Insomnia: Pathophysiology and implications for treatment

Insomnia: Pathophysiology and implications for treatment

ARTICLE IN PRESS Sleep Medicine Reviews (2007) 11, 71–79 www.elsevier.com/locate/smrv THEORETICAL REVIEW Insomnia: Pathophysiology and implications...

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ARTICLE IN PRESS Sleep Medicine Reviews (2007) 11, 71–79

www.elsevier.com/locate/smrv

THEORETICAL REVIEW

Insomnia: Pathophysiology and implications for treatment Thomas Roth, Timothy Roehrs, Ron Pies Sleep Disorders and Research Center, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA

KEYWORDS Insomnia; HPA axis; Hyperarousal

Summary Interest in developing a greater understanding of the pathophysiogical mechanisms underlying primary insomnia has increased. Recent evidence indicates that there may be some neuroendocrine and clinical similarities between primary insomnia and major depressive disorder, that abnormal corticotropin releasing factor (CRF) activity occurs in major depression, and that CRF hyperactivity appears to mediate the hyperarousal seen in primary insomnia. These findings all point to the possibility of hypothalamic–pituitary–adrenal (HPA) axis and CRF overactivity in both disorders. More recent findings have strengthened the evidence that primary insomnia may be linked with mood disorders and is associated with HPA axis overactivity and excess secretion of CRF, adrenocorticotropin releasing hormone, and cortisol. These insights have implications for managing chronic primary insomnia, such as use of antiglucocorticoid agents. & 2006 Elsevier Ltd. All rights reserved.

Introduction Despite more than 30 years of research into the nature of insomnia, our understanding of its basic pathophysiology has lagged behind that of other sleep disorders, such as narcolepsy and sleep apnea.1 In part, this discrepancy stems from the heterogeneous nature of insomnia, which is both a primary condition with a pathophysiology, and a condition co-existing with numerous medical and psychiatric disorders. The course of the co-existing Corresponding author. Tel.: +1 313 916 5171;

fax: +1 313 916 5167. E-mail address: [email protected] (T. Roth).

medical or psychiatric disease may be modulated by the course of the sleep disturbance.2–4 In addition, insomnia has been found to precede the onset of major depression.5–7 The Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) defines the term primary insomnia as difficulty initiating or maintaining sleep, or non-restorative sleep, that results in clinically significant distress or impairment in social, occupational, or other important areas of functioning (American Psychiatric Association, 2000). DSM-IV-TR specifies that primary insomnia cannot occur exclusively during the course of narcolepsy, breathing-related sleep disorder, circadian rhythm disorder, or a parasomnia,

1087-0792/$ - see front matter & 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.smrv.2006.06.002

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T. Roth et al. Table 1

DSM-IV-TR diagnostic criteria for primary insomnia.

(A) The predominant complaint is difficulty initiating or maintaining sleep, or non-restorative sleep, for at least 1 month. (B) The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. (C) The sleep disturbance does not occur exclusively during the course of Narcolepsy, Breathing-related Sleep Disorder, Circadian Rhythm Sleep Disorder, or a Parasomnia. (D) The disturbance does not occur exclusively during the course of another mental disorder (e.g., Major Depressive Disorder, Generalized Anxiety Disorder). (E) The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition. Reprinted with permission from American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision. Washington, DC: 2000; 604.

or during the course of another mental disorder (e.g., major depression), and it cannot be due to a general medical condition or substance use disorder (Table 1). Primary insomnia has been conceptualized as sleep disturbance not arising from a medical, psychiatric, circadian, behavioral, or pharmacologic cause, or from a primary sleep disorder.8 The DSM-IV-TR criteria inform clinicians what primary insomnia is not, but do not define what it is, beyond a complaint of difficulty initiating or sustaining restful sleep lasting more than a month. It is unclear what pathophysiologic mechanisms drive primary insomnia and what implications these have for insomnia morbidity and treatment. This paper provides a brief overview of the epidemiology, morbidity, and risk factors associated with insomnia, and will also briefly highlight the specific research still needed in each of these areas. Next the paper discusses the question of primary insomnia etiology, focusing on the critical role of hyperarousal and abnormal corticosteroid regulation—a pathophysiology that may be the unifying link between primary insomnia, depression, and perhaps other disorders. Finally, the implications of this new research will be explored as it relates to insomnia pharmacotherapy.

