wave sleep and increased REM sleep and sleep fragmentation. Taken together, this evidence suggests that melatonin, a major hormone involved in the regulation of sleep, merits consideration as one of the triggering factors underlying the pathogenesis of MDD and bipolar depressive disorder (Srinivasan et al., 2006). 7. Melatonin in MDD The nature of disruption of melatonin secretion in MDD has been under intensive study ever since Wetterberg and his co-workers proposed MDD as a “low melatonin syndrome”, a concept that focuses on low melatonin secretion as a biological marker for depression (Wetterberg, 1979). A number of studies have reported low nocturnal melatonin secretion in depressives (Venkoba rao et al., 1983; Claustrat et al., 1984; Nair et al., 1984; Brown et al., 1985; Beck-Friis et al., 1985; Sack and Lewy, 1988). However, increases in melatonin secretion in depressives has also been reported (Rubin et al., 1992; Shafii et al., 1996; Sekula et al., 1997; Crasson et al., 2004). The differences could be ascribed to changes in depressive symptomatology or to the pattern of melatonin secretion, inasmuch as there are studies showing that daytime melatonin secretion in depressives is increased (Crasson et al., 2004). In a large scale study involving 382 postmenopausal women, the participants were asked to collect, measure and record every fractional urine voiding volume over two 24-h intervals in the course of the week, approximately 3 days apart (an average of ten specimens per 24 h) to measure urinary 6-sulfatoxymelatonin excretion (Tuunainen et al., 2002). 6Sulfatoxymelatonin is the major melatonin metabolite in urine and is regarded as an index of melatonin secretion rate (Bojkowski and Arendt, 1990). A positive family history of depression was associated with a longer duration of urinary 6-sulfatoxymelatonin excretion (Tuunainen et al., 2002). The association of depression and sleep disturbances was evaluated in 459 postmenopausal women, in which lower levels of illumination were found to be associated with more complaints of sleep and depressive symptoms (Kripke et al., 2004). Bright light treatment of women suffering from antepartum depression not only advanced the rhythm of melatonin secretion, but also mitigated depressive symptoms (Epperson et al., 2004). Studies of sleep in recurrent depressive and bipolar disorders have been useful for constructing hypotheses about the etiology and pathophysiology of the disease. A marked reduction in sleep during the night immediately before switching from depression to mania was noted in bipolar depressive patients (Bunney et al., 1970; Sitaram et al., 1978; Wehr and Goodwin, 1979). Measurements of melatonin levels have shown significantly lower levels in unipolar and bipolar depressive patients (Beck-Friis et al., 1985; Souetre et al., 1989). Phase advances in melatonin secretion have also been noted in bipolar depressive patients (Lewy et al., 1979; Kennedy et al., 1989). The significance of the association of sleep disturbances and melatonin levels in bipolar depressive patients remains to be fully elucidated. Exogenous melatonin administration affects the phase of the circadian oscillator regulating sleep/wakefulness (Arendt and Skene, 2005; Cardinali et al., 2006). Kayumov et al. (2001) studied eight depressed patients with an established diagnosis of delayed sleep phase syndrome, and whose sleep onset time and wake time were very much delayed. Melatonin treatment not only improved the total sleep time but also decreased the depressive symptoms (Kayumov et al., 2001), thus showing a relationship between sleep disturbance and the depressive symptomatology. 8. Antidepressants and sleep: role of the novel melatonergic antidepressant agomelatine As noted above, sleep disturbances are key features of depressive symptomatology with more than 80% of depressed patients complaining of sleep disturbances (Reynolds and Kupler, 1988). Persistent insomnia is also one of the main causes for increased risk of relapse and recurrence of depression and also for increased risk of suicide in adults (Wingard and Berkman, 1983; Ford and Kamerow, 1989; Breslau et al., 1996). It is well known that most depression severity rating scales focus on insomnia or reduced total sleep time (Armitage, 2007). Disturbed sleep is one of the diagnostic criteria in the DSM-IV for major depressive disorder. Decreases in sleep efficiency, slow wave sleep and total sleep time, and increases in awakenings and in sleep onset latency time, have all been documented in patients with MDD (Lam, 2006). Although some studies show persistence of sleep architecture abnormalities even during remission phase (Rush et al., 1986) the improvement in the clinical state (Kupfer et al., 1981) or relapse (Cairns V. Srinivasan et al. / Psychiatry Research 165 (2009) 201–214 et al., 1980) are preceded by sleep changes. Hence the administration of an appropriate antidepressant that improves sleep efficiency as well as reducing depressive symptomatology is very important for correcting the underlying neurochemical or neurophysiological abnormalities in MDD. Classical antidepressants can influence sleep. However, the effects are diverse and vary among compounds. Some of them that are in clinical use improve the sleep of depressed patients after about 3 to 4 weeks of treatment, but their greatest effects are on REM