Schizophrenia affects about 1% of the general population. The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5)1 delineates five core symptom clusters in schizophrenia. These include (1) delusions, (2) hallucinations, (3) disorganized speech, (4) disorganized behavior, and (5) negative symptoms. Patients with schizophrenia often suffer significant social and occupational dysfunction as manifested by interpersonal deficits, failure to advance in school, and occupational difficulties, which result in financial burdens.2–6 In addition to positive, negative, and cognitive symptoms, sleep difficulties are commonly seen in patients with schizophrenia. All too often, clinicians focus their attention on positive symptoms, failing to address equally disabling comorbidities such as depression, anxiety, cognitive deficits, and sleep difficulties. Patients with schizophrenia also tend to have increased occurrence of cardiometabolic abnormalities and sleep disorders.7–9
Additionally, patients have been shown to have abnormalities of sleep architecture that may precede the onset of psychotic symptoms, suggesting a possible etiologic role in the pathophysiology and evolution of this disorder.10–12 Hence, sleep abnormalities may play an important role in identifying at-risk patients—those in the prodromal phase and possibly in prevention and treatment of the illness altogether.10
Sleep difficulties are estimated to occur in 30% to 80% of patients with schizophrenia.7 These disruptions to sleep cannot be fully explained by medication side effects alone.8 For example, antipsychotics may cause sedation, yet up to 55% of those on sedating therapeutics still report sleep disruption.8,9 Sleep issues may emerge during any and all stages of the illness, including the prodrome, first episode, acute recurrences, and even during remission.10–15
Subjective Sleep Complaints
The vast majority of patients with schizophrenia complain of some form of sleep difficulty with insomnia being a frequent complaint. In fact, one hallmark of the prodromal phase is severe insomnia. Similarly, insomnia is a major risk factor for impending relapse of psychosis.16,17 Other common sleep complaints include restless, nightmares, nonrestorative sleep, initial and middle insomnia, early morning awakening, and poor sleep efficiency, with increased time in bed.7,17–19 Although a number of patients with schizophrenia may report longer and better sleep on antipsychotics, many continue to report significant sleep difficulties, including early and middle insomnia.18
People with schizophrenia demonstrate a number of abnormalities on sleep electroencephalogram. Increased sleep latency is a common finding.7,19 Decreased rapid eye movement (REM) latency is often present as well.7,19 Studies also demonstrate decreased slow-wave sleep and slow wave events in patients with schizophrenia.8,10,11,20–24 Additionally, total sleep time is diminished.7,19
Recent studies have demonstrated a reduction in the number of sleep spindles in those with schizophrenia.25–27 Sleep spindles are 11 to 16 Hz oscillations of brain activity seen in stage 2 of non-REM sleep. They are formed in the reticular nucleus of the thalamus. Sleep spindle activity is decreased in chronically medicated schizophrenia patients, patients in the early course of the illness who are not on medications, and in first-degree relatives of those with schizophrenia.25 Positive symptom severity has been inversely related to spindle activity.26,27 Additionally, reduced spindle activity has been associated with a number of cognitive deficits in the illness. Finally, reduced spindle activity has been shown to correlate with diminished sleep-dependent motor procedural memory consolidation25,27 and decreased recognition memory for words learned prior to sleep.21,25
Circadian Rhythm Dysfunction
Multiple studies have demonstrated that patients with schizophrenia have circadian rhythm dysfunctions. These include advanced and delayed sleep onset, desynchronized sleep/wake patterns, and free running sleep-wake cycles.22,28–31 Such circadian rhythm abnormalities may be caused by a decreased exposure to light due to psychotic symptoms, abnormalities in melatonin, and dysfunction of the suprachiasmatic nucleus.
Clinical Ramifications of Sleep Problems in Schizophrenia
Sleep dysfunction in schizophrenia leads to a worsening clinical picture. There is evidence that disrupted sleep frequently precedes the onset of the first-psychotic break. Profound insomnia is often the first symptom before the start of positive symptoms. Sleep dysfunction may also be a precipitating factor for psychotic decompensation.32 Hence, if an otherwise stable patient develops difficulties sleeping, the clinician should be aggressive in treating it.
