Clinical manifestations

Presentation and course

Sleep complaints are common in general medical, psychiatric, and neurologic clinics. Common sleep symptoms include insomnia or hypersomnia, nightmares, and excessive nighttime movements.

Many psychiatric conditions include sleep-related complaints (see table 1). Patients can present with problems initiating or maintaining sleep, problems with sleep quality (ie, not feeling rested), daytime hypersomnolence or added movements, or sleep behaviors.

Table 1. Psychiatric Disorders with Sleep Symptoms

Class	Psychiatric disorders	Sleep complaints	Observed changes in sleep architecture
Mood disorders	Major depressive disorder	Hypersomnia, insomnia, circadian early phase	Prolonged sleep latency, increased REM density
	Bipolar affective disorder	In mania: decreased need for sleep, insomnia circadian delayed phase In depression: insomnia hypersomnia, circadian delayed and irregular phases, nightmares	Reduced total sleep time; shortened REM latency
Anxiety and related disorders	Generalized anxiety disorder	Insomnia, poor sleep quality	Increased sleep latency, decreased sleep continuity
	Panic disorder	Insomnia, nighttime awakenings	Non-REM panic attacks; longer sleep latency, reduced total sleep time, reduced sleep efficiency
	Separation anxiety disorder	Difficulty sleeping without attachment figure nearby	Insufficient data
	Social anxiety	Insomnia	Insufficient data
	Posttraumatic stress disorder	Insomnia, nightmares	Reduced sleep continuity, less sleep depth, and changes in REM sleep
	Acute stress disorder	Insomnia, nightmares	Insufficient data
	Adjustment disorders	Insomnia, poor sleep quality	Insufficient data
	Obsessive-compulsive disorder	Insomnia, late chronotype, late circadian phase	Insufficient data
Psychotic disorders	Schizophrenia	Insomnia, hypersomnia, circadian delayed or irregular phases	Reduced sleep depth and sleep continuity
	Schizoaffective disorder	Decreased need for sleep/total sleep time with mania	Insufficient data
Substance use disorders	CNS depressants (alcohol, opiates, sedative-hypnotics) intoxication and with chronic use	Insomnia, hypersomnia (depending on pattern of use and time from last dose)	Insufficient data
	CNS stimulants (cocaine, amphetamines)	Insomnia/hypersomnia, (depending on pattern of use)	Insufficient data
Trauma-based disorders	Posttraumatic stress disorder	Insomnia, nightmares	Reduced sleep continuity, less sleep depth, and changes in REM sleep
	Acute stress disorder	Insomnia, nightmares	Insufficient data
	Adjustment disorders	Insomnia, poor sleep quality	Insufficient data
Neurodevelopmental disorders	Autism spectrum disorder	Insomnia, poor sleep quality, irregular and delayed circadian phases	Reduced sleep efficiency, decreased REM and slow wave sleep duration
	Attention deficit and hyperactivity disorder	Insomnia, sleep-disordered breathing and restless legs syndrome/periodic limb movements, treatment-related insomnia, delayed circadian phases	Insufficient data
Neurocognitive disorders	Alzheimer disease and other dementias	Abnormal sleep-wake cycles, insomnia hypersomnia, irregular circadian phases	Abnormal circadian rhythms (day/night reversal), fragmented sleep
	Diffuse Lewy body dementia and Parkinson disease	Movements during sleep, acting out dreams	REM sleep behavior disorder
Disorders of consciousness	Delirium	Abnormal sleep-wake cycles	Abnormal circadian rhythm, high arousal and awakening index, reduced slow wave sleep and REM sleep

Mood disorders.

Depression. Sleep disturbances (insomnia or hypersomnia) and fatigue are among the diagnostic criteria for major depressive episodes (04). Insomnia is considered an independent risk factor and plays an important role in relapses and recurrences, as it is considered an early sign occurring before both depressive and manic episodes (40; 65). A study of more than 3700 adults with major depressive disorder found that nearly 85% of patients reported symptoms of insomnia (85). Twenty-seven percent of patients reported experiencing all 3 of the major types of insomnia (sleep-onset, mid-nocturnal, and early morning insomnia), with mid-nocturnal insomnia being the most commonly reported type. In a large, community-based cohort study of elderly persons, both short-duration (less than 6 hours per night) and long-duration (9 or more hours per night) sleepers were more likely to have a depressive disorder, including major depressive disorder, minor depressive disorder, or dysthymia, than those sleeping 7 to 8 hours per night (92). Depressed patients also spent more time in bed than those without depression in this study. The severity of illness, cognitive impairments, feelings of hopelessness, lack of resilience, higher likelihood of substance abuse, aggressive and impulsive behavior, difficulties regulating emotions, and increased risk of suicide have all been linked to insomnia (62; 64; 65). In addition, insomnia is associated with a more challenging course and lower response rates to antidepressant treatment in mood disorders (82). Circadian rhythm dysregulation is also typical of depression, especially in the early phases, which are often combined with insomnia and hypersomnia (35). A recent meta-analysis showed that cognitive behavioral treatment for insomnia (CBT-I), which is the first-line treatment for chronic insomnia (76), is effective in treating insomnia and depressive symptoms when insomnia is comorbid with mood disorders (41).

