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PRIORITY PRESS - 28th CINP World Congress of Neuropsychopharmacology

Stockholm, Sweden / June 3-7, 2012

Stockholm - It has long been argued that human health and well-being are tied to synchronization of circadian rhythms. This is particularly relevant in depressive patients in whom circadian rhythms are often profoundly disrupted. This observation is supported by the fact that core symptoms of depression include sleep-wake disturbances. In addition, it has been shown that individuals who go to bed and rise late have a greater risk of depression than those who follow more common circadian rhythms. The evidence that both melatonergic (MT₁/MT₂) and serotonergic (5-HT_2c) receptors are concentrated in the area of the brain involving circadian rhythm regulation has recently drawn attention to these areas as targets for antidepression therapy. A new class of therapy associated with resynchronization of circadian rhythm through synergistic actions on the melatonergic and serotonergic neurotransmitter systems is a bright prospect for viable new treatments.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Biological clocks exhibiting circadian rhythms exist in virtually all tissues where a series of clock-like genes generate these rhythms. Human physiology is thus organized into certain circadian rhythms that emerge out of the rhythmical change between day and night, according to Prof. Göran Hajak, University of Regensburg, Germany. “Even a single cell is able to have a rhythmic gene expression,” he stated. He maintained that much of human function is dependent on the ability of gene function to maintain circadian rhythms. It is for this reason that the human body has a central master clock located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus and the inherent rhythm of the SCN is constantly adjusted to recurring daily environmental stimuli, the most powerful of which is daylight.

Disturbance of Circadian Rhythms and Depression

In Prof. Hajak’s view, human health overall and mental health specifically are very much related to the fact that humans possess this synchronizing power. “We may have single biorhythms but all together, they must be properly synchronized to achieve normal physiology and normal psychology,” he affirmed. Regarding patients with depression, it becomes readily apparent that there is a profound disturbance of circadian rhythms, as many depressive symptoms have a temporal pattern that parallels circadian malfunction.

Among circadian malfunctions are the common sleep disturbances seen in depression, including difficulty initiating and maintaining sleep and early morning awakening. The most prominent circadian pattern in human behaviour is the sleep-wake cycle, for which clock genes affect both circadian and homeostatic function (Medicographia 2010;32:146-51). Additionally, many depressed patients have impaired daytime activity, loss of appetite and diurnal mood changes, depressed mood often being worse in the morning.

“All of these symptoms are central to the core of depression and they can be very easily understood as a circadian rhythm disorder,” Prof. Hajak told delegates. “When the central internal clock is working properly, the core body temperature—a direct reflection of circadian rhythm function—declines in the evening hours; it is low during the night to allow for restoration of human physiology and then increases during the daytime when people need to be active,” he explained.

Elevated core body temperature with diminished amplitude is the most consistently observed circadian abnormality in depression, according to Prof. Hajak. Secretion of melatonin by the pineal gland, a function of the central pacemaker as well, is also reduced in patients with depression. The severity of depression as measured by the Hamilton Rating Scale for Depression (HAM-D) also correlates with circadian misalignment: the more delayed the pacemaker relative to the timing of sleep, the more severe the depressed state.

Some individuals are at greater risk for depression than others as up to 10% of people are so-called “ night owls” and prefer to perform major activities in the evening, contrary to those (approximately 50%) who are morning or “lark” people, with the balance considered “intermediate.” Several investigators have now shown that there is a positive correlation between increasing “eveningness” and increasing risk of depression. The propensity towards being a “night owl” as opposed to a “lark” may also be genetically determined.

The Genetic Link

In comparing genetic aberrations in clock genes between depressive patients and controls, investigators found that depressive patients with clock gene mutations tend to be much more active in the evening. Their circadian systems also do not shut down at night compared to those without the mutation, so their systems are not fully restored during the night. Individuals with the same mutation also respond differently to negative stimuli than those who do not have the mutation, suggesting that emotional responsiveness in patients who have clock gene mutations is different from those in whom clock gene mutations are absent, Prof. Hajak explained.

