Chapter 131 Schizophrenia

Abstract

Schizophrenia is perhaps the most devastating neuropsychiatric illness. Worldwide, its prevalence rate is about 1%. Although its etiology remains unknown, schizophrenia is considered a neurodevelopmental disorder involving the interplay of susceptibility genes and environmental factors. There is a wide range of pathologic findings, but there is no specific or diagnostic laboratory abnormality. Consequently, schizophrenia remains a clinical diagnosis, and its defining symptoms are typically delusions and hallucinations in the absence of extreme emotion. Cognitive impairment or thought disorder is also considered a cardinal symptom.

Sleep patterns in schizophrenic patients can be markedly disturbed. In times of severe psychotic agitation, schizophrenic patients often experience a profound insomnia or total sleeplessness. They can also develop sleep–wake reversals, with a preference for sleeping during the day. Severe insomnia is one of the prodromal symptoms associated with psychotic relapse or exacerbation. Clinically stable, medicated patients with schizophrenia can also experience ongoing sleep disturbance, particularly early and middle insomnia. Many polysomnographic abnormalities have been identified, but none are diagnostic of schizophrenia. Such abnormalities include poor sleep efficiency, slow-wave sleep deficits, and short rapid eye movement (REM) sleep latencies. The most consistently observed sleep abnormality is early insomnia or difficulty attaining a state of persistent sleep.

Although some schizophrenic patients have a full recovery after an initial psychotic episode, the majority require long-term treatment with antipsychotic medications. These agents are classified as first-generation or second-generation antipsychotics. They differ in their receptor binding profiles, clinical efficacy, and range of side effects. Relative to the second-generation antipsychotics, first-generation antipsychotics are thought to produce more extrapyramidal side effects and tardive dyskinesia. Several second-generation antipsychotics are associated with significant weight gain and abnormal glucose regulation, including diabetes.

Schizophrenic patients also suffer from a range of intrinsic and extrinsic dyssomnias including inadequate sleep hygiene, irregular sleep–wake patterns, parasomnias, obstructive sleep apnea, restless legs syndrome (RLS), and periodic limb movements during sleep (PLMS). The second-generation antipsychotics include agents that can induce or exacerbate sleep-disordered breathing, RLS, or PLMS. Sleep specialists should treat schizophrenic patients who have dyssomnias in the same manner as they do other patients.

In many ways, the dream experience is similar to psychosis. Hallucinations, perceptual distortions, bizarre thinking, and temporary delusions intermingle with more normal thought and perceptual processes. Consequently, the discovery of REM sleep and its associated dream reports ¹ not only ushered in the modern era of sleep research but also engendered many of the seminal studies of the sleep of schizophrenics. These studies²^–⁵ explored the hypothesis that the pathogenesis of schizophrenia might rest with REM sleep abnormalities or, more directly, with the intrusion of the dream state into waking. These early polysomnographic (PSG) studies of sleep in schizophrenic patients found no gross abnormalities of REM sleep or any evidence of an intrusion of REM sleep into wakefulness. However, in subsequent years, a large body of research revealed other abnormalities more consistently characteristic of the sleep patterns in schizophrenia.

Schizophrenia is associated with immense human and economic cost. It is also associated with severe insomnia, particularly during episodes of psychotic exacerbation. This chapter provides an overview of the clinical features of schizophrenia and associated risk factors and neuropathology. It also describes the sleep abnormalities characteristic of schizophrenia and their neurobiological correlates. Finally, we address the issues surrounding antipsychotic medications and their side effects, particularly those associated with the development of comorbid dyssomnias.

Epidemiology and Risk Factors

Most studies of schizophrenia suggest a prevalence rate of 5 cases per 1000 people.⁶ Lifetime prevalence is approximately 1% worldwide.⁶ Estimated annual new case appearance, or incidence, is 0.35 cases per 1000 population.⁶ Schizophrenia is equally common in both sexes. Although the age of onset is usually in the second decade of life, the disorder seems to begin earlier in male than in female patients.

Although the etiology of schizophrenia remains unknown, several factors are associated with an increased likelihood for developing schizophrenia. First, a genetic predisposition greatly elevates the risk for developing schizophrenia. Family, twin, and adoption studies provide strong evidence that schizophrenia is highly heritable. The prevailing genetic model of the etiology of schizophrenia suggests that multiple combinations of common mutations among candidate genes act together to increase the risk of developing the disease. A single genetic mutation would not be necessary or sufficient for developing schizophrenia.⁷ Multiple combinations of common susceptibility genes, interacting with one another, suggest that multiple forms of schizophrenia might exist. In contrast, research suggests that highly penetrant, individually rare mutations, even of recent origin, can predispose to schizophrenia. These mutations, which vary from person to person, were largely involved in networks controlling neurodevelopment.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.

