insomnia research article

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• World Psychiatry
• v.18(3); 2019 Oct

The assessment and management of insomnia: an update

Andrew d. krystal.

1 Department of Psychiatry, University of California San Francisco School of Medicine, San Francisco, CA, USA

2 Department of Neurology, University of California San Francisco School of Medicine, San Francisco, CA, USA

Aric A. Prather

Liza h. ashbrook.

Insomnia poses significant challenges to public health. It is a common condition associated with marked impairment in function and quality of life, psychiatric and physical morbidity, and accidents. As such, it is important that effective treatment is provided in clinical practice. To this end, this paper reviews critical aspects of the assessment of insomnia and the available treatment options. These options include both non‐medication treatments, most notably cognitive behavioral therapy for insomnia, and a variety of pharmacologic therapies such as benzodiazepines, “z‐drugs”, melatonin receptor agonists, selective histamine H1 antagonists, orexin antagonists, antidepressants, antipsychotics, anticonvulsants, and non‐selective antihistamines. A review of the available research indicates that rigorous double‐blind, randomized, controlled trials are lacking for some of the most commonly administered insomnia therapies. However, there are an array of interventions which have been demonstrated to have therapeutic effects in insomnia in trials with the above features, and whose risk/benefit profiles have been well characterized. These interventions can form the basis for systematic, evidence‐based treatment of insomnia in clinical practice. We review this evidence base and highlight areas where more studies are needed, with the aim of providing a resource for improving the clinical management of the many patients with insomnia.

Insomnia is defined as a complaint of difficulty falling or staying asleep which is associated with significant distress or impairment in daytime function and occurs despite an adequate opportunity for sleep 1 , 2 . It is a common condition, with an approximate general population point prevalence of 10% 3 , 4 , 5 , 6 .

In the vast majority of cases, insomnia co‐occurs with psychiatric or physical conditions. Although it had long been believed that, when this was the case, insomnia was a symptom of those conditions, the available evidence suggests that the relationship between such conditions and insomnia is complex and sometimes bidirectional 7 , 8 , 9 , 10 . In fact, insomnia is a risk factor for major depression, anxiety disorders, substance use disorders, suicidality, hypertension and diabetes 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 . On this basis, as well as due to the fact that insomnia is associated with impairments in quality of life and an increased risk for accidents and falls, it is recommended that treatment be targeted specifically to addressing insomnia whenever it is present, including when it occurs along with physical or psychiatric conditions 24 , 25 .

For those who meet the diagnostic criteria for insomnia, a number of empirically supported treatments are available. These include non‐medication therapies as well as medication options 25 , 26 , 27 , 28 . The public health impact of this condition in terms of prevalence, morbidity and consequences on health and quality of life highlights the need to effectively diagnose and treat it in clinical practice. This paper reviews the state of the art for optimally diagnosing and treating insomnia based on the available research evidence.

DIAGNOSTIC CRITERIA FOR INSOMNIA

The clinical diagnosis of insomnia is based on the complaint of trouble falling asleep, trouble staying asleep, or early morning awakening, and resultant daytime dysfunction 1 , 2 .

This daytime dysfunction can manifest in a wide range of ways, including fatigue, malaise; impairment in attention, concentration or memory; impaired social, family, occupational or academic performance; mood disturbance, irritability, sleepiness, hyperactivity, impulsivity, aggression, reduced motivation, proneness for errors, and concerns about or dissatisfaction with sleep 2 .

The sleep disturbance must occur despite adequate opportunity for sleep in a safe, dark environment. Duration is also key to the diagnosis: to meet criteria for chronic insomnia according to the third edition of the International Classification of Sleep Disorders (ICSD‐3) or for persistent insomnia according to the DSM‐5, symptoms must be present at least three days per week for at least three months. Short term insomnia (ICSD‐3) or episodic insomnia (DSM‐5) has the same criteria as chronic insomnia, but lasts for fewer than three months.

If the sleep complaints are completely explained by another physical, psychiatric or sleep disorder, the patient does not meet diagnostic criteria for insomnia. However, insomnia is not solely a symptom of other mental disorders as was once thought 29 . Even if another disorder was the trigger or is present some of the time, if insomnia is sufficiently severe to warrant independent clinical attention, it should be recognized as a separate, comorbid disorder.

Previously, both the ICSD and the DSM described various subtypes of insomnia. These included psychophysiologic insomnia, paradoxical insomnia, idiopathic insomnia, behavioral insomnia of childhood, insomnia due to a mental disorder, insomnia due to a medical disorder, and insomnia due to a drug or substance. However, the mechanism of insomnia is poorly understood, and the various subtypes are difficult to differentiate in clinical practice 30 . Therefore, the subtypes were consolidated into chronic insomnia (ICSD‐3) and persistent insomnia disorder (DSM‐5) in the most recent editions of the manuals.

A subtype of insomnia with objectively short sleep has been described and stands out for its probable association with increased morbidity. These individuals meet criteria for chronic insomnia and, by objective measure, sleep on average less than six hours per night. This combination of insomnia with short sleep duration has been linked to hypertension, type 2 diabetes, and worse neurocognitive function 17 , 31 , 32 . Therefore, this may ultimately become a separate category in future versions of insomnia classifications.

DEMOGRAPHICS OF INSOMNIA

Symptoms of insomnia are common, with about one in three people reporting some symptoms in the previous year 33 , 34 . The point prevalence of a formal diagnosis of insomnia is 6‐15%, though occurrence rates vary by definition used 35 .

When looking at only nighttime complaints, rates are far higher. In a large population sample in France, 57% complained of trouble falling asleep, 53% of trouble staying asleep, and 41% of non‐restorative sleep, though only 19% met DSM‐IV criteria of at least one complaint three times per week for one month 36 .

For many, insomnia is a persistent condition, with 74% reporting symptoms for at least one year 37 . Persistence is more common in women, the elderly, and those with more severe insomnia. In a 3‐year study, over half of participants did remit, but there was a 27% relapse rate 37 . Family history of insomnia is also common, occurring in 35% of individuals 38 .

Women more commonly report symptoms of insomnia and daytime consequences, and are more likely to be diagnosed with insomnia than men. The male‐to‐female ratio is 1:1.4 for insomnia symptoms and 1:2 for insomnia diagnosis 5 . In both men and women, the prevalence of insomnia increases with age 5 , 39 , 40 .

Insomnia is associated with lower income, lower education, and being divorced or widowed 5 , 36 , 41 . It is also strongly associated with physical disorders, with half of those with insomnia also reporting multiple physical problems 34 , 41 . People with insomnia are more likely to rate their health poorly 42 , 43 .

Insomnia is very strongly associated with mental disorders, most commonly depression, anxiety and post‐traumatic stress disorder. Across cultures, most people with major depression report insomnia 44 , and those with insomnia are more likely to have depressed mood 42 , 43 , 45 , 46 , 47 . Insomnia is also a predictor for developing mental health problems, including depression, anxiety, bipolar disorder and suicide 45 .

CLINICAL ASSESSMENT OF INSOMNIA

Chief complaint.

The chief complaint for those with insomnia is typically difficulty initiating or maintaining sleep, early morning awakening or simply unrefreshing sleep. Early morning awakening is waking at least 30 minutes prior to the desired time, accounting for habitual bedtime, total sleep time, and premorbid pattern.

The specific complaint may vary over time and often includes more than one sleep concern. The duration, frequency and severity of this concern should be elucidated as well as exacerbating and relieving factors. Complaints of insomnia often arise only when probed during evaluation of another disorder, despite the impact of insomnia on multiple health issues.

Current sleep history

A good current sleep history is essential to confirm the diagnosis and determine the best treatment for a patient with insomnia. This includes sleep/wake schedule, bedtime routine, nocturnal behavior, and daytime dysfunction.

Sleep/wake schedule

A detailed account of time to bed, time to sleep, frequency of night awakenings, time to return to sleep, time waking in the morning, and time out of bed should be obtained.

What the patient does when not falling asleep is also important. For example, a patient who gets out of bed and eats ice cream or watches a favorite show when not sleeping is providing positive reinforcement for being awake, which is counterproductive. This can be a behavior to target and eliminate during treatment.

The sleep/wake schedule should be obtained for both work/school days and weekends or vacations. A large variation may signal a circadian rhythm disorder and serve as a target for intervention.

Does the patient nap during the day? If taking a nap later in the day, this may be decreasing sleep drive in the evening and can also be a target for intervention. If the patient reports a strong propensity to fall asleep during the daytime, this raises concern for another sleep disorder.

Bedtime routine

It is important to have the right conditions to ensure proper sleep. While someone with true insomnia will not be effectively treated by simply providing a dark, quiet environment, the clinician – in order to confirm the diagnosis – must ensure that poor sleep is not due to poor sleep conditions.

Detailing the bedtime routine may also highlight areas for intervention during the treatment phase. For example, mobile phone use is associated with shorter sleep duration 22 .

Nocturnal behavior

What does the patient do when not sleeping at night? Are there other behaviors overnight, such as snoring or leg kicking, that may signal alternative or concomitant diagnoses?

Input from a bed partner can also be helpful. In a patient who reports being awake the entire night, a bed partner often observes long periods of sleep, suggesting there may be some sleep state misperception.

Daytime dysfunction

Daytime dysfunction is part of the formal criteria for insomnia and must be assessed. This includes worsened quality of life, concerns about memory, fatigue, mood, and success at work or school.

The 3P model

The 3P model, a behavioral model of insomnia developed by Spielman 48 , can help the clinician focus a sleep history 49 . The model highlights why insomnia occurs in certain individuals and what allows acute insomnia to become chronic insomnia.

The three Ps occur in temporal order: factors predisposing an individual to insomnia, factors precipitating an acute episode of insomnia, and factors perpetuating the insomnia from acute to chronic. Predisposing factors include genetic and personality traits leading to physiologic and cognitive hyperarousal 50 , 51 . Precipitating factors are the triggers after which the insomnia cycle begins and are typically stressful events, though they can be positive, ranging from the loss of a loved one to retirement or marriage. Perpetuating factors allow the insomnia to continue, even when the trigger is removed. These factors include behaviors and thought structures that may appear to offer short‐term relief yet cause long‐term harm, such as increasing time in bed and reducing daytime activity.

Past medical history

There is a large interplay between many physical or psychiatric conditions and insomnia, and typically it is thought that a bidirectional relationship exists in which the physical or psychiatric condition exacerbates insomnia and vice versa. A huge range of physical comorbidities – including pulmonary, cardiac, gastrointestinal, endocrine, neurological, musculoskeletal and genitourinary – can contribute.

It is important to ensure that the management of these comorbid conditions is optimized when treating insomnia.

Medications

Numerous medications can impact sleep, and a thorough medication list, including over‐the‐counter medications and substances of abuse, should be elicited.

Antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs) and monoamine oxidase inhibitors (MAOIs) can cause sedation or stimulation, with individual variability. Therefore, a patient may consider moving a daily dose from morning to evening or vice versa to determine how this impacts sleep.

Over‐the‐counter allergy medications often contain stimulants such as pseudoephedrine or phenylephrine, and patients may not realize that this can contribute to insomnia. Withdrawal can also contribute, such as from alcohol, benzodiazepines or opioids. Pulmonary medications, including albuterol and theophylline, can cause insomnia as well.

While insomnia is reported as a side effect of antihypertensive medications, and beta‐blockers are known to reduce melatonin levels, there is mixed evidence about the direct impact of these medications on sleep 5 , 52 , 53 .

Social history

Occupation is key to the sleep history, to ensure driving safety in patients reporting daytime sleepiness. Work or school hours are also important, as variation in these hours, shift work, and frequent travel across time zones can all disturb sleep.

Use of nicotine, caffeine, alcohol and other substances should also be noted.

Physical examination

Insomnia is not associated with any specific features on physical or mental status examination. The examination can, however, provide information about alternative diagnoses and comorbid conditions. Assessments to consider include body mass index, neck circumference and airway exam for obstructive sleep apnea 54 .

Differential diagnosis

Three criteria must be met for a diagnosis of insomnia: complaint of trouble falling or staying asleep, adequate opportunity for sleep, and daytime dysfunction. If a patient reports trouble sleeping for the expected 7‐8 hours but does not have daytime consequences, he/she may be a short sleeper. On the other hand, if there are insufficient hours of sleep and daytime dysfunction, but the patient is able to sleep when provided opportunity, this is likely to be behaviorally induced insufficient sleep. Function during vacations and weekends can be helpful to differentiate these.

Other sleep disorders that can present with the complaint of insomnia include circadian rhythm sleep‐wake disorders, restless leg syndrome, periodic leg movement disorder, and obstructive sleep apnea.

Helpful questions to distinguish circadian disorders include the time to bed and awake on weekends, holidays and vacations in contrast to work or school days and whether there is a normal duration of refreshing sleep once the patient does fall asleep. If sleeping from 3 am to 10 am provides refreshing sleep and yet the patient gets in bed at midnight and hopes to rise at 7 am, but cannot fall asleep for several hours, a delayed sleep‐wake phase disorder may be involved and the misaligned internal rhythm should be the target for treatment.

