Schizophrenia and Its Associated Sleep Disorders

Schizophrenia and Its Associated Sleep Disorders

Chapter 57

KATHLEEN L. BENSON

Epidemiologic Overview

Course and Outcome

Schizophrenia is one of the most devastating and costly mental disorders. Although recent decades have seen advancements in pharmacologic treatment, schizophrenia is still neither preventable nor curable. Schizophrenia has an early onset and patients can anticipate lifelong mental disability and suffering as well as social and economic marginalization. In addition to the immense human cost, schizophrenia is also associated with costs of higher morbidity and mortality rates. Epidemiologic studies of schizophrenia suggest estimates of both prevalence and incidence.1 Mean lifetime prevalence has been estimated at 5.5 cases per 1000 population. Incidence, or annual new case appearance, has been estimated at 15.9 cases per 100,000 population. Incidence estimates broadly taken suggest that schizophrenia is more common in males than females, with a male-to-female ratio of 1.4, or three men for every two women affected. Finally, all-cause mortality estimates suggest that schizophrenics have a two- to threefold increased risk of dying, with a large portion of this increased mortality rate due to suicide.

The course and outcome of schizophrenia as presented here have been synthesized and summarized from a variety of sources.3-6 The onset of schizophrenia typically occurs in the late teens through the middle thirties. The onset may be abrupt or can begin with a slowly developing prodromal phase associated with subtle changes in behavior, mild thought disorder, and social withdrawal. The active phase may ensue with the presentation of positive symptoms such as hallucinations and delusions. Although active symptoms may recur episodically (relapse or acute exacerbation), some amount of psychoticism usually persists during the waning or residual phase of the illness. In the long run, positive symptoms may decline, but negative symptoms such as affective flattening and avolition may increase with the progression of the disease. Although it is commonly assumed that the diagnosis of schizophrenia is synonymous with a negative outcome, for most patients advances in pharmacologic treatment have resulted in fewer and briefer hospitalizations. Overviews of long-term studies4-6 suggest that 18% to 27% of patients may even have a full recovery, while another 20% may remain seriously impaired or require long-term institutionalization. About 50% to 60% may recover to levels at which they can function occupationally and socially but may require outpatient interventions or rehospitalization with any subsequent relapse. Prognostic indicators of better outcome include more acute onset, episodic course, female sex, and lack of family history of schizophrenia. Poorer outcomes have been linked to poor premorbid functioning, baseline negative symptoms, longer duration of no treatment, as well as the presence at onset of neurologic soft signs.4-6

Diagnosis Popular culture frequently misconstrues schizophrenia as “split personality” or “multiple personality.” In actuality, the term schizophrenia represents the splitting or disintegration of normal thought processes such that cognitive impairment or formal thought disorder is believed to be the fundamental or defining symptom of the illness. The American Psychiatric Association is the recognized source of the current clinical criteria used to diagnose schizophrenia. These criteria listed in the Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition (DSM-IV)2 are presented in Box 57-1. The characteristic or defining symptoms of the illness are defined within Criterion A and encompass two main categories: positive symptoms and negative symptoms. Positive symptoms reflect a “psychotic dimension” that includes hallucinations and delusions and a “disorganization dimension” that includes disorganized speech and catatonic behavior. Negative symptoms include affective flattening (“restrictions in the range and intensity of emotional expression”), avolition (“restrictions in the initiation of goaldirected behavior”), and poverty of speech (“restrictions in the fluency and productivity of thought and speech”). Diagnostic Criterion B specifies an overlapping marked deterioration in occupational and social functioning. Schizophrenia is also a diagnosis of exclusion because psychotic disturbances attributable to a variety of medical, psychiatric and substance abuse disorders must be eliminated.

Etiologic Factors Although the etiology of schizophrenia remains unknown, risk factors associated with the development of the disease include both genetic and environmental factors. Schizophrenia is clearly familial. Family, twin, and adoption studies provide strong evidence that schizophrenia is highly heritable. Metaanalysis of twin studies has examined the impact of genes and environment on liability to schizophrenia and estimated genetic heritability to be 81% and shared environmental influences to be 11%.7 Genome-wide association studies suggest that the genetic architecture of schizophrenia may include multiple common variants, each of small effect but acting together to increase the risk of developing the disease; genetic 705

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SECTION 13  •  Therapy of Sleep Disturbances Associated with Psychiatric Disorders