Among the environmental factors that might play a role in the development of schizophrenia are obstetric complications and viral infection.⁶ Obstetric complications could include premature birth, low birth weight, trauma, and poor oxygenation. Some hypothesize that schizophrenia is an autoimmune disease potentially triggered by maternal antibodies to viral infection.⁹ A better understanding of both genetic and environmental risk factors and their interaction should open a window on the etiology and pathophysiology of the disease.

Diagnosis

The term schizophrenia derives from Bleuler’s description of the splitting or disintegration of normal thought processes.¹⁰ His belief that cognitive impairment or thought disorder is the defining symptom of schizophrenia shaped the course of diagnostic criteria developed during the 20th century. Current criteria for the diagnosis of schizophrenia are defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR; Box 131-1).¹¹ As reviewed by Black and Andreasen,¹² schizophrenia is a clinical diagnosis because there are no specific laboratory abnormalities diagnostic of the disorder. It is also, in large part, a diagnosis of exclusion, eliminating psychotic disturbances attributable to a variety of medical, psychiatric, and substance-abuse disorders. In addition, the number and diversity of symptoms complicates the clinical presentation.

Box 131-1

Adapted from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Press; 2000.

DSM-IV Diagnostic Criteria for Schizophrenia

Social or 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. When the onset is in childhood or adolescence, failure to achieve expected level of interpersonal, academic, or occupational achievement is the criterion.

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 criteria for active-phase symptoms and may include periods of prodromal or residual symptoms. During these prodromal or residual periods, the signs of the disturbance may be manifested by only negative symptoms or two or more active-phase symptoms presented in an attenuated form (e.g., odd beliefs, unusual perceptual experiences).

Schizoaffective and Mood Disorder Exclusion

Schizoaffective disorder and mood disorder with psychotic features have been ruled out because either no major depressive, manic, or mixed episodes have occurred concurrently with the active-phase symptoms or if mood episodes have occurred during active-phase symptoms, their total duration has been brief relative to the duration of the active and residual periods.

Substance and 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.

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-TR, Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision.

To simplify the task of the clinician, characteristic symptoms ¹¹ (see Box 131-1) are organized into two main categories, positive and negative symptoms. According to DSM-IV, “positive symptoms appear to reflect an excess or distortion of normal functions, whereas the negative symptoms appear to reflect a diminution or loss of normal functions.” Positive symptoms can be further subdivided into a psychotic dimension that includes hallucinations and delusions and a disorganization dimension that includes disorganized speech and behavior. Negative symptoms include flattening of affect, avolition, and poverty of speech. The second diagnostic criterion¹¹ (see Box 131-1) reflects a marked deterioration in occupational and social functioning.

The sleep abnormalities found in schizophrenia lack diagnostic specificity. Consequently, they do not reliably differentiate schizophrenia from other psychiatric disorders. It is unlikely, therefore, that a sleep clinic would be asked to diagnose schizophrenia. However, the sleep clinic could help differentiate schizophrenia from narcolepsy, which can manifest with a strong hallucinatory component.¹³

Pathogenesis

The etiology of schizophrenia is poorly understood, but accumulating evidence has revealed a wide range of brain abnormalities.⁶^,¹² Brain structural abnormalities have been found in postmortem studies and in living subjects by computed tomography (CT) and magnetic resonance imaging (MRI).¹¹^,¹² Regarding the latter, structural dysmorphologies have included enlarged lateral and third ventricles; loss of total gray matter, frontal, and temporal lobe volume; and a reduction in total brain size. These findings seem to be present at the onset of illness and cannot be attributed to progressive degeneration; however, most findings are nonspecific and are observed in other psychiatric disorders. Functional imaging studies using positron emission tomography (PET) or regional cerebral blood flow have observed decreased metabolism in the frontal cortex (hypofrontality) and left hemisphere dysfunction.