sleep, with less consistent changes seen in NREM sleep (Lam, 2006). Compounds such as mianserin, nefazodone, and trazodone (5-HT antagonists) may promote sleep and improve its continuity (Argyropoulos and Wilson, 2005). However, the majority of available drugs generally produce unwanted negative effects on sleep (Lam, 2006). Antidepressants such as TCAs or selective serotonin reuptake inhibitors (SSRIs) suppress REM sleep and increase REMOL (Sonntag et al., 1996; Trivedi et al., 1999; Armitage et al., 2000). Detailed analyses have revealed that drugs such as SSRIs (which are the most widely prescribed antidepressants) have adverse effects on sleep, and the depression associated insomnia is often worsened by the use of these drugs (Lam, 2006; Moltzen and BangAndersen, 2006). Hence, caution should be exercised in choosing an antidepressant. An ideal agent should not only mitigate symptoms of depression, but should also decrease sleep onset difficulties, reduce wakefulness after sleep onset, improve sleep quality and promote a feeling of freshness on the day after (Kupfer, 2006). Prolonged treatment with antidepressants such as desipramine, clomipramine and fluoxetine has been shown to affect the distribution of melatonin receptor mRNAs in the brain. Most of the drugs increase the amount of MT1 receptor mRNA in hippocampal regions (Imbesi et al., 2006). The extent to which the antidepressant response to a particular drug depends upon the distribution of melatonin receptors in the brain merits further detailed investigation (Hirsch-Rodriguez et al., 2006). Agomelatine is a naphthalenic compound chemically designated as N-[2-(7-methoxynaphth-1-yl) ethyl]acetamide. It has been found to be effective as an antidepressant not only in animal models of depression, but also in patients with MDD. Agomelatine is a novel antidepressant drug which acts simultaneously as a melatonin MT1 and MT2 receptor agonist and as a 5HT2C antagonist (Yous et al., 1992; Millan et al., 2003). This dual mechanism of action is unique and is the basis of both its antidepressant efficacy and its capacity to 207 mitigate sleep–wakefulness rhythm disorders (Krauchi et al., 1997). Agomelatine has been found to be effective in several animal models of depression such as learned helplessness (Bertaina-Anglade et al., 2002), chronic mild stress (Papp et al., 2003), forced swimming (Bourin et al., 2004), psychosocial stress in tree shrews (Fuchs et al., 2006) and transgenic mice with decreased glucocorticoid receptor (GR) expression (Barden et al., 2005). The latter model is based on evidence indicating that a malfunction of the GR system can be instrumental in depression (Pepin et al., 1992). The antidepressant activity of agomelatine was assessed in this transgenic mouse model by using a forced swimming test (Barden et al., 2005). In the same model, agomelatine was investigated for anxiolytic properties in the elevated plus maze. The effects of agomelatine were compared to those of desipramine or melatonin. Drugs were injected daily to mice i.p. at a 10 mg/kg dose for 21 to 42 days, 2 h before the onset of the dark period. Treatment with agomelatine reversed the decreased mobility seen in the transgenic mice in the forced swimming test, the effect being comparable to that of melatonin or desipramine. Both the number of open arm entries and the total time spent in open arms of the elevated plus maze were greatly increased in transgenic mice, and agomelatine was effective in reversing the transgenic mouse behavioral changes noted in the elevated plus maze (Barden et al., 2005). In the same study, agomelatine accelerated readjustment of circadian cycles of temperature and activity of transgenic mice following an induced phase-shift, the effect of agomelatine being more potent than that of melatonin (Barden et al., 2005). This resynchronizing effect of agomelatine is of considerable therapeutic value since an internal desynchronization of circadian rhythms (i.e., loss of synchronization between two or more rhythms so that they freerun with different periods within the same organism) is presumably implicated in the pathophysiology of depressive disorders (Wehr and Wirz-Justice, 1982; Lader, in press). Therefore, the antidepressant action of agomelatine could depend partially on its chronobiotic properties. In a multicenter, multinational placebo-controlled study involving 711 patients from different European countries, agomelatine at doses of 25 mg/day was found to be very effective for improving depressive symptoms (Loo et al., 2002). Its antagonism of 5-HT2C receptors coupled with its action on melatonergic receptors in the SCN, which can reset the disturbed circadian rhythms, accounts for agomelatine's therapeutic efficacy in more complex cases of depression (Rouillon, 2006). Because of its rapid promotion of symptom relief, agomelatine is 208 V. Srinivasan et al. / Psychiatry Research 165 (2009) 201–214 an ideal choice for clinical cases of depression in which sleep disturbance is a prominent feature (Pandi-Perumal et al., 2006). Effects on sleep require a distinction between chronobiological aspects and those related to sleep stages. Concerning sleep architecture, different findings have been reported. In an earlier study (Cajochen et al., 1997), the acute administration of agomelatine for a single night resulted in increases in REM sleep without