Insomnia in patients with schizophrenia: current understanding and treatment options

https://doi.org/10.1016/j.pnpbp.2019.01.016Get rights and content

Highlights

  • Elevated rates of insomnia in schizophrenia contribute to poor clinical outcomes.

  • Comorbid insomnia is a valuable therapeutic target in patients with schizophrenia.

  • More research is needed to assess the use of suvorexant in this patient population.

Abstract

In patients with schizophrenia, insomnia is a common yet often overlooked comorbidity. With sleep disturbances inextricably linked to increased severity of schizophrenia and worsening clinical outcomes, insomnia is an important therapeutic target within this patient population. Thus, through a review of the current literature, this paper reiterates the important etiological link between these two conditions, while evaluating the safety, efficacy, and limitations of current therapeutic options for the treatment of comorbid insomnia in schizophrenia. Despite the continued use of benzodiazepine receptor agonists (BZRAs) for insomnia, the use of other therapies such as Cognitive Behavioral Therapy for Insomnia (CBT-I) and suvorexant warrants increased consideration. More large-scale clinical trials are needed to assess the efficacy of such therapeutic options in the schizophrenia patient population.

Introduction

Although often overlooked, insomnia is a common comorbid condition in patients with schizophrenia. Accumulating evidence has suggested that sleep disturbance can be a risk factor for, or a prodromal symptom of psychosis; it can also aggravate psychotic symptoms, therefore interfering with the treatment of schizophrenia (Reeve et al., 2018). Symptoms related to disordered sleep, including reduced sleep time and quality of sleep, often go untreated and persist as chronic, clinically significant insomnia (Kaskie et al., 2017). Findings in polysomnography (PSG) studies such as increased sleep latency, reduced rapid eye movement (REM) latency, and reduced spindle activity correlate with the elevated rates of sleep disturbance and sleep disorders among patients with schizophrenia (D'Agostino et al., 2018). Notably, observed abnormalities in these polysomnographic traits have been shown to be heritable, thus further strengthening the argument for an etiological link between insomnia and schizophrenia (Manoach et al., 2014). Clinical interest in this relationship has grown with the understanding that the presence of sleep disturbance, especially clinically significant insomnia, corresponds with reduced quality of life (QOL) and likely worse clinical outcomes for patients with schizophrenia (Xiang et al., 2009; Subramaniam et al., 2018). As such, the development of viable treatment options to alleviate comorbid insomnia is important in the schizophrenia patient population.

Up to 80% of patients with schizophrenia experience insomnia-related symptoms, including an inability to fall or stay asleep, or daytime somnolence (Cohrs, 2008). Insomnia is a disorder specifically defined by these characteristic symptoms, with acute insomnia typically lasting less than 4 weeks and chronic insomnia characterized by a longer-term pattern of disrupted sleep that lasts for over 6 months. The greater extent to which symptoms persist and affect daily function in insomnia distinguish the disorder from subthreshold or transient struggles with sleep (Soehner et al., 2013). Thus, increased symptoms of sleep disturbance also correspond with a greater prevalence of clinical insomnia in patients with schizophrenia, with even conservative estimates ranging from 30 to 40% compared to a prevalence of about 10% in the general population (Xiang et al., 2009). A recent 2018 study estimated clinical insomnia in a population of patients with first episode psychosis at 22.6% (Subramaniam et al., 2018).

Several neurobiological mechanisms help to explain the comorbid insomnia observed in patients with schizophrenia. Research has shown that the thalamus, a structure integral for sleep regulation, is consistently reduced bilaterally among schizophrenia patients (Byne et al., 2009). Thalamic abnormalities are just one suggested neurobiological mechanism that potentially explains the intricate link between schizophrenia and insomnia. Other proposed mechanisms include dopamine dysregulation in schizophrenia and its simultaneous role in the sleep-wake cycle, with the dopaminergic D2 receptor, in particular, playing a specific role in REM sleep (Lima et al., 2008; Monti et al., 2013). Overactivity of the D2 receptor, along with enhanced sensitivity of dopaminergic neurotransmission, could contribute to symptoms of insomnia (Yates, 2016). Human and animal models have shown that elevated dopamine levels in the brain disrupt sleep and circadian rhythms, whereas sleep disruption also increases dopamine release and sensitivity (Harvey et al., 2011). Thus, while the exact mechanism has not been clearly elucidated, dopaminergic overactivity seems to provide a viable hypothesis linking schizophrenia and insomnia. Antipsychotic agents, which block dopamine D2 receptors, often alleviate both schizophrenia and insomnia-related symptoms (Abi-Dargham and Laruelle, 2005).

