Sleep and Circadian Medicine Time of Day in the Neurologic Clinic

INTRODUCTION

Rhythms in the Brain

Much of human biology is organized around the 24-hour day. Exercise, eating, digestion, and sleep occur at particular times, requiring highly ordered physiology. To achieve this, “clocks” throughout the body synchronize with 24-hour cycles in light, activity, and other salient cues to enable appropriately aligned and adaptive biological functions.

The central clock in the suprachiasmatic nucleus (SCN) of the hypothalamus receives light input from the retina and transmits time-of-day cues to cellular clocks throughout the rest of the brain and body.¹ In this way, the SCN organizes sleep-wake timing and also many aspects of peripheral physiology. At the cellular level, the clock is a feedback loop involving transcriptional activators (BMAL1, CLOCK, NPAS2) and repressors (CRYs and PERs) that generates a 24-hour molecular oscillation and drives waves of expression in thousands of target genes. Half of mammalian protein-coding genes are rhythmically expressed somewhere in the body,^2,3 driving dozens of physiologic functions.⁴

In the brain, key steps in intercellular signaling are time-of-day regulated, from transmitter synthesis^5,6 to degradation^7,8 (Fig. 1A). Other fundamental neural processes, including endocytosis/exocytosis,⁹ waste removal,^10,11 regulation of synaptic strength,^12–14 and permeability of the brain¹⁵ and cerebrospinal fluid¹⁶ to blood, also show daily variation. Therefore, it is not surprising that circadian disruption and neurologic disease often go hand in hand. Most neurodegenerative (eg, Alzheimer, Parkinson, Huntington) and psychiatric diseases (eg, schizophrenia, bipolar disorder, and depression) are accompanied by sleep fragmentation and circadian rhythm disorders (SFCRDs) (as reviewed in Refs.^17–19). Many of these diseases are without effective therapies, increasing in prevalence, and represent enormous unmet medical needs.

Fig. 1.

Daily variation in mammalian neurotransmission. (A) Protein-level 24-hour variation at points in neurotransmitter life cycle: synthesis, packaging/release, reception, reuptake, and catabolism. (B) Standard medical therapies in neuropsychiatric or neurodegenerative disease. Those listed have primary targets whose abundance and/or function were shown to be time dependent somewhere in the mammalian brain (see Table 1). DOPA, dihydroxyphenylalanine; 5-HT, serotonin; 5-HTT, serotonin transporter; AChE, acetylcholinesterase; AChEI, acetylcholinesterase inhibitor; E, epinephrine; MAOA, monoamine oxidase A; MAOI, monoamine oxidase inhibitor; NDRI, norepinephrine and dopamine reuptake inhibitor; NE, norepinephrine; NMDAR, N-methyl-D-aspartate receptor; SNRI, selective serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TH, tyrosine hydroxylase.

Circadian Disruption: Chicken or Egg?

Although the association between neurologic disease and SFCRD is well established,^20–22 the direction of causation remains uncertain. This association was a topic in prior reviews^17,23–25 and continues to pose a challenge in research and patient care.

There is genetic evidence that disruptions to the circadian system may be causal factors in the development of mental illness. Single nucleotide polymorphisms (SNPs) in several human circadian clock genes (CLOCK, BMAL1, NPAS2, PER2, CRY1, TEF, RORB) were associated with incidence and severity of attention-deficit/hyperactivity disorder (ADHD),^26,27 schizophrenia,^28,29 major depressive disorder (MDD),³⁰ bipolar disorder (BP),^31,32 posttraumatic stress disorder,³³ and seasonal-affective disorder.³⁴ All these diseases are complex, multigenic, and distinct from one another. It is noteworthy that so-called circadian entrainment was the top enriched pathway from the small set of 23 clinically relevant genes common to bipolar disorder (BP), schizophrenia, and autism.³⁵

Studies of shift workers provide additional support for a causal link between circadian disruption and mental illnesses. Rotating schedules can lead to the loss of proper temporal coordination between organ systems (ie, circadian misalignment). These people have an increased risk of major depression and other mood disorders,^36,37 likely a consequence of chronic circadian misalignment.