Globally, data indicate that pharmacological treatment of insomnia in mood disorders can also lead to improvements in insomnia symptoms and potentially even in depressive symptomatology. Among GABAergic compounds, eszopiclone has the most evidence supporting its effectiveness in treating insomnia and depressive symptoms when combined with an SSRI in patients with insomnia and major depression. Five randomized controlled trials involving nearly 2000 patients demonstrated that co-administration with an SSRI led to a quicker onset of antidepressant response and a more significant antidepressant effect (32). Among melatonin receptor agonists, melatonin 2-10 PR could potentially serve as an adjunctive therapy for insomnia symptoms in patients with mood disorders, specifically unipolar or bipolar depression. Combining it with antidepressants may also prove beneficial in alleviating depressive symptoms (66). In general, the results related to the effects of dual orexin receptor agonists (DORAs) on insomnia symptoms in the context of mood disorders are very promising. Specifically, both suvorexant and daridorexant have displayed the potential to improve mood symptoms when used to manage insomnia. Daridorexant, especially, has shown to be effective in alleviating both insomnia and mood symptoms in people with unipolar and bipolar depression and has also had a positive impact on manic symptoms (63). Both suvorexant and daridorexant could be beneficial when switching from or discontinuing benzodiazepines in patients with insomnia and mood disorders (63).

Bipolar affective disorder. Sleep disturbance is a cardinal feature of bipolar disorder and part of the diagnostic criteria. During acute mania, patients exhibit markedly reduced sleep time and report a reduced need for sleep and insomnia (70). Even when euthymic, sleep disturbance is common and may affect daytime functioning, with insomnia, hypersomnia, and circadian rhythm dysregulation (38; 35). Both insomnia and hypersomnia have been reported in patients with bipolar depression (38), together with circadian rhythm alterations. Chronotherapeutics, such as light therapy, melatonin agonists, and CBT-I adapted for bipolar patients, are suggested for sleep disorders in bipolar patients (35).

Schizophrenia. Many patients with psychosis have complaints about their sleep, usually due to a problem of sleep onset and maintenance insomnia. The complaint may also involve unsatisfactory sleep related to fragmentation and schedule changes brought about by acute psychosis. In addition, the persistence of sleep complaints in treated schizophrenia is associated with a greater risk of recurrence of psychotic symptoms after antipsychotic withdrawal (16).

The relationship between insomnia and schizophrenia is often viewed as bidirectional; schizophrenia exacerbates sleep disturbances, whereas insomnia can also conversely worsen schizophrenia symptoms (40). Insomnia might emerge during any stage of the illness, including the prodrome, first episode, acute recurrence, and even during remission stages. Severe insomnia is a hallmark of the prodromal phase of psychosis, and it is also a major risk factor for relapse of psychosis. Sleep disturbances have also been associated with exacerbated symptoms in schizophrenia, particularly positive symptoms, including delusions, hallucinations, disorganized thinking, and behavior, or with negative symptoms and cognitive dysfunctions (65). Addiionally, insomnia is associated with increased suicidal ideation and lifetime suicide attempts in patients with schizophrenia. Growing evidence suggests that insomnia may put individuals at a significantly greater risk of developing psychosis; in particular, the relationship between adolescent insomnia and psychotic-like experiences has been shown (65). Studies have also demonstrated that insomnia experienced in adolescents places these individuals at a clinically high risk of future psychosis. A recent meta-analysis confirmed that the early stage and at-risk population of schizophrenia presents with significant impairments of subjective sleep quality continuity, duration, and initiation. Indeed, more precisely, these patients with clinical ultra-high risk and a first episode of psychosis had a lower sleep quality, shorter total sleep time, lower sleep efficiency, longer sleep onset latency, and longer duration of wake after sleep onset (28).

Anxiety and related disorders. Sleep complaints are common in anxiety disorders. Symptoms of insomnia are reported by more than 75% of patients with generalized anxiety disorder (07). Objective studies suggest that patients with generalized anxiety disorder have decreased total sleep time and increased latency to sleep, which correlates with patient reports of ruminating when trying to fall asleep (21).

Since DSM-III was published, insomnia has been one of the key diagnostic criteria for general anxiety disorder. Available data show that insomnia is associated with increased odds of general anxiety disorder (40). Though scarcely investigated, insomnia has been reported in 15% to 85% of patients with general anxiety disorder among adults and up to 87% in children and adolescents (61). Insomnia is related to general anxiety disorder severity and higher risk of comorbidities, such as depressive symptoms and alcohol use, and with resistance to general anxiety disorder treatments. Different therapeutic approaches have been proposed for insomnia treatment in general anxiety disorder. In particular, CBT-insomnia and eszopiclone, when combined with general anxiety disorder therapy, have been effective in treating both insomnia and general anxiety disorder symptomatology, whereas other therapeutic approaches have been proposed, such as gabapentin, pregabalin, or rTMS (repetitive transcranial magnetic stimulation) in few studies.