Insomnia: epidemiology, morbidity, and risk factors Epidemiology Prevalence estimates for insomnia range from 10% to 50% of the adult population. Summaries of the epidemiologic evidence conclude that 10–13% of the adult population suffers from chronic insomnia, and an additional 25–35% has transient or occasional insomnia.9,10 It is estimated that 75% of

population-based chronic insomnia is associated with psychiatric and medical diseases, or with primary sleep disorders and primary insomnia accounts for approximately 25% of all chronic insomnia.11 Thus, primary insomnia is estimated to occur in 1–2% of the general population,11 while it accounts for as much as 25% of all chronic insomnia cases.8 Insomnia generally does not resolve spontaneously. Half the adult population experience trouble sleeping at some time in their life, and approximately one-third report that the problem has lasted more than a year12. For those with insomnia characterized by poor sleep at least 3 nights/week and subjective daytime impairment, the problem persists from 2 to 6 years;12 durations over 2 years were typical for more than half of those reporting moderate to severe symptoms.12 In retrospective reports, individuals with severe symptoms report having sleep difficulties for at least 1 year, with 40% suffering for more than 5 years. In various longitudinal reports, up to 80% of individuals with severe insomnia experienced no remission over time.70

Morbidity Studies using standardized assessment instruments show that insomnia patients consistently report significantly decreased daytime functioning, with deficits across a large number of emotional, social, and physical domains and with a severity similar to other chronic diseases.13–15 They describe difficulties with memory, concentration, attention, and reasoning.16 Objective measurements, as described below, have failed to confirm these patient reports and demonstrate variable or no impairment with objective assessment. Patients with chronic insomnia generally show signs of hyperarousal, with normal to prolonged

ARTICLE IN PRESS Insomnia: Pathophysiology and implications for treatment daytime sleep latencies on multiple sleep latency tests compared with normal sleeping control subjects.17–19 Patients with insomnia also perform as well as normal sleepers on a wide variety of tasks. In small cohort studies, no difference was noted between these groups in cognitive, psychomotor, or memory tasks. Specifically, results for insomniacs and controls were similar on digit-symbol substitution tests, pegboard testing, card sorting, addition, logical reasoning, divided attention, and visual vigilance tasks.20 What does appear to differ between insomniacs and aged-match normals is the ability to accurately self-rate performance. Good sleepers are better judges of how well they have or will perform on tasks following a good or poor night’s sleep, while people with insomnia typically overestimate their impairment and underestimate their performance.21 Insomnia is an important covariate of poor physical and emotional health. For example, comorbid sleep disturbance in dementia or Parkinson’s disease is problematic for both the patient and the caregiver. Conversely, it is possible that appropriate treatment of sleep disturbances in these patients may aid in delaying institutionalization, may help reduce nursing care costs, and may improve quality of life for both patient and caregiver.22 With respect to psychiatric disorders, a large body of data suggests that sleep disturbance and depression may be associated,5,6 and insomnia associated with major depression increases the risk of adverse outcomes, such as depressive relapse or suicide.23–25 Beyond the individual sufferer, chronic insomnia adversely affects society in both direct and indirect ways. The estimated total direct cost attributable to insomnia in the United States was approximately $14 billion in 1995.26 Healthcare services for insomnia constituted approximately $12 billion of the direct costs; the use of sleep-promoting agents accounted for the remaining $2 billion.26 Insomnia is linked to increased rates of hospitalization, healthcare use, and absenteeism at work,24 as well as increased healthcare costs.27 The cost of insomnia in terms of lost productivity and accidents was estimated as $80 billion.28