Symptoms of restless leg syndrome include an urge to move the legs at least partially relieved by moving them, typically preceded by an abnormal leg sensation, and typically occurring during times of rest at the end of the day. As the syndrome can cause trouble falling asleep, it should be ruled out or treated directly.

Obstructive sleep apnea can present with symptoms of insomnia, more commonly in women than men. Presence of snoring, frequent awakenings, witnessed apneas should be discussed and, if concern is present, polysomnography should be performed 55 , 56 .

Insomnia assessment tools

Sleep diary.

Sleep diary is a form compiled by the patient, usually for at least two consecutive weeks, in which he/she notes down the time that he/she went to bed, the time of lights out, time to sleep, time and duration of awakenings overnight, time awake in the morning, time out of bed, naps, perceived duration of sleep, and sometimes quality and depth of sleep. The use of sleep aids and alcohol is sometimes included.

This can be very useful for the diagnosis of insomnia and is core to the treatment, because it helps to characterize the specific nature of the sleep problem, delineate maladaptive behaviors and provide an indicator of treatment outcome. If a circadian rhythm disorder is being considered, a sleep diary can be very useful for making the correct diagnosis.

Actigraphy is a device, typically worn on the wrist, that records movement and employs an algorithm to estimate sleep and wake periods.

It has satisfactory reliability with the “gold standard” polysomnography in good sleepers who spend little time awake and still, but not in those with sleep difficulties where significant periods of waking stillness occur 57 , 58 , 59 , 60 . It is often combined with a light sensor to provide an estimate of the latency from lights out to sleep onset.

Actigraphy is not required in the evaluation of insomnia, but it can be useful for a patient whose sleep log or history is not reliable or when circadian disorders are suspected.

Personal monitoring devices

Commercially available devices that purport to measure sleep, often differentiating between light and deep sleep, are increasingly available. There are little published data indicating the performance of nearly all of these consumer devices and thus the accuracy of the information regarding sleep and wake periods is unknown.

Limited data suggest that some of these monitors do not accurately reflect sleep architecture, sleep efficiency or sleep latency, and tend to overestimate sleep duration in normal sleepers with far worse accuracy in insomnia patients 61 , 62 . Therefore, these devices are not recommended to make clinical decisions until there are rigorous studies establishing validity and reliability. The ease of use and consumer enthusiasm, however, does suggest that these devices may play an increasing role in evaluation and treatment moving forward.

Polysomnography

Polysomnography is the gold standard to distinguish sleep from wake. It is not needed for the diagnosis of insomnia, which is based on patient self‐report. This is because indices traditionally derived from polysomnographic data do not reflect the sleep problems reported by approximately 40% of insomnia patients 63 .

Polysomnography can be helpful to rule out other possible explanations for poor sleep, such as sleep apnea or periodic leg movement disorder. Therefore, it may be indicated when there is concern for sleep apnea or when a patient is not responding to treatment as expected.

Questionnaires

There are multiple questionnaires that can aid in the evaluation of insomnia.

In many sleep clinics, every patient completes the Epworth Sleepiness Scale 64 , given the safety concern of daytime sleepiness when driving or operating heavy machinery. The Insomnia Severity Index 65 is commonly used in research as an outcome measure. The Dysfunctional Beliefs and Attitudes about Sleep 66 can help provide additional information to guide treatment. The Pittsburgh Sleep Quality Index 67 is also commonly used to collect information about self‐perceived sleep quality.

MANAGEMENT OF INSOMNIA

When a patient is diagnosed with insomnia, treatment may be initiated with one of a number of available interventions. These can be broadly categorized as non‐medication treatments and pharmacological therapies. In the sections below we review these interventions, focusing on the available evidence from blinded controlled trials indicating their efficacy and adverse effects.

Non‐medication treatments

There are several different non‐pharmacological treatment regimens that have been tested and implemented to treat insomnia. Here, we review the components and evidence supporting the non‐medication treatment with the best empirical background and most widespread use, i.e. cognitive behavioral therapy for insomnia (CBT‐I).

Employed in a variety of formats, CBT‐I has been found to be effective in reducing insomnia and improving sleep across a wide array of clinical populations 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 . Consequently, the American College of Physicians has recommended this intervention as the first line treatment for adults with insomnia 74 .

CBT‐I has been found to be as effective in the short term as pharmacological treatments, with better long‐term persistence of benefit after the end of treatment 72 . Further, unlike nearly all medications, this therapy has relatively minimal side effects. Here, we provide a clinical review of the components of CBT‐I followed by evidence of its efficacy, including its effectiveness among patients with comorbidities, and its use across different treatment modalities.

CBT‐I is typically delivered over roughly four to seven sessions. It is unclear how many sessions confer optimal benefit, though evidence suggests that fewer than four sessions are not generally sufficient 69 , 78 .

Educational components of CBT‐I

While most patients with insomnia are likely aware of some of the behaviors that fall into the sleep hygiene category, it is important to provide them with the relevant education. This includes the importance of establishing a conducive sleep environment by keeping the bedroom dark, quiet and cool.

Patients should also be reminded not to consume sleep disturbing substances, such as caffeine, nicotine and alcohol, particularly close to bedtime. Similarly, vigorous exercise three to four hours prior to bedtime should be avoided.

Additionally, a wind down routine can be helpful in readying a patient for bed. This should include discontinuation of arousing activities, including exposure to bright light (e.g., computer screen), which can negatively affect one's circadian rhythms.

Behavioral components of CBT‐I

Stimulus control.

Conditioned arousal is one of the key factors implicated in the pathogenesis of insomnia. Repeated pairing of the bed/bedroom and experiences of physiologic arousal, fear, anxiety and frustration leads to the bed serving as a learned cue or conditioned stimulus for arousal, which is incompatible with sleep onset and maintenance.

In order to eliminate this conditioned response, patients are recommended to remove themselves from the bed and bedroom if not sleepy and sit somewhere quiet until the feeling of sleepiness returns. Similarly, at bedtime, the patients are recommended not to go to bed unless they feel sleepy. Use of the bed and bedroom is restricted to sleep and sex, which means that patients are recommended not to do other activities in bed, including read or watch television. Additionally, patients are recommended to wake up the same time each morning, seven days per week, and get out of bed within 10 to 15 minutes upon awakening.

Sleep restriction

Another common contributor to the development and preservation of insomnia is the tendency for patients to spend excess time in bed. On the surface, this makes reasonable sense given that the patients yearn to “catch” sleep whenever they can. Unfortunately, excess time in bed results in conditioned arousal and fragmented sleep.

In order to effectively carry out this technique, patients should provide at least one week of sleep diaries (though two weeks are preferred). The goal is to reduce a patient's time in bed to the reported total sleep time. For instance, if a patient's diary report indicated an average total sleep time of six hours but a time in bed of nine hours (bedtime 9 pm and wake time 6 am), the new sleep schedule would provide a time in bed of six hours (bedtime midnight and wake time 6 am).

Importantly, patients are recommended to not go to sleep until the new prescribed bedtime and only when sleepy. In choosing the sleep opportunity window, it is important to take into account the patient's chronotype.

Due to safety concerns related to sleep restriction (e.g., cognitive deficits, drowsy driving), a minimum time in bed of five hours has been used in the literature 79 . In addition, sleep restriction may exacerbate comorbidities. For instance, sleep restriction has been shown to lower seizure thresholds, increase pain sensitivity, and precipitate mania in patients with bipolar disorder 80 , 81 , 82 .

Patients are recommended to complete sleep diaries throughout treatment. Their time in bed schedule should be reviewed in each subsequent CBT‐I session, with sessions occurring every one to two weeks. The sleep diaries allow the clinician to calculate their average sleep efficiency, which is the percentage of time a patient is asleep given his/her time in bed. We recommend 85% or higher in average sleep efficiency as a metric for “good” sleep quality and a threshold to be met prior to adjusting the time in bed recommendation.

Once it is established that a patient's sleep efficiency is sufficiently high, the clinician can begin to increase the time in bed, typically by altering the prescribed bedtime by 15 min each time and tracking the patient's improvement in subjective sleep quality and daytime sleepiness.

Sleep restriction is typically the aspect of CBT‐I that suffers the most from non‐adherence. In the event that a patient is unable or unwilling to carry out the prescribed time in bed, sleep compression can also be used. This technique consists of slowly decreasing time in bed over time in order to meet the original prescribed time, and may be more palatable to patients, particularly those with significant anxiety about losing further sleep opportunity.

Relaxation and paradoxical intention

These behavioral techniques complement stimulus control and sleep restriction by providing the patient with tools for decreasing arousal prior to bedtime and in the event of nighttime awakenings.

Relaxation techniques vary, but typically include diaphragmatic breathing, the tensing and relaxing of muscle groups, and possibly visual imagery. Paradoxical intention is premised on the idea that anxiety about falling asleep is inhibiting sleep onset. Using this technique, patients are asked to stay awake as long as possible, which leads to reduced anxiety and easier sleep onset.

Cognitive components of CBT‐I

Maladaptive beliefs and thoughts about sleep are typically addressed throughout treatment. It is important for a clinician to attend to sleep‐related worries, as they tend to drive the inappropriate behaviors that perpetuate insomnia. Unrealistic expectations about sleep and catastrophic thinking about the consequences of sleep loss are among these worries.

One technique for countering catastrophic thoughts is by examining evidence from the patient's experience. For instance, if a patient has the belief that a poor night of sleep will leave him/her unable to be effective in his/her job, a clinician could help the patient identify instances when he/she was able to perform sufficiently despite a poor night of sleep. Additionally, providing patients with tools to reduce worry at bedtime can be helpful.

Another technique, known as a constructive worry exercise, requires patients to list in the early evening three or more problems that they believe will likely keep them up at night. For each problem, patients list the next step towards a solution. The exercise is folded and put away and, if patients awake during the night, they are to remind themselves that they have already taken the necessary step towards resolving that problem at their “problem‐solving best” (i.e., not in the middle of the night).

Evidence of efficacy of CBT‐I

Several meta‐analytic reviews support the efficacy of CBT‐I compared to active control conditions and usual care 68 , 69 , 70 , 72 , 78 , 79 , 80 , 81 . In a recent meta‐analysis, van Straten et al 68 pooled data from 87 randomized controlled studies that used at least one component of CBT‐I, which included 3,724 patients and 2,579 non‐treated controls. The strongest effects were improvements in insomnia symptoms, as measured using the Insomnia Severity Index (Hedges’ g=0.98), sleep efficiency (g=0.71), wake after sleep onset (g=0.63), sleep onset latency (g=0.57), and subjective sleep quality (g=0.40). A small effect was observed for changes in total sleep time (g=0.16).

Further, data suggest that CBT‐I is effective among individuals with psychiatric and physical comorbidities 70 , with some accruing evidence that it may have positive effects on comorbid outcomes 82 , 83 . CBT‐I benefits are stronger for psychiatric than physical comorbidities 70 .

CBT‐I has been delivered using a number of different formats, including face‐to‐face individual, group and digitally delivered therapy. In addition, self‐help manuals, books and videos have been developed, which allow patients to carry out treatment on their own. In general, all modalities are effective, though there is some evidence to suggest that face‐to‐face therapy outperforms self‐help. Digitally delivered CBT‐I appears to produce effects comparable to in‐person therapy 84 , 85 ; however, it is likely that in‐person supervision may be required for more complicated cases 86 .

Pharmacological therapies

A number of medications from several different classes have undergone randomized, double‐blind, placebo‐controlled trials in patients with insomnia. Those for which a statistically significant therapeutic effect compared with placebo was reported appear in Tables ​ Tables1 1 and ​ and2. 2 . In addition, there are a number of medications commonly used to treat insomnia that have not been demonstrated to have efficacy in at least one double‐blind, randomized, placebo‐controlled trial. These appear in Table ​ Table3 3 .

Double‐blind placebo‐controlled trials demonstrating efficacy in the treatment of younger adults with insomnia

BDZ – benzodiazepine

Double‐blind placebo‐controlled trials demonstrating efficacy in the treatment of older adults with insomnia

Medications used to treat insomnia not demonstrated to have efficacy in at least one double‐blind placebo‐controlled trial in insomnia patients

FDA – US Food and Drug Administration

In this section we review the characteristics of all of these medications (benzodiazepines, “z‐drugs”, melatonin receptor agonists, selective histamine H1 antagonists, orexin antagonists, antidepressants, antipsychotics, anticonvulsants, and non‐selective antihistamines) and present the available evidence regarding their efficacy and safety as a basis for clinical decision making.

Benzodiazepines

Benzodiazepines are a group of compounds with a similar chemical structure. Their sleep enhancing effect is a result of positive allosteric modulation of the gamma‐aminobutyric acid (GABA) type A receptor 138 , 139 . These agents exert this modulation by binding to a specific site on the GABA‐A receptor complex (referred to as the benzodiazepine binding site), thereby changing the conformation of the receptor constituent proteins, which leads to an enhancement of the inhibition occurring when GABA binds to these receptors 140 , 141 . This enhancement of inhibition is associated with a broad set of dose‐dependent clinical effects, including sedation, anxiety reduction, seizure inhibition and myorelaxation 139 , 140 , 142 .