Similarly, 70% of patients with panic disorder also report sleep disturbances (59). Patients with panic disorder exhibit increased sleep latency and decreased efficacy, with decreased total sleep time. Patients may experience nocturnal panic attacks that may further disrupt sleep (21). Available data show that insomnia symptoms are associated with increased odds of panic disorder and agoraphobia, and their frequency may range from 12% to more than 80% in patients. There is also support for the link between insomnia and panic disorder severity, which may mediate the link with depression and resistance to panic disorder treatments.

Trauma-based disorders. Up to 90% of patients with posttraumatic stress disorder report problems with sleep (55). Indeed, DSM-5 indicates that insomnia and nightmares are diagnostic features of posttraumatic stress disorder (04). The range of sleep changes after trauma extends beyond nightmares and includes insomnia, frequent awakenings, decreased sleep efficiency, and disruptive sleep behaviors. Conditions such as periodic limb movement disorder and obstructive sleep apnea are frequently comorbid with posttraumatic stress disorder (21; 53). Data showed that insomnia may predict subsequent PTSD (61). A meta-analysis of 75 studies estimated that the prevalence of insomnia in PTSD was 63%. Insomnia may contribute to maladaptive stress and emotional responses in PTSD and may complicate its trajectory, increasing the risk of depression, substance use disorder, or suicidal risk. Standard PTSD treatments may decrease insomnia symptoms, but residual insomnia is frequent. Intervention targeting trauma-specific insomnia produces significant short-term effects, including substantial reductions in PTSD symptoms and insomnia severity.

Cognitive behavioral therapy combined with imagery rehearsal therapy or eszopiclone as adjunct therapies resulted in the most effective treatments for insomnia in PTSD (61). Insomnia is now considered a risk factor for obsessive-compulsive disorder, including the perinatal period and the pandemic episodes. Insomnia is frequent in patients with obsessive-compulsive disorder and may affect 30.8% to 70% of them. Insomnia was most related to obsessive-compulsive symptoms compared to other sleep disturbances, such as delayed bedtime and nightmares. This relationship was particularly strong between insomnia and the obsessions and unacceptable thoughts domain of obsessive-compulsive disorder and with the severity of obsessive-compulsive disorder. Similar to other anxiety disorders, the therapeutic approach for obsessive-compulsive disorder may improve insomnia symptoms, but a proportion of the patients suffered from residual symptoms of insomnia after treatment. Hence, a specific insomnia approach has been suggested for obsessive-compulsive disorder.

Neurodevelopmental disorders.

ADHD. Parents commonly report sleep problems in their children with attention deficit hyperactivity disorder. Compared with controls, children with the combined type of ADHD have significantly greater difficulties with enuresis, decreased total sleep time, and increased sleep latency (52). Children with the inattentive type may sleep more than normal and have greater daytime sleepiness than controls (52). Children with ADHD have more movements in sleep than controls (20). Although sleep disturbances may impact up to 70% of children with ADHD, the relationship is complicated and likely multifactorial. Insomnia and circadian rhythm dysregulation may also affect most adults with ADHD (84). Sleep problems may be part of the ADHD pathology or result from treatment of ADHD with stimulant medications, and comorbid conditions, such as sleep apnea, may mimic or exacerbate ADHD symptoms (90).

Autism. Sleep disturbances are found in over 70% of children with autism. Sleep studies indicate reduced sleep efficiency, less slow wave and REM sleep, and more desaturations (01). Sleep disturbances also affect adults with autism spectrum disorders, and circadian rhythm alterations are aspects of insomnia (12).

Substance use disorders. Systematic and narrative literature reviews suggest that substance use disorders, including alcohol, opioids, cannabis, cocaine, or sedative-hypnotic-anxiolytic drugs, share a bidirectional relationship with insomnia and circadian sleep alterations (72; 34). Insomnia can occur before substance dependence or abuse and be associated with withdrawal and relapse. Furthermore, sleeplessness has been associated with ill physical well-being and may also open the door to other addictive side effects. In addition, insomnia has been associated with numerous adverse outcomes in the general population that may also impact patients with substance use disorders, such as decreased well-being and quality of life, occupational functioning, work performance, increased injuries, and poorer physical and mental health. The prevalence of insomnia varies from 30% to 85% in patients with substance use disorder.