Risk factors for insomnia Increasing age, female gender, medical and psychiatric disease, and shift work all independently predict risk for developing chronic insomnia in epidemiological studies as summarized by Roth and Roehrs.8 In one large-scale population study (N ¼ 9851), women were 1.6 times more likely

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to suffer from insomnia than men. Although specific risk factors differed somewhat by gender, that is, risk factors in women included being a housewife and being divorced, while in men they included having less education and being retired. Prevalence increased with age in both sexes.29 Insomnia is more prevalent in older populations, and several authors have noted that the elderly are prone to a number of concomitant risk factors, such as increased prescription drug use, somatic disorders, neurological decline, reduced exposure to outdoor light, and polyphasic sleep-wake patterns.30 Lack of physical activity also may play a role in the age-related increase in insomnia prevalence.31 Longitudinal data suggest that reduced physical activity, independent of social engagement or interaction, represents a strong risk factor for development of insomnia in elderly individuals.31 In addition to female gender and advancing age, psychosocial factors, such as family quarrels and illness, and excessive home or workplace demands independently predict insomnia.32 Finally, poor physical health was associated with insomnia in several epidemiological studies.33,34

Hyperarousal in insomnia Chronic primary insomnia has been characterized as a state of hyperarousal. The hyperarousal can be seen in various signs of peripheral and central activation (see Table 2) and with various symptom and behavioral manifestations such as excessive worry and reactivity.10 An underlying pathophysiology for the hyperarousal, as described below, has been hypothesized. The hyperaroused state of insomnia differs from the daytime sleepiness and impaired performance that results from sleep restriction, fragmentation, and deprivation in non-insomniacs. In a previous paper, Richardson and Roth1 proposed a model suggesting that increased corticotropin releasing factor (CRF) activity is responsible for the pathogenesis of primary insomnia. The theory was based on three interwoven strands of evidence: (1) observation of some clinical and neuroendocrine similarities between primary insomnia and major depressive disorder (MDD); (2) abnormal CRF regulation in the pathogenesis of major depression; and (3) findings showing that hyperactivity of CRF neurons (specifically those innervating the locus coeruleus) can account for several clinical features of insomnia, including hyperarousal and sleep disturbance.

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T. Roth et al.

With respect to the third point, hyperarousal appears to distinguish patients with primary insomnia from controls, as evidenced by prolonged sleep latency during the day despite fragmented and decreased nocturnal sleep.18,38 Furthermore, patients with chronic insomnia show a variety of physiologic markers suggesting sympathetic nervous system hyperarousal (Table 2). Also, both animal and human data suggest that the hypothalamic–pituitary–adrenal (HPA) axis is overactive in insomnia.1 For example, patients with primary insomnia show elevated levels of urinary free cortisol, which correlates with the amount of nighttime wakefulness.35 Based on these findings, it is hypothesized that (1) CRF hyperactivity, arising through either a genetic diathesis or early stressors, leads to an exaggerated CRF response to stress; (2) subsequent re-exposure to stress leads to amplification of the abnormal stress response, perhaps via pathological changes in the hippocampus; and (3) this sequence leads to marked difficulty sleeping when stressed, exaggerated and prolonged sleep disturbance following stress, and ultimately to chronic primary insomnia.1