modifications of NREM sleep. In a more recent PSG study of depressive patients, agomelatine treatment in doses of 25 mg/day for 6 weeks improved both sleep quality and continuity. It also increased the duration of NREM sleep without modifying REM sleep (Salva et al., 2007). These findings demonstrate that while agomelatine's chronic and acute actions appear to be different, its sleep-promoting benefits remain constant. The chronobiotic potential of agomelatine, which is not surprising in view of its melatonergic agonist effects, also extends to the synchronization of various body functions, a phenomenon which has been documented in at least one study (Leproult et al., 2005). The available evidence thus suggests that agomelatine is involved not only in sleep regulation but also promotes wakefulness (Dubocovich, 2006). An ideal sleep-promoting compound should not cause hangover effects nor impair daytime activity. Agomelatine appears to approach this ideal inasmuch as in two studies it only occasionally caused mild fatigue (Pjrek et al., 2007), while improvements in daytime alertness were observed in other cases (Kupfer, 2006). The advantageous property of melatonergic agonists is that they promote sleep, at reasonable doses, only in the appropriate circadian phase, a characteristic also found with another MT1/MT2 agonist, ramelteon, which is, however, devoid of the 5-HT2C receptor antagonism (Pandi-Perumal et al., 2007). On the other hand, any antidepressant efficacy of agomelatine requires a continual action during daytime. On a solely chronobiological basis, agomelatine should not behave differently from an agent like ramelteon, which does not exhibit antidepressive properties (PandiPerumal et al., 2007). Therefore, agomelatine may continually modulate the serotonergic system during the day, without inducing sleepiness. Agomelatine's effects appear to be mediated physiologically inasmuch as this single compound, which also antagonizes 5-HT2C receptors at night, acts differently in different circadian phases. These effects are in contrast to the mechanism of more traditional antidepressants which elevate the daytime mood of patients by activating the CNS. Consequently, if these drug effects are sustained into the night their mode of action can impair sleep quality (Ruhe et al., 2007). By contrast, agomelatine thus has a dually phased mechanism of action. At night, its sleeppromoting melatonergic effects prevail over its potentially antihypnotic 5-HT2C antagonism, whereas during the day, its antidepressant action via 5-HT2C inhibition is uncoupled from melatonin's nocturnal actions. This sequential mode could be regarded as a major advantage of agomelatine over other antidepressants (Millan, 2006). An enhanced level of sleep quality elevates the patient's mood in the morning and thus, while the antidepressant effect via 5-HT2C inhibition prevails during the daytime hours, he experiences an improved quality of life. Another, perhaps substantial, advantage of agomelatine is that it has concomitant, neurogenic action in the hippocampus. This effect may underlie its antidepressant and anxiolytic properties (Banasr et al., 2006) and can have value for long-term antidepressant therapy. The effectiveness of agomelatine's melatonergic and selective antiserotonergic action has been confirmed in a number of clinical trials. In a double-blind multicenter trial involving a large population of MDD patients (n = 165), the efficacy of agomelatine (25 mg/day) was compared to that of venlafaxine (75 mg/day) (n = 167) in terms of subjective sleep onset and sleep quality. At the end of one week, agomelatine treatment significantly improved subjective assessments of sleep onset and quality when compared to venlafaxine. The improvement in sleep quality with preserved daytime alertness as noted in this study was significant. A reduction in depressive symptoms was shown by decreases in scores on the Hamilton depression rating scale, which dropped from 20.0 to 11. ± 9.9 following agomelatine treatment (Guilleminault, 2005). Moreover, agomelatine improved sleep even before it elevated the mood thus suggesting that the improvement of sleep in depressed patients can be a prerequisite for improving their clinical status (Lam, 2006). The superior efficacy of agomelatine over other antidepressants has been consistently supported by many investigations (Norman and Burrows, 2007). The drug was also found to display excellent tolerability at a daily dose of 25 mg and did not exhibit significant side effects to the extent and severity observed with other antidepressants such as SSRIs (Zupancic and Guilleminault, 2006; Pjrek et al., 2007). In particular, it did not produce sexual side effects (Montgomery, 2006), constipation, body weight gain, orthostatic hypotension or memory disorders (Hamon and Bourgoin, 2006). Moreover, agomelatine did not induce habituation nor addiction; for instance, in preclinical tests it was not self-administered V. Srinivasan et al. / Psychiatry Research 165 (2009) 201–214 by rhesus monkeys (Wiley et al., 1998) and accordingly, did not cause discontinuation symptoms (Montgomery et al., 2004). Although there has been no evidence of mental side effects associated with agomelatine an issue which remains to be explored is its potential toxicity (e.g. hepatotoxicity) following long-term use. Inasmuch as agomelatine is a naphthalenic compound, it should act on the P450 system and therefore its effects should be monitored closely. 