Of the benzodiazepine medications, triazolam, flurazepam, temazepam, quazepam and estazolam have been demonstrated to have therapeutic effects on both sleep onset and maintenance in double‐blind, placebo‐controlled trials in younger adults (Table ​ (Table1). 1 ). In older adults, triazolam and flurazepam have been found to have therapeutic effects on sleep onset and maintenance in double‐blind, placebo‐controlled trials, whereas temazepam has been demonstrated to have therapeutic effects on sleep maintenance only (Table ​ (Table2 2 ).

For many years the prevailing view of these medications, and medications used for the treatment of insomnia in general, was that they were inevitably associated with tolerance (i.e., loss of therapeutic benefit over time) and dependence (i.e., withdrawal symptoms upon discontinuation) when used nightly on a long‐term basis 143 . Until relatively recently, little data were available to actually assess whether this was the case 25 . As data have become available, it has been clear that tolerance and dependence do not inevitably occur and are not characteristic of long‐term nightly insomnia pharmacotherapy.

However, data on long‐term treatment are only available for some medications, and the available information leaves open the possibility that dependence does occur in some individuals 25 . This limitation is particularly notable for benzodiazepines: the longest nightly treatment study of a benzodiazepine was an 8‐week trial of temazepam, where dependence was not observed 126 . Studies of 2‐4 weeks duration were carried out with triazolam (three trials) and flurazepam (one trial), without evidence of dependence occurring 87 , 121 , 122 .

The adverse effects of benzodiazepines are dose‐dependent and reflect their broad central nervous system inhibitory activity. They include sedation, psychomotor impairment, and potential for abuse by a small subset of the population 143 . The anxiolytic and myorelaxant effects can be useful in those with comorbid anxiety or pain.

Among the available options, these agents are relatively effective at treating sleep onset problems and, as a result, may be needed in some individuals with this type of sleep problem. The only relative contraindication to their use is a history of polysubstance abuse or a specific predisposition to benzodiazepine abuse.

“Z‐drugs”

These agents are an unrelated group of compounds which act by the same mechanism as benzodiazepines, but do not share the benzodiazepine chemical structure 138 , 139 , 140 , 141 , 142 . There is some evidence that they may differ somewhat from benzodiazepines in that their action is relatively restricted to subsets of GABA‐A receptors. As a result, they may have less broad clinical effects 25 , 138 , 139 , 140 , 141 , 142 .

Double‐blind, placebo‐controlled trials demonstrate the efficacy of zaleplon for sleep onset, and of zolpidem extended‐release, zopiclone and eszopiclone (the S isomer of zopiclone) for sleep onset and maintenance in both younger and older adults. Zolpidem has a documented efficacy for sleep onset and maintenance problems in younger adults, but for sleep onset problems only in older adults (Tables ​ (Tables1 1 and ​ and2 2 ).

More data on long‐term treatment are available for “z‐drugs” than for benzodiazepines. The sustained efficacy of eszopiclone and zolpidem has been demonstrated in studies of nightly dosing up to one year in duration without any evidence of dependence occurring, nor was dependence found in a 6‐month study of non‐nightly treatment with extended‐release zolpidem 102 , 106 , 107 .

The potential adverse effects of the “z‐drugs” are the same as the benzodiazepines. Because of the relatively narrower effects of some of these agents, they may not be as helpful as benzodiazepines in addressing concomitant anxiety or pain. This appears to be the case for zolpidem. However, eszopiclone and zolpidem extended‐release have been found to have therapeutic effects on pain, anxiety and depression concomitant with insomnia 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 .

Like benzodiazepines, these agents are relatively more effective than other options in treating problems with sleep maintenance, and may be problematic in those predisposed towards substance abuse.

Melatonin receptor agonists

There are two melatonin receptor agonists used in the treatment of insomnia: melatonin and ramelteon.

Melatonin is a hormone that is taken by many individuals with insomnia. Normally, it is released by the pineal gland during the dark period of the day. It binds predominantly to the MT1 and MT2 receptors, though the mechanism by which this might enhance sleep is not well understood 152 .

No clear dose‐response relationship has been established for the use of melatonin for treating insomnia, and there is some evidence that sleep enhancement may depend on the time of day and may not occur until 3‐4 hours after administration 153 , 154 , 155 .

A substantial number of studies have evaluated the effects of a variety of dosages, administration times, and both immediate and prolonged release formulations of melatonin in individuals with sleep problems 156 , 157 . The available evidence suggests that this agent has a clear therapeutic effect in individuals with delayed sleep‐phase syndrome, that it has an excellent safety profile, and that there may be a modest therapeutic effect on sleep onset latency in individuals with insomnia (although it remains unclear whether this effect is of clinical significance). Some preliminary evidence supports the use of melatonin to treat sleep problems in children with neurodevelopmental disorders, in whom this agent has been established to have an excellent safety profile 158 , 159 , 160 , 161 , 162 , 163 .

The most common adverse effect of melatonin is headache, and slowing of reaction time and sedation can occur during the day. Melatonin is without abuse potential, so it could be administered to abuse‐prone individuals with insomnia. Because it is a hormone that regulates reproductive function, when taken in higher dosages it can in theory impair fertility. Therefore, it has been recommended that it not be taken in those attempting to conceive 164 , 165 , 166 , 167 .

Like melatonin, ramelteon is an agonist at MT1 and MT2 receptors. However, it is a substantially more potent agonist at these receptors than melatonin. Double‐blind, placebo‐controlled trials demonstrate the efficacy of ramelteon for sleep onset insomnia in both younger and older adults (Tables ​ (Tables1 1 and ​ and2). 2 ). Efficacy has been more consistently found with polysomnographic measures than self‐report measures of sleep onset. Nightly treatment for six months was evaluated and no evidence of dependence phenomena was reported 111 .

Ramelteon has a relatively benign profile of adverse effects, among which the most commonly reported are headache, sedation, fatigue and nausea. It does not have significant abuse potential and could be used for abuse‐prone individuals with sleep onset problems, though no studies have evaluated its therapeutic effects in this population. Due to its good safety profile, it may be considered for use in individuals with difficulty in sleep onset only.

Selective H1 antagonists

The only highly selective histamine H1 receptor antagonist that has been systematically studied is doxepin in the 3‐6 mg dosage range 25 .

Doxepin, originally developed as an antidepressant in dosages of 75‐150 mg/day, has H1 antagonism as its most potent pharmacological effect 168 . As a result, as the dosage is decreased, this agent becomes an increasingly specific H1 antagonist 168 .

Double‐blind, placebo‐controlled trials carried out in both younger and older adults, using both self‐report and polysomnographic endpoints, demonstrate the sleep maintenance efficacy of this medication in the 3‐6 mg range (Tables ​ (Tables1 1 and ​ and2). 2 ). It is notable that the therapeutic effects appear to be largest towards the end of the night, without increasing morning impairment. As such, this agent appears to be uniquely well suited for use in individuals waking up towards the end of the night and having difficulty returning to sleep. Studies of up to 3‐month duration of nightly treatment have been carried out without dependence occurring 136 .

The most common adverse effect reported in younger adults is daytime sedation. However, in older adults there were no adverse effects reported more frequently with doxepin 3 mg compared to placebo. As such, older adults with early morning awakening would be a particularly appropriate group to treat with this medication. Also, given its potent H1 antagonism, doxepin could also be considered for use in people with insomnia occurring with allergy symptoms. As this agent is without abuse potential, it could also be used in patients with sleep maintenance problems who are prone to abuse, although no data exist on its use in this population.

Orexin receptor antagonists

The name “orexins” was given to two peptides that were relatively recently discovered to arise from the neurons of the lateral hypothalamus and to promote wakefulness/arousal 118 , 119 , 120 . Agents which are orexin receptor antagonists are sleep promoting, owing to their ability to block the arousal mediated by the orexins.

Suvorexant is an agent which blocks both types of orexin receptors (orexin A and B) and has been demonstrated in double‐blind placebo‐controlled trials to have therapeutic effects on sleep onset and maintenance (including in the last third of the night) in both younger and older insomnia patients, at dosages from 10 to 40 mg (Tables ​ (Tables1 1 and ​ and2). 2 ). This includes a placebo‐controlled trial of nightly treatment for a year, which demonstrated sustained therapeutic effects and no significant rebound insomnia on discontinuation 120 .

The adverse effect of suvorexant that is of most importance is daytime sedation. Available studies suggest that this agent is associated with some abuse potential that is roughly comparable to that of zolpidem, so that it is probably best avoided in people predisposed to abuse.

Suvorexant is the only agent with therapeutic effects in the last third of the night without substantially increasing morning sedation that also has a robust therapeutic effect on sleep onset. As such, it could be considered for use in those patients with both sleep onset difficulties and early morning awakening.

Antidepressants

There are several medications originally developed for the treatment of major depressive disorder that are commonly used for treating insomnia. These agents may produce sleep enhancing effects by blocking the receptors for neurotransmitters that are wake enhancing, such as norepinephrine, histamine, acetylcholine and serotonin 25 .

The antidepressants most commonly used to treat insomnia are trazodone 50‐150 mg, doxepin 10‐75 mg, mirtazapine 15 mg, and amitriptyline 10‐100 mg 25 . Of these agents, only doxepin 25‐50 mg has been demonstrated to have therapeutic effects in insomnia patients in at least one placebo‐controlled, double‐blind, randomized trial, and this study was small (N=47) (Table ​ (Table1 1 ).

Although trazodone is widely prescribed in the treatment of insomnia, it has not been found to have therapeutic effects in insomnia patients in any randomized, double‐blind, placebo‐controlled trial. It was evaluated in one such trial in younger adults, but significant effects compared with placebo were not found 97 . This should not be interpreted as definitive evidence that it lacks therapeutic effects in insomnia. In fact, that study evaluated only one dose of trazodone (50 mg), whereas clinically a range of doses from 50 to 150 mg is prescribed 25 .

There are data available on the efficacy and side effects of the S isomer of mirtazapine, which is not currently available for prescription. S‐mirtazapine, like doxepin, is a selective H1 antagonist and has been evaluated in a dosing range far below the antidepressant dosage, at which it is expected to have only H1 antagonist effects of clinical significance 169 , 170 , 171 . Placebo‐controlled, randomized, double‐blind trials carried out with this agent suggest that, like doxepin, it has robust effects on sleep maintenance, with less pronounced therapeutic effects on sleep onset 169 , 170 , 171 .

The adverse effects of the antidepressants used to treat insomnia vary. All of them can cause daytime sedation, and most may cause orthostatic hypotension. The tricyclic antidepressants doxepin (25‐50 mg) and amitriptyline can cause dry mouth, constipation, blurred vision, urinary retention, cognitive impairment, arrhythmias, and increased appetite/weight gain 25 . Mirtazapine's most important adverse effects tend to be sedation and increased appetite/weight gain. Trazodone's most important adverse effects include sedation and orthostatic hypotension; it may also induce priapism 25 .

As none of these agents has significant abuse potential, they can be considered in people with a predisposition to substance abuse. They can also be considered for use in patients who fail usual therapy or have concomitant conditions such as mood, anxiety or pain difficulties, owing to their broad pharmacological effects 25 . Doxepin and amitriptyline should be used with caution in individuals prone to cognitive impairment, urinary obstruction or glaucoma. The use of all these agents is problematic in patients with bipolar depression, because of the risk of precipitating mania 172 .

Antipsychotics

Antipsychotics are a group of medications developed for treatment of psychotic conditions that are sometimes used in clinical practice to treat insomnia, generally at a dosage lower than that typically used to treat individuals with psychosis 25 . These agents may have therapeutic effects in insomnia due to their broad antagonism of wake promoting neurotransmitter receptors, such as dopamine, histamine, serotonin, cholinergic and adrenergic receptors.

The antipsychotic medications that are most commonly used to treat insomnia in clinical practice are quetiapine 25‐250 mg and olanzapine 2.5‐20 mg. There are no rigorous double‐blind, randomized, placebo‐controlled trials demonstrating the efficacy of any antipsychotic medication for the treatment of insomnia.

A few small studies of quetiapine have been carried out. This agent was reported to improve wake time after sleep onset as compared to placebo in a trial of 20 patients with alcohol use disorder in recovery and sleep disturbance 173 . A double‐blind, randomized, placebo‐controlled trial of quetiapine 25 mg was also carried out in 13 patients with primary insomnia and demonstrated an advantage for quetiapine on sleep latency and total sleep time, although neither reached statistical significance 174 .

The primary side effects of these agents include sedation, orthostatic hypotension, dry mouth, tachycardia, increased appetite/weight gain, agitation, dizziness, constipation and akathisia. More concerning, though far less common, is the risk of tardive dyskinesia. The increased risk of cerebrovascular events in patients with dementia should also be taken into account.

As these agents are without abuse potential, they can be considered for use in people who are abuse‐prone. They are best suited, however, for insomnia occurring in patients with psychosis or bipolar disorder.

These agents should be used with caution in those with dementia, hypotension or at risk for myocardial infarction, closed‐angle glaucoma, constipation or urinary retention.

Non‐selective antihistamines

Non‐selective antihistamines that are often used to treat insomnia include diphenhydramine and doxylamine, which are ingredients in many over‐the‐counter insomnia therapies. Both of these agents have, in addition to H1 antagonism, clinically relevant M1 muscarinic cholinergic antagonism.

