**6. Importance of time administration of drugs in the treatment of neuropsychiatric diseases**

As mentioned before, human beings have a rhythmic expression in their physiology and behavior. In homeostasis states, this endogenous rhythmicity is synchronized by cyclic environmental factors. This coupling provides several advantages: anticipating cyclical changes in the background and facilitating the organism's adaptation to its environment. This rhythmicity has systems that allow measuring the passage of time, and it is regulated by environmental signals (exogenous) that act as external synchronizers. These rhythms oscillate approximately every 24 h, and among these, the most important is the light-dark cycle or cycle circadian. This concerted, internal, and external rhythmic expression is essential to maintain a healthy state. There is strong evidence that supports the idea that the disruption or chrono-disruption of this adaptive mechanism is detrimental to health and has, among other consequences, sleep disorders, which can lead to cognitive deterioration. It has also been associated with an increased risk of cardiovascular disease, hypertension, metabolic conditions such as diabetes, cancer, obesity, and affective disorders such as anxiety and depression, increasing the prevalence of neuropsychiatric disorders such as schizophrenia and major depression.

The synchronization of circadian rhythms with pharmacotherapy is crucial for neuropsychiatric and affective disorders treatment since it is about combining the maximum benefit with the minimum time complexity of the treatments.

Adequate coordination between drug administration schedules to obtain an optimal therapeutic response has been little explored and currently represents a challenge for chrono-pharmacology.

Desynchronization between the times of administration and the potential pharmacological effects could be one of the reasons why a high percentage of patients with major and bipolar depression (MD) are resistant to treatment, as well as the chronic recurrence of depressive and seasonal disorders. Chronotherapeutic strategies that reset the internal clock may have a specific advantage for treating depression and other mental disorders.

For instance, seasonal affective disorder (SAD) is a sub-type of depression in which individuals experience depressive symptoms and show hypersomnia only in the winter months, in which the period of darkness is more extended than at other times of the year. In a pioneering study, Rosenthal and coworkers [65] found that treatment with bright environmental light suppresses the endogen melatonin secretion and reverses the winter depressive symptoms of patients with SAD. In contrast, light too dim to suppress endogen melatonin is therapeutically ineffective.

This same paper described the antidepressant effects of phototherapy in eight SAD patients by oral melatonin administration. However, in another study with 19 SAD patients, the authors did not find any therapeutic difference between the atenolol, a beta-adrenergic blocker, which inhibits melatonin secretion, and placebo. In contrast, research with seven SAD patients showed that the antidepressant effects of phototherapy were not photoperiodic and appeared to be independent of melatonin suppression. Authors conclude that melatonin can mediate the effects of shortening days on the winter symptoms of SAD and that the modification of melatonin secretion by bright light mediates its antidepressant effects and gives evidence that melatonin secretion may be abnormal in SAD [65].

Multiple factors can disrupt this chronicity because of imbalances in the sleepwake cycle. Disruption of circadian cycles has also been associated with affective disorders.

*Circadian Modulation of Neurodevelopment in the Adult Human Brain: Importance of Melatonin DOI: http://dx.doi.org/10.5772/intechopen.102859*

Depression disorders are characterized by a broad range of symptoms, including altered mood, loss of cognitive functions, and recurrent thoughts of death or suicide. The relationship between chrono-disruption and the etiology of depression is not yet clear. However, evidence suggests that existing pharmacotherapies such as lithium and antidepressants such as melatonin and agomelatine act on the circadian system.

Although it is known that melatonin is a mediator of photoperiodic changes on seasonal rhythms in animals, a gradual increase in circulating levels of melatonin occurs after lights off, reaching its maximum around the middle of the dark phase. There is contradictory evidence about the antidepressant effect of melatonin itself. We found that the melatonin administration in mice at two *Zeitgeber times* (*ZT* = 0 lights on; 12:12 L/D), 1 h before the beginning (*ZT*11) and at the middle (*ZT*18) of the dark phase after either a single or a three-dose treatment, produces a robust antidepressant-like effect in the tail suspension and the forced swimming tests. When a single dose of melatonin (4 mg/kg) was administered at *ZT* 11 produced an antidepressant-like effect in two paradigms. However, when melatonin was administered at *ZT* 18, it was ineffective in the forced swimming test. Required a higher dose of melatonin (16 mg/kg) to observe their antidepressant effect in the tail suspension test. In contrast, repeated doses of melatonin (*ZT* 18, *ZT* 11, and *ZT* 18) were necessary to produce the antidepressant effect in the forced swimming test. These results highlight the importance of the timely administration of melatonin could improve its antidepressant-like effect [66].