Shift work is also associated with the risk of dementia,^38,39 suggesting that SFCRD may be a primary contributor in neurodegenerative disease as well. In Parkinson and Lewy body disease, rapid eye movement (REM) sleep disorders can manifest decades before the hallmark parkinsonian symptoms.⁴⁰ Early (presymptomatic) SFCRD is also seen in Alzheimer disease (AD) and other neurodegenerative disorders.^41,42 However, experiments in animals showed that early does not necessarily imply causal.^43,44 For example, in a mouse model of AD, the deposition of β-amyloid preceded the onset of sleep abnormalities, and its removal restored normal circadian rhythms.⁴⁴

So, is SFCRD a primary contributor to neurodegenerative disease? It is difficult to say. Two studies linked SNPs in BMAL1 and CLOCK with incidence of AD,^45–47 but the associations were only significant in the subpopulation without the AD-risk allele apolipoprotein E (APOE e4). Although small, these studies suggest that the impact of genetic disruptions to the clock on dementia depends on genetic makeup, as expected in a multifactorial disease. Regardless of underlying cause, abnormal sleep-wake patterns can occur very early in neurodegenerative disease, predict risk of progression (in both animal^48–50 and clinical studies^51,52), and are a major primary complaint from patients seen in neurology clinics.

Where Do Sleep and Circadian Medicine Fit in?

Sleep medicine is an interdisciplinary field based on the diagnosis and treatment of sleep disorders. Therapeutic modalities are broad and may or may not directly address circadian disruption (eg, cognitive behavior therapy for insomnia, medical therapy for symptoms of narcolepsy, or surgical therapy for resistant obstructive sleep apnea). In contrast, circadian medicine is intended to specifically incorporate knowledge of 24-hour biological rhythms to administer more effective treatment.

There are 2 broad approaches for circadian medicine. In the first, the therapeutic target is directly or indirectly the molecular oscillator (discussed later). Light therapy for phase disorders is the hallmark example and is effective at consolidating sleep in dementia.⁵³ In addition to light, drugs (eg, melatonin, zolpidem, tasimelteon) and diet⁵⁴ can also modulate the clock’s amplitude or phase to potentially influence neurologic health.

A second approach in circadian medicine is intended to harmonize treatment with the clock’s rhythmic outputs (discussed later). Timing the administration of a drug to coincide with peak levels of its physiologic target showed clinical benefits in hypertension, hypercholesterolemia, cancer, and several other areas.⁵⁵ Some of the key pathways targeted by standard-of-care drugs in neurology (monoamine and gamma-aminobutyric acid [GABA] neurotransmission, and others) are circadian regulated in the mammalian brain (Fig. 1). Can time of day be leveraged to improve existing treatments?

This article highlights how advances in circadian biology might translate to neurologic patient care. It focuses on neuropsychiatric and neurodegenerative conditions because they (1) share the common feature of SFCRD, and (2) are areas of high unmet medical need.

TREATING THE BRAIN’S CLOCK

Multiple factors lead to SFCRD in patients with dementia, including normal age-related changes, disease pathophysiology, medical comorbidities, side effects from medications, environmental and behavioral factors (eg, inadequate sleep hygiene), or some combination thereof.⁵⁶ Regardless of cause, sleep disorders impair cognition⁵⁷ and are a common cause of institutionalization in patients with dementia.⁵⁸ Consolidating sleep can markedly improve quality of life for the patients and caregivers.⁵⁹ However, clinicians face major challenges in achieving this.

Which Therapy in Which Patients, and When?

Options for treating sleep disruption include drug or light therapy, cognitive-behavioral intervention, and sleep hygiene recommendations. Although each of these affects the circadian clock, the mechanisms (and outcomes) are varied. Problematically, it is not clear which patients are the best candidates for a particular treatment. For example, sedative-hypnotics (ie, benzodiazepines) are widely used to treat sleep onset insomnia.⁶⁰ The Canadian Institute for Health reported 15% benzodiazepine use in the community, increasing to 30% in long-term care facilities⁶¹ where half of the residents aged 80 years or older have dementia.⁶² However, the American Academy of Sleep Medicine (AASM) strongly recommends against sleep-promoting medications to treat sleep-wake rhythm disorder in elderly demented patients⁶³ because of fallrelated injuries⁶⁴ and impaired cognition.⁶⁵ This type of discordance between guidelines and practice is common in sleep medicine, and likely caused by reliance on therapies that are not well supported by large clinical trials and treatment practices that are driven by anecdotal experience.

The use of nonpharmacologic therapies for SFCRD in neurodegenerative disease is also equivocal. The AASM recommends bright light therapy (BLT) for patients with sleep and circadian rhythm disorders,^66,67 which can improve total sleep time in patients with dementia.⁶⁸ However, BLT was not effective for all SFCRD-related symptoms (eg, daytime behavior) in this patient population, and in some cases even exacerbated the symptoms.⁶⁹ How can the inconsistent results be explained?