There are highly limited data establishing the insomnia efficacy of these drugs. A therapeutic effect of diphenhydramine 50 mg on self‐reported number of awakenings, but not sleep quality, total sleep time or sleep onset latency, was reported in a placebo‐controlled cross‐over study in 20 older primary insomnia patients 175 . Diphenhydramine 25 mg was also evaluated in a parallel‐group study along with a combination of valerian and hops in 184 insomnia patients, and found to have a significant effect vs. placebo on self‐reported sleep efficiency, but not self‐reported or polysomnographic sleep onset latency, total sleep time, or polysomnographic sleep efficiency 176 .

The most important adverse effects of these medications are sedation, dizziness, psychomotor impairment, cognitive impairment, dry mouth, blurred vision, constipation, urinary retention and weight gain. Less common side effects of diphenhydramine include agitation and insomnia, whereas doxylamine has been linked in case reports to coma and rhabdomyolysis 177 .

As these agents do not have significant abuse potential, they can, in theory, be considered for use in substance abuse‐prone insomnia patients. They are best suited for use in those with insomnia occurring in the setting of allergy symptoms or upper respiratory infections. They are best avoided in those with closed‐angle glaucoma, decreased gastrointestinal motility, urinary retention, asthma and chronic obstructive pulmonary disease.

Anticonvulsants

Some agents originally developed for treatment of seizures are at times used in the management of insomnia. They include gabapentin and pregabalin, whose potential therapeutic effects in insomnia are ascribed to a decreased release of glutamate and norepinephrine through binding to the alpha‐2‐delta subunit of N‐type voltage‐gated calcium channels 178 , 179 .

There are no double‐blind, randomized, placebo‐controlled trials evaluating the efficacy of these agents in insomnia patients. Two double‐blind, randomized, placebo‐controlled trials were carried out evaluating the effects of gabapentin 250‐500 mg on sleep disturbance created by putting people to bed five hours earlier than usual (five‐hour phase advance model). They reported that this agent significantly improved both self‐reported and polysomnographic wake time after sleep onset and total sleep time compared with placebo, but not sleep onset latency 180 , 181 .

Therapeutic effects of gabapentin and pregabalin on sleep disturbance have also been reported in studies of patients with pain, restless legs syndrome, generalized anxiety disorder, and epilepsy 182 , 183 , 184 , 185 .

The most important side effects of gabapentin are sedation, dizziness, ataxia and diplopia, whereas the most important adverse effects of pregabalin include sedation, dizziness, dry mouth, cognitive impairment and appetite increase. Pregabalin appears to have some abuse potential, whereas this is not the case for gabapentin 186 .

These agents could be considered for use in insomnia occurring in patients with pain, partial seizures or restless legs syndrome. There is some evidence supporting the use of pregabalin to treat insomnia occurring in those with alcohol use disorder 187 , 188 . Both of these medications should be avoided in patients with impaired renal function.

UNMET NEEDS

Insomnia is a common and often debilitating disorder that is associated with significant adverse consequences for physical health and well‐being. Fortunately, there are behavioral and pharmacological treatments available for treating this condition. In this paper we reviewed the evidence base for those treatments in order to provide a resource for practitioners, with the hope that this would improve the clinical management of insomnia. However, our review also illustrates that there are a number of important gaps in the research carried out to date.

We lack information on the specific effects of the various components of CBT‐I which might allow greater treatment efficiency and tailoring. While meta‐analyses demonstrate the value of CBT‐I, they also note significant heterogeneity. Variability in CBT‐I components across trials makes it difficult to determine which aspects are most responsible for the observed benefits. As such, there is a need for studies aimed at providing this information.

There are also a number of key gaps related to pharmacotherapy. The most glaring one is that we lack any double‐blind, placebo‐controlled, randomized trial demonstrating the efficacy of any pharmacological treatment for insomnia in children or adolescents. There is clearly an urgent need to carry out these studies in order to guide effective clinical practice in younger individuals with insomnia.

Another gap in insomnia pharmacotherapy research is that we lack rigorous double‐blind, placebo‐controlled trials of a number of agents commonly used to treat this condition in clinical practice. This includes agents such as trazodone, quetiapine and gabapentin. It would be of great value to those clinicians who tend to prescribe these medications if they had data delineating their risks and benefits to help guide their clinical decision making.

We also lack studies of the pharmacological treatment of insomnia in the setting of several key conditions where this treatment is very often needed, such as dementia, mild cognitive impairment and substance use disorders.

A final critical gap in our knowledge base reflected in our review is that we lack research to help guide personalization of therapy. The vast majority of studies carried out evaluate a single therapy vs. a placebo or another control intervention. More trials are needed comparing effective treatments and aimed at optimally matching treatments to specific patient types, so that we can move to greater personalization in clinical practice.

Insomnia disorder: clinical and research challenges for the 21st century

Affiliations.

• 1 "Vita-Salute" San Raffaele University, Milan, Italy.
• 2 Neurology - Sleep Disorders Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
• 3 Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland.
• 4 Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
• 5 Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, Bergen, Norway.
• 6 Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
• 7 Institute of Biomedicine, University of Southern Switzerland, Lugano, Switzerland.
• 8 Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Social Foundation Bamberg, Bamberg, Germany.
• 9 Center of Sleep Medicine, Sleep Research and Epilepsy, Klinik Barmelweid, Barmelweid Academy, Barmelweid, Switzerland.
• 10 Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
• 11 Adelaide Institute for Sleep Health, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.
• 12 University Hospital of Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland.
• 13 Department of Psychiatry, Behavioral Sleep Medicine Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
• 14 Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
• 15 Institute of Pneumology at the University of Cologne, Solingen, Germany.
• 16 Department of Psychiatry and Psychotherapy, Medical Centre-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
• 17 IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
• 18 Department of Sleep and Cognition, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
• 19 Departments of Integrative Neurophysiology and Psychiatry, Center for Neurogenomics and Cognitive Research, Amsterdam UMC, Amsterdam Neuroscience, VU University, Amsterdam, The Netherlands.
• 20 Sleep Research and Treatment Center, Department of Psychiatry, Penn State Hershey Medical Center, College of Medicine, Pennsylvania State University, Hershey, PA, USA.
• 21 Ente Ospedaliero Cantonale (EOC) Head Office, Bellinzona, Switzerland.
• 22 Department of Neurology, Inselspital University Hospital, University of Bern, Bern, Switzerland.
• 23 Department of Neurology, Sechenov University, Moscow, Russia.
• PMID: 33619858
• DOI: 10.1111/ene.14784

Background and purpose: Insomnia is a common and debilitating disorder that is frequently associated with important consequences for physical health and well-being.

Methods: An international expert group considered the current state of knowledge based on the most relevant publications in the previous 5 years, discussed the current challenges in the field of insomnia and identified future priorities.

Results: The association of trajectories of insomnia with subsequent quality of life, health and mortality should be investigated in large populations. Prospective health economics studies by separating the costs driven specifically by insomnia and costs attributable to its long-term effects are needed. Ignoring the heterogeneity of insomnia patients leads to inadequate diagnosis and inefficient treatment. Individualized interventions should be promoted. More data are needed on both the impact of sleep on overnight effects, such as emotion regulation, and the potential compensatory effort to counteract diurnal impairments. Another gap is the definition of neurocognitive deficits in insomnia patients compared to normal subjects after chronic sleep loss. There are also a number of key gaps related to insomnia treatment. Expert guidelines indicate cognitive-behavioural therapy for insomnia as first-line treatment. They neglect, however, the reality of major healthcare providers. The role of combined therapy, cognitive-behavioural therapy for insomnia plus pharmacological treatment, should be evaluated more extensively.

Conclusion: Whilst insomnia disorder might affect large proportions of the population, there are a number of significant gaps in the epidemiological/clinical/research studies carried out to date. In particular, the identification of different insomnia phenotypes could allow more cost-effective and efficient therapies.

Keywords: cognitive-behavioral therapy for insomnia; insomnia; insomnia treatment; phenotypes; sleep.

© 2021 European Academy of Neurology.

• Cognitive Behavioral Therapy*
• Prospective Studies
• Quality of Life
• Sleep Initiation and Maintenance Disorders* / diagnosis
• Sleep Initiation and Maintenance Disorders* / epidemiology
• Sleep Initiation and Maintenance Disorders* / therapy
• Treatment Outcome

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Perspective article, patricia lacks' contributions to evidence-based practice for insomnia.

• 1 Department of Psychology, Brigham Young University, Provo, UT, United States
• 2 Department of Psychology, Loyola University Maryland, Baltimore, MD, United States

In the 1980s, Patricia Lacks (February 22, 1941–December 3, 2016) began a systematic program of research at Washington University in St. Louis to identify the causes of insomnia and effective treatments. Her treatment outcomes research culminated in the publication of the first detailed cognitive-behavioral treatment manual for insomnia, Behavioral Treatment for Persistent Insomnia . This paper focuses on the history of Dr. Lacks and her contributions to the field of insomnia research and practice.

1. Background

Patricia (Pat) Lacks was born Patricia J. Everett in Oregon on February 22, 1941; months before Pearl Harbor and the entrance of the United States into World War II. Due to her father's role in the Air Force, her family moved frequently during her childhood. She lived in over a dozen places throughout the U.S. and abroad in Japan and Brazil. She was a dedicated student. Drawn to science early in life, she confronted negative attitudes toward women early and often in her academic pursuit of it. She viewed psychology as a serious science and obtained her B.S. in Psychology and Ph.D. in Clinical Psychology at Washington University in St. Louis. In 1966, when she obtained her Ph.D., women represented only 1/5 of those earning doctoral degrees in psychology ( Scarborough, 1992 ). Her dissertation investigated differences in stimulus generalization among psychiatric patients ( Brilliant, 1966 , 1968 ). After completing her doctorate, Dr. Lacks worked for Washington University for 20 years, while raising her 2 children. She also maintained a part-time private practice treating insomnia, depression, and obesity. Dr. Lacks worked for many years as an adjunct faculty member before entering the tenure track. In collaboration with Amy Bertelson Ph.D., she developed a program of research around insomnia treatment outcome studies. Her interest in insomnia grew, in part, out of her own struggles with sleep, including sleep difficulties associated with parenting young children. Her insomnia work was part of a Zeitgeist of sleep research that occurred in the St. Louis area in the 1980s, including sleep research being conducted by colleagues at Washington University, the newly established Deaconess Sleep Disorders and Research Center in St. Louis, and St. Louis University. It was an exciting and productive time for her, her colleagues, and her students. However, she expressed difficulty in obtaining research funding for her psychological work on insomnia ( Lacks, 1987 ). Although by the 1980s women were equally represented among those receiving advanced degrees in psychology, women psychologists at Dr. Lacks' career stage remained underrepresented in leadership and status ( Scarborough, 1992 ). There were few women in the Psychology Department at Washington University and Dr. Martha Storandt was the only tenured woman on the faculty at that time. Dr. Lacks and others felt that there was an atmosphere of unfriendliness toward professional women. There was also a sense that her family commitments, including leaving work each day to provide childcare, were viewed unfavorably. After 7 years of dedicated insomnia research, she experienced a lack of recognition for the merits of her work from the Department of Psychology and was denied tenure, much to the dismay of many of her peers and students. She remained in the department as an adjunct faculty member for several years until her children graduated from high school, at which time she retired from Washington University. She moved to California with her husband, where she worked as a clinician for The Sleep Disorders Center of Santa Barbara. She also taught classes at UC Santa Barbara and Antioch University. She spent much of her adult life with her third husband, Paul Gawronik. After a 10-year battle with Alzheimer's disease, she died at the age of 75.

2. Contributions to the field of sleep research and practice

2.1. emphasis on the psychological aspects of insomnia.

Dr. Lacks was a brilliant psychologist, accomplished writer, beloved teacher, skilled clinician, and caring mentor. She made notable contributions to the field of clinical psychology, including her book Bender Gestalt Screening for Brain Dysfunction ( Lacks, 1984 , 1999 ). At the time, it was the first major manual on Bender Gestalt assessment in over 30 years. She also published articles in the scientific literature in the areas of psychological assessment and treatment ( Brilliant and Gynther, 1963 ; Gynther and Brilliant, 1967 ; Lacks, 1982 ; Lacks and Storandt, 1982 ; Levine et al., 1983 ).