Substances like alcohol, cocaine, and heroin are more frequently used by people with insomnia than by people who are generally well-rested. Self-medication attempts can be made to facilitate sleep or reduce the physical and emotional burden resulting from sleep difficulties. Often, alcohol is used to initiate sleep. However, chronic alcohol use is associated with changes in sleep onset and maintenance (10). Complaints of hypersomnia, fragmented sleep/wake cycle, and parasomnias may also occur. Alcohol use disorder is also associated with obstructive sleep apnea. Independent of other factors, insomnia is also a predictor of relapse to alcoholism (10; 15). The duration and quality of sleep are greatly impacted by persistent drug use, and these detrimental effects can also be observed during withdrawal. The effect is dose-dependent, but most drugs alter sleep duration at various stages or the timing of REM and NREM sleep cycles (72; 34).

Prognosis and complications

Sleep disturbances complicate the clinical course of psychiatric disorders. They are associated with poor response to psychotherapy and pharmacotherapy for depression (24; 89; 11; 78; 65) and negatively impact functioning in posttraumatic stress disorder (18; 46). Long (10 or more hours) and short (6 or fewer hours) sleep duration is associated with persistence of anxiety and depression over a 2-year period (93). Insomnia, nightmares, and other sleep disturbances are associated with an increased risk for suicidal ideation, suicide attempts, and completed suicide (68). Treatment of the psychiatric disorder does not always lead to improvements in sleep, as observed in studies of patients with mental comorbidities. Indeed, insomnia is the most commonly reported residual symptom of depression (42). Individuals who report residual sleep disturbances following remission of depression have a poorer quality of life (49) and an increased risk for relapse (27; 26). In these cases, sleep disturbance may persist with the development of perpetuating factors such as substance abuse, poor sleep hygiene, or as a consequence of the medications used to treat the psychiatric disorder. Therefore, independent treatment of sleep disturbance is warranted for some patients, particularly those whose sleep problems persist after their psychiatric condition has remitted.

Importantly, sleep disorders such as insomnia (79; 65), sleep-disordered breathing (95), circadian rhythm dysregulation, and nightmares can be successfully treated in individuals with psychiatric illness (35). A major complication of sleep disorders associated with psychiatric illness is a missed diagnosis of a treatable but comorbid organic condition such as obstructive sleep apnea. If the psychiatric diagnosis is pursued alone, a "refractory" case results, leaving the undiagnosed organic pathology to worsen. Similarly, patients presenting with insomnia should be screened for other conditions such as anxiety, depression, and trauma-based disorders as well.

Clinical vignette

JW, a single, 25-year-old female with bipolar type I disorder, had been relatively stable for 3 years on a regime of lithium 600 mg twice daily and Ambien (zolpidem) 10 mg at bedtime. She had not had a distinct mood episode since her last episode of bipolar mania 3 years prior. She obtained 7 to 8 hours of sleep at night and was satisfied with her job as a respiratory therapist working for a durable medical equipment company.

After the company went out of business, JW took a job as a sleep technician at a growing sleep disorders center. The new job involved working 8 pm to 6 am Tuesday through Friday. JW could only sleep 5 to 6 hours after her shift, even with the aid of zolpidem. She slept about 7 hours on nights she was not working.

Three days before presentation, JW felt unusually energized as she was finishing her shift. She drove home and spent the next 16 hours cleaning her house from top to bottom. JW then slept for an hour and went to a dance club. She left the dance club when it closed at 3 am and returned to her house, where she slept for 2 hours. She exercised extensively the next day and showed up at the sleep center that night. She told her coworkers she was there because she was now the owner of the sleep center, and she wanted to make sure they were doing their jobs right. She was talking rapidly and pacing. JW became agitated when the other sleep technicians refused to take orders from her. The medical director was called. He, with great difficulty, was able to convince her to go to the emergency room. The medical director and a technician drove her to the emergency room, where treatment was begun for a manic episode.

Comment. JW developed a manic episode with symptoms of grandiosity, decreased need for sleep, rapid speech, and increased goal-directed activity. A change in sleep habits can precipitate a bipolar mood episode. Night work and shift work have a destabilizing influence on bipolar disorder.

Biological basis

Etiology and pathogenesis

The etiology of sleep abnormalities in psychiatric disorders is believed to be bidirectional.

Genetic vulnerability for psychiatric disorders and insomnia or circadian sleep dysregulation may overlap. There is emerging evidence for an insomnia-specific polygenic effect on anxiety-mood disorder vulnerability and of a circadian clock gene mutation effect on mood disorder vulnerability (65).