first finding demonstrated that in normal male subjects infusions of either cortisol or adrenocorticotropic hormone (ACTH) reduced rapid eye movement (REM) sleep compared with placebo infusions.43 The second result suggested that intravenous CRF may lead to blunted growthhormone secretion and reduced slow-wave sleep in normal men.44 Importantly, these effects resembled effects seen among hypercortisolemic depressives; setting the stage for subsequent hypotheses linking primary insomnia with mood disorders.44 These findings in healthy normals indicate that experimentally induced elevations in ACTH and CRF are disruptive of sleep. In patients with primary insomnia elevated HPA neuroendocrine levels have been found. A recent investigation studied plasma cortisol levels in seven men (age 40.078.2 years) with severe, chronic primary insomnia compared with seven healthy male controls (age 35.9711.2 years).45 The patients with insomnia had significantly increased evening and nocturnal plasma cortisol concentrations and reduced duration of the quiescent period of circadian cortisol secretion compared with controls. The authors viewed these findings as ‘‘ya neuroendocrine counterpart of the postulated psychophysiological hyperarousal’’ of primary insomnia. The increased plasma cortisol in these insomniac patients was perpetuated by diminished negative feedback inhibition of cortisol on CRF, a finding also seen in elderly subjects and patients with depression.46,47 The authors further proposed that the reduced negative feedback may lead to chronically increased CRF levels, thus inducing and maintaining elevated cortisol levels in people with insomnia.45 Chronic insomnia is also associated with increased plasma levels of ACTH and cortisol.48 In fact, higher cortisol levels were correlated with reduced sleep efficiency.48 These results are consistent with insomnia being a central nervous system hyperarousal disorder rather than simply a disorder of sleep loss. Thus, the goal of insomnia treatment should not only be to improve nighttime sleep, but also to decrease the overall level of physiologic and emotional arousal.48 These data indicate that basal levels of ACTH and cortisol are elevated in insomniacs relative to normals.

Pathophysiology of the HPA axis: findings in primary insomnia

Insomnia, hyperarousal, and mood disorders

Two findings in healthy, normals suggest a linkage between primary insomnia and mood disorders. The

The most common comorbidity associated with chronic insomnia is psychiatric disorder, specifically

Table 2 Physiologic evidence of sympathetic nervous system hyperarousal in insomnia. Parameter

Recent studies

Elevated levels of circulating catecholamines Increased basal metabolic rate Increased body temperature Altered heart rate variability/reduced RSA Elevated beta EEG frequency/cortical activation on EEG

Vgontzas et al.35

Bonnet and Arand36 Lushington et al.37 Lichstein et al.38 and Bonnet and Arand39 Nofzinger et al.40 Perlis et al.41 Nofzinger42

Abbrevations: EEG ¼ electroencephalograph; RSA ¼ respiratory sinus arrhythmia.  Reduced RSA indicates reduced parasympathetic tone, associated with increased stress.

ARTICLE IN PRESS Insomnia: Pathophysiology and implications for treatment depression.8 Recent epidemiological studies provided strong evidence that insomnia is an independent predictor of incident depression.5,6 The occurrence of insomnia symptoms for a period of more than 2 weeks is predictive of increased risk for depression over the subsequent 1–3 years.49 The question remains, however, whether insomnia causes depression or depression causes insomnia, or if either condition may cause the other. It is also likely that an individual is vulnerable to both insomnia and depression because of some similarities in pathology. Specifically, the overactivation of the HPA axis appears to underlie both conditions.8 The insomnia literature tends to regard depression as a homogeneous entity. Yet, the history of psychiatry is replete with attempts to delineate subtypes of depression, for example, unipolar/ bipolar; endogenous/reactive; melancholic/nonmelancholic; psychotic/non-psychotic; and typical/atypical. There is no a priori reason these clinical syndromes, to the extent that they represent discrete nosological entities, should have identical pathophysiologies, much less identical alterations in HPA function. Yet the study of HPA dysfunction in the major subtypes of depression has been quite limited. A recent review noted that psychotic depression is specifically associated with HPA dysfunction.50 In particular, patients with psychotic depression tend to show high rates of non-suppression on the dexamethasone suppression test (DST), markedly elevated post-dexamethasone cortisol levels, and high levels of 24-h urinary free cortisol. These findings do not appear to result merely from high levels of depression or from the presence of endogenous features, such as absence of a precipitant.51,52 In contrast, the rates of DST non-suppression in dysthymic disorder have generally been similar to those observed in control subjects,50 though not all studies support this conclusion.53 Previous research indicated that melancholic depression is a syndrome in which the stress response is hyperactive; patients are anxious, anorectic, unresponsive to psychosocial stimuli, more depressed in the morning, and exhibit insomnia symptoms. Melancholic patients tend to show an overactive CRF system and decreased growth hormone. In contrast, patients with atypical depression tend to be lethargic, fatigued, hyperphagic, reactive to the environment, more depressed in the evening, and exhibit hypersomnia.54,55 A recent study assessed HPA function in these two types of depression, and found both phenomenological and neuroendocrine