BOX 57-1  DSM-IV Diagnostic Criteria for ­Schizophrenia A. Characteristic symptoms: Two (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated): 1. Delusions 2. Hallucinations 3. Disorganized speech (e.g., frequent derailment or ­incoherence) 4. Grossly disorganized or catatonic behavior 5. Negative symptoms (i.e., affective flattening, alogia, or avolition) note: Only one Criterion A symptom is required if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on the person’s behavior or thoughts, or two or more voices conversing with each other. B. Social/occupational dysfunction: For a significant portion of the time since the onset of the disturbance, one or more major areas of functioning such as work, interpersonal relations, or self-care are markedly below the level achieved before the onset (or when the onset is in childhood or adolescence, failure to achieve expected level of interpersonal, academic, or occupational achievement). C. Duration: Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase symptoms) and may include periods of prodromal or residual symptoms. During these prodromal or residual symptom periods, the signs of the disturbance may be manifested by only negative symptoms or two or more symptoms listed in Criterion A presented in an attenuated form (e.g., odd beliefs, unusual perceptual experiences). D. Schizoaffective disorder/mood disorder exclusion: Schizoaffective disorder and mood disorder with psychotic features have been ruled out because either (1) no major depressive, manic, or mixed episodes have occurred concurrently with the active-phase symptoms; or (2) if mood episodes have occurred during active-phase symptoms, their total duration has been brief relative to the duration of the active and residual symptom periods. E. Substance/general medical condition exclusion: The disturbance is not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition. F. Relationship to a pervasive developmental disorder: If there is a history of autistic disorder or another pervasive developmental disorder, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations are also present for at least 1 month (or less if successfully treated). DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Modified with permission from the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Press, 2000.

architecture may also include highly penetrant, individually rare variants.8 Because the concordance rate for monozygotic twins only approaches 50%, genetic makeup alone is not sufficient for the development of schizophrenia, and nongenetic or sporadic forms of the disorder must exist.

Environmental factors that might play a role in the etiology of schizophrenia include obstetric complications (e.g., premature birth, low birth weight, preeclampsia, and hypoxia) as well as prenatal or gestational exposure to infection. Seasonality of birth, with winter-spring births as a risk factor for schizophrenia, suggests that maternal influenza infection during pregnancy might compromise fetal brain development. Exposure to other microbial infections (e.g., toxoplasmosis and genitourinary diseases) during the gestational period might also compromise neurodevelopment. Although infections might have direct effects on the fetus, it is more likely that the mother’s immune response to the infection (production of serum antibodies and cytokines) might contribute even more directly to developmental brain damage.9 Although family history and environmental factors may be viewed as separate but contributory risk factors, there is strong evidence that genetic risk and prenatal exposure to infection might interact synergistically to elevate the risk of developing schizophrenia.10 Both etiologic factors—genetic risk and environmental exposure to prenatal infection—are consistent with the prevailing model, which views schizophrenia as a neurodevelopmental disorder.11,12

Pathophysiology Although decades of study have revealed a wide range of pathology, there is no specific laboratory finding diagnostic of schizophrenia. Documented abnormalities2,5,6,13,14 include a wide range of neuropsychologic and cognitive deficits in such areas as attention, memory, and psychomotor abilities; neurophysiologic deficits in perception and processing of sensory stimuli such as abnormalities in smooth pursuit eye movements and evoked potentials; brain structural abnormalities such as ventricular enlargement, decreased volumes of gray and white matter, decreased thalamic volume, and focal abnormalities of temporal lobe regions; functional brain abnormalities such as reduced metabolic activity of the prefrontal region (hypofrontality); and widespread abnormalities of neuronal synchrony and circuitry. Documented abnormalities of several neurotransmitter systems have also been published, but investigations of the dopamine (DA) system have been the most extensive. Such investigations were driven by two early observations: first, the potency of antipsychotic (AP) medication correlates with their degree of DA D2 receptor blockade; and second, DA-enhancing drugs such as amphetamines can mimic paranoid schizophrenia. Broadly speaking, the DA hypothesis, as currently conceptualized, attributes schizophrenia to an imbalance between subcortical and cortical DA systems with hyperstimulation of subcortical mesolimbic DA D2 receptors associated with positive symptoms and understimulation of prefrontal cortex DA D1 receptors associated with negative symptoms and cognitive impairment.15

Characteristic Sleep Patterns Abnormal sleep patterns also rank as one of the major pathophysiologic findings in schizophrenia. Typically, marked sleep disruption accompanies the presence of psychotic symptoms with psychotic agitation being associated with periods of total sleeplessness. When psychotic symptoms are less severe, sleep patterns are frequently characterized by a pronounced insomnia—long sleep onset latencies, reduced total sleep time