Dr. Lacks' career shifted to insomnia in 1980, during a time when conceptual definitions of insomnia were nascent and diverse. A year earlier the Association of Sleep Disorders Centers (ASDC) published a nosology of sleep and arousal disorders that classified insomnia-related disorders (insomnias) under the “Disorders of Initiating and Maintaining Sleep (DIMS)” classification, one of the 4 provisional categories ( Association of Sleep Disorders Centers the Association for the Psychophysiological Study of Sleep, 1979 ). The 1980 edition of the Diagnostic and Statistical Manual for Mental Illnesses included the ASDC nomenclature in the appendix ( American Psychiatric Association, 1980 )— a reflection perhaps of the growing recognition that mental or psychological aspects play a role in sleep disorders. Initially, she viewed insomnia as a subjective symptom ( Lacks, 1987 ). For Dr. Lacks, the unifying factor of the DIMS was that they resulted in a final common pathway of sleeplessness, which for her included disturbed sleep (i.e., difficulty going to sleep, difficulty remaining asleep, and difficulty going back to sleep when awakened in the night) and diminished sleep (i.e., short sleep duration). Although the ASDC nomenclature parceled out 9 DIMS subcategories, she believed that psychological treatment was most appropriate for the subclassification of subjective insomnia and psychophysiological insomnia. She noted that many instances of insomnia have physiological origins requiring medical evaluation and treatment. With the publication of the International Classification of Sleep Disorders in 1990 ( American Sleep Disorders Association Diagnostic Classification Steering Committee, 1990 ), her perspective evolved with the field in viewing insomnia as a diagnosable disorder, albeit a heterogeneous one. Shedding tangential correlates of insomnia (e.g., short sleep duration), her final publication on insomnia adopted an empirical definition of insomnia as involving “sleep onset latency or wake time after sleep onset >30 min/night, a minimum of 3 nights per week), chronic (at least 6 months), and produces a complaint of daytime impairment (fatigue, performance, and mood decrements)” ( Lacks and Morin, 1992 ). Despite the evolution in the nosology of insomnia over the years, her research and clinical approach latched onto the core aspects of insomnia that remain relevant today.

While much of the sleep research and clinical treatments of insomnia prior to 1980 viewed insomnia as a physiological disorder and focused largely on pharmacological interventions, Dr. Lacks emphasized the psychological aspects of insomnia. She spearheaded an effort spearheaded an effort to manualize psychological treatments for insomnia and experimentally test their efficacy and effectiveness using randomized control trials. The results of her treatment outcome studies for insomnia appeared in 1983 ( Lacks et al., 1983a , b ; Puder et al., 1983 ). That same year, Sleep Disorders: Basic and Clinical Research was published ( Chase and Weitzman, 1983 ), in which the section on insomnia treatment focused entirely on pharmacological options and failed to mention non-pharmacological interventions at all. In stark contrast, Dr. Lacks recommended withdrawal from sleep medication as a prerequisiteprerequisite for beginning psychological treatment for insomnia. She tirelessly highlighted the risks, common problems, and limited utility of sleep medications for the treatment of persistent insomnia; even going as far as to suggest that helping clients gradually withdrawal from sleep aids can resolve the original sleep problem. To help understand the psychological factors in treatment seeking individuals with insomnia, one of her studies used the MMPI to investigate how personality differed in those with sleep onset insomnia from controls ( Levin et al., 1984 ). Results broadly replicated previous studies that compared good sleepers to poor sleepers or individuals with chronic insomnia symptoms, showing that insomnia is associated with neurotic personality features including greater anxiety, more concern with bodily sensations, depressed mood, feelings of inadequacy, inferiority, and lack self-confidence ( Monroe, 1967 ; Chauvin et al., 2015 ).

2.2. Publication of the first CBTI manual

Dr. Lacks seminal contribution was the publication of the first detailed clinical guidebook for insomnia assessment and treatment, Behavioral Treatment for Persistent Insomnia ( Lacks, 1987 ). Designed to train the non-specialist, this publication represented the culmination of her knowledge, experience, and wisdom acquired during her 6 years of treatment outcome research on insomnia. Her clinical guidebook reads like a scholarly article, thorough in its summary of the extant literature and evidence-based in its recommendations. Although the title of the book might appear behaviorist in orientation, a closer read reveals a cognitive-behavioral approach that was nuanced, comprehensive, and incorporating biological, environmental, behavioral, and cognitive factors. Her work built on over 20 years of prior research that had been conducted on non-pharmacological treatments for insomnia. To produce the manual, she pulled from and credited the work of other psychologists in the field including Drs. Richard Bootzin, Peter Hauri, Thomas Borkovec, Kenneth Lichstein, Charles Morin, James Walsh, Collin Espie, Bernie (Bernie) Webb, and many other scholars in sleep science to effectively summarize for the current and next generation of clinicians the core information required to understand, assess, and treat insomnia competently. To create a comprehensive program, she connected the reader with the client's experience, created assessment measures, incorporated multiple components into a cohesive treatment program, and outlined session scripts with descriptions and helpful pointers for how to effectively administer the treatment, much of which that has stood the test of time.

2.3. Insomnia characterization

In her treatment manual, she provided a characterization of a typical individual with chronic insomnia, while preserving nuance for each individual case. She recognized the importance of individual differences in demographics (age, sex, employment, socioeconomic status), physiology, mental health, personality styles, experiences, attitudes, preferences, substance use, and culture context when conceptualizing the cause of insomnia and treating it. She highlighted the importance of the cognitive, experiential, and phenomenological aspects of insomnia to its etiology and treatment. For Dr. Lacks that there were at least 5 factors that contributed to some degree in most individuals with insomnia: somatic arousal, emotional arousal, performance anxiety, self-efficacy, and cognitive arousal ( Cook and Lacks, 1984 ). Her book appeared in the same year as Spielman and colleagues' articles that describe sleep restriction and the 3P model of insomnia ( Spielman et al., 1987a , b ). Dr. Lacks too, described how behavioral and cognitive changes in response to acute sleep difficulties are key to the vicious cycle of insomnia. She described a typical sequence of insomnia precipitation and maintenance as (1) a temporary sleep problem; (2) resulting in worry about being able to sleep and consequences of insufficient sleep; (3) changes in thinking patterns exacerbating sleep difficulties; (4) unpleasant feelings and cognitive arousal become associated with the bed and bedroom; (5) behavioral changes in response to sleep loss including napping, curtailing daytime activities, going to bed early, and sleeping in, result in erratic sleep patterns; (6) self-efficacy erodes, daytime impairments increase including feelings of inadequacy and depression; (7) often in desperation recourse to sleeping aids fails; and (8) finally after over a decade the “person's life becomes one large exacerbation cycle and downward spiral” before reaching an insomnia therapist ( Lacks, 1987 , pp. 56–57). Her description of the lived experience of individuals with insomnia remains palpable, including the social stigma of insomnia, the neglect they experience from the medical community, the loneliness endured during the night and feeling like they are the only ones unable to sleep, the dismissal of insomnia problems by friends and family, and the dislike of being labeled “insomniacs.”

2.4. Development of insomnia assessments

Dr. Lacks emphasized a scientist-practitioner approach to treating insomnia involving detailed assessment of the clients' personal, sleep, psychological, and medical history using a semi-structured clinical interview, daily sleep diaries, and questionnaires. The semi-structured clinical interview and sleep diary she published within the manual were used and modified by subsequent insomnia researchers ( Fichten et al., 2001 , 2005 ). Although several versions of the sleep diary had been widely used in sleep research and clinical practice for decades ( Monroe, 1967 ), to our knowledge, Dr. Lacks published the first manuscript that specifically focused on the sleep diary—outlining its nebulous history/origins and its clinical use in insomnia ( Lacks, 1988 ). Recognizing the importance of accurate prospective data in guiding treatment, she provided her participants with stamped and addressed envelopes to mail their sleep diaries back to the clinic each day, similar to procedures used in other labs at the time ( Lick and Heffler, 1977 ). Weekly assessments of adherence to treatment recommendations were emphasized to guide the intervention, improve adherence, and reinforce and solidify treatment gains. She also recommended psychological measures (e.g., the Beck Depression Inventory and State-Trait Anxiety Inventory) and insomnia-specific questionnaires be used before and after treatment to assess the sleep problem and measure intervention effectiveness ( Lacks, 1987 ). She believed that assessment of pre-sleep cognitive/somatic arousal, self-efficacy, and sleep hygiene were key to effective treatment. To assess the latter 2 constructs, she developed two novel questionnaires.

First, recognizing the importance of cognitive factors in insomnia etiology and treatment outcomes, she introduced the concept of self-efficacy to sleep research ( Cook and Lacks, 1984 ). Self-efficacy, as described by psychologist Albert Bandura, Ph.D. ( Bandura, 1977 ), refers to an individual's belief about their ability to do something. Dr. Lacks argued that low self-efficacy and high-performance anxiety around sleep were often primary elements in the maintenance of insomnia and key to its treatment. She describes the paradox of insomnia, in which individuals with insomnia have a strong desire for sleep, they often have superior knowledge about sleep, and yet seem to prioritize sleep less in their behavior ( Lacks and Rotert, 1986 ). A major aim of her approach was to increase self-efficacy and turn the participant into a “personal scientist” with greater self-awareness and capability of using skills and behavioral experiments to improve their sleep. Her statement to clients that “Very little that is worth having in life comes without effort. Again, we reiterate that long standing habits cannot be changed without consistent and persistent effort” (p. 120) encapsulates her emphasis on self-control in her treatment approach. Dr. Lacks believed that the therapist's ability to increase self-efficacy was key to the treatment, making it superior to self-help books available at the time. She developed the Self-Efficacy Scale, which included items on individuals' beliefs about their ability to carry out treatment recommendations and reach sleep-related goals ( Lacks, 1987 , p. 79). Based on her clinical experience and the research with this scale, she concluded that a change in self-efficacy around sleep was one of the most consistent and profound impacts of her treatment for insomnia. She stated, “The most frequent expressed outcome by clients in our program has been the transformation from feeling one is a helpless victim to a sense of being in charge and control again ( Lacks, 1987 , p. 88). The Self-Efficacy Scale was later validated in older adults ( Fichten et al., 2001 ) and remains in use to the present ( Ghose et al., 2022 ). Furthermore, in the scholarship of one of her student's, sleep-health efficacy has been shown to play a role in both parenting and infant sleep and in early adolescents' sleep health ( Wolfson et al., 1992 , 2015 ).

Second, influenced by the work of Peter Hauri, Ph.D., sleep hygiene was an important component of her approach. Sleep hygiene advice was extant at the time, but she recognized the importance of providing evidence-based recommendations and tailoring them to specific cases. Her team published the first sleep hygiene questionnaire for use in individuals with insomnia: The Sleep Hygiene Awareness and Practice Scale (SHAPS) ( Lacks, 1987 ). This three-part questionnaire assessed (1) general knowledge of sleep hygiene, (2) knowledge of what substances contain caffeine, and (3) sleep hygiene practices. Although requiring revision to address psychometric limitations, SHAPS has been useful in gaining a better understanding of insomnia, guiding insomnia interventions, and informing subsequent measures of sleep hygiene ( Brown et al., 2002 , 2006 ; Spielman et al., 2003 ; Berger et al., 2009 ; Yang et al., 2010 ; Otte et al., 2016 ). Her work using this questionnaire, along with many since, support the current clinical position that addressing sleep hygiene factors may be best viewed as necessary, rarely sufficient for the resolution of insomnia ( Lacks and Rotert, 1986 ).

2.5. Promotion of multi-component treatments for insomnia

Dr. Lacks treatment manual offered a complete multi-component treatment program for insomnia. Stimulus control ( Bootzin, 1972 ), an operant conditioning method wherein sleep is thought to reward pre-sleep behaviors, was the core feature of Lacks' treatment approach, one that she considered most important. However, she seemed to view stimulus control more as a therapeutic procedure than a technical behaviorist construct. Far more than that found in the description of Bootzin (1972) and Bootzin and Nicassio (1978) , Dr. Lacks rationale for stimulus control provided to clients has a ring of classical conditioning:

Much of what we do is influenced by the time and the place we are in. The stimulus, or characteristic of a stimulus gets paired with the behavior that occurs in that situation the characteristics of the situation then become a signal or cue for that behavior…For people who have insomnia, the bed and bedroom may have become a signal for other activities…After the disruption or stress is over, poor sleep, frustration, and any activities that the poor sleeper may have performed while waiting for sleep (e.g., reading, watching television) remain associated with the bed and the bedroom. Subsequently, the bed remains a cue for these nonsleeping behaviors and for being awake…With stimulus control you will learn to reassociate the bed and the bedroom with rapid sleep onset. The bed and bedroom will be weakened as cues for other activities. You will learn to maximize the cues that are associated with feeling sleepy and falling asleep, and to decrease the cues that are associated with staying awake” ( Lacks, 1987 , pp. 95–96).

Of note, is the absence of any mention of sleep itself as a reward for pre-sleep behavior. Indeed, one of her other publications questioned whether reestablishing the bed as a discriminative stimulus for sleep was the active ingredient in stimulus control ( Davies et al., 1986 ). She also noted that some aspects of standard stimulus control procedures used in clinical trials do not necessarily fit within an operant paradigm. Reflecting her nuanced understanding of insomnia and its treatment, she separated several of the traditional stimulus control procedure and listed them as sleep hygiene recommendations in her manual including don't go to bed until sleepy, get up at the same time each morning, and do not take naps.