One possibility is that clinicians have not fully delineated the appropriate timing of treatment. Guidelines for BLT recommend exposure before bedtime (to delay sleep phase) or on awakening (to advance sleep phase).⁶⁷ Critically, in order for BLT to impose strong and properly phased sleep-wake rhythms, it must be administered in narrow windows of circadian clock time, which presents a challenge. For example, in elderly patients with irregular sleep-wake patterns, it is difficult to measure circadian phase using current clinical tools, and therefore difficult to know when BLT is likely to be most effective. This difficulty is further complicated by the SCN becoming less responsive to light stimuli as people age,⁷⁰ emphasizing the importance of proper timing of administration in this population.

Are Some Therapies Worsening Sleep Fragmentation and Circadian Rhythm Disorders?

All of the major psychotherapeutic drug classes can affect sleep architecture (Table 1). For example, treatment-induced insomnia occurred in close to a quarter of patients taking venlafaxine for generalized anxiety disorders.⁷¹ Although the mechanisms are broadly understood (eg, GABA agonists produce sedative effects), the specific effects on the central clock and sleep homeostat are not clear. This uncertainty is important when clinicians are trying to determine the primary and secondary causes of sleep disruption: will this patient require (1) therapy for a primary sleep disorder or (2) changes to medications prescribed for the neurologic disease? It is even more complex in patients that require polydrug therapy.

Table 1.

Effects of common psychotherapeutic drug classes on sleep

Drug Class	Time to Sleep Onset	Sleep Continuity	Slow Wave Sleep	REM Sleep
SSRI	Increased	Decreased	Decreased	Decreased
SNRI	Unchanged	Decreased	Decreased	Decreased
MAOI	Increased	Decreased	Unchanged	Decreased
TCA	Decreased	Increased	Unchanged	Decreased
Trazodone	Decreased	Increased	Increased	Decreased
Antipsychotic	Decreased	Increased	Increased	Decreased
Anxiolytic	Decreased	Increased	Decreased	Decreased

These are general class effects on sleep. Each drug has its own profile.

Abbreviations: MAOI, monoamine oxidase inhibitor; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Adapted from Barkoukis TJ, Avidan AY, service) S (online. Review of Sleep Medicine; with permission.

There is an even broader challenge here: because of the inextricable link between sleep, circadian rhythms, and neural function, it is not always clear what is being treated. Indeed, recent studies suggest that the benefits from some psychotherapeutics (eg, lithium, selective serotonin reuptake inhibitors [SSRIs]) may derive from their effects on the circadian system.⁷² The SSRI citalopram, prescribed for depression and anxiety, acutely increased the sensitivity of the human circadian system to light,⁷³ which may realign the circadian clock and contribute to the drug’s antidepressant effect.

Moving Sleep and Circadian Medicine Forward

Advancements in sleep medicine will depend on improved approaches to (1) measure internal circadian phase, (2) reliably shift circadian phase, (3) strengthen rhythms (ie, amplitude), and (4) understand how SFCRD fits in the context of other diseases (eg, neurodegeneration).

Current methods for determining internalcircadian phase are limited and not used clinically. The gold-standard dim-light melatonin onset (DLMO) assay is based on the circadian clock–regulated evening increase in melatonin levels⁷⁴ and requires the serial sampling of saliva over a 24-hour period. DLMO is time consuming, costly, difficult to standardize, and therefore rarely used to diagnose circadian rhythm disorders. However, lastyear3separatestudiesshowedthefeasibilityofgeneexpressionsignaturesfrom1or 2minimallyinvasive(skinorblood)samplestodetermineaperson’scircadianphase.^75–77 As mentioned, the efficacy of BLT, and potentially all therapies aimed at circadian realignment, depends on the time at which they are administered. A single-sample point-of-use biomarker could therefore have broad diagnostic and therapeutic value.

In addition to light, exercise and feeding can influence the circadian clock. Although not routinely used in practice, exercise can help consolidate sleep in the elderly.^78,79 The type and timing of nutrient intake can also influence circadian clocks in health.^49,80 In order to determine the use for these newer methods to treat SFCRD, larger clinical trials must be completed. New methods for determining circadian time should lead to guidelines for how and when these therapies should be given.

Circadian disruption occurs presymptomatically in AD,⁴¹ as mentioned. Several genes implicated in neurodegenerative (and neuropsychiatric) disease are circadian regulated in mice,² including AD-risk genes β-secretase enzyme 1 (Bace1), Bace2, and APOE in the hippocampus.⁸¹ There is evidence that genetically disrupted clock function can predispose to neurodegeneration.^45,47,82 Can treatment of SFCRD, if early and effective, attenuate or delay AD?