CHAPTER 57  •  Schizophrenia and Its Associated Sleep Disorders

(TST), and sleep fragmented by episodes of waking. Furthermore, the onset of relapse is often signaled by an increasing insomnia.16 In addition, clinically stable, medicated patients subjectively report sleep disturbance, notably early and middle insomnia.17 Often schizophrenics sleep during the day and remain awake at night; these sleep-wake reversals correlate with subjective complaints of poor sleep quality.18 Poor sleep quality is also related to a higher incidence of nightmares.19 Co-morbid alcohol and substance abuse, not uncommon in schizophrenia, also disturb sleep and may precipitate relapse. In contrast to subjective reports, objective assessments of sleep patterns have been derived from overnight in-laboratory polysomnographic (PSG) study. Although these PSG studies have differed in many respects such as protocol design, patient characteristics (e.g., age, medication status and history, as well as clinical features and history), type of control group, sample size and related statistical power, and algorithms to quantify sleep parameters, they have revealed a wide range of dyssomnias that are consistent with subjective complaints. In the next section, the discussion highlights some of the major PSG findings and refers the reader to more comprehensive reviews.20-22

Measures of Sleep Maintenance



• Poor sleep efficiency is 21defined as a reduction in TST relative to time in bed. sleep onset • Early, middle, and late insomnia is seen, with17,21 insomnia being the most typically reported. • Residual insomnia has been reported17,21in patients maintained on antipsychotic medication. • A resurgence of more severe insomnia is one of the prodromal signs of impeding psychotic relapse and is frequently the result of the discontinuation of antipsychotic medication.16

Abnormalities of NREM Sleep

• Slow wave sleep (SWS) is that portion of non–rapid eye

movement (NREM) sleep characterized by high-amplitude, low-frequency brain waves. SWS deficits are frequently, but not consistently, observed in PSG recordings of schizophrenic patients.22 Although prior exposure to, or withdrawal from, AP medications has been advanced to explain these inconsistencies, SWS deficits have been observed in first episode, AP-naive patients with schizophrenia.23 Studies of total sleep deprivation in healthy subjects have shown that SWS increases in proportion to the amount of prior waking.24 The homeostatic model of SWS was advanced by Feinberg25 in 1974 and maintains that a homeostatic drive builds up during waking and dissipates in SWS across successive NREM sleep cycles. Thus, the SWS homeostatic response might serve a restorative role in the central nervous system. SWS deficits might mean that the integrity of homeostatic regulatory mechanism and its related restorative functions are impaired in schizophrenia. On a theoretical level, SWS deficits may be associated with possible microstructural brain abnormalities. Consistent with schizophrenia as neurodevelopmental disorder, Feinberg26 has proposed that schizophrenia

•  •  •  • 

•  • 

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may result from excess synaptic pruning, that is, a malfunction in the normal maturational process of synaptic elimination during the second decade of life. Excess synaptic pruning would result in less capability for synchronous electroencephalographic (EEG) slow wave activity and a resulting SWS deficit.26

REM Sleep Onset Latency

• Rapid eye movement (REM) sleep onset latency is defined

as the elapsed time between sleep onset and the onset of the first REM sleep period, alternatively viewed as the length of the first NREM sleep period. Significantly shortened REM latencies have been observed in approximately one half of studies comparing the sleep of unmedicated patients with schizophrenia to that of nonpsychiatric and psychiatric control subjects.22 Shortened REM latencies may be the result of an active advance of REM sleep mechanisms.22 Shortened REM latencies may also reflect the passive advance of the first REM sleep period due to SWS deficits in the first NREM period.27

•  •  • 

REM Sleep Time and REM Sleep Eye Movement Activity

• Relative to nonpsychiatric control subjects, REM sleep

time in patients with schizophrenia is neither significantly augmented nor reduced.20,21 Both visual and computer-automated scoring of REM sleep eye movements have shown no differences in REM sleep eye movement density between schizophrenics, nonpsychiatric control subjects, and patients with major depressive disorder, a psychiatric control group.28,29

• 

Pharmacologic Treatment Broadly stated, most patients diagnosed with schizophrenia are treated with one or more AP agents (Box 57-2). An expansive review of these agents is beyond the scope of this chapter; however, the reader is referred to other sources such as Miyamoto and associates30 to explicate their chemical designs and receptor binding profiles, which in turn are associated with differential side effects and clinical outcome.

