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Treatment-Resistant Insomnia: A Common Undefined Condition

      Insomnia is a highly prevalent sleep disorder associated with a significant public health burden. Approximately a third of the general population experiences insomnia, and about 10%-15% of adults are labeled as having chronic insomnia.
      • Dopheide JA.
      Insomnia overview: epidemiology, pathophysiology, diagnosis and monitoring, and nonpharmacologic therapy.
      Despite the decline in the use of sedative hypnotic drugs between 2015 and 2019, the emergence of COVID-19 in late 2019 has in all likelihood aggravated sleeping difficulties and accelerated the rate of new cases of insomnia, as evidenced by a 14.8% increase in sleep medication prescriptions since the onset of the pandemic, according to new data from Express Scripts.

      America's state of mind: U.S. trends in medication use for depression, anxiety and insomnia. Available at:https://www.express-scripts.com/corporate/articles/americas-state-mind-use-mental-health-medications-increasing-spread-coronavirus. Accessed 6/2/2021.

      There is little doubt that insomnia has deleterious impact on overall quality of life. The presence of insomnia has been linked to cognitive and functional impairments, decrements in social and emotional well-being, and serious health conditions.
      • Dopheide JA.
      Insomnia overview: epidemiology, pathophysiology, diagnosis and monitoring, and nonpharmacologic therapy.
      Epidemiologic evidence from the past 2 decades has demonstrated a significant correlation between insomnia and incident cardiovascular morbidity and mortality, including hypertension, coronary heart disease, and heart failure.
      • Dopheide JA.
      Insomnia overview: epidemiology, pathophysiology, diagnosis and monitoring, and nonpharmacologic therapy.
      ,
      • Javaheri S
      • Redline S.
      Insomnia and risk of cardiovascular disease.
      Similarly, the negative effect of insomnia on mental health is evidenced by its association with the increased risk of anxiety, depression, weight gain, and alcoholism.
      • Britton A
      • Fat LN
      • Neligan A.
      The association between alcohol consumption and sleep disorders among older people in the general population.
      As a result, the economic burden due to reduced productivity, higher rate of absenteeism, and increased work-related accidents is estimated in billions of dollars annually.
      • Dopheide JA.
      Insomnia overview: epidemiology, pathophysiology, diagnosis and monitoring, and nonpharmacologic therapy.
      Although existing guidelines and recommendations target the management of insomnia per se, the existing body of literature does not often distinguish between treatment-naïve and treatment-resistant insomnia. Outcome assessments of randomized clinical trials involving cognitive behavioral therapy (CBT), pharmacological agents, or both, demonstrate a clinically meaningful response rate between 50% and 75%; however, these studies rarely extend beyond 12 months.
      • Rios P
      • Cardoso R
      • Morra D
      • et al.
      Comparative effectiveness and safety of pharmacological and non-pharmacological interventions for insomnia: an overview of reviews.
      At least a quarter of these patients experience a relapse within the first year, more so in those who were on sedatives and hypnotics than those who received psychobehavioral treatment.
      • Reynolds SA
      • Ebben MR.
      The cost of insomnia and the benefit of increased access to evidence-based treatment: cognitive behavioral therapy for insomnia.
      Further, most of the clinical trials exclude patients with severe comorbid conditions or who have failed prior therapy.
      • Rios P
      • Cardoso R
      • Morra D
      • et al.
      Comparative effectiveness and safety of pharmacological and non-pharmacological interventions for insomnia: an overview of reviews.
      In clinical practice, insomnia is defined as difficulty falling asleep, difficulty in maintaining sleep, or lacking restorative sleep associated with subjective daytime sleepiness, fatigue, difficulties in cognitive functions, or mood disturbances despite an adequate opportunity for sleep. These symptoms must be present for at least 3 days per week for at least 3 months to establish the diagnosis of chronic insomnia.
      American Academy of Sleep Medicine
      International Classification of Sleep Disorders.
      Prior to the publication of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), insomnia was categorized as either a primary sleep disorder or secondary to other ailments (referred to also as comorbid insomnia), including medical and psychiatric disorders, and insomnia due to medication or drug use.
      NIH State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults statement.