Agomelatine is an antidepressant that acts as an agonist on the melatonin receptors and as a 5HT2C receptor antagonist. Several studies suggest that the antidepressant effect caused by agomelatine results from the resynchronization of circadian rhythms that are disturbed in depressed patients ameliorating symptoms of depression. In contrast to other antidepressants, this has shown low relapse rates upon discontinuation and high tolerability. Furthermore, agomelatine treatment improves the amplitude of the circadian (rest/activity) sleep/wake cycle and diminishes the depression and anxiety symptoms in comparison with sertraline treatment [67].

There is strong evidence about the association between sleep disturbances and depression; in depressive disorder (MDD), the desynchronization of circadian rhythms occurs, producing disturbed sleep and insomnia, and these symptoms improve markedly with melatonergic (MT1 and MT2) and 5HT2C agonist treatment such as melatonin and agomelatine, which act as modulating the circadian rhythmicity.

The foregoing gives evidence of the disruptions of the sleep-wake cycle (sleep architecture and timing) and residual symptoms may prevent the attainment of high-quality remission and delay recovery from MDD.

Benedetti and coworkers studied the effect of morning light therapy or placebo combined with the serotonin reuptake inhibitor citalopram in treating patients affected by a major depressive episode without psychotic features. They found that the combination of this antidepressant and light treatment was more effective than citalopram alone or placebo in the treatment of major depression, administered with an optimized timing of administration, and low-intensity light treatment that significantly hastened and potentiated the effect of citalopram. This evidence provides the clinical psychiatrists with an augmenting strategy, effective and devoid of side effects [68].

Alterations in circadian rhythmicity have been little studied in patients with schizophrenia, in which sleep disorders are common, with an 80% prevalence that often responds to circadian disruption.

This study showed that the variability of sleep-wake time is notably more significant and more remarkable in the schizophrenia group than in the people without the disorder [69].

In addition, polysomnography studies have shown that these patients present a higher sleep latency, diminished total sleep time, lower efficiency, more interruptions, a shorter duration, and latency of REM dreams, as well as a lower proportion of slow-wave sleep than people without this condition. Also, deficit sleep spindles in schizophrenia people could be an endophenotype of this disorder.

In a study of rest activity, a cohort of patients with schizophrenia matched with healthy subjects, Wulff and coworkers [69] showed that there is clear evidence of sleep and circadian rhythm disruption in schizophrenia patients, over half the cohort, tested showed severe circadian misalignment, including the melatonin cycle.

Compared rest-activity patterns in a cohort of patients with schizophrenia with matched healthy unemployed controls showed significant sleep/circadian disruption in all 20 patients studied. Of these, half showed severe circadian misalignment in sleep-wake and melatonin cycles, demonstrating that abnormal entrainment of the circadian system is prevalent in schizophrenia.

Although the results are not conclusive yet and more research is needed in this regard, chronotherapy is a relatively recent proposal to optimize pharmacological treatments based on the biological clock to maximize the pharmacological response or produce adjustments when there is a desynchronization in the biological functions that are affected in illnesses, including mental disorders. Therefore, it is necessary to adequately coordinate medication administration schedules to obtain the maximum pharmacological results and increase treatment adherence.

### **7. Conclusion**

Evidence presented in this chapter indicates that neuroplasticity is modulated by an external *Zeitgeber*, the photoperiod, and synchronized by melatonin which is an endogenous synthesized molecule during the dark phase. Notably, functions such as neurogenesis, dendrite, axonal, and synaptogenesis are upregulated during the dark phase of the photoperiod and by 100 nanomolar concentrations of melatonin, which is the concentration reached in the cerebrospinal fluid during the dark phase of the photoperiod. Nowadays, neuroplasticity is considered an important tool for the treatment of neuropsychiatric diseases to repair damaged circuitry in the brain of these subjects. Therefore, since melatonin can increase all the stages of neuroplasticity at pharmacological concentrations, it is possible for the use of this indolamine as an adjuvant for the treatment of neuropsychiatric diseases where chrono-disruption is one of the main symptoms evidenced by alterations in the sleep/wake cycle, the motor activity and the pineal secretion of melatonin among other rhythms important for the good quality of life.

### **Acknowledgements**

Funded by Consejo Nacional de Ciencia y Tecnología (CONACyT) Grant No. 290526 to GBK. CONACyT had no further role in review design, in the collection, analysis and interpretation of data, neither in the writing of the report, nor in the decision to submit the paper for publication.

*Circadian Modulation of Neurodevelopment in the Adult Human Brain: Importance of Melatonin DOI: http://dx.doi.org/10.5772/intechopen.102859*