First-Generation Antipsychotics First-generation antipsychotics (FGAs) came into use in the 1950s with the introduction of chlorpromazine, the first recognized AP agent. This introduction not only shifted treatment regimens from practices such as electroconvulsive therapy and psychosurgery to psychopharmacology, but also made possible the large-scale deinstitutionalization of patients with schizophrenia. Following the release of chlorpromazine, other FGAs were approved for the treatment of schizophrenia. What the FGAs have in common is a high affinity for binding to the DA D2 postsynaptic receptor. DA receptor occupancy by FGAs not only predicts their therapeutic response, but also predicts their adverse effects. These effects include extrapyramidal side effects (EPS) such as akathisia, dystonia,

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SECTION 13  •  Therapy of Sleep Disturbances Associated with Psychiatric Disorders

BOX 57-2  First- and Second-Generation Antipsychotics

Agent

Usual Adult Daily ­Maintenance Dose (mg)

Elimination ­ alf-Life (hr) H

First-Generation Antipsychotics Chlorpromazine (Thorazine) 50-400 Fluphenazine (Prolixin) 1-15 Haloperidol (Haldol) 1-15 Perphenazine (Trilafon) 8-24 Thioridazine (Mellaril) 50-400 Thiothixene (Narvane) 6-30 Trifluoperazine (Stelazine) 4-30

16-30 15-30 12-36 8-20 7-20 10-20 10-20

Second-Generation Antipsychotics Aripiprazole (Abilify) 10-30 Clozapine (Clozaril) 200-600 Olanzapine (Zyprexa) 5-20 Paliperidone (Invega) 6-12 Quetiapine (Seroquel) 150-750 Risperidone (Risperdal) 2-8 Ziprasidone (Geodon) 80-160

75 6-26 21-54 23 6 3-20 4-10

and parkinsonism. A more damaging side effect linked to D2 receptor blockade is tardive dyskinesia (TD). The FGAs may also be associated with a rare but potentially fatal side effect called the neuroleptic malignant syndrome. Furthermore, the FGAs are associated to varying degrees with cholinergic side effects, including sedation, changes in blood pressure and myocardial conduction, sexual dysfunction, and weight gain. These FGA-associated side effects are one of the principal reasons for treatment noncompliance. Finally, the mechanism of action of FGAs needs further explication because the gradual onset of their therapeutic efficacy is not consistent with their rapid blockade of DA D2 receptors.

Second-Generation Antipsychotics The development of the second-generation antipsychotics (SGAs) was motivated by several factors: (a) many patients with chronic schizophrenia had an inadequate response to traditional FGA treatment; (b) although FGAs were successful in treating positive symptoms, they appeared less successful in treating negative symptoms; and (c) FGA-associated side effects such as EPS and TD were, as mentioned previously, a source of noncompliance and difficult management issues. Between 1989 and 2006, seven SGAs were approved by the FDA for the treatment of schizophrenia. In contrast to the FGAs, the SGAs have a broader spectrum of activity with differential effects on DA, serotonin (5-HT), and α-adrenergic, cholinergic, and histaminic receptors, as well as the various subtypes of the aforementioned neurotransmitters. Relative to the FGAs, the SGAs are characterized by weaker affinity for the DA D2 receptor and stronger affinity for 5-HT receptors, particularly the 5-HT2A receptor. For this reason, the SGAs, as a group, are known as “atypical” APs. Although the SGAs appear to have some advantage over the FGAs in the treatment of negative symptoms, cognitive dysfunction, and relapse prevention, the pharmacologic mechanisms responsible for their therapeutic properties have not been definitively identified. Furthermore, the

differential receptor profile of the SGAs relative to the FGAs is associated with another set of serious side effects. Patients taking clozapine may be at risk of agranulocytosis or of seizures at higher doses. More commonly, the SGAs are associated with weight gain, dyslipidemias, and impaired glucose regulation including type 2 diabetes mellitus. Weight gain may be particularly striking and puts the patient at increased risk of developing sleep-related breathing disorders and other obesity-related morbidities. Relative to the FGAs, the incidence of EPS and TD in SGA-treated schizophrenics is reduced, but EPS and TD are not uncommon with SGAs at higher doses. On a final note, there is pressing need for more head-tohead comparisons of FGAs and SGAs in terms of their efficacy, side effects, and cost. The National Institute of Mental Health-sponsored Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study31 compared one FGA to several SGAs in terms of efficacy and side effects. The CATIE study found no significant difference in efficacy between the FGA perphenazine and three SGAs (risperidone, quetiapine, and ziprasidone). Although olanzapine was more effective than perphenazine, it was associated with greater weight gain and metabolic morbidity. At present (circa 2010), SGAs are considered first-line treatment for schizophrenia. Relative to FGAs, they appear to offer better compliance and fewer hospitalizations.