LEVERAGING THE CLOCK’S RHYTHMIC OUTPUT

Timing Treatment to Target Dynamics

Timing treatment to coincide with daily rhythms in clock output is not new. The short-acting statin, simvastatin, is more effective at reducing lipid levels if taken at night, when its target, the rate-limiting enzyme in cholesterol biosynthesis, is at its peak levels.⁸³ However, apart from simvastatin, which has US Food and Drug Administration–labeled time-of-day dosing instructions, circadian time has had very little role in drug development or clinical practice. One reason for this is a lack of understanding about how the circadian clock regulates human physiology and pathophysiology.

However, a series of advances have renewed translational interest. First, circadian regulation is far more pervasive than previously appreciated.^2,4 In a multitissue time-series study in mice, nearly half of the protein-coding genome was circadian regulated somewhere in the body. In the nervous system alone, many basic neural functions have been shown to vary by time of day, as mentioned earlier. Second, genome-wide and systems-wide circadian profiling, historically limited to time-series studies in animal models, is now feasible in humans. A recent study by our group applied a bioinformatic approach called cyclic ordering by periodic structure (CYCLOPS)⁸⁴ to assemble a population-scale atlas of circadian gene expression across 13 different human tissue types.³ The study found ~1000 genes that were rhythmically expressed somewhere in the human body that encode known drug targets.

Are there neurologic therapies whose efficacy or safety might depend on time of dosing?

Time for Targeting Neurotransmission

Monoamine neurotransmission is a major therapeutic target in neurology. Six different serotonin-specific and norepinephrine-specific reuptake inhibitor drugs(indicated for depression, anxiety, and other mood disorders) are among the top 50 most prescribed drugs in the United States.⁸⁵ The first SSRI (fluoxetine/Prozac) was developed in the 1970s⁸⁶ based on evidence of low serotonin and/or norepinephrine levels in depression.⁸⁷ However, although widely prescribed, many patients (most, by some accounts) do not benefit from SSRI therapy.⁸⁸

Accumulating evidence has shown that monoamine transmitters are circadian regulated in brain loci implicated in arousal and mood, as reviewed by Albrecht⁸⁹ (Fig. 1B; Table 2). However, knowledge of these 24-hour dynamics has not factored into clinical practice or drug development. Most SSRI/serotonin norepinephrine reuptake inhibitor formulations are long acting (half-lives >12 hours). Could a short-acting SSRI be used to restore normal 24-hour rhythms in synaptic serotonin? In a mouse model of moodlike behavior, effects of the short-acting SSRI milnacipran were circadian-time dependent.⁹⁰ Future studies should test whether these findings are generalizable. Several other drug classes routinely prescribed in neuropsychiatric and neurodegenerative disease also target time-dependent physiology (see Fig. 1B, Table 2).

Table 2.

Drug classes with time-dependent targets in mammalian brain tissues

Drug Class	Approved Uses	Time-dependent Target (Protein Levels or Function)	Study
SSRI/SNRI	MDD, GAD, SAD, PD, OCD, PMDD, PTSD, bulimia nervosa	5-HTT	Cortex (human)103
NDRI	MDD	DAT	Striatum (mouse)104
Methylphenidate	ADD, narcolepsy	DAT	Striatum (mouse)104
Amphetamine	ADD, narcolepsy	Vesicle recycling machinery	SCN (mouse)9
MAOI	MDD, atypical depression, BP, AD, PD	MAOA	VTA, striatum (mouse)7
AChEI	AD, LBD, PD, MG, SCZ	AChE	Cerebrum, cerebellum, medulla, optic lobe (rat)8
NMDAR antagonist	AD, PD, drug-induced extrapyramidal reactions	NMDARs	SCN, motor cortex (rat)105–106
Benzodiazepine	Insomnia, GAD, PD	GABAA receptors	Cerebral cortex, SCN (hamster)107,108
Biogenic amine	PD	TH	VTA, nucleus accumbens, pineal gland (rat)109,110

References are not exhaustive, and many other known targets of these drugs in neuropsychiatric and neurodegenerative disease were shown to be circadian regulated at the transcriptional level but are not shown here.

Abbreviations: AChE, acetylcholinesterase; AChEI, acetylcholinesterase inhibitor; ADD, attention-deficit disorders; BP, bipolar disorder; DAT, dopamine transporter; GAD, generalized anxiety disorder; 5-HTT, serotonin transporter; LBD, Lewy body dementias; MAOA, monoamine oxidase A; MG, myasthenia gravis; NDRI, norepinephrine and dopamine reuptake inhibitor; NMDAR, N-methyl-D-aspartate receptor; OCD, obsessive-compulsive disorder; PD, panic disorder; PMDD, premenstrual dysphoric disorder; PTSD, posttraumatic stress disorder; SAD, social anxiety disorder; SCZ, schizophrenia; TH, tyrosine hydroxylase; VTA, ventral tegmental area.

