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The Implications of Chronobiology for Psychiatry 56 CASPONSOREDT BY CMEE LLC • PSYCHIATRICG TIMESO • OCTOBER 2011RY The Implications of Chronobiology for Psychiatry by Anna Wirz-Justice, PhD vides the temporal organization necessary for uli that act on biological rhythms (eg, light) or optimum behavior—the right function at the right direct manipulations of sleep to treat psychiatric hronobiology—the science of daily time. disorders. (circadian), monthly, tidal, and season- The field of chronobiology is exemplary in Biological rhythms are not new to psychiatry. al rhythms—has undergone exponen- its bench-to-bedside translational approach. The 19th century German psychiatrists, in par- C tial growth in the past decade, with Groundbreaking research into the genetic clock- ticular, collected enormous numbers of case stud- major discoveries at the molecular and neuroana- work covers all phyla, from cyanobacteria to the ies that demonstrated periodicity in psycho- tomic level. The most ubiquitous rhythms are weed Arabidopsis, utilizing the rich mutant pos- pathology. In 1960, Menninger-Lerchenthal1 those linked to the 24-hour day-night cycle. sibilities in fruit flies and mice and scanning for proposed a hypothalamic neuroendocrine mecha- These circadian rhythms manifest themselves at polymorphisms of clock genes in clinical disor- nism to underlie the astonishing precision of every hierarchical level: from the general popula- ders. On the basis of this research, novel, non- daily and seasonal rhythms in clinical symptoms tion (eg, more traffic accidents late at night) to the pharmacological treatments for chronobiological and behavior—a very prescient prediction that individual (eg, the sleep-wake cycle), in each disorders have been developed. Chronothera- has been characterized in detail by modern re- organ, cell, and molecule. Rhythmic change pro- peutics is defined as controlled exposure to stim- search. CREDITS: 1.5 LEARNING OBJECTIVES claim only the credit commensurate with the extent of their After completing this activity, participants should be able to: participation in the activity. RELEASE DATE: October 15, 2011 • Better appreciate what constitutes chronobiology Physician assistants, nurse practitioners, and nurses EXPIRATION DATE: October 15, 2012 • Understand how the circadian system works, including may participate in this educational activity and earn a the related neurobiology (eg, suprachiasmatic nuclei, FACULTY certificate of completion, as AAPA, AANP, and ANCC zeitgeber, circadian oscillators) and its involvement in accept AMA PRA Category 1 Credits™ through their Anna Wirz-Justice, PhD, Emeritus Professor of Psychiatric sleep regulation reciprocity agreements. Neurobiology, Centre for Chronobiology, Psychiatric • Recognize the importance of the relationship between Clinics, University of Basel, Switzerland biological rhythms, sleep, and affective disorders DISCLAIMER The opinions and recommendations expressed by faculty DISCLOSURES • Implement treatment options and strategies for affective disorders, in particular light therapy and wake therapy and other experts whose input is included in this activity Dr Wirz-Justice has no relationships to disclose relating to the are their own and do not necessarily reflect the views of COMPLIANCE STATEMENT subject matter of this article. Applicable CME LLC staff have the sponsors or supporter. Discussions concerning drugs, This activity is an independent educational activity under no relationships to disclose relating to the subject matter of dosages, and procedures may reflect the clinical the direction of CME LLC. The activity was planned and this activity. experience of the faculty or may be derived from the implemented in accordance with the Essential Areas and This activity has been independently reviewed for balance. professional literature or other sources and may suggest policies of the Accreditation Council for Continuing uses that are investigational in nature and not approved TARGET AUDIENCE Medical Education (ACCME), the Ethical Opinions/ labeling or indications. Activity participants are This continuing medical education activity is intended for Guidelines of the AMA, the FDA, the OIG, and the PhRMA encouraged to refer to primary references or full psychiatrists, psychologists, primary care physicians, Code on Interactions with Healthcare Professionals, thus prescribing information resources. nurse practitioners, and other health care professionals assuring the highest degree of independence, fair who seek to improve their care for patients with mental balance, scientific rigor, and objectivity. METHOD OF PARTICIPATION health disorders. Participants are required to read the entire article and to ACCREDITATION STATEMENT complete the posttest and evaluation to