Whether circadian rhythm disturbances trigger depression or whether they arise as a consequence of the illness is still being debated. “Both are possible,” Prof. Hajak indicated in an interview. “If you alter your circadian rhythm by having long-term insomnia, this might result in depression. But if you have depression, depression itself feeds back on a negative circadian rhythm so it is a vicious cycle where one worsens the other.” What is clear is that chronotherapeutic strategies such as sleep deprivation that help reset the internal clock and normalize circadian disturbances can rapidly and dramatically reduce depressive symptoms in many patients, he noted.

Rationale for an Agent with Chronobiologic Properties

Certain antidepressants may also possess chronobiologic properties. In bipolar depression, for example, lithium has been shown to change circadian rhythms and there is now evidence that its chronobiological effects in bipolar depression are essential to achieve a therapeutic effect. This observation, along with supportive experimental studies with compounds that alter melatonergic activity, have provided some of the basis for developing agents that exert an antidepressive effect by normalizing circadian rhythms.

In fact, there is a high concentration of melatonergic and 5-HT_2c receptors in the SCN and all 3 receptors are involved in circadian rhythm regulation, according to Prof. Giorgio Racagni, University of Milan, Italy (World J Biol Psychiatry 2011;12:574-87). It is well established that melatonin binding to MT₁/MT₂ (melatonergic) receptors in the SCN suppresses neuronal activity, which is important for the reduction in circadian activity when sleeping.

It is likely that serotonergic pathways help coordinate circadian rhythms to light stimuli as well. Given the association between depression and circadian rhythm disturbances, “it is of interest that melatonergic and 5-HT_2c receptors regulate both processes… presenting valid therapeutic targets in depression,” Prof. Racagni remarked.

This work has produced efforts to develop a new class of antidepressants called melatonergic MT₁/MT₂ receptor agonists. Some of these agents are designed to combine both melatonergic and serotonergic activity. For example, agomelatine (approved in Europe but not yet in Canada) is one of the best-studied of these agents. It is a 5-HT_2c antagonist and agonist of both MT₁/MT₂ receptors. It is notable that if MT antagonists are co-administered with this agent, its antidepressant efficacy is compromised, an observation that supports the idea that both MT₁/MT₂ and the 5-HT_2c act in synergy to produce its antidepressant action.

An elegant series of experiments has been conducted to better understand the specific effects of MT₁/MT₂ receptor agonism with or without serotonergic effects. For example, Prof. Racagni and colleagues have demonstrated a synergistic activity when both receptor types are acted upon relative to either alone, including increased neurogenesis, stimulation of brain-derived neurotrophic factor, upregulation of activity-regulated cytoskeleton-associated protein and attenuation of stress-induced glutamate release in the cortex.

Interestingly, it is possible that at least some of the traditional antidepressants share an ability to improve circadian rhythms. However, “this effect is not optimized,” noted Prof. Racagni, which is the basis for pursuing a new class of drug. The clinical trials with the first agent in this class—along with the experimental studies with other agents that affect this pathway—suggest that MT₁/MT₂ receptor agonism “represents an entirely new approach for the treatment of depression, correcting circadian rhythm disturbances within depression with subsequent relief of depressive symptoms,” Prof. Racagni concluded.

Summary

All antidepressants affect the major neurotransmitters implicated in mood disorders to varying degrees of selectivity. However, approximately 30% of patients with major depressive disorder remain unresponsive to antidepressant therapy and <50% of patients receiving traditional antidepressants achieve full remission. A new class of antidepressant with agonist activity on MT₁/MT₂ receptors appears promising for exerting benefits through a new mechanism of action. Combined with synergistic mechanisms, such as 5-HT_2c antagonism, these agents may demonstrate efficacy in the substantial proportion of patients poorly controlled on current options.

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