Neuroanatomical circuitry involved in insomnia and circadian rhythm dysregulation may contribute to psychopathology. Accumulating neuroanatomical findings suggest there is likely overlap between circuitries of sleep regulation, anxiety, and mood. Although sleep is critical to the development of these neuroanatomical areas for their plasticity and synaptic balance during adult life (02), insomnia has been related to maladaptive neuroplasticity in both neurodevelopment and adult life. This may lead to impaired emotional, immune, and endocrine pathways (62; 67). Benca and colleagues have reviewed polysomnographic findings in psychiatric disorders (08). Patterns in depression consist of disturbances in sleep continuity (increased latency, decreased sleep efficiency, increased awakenings with early morning awakenings), abnormal distribution of slow-wave sleep, and abnormalities of rapid eye movement sleep (reduced REM latency, abnormal distribution of REM sleep with increased REM percentage of total sleep time, and increased REM density). High-density electroencephalography has shown that females with depression have increased slow-wave activity in bilateral prefrontal regions relative to healthy controls, whereas there are no differences in slow-wave activity between depressed males and healthy controls (69). Continuity disturbances tend to parallel the severity of depression, whereas reduced REM latency and slow-wave sleep tend to persist during remission. In anxiety disorders, the most common finding is sleep continuity disturbance, although inconsistent abnormalities of REM sleep are prominent in studies of posttraumatic stress disorder. Patients with alcohol use disorder display sleep continuity disturbances, decreased slow-wave sleep, and decreased REM sleep, and disturbances may persist after years of abstinence. The presence of insomnia is associated with higher craving for alcohol, which is reduced with sleep aids (39). The sleep patterns of schizophrenia are characterized by decreased REM latency, decreased stage 4 or slow-wave sleep, and sleep continuity abnormalities. Polysomnographic studies of unmedicated manic patients have found shortened total sleep time, shortened REM latency, and increased time awake in bed (70).

There is strong evidence for muscarinic (cholinergic) involvement in short REM sleep latency. Patients with depression and schizophrenia show a substantial shortening of the already short REM sleep latency when given muscarinic agonist drugs (77; 81). Levels of an abnormal plasma cholinesterase isozyme in patients with schizophrenia correlate with REM latency (44). A polymorphism of the muscarinic receptor 2 gene was found to be associated with major depression in women (19).

Similar sleep alterations have been found in insomnia, presenting a link with the psychopathology of REM sleep instability (75). Because increased REM pressure is a transdiagnostic phenomenon across various mental disorders, such as depression, schizophrenia, borderline personality disorder, and substance dependency, this has been hypothesized as the pathway linking insomnia to mental disorders (75).

Neuromodulators of sleep regulation or psychopathology. Orexin dysfunction has been hypothesized to be implicated in the hyperactivation of arousal-promoting systems in insomnia and pathophysiology (13). Several other potential mechanisms through which sleep alterations might increase the risk or perpetuation of mental disorders have been hypothesized. Insomnia, sleep loss, and circadian sleep dysregulation may be linked to stress and hyperactivation of the inflammatory system, monoamine neurotransmission alterations, hypothalamic-pituitary-adrenal-axis abnormalities, glutamatergic and orexinergic dysregulation, brain neurotrophic factors alterations, and brain neuroplasticity dysfunction (70; 65).

Studies utilizing functional brain imaging have shown an overlap between abnormal regions involved in psychiatric disorders and those known to be involved in sleep regulation. Abnormalities of central monoaminergic systems, especially serotonin, have been implicated in the pathogenesis of depression, and these systems play critical roles in sleep regulation (48; 02).

Epidemiology

Insomnia disorder may affect 10% of the population (76). Insomnia is the most frequent sleep disorder in mental disturbances and may affect 80% to 100% of people during the acute mental phases and 45% to 55% during the bipolar inter-episode period. Insomnia is highly prevalent in individuals experiencing anxiety, affecting more than 80% of patients with general anxiety disorder and 70% with panic disorder (65). Insomnia and sleep disturbances are common in patients with schizophrenia and psychotic spectrum disorders, with estimates for the prevalence varying from 36% to 80%. In patients with substance use disorder, the prevalence of insomnia ranges from 30% to 85%, depending on the substance of abuse. Among circadian rhythm disorders, phase delay disorder seems to be the most frequent, with a prevalence of 0.17% in the general population. Phase delay disorder affects 5% to 15% of patients with bipolar disorder at different stages of the course, also affecting patients in the interval phases, up to 33% of patients with ADHD, and 20% of patients with autism spectrum disorder and schizophrenia (84; 35). Irregular sleep rhythm is rare in the general population and common in patients with mood disorders, ADHD, and autism spectrum disorder.

Prevention

Insomnia and sleep disturbances increase the risk for the first onset of depression, anxiety disorders, and substance abuse (09; 43; 40) and predict relapse to depression and alcoholism (10; 27; 65). Treatment of these disorders may, thus, help prevent the development of many psychiatric conditions and improve clinical course for patients whose psychiatric disorder has remitted. Early treatment and education may help prevent comorbidity (eg, substance abuse, poor sleep hygiene).

Good sleep hygiene may prevent exacerbation of sleep disturbances. As mentioned, maintaining consistent sleep habits is especially important in preventing manic episodes in bipolar affective disorder.