Abnormalities of neurotransmitter systems have also been extensively investigated. For many years, the prevailing theory of schizophrenia has centered on the dopamine system. The dopamine (DA) hypothesis of schizophrenia derived from two observations. First, the potency of standard antipsychotic medication correlates with the amount of D₂ receptor blockade. Second, drugs such as amphetamines, which enhance DA activity, can cause a psychosis that mimics paranoid schizophrenia and can exacerbate schizophrenic symptoms. The hypothesis holds that psychotic symptoms such as hallucinations and delusions are associated with hyperactivity of the mesolimbic DA system. Serotonin (5-hydroxytrypamine [5-HT]) and norepinephrine have also been associated with the pathophysiology of schizophrenia because the potency of second-generation antipsychotics has been linked to 5-HT and alpha-adrenergic receptor blockade. Finally, the role of the excitatory neurotransmitter glutamate in the pathophysiology of schizophrenia is gaining greater credence in part because several of the recently identified schizophrenia susceptibility genes target glutamatergic transmission.^7,^8,¹⁴ Agonists of metabotropic glutamate receptors (mGluRs) are currently being investigated as treatments for schizophrenia.¹⁵ Metabotropic glutamate receptor agonists actually decrease brain excitability. They also have profound effects on the sleep electroencephalogram (EEG), diminishing REM sleep and non-REM (NREM) fast frequencies in the rat.¹⁶

Because no discrete pathologic abnormality has emerged as an etiologic factor, schizophrenia may be an abnormality of neuronal connectivity ¹⁷ or of integrative neuronal circuits.¹⁸ Neither of these theories is inconsistent with the broader and prevailing view that schizophrenia is a neurodevelopmental disorder.¹⁹^,²⁰ Although abnormal events can occur early in development (prenatal or perinatal), maturational abnormalities can appear during the second decade of life²¹ or even into middle age.²²

Clinical Course and Prevention

In the prevailing pathophysiologic model, schizophrenia is viewed as a neurodevelopmental disorder with onset typically (but not always) in late adolescence. The onset may be abrupt or insidious—that is, beginning with a prodromal phase characterized by subtle changes in behavior, mild thought disorder, and social withdrawal. The prodromal phase is followed by an active phase marked by positive psychotic symptoms such as hallucinations and delusions. This phase can wax and wane, but some degree of psychoticism usually persists during the waning or residual phase. Positive symptoms (relapse or acute exacerbation) can recur episodically. Over the course of the illness, positive psychotic symptoms can gradually decline; in contrast, negative symptoms such as affective flattening and avolition tend to increase with the progression of the disease.

For about 50% of patients, the onset of the illness is both progressive and insidious; for the remainder, the onset is acute, with little or no prodromal syndrome. Also, for about 50% of patients, the course of the illness is continuous; for others the course is marked by episodic flare-ups. The likelihood of relapse has been associated with stressful life events, a critical and hostile family environment, and drug abuse.

If a positive outcome is defined as the absence of psychotic symptoms and normal levels of social functioning, long-term follow-up studies suggest that 20% to 30% of patients have a full recovery. Another 20% to 30% of patients recover to levels where they can function occupationally and socially, but they have residual symptoms. Approximately 50% continue to show moderate to severe dysfunction requiring numerous outpatient interventions or rehospitalization with each relapse. Approximately one fifth require long-term institutionalization. Although the atypical antipsychotics can lower the number of hospitalizations, antipsychotic treatment does not fundamentally alter these outcomes. A better outcome has been associated with acute onset, episodic course, female sex, and lack of family history of schizophrenia.

The course of illness in schizophrenia can include dysphoria or depressive episodes, particularly early in the course. Relative to other major psychiatric disorders, schizophrenic patients tend to marry less, are more likely found in an institutional setting, and have poorer occupational functioning. Schizophrenic patients also have a higher mortality rate owing to suicide as well as physical illness.

Schizophrenia is probably the most devastating of all psychiatric illnesses. We can neither cure this disorder nor prevent its occurrence. Most schizophrenics, after an early onset, can anticipate lifelong mental disability as well as social and economic marginalization.