New Directions in Antipsychotic Drug Development Although the last 50 years have witnessed major advances in the pharmacologic treatment of schizophrenia, limitations of efficacy as well as the morbidities of adverse effects have motivated the development of more novel medications covering a wide range of neurobiologic systems. It has been suggested that aripiprazole, although classed with the SGAs in Box 57-2, actually represents the next generation of APs because it is a partial dopamine agonist and, as distinct from the other SGAs, has an affinity for DA D2 receptors far in excess of serotonin receptors. In addition to DA, the role of the excitatory neurotransmitter glutamate in the pathophysiology of schizophrenia is being widely examined.32

Treating Co-Morbid Psychiatric Illness As mentioned previously, SGAs are currently first-line treatment for patients with schizophrenia; however, optimization of therapeutic response may require augmentation with additional AP agents. For many patients with schizophrenia, the efficacy of APs to treat negative symptoms and cognitive dysfunction is limited; consequently, adjunct psychoactive agents may also be prescribed. Also, other psychoactive agents may be enlisted to treat co-morbid psychiatric illness. For example, adjunct mood stabilizers such as valproate may be prescribed for schizophrenics with problems of impulse control and those with schizoaffective disorder. Patients with schizophrenia are also at high risk for suicidal behavior and co-morbid depression; for these patients adjunct antidepressants may be prescribed. Finally, it is not uncommon for schizophrenics to also be enrolled in dual diagnosis programs to treat co-morbid problems of alcohol and substance abuse.

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CHAPTER 57  •  Schizophrenia and Its Associated Sleep Disorders

BOX 57-3  Effect of First- and Second-Generation Antipsychotics on Major Polysomnographic Sleep Variables Agent

SL

TST

SLP%

WASO

#Wakes

S1

S2

SWS

RL

REM

First-Generation Antipsychotics Chlorpromazine Thiothixene or Haloperidol Flupentixol or Haloperidol Haloperidol

↓ ↓↓ ↓ ↓

↑ ↑ ns ↑ ↑

↑↑ ↑ ns

↓ ns ns ns ns

ns ns ns

ns ns ↑ ↑

ns ns ns ns ↓

↑ ↑ ns ns ns

↑ ↑↑ ns ↑

ns ns ns ns

↓

↑↑↑ ↑ ↑ ↑ ns ↑

↑↑↑ ↑ ↑ ↑ ns ↑

↓↓ ↓ ns ↓ ns ↓

↓ ns ns ↓

↓ ↓ ns ns ↓

↑↑↑ ↑ ↑ ↑ ns ↑

↓ ↑↑ ns ns ↑ ↑

↑ ns ns ns ↑

↑ ↑ ↓ ns ↓

Second-Generation Antipsychotics Clozapine Olanzapine Paliperidone Quetiapine* Risperidone† Ziprasidone*

↓ ↓ ns ns

*Studied only nonpsychiatric control subjects. †Risperidone relative only to haloperidol. NREM, non-REM sleep; ns, no significant change in mean value relative to a baseline or placebo condition; REM, rapid eye movement sleep time; RL, REM latency; S1, NREM sleep stage 1; S2, NREM sleep stage 2; SL, sleep onset latency; SLP%, percentage of time asleep relative to time in bed; SWS, NREM slow wave sleep; TST, total sleep time; #Wakes, number of awakenings; WASO, waking minutes after sleep onset.

Effects of Antipsychotics on Sleep Patterns Objective Findings Although the clinical efficacy of FGAs and SGAs has been amply documented, objective evidence that these agents counteract the insomnia and other sleep abnormalities associated with schizophrenia is particularly sketchy. The 13 available studies are summarized in Box 57-3. Arrows indicate significant increases or decreases in mean values; “ns” indicates no significant change in mean value relative to a baseline or placebo condition. The reader is encouraged to view this summary with caution. Double-blind, placebo-controlled studies are rare, sample sizes are small, and head-to-head comparisons of different APs have rarely been undertaken. Not all studies have utilized subjects as their own control group (longitudinal protocol); instead, most have utilized cross-sectional comparison groups. Note also that quetiapine and ziprasidone were studied only in nonpsychiatric control subjects; as yet, aripiprazole has undergone no PSG evaluation in schizophrenics or control subjects. In general terms, FGAs appear to improve measures of sleep maintenance by increasing TST and sleep efficiency (SE) and by reducing both sleep latency (SL) and the amount of time waking after sleep onset.33-37 The FGAs may also increase REM latency. The sole study of chlorpromazine suggested an ability to increase SWS time.33 Broadly stated, SGAs also appear to have sedating properties. From among the SGAs, the effect of clozapine on the sleep of patients with schizophrenia has been the most widely studied.36,38,39 Clozapine appears to have a strong consolidating effect on sleep, with three studies documenting increases in TST, SE, and NREM stage N2. Clozapine may also decrease both SL and wake time after sleep onset. Olanzapine has also been shown to be a sleep-promoting agent with increases in TST, SE, and SWS.40,41 In the only head-to-head comparison of two AP agents, a significant enhancement of SWS was