Differential diagnosis

Periodic limb movement disorder and obstructive sleep apnea are more common in patients with posttraumatic stress disorder than in the general population (50). Obstructive sleep apnea can produce severe daytime somnolence and cognitive impairment, which together resemble psychomotor retardation, a diagnostic feature of both depression and bipolar disorder or poor concentration with ADHD. Symptoms of sleep apnea, including snorting or stopping breathing while asleep, are associated with depressive symptoms (96).

Narcolepsy shares features with several psychiatric syndromes. These shared features, especially hallucinations, can be a source of diagnostic confusion. Most patients with narcolepsy have full insight into their hypnagogic hallucinations. They are unusually realistic 3-dimensional visual hallucinations and often surface with multimodal sensory features (sound, touch, taste, smell). At times, they are overlaid on perceptions of the actual environment, giving rise to delusional interpretations of ghosts and the like (30). Hallucinations in schizophrenia can include visual components but more commonly involve disembodied voices that converse with the patient, comment about him or her, or give instructions. Delusions tend to be elaborate and highly implausible, whereas psychotic patients with narcolepsy tend to restrict their delusions to a simple explanation of the repetitive hallucinations ("secondary delusions"). Occasionally, patients presenting with what appears to be hypomania (irritability, hyperactivity, rapid speech, etc.) are found to have narcolepsy after sleep laboratory testing. Such patients may never have regarded themselves as “sleepy.”

Sleep disturbances may coexist with psychiatric disorders and medical disorders, including pain disorders, prostatic hypertrophy, nocturnal asthma, cardiopulmonary disease, and hyperthyroidism. Medications used to treat psychiatric disorders, such as SSRIs, can disrupt sleep either directly through their activating effect or indirectly through the worsening of restless legs syndrome or periodic limb movement disorder.

Diagnostic workup

Patients presenting with sleep complaints should receive a full evaluation with thorough medical and psychiatric review of systems. A careful sleep history is necessary to understand sleep patterns and any behaviors that may be contributing (ie, using full spectrum screens before bed, caffeine, and alcohol and other substance use, including over-the-counter medications).

A physical examination is important in all patients to evaluate for any signs or symptoms of any condition that may be associated with changes in sleep as primary sleep disorders can mimic some psychiatric symptoms or be co-occurring.

Daily sleep logs or diaries maintained over a 1- to 2-week period can aid in diagnosing insomnia as suggested by subjective report of difficulty falling asleep or maintaining sleep in conjunction with daytime impairments due to poor sleep. Individuals with bipolar disorder who report difficulty falling or staying asleep or short sleep duration (eg, less than 6 hours) without daytime impairment or excessive daytime sleepiness may be experiencing mania or hypomania. Sleep logs should correlate with presentation of pressured speech, expansive affect, increased goal-directed activity, and other symptoms that are part of mania. Sleep logs should be used to evaluate circadian sleep alterations in patients with mental disturbances because they are so frequent. A special question on dreaming activity should be included in mental disturbance examinations because bad dreams or nightmares may be often present in mental disturbances.

A polysomnogram and multiple sleep latency test may be indicated if a specific sleep disorder, such as narcolepsy, periodic limb movement disorder, or sleep apnea, is suspected or when the sleep disturbance persists despite treatment of the underlying psychiatric disorder. Although some psychotic patients may not easily comply with sleep laboratory procedures, most such patients can be studied if given more attention by the technicians.

Management

The management of sleep disturbance in psychiatric disorders depends on the type of sleep disorder. Cognitive and behavioral therapy for insomnia is considered the first line of treatment, and data sustain its efficacy when insomnia is comorbid with mental disturbances (Hertenstein et a 2022). Cognitive behavioral therapy for insomnia (CBTi) is a highly effective nonpharmacological treatment option for insomnia (54). Typically, short-term (4 to 8 sessions) cognitive behavioral therapy for insomnia integrates cognitive and behaviorally-based treatment modalities to target the factors believed to perpetuate insomnia. The behavioral components include sleep restriction, stimulus control procedures, and relaxation training. The cognitive component of therapy consists of educating the patient about the role of negative sleep-related thoughts in perpetuating sleep problems. Patients are also educated about sleep hygiene, which refers to daytime habits (eg, exercise, napping, substance use close to bedtime) and environmental circumstances (eg, temperature regulation, bed comfort) that can help or hinder sleep.

Treatment of insomnia using cognitive behavioral therapy for insomnia improves sleep in patients with comorbid psychiatric conditions, including depression, posttraumatic stress disorder, and alcoholism (05; 51; 86). For individuals with depression, it enhances treatment response to antidepressant medications and improves remission rates (51).

Internet-based cognitive behavioral therapy for insomnia has been studied and found to be an effective treatment for insomnia (31). Unguided, digitally-delivered cognitive behavioral therapy for insomnia has effects that persist up to 18 months after intervention (94). Treatment of insomnia with computer-based cognitive behavioral therapy for insomnia was found to reduce incident depression at 1-year follow-up (17).

Drugs indicated for the treatment of insomnia include benzodiazepines and benzodiazepine receptor agonists, also known as Z Drugs.