Timing Off Targets and Drug Disposition

Alternatively, drug delivery can be timed to coincide with trough levels of an undesired target. The idea here is that adverse drug-related events can be minimized if drug exposure is out of phase with the mechanisms responsible for the adverse events. A study of the influence of dosing time on the effects of the antipsychotic aripiprazole (ARPZ) provides (retrospective) clinical support for this strategy.⁹¹ ARPZ can cause metabolic abnormalities because of off-target antagonism of D2 dopamine receptors (D2Rs) in the pancreas. This antagonism can lead to weight gain, a primary reason for drug discontinuation. The study found that patients who took ARPZ at bedtime had worse metabolic outcomes (poor lipid profiles) compared with morning dosing.⁹¹ The precise mechanism needs to be verified, but it was proposed that pancreatic D2R levels are clock regulated, highest at bedtime, and thus antagonism at this time leads to abnormally increased insulin levels during sleep and consequent metabolic dysregulation.

Another approach is to harmonize the administration of a drug with rhythms in its disposition. Passage through the blood-brain barrier (BBB) is a challenge in drug development; increased doses can deliver more drug to the central nervous system (CNS), but toxicity in the periphery can be dose limiting. Recent work in Drosophila showed a clinically relevant time dependency in BBB permeability,⁹² and evidence suggests a similar mechanism may exist in mammals.¹⁵ Time-dependent BBB permeability could be leveraged to improve therapeutic windows for both CNS-targeting and peripheral nervous system (PNS)–targeting drugs. As an example of the latter, there is a need in peripheral neuropathic pain for drugs with better-tolerated CNS-side-effect profiles.^93,94 Future models will define the scope of potential benefit from harmonizing treatment with BBB permeability.

Very few clinical trials have tested the influence of time of day on CNS-targeting and PNS-targeting agents.^95–98 As the understanding of circadian-expressed targets and physiology in neurologic disease expands, so does the potential for time-stipulated therapy.

CONCLUDING THOUGHTS

The next Decade: Implementing Circadian Medicine

There are unmet needs for more effective therapies in several areas of neurology. Drug development in neurodegenerative disease is marked with pivotal failures,⁹⁹ and controversy surrounds the clinical value of standard-of-care therapies in mental illness.¹⁰⁰ In 2018, soon after unsuccessful attempts to translate molecular targets into efficacious new therapies, Pfizer, the world’s third largest pharmaceutical company, announced plans to abandon all research and development into new neuroscience programs.¹⁰¹

Circadian medicine alone is not a panacea. However, recent advances in the understanding of 24-hour dynamics in physiology and disease create a path for near-term improvements in medicine. This article concludes with 3 specific clinical scenarios of how technologic advances in circadian biology might change patient care in the next decade.

1. By administering a single minimally invasive test for internal time, a clinician diagnoses circadian sleep-wake phase disorders in patients.Biomarkers of internal time based on gene expression signatures can replace DLMO, actigraphy, and unreliable sleep diaries.

2. The neurologist stipulates timing of light therapy, exercise, and feeding to strengthen clock function in a patient with low-amplitude or irregular sleep-wake rhythms, such as in neurodegenerative disorders.The circadian clock in the SCN is maximally sensitive to light-resetting during narrow windows of time (phases). With an accurate test for internal phase, treatment can be delivered at the most appropriate time.

3. Guided by a map of 24-hour dynamics in 5-HT neurotransmission in the brain, researchers initiate a clinical trial to test administration-time dependency of SSRIs in depression. Current maps of circadian dynamics in the human brain remain poorly resolved, but this is likely to change. Genomic repositories are ever growing, some with extensive coverage across brain regions (eg, GTEx¹⁰²). A circadian human brain atlas is foreseeable, and should spark mechanism-based prospective trials in circadian medicine.

KEY POINTS.

• Fundamental neural processes are normally time-of-day regulated, likely explaining the tight link between disrupted circadian rhythms and neurologic disease.

• Time of day is rarely considered for central nervous system–targeting therapies. Circadian medicine incorporates knowledge of 24-hour biological rhythms to administer more effective treatment.

• It is conceivable that (1) determining a patient’s internal circadian time, and (2) prescribing time-stipulated therapy will be common practice in neurology clinics in the coming decade.