Sleep-Related Features

Subjective Sleep Complaints

With the onset of psychotic symptoms, and with each subsequent relapse, sleep is usually markedly impaired. The sleep of schizophrenic patients who are in a state of psychotic agitation usually, but not invariably, is manifested by prolonged periods of total sleeplessness. In times of less severe psychotic agitation, sleep is often characterized by a pronounced insomnia—long sleep-onset latencies, reduced total sleep time, and sleep fragmented by bouts of waking. Recurrence or exacerbation of symptoms is often heralded by increasing insomnia. Even among clinically stable, medicated patients with schizophrenia, ongoing subjective sleep disturbance is common, particularly early and middle insomnia.²³ There may also be a reversal of sleep and wake so that the patient sleeps during the day and remains awake at night. Subjective complaints of poor sleep quality are correlated with sleep–wake reversals.²⁴

Schizophrenic patients also complain of poor sleep quality, including restlessness and agitation, disturbing hypnagogic hallucinations, and nightmares. Subjectively assessed poor sleep quality is predictive of self-assessed poor quality of life and impaired coping skills.²⁵^,²⁶ Although there are no systematic studies, anecdotal clinical reports suggest that alcohol and substance abuse can disturb sleep and cause the patient to relapse. Alternatively, use of these drugs may be an attempt to self-medicate and attenuate the psychic misery of this illness.

Polysomnographic Features

Polysomnographic studies have provided a comprehensive and objective description of the range of dyssomnias found in schizophrenia, and they have been broadly consistent with subjective complaints. However, these PSG studies have, on occasion, produced discrepant findings, owing perhaps to differences in protocol design, composition of control groups, sample size, inclusion criteria (e.g., age, medication status and history, clinical features, and clinical history), as well as algorithms to quantify sleep parameters. In this section, we rely on meta-analyses ²⁷^,²⁸ and a review²⁹ to summarize the diversity of these findings.

The reader should note that sleep stages reported in this chapter are based on the sleep scoring rules and terminology which prevailed before 2007 and which are broadly consistent with those developed by Rechtschaffen and Kales.³⁰ They are designated classic terminology in Table 131-1. In 2007, the American Academy of Sleep Medicine revised the rules and terminology for the scoring of sleep stages.³¹ An overview of this revision is presented in Chapter 141. Table 131-1 provides a simplified translation of classic to revised terminology.

Table 131-1 Comparison of Sleep Stage Designations

CLASSIC TERMINOLOGY	REVISED TERMINOLOGY
Wakefulness	Stage W
Stage 1 sleep	Stage N1 (NREM 1 sleep)
Stage 2 sleep	Stage N2 (NREM 2 sleep)
Stage 3 sleep	Stage N3 (NREM 3 sleep)
Stage 4 sleep	Stage N3
Slow wave sleep	Stage N3
Stage REM sleep	Stage R (REM sleep)

Total Sleep, Sleep Maintenance, and Sleep Continuity

Polysomnographic studies have shown that the sleep of schizophrenic patients is characterized by poor sleep efficiency. Often this takes the form of a reduction in total sleep time as well as early, middle, and late insomnia. The most consistently reported abnormality is early insomnia or difficulty reaching a state of persistent sleep. Many of these empirical studies have evaluated schizophrenic patients who were treated with antipsychotics, suggesting that some degree of residual insomnia is not an uncommon outcome of standard treatment. Note that severe insomnia is one of the prodromal signs of impending psychotic decompensation or relapse subsequent to discontinuing antipsychotic medication.³²^–³⁴

Abnormalities of REM Time and REM Eye Movements

Despite early speculation regarding potential REM sleep abnormalities in schizophrenia, studies comparing schizophrenic patients with healthy control subjects have consistently shown that REM sleep time is not systematically augmented or reduced.²⁷^,²⁸ Eye movements during REM sleep have also been studied. Visual scoring of REM sleep eye movements report no difference in density of eye movements between schizophrenic patients and control subjects.³⁵^,³⁶ An automated eye-movement detection system³⁷ yielded the same conclusion, but it extended the observation, finding no differences in eye movement density in schizophrenic patients, nonpsychiatric control subjects, and patients with major depressive disorder.

REM Sleep Latency

Many PSG studies have quantified the latency to the onset of the first REM sleep period.²⁷^–²⁹ Several have compared the REM latency of unmedicated schizophrenic patients with that of nonpsychiatric control subjects. Approximately half have reported significant between-group differences, with the schizophrenic patients demonstrating abnormally short REM latency. Even in studies finding no between-group differences, a bimodal distribution of REM latency values in schizophrenic patients has been observed, suggesting that there are subgroups of schizophrenic patients with sleep-onset REM periods.³⁵^,³⁸ Short REM latency might represent an active, or primary alteration of REM sleep mechanisms. Alternatively, as suggested by Feinberg and colleagues,³⁹ a slow-wave sleep (SWS) deficit in the first NREM period might permit the passive advance or early onset of the first REM period.