Overall illness severity has been associated with decreased amount of sleep, decreased slow-wave sleep and decreased REM latency.17 Positive symptoms have been linked to increased sleep latency, high frequency of REM activity, decreased sleep efficiency, and decreased REM latency.17 Decreased slow wave activity and decreased REM latency have been correlated with negative symptoms.17 Decreased slow wave sleep and increased sleep latency have been associated with disorganized thought processes.17,19 Quality of life measures have even been directly related to sleep quality, after antipsychotic adverse events and depression have been factored out.7
Poor sleep is known to affect cognition.33 As noted above, sleep spindle activity is decreased in schizophrenia and this has been directly correlated to a drop-off in motor procedural memory.27,34–37 Motor procedural memory is a part of the long-term memory of how we perform motor skills. Procedural memory has also been referred to as automatic or unconscious memory and is a key part of the long-term memory necessary to perform motor skills.
In contrast to motor memory, declarative memory is defined by a conscious process of recall. Examples include knowledge and facts. It is well established that declarative memory is often impaired in schizophrenia and is one of the most significant risk factors for functional disability. Göder et al.21 assessed for a link between decreased sleep spindles and picture memory consolidation and found that patients with schizophrenia had deficits in sleep memory consolidation, correlated with decreased sleep spindles. In fact, the study showed that both declarative and procedural memory correlate directly with decreased sleep spindles.
A more recent study showed that those with schizophrenia early in the course of illness and not taking antipsychotic medication had decreased sleep spindles. The decreased sleep spindle activity was correlated with multiple cognitive deficits including verbal IQ25 and the finding was present in first-degree relatives as well.
Sleep Disorders in Schizophrenia
A number of sleep disorders are seen in patients with schizophrenia. These include obstructive sleep apnea (OSA), restless legs syndrome (RLS), periodic limb movement disorder (PLMD), and excessive daytime sleepiness, which is represented by disorders of intrinsic hypersomnia. These disorders may be primary or a result of treatment with antipsychotic medications.
OSA is caused by obstruction of the upper airway leading to cessation of breathing (apnea episodes) that leads to hypoxia. It is the most common form of sleep apnea. The gold standard for diagnosis is polysomnography. In the general population, 2% to 7% are affected.38 The number of people with schizophrenia who are affected varies but is significantly higher than that percentage.39 In the largest inpatient study to date, of 46 inpatients with schizophrenia, 57.1% of women and 46.2% of men had OSA.39 OSA was seen in 14.9% of the outpatients with schizophrenia in a study by Annamalai et al.40 Other studies have demonstrated higher prevalence of OSA in patients with schizophrenia compared to the general population.41,42 Schizophrenia has not been demonstrated to be an independent risk factor for OSA. Rather, obesity may be the mediating factor for increased risk of OSA. Patients with schizophrenia are frequently taking antipsychotic medication, which may lead to obesity, but they are frequently more sedentary as well, which may similarly explain the increase in weight.
RLS is comprised of uncomfortable sensations in the legs or urges to move the legs, which is usually worse in the evening or at night. The unpleasant sensations are partially or completely relieved by movement of the legs. It is vital for the clinician to differentiate RLS from akathisia. RLS often presents as discomfort in the legs with a feeling of crawling, itching, and/or creeping that is usually relieved with movement. In contrast, akathisia is an internal sense of restlessness that may increase motor activity but that movement fails to provide relief.
PLMS is an involuntary movement of the limbs, usually the lower extremities, during sleep that occurs at regular intervals. Antipsychotic medications have been shown to precipitate RLS and PLMS.43–46 There is no evidence that the diagnosis of schizophrenia is a risk factor for RLS and PLMD.
Hypersomnia disorders, another group of disorders with increased incidence in those with schizophrenia, is characterized by persistent sleepiness and corresponding fatigue. Although it may be a result of the illness itself, it can also be attributed to antipsychotic medication or another sleep disturbance such as insomnia or circadian rhythm dysfunction. All antipsychotic medications have the potential to cause sedation; some more than others. Clozapine, chlorpromazine, quetiapine, and olanzapine pose the highest risk for sedation. Those with a lower propensity toward sedation include paliperidone, iloperidone, aripiprazole, and lurasidone. Hypersomnolence may lead to a number of problems, including decreased cognition and corresponding disruptions in one's ability to function at work and other activities. Of particular concern, it can be a precipitant of motor vehicle accidents.47
Evaluation of Sleep Problems and Sleep Disorders in Schizophrenia
Given the high prevalence and significance of sleep problems in schizophrenia, all affected people should be assessed for signs and symptoms of sleep dysfunction. Clinicians should query about the amount and quality of sleep, daytime hypersomnia, and screen for initial, middle, and terminal insomnia. Circadian rhythm disruptions may also be present and should be assessed appropriately. A comprehensive history should include caffeine and alcohol/drug use, level of physical activity, screening for comorbid psychiatric symptoms, psychosocial stressors, medical conditions, medications, and overall sleep hygiene. A screening physical examination is also recommended that includes height, weight. and description of body habitus.