9. Agomelatine in sleep disturbances of SAD Seasonal affective disorder (SAD) or winter depression has been defined as a seasonal pattern of recurrent major depressive episodes that occur during winter/fall in the absence of seasonal psychosocial stressors, and with a full remission of symptoms in the spring/summer (American Psychiatric Association, 1994). A seasonal pattern can also occur in MDD and bipolar depressive disorder (Sohn and Lam, 2005; Lader, in press). Epidemiological studies show that the incidence of SAD in the general population is 15 to 25% (Axelsson et al., 2002; Magnusson and Boivin, 2003). Patients with SAD manifest atypical depressive symptoms such as carbohydrate craving, hypersomnia, hyperphagia or weight gain (Rosenthal et al., 1984). Sleep disturbances are the hallmark of SAD and include hypersomnia, difficulty in waking up in the morning and daytime sleepiness during the winter season. These abnormal features disappear or are even reversed throughout the summer remission with the opposite symptoms of hyposomnia or insomnia (Rosenthal et al., 1984). Hypersomnia and late awakening are regarded as signs of both a phase delay and prolongation of melatonin secretion (Putilov and Danilenko, 2005). The phase delay of circadian rhythms relative to sleep that is documented in patients with SAD has been given as possible explanation for hypersomnia (Avery et al., 1997). It is well known that in human chronobiological studies both core body temperature and melatonin secretion are used as “markers” for assessing circadian phase position. The phase delay of the circadian pacemaker relative to timing of the habitual sleep–wake cycle has been postulated to be a major contributing factor in the pathophysiology of SAD (Koorengevel et al., 2002). In some studies (Lewy et al., 1987, 1998; Sack et al., 1990) the dim light melatonin onset (DLMO) test has revealed that in patients with SAD the melatonin secretory pattern is phase delayed. Other studies (Checkley et al., 1993; Eastman et al., 1993; WirzJustice et al., 1996; Thompson et al., 1997) however 209 have not confirmed this finding. SAD patients have been shown to exhibit longer periods of melatonin synthesis at night during winter as compared to summer (Wehr et al., 2001) thus suggesting that patients with SAD generate a “biological signal” with change in season in a manner similar to that of photoperiodic mammals. Bright light treatment has been shown effective in correcting not only the phase abnormality of SAD patients but also their depressive symptoms as well. In a 4week long study it was found that application of bright light (2500 lx) for 2 h in the morning (0600–0800 h) normalized circadian rhythmicity in core body temperature, cortisol and mood (Avery et al., 1997). Similarly, application of bright light for 7 days in the morning (0600–0800 h) improved scores in the Structured Interview Guide for the Hamilton Depression Rating Scale, SAD version (SIGH-SAD) in SAD patients (Rice et al., 1995). A significant correlation between the magnitude of phase advances of melatonin secretion after morning light and the improvement in the depression scores was observed (Terman et al., 2001). Bright light of high intensity (10 000 lx) was applied in that study for about 30 min. Terman et al. (2001) suggested that the best treatment for winter depression was to expose the patients to bright light 8.5 h after DLMO. Following the identification of agomelatine as a MT1/MT2 melatonergic agonist with antidepressant properties, its efficacy was tested in 37 acutely depressed SAD patients (Pjrek et al., 2007). In an open study with agomelatine (25 mg/day in the evening) over 14 weeks, treatment outcome was assessed by the SIGH-SAD scale and Circscreen, a self-rating scale for the assessment of sleep and circadian rhythm disorders (Laredo et al., 2002). Agomelatine led to a progressive and statistically significant decrease of SAD symptoms from week 2 onward. Overall, treatment with agomelatine yielded a response rate of 75.7% and a remission rate of 70.3%. Throughout the study only one adverse event (mild fatigue) was related to the drug (Pjrek et al., 2007). These results indicate that SAD can be effectively and safely treated with agomelatine. 10. Conclusions Epidemiological and electroencephalographic studies implicate serious sleep disturbances as one of the major underlying causes in MDD and bipolar disorder. Physiological sleep regulatory mechanisms include the active role of the SCN and modulatory effects of melatonin on the electrical activity of the SCN. Disturbances in the rhythm and the amplitude of melatonin secretion could account for symptomatic disturbances to 210 V. Srinivasan et al. / Psychiatry Research 165 (2009) 201–214 both sleep and mood. Antidepressants that are in use today have both beneficial and adverse effects on sleep. The recently introduced melatonergic antidepressant agomelatine with its melatonin agonist property and 5HT2C antagonist property has shown effectiveness for reducing symptoms. Additionally it has a demonstrated superiority over other antidepressants for improving sleep quality. It also has been found effective in alleviating sleep problems of patients with SAD. 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