In addition to possible neurobiological mechanisms described above, other factors, such as psychosocial stress, substance abuse, and psychotic experiences, may also contribute to the high prevalence rate of insomnia in patients with schizophrenia. Stressful life events are closely associated with the onset of chronic insomnia, and thus the high-stress environment that predisposes individuals to developing schizophrenia likely contributes to the high risk of insomnia in this patient population (Lim et al., 2009). Psychotic symptoms, such as hallucinations and delusions, can precipitate sleep disturbances and insomnia (Afonso et al., 2011). In addition, negative symptoms of schizophrenia, such as avolition, may lead to excessive daytime inactivity that interferes with nighttime sleep. Cognitive deficits in patients with schizophrenia can contribute to poor sleep hygiene, which further complicate the sleep pattern and quality in these patients (Waite et al., 2016). Furthermore, substance-induced insomnia has been well documented (Volkow, 2009); the elevated rates of substance use in patients with schizophrenia also could contribute to insomnia (Bahorik et al., 2017; Thoma and Daum, 2013).

This review seeks to reiterate the important link between schizophrenia and insomnia, examine the currently available treatment options for insomnia in patients with schizophrenia, and look at the associated challenges that come with treating insomnia in this patient population. The studies included in this review were published between 1981 and 2018, and identified by PubMed searches using combinations of the keywords “schizophrenia,” “insomnia,” “pharmacotherapy,” “orexin-hypocretin pathway,” “benzodiazepines,” “suvorexant,” “psychosis,” “alternative medicine,” and “psychotherapy”. Insomnia was a search term included in all queries (e.g. Insomnia AND Pharmacotherapy AND schizophrenia). A variety of review papers, meta-analyses, and original articles were obtained from these broad initial searches. In order to identify articles specifically pertaining to the stated aims of this review, another search was conducted to identify articles which included relevant search terms in the title and abstract. Among this narrower grouping, articles were selected for full-text review based on their relevance to the aims of this review and scientific rigor of study design. Only articles that included queried key terms in the title and abstract were considered for full-text review. A total of 17,095 articles were identified which matched the search criteria and 104 full-text articles were reviewed (Table 1).

Section snippets

Insomnia in schizophrenia: clinical implications

The relationship between insomnia and schizophrenia is often viewed as bidirectional: schizophrenia exacerbates sleep disturbances while insomnia also can conversely worsen schizophrenia symptoms (Cosgrave et al., 2018). A diathesis-stress model of insomnia suggests that cognitive intrusion and psychotic symptoms can act as significant risk factors for incident insomnia (Reeve et al., 2015). On the other hand, as an aggravator of schizophrenia's core symptoms, insomnia's effects on illness

Pharmacotherapy options

There are a range of pharmacological treatment options for insomnia. The most widely used medications for chronic insomnia currently include benzodiazepines and benzodiazepine receptor agonists (BZRAs). Suvorexant, an orexin receptor antagonist, is a novel treatment that became available recently. Other FDA approved medication options indicated for insomnia treatment include barbiturates, ramelteon, and doxepin.

Efficacy

Cognitive Behavioral Therapy for Insomnia (CBT-I) alleviates insomnia-related symptoms through strategies such as cognitive restructuring, stimulus control, and relaxation training. Sleep hygiene remains a significant issue in schizophrenia, and thus targeting maladaptive coping strategies and intrusive thoughts may allow for clinically significant decreases in insomnia (Izuhara et al., 2018). Behavioral interventions such as activity modification are particularly important to improve negative

Acupuncture

Acupuncture is a form of alternative medicine that has been utilized in insomnia treatment. In a meta-analysis of 46 randomized trials that included 2822 patients with primary insomnia, acupuncture was as effective as pharmacotherapy in improving average sleep duration. Acupuncture in combination with pharmacotherapy demonstrated a greater effect than pharmacotherapy alone on total sleep duration. In the vast majority of these clinical trials, there was no significant difference in the

Conclusion

Patients with schizophrenia experience alarmingly elevated rates of insomnia, a comorbidity that often exacerbates the symptoms of an already debilitating disease, ultimately leading to poor clinical outcomes. While there is a huge demand to treat insomnia in patients with schizophrenia, commonly used pharmacological options such as benzodiazepines and BzRAs may not be safe for long-term use in this patient population. Suvorexant, an orexin receptor antagonist, seems to be promising in treating

Acknowledgements

None.

Conflict of interest

XF has received research support or honoraria from Alkermes, Neurocrine, Avanir, Allergen, and Janssen. IR and AC report no competing interests.

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