Pharmacological therapy beyond agents used to treat the underlying psychiatric disorder may benefit some patients. Medications for sleep can be divided into GABAergic medications, melatonin/agonists, sedating antihistamines, and, more recently, orexin-antagonists.

Benzodiazepines or benzodiazepine receptor agonists, such as zolpidem or zaleplon, may be used, preferably on a short-term or intermittent basis. They should be avoided in any patients who have a history of alcohol or sedative/hypnotic use disorders, the elderly, or patients with respiratory disease. The benzodiazepine receptor agonist eszopiclone has been studied in patients with coexisting insomnia and major depressive disorder. During an 8-week trial involving this population, eszopiclone combined with fluoxetine improved wake time after sleep onset, total sleep time, sleep latency, and depression rating scale scores compared to patients taking fluoxetine alone (32). In addition to being studied in patients with coexisting major depressive disorder and insomnia, eszopiclone has also been shown to be an effective hypnotic in patients with generalized anxiety disorder and coexisting insomnia (71). When administered with an SSRI, eszopiclone significantly improved insomnia and depressive symptoms in patients with major depression, whereas zolpidem improved insomnia symptoms but not mood symptoms. Treatment of insomnia with these agents beyond 3-4 weeks is not endorsed in Europe by drug regulating authorities because of the related adverse events and the emergence of tolerance/rebound and abuse/dependency. The hypnotic eszopiclone has received an extended use (8 to 12 weeks) approval.

In Europe, a prolonged-release formulation of melatonin 2 mg can be prescribed for long-term (3 months) treatment of insomnia in patients over 55 years of age. These were studied in patients with bipolar and unipolar depression. For unipolar or bipolar depression, melatonin may be recommended as an adjuvant treatment for insomnia symptoms. Regarding the melatonin formula, prolonged release at 2 to 10 mg should be preferred for insomnia treatment in mood disorders. Higher doses of melatonin (more than 2 mg prolonged-release) might be needed in mood disorders compared to patients with insomnia disorder in relation to polymorphisms of circadian clock genes or to mutations in melatonin pathway-related genes and receptors that characterize patients with mood disorders. Conflicting results are presented for ramelteon (56).

Orexin receptor antagonists (DORAs) have been proposed for the treatment of depression, showing antidepressant-like activity in animal models (13). In humans, the efficacy of suvorexant has been investigated in different studies in patients with insomnia. A significant improvement in self-reported sleep quality, duration, and continuity was found after 1 week of treatment with suvorexant 15 mg or 20 mg. Similarly, in three studies, the DORA daridorexant 50 mg was shown to also improve insomnia and mood symptoms in patients with unipolar and bipolar depression treated with SRRIs and mood stabilizers (63).

In addition, it would also be helpful to address circadian rhythm alterations that are often associated with insomnia in mood disorders. In this framework, the importance of integrating insomnia treatment with chronotherapeutics in mood disorders emerges (35). These interventions include CBT-I, which may be a particularly useful intervention to stabilize sleep and circadian rhythms even in bipolar depression, along with light therapy and sleep deprivation. The maintenance of a stable sleep/wake cycle and regularization of the circadian rhythm are key components of effective psychotherapy for bipolar disorder. Daily sleep diaries can be helpful to track the sleep/wake cycle in patients with bipolar disorder. Interpersonal and social rhythm therapy is most effective for mood episode prophylaxis in the maintenance phase of bipolar disorder and in individuals without significant medical comorbidity or anxiety (33). A pilot study found that “dark therapy,” which is 14 hours of enforced darkness from 6 pm to 8 am for 3 consecutive nights, was a useful add-on therapy for inpatients with bipolar mania (06).

Continuous positive airway pressure is the gold-standard treatment for sleep-disordered breathing. Treatment of sleep-disordered breathing using continuous positive airway pressure in individuals with depression is associated with a reduction in depression symptoms, even in patients whose depression was resistant to pharmacotherapy (37).

There is growing evidence that CBT-I may reduce anxiety symptoms in healthy individuals and those experiencing anxiety/anxiety-related disorders (41).

In the short-term, pharmacological options include the use of benzodiazepines and non-benzodiazepine allostatic modulators of the GABA receptor with conflicting results except for eszopiclone. Randomized clinical trials were conducted in individuals with general anxiety disorder and PTSD. Studies have shown that the co-administration of eszopiclone and an SSRI was effective in insomnia and anxiety symptoms. Melatonin has not been evaluated as a treatment for insomnia in anxiety disorders, including generalized anxiety disorder, obsessive-compulsive disorder, social phobia, specific phobia, or posttraumatic stress disorder. DORAs are emerging in anxiety and related disorders, and both suvorexant and daridorexant were shown to improve insomnia and anxiety symptoms as well (61; 63).