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distinctions. Atypical depression was generally characterized by down-regulated HPA axis and CRF deficiency.56 In effect, melancholic depression can be viewed as a prolonged and intensified stress response that is not susceptible to the usual counter-regulatory restraints. Atypical depression, on the other hand, can be viewed as a state of stress system hypoactivity that is too easily susceptible to counter-regulatory restraints. Interestingly, reduced cortisol levels and down-regulation of the HPA axis also exist in posttraumatic stress disorder.57

HPA hyperfunction: treatment implications for depression and insomnia As HPA overactivity is a common factor in primary insomnia and some subtypes of depression, it seems reasonable to ask whether both disorders might respond to the same therapeutic intervention. Two important questions related to these issues come to mind. First, would strategies that reduce HPA activity and/or glucocorticoid effects ameliorate both major depression and primary insomnia? Second, as HPA overactivity is an integral feature of insomnia, how effective are the currently available pharmacologic and behavioral treatments at reducing this overactivity? To answer the first question, an examination of the growing body of literature on the use of antiglucocorticoid agents in the treatment of psychotic depression is warranted. Mifepristone (RU-486), a potent glucocorticoid receptor antagonist, rapidly reversed psychotic symptoms in a study of patients with delusional depression.58 Other antiglucocorticoid agents, such as aminoglutethimide, metyrapone, and ketoconazole, have shown some efficacy in heterogeneous depressed populations.50 For example, a double-blind study of depressed patients found that ketoconazole was superior to placebo.59 This was true, however, only in the subset of patients with hypercortisolemia. The relatively rapid onset of glucocorticoid receptor antagonists (1 week or less) is an advantage compared with the more gradual improvement seen with antidepressant/antipsychotic combinations.60 Although the literature describing the use of antiglucocorticoid strategies in bipolar disorder is limited, successful treatment of a patient with refractory bipolar II depression was achieved through addition of ketoconazole to a regimen of lithium and phenelzine.61 Interestingly, improvement was correlated

ARTICLE IN PRESS 76 with decreases in urinary free cortisol levels, and discontinuation of ketoconazole was associated with relapse. To our knowledge, no published placebo-controlled studies exist that examine the sleep efficacy of antiglucocorticoid agents in depressed patients. However, one study assessed 29 patients diagnosed with treatment-resistant major depression, of whom 17 completed treatment with one or more antiglucocorticoid agents (aminoglutethimide, ketoconazole, or either of these plus metyrapone).62 Eight completers were psychotic; nine were nonpsychotic. Improvement was noted on overall Hamilton Depression Scale scores, including improvement of the three sleep-related items. Somewhat surprisingly, nonpsychotic patients improved more than psychotic patients. A follow-up study described the neuroendocrine responses in this same cohort.63 Improvement in depression was not consistently correlated with changes in serum cortisol, but was associated with declines in levels of dehydroepiandrosterone. In summary, while the therapeutic effects of antiglucocorticoid agents in depression is not very strong and have not been tested in insomnia these do suggest that strategies to reduce HPA activity and/or glucocorticoid warrant study in insomnia. The answer to the second question is simple; there are no published, placebo-controlled studies examining HPA axis and hypercortisolemia in people with well-defined chronic or primary insomnia. However, the effects of loprazolam (a benzodiazepine not available in the US) (1 mg) and triazolam (0.5 mg) were studied in nine poor sleepers over a 3-week period.64 Total overnight urinary cortisol was lower during active treatment, and cortisol levels significantly rebounded to above-baseline upon drug discontinuation. Similarly, a placebocontrolled study found that temazepam (20 mg) significantly inhibited peak serum cortisol levels and ACTH after CRF administration in healthy volunteers, but not in patients with Cushing’s syndrome.65 Although there are no published data examining the effect of non-benzodiazepine hypnotics on HPA function in insomnia, there are some related data. Zolpidem (10 mg) use did not appear to affect plasma cortisol levels in a study of hormonal response to exercise after partial sleep deprivation.66 Similarly, the popular over-the-counter agent melatonin does not appear to significantly affect glucocorticoid secretion.67 While the sedating tricyclic antidepressants are not approved for the treatment of insomnia, several studies using these agents have shown