observed in schizophrenics treated with risperidone relative to those treated with haloperidol; significant differences in other sleep variables were not observed.42 PSG studies of paliperidone’s effects on the sleep patterns in patients with schizophrenia revealed increased TST, SE, NREM stage 2, and REM sleep minutes; also observed were decreased SL, number of awakenings, and NREM stage 1.43 PSG studies of quetiapine, ziprasidone, and aripiprazole have not been evaluated in patients with schizophrenia. However, in PSG studies of healthy control subjects, quetiapine and ziprasidone have augmented TST, SE, and NREM stage 2 and decreased the amount of wake time after sleep onset.44,45 Such effects suggest that improvements in both sleep induction and consolidation might be expected in patients with schizophrenia.

Subjective Complaints Residual Insomnia As previously noted, insomnia is one of the cardinal features of schizophrenia. Difficulty falling asleep is the most frequent complaint, but restless sleep and increased bouts of waking after sleep onset are often described. These indices of hyperarousal have been associated with clinical measures of psychosis.46,47 Commonly the mental health practitioner must balance clinical efficacy of an AP agent against a range of potential adverse effects and thus will prescribe a maintenance dose that is the lowest clinically effective dose. As a result, some degree of untreated hyperarousal and associated insomnia may be present in schizophrenics on maintenance doses of APs. The CATIE study31 reported that rates of insomnia in AP-treated schizophrenics ranged from 16% to 30%. Although some residual hyperarousal may contribute to these insomnia rates, some APs (e.g., aripiprazole) may themselves may have associated side effects of insomnia, disturbed sleep, and anxiety.48 Clinicians may take one or more approaches to treat comorbid insomnia: (a) change the dose of the treating AP

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SECTION 13  •  Therapy of Sleep Disturbances Associated with Psychiatric Disorders

agent; (b) switch to a different, more sedating AP agent; or (c) prescribe a low dose of an adjunct, more sedating AP. Head-to-head objective data on the sedative properties of currently approved APs are not available; however, patient reports as well as receptor-binding profiles (antihistaminergic and anti-α1-adrenergic properties) suggest that chlorpromazine, ­clozapine, olanzapine, and quetiapine are among the more sedating AP agents.30,48 Clinicians might also consider adjunct use of an anxiolytic or a sedative hypnotic.49 Note that these agents should be prescribed cautiously, particularly for those schizophrenics with a sleep-related breathing disorder or a history of alcohol or drug abuse. In addition, investigational studies suggest that melatonin might serve as an adjunct treatment for residual insomnia. Melatonin is the principal hormonal product of the pineal gland. Abnormal nocturnal secretory patterns of melatonin have been associated with insomnia. Consequently, abnormal patterns of melatonin secretion might also occur in schizophrenia. This hypothesis prompted study of nocturnal melatonin production in schizophrenics; these studies observed that the nighttime peak in melatonin secretion was blunted, and that normalization of melatonin production levels did not occur following clinical improvement with AP treatment.50,51 In two studies, exogenous melatonin was used as an adjunct treatment for residual insomnia in AP-treated schizophrenics; these studies reported that melatonin replacement was associated with improved sleep maintenance as measured by actigraphy52 and by self-report.53 Sedation as a Side Effect of Antipsychotic Drug Treatment Rates of AP-related somnolence in patients with schizophrenia were also reported in the CATIE study; these rates ranged from 24% to 31%.31 Although somnolence may be symptomatic of an underlying sleep disorder, sedation in AP-treated schizophrenics may be a direct side effect of AP treatment. As mentioned in the previous section, the SGAs clozapine, olanzapine, and quetiapine are recognized sedating medications. The remaining SGAs are associated with lower rates of somnolence. Sedation as a side effect of FGA treatment is associated with high-milligram, low-potency agents such as chlorpromazine and thioridazine. In contrast, the low-milligram, highpotency FGAs such as haloperidol are associated with less somnolence. It is important to note that levels of somnolence are also affected by the half-life of the agent, amount of drug, and dosing schedule. Somnolence secondary to AP treatment is usually addressed by changing AP medication or reducing its dosage. Case studies suggest that aripiprazole when added to ongoing clozapine therapy may improve psychotic symptoms while decreasing clozapine-associated sedation.54 Modafinil is a wakefulness-promoting agent that has been approved by the FDA to treat the daytime sleepiness associated with narcolepsy. Because modafinil might also improve daytime sleepiness in an off-label condition such as AP-­ associated somnolence, research protocols have been designed to study the effect of modafinil as an adjunct to AP treatment. Modafinil was shown to increase wake time, reduce TST, and reduce fatigue in case studies55 and in an open-label pilot study56 of AP-treated schizophrenics. In contrast, a doubleblind, placebo-controlled trial of modafinil as an adjunct to AP treatment only observed a nonsignificant trend toward less nighttime and daytime total sleep.57 Although these studies