The other major components included in her manual were (1) the therapist, (2) group process, (3) sleep education, (4) self-monitoring, (5) self-control, (6) reduction of performance anxiety, and (7) sleep hygiene. In addition, she incorporated several other elements into her treatment approach, including establishing a pre-bed routine, encouraging exercising, scheduled worry time away from the sleep environment, relaxation, and medication withdrawal. For older adults she recommended they wake up at the same time each morning and “keep regular schedules of eating, meeting friends, volunteering their time, taking walks, and any other potential activities” to “regularize [the] sleep rhythm [and] promote an active, less sedentary, stimulating life that will serve to enhance sleep” ( Lacks, 1987 , pp. 128). Although sleep restriction was not included as a distinct element, she too recognized the importance of restricting time in bed to the individual's sleep need, at a regular time of day ( Lacks, 1987 ). Inspired by Albert Ellis' work, her approach was also strikingly cognitive involving promoting the treatment with persuasion, normalizing insomnia, reducing mental arousal, reframing, counterdemand instructions including emphasizing that things are likely to get worse before they get better and that improvements should not be expected until the fourth week, encouraging problem-solving, contrasting valuation of long- vs. short-term sleep goals, discouraging clockwatching, discriminating factors associated with good and poor nights of sleep using the sleep diary, eliciting commitments from clients, fostering self-efficacy, and utilizing cognitive control strategies. Dr. Lacks proposed that other stand-alone treatments designed to address cognitive arousal may be beneficial to clients as well ( Davies et al., 1986 ), and recommended that cognitive refocusing ( Zwart and Lisman, 1979 ) and progressive muscle relaxation ( Bernstein and Borkovec, 1973 ) be administered in “successive sieves,” following stimulus control in waves, abbreviated by a consolidation period between each treatment ( Lacks, 1987 , pp. 122–125). Although her manual did not include cognitive restructuring, it emphasized both behavioral and cognitive components in her conceptualization and treatment of insomnia. Thus, Behavioral Treatment for Persistent Insomnia represents the first published cognitive-behavioral therapy for insomnia (CBTI) manual.

2.6. Group treatment for insomnia

To our knowledge, Dr. Lacks developed the first intervention for insomnia that incorporated group process as a treatment component. She believed that insomnia treatment was best conducted in the group setting, with group size ranging from five to seven members ( Lacks, 1991 ). She argued that the group setting helped address client's feelings of being alone in their insomnia and fostering peer pressure and support within the group. Her group approach to insomnia treatment was directive and exacting (e.g., intolerant of non-adherence). It was not, however, rule-governed; rather, she focused on applying the principles of the treatment known to work and adapting the sleep recommendations to each sleeper's motivations and circumstances. For example, she provides insightful recommendations for adapting the treatment to older adults for optimal effects, including providing age-relevant psychoeducation, adapting material presentation to accommodate age-related impairments in vision and hearing, spending more time on important treatment components, and simplifying the treatment and logs to essential elements. She also recognized that the approach outlined in her manual could be readily applied to individual therapy and provided valuable insights in ways her approach could be adapted to different therapeutic styles.

2.7. Treatment outcome studies and insomnia research

Along with other research teams conducting treatment outcome research before and during the 1980s, Dr. Lacks and her colleagues revealed that non-pharmacological treatments for insomnia are efficacious ( Lacks and Powlishta, 1989 ). Her team investigated the relative impact of several types of insomnia interventions including stimulus control, progressive relaxation, paradoxical intention, sleep hygiene, and countercontrol ( Lacks et al., 1983a , b ; Davies et al., 1986 ; Schoicket et al., 1988 ). These non-drug studies were among the largest and best controlled at the time, allowing them to helped establish stimulus control as an evidence-based treatment for insomnia, including for those with sleep maintenance problems ( Espie, 1991 ). She also helped debunk myths about treatment of insomnia in older adults. In contrast to the view that older adults with insomnia should be treated pharmacologically or in their own group setting, she demonstrated that independent and educated older adults do in fact respond to stimulus control ( Puder et al., 1983 ) and that they can be treated together with young adults in insomnia group treatment ( Davies et al., 1986 ). Dr. Lacks was down-to-earth, eschewing a dogmatic theoretical orientation, and focused instead on empirical evidence and practical wisdom. A true critical thinker, she had incredible integrity, looking beyond “statistical significance” to honestly assess the clinical significance of her work. She concluded that only about 50% of participants in her 7 treatment studies experienced reliable changes ( Lacks, 1987 ). Showing greater concern for the improvement of society than that of her book sales, she acknowledged the limitations of her research and treatment approach. She encouraged the development of new evidence-based and more comprehensive multicomponent treatments to improve insomnia outcomes ( Lacks and Morin, 1992 ).

Dr. Lacks developed the first detailed treatment manual for insomnia, providing a structured and practical approach to clinically manage insomnia ( Lacks, 1987 ). Her work contributed to the foundation on which modern CBTI and evidence-base practice for insomnia was built in subsequent decades ( Perlis and Lichstein, 2003 ). During her active research years, she was well-recognized and well-respected in the discipline for her treatment studies research (K. Lichstein, personal communication). Her invitation to write the insomnia review for the Journal of Consulting and Clinical Psychology was an honor and reflects the respect she garnered. Her research, particularly her early studies supporting stimulus control as an efficacious treatment for insomnia, are also well recognized in the literature and historical accounts of Behavioral Sleep Medicine (BSM) ( Stepanksi and Perlis, 2003 ; Stepanski, 2003 ; Morin et al., 2006 ). Her manual and most of her insomnia research articles were cited and well-represented in subsequent foundational guidebooks for insomnia assessment and treatment ( Espie, 1991 ; Morin, 1993 ). She is also currently remembered as being ahead of her time in her emphasis on sleep self-efficacy in insomnia treatment. However, some aspects of her historical contributions to the field of insomnia have been overlooked, including recognition for weaving a cognitive orientation into stimulus control treatment, thereby publishing the first CBTI manual, scripting a classical conditioning description of stimulus control widely used by therapists today, and introducing group therapy as a component of insomnia treatment. In the History of the Development of Sleep Medicine in the United States published in in the Journal of Clinical Sleep Medicine , Dr. Bootzin's stimulus control and the treatment studies conducted by Dr. Lacks and others showing its efficaciousness were not mentioned in the history of insomnia treatment research ( Shepard Jr et al., 2005 ). To our knowledge, Dr. Lacks has not been recognized via awards for her contributions and this is the first publication acknowledging her as a pioneering woman in the field of insomnia research and sleep medicine.

The venues through which her work was published (i.e., books, psychology journals, and psychological conferences, as opposed to sleep journals and sleep meetings) and the circumstances of her employment at Washington University (i.e., limited funding for large-scale treatment studies and shortened research career due to tenure denial) likely limited her visibility in the field. There is also evidence “that women's scientific contributions are systematically less likely to be recognized” across disciplines ( Ross et al., 2022 ), and this cannot be ruled out as a contributing factor. Based on interviews with those close to her at the time, her decision to promote her work outside of the sleep community was influenced, at least in part, by her perception that the field of sleep medicine was male-oriented. The annual Association for the Psychophysiological Study of Sleep (APSS) meetings, which evolved into the SLEEP conferences in 1986, were well attended during the peak of Dr. Lacks' career. However, she did not attend because she did not feel that women were well recognized. While the American Psychological Association was attentive to the issues and significant role of women in the profession as early as 1973, evidenced by the founding of the Committee on Women in Psychology (CWP) ( Scarborough, 1992 ), the first recognized organization in the sleep community, Women in Sleep and Rhythms Research (WiSRR) was not acknowledged until the mid-1990s, after Dr. Lacks' time. Her identity as a psychologist may have also played a factor in her conference selection and publication venues. The rebranding of the Sleep Research Society in the 1980s removed “psychophysiological” from its name; this was perhaps symbolic of psychology's place in the evolving field of sleep medicine. Like many psychologists doing insomnia research at that time, she promoted her work at psychology conferences including at the Association for Advancement of Behavioral Therapies, which limited her interactions with other sleep scientists. Nevertheless, her psychological perspective had an impact on contemporary and subsequent insomnia researchers. For example, Dr. Walsh one of her former colleagues described how her work and arguments persuaded him to begin to consider the psychological aspects of insomnia and its treatment (J Walsh, personal communication).

During her research career, Dr. Lacks mentored, taught, and supervised many undergraduate and graduate students, including Amy R. Wolfson, Ph.D. (author), who would go on to make many important contributions to the field of sleep and circadian rhythms, particularly in children and adolescents. As a mentor, Dr. Lacks was supportive, encouraging, enthusiastic, efficient, and demanding of rigor ( Behrendt, 1978 ; Cook, 1985 ; White Cook, 1985 ; Schoicket, 1986 ; Wolfson, 1987 ). Most of her insomnia-related publications included student co-authors, whom she described as being more like colleagues than research assistants ( Lacks, 1987 ). She encouraged her students to develop a relentless curiosity, be willing to make mistakes, and pursue one's passion—advice she modeled in her own life ( Wolfson, 2015 ). Moreover, she was deeply devoted to mentoring her women graduate students in their scholarship, clinical work, and career advice. For example, she was known for reminding them that “women can have it all: career, friends, and family, but never more than two of the three successfully at the same time” (RD Sulser, personal communication). Another former student noted that she “was one of our best professors in that she prepared us to be clinicians and teachers; She was also an excellent role model for me as a woman” (A Hauger, personal communication).

Many in the current generation may be unaware of the extent to which Dr. Lacks' clinical approach to insomnia has influenced its current treatment. Nevertheless, for those who know her work, she is an inspiration, particularly to women in the field of insomnia research and clinical practice. As a woman, a psychologist, and an insomnia researcher, she was a pioneer in sleep research, particularly in the areas that would become Behavioral Sleep Medicine and Sleep Psychology. Although perhaps not identifying as a “sleep researcher” during her time, she is a welcome guest at the banquet table of sleep research in the annals of history.

Data availability statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

Author contributions

DK wrote the first draft of the manuscript, and conducted the background research including a literature review and interviews. AW conducted a background literature review and interviews, provided personal insights, and helped write and edit the manuscript. All authors contributed to the article and approved the submitted version.

Acknowledgments

We thank those who shared their knowledge and experiences about Dr. Lacks during interviews Paul Gawronik, James Walsh, and Charles Morin. We also thank those who shared their thoughts about her via email including Drs. Kenneth Lichstein, Amy Bertelson, Sidney Nau, Colin Espie Thomas Borcovec, Rachel Manber, Catherine Fichten, Angela Hauger, Ruth Davies Sulser, Spencer Dawson, Jessica Dietch. Joseph Dzierzewski, and Jessica Levenson. This information was invaluable in contextualizing Dr. Lacks' history. We acknowledge with gratitude the behind-the-scenes work of Kate Homer, Jared Cruickshank, Kiziah Pugmire and Jonah Harris in gathering background information, conducting interviews for this project, and/or providing editorial comments. We also thank Dr. Ludy Benjamin for providing editorial comments.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: insomnia, history, Sleep Psychology, Behavioral Sleep Medicine, treatment outcomes studies

Citation: Kay DB and Wolfson AR (2023) Patricia Lacks' contributions to evidence-based practice for insomnia. Front. Sleep 2:1125054. doi: 10.3389/frsle.2023.1125054

Received: 15 December 2022; Accepted: 31 January 2023; Published: 23 February 2023.

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Copyright © 2023 Kay and Wolfson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Daniel B. Kay, daniel_kay@byu.edu

‘Sleeping on it’ really does help and four other recent sleep research breakthroughs

Marie Skłodowska-Curie Senior Research Fellow, University of York

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Dan Denis receives funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 101028886.

University of York provides funding as a member of The Conversation UK.

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Twenty-six years. That is roughly how much of our lives are spent asleep. Scientists have been trying to explain why we spend so much time sleeping since at least the ancient Greeks , but pinning down the exact functions of sleep has proven to be difficult.

During the past decade, there has been a surge of interest from researchers in the nature and function of sleep. New experimental models coupled with advances in technology and analytical techniques are giving us a deeper look inside the sleeping brain. Here are some of the biggest recent breakthroughs in the science of sleep.

1. We know more about lucid dreaming

No longer on the fringes, the neuroscientific study of dreaming has now become mainstream.

US researchers in a 2017 study woke their participants up at regular intervals during the night and asked them what was going through their minds prior to the alarm call. Sometimes participants couldn’t recall any dreaming. The study team then looked at what was happening in the participant’s brain moments before waking.

Participants’ recall of dream content was associated with increased activity in the posterior hot zone, an area of the brain closely linked to conscious awareness . Researchers could predict the presence or absence of dream experiences by monitoring this zone in real time.

Another exciting development in the study of dreams is research into lucid dreams, in which you are aware that you are dreaming. A 2021 study established two-way communication between a dreamer and a researcher. In this experiment, participants signalled to the researcher that they were dreaming by moving their eyes in a pre-agreed pattern.

The researcher read out maths problems (what is eight minus six?). The dreamer could respond to this question with eye movements. The dreamers were accurate, indicating they had access to high level cognitive functions. The researchers used polysomnography , which monitors bodily functions such as breathing and brain activity during sleep, to confirm that participants were asleep.

These discoveries have dream researchers excited about the future of “interactive dreaming”, such as practising a skill or solving a problem in our dreams.

Read more: As we dream, we can listen in on the waking world – podcast

2. Our brain replays memories while we sleep

This year marks the centenary of the first demonstration that sleep improves our memory . However, a 2023 review of recent research has shown that memories formed during the day get reactivated while we are sleeping. Researchers discovered this using machine learning techniques to “decode” the contents of the sleeping brain.

A 2021 study found that training algorithms to distinguish between different memories while awake makes it possible to see the same neural patterns re-emerge in the sleeping brain. A different study, also in 2021, found that the more times these patterns re-emerge during sleep, the bigger the benefit to memory.