Screening questionnaires may aid in the detection of sleep problems and multiple such instruments are available, including the Epsworth Sleepiness Scale (ESS) (8 questions), the Insomnia Severity Index (ISI) (7 questions), Berlin Questionnaire (10 questions), STOP (Snore, Tired, Observed apneas, blood Pressure) Questionnaire (4 questions), STOP-BANG (Blood pressure, body mass index, Age, Neck circumference, Gender) Questionnaire, and the Pittsburgh Sleep Quality Index (PSQI) (19 items). The ESS is a patient-administered rating scale that assesses daytime sleepiness and sleep propensity. Similarly, ISI is a patient-rated scale that assesses the level of insomnia. The Berlin Questionnaire, STOP, and STOP-BANG are all screening tools for OSA. The PSQI gauges sleep quality over a 1-month period.
Additional diagnostic instruments provide more objective measures in the assessment of sleep. Polysomnography and other more intensive and costly examinations can be invaluable in making more definitive diagnoses of various primary sleep disorders like OSA. The Multiple Sleep Latency Test provides an indirect measure of excessive daytime sleepiness by measuring sleep onset latency in sequential, timed naps. It is used in the diagnosis of narcolepsy. Use of actigraphy has grown considerably over the past 20 years, in part due to ease of administration in the home environment. The nonintrusive watch-shaped device is worn on the wrist and records movement to estimate daytime sleepiness and circadian rhythms.
Treatment of Sleep Problems and Disorders in Schizophrenia
As an initial step in treatment, medical conditions that may be contributing to the sleep dysfunction should be addressed. Multiple medical conditions have been shown to cause sleep problems. Nasal and sinus allergies often cause insomnia. Hypothyroidism and hyperthyroidism may cause hypersomnia or insomnia. Coronary artery disease and congestive heart failure may cause insomnia as well as circadian disturbances. Diabetes with fluctuating sugars has long been known to cause insomnia. There are a host of other examples including arthritis, asthma, gastroesophageal reflux disease, chronic pain, and asthma. These medical comorbidities have been shown to be more prevalent in patients with schizophrenia.
Once medical comorbidities have been addressed, proper sleep hygiene and contributing over-the-counter (OTC) medications should be explored. Caffeine is well known to cause insomnia and its use should be limited to earlier in the day. OTC medications such as pseudoephedrine often cause insomnia and should be discontinued or changed to another class of medication if medically necessary.
Several classes of prescription medication have been implicated in sleep disruption. Patients with schizophrenia are often prescribed statins, beta blockers, angiotensin converting enzyme (ACE) inhibitors, and selective serotonin reuptake inhibitors (SSRIs). Statins may cause insomnia and nightmares. Adverse effects of beta blockers include awakenings and nightmares. ACE inhibitors can lead to a dry cough, which may interrupt sleep. SSRIs are associated with insomnia. In cases where a medication is the presumed cause of sleep dysfunction, alternatives should be pursued whenever practical.
OSA should be managed with continuous positive airway pressure (CPAP). The administration of CPAP in a patient with baseline paranoia, such as may be present in schizophrenia, can pose particular challenges. Nonetheless, supportive encouragement can be effective and newer, more comfortable devices can increase compliance. Other treatment alternatives like lifestyle modifications, positional therapy, use of oral appliances, and consultation with an ear, nose, and throat specialist should be explored in patients who are not candidates for CPAP.
Pharmacotherapy for sleep disturbances begins with antipsychotic medications, which alone may improve sleep. They have been shown to increase total sleep time and decrease sleep latency and awakenings.48 Hence, olanzapine, clozapine, chlorpromazine, quetiapine, and asenapine, the more sedating atypical medications, are more frequently used when sedation is a desirable side effect. However, care should be taken to avoid other untoward effects such as cognitive decline and an increase risk of falls.49
Melatonin has also been shown to improve sleep in patients with schizophrenia. Studies have shown that this natural remedy increases sleep efficiency, decreases awakenings, reduces sleep latency, and increases total sleep time.50 An added advantage of melatonin is that it may diminish antipsychotic-induced metabolic effects.51
Sleep problems are common in patients with schizophrenia. The nature of sleep dysfunction is poorly understood in this population. The studies are not conclusive, but the most consistent findings include insomnia, decreased spindles, and abnormalities of sleep architecture. OSA and RLS are also common in these patients. Clinicians often fail to diagnose sleep disorders in patients with schizophrenia. We recommend that all patients with schizophrenia be screened for sleep disorders. More studies are needed to see if treating sleep problems will benefit quality of life in patients with schizophrenia.
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