BOX 57-4  Sleep Disorders Associated with ­Schizophrenia Direct effects of antipsychotic treatment • Residual insomnia or untreated hyperarousal • Sedation as a side effect of antipsychotic drug treatment Sleep-related movement disorders • Restless legs syndrome • Periodic limb movement disorder Sleep-disordered breathing Parasomnias • Somnambulism • Sleep-related eating disorder Poor sleep hygiene

suggest that modafinil might be beneficial in offsetting the sedative effects of some APs, the use of modafinil as an adjunct to AP treatment in schizophrenia is not FDA approved and its use demands further study given that stimulant drugs might exacerbate psychosis in patients with schizophrenia.58

Co-Morbid Sleep Disorders The previous sections discussed both insomnia and sedation as effects of AP treatment in schizophrenia. But patients with schizophrenia may also suffer from a range of additional comorbid sleep disorders. These co-morbid conditions may encompass sleep-related movement disorders, sleep-related breathing disorders, parasomnias, and sleep disorders associated with poor sleep hygiene, alcohol/substance abuse, and circadian rhythm disorders (Box 57-4). Baseline prevalence rates of these sleep disorders in schizophrenics who are naïve to AP treatment have never been established; however, it is clear that many of these co-morbid sleep disorders have been induced by or exacerbated by AP treatment.

Sleep-Related Movement Disorders Both restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) are sleep-related movement disorders associated with sleep disturbance. RLS is characterized by an urge to move the legs and is often associated with unpleasant sensations in the legs. RLS occurs or worsens when the patients is at rest. It is immediately but temporarily relieved by activity such as walking or moving the legs. It has a circadian component with worsening in the evening and night. As such, RLS is associated with sleep onset insomnia because it profoundly interferes with the ability to attain a state of persistent sleep. About 80% to 90% of patients with RLS also experience periodic limb movements (PLMs). PLMs are periodic episodes of repetitive limb movement (usually the lower extremities) occurring most typically during NREM sleep. The disorder, PLMD, may be associated with autonomic or cortical arousals or outright awakenings. Consequently, PLMs can be associated with complaints of restless or unrefreshing sleep. For many years, the pathophysiology of schizophrenia has centered on the dopamine hypothesis of schizophrenia owing primarily to the relationship between the clinical potency of AP agents and the blockade of the DA D2 receptor.

CHAPTER 57  •  Schizophrenia and Its Associated Sleep Disorders

In this context, psychoticism has been attributed to pathologic hyperstimulation of subcortical mesolimbic DA D2 receptors. In contrast, because RLS and PLMD respond to DA agonists, the pathophysiology of RLS and PLMD may reflect a DA deficiency.59 It is not surprising then that D2 receptor blockade associated with AP agents might induce RLS and PLMD in AP-treated schizophrenics. In confirmation, studies have determined that the prevalence rates of RLS in AP-treated schizophrenics are more than twice that of healthy control subjects.60 Prevalence rates of PLMD in schizophrenics are not as well known because the diagnosis of PLMD requires overnight PSG study. In contrast, the diagnosis of RLS is made by clinical interview. Two published reports suggest that prevalence rates of PLMD in schizophrenics treated with FGAs are in the range of 13% to 14%.61,62 Recent studies have reported the development of RLS and PLMD in patients taking SGAs such as risperidone,63 olanzapine,64-67 quetiapine,68 and clozapine.69 Olanzapine has also been associated with the induction of restless arms syndrome.70 The standard treatment for RLS and PLMD are DA agonists such as ropinirole and pramipexole; however, for patients with schizophrenia, DA agonists are not firstline choices. In schizophrenic patients who develop RLS and PLMD following AP management, clinicians might consider a reduction in AP dose or a change to a different AP agent. Adjunct treatments such as clonazapam might also be considered. Patients should also be evaluated for possible iron deficiency, a known risk factor for the development of RLS,71 and be encouraged to limit use of substances such as caffeine that might worsen sleep-related movements. Although DA agonists such as ropinirole and pramipexole should not be the first choice of treatment for patients with schizophrenia who develop RLS or PLMD, it is possible that such agents might be necessary when their benefits outweigh the risk. Finally, akathisia is a common side effect of many AP agents. Akathisia is characterized by generalized inner disquiet and motor restlessness evidenced by fidgeting and pacing; it can induce significant sleep disruption. RLS can be distinguished from akathisia because RLS is associated with symptomatic relief by movement, and unlike akathisia, it is associated with a circadian worsening of symptoms in the evening or at night. Pharmacologic treatment of AP-induced akathisia may include anticholinergic agents (e.g., benztropine), β-adrenergic antagonists (e.g., propranolol), and benzodiazepines (e.g., clonazepam).72