In other approaches, scientists have been able to reactivate certain memories by replaying sounds associated with the memory in question while the participant was asleep. A 2020 meta-analysis of 91 experiments found that when participants’ memory was tested after sleep they remembered more of the stimuli whose sounds were played back during sleep, compared with control stimuli whose sounds were not replayed.

Research has also shown that sleep strengthens memory for the most important aspects of an experience, restructures our memories to form more cohesive narratives and helps us come up with solutions to problems we are stuck on. Science is showing that sleeping on it really does help.

3. Sleep keeps our minds healthy

We all know that a lack of sleep makes us feel bad. Laboratory sleep deprivation studies, where researchers keep willing participants awake throughout the night, have been combined with functional MRI brain scans to paint a detailed picture of the sleep-deprived brain. These studies have shown that a lack of sleep severely disrupts the connectivity between different brain networks. These changes include a breakdown of connectivity between brain regions responsible for cognitive control , and an amplification of those involved in threat and emotional processing .

The consequence of this is that the sleep-deprived brain is worse at learning new information , poorer at regulating emotions , and unable to suppress intrusive thoughts . Sleep loss may even make you less likely to help other people . These findings may explain why poor sleep quality is so ubiquitous in poor mental health .

4. Sleep protects us against neurodegenerative diseases

Although we naturally sleep less as we age , mounting evidence suggests that sleep problems earlier in life increase the risk of dementia.

The build-up of β-amyloid, a metabolic waste product , is one of the mechanisms underlying Alzheimer’s disease. Recently, it has become apparent that deep, undisturbed sleep is good for flushing these toxins out of the brain. Sleep deprivation increases the the rate of build-up of β-amyloid in parts of the brain involved in memory, such as the hippocampus . A longitudinal study published in 2020 found that sleep problems were associated with a higher rate of β-amyloid accumulation at a follow-up four years later . In a different study, published in 2022, sleep parameters forecasted the rate of cognitive decline in participants over the following two years.

5. We can engineer sleep

The good news is that research is developing treatments to get a better night’s sleep and boost its benefits.

For example, the European Sleep Research Society and the American Academy of Sleep Medicine recommend cognitive behavioural therapy for insomnia (CBT-I). CBT-I works by identifying thoughts, feelings and behaviour that contribute to insomnia, which can then be modified to help promote sleep.

In 2022, a CBT-I app became the first digital therapy recommended by England’s National Institute for Health and Care Excellence for treatment on the NHS.

These interventions can improve other aspects of our lives as well. A 2021 meta-analysis of 65 clinical trials found that improving sleep via CBT-I reduced symptoms of depression, anxiety, rumination and stress.

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Better sleep is linked with lower loneliness levels

The relationship between sleep and loneliness is stronger in younger adults.

A new study to be presented at the SLEEP 2024 annual meeting found that better sleep health was associated with lower levels of loneliness, and this association was stronger among younger adults.

Results indicate that better sleep health was associated with significantly lower total loneliness, emotional loneliness and social loneliness. While better sleep health was associated with lower total and emotional loneliness across ages, this association was stronger for younger adults. However, age did not moderate the association between sleep health and social loneliness.

"Loneliness is an urgent public health crisis, and there is a pressing need for providers to better understand and treat it," said lead author and principal investigator Joseph Dzierzewski, who has a doctorate in clinical psychology and is vice president of research at the National Sleep Foundation in Washington, D.C. "Our results highlight the important role that sleep plays in understanding loneliness across the adult lifespan. Perhaps efforts to improve sleep health could have a beneficial effect on loneliness, especially for young people."

According to the American Academy of Sleep Medicine, sleep is essential to health. The AASM and the Sleep Research Society recommend that adults should sleep seven hours per night on a regular basis to promote optimal health, productivity and daytime alertness.

The study involved 2,297 adults with a mean age of 44 years; 51% were male. Participants completed an online sleep health questionnaire and loneliness scale. The researchers analyzed the results using correlation and linear regression analyses along with moderation analyses.

In 2023 an advisory from the U.S. surgeon general warned about a public health crisis of loneliness, isolation, and lack of connection. It noted that even before the onset of the COVID-19 pandemic, approximately half of U.S. adults reported experiencing measurable levels of loneliness.

According to the authors, efforts and programs that aim to reduce loneliness should include an emphasis on promoting sleep health, especially in younger adults.

"Why younger adults might experience more sleep-related benefits to loneliness than older adults is unknown and intriguing -- certainly worth further investigation," Dzierzewski said.

The research abstract was published recently in an online supplement of the journal Sleep and will be presented Monday, June 3, during SLEEP 2024 in Houston. SLEEP is the annual meeting of the Associated Professional Sleep Societies, a joint venture of the American Academy of Sleep Medicine and the Sleep Research Society.

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Materials provided by American Academy of Sleep Medicine . Note: Content may be edited for style and length.

Journal Reference :

• Spencer Nielson, Julia Boyle, Joseph Dzierzewski. 0746 Rested and Connected: An Exploration of Sleep Health and Loneliness Across the Adult Lifespan . SLEEP , 2024; 47 (Supplement_1): A319 DOI: 10.1093/sleep/zsae067.0746

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Impact of Interventions on Sarcopenia from the Perspective of Older Persons: A Systematic Literature Review

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• Published: 28 May 2024

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• G. L. Doza 1 ,
• S. van Heden 2 ,
• F. Oliveira Felix 1 ,
• V. Singh 1 &
• Charlotte Beaudart   ORCID: orcid.org/0000-0002-0827-5303 2  

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Current interventions targeting sarcopenia are diverse, incorporating a blend of nutritional, exercise, and pharmacological strategies. Although muscle mass, muscle strength, or functional performance typically serve as the primary endpoints, regulatory agencies have recently emphasized integrating Patient-Reported Outcome Measures (PROMs) as primary or secondary outcomes in interventional studies. This shift acknowledges the importance of PROMs and Patient-Reported Experience Measures (PREMs) in assessing intervention effectiveness and aligns with patient-centered healthcare models. The aims of this systematic review are 1) to identify all sarcopenia-designed interventional studies that used PROMs/PREMs as the primary or secondary outcome, 2) to identify the different PROMs/PREMs used within those studies, and 3) to summarize the effects of sarcopenia-designed interventions on PROMs/PREMs of sarcopenic participants. For that, a systematic search of databases (Medline, EMBASE, Review- Cochrane Central of Register of Controlled Trials, and PsychINFO (Via Ovid)) was conducted in September 2023. The review followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement, and the protocol was registered on Open Science Framework ( https://osf.io/zxgwm/ ). The systematic review identified 17 RCTs as sarcopenia-designed interventional studies reporting PROMs. PROMs covered the assessment of various aspects, including quality of life, depressive symptoms, loneliness/social isolation, daytime sleepiness, insomnia impact, and sleep quality/disturbance. Only one sarcopenia-specific PROM, namely the SarQoL, was reported. The effect of sarcopenia-designed interventions on PROMs showed considerable heterogeneity, underscoring the need for standardization in sarcopenia research by developing a Core Outcome Set (COS). COS in sarcopenia studies would ensure consistent and comparable findings, ultimately enhancing the reliability and effectiveness of interventions.

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Introduction

I n 2016, sarcopenia was recognised as a disease with an International Classification of Disease, Tenth Revision, Clinical Modification (ICD-10-CM) code ( 1 ). As global life expectancy continues to rise, sarcopenia presents itself as a significant public health challenge ( 2 ). The various consequences of sarcopenia, ranging from the development of physical disability to nursing home admission, depression, hospitalisation, and mortality, are anticipated to significantly impact the quality of life for affected individuals ( 3 , 4 ). Within the context of health systems shifting towards a more patient-centred model of care, it is crucial to consider the impact of diseases, such as sarcopenia, on patients’ quality of life and directly perceived outcomes, ( 5 ). In this context, patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) emerge as invaluable tools for capturing patients’ perspectives on their health and experiences. PROMs and PREMs aim to report on diseases and symptoms, treatment side effects (such as pain, fatigue, or anxiety), functional outcomes (physical, sexual, social, role, emotional, or cognitive functioning), or multidimensional constructs like HRQoL or health utility ( 6 ).

Using PROMs and PREMs as endpoints in clinical studies may improve the understanding of patient’s experience by providing information that may not be captured through biomedical methods due to the difficulty of observing certain aspects and their subjective nature ( 6 ). This approach may support healthcare professionals and future patients in choosing the most suitable treatment by giving a clearer view of patient’s experiences and identify any unmet needs or areas in healthcare that require improvement ( 6 ). Therefore, using PROMs and PREMs in interventional clinical studies on sarcopenia contribute to a more comprehensive understanding of clinically perceived benefits, fostering an assessment of treatment efficacy. Government regulatory agencies, including the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) ( 7 , 8 ), have advocated for the incorporation of PROMs as primary or secondary outcomes in interventional studies. The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group further also recommends using co-primary endpoints, combining a measure of physical performance with PROMs in all phases III clinical trials for sarcopenia ( 9 ).

The current approach to managing sarcopenia involves a multifaceted strategy to mitigate its impact on individuals’ health and well-being. Interventions are diverse, incorporating a blend of nutritional, exercise, and pharmacological strategies. Many of these approaches raise numerous questions regarding their effectiveness, particularly in patient-centred management.

Although several studies demonstrate improvements in various parameters such as muscle mass, strength, and physical performance, there are still uncertainties about their impact on enhancing patients’ overall HRQoL ( 10 ).

This systematic review addresses the need to understand the impact of sarcopenia interventions from patient’s perspective. We therefore aimed 1) to identify all sarcopenia-designed interventional studies that used a PROMs/PREMs as the primary or secondary outcome; 2) to identify the different PROMs/PREMs used within those studies and 3) to summarize the effects of sarcopenia-designed interventions on PROMs/PREMs of sarcopenic participants.

The 2020 Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement ( 11 ) has been followed throughout the whole procedure of this systematic review (completed PRISMA checklist available in Appendix 1). The review protocol has been registered on the Open Science Framework ( https://osf.io/zxgwm/ ).

Literature Search

The electronic databases MEDLINE, EMBASE, Review-Cochrane Central of Register of Controlled Trials, and APA PsycINFO (via OVID platform for all the mentioned bibliographic databases) were searched in September 2023 for any study who have used a PROMs/PREMs in a clinical trial aiming at the management of sarcopenia. The search strategy employed for searching in Medline (Ovid) is available in Appendix 2. The search strategy was further adapted to fit the requirements of each database. Additionally, a manual search within the bibliography of relevant papers was performed in order to complete the bibliographic search. Moreover, we also conducted forward references searching of included studies using Web of Science to identify other research that has referenced any article of interest. We also searched on clinical trial registries ( www.clinicaltrial.gov ) for potential unpublished studies.

Study selection

The search results from the electronic sources and hand searching were imported into Covidence software for data management. Covidence is a web-based collaboration software platform that streamlines the production of systematic and other literature reviews ( https://support.covidence.org/help/how-can-i-cite-covidence ). During the initial screening phase, three reviewers (G.L.D., F.O.F, V.S.) independently assessed the title and abstract of each obtained reference to eliminate articles irrelevant to the systematic review. Rigorous inclusion criteria were applied, as outlined in Table 1 . In the subsequent step, the three reviewers individually examined the full text of each article that had not been excluded in the initial stage, selecting studies that fulfilled the inclusion criteria. Any discrepancies in article selection were resolved through discussion and consensus.

Studies were excluded if they included individuals with acute sarcopenia or diagnosed sarcopenia based solely on a single biomarker (e.g., muscle mass only). Additionally, exclusion criteria applied to studies that relied only on a screening tool (e.g., the SARC-F) without further diagnosing the condition, studies that recruited pre-/post-operative hospitalised or disease-specific participants, studies exclusively focused on the diagnosis of sarcopenic obesity, and studies that examined PROMs/PREMs using qualitative research methods.

Data extraction

Data extraction was carried out by three independent reviewers (G.L.D., F.O.F, V.S.) using a standardised form, which had been pretested on a sample of 4 studies.

The following data were extracted: article information (authors, journal name, years of publication, title, country), study description (objective, design, and duration), population characteristics (general description and sarcopenia diagnosis), outcomes (type of PROMs/PREMs), funding details, information on conflicts of interest, and the study’s conclusion. To include as many studies as possible in our systematic review, we systematically contacted authors or co-authors when information was missing in the full-text paper.

Risk of Bias Assessment

The same three independent reviewers assessed trials’ risk of bias using the Cochrane Risk of Bias Tool 2.0 ( 12 ). This tool assesses five domains for each study: randomisation process, deviation from intended interventions, missing outcome data, measurement of the outcome and selection of the reported results. When a study included various PROMs, the focus was primarily on assessing the quality-of-life outcome. For studies featuring a single PROM, the assessment specifically targeted that particular outcome. In case of conflicts, resolution was achieved through consensus, with the option of involving a third party (C.B.).

Data Synthesis

Due to the diverse range of treatments included in this systematic review, conducting a direct comparison using meta-analytic statistics was impossible. Consequently, the findings were summarised and explained narratively.