Administration of prazosin, an alpha-1 adrenergic antagonist, has shown some evidence to support its use to prevent nightmares at doses of 1 to 20 mg/day in several small studies; it also decreased the intensity and frequency of posttraumatic stress disorder-related nightmares and improved subjective sleep quality (25). A study did not show an effect of prazosin to combat posttraumatic stress disorder (73). Imagery rehearsal therapy, targeting nightmares and sleep disturbance in individuals with posttraumatic stress disorder, improves sleep, nightmares, and daytime functioning (45; 22; 14). Combining imagery rehearsal therapy and cognitive behavioral therapy for insomnia improves sleep quality more than imagery rehearsal alone (14).

Onemeta-analysis demonstrated that cognitive behavioral therapy is effective for the treatment of insomnia in patients with clinical diagnoses of different psychiatric disorders, including schizophrenia. Indeed, in most patients with schizophrenia and insomnia, the usual treatment is the supplementation of antipsychotics with benzodiazepines or Z-drugs. However, prolonged benzodiazepine administration has been associated with various adverse reactions, including sedation and cognitive impairment, and the effects of antipsychotics on sleep are not well established. Therefore, the established pharmacological pathways for the treatment of insomnia in schizophrenia are still under evaluation. Some evidence suggests melatonin 2 mg prolonged-release administration for insomnia treatment in schizophrenia. Because melatonin may have chronobiotic properties, it may be useful in schizophrenia. Data on insomnia treatment suggest that the prolonged-release melatonin formulation at 2 mg is effective in improving sleep symptoms in schizophrenic patients (66). The interaction between orexin and dopaminergic neurons in the midbrain, thalamocortical area, and amygdala suggests a potential role for orexinergic neurons in modulating dopaminergic neurons. The preclinical evidence indicates a deficiency of orexins in schizophrenia, suggesting that DORAs may be useful in the management of insomnia associated with schizophrenia. Manipulations of sleep can have a positive impact on treating schizophrenia by promoting the restorative effects of sleep on cognition, metabolism, and immune function and by decreasing hyperarousal (13).

The therapeutic approach remains a significant obstacle for insomnia and circadian sleep disorders in the context of substance use disorders. CBT-I is the recommended first-line treatment for combined insomnia and substance use disorder, especially for alcohol use disorder. The treatment options available for insomnia symptoms and disorders in substance addiction are limited, primarily because conventional hypnotics that target benzodiazepine receptors are associated with abuse potential, withdrawal effects, and the potential for overdose.

It has been demonstrated that melatonin supplementation holds significant value in managing sleep and circadian rhythm disorders in these patients, although the current studies are limited. The ability of melatonin to mitigate different aspects of addiction neurobiology has been extensively studied in animal studies. Studies have reported the efficacy of melatonin supplementation in controlling drug-seeking behavior, opiate withdrawal/relapse, behavioral sensitization, sleep regulation, circadian rhythm disorders, and neuroplasticity in brain areas linked to reward and emotion regulation. Although melatonin did not increase the likelihood of discontinuation of benzodiazepine, it did enhance sleep quality, particularly in subjects who continued to utilize benzodiazepine. Prolonged-release melatonin at 2 mg may be useful during benzodiazepine discontinuation and may improve sleep quality during benzodiazepine withdrawal. The use of melatonin in the treatment of sleep disturbances in patients with alcohol use disorder has been discussed in a review (66).

The use of antagonists of orexin receptors is becoming a promising strategy for treating drug addiction (13). Within this framework, animal studies demonstrated that DORAs reduced acute cocaine-induced impulsivity, decreased motivational and hedonic properties of cocaine, reduced relapse from alcohol, and enhanced disrupted sleep in relation to alcohol withdrawal. Several studies regarding this topic are currently underway. Two studies focused on the administration of daridorexant or suvorexant with alcohol use in healthy individuals. In contrast, in another study, suvorexant was administered to individuals with cocaine use disorder in an experimental protocol involving cocaine assumption. Suvorexant (10 mg, 20 mg) increased self-administration of 10 mg/70 kg cocaine and decreased oral temperature but did not significantly alter any other effects of cocaine. DORAs have the potential to emerge as a promising resource in the treatment of drug addiction, as they target both specific mechanisms and comorbid or withdrawal-related sleep problems. However, further research is required to evaluate their efficacy and safety in patients with substance use disorder.

Special considerations

Pregnancy

Symptoms of depression and anxiety, along with their associated sleep disturbances, may be worsened by pregnancy but tend to be particularly severe in the postpartum period. Women are at particular risk for insomnia and sleep-disordered breathing during pregnancy due to physiological changes (57; 60). Insomnia and poor sleep quality during pregnancy and postpartum are associated with symptoms of depression and anxiety (29; 67). For women with a prior history of depression, experiencing poor sleep quality in the early postpartum period increases the risk for relapse (58). Treating insomnia with cognitive-behavioral therapy is associated with improvements in both sleep and postpartum depression symptoms (87; 67).