Somnolence Associated with Sleep-Related Breathing Disorder Increased somnolence associated with the receptor binding profile of certain APs was addressed in a previous section. However, somnolence in AP-treated schizophrenics may also indicate the presence of a sleep-related breathing disorder (SBD) that has been exacerbated or induced by an AP agent. A common adverse effect of AP treatment is the emergence of obstructive sleep apnea syndrome (OSAS). Prevalence rates of OSAS in schizophrenics never exposed to AP agents are unknown. However, a wide range of high prevalence rates for OSAS have been reported in studies that enrolled patients with schizophrenia in research protocols (rates of 17%,61 19%,73 and 48%62). In a study of schizophrenic patients referred to a

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sleep clinic for a suspected sleep disorder, more than 46% had a respiratory disturbance index (RDI) greater than 10 events per hour of sleep; the mean RDI was 64.8 events per hour of sleep, and the best predictor of RDI was obesity.74 One of the adverse side effects of AP treatment is weight gain, which can occur following the use of certain FGAs and SGAs such as clozapine, olanzapine, thioridazine, chlorpromazine, and risperidone.75 More recent data suggest that quetiapine should be added to this list.76 Clozapine and risperidone have been associated not only with significant morbid obesity but also with the development of moderate to severe SBD.77 Weight gain is one of a constellation of factors associated with insulin resistance and known as the metabolic syndrome. The metabolic syndrome increases not only the risk of obesity and SBD but also the risks of impaired glucose tolerance, type 2 diabetes, and coronary heart disease. These AP-related adverse effects are consistent with the heightened mortality rate associated with schizophrenia. Published reports found significant weight loss and improved metabolic measures when aripiprazole was substituted for olanzapine78 or when aripiprazole was added as an adjunct to olanzapine.79 Although daytime sleepiness is a relatively frequent side effect seen in schizophrenics treated with APs, clinicians must consider the differential diagnosis of co-morbid OSAS for those patients who are obese by history or who have gained weight during the course of AP treatment. OSAS in patients with schizophrenia has been treated effectively with nasal continuous positive airway pressure (CPAP); these patients have shown relatively good compliance and significant clinical improvement.80,81

Parasomnias Somnambulism is associated with a partial arousal from SWS. Psychotropic agents that increase SWS may predispose schizophrenics to somnambulistic behaviors. Somnambulism has been reported to occur following the addition of lithium to FGAs82 and following treatment with olanzapine.83 Both lithium and olanzapine have also been credited with SWS enhancement. Clonazepam has been reported to ameliorate AP-induced somnambulism,84 but hypnotics should be prescribed with caution if there is co-morbid SBD. Another parasomnia, sleep-related eating disorder, may be induced by APs such as haloperidol,85 olanzapine,86 and risperidone.87 Treatment options for sleep-related eating disorders might include topiramate or a sedative agent.

Poor Sleep Hygiene Many schizophrenics exhibit sleep-wake reversals, sleeping during the day and remaining active at night. Others may exhibit polyphasic sleep patterns with extended periods of daytime napping that interfere with subsequent consolidation of nocturnal sleep. Although daytime napping might indicate AP-associated sedation or somnolence associated with a sleep disorder such as OSAS, many schizophrenic patients lack daytime structure and may prefer to avoid social interactions. As a result, they may develop bad habits in relation to daytime napping and the circadian assignment of their major sleep period. Excess caffeine intake and the use of alcohol or psychoactive drugs such as cannabis and cocaine can further erode good sleep hygiene. Both mental health and sleep medicine

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SECTION 13  •  Therapy of Sleep Disturbances Associated with Psychiatric Disorders

specialists should be cognizant of the fact that most patients with schizophrenia can benefit from sleep hygiene counseling.

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