The search strategy initially identified 2,006 records, with 1,646 records remaining after removing duplicates. Upon screening the titles and abstracts of these records, 77 were considered potentially eligible. Following a thorough evaluation of the full texts of these 77 articles, 60 were excluded and a total of 17 studies met the eligibility criteria and were included in this systematic review. A list of excluded studies and their reasons for exclusion is available on the Open Science Framework deposit ( https://osf.io/zxgwm/ ). Authors from three included paper were contacted by email for additional information or details about their analyses. They all responded positively to our request, providing us enough information to ensure the inclusion of their paper in the current manuscript. Manual search yielded no new reference. Flowchart of study selection is available in Figure 1 .

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) flowchart of study selection

Studies characteristics

The 17 randomized-controlled trials (RCTs) included, published between 2015 and 2023, are detailed in Table 3 and Table 4 ( 13 – 24 ). Trial durations ranged widely, spanning 8 ( 18 ) to 156 ( 20 ) weeks, and study design comprised 2 to 5 groups. The intervention was singular or combined, including medications (n=2, 11.76% ( 25 , 26 )), nutritional supplementation (n=6; 35.3% ( 13 – 18 )), exercise program (n=4, 23.53% ( 23 , 24 , 27 , 28 )) and a combination of exercise and nutritional supplements (n=5, 29.41% ( 19 – 22 , 29 )). At the same time, the control group received isocaloric products/placebos, isocaloric products/placebo combined with an exercise program, or exercise programs alone. The number of participants ranged from 28 ( 23 ) to 1519 ( 20 ). Only one study exclusively enrolled females ( 19 ). Although the targeted population across included studies was sarcopenic, variations were observed in age categories (≥ 60 years, ≥ 65 years, ≥ 70 years) and living conditions encompassing community-dwelling individuals (76.47%), residents of care institutions (11.76%), and candidates for in-patient rehabilitation (5.88%). Regarding sarcopenia diagnosis, 13 studies adhered to a recommended definition by scientific societies, with 4 using AWGS ( 13 , 21 , 25 , 29 ), 8 using EWGSOP 1 or 2 ( 16 , 18 , 19 , 22 , 23 , 26 – 28 ), and 1 using FNIH criteria ( 20 ). Other studies used at least two biomarkers to diagnose sarcopenia but did not mention their adherence to a scientific-societies consensual definition.

None of the included studies presented any high risk of bias for any of the investigated domain (Figure 2 ).

Results of risk of bias assessment of included studies

PROMs/PREMs characteristics

The 17 included studies reported PROMs as outcomes, but none of them reported any PREMs. PROMs utilized in the studies covered assessments of various concepts including HRQoL (SF-12, SF-36, EQ-5D, SarQoL) ( 13 – 22 , 24 – 29 ), depressive symptoms (GDS, BDI) ( 17 , 30 ), loneliness/social isolation (UCLA) ( 30 ), daytime sleepiness (ESS) ( 23 ), insomnia impact (ISI) ( 23 ), and sleep quality/disturbance (PSQI) ( 23 , 24 ). The majority of PROMs employed in these studies were generic, with the exception of one study that utilized a sarcopenia-specific PROM called SarQoL ( 27 ). Table 2 provides a brief overview of these various PROMs.

PROMs were mainly used as secondary outcomes. Nevertheless, 5 studies listed multiple primary outcomes among which one or more PROMs were listed. Only Pinheiro et al. ( 19 ) used exclusively PROMs as primary endpoint (i.e. depression, loneliness and HRQoL).

Results of interventions on primary endpoint

The nature of the primary endpoint varied widely across trials, but in the majority of trials, primary outcome was defined by a physical measurement (i.e. change in gait speed, change in SPBB test, etc.). Further details are provided in Table 3 and Table 4 .

Nine RCT reported a significant improvement of the primary endpoint following exercise-based intervention ( 20 , 23 , 24 , 27 , 28 ), nutrition-based intervention ( 15 , 18 , 31 ) or a combination of exercise and nutrition-based intervention ( 21 ) (Table 3 ). In four of these studies, no further improvement was observed on PROMs (neither HRQoL ( 18 , 20 , 21 , 31 ) nor depression ( 31 )). The other five RCTs highlighted both an improvement in the primary endpoint and in PROMs, reflecting that the proposed intervention may be effective in counteracting sarcopenia and its impact on PROMs. De Sa Souza et al. ( 23 ) reported a significant effect of a 12-week intervention with resistance exercise training on the Insomnia Severity Index (ISI) and the Sleep Quality Disturbance (PSQI) compared to the control group. Flor-Rufino et al. ( 28 ) reported that 26 weeks of high-intensity resistance training may improve muscle strength, gait speed, maximum expiratory pressure alongside the EQ-5D VAS, despite reporting no effect on the EQ-5D utility index. Tsekoura et al. ( 27 ) reported that a 12-week group-based exercise and individualized home-based exercise may be effective in improving calf circumference, Time up and Go test, 4-meter gait speed, muscle mass index, muscle strength, and HRQoL PROM, as reported by the SarQoL questionnaire. Tung et al. ( 24 ) reported that a 26-week vital acupunch exercise program may be effective in improving muscle mass, muscle strength, and sleep quality as reported by the PSQI PROM. Finally, one nutrition-based intervention, published by Bo et al. ( 15 ), using a 24-week intervention with supplements containing whey protein, vitamin D and vitamin E, reported a significant improvement in muscle strength and muscle mass index alongside a significant improvement in HRQoL physical and mental component scales of the SF36 questionnaire.

The other 8 RCTs did not report any significant improvement on the primary endpoint (i.e. SMI, handgrip strength, SPPB test 30-second chair stand test, gait speed) nor on the PROMs either (Table 4 ). None of the pharmacological intervention-based RCTs (i.e. using Bimagrumab 700mg monthly ( 25 ) or perindopril/leucine ( 26 )) reported improvement in the primary endpoint or in PROMs.

The objective of this study was to identify sarcopenia-focused interventional studies utilizing PROMs and PREMs as primary or secondary outcomes. This systematic literature review aimed to provide a comprehensive overview of the impact of sarcopenia-designed interventions on outcomes directly considered as relevant by patients suffering from sarcopenia. Seventeen sarcopenia-designed RCTs encompassing interventions such as medication (11.76%), nutritional supplementation (35.3%), exercise programs (23.53%), and a combination of exercise and nutritional supplements (29.41%) were identified. Surprisingly, none of the 17 studies incorporated PREMs but all of them utilized PROMs, mainly as secondary outcomes. The selected PROMs covered diverse concepts, including HRQoL (88.23%), depressive symptoms (17.65%), loneliness/social isolation (5.88%), and sleep quality/disturbance (11.76%).

Out of the 17 sarcopenia-targeting RCTs utilizing PROMs as primary or secondary endpoints, half of them (i.e., 9/17) reported a positive impact of the intervention on sarcopenia parameters (i.e., improvement of muscle mass, muscle strength, or physical performance), and approximately 30% of them (i.e., 5/17) further reported an improvement in PROMs. One hypothesis that could explain these results might be that, with the exception of one study employing a sarcopenia-specific PROM called SarQoL, most reported PROMs were generic. Generic instruments provide a broad assessment of HRQoL in populations and enable comparisons with other conditions, but their generic nature makes them less likely to reflect the impact of the intervention compared to a specific instrument. Specific questionnaires are more sensitive to change. Currently, only three specific PROMs for sarcopenia are documented in the scientific literature, which explains their limited utilization in clinical trials. First, the Age-Related Muscle Loss Questionnaire (ARMLQ - SARCOPRO) has been developed by Evans et al. ( 32 ) in 2011 to assess functional impacts of reduced muscle strength. Only the content validity of this PROM has been reported, leaving the other psychometric properties, such as validity, reliability and responsiveness to change unexplored. Second, the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical function item bank, funded by the NIH ( 33 ), has been validated for measuring physical function. However, the appropriate context of use and the fit-for-purpose measurement in sarcopenia have not been reported thus far. Thirdly, the SarQoL, a specific quality of life questionnaire for sarcopenia, stands as the only validated PROM currently available. Translated into more than 35 languages and validated across 19 different populations, this PROM is recommended for use in both clinical and research practices ( 34 – 36 ).

The international COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) initiative ( 37 ) provides guidelines for selecting the most appropriate PROM in research and clinical settings. COSMIN taxonomy covers key psychometric properties, including reliability (such as reliability, measurement error, and internal consistency), validity (such as content validity, criterion validity, and construct validity), and responsiveness. However, the mere existence of a PROM doesn’t ensure its suitability for measuring a specific concept related to PROMs. In clinical trials targeting sarcopenia management using a PROM as a primary or secondary endpoint, it is crucial to verify that the PROM has been properly developed and validated according to established guidance. In the context of interventional studies, the PROM’s responsiveness to change of a PROM is paramount. The instrument should be sensitive enough to detect any change in the measured concept. For this reason, an ESCEO working group, composed by key experts in the field of clinical trials for sarcopenia, recommends the use of specific PROMs in clinical trials aiming at the management of sarcopenia ( 9 ).

The existing diversity in outcome measures underlined in this systematic review also underscores the critical need for standardization in sarcopenia research. The development and adoption of a Core Outcome Set (COS) play a pivotal role in achieving this standardization. The absence of a COS for sarcopenia significantly contributes to the observed variability in PROMs across studies. The COMET (Core Outcome Measures in Effectiveness Trials, https://www.comet-initiative.org/ ) initiative actively promotes the creation and use of COS, recognizing its numerous advantages ( 38 ). COS serves as a valuable tool in averting ineffective interventions and addressing outcome-reporting bias by providing a predefined list of essential outcomes for measurement in Randomized Controlled Trials (RCTs) ( 39 ). Its implementation enhances the ability to conduct more consistent systematic reviews or meta-analyses, facilitating robust comparisons across studies and improving the reliability and generalizability of research findings ( 39 ). Developing a COS specific to sarcopenia is indispensable not only for establishing uniformity in outcome reporting but also for enhancing the validity and reliability of study results.

This review also brings to light a significant aspect of sarcopenia research: Patient-Reported Experience Measures (PREMs) were not reported in any of the included studies. The underreporting of PREMs in sarcopenia can be attributed to several factors, including researchers’ skepticism, resource limitations, insufficient funding, reluctance to overburden patients, uncertainties about how to utilize PREMs results, and an evident lack of standardization ( 40 ). However, addressing the underreporting of PREMs in sarcopenia research requires a broader recognition of the importance of patient perspectives in evaluating intervention effectiveness. Adopting a patient-centered approach is crucial, as neglecting the patient’s experience during an interventional trial can impede shared decision-making in sarcopenia research. Shared decision-making (SDM) explicitly involves patients and clinicians in decisions regarding diagnostic and treatment options ( 41 ) by integrating patients’ values and preferences ( 42 ). Developing a standardized tool to address this issue could overcome barriers to PREMs implementation and contribute to a more comprehensive and patient-centered approach to sarcopenia studies.

Limitations

This study is constrained by its reliance solely on published literature, potentially overlooking additional interventional studies that are either ongoing or completed but unpublished. Furthermore, our inclusion criteria focused on interventional studies explicitly reporting PROMs or PREMs as primary or secondary outcomes, preventing us from offering a comprehensive prevalence of studies employing such outcomes. Consequently, it remains uncertain whether the use of PROMs is a common or less widespread practice in sarcopenia research. Additionally, the substantial variability in the PROMs used across these studies posed a challenge to conducting a meta-analysis. The differences in outcome measurement instruments between studies created obstacles in synthesizing quantitative data. This emphasizes the critical need for heightened standardization of measurement tools in sarcopenia research. Enhancing standardization would not only facilitate future meta-analyses but also promote comparability across studies, addressing a significant challenge in the current landscape.

In addressing the impact of sarcopenia intervention on PROMs/PREMs, this study identified 17 sarcopenia-designed interventional trials employing diverse strategies such as medication, nutritional supplementation, and exercise. None of these studies used a PREM as primary or secondary outcome. PROMs were exclusively use in those studies covering aspects like HRQoL, depressive symptoms, loneliness and sleep quality. The varied effect on PROMs highlights the need for standardization in sarcopenia research. Developing a Sarcopenia Core Outcome Set is important to ensure consistent, comparable findings, enhancing the intervention’s reliability and effectiveness.

Data availability and transparency: All materials related to this work are freely available on the Open Science Framework deposit.

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G. L. Doza, F. Oliveira Felix & V. Singh

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Authors contribution: C.B. designed the study, the protocol, run the different search strategies. G.L.D, F.O.F and V.S. screened the studies and extracted the data. S.vH. helped in the interpretation of data, manual search and risk of bias assessment. G.L.D and C.B. wrote the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Charlotte Beaudart .

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Conflict of Interest: Charlotte Beaudart is stakeholder of SARQOL SRL, a spin-off of of the University of Liège, in Belgium, in charge of the interests of SarQoL, a specific health-related quality of life questionnaire for sarcopenia. However, she has never received any financial compensation for this role.

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Doza, G.L., van Heden, S., Oliveira Felix, F. et al. Impact of Interventions on Sarcopenia from the Perspective of Older Persons: A Systematic Literature Review. J Frailty Aging (2024). https://doi.org/10.14283/jfa.2024.47

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Received : 27 March 2024

Accepted : 13 May 2024

Published : 28 May 2024

DOI : https://doi.org/10.14283/jfa.2024.47

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