T. Roth et al. effects on the HPA axis. The effects of oral and intravenous doxepin (25 mg) on nocturnal sleep and plasma cortisol secretion were studied in 10 patients with chronic primary insomnia.68 Both doxepin formulations improved sleep and reduced mean cortisol levels from 9.071.7 to 7.571.6 mcg/l (single IV infusion) and 7.072.0 mcg/l (oral doxepin for 3 weeks). The authors concluded that normalization of HPA axis function partially mediated the sleep-improving effects of doxepin. Similarly, another study hypothesized that the atypical tricyclic trimipramine may be of value in primary insomnia because of its ability to inhibit nocturnal cortisol secretion.69 Clearly, more controlled studies of hypnotic agents as well as behavioral treatments are necessary to determine their effects on HPA function.

Conclusion Chronic insomnia is a highly prevalent, yet incompletely understood condition. People with insomnia report significantly impaired daytime function across a number of emotional, social, and physical domains. These deficits reported by insomnia sufferers are additionally associated with enormous personal and societal costs. Several studies show that insomnia is an important predictor of poor physical and emotional health and that insomnia may independently alter the course of affective disorders. Recent evidence suggests that insomnia and some types of depression may have common pathological processes that make an individual vulnerable to both conditions. Specifically, overactivation of the HPA axis appears to underlie both insomnia and depression. If confirmed in large, well-controlled studies of primary insomnia, these findings may have important therapeutic implications. We may find that some currently available hypnotic agents are better able to reduce inappropriate HPA activation and thus may be more effective than others for insomnia and comorbid depression. Since no randomized, controlled, headto-head studies of hypnotic agents and their effects on HPA overactivity/hyperarousal exist, this should be a priority for future research. It remains to be seen whether benzodiazepine receptor agonists reduce HPA overactivation in insomnia. If so, such agents may play a more important role than previously thought in the management of both primary insomnia and insomnia comorbid with depression.

ARTICLE IN PRESS Insomnia: Pathophysiology and implications for treatment

Practice points 1. In managing insomnia it is important to recognize that insomnia is not merely a symptom of another disorder but a disorder of hyperarousal. Hence, treatment should be directed at the insomnia AS WELL as the comorbid disorder. 2. Patients with insomnia are at increased risk of developing affective disorders. Hence, monitoring depressive symptoms in insomnia patients may help identify depression early in its evolution. 3. As hyperarousal may precede the full blown manifestation of insomnia, treating transient sleep problems may help stop the spiral to chronic insomnia.

Research agenda 1. Treatment studies in insomnia need to focus not only on measures of sleep induction and maintenance but also on measures of physiological function during sleep especially those impacted by the HPA system. 2. Studies are needed to determine the impact of insomnia therapy on the efficacy and timing of an antidepressant response. Can improving sleep augment antidepressant response or even prevent depressive relapse in patients with insomnia and comorbid depression? 3. Research is needed to determine if hyperarousal is unique to primary insomnia or is common to all insomnias including those that are co-morbid with another medical or psychiatric disorder.

Acknowledgements The authors would like to acknowledge that they received compensation from Sepracor for the services they provided in support of the development of this manuscript. The authors wish to acknowledge H. Heith Durrence for his assistance in preparing this manuscript.

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