earn a certificate of GOAL STATEMENT This activity has been planned and implemented in accor- completion. A passing score of 80% or better earns the This activity provides information that will enable dance with the Essential Areas and policies of the ACCME participant 1.5 AMA PRA Category 1 Credits™. A fee of participants to treat depressive patients with novel through the joint sponsorship of CME LLC and Psychiatric $15 will be charged. Participants are allowed 2 attempts nonpharmacological chronotherapeutic measures. Times. CME LLC is accredited by the ACCME to provide to successfully complete the activity. continuing medical education for physicians. ESTIMATED TIME TO COMPLETE SPONSORED BY The activity in its entirety should take approximately 90 CREDIT DESIGNATION minutes to complete. CME LLC designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should To earn credit online, go to www.PsychiatricTimes.com/cme. OCTOBER 2011 PSYCHIATRIC TIMES 57 CATEGORY1 The circadian system sitive to blue light.7 One important pathway from chomotor speed, cognitive flexibility, and execu- A master pacemaker, or biological clock, resides the SCN leads to the pineal gland, where the hor- tive function (Figure 3), there was a high correla- in the hypothalamic suprachiasmatic nuclei mone melatonin is synthesized at night. Melato- tion between the degree of consolidated circadian (SCN) and generates circadian rhythms in the en- nin secretion is suppressed by light and feeds rhythms (as measured by relative amplitude of tire organism (Figure 1).2 One of the most obvi- back onto melatonin receptors in the SCN.6 the day/night difference), and cognitive function- ous outputs of the biological clock is the sleep- The primary characteristic of a zeitgeber is ing in these patients with schizophrenia. wake cycle. The timing and architecture of sleep that it can shift the phase of circadian rhythms in Nonphotic zeitgebers, such as physical exer- is regulated by interactions between the circadian different directions, depending on time of day. cise, sleep, and food, also contribute to entrain- clock and a homeostatic process of rising sleep Both light and melatonin are zeitgebers. Morning ment of peripheral clocks. Social zeitgebers, such pressure that depends on the duration of prior light and evening melatonin administration ad- as jobs and social demands, act indirectly on the wakefulness and dissipates during sleep.3 vance the clock to earlier; evening light and SCN, since they determine the timing of meals, A clock gene network in the SCN encodes for morning melatonin administration delay the sleep, physical activity, and outdoor and indoor endogenous periodicity, usually slightly longer clock to later (thus their use for combating jet light exposure, and they have been construed as a than 24 hours, and requires daily synchronization lag). therapeutic option.10 to the external day-night cycle.2 Circadian regula- tion interacts with, and is determined by, neu- rotransmitter function; for example, the SCN re- ceives serotonergic input from the raphe nuclei Wake therapy is the most rapid that may modulate the response of the SCN to light and nonphotic stimuli. CNS serotonin turn- antidepressant known: approximately 60% over undergoes marked circadian and seasonal rhythmicity and is rapidly stimulated by light ex- posure.4 Direct serotonergic manipulation by an of patients respond with marked SSRI can reset the clock in vitro.5 The major synchronizing agent, or “zeitge- improvement within hours, a finding that ber,” for the SCN is light, transmitted directly from the retina via the retinohypothalamic tract.6 The photic input to the SCN is nonvisual. Thus, has been replicated in thousands of cases. classic cone and rod photoreceptors, important for vision—color, movement, shape, edges— play a secondary role to novel circadian photore- Even though the SCN is the so-called master Biological rhythms and ceptors located in retinal ganglion cells. These clock, circadian oscillators are found in every affective disorders contain the photopigment melanopsin that is sen- organ and in every cell (Figure 1).2 Moreover, Periodicity is most striking in affective disorders: each organ has its own appropriate zeitgeber. illness recurrence ranges from seasonal depres- Figure The human Light is the major zeitgeber for the SCN, but it sion to rapid-cycling manic-depressive episodes. does not affect the clock in the liver—the zeitge- The symptoms of diurnal variation of mood and 1 circadian system ber for the liver is food. Adequate temporal orga- early morning awakening suggest rhythmic dys- nization is important for coordinating functions function. Circadian rhythms, including hormonal that need to occur together and for separating secretion, neurotransmitter
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