      This distinction was based on the premise that insomnia will resolve with appropriate treatment of the comorbid condition. However, results of clinical studies addressing comorbid insomnia showed that nearly 71% of individuals with insomnia at baseline continue to report insomnia, and more than 50% still have insomnia up to 2 years later.
      • Nierenberg AA
      • Husain MM
      • Trivedi MH
      • et al.
      Residual symptoms after remission of major depressive disorder with citalopram and risk of relapse: a STAR*D report.
      With the introduction of the DSM-5, the distinction between primary and secondary insomnia has been effaced. Instead, the multiaxial system that dominated the DSM-4 gave way to a unitary diagnosis of insomnia disorder with concurrent specification of clinically comorbid conditions.
      Currently, there is no standardized definition for treatment-resistant insomnia. Neither the American Academy of Sleep Medicine
      • Sateia MJ
      • Buysse DJ
      • Krystal AD
      • Neubauer DN
      • Heald JL.
      Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline.
      or the European guideline for the diagnosis and treatment of insomnia
      • Riemann D
      • Baglioni C
      • Bassetti C
      • et al.
      European guideline for the diagnosis and treatment of insomnia.
      offers a distinct definition for those who exhibit persistent symptoms despite adequate therapy. Clinical studies have referred to these patients as having treatment-resistant insomnia, refractory insomnia, residual insomnia, or persistent insomnia.
      • Nierenberg AA
      • Husain MM
      • Trivedi MH
      • et al.
      Residual symptoms after remission of major depressive disorder with citalopram and risk of relapse: a STAR*D report.
      ,
      • Krakow B
      • Ulibarri VA
      • Romero E
      Persistent insomnia in chronic hypnotic users presenting to a sleep medical center: a retrospective chart review of 137 consecutive patients.
      ,
      • Vellante F
      • Cornelio M
      • Acciavatti T
      • et al.
      Treatment of resistant insomnia and major depression.
      These terms are often used interchangeably. While persistent residual insomnia is applied to treatment-resistant insomnia following insomnia-targeted therapy, the term is also used to refer to persistent symptoms of difficulty initiating or maintaining sleep after management of the underlying comorbid conditions irrespective of whether treatment of insomnia per se has been provided. The complexity of defining “treatment-resistant” insomnia is further compounded by the fact that there are two approved modalities for managing insomnia. Although both CBT and pharmacotherapy are efficacious, at least in the short-term, the lack of response to one modality may not necessarily represent a case of treatment-resistant insomnia. Accordingly, what criteria would have to be met for insomnia treatment to be defined as resistant, and should both modalities be administered, whether consecutively or concomitantly, before the term is applied? To add another dimension to this construct, the criteria to define patients who failed insomnia pharmacotherapy have included a minimum of used prescribed hypnotics between 3 to 6 months, yet there is no time limit defined for those who received CBT. Should the definition take into consideration the duration of therapy, the number of interventions provided, or both?
      There are currently several self-reported questionnaires available for assessing insomnia symptoms and severity, with built-in constructs designed to decipher the etiology of insomnia. Selecting the appropriate instrument is paramount for determining treatment resistance when comparing therapeutic regimens. With more than 31 instruments identified, the psychometrics testing for several of the available sleep instruments remains incomplete, particularly regarding responsiveness and interpretability.
      • Ali RM
      • Zolezzi M
      • Awaisu A.
      A systematic review of instruments for the assessment of insomnia in adults.
      Considering that the instruments upon which the lack of response to insomnia treatment is based on are not always insomnia-specific assessment tools, comparison of different therapeutic regimens is needed.
      The long-term prognosis of treatment-resistant insomnia is not well documented; however, persistent, residual, or treatment-resistant insomnia has been associated with poor quality of life and depressive relapse. Unless a precise nomenclature is established, progress toward a precision medicine in insomnia will remain limited in scope.

      Acknowledgments

      The views expressed in this manuscript do not communicate an official position of the US Department of Veterans Affairs.

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