Primary Psychiatry: Treatment of Insomnia

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Treatment of Insomnia
Mauricio Infante, MD, and Ruth Benca, MD, PhD

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Sunil Saxena, MD Saurabh Kaushik, MD Richard B. Rosse, MD Yujuan Choy, MD Eric D. Peselow, MD Thomas Roth, PhD

Insomnia is more common in psychiatric patients than in those with other medical disorders. It is possible that the higher incidence of insomnia observed in patients with psychiatric disorders is related to the use of psychotropic drugs. Chronic insomnia in psychiatric patients does not necessarily resolve even with remission of the underlying psychiatric illness. Awareness of various treatment options, including behavioral and pharmacologic therapies, will allow for more appropriate treatment selection for patients with chronic insomnia. Learning Objectives: Explain the importance of behavioral and pharmacologic approaches in the treatment of insomnia. Describe treatment strategies for insomnia, including sleep hygiene recommendations Inform the reader about FDA-approved agents to treat primary insomnia as well as other medications that may be useful in the treatment of insomnia Target Audience: Primary care physicians and psychiatrists. Accreditation Statement: Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Mount Sinai School of Medicine designates this educational activity for a maximum of 3.0 Category 1 credit(s) toward the AMA Physicians Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Credits will be calculated by the MSSM OCME and provided for the journal upon completion of agenda. It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence, objectivity, and scientific rigor in all its sponsored activities. All faculty participating in sponsored activities are expected to disclose to the audience any real or apparent conflict-of-interest related to the content of their presentation, and any discussion of unlabeled or investigational use of any commercial product or device not yet approved in the United States. To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME quiz. To obtain credits, you should score 70% or better. Termination date: August 31, 2007. The estimated time to complete all three articles and the quiz is 3 hours.

Abstract
Chronic insomnia is a common complaint in psychiatric practice. The management of patients with
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Primary Psychiatry: Treatment of Insomnia

insomnia should promote sleep as well as restore normal daytime function. Most treatment modalities, including behavioral and pharmacologic approaches, have been validated in patients with primary insomnia, but may also be helpful in patients with secondary insomnia or insomnia comorbid with medical and psychiatric conditions. Behavioral therapies appear to have longer-lasting efficacy after cessation of treatment, and should therefore always be considered. Hypnotics are approved for the shortterm treatment of insomnia; they are generally used in the treatment of acute or transient types of insomnia, but are increasingly being used for chronic insomnia as well. In the presence of psychiatric disorders or other sleep disorders, other options such as antidepressants, antipsychotics, or anticonvulsants may help promote sleep.

Introduction
Chronic insomnia is a prevalent complaint in psychiatric practice, since most psychiatric disorders are characterized by sleep disturbance. Insomnia secondary to or comorbid with psychiatric illness is one of the most common forms of chronic insomnia.1 Appropriate treatment requires identification of the factors implicated in the etiology of each case of insomnia. Insomnia has traditionally been classified as primary or secondary, based on presumed etiologies. Secondary insomnia encompasses sleep disturbance caused by mental, neurological, or other medical disorders; since causality is often difficult to establish, insomnia occurring with other disorders is also referred to as comorbid insomnia. The management of patients with insomnia should aim both at promoting sleep as well as restoring normal daytime function. Management of primary medical and psychiatric (eg, mood or substance abuse disorders) disorders should be the initial target of intervention in cases of secondary insomnia. However, specific treatments to improve sleep initiation or maintenance are often required in these patients as well. It is still not clear whether the treatment of insomnia improves the course of medical or psychiatric problems, but there is increasing evidence that treatment does not worsen disorders, such as depression.2 In fact, treating insomnia may prevent manic episodes in bipolar disorder.3 Furthermore, resolution of insomnia is associated with improvement in self-perceived health in geriatric subjects.4 Management interventions can be divided into behavioral and pharmacologic treatment approaches. Although most treatments, both pharmacologic and behavioral, have been validated in patients with primary insomnia, they are also used in patients with secondary insomnia disorders. Practice parameters for the nonpharmacologic treatment of chronic insomnia were published by the American Academy of Sleep Medicine in 1999.5 However, guidelines for the pharmacologic treatment of insomnia have not been updated in the last 20 years and no guidelines exist for chronic treatment of insomnia, perhaps due to the paucity of long-term efficacy studies. Therefore, pharmacotherapy has been the most commonly used approach to treat insomnia, including both acute and chronic types. Currently, hypnotics are approved for the short-term treatment of insomnia and are generally the treatment of choice for acute or transient types of insomniaconditions that are largely caused by various psychosocial stressors. Hypnotics and other medications are also used to treat chronic insomnia, although relatively little data are available for this indication. Initial improvement may occur more rapidly following treatment with hypnotic medications in comparison to behavioral treatments, such as relaxation and sleep hygiene education.6 Treatment effects over periods of 48 weeks are similar for both therapeutic modalities, as well as in combination.7 However, nonpharmacologic therapies appear to have longer-lasting efficacy after cessation of treatment and should therefore always be considered.6-8

Behavioral Treatment
A variety of behavioral treatments have been developed for the treatment of insomnia (Table 1), and when used individually or in combination, can lead to significant improvement in sleep. Several metaanalyses of behavioral treatments for primary insomnia suggest that both individual procedures as well as multi-component approaches lead to improvements in various aspects of sleep. Effect sizes are also comparable to those obtained with pharmacotherapy.9-11

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Primary Psychiatry: Treatment of Insomnia

In 1999, The American Academy of Sleep Medicine published practice parameters for the nonpharmacologic treatment of insomnia.5 Treatment methods were graded according to the available empirical evidence and classified in one of three categories of recommendations: standard (evidence of randomized, well-designed trials with low-a and low-b errors or overwhelming evidence of randomized trials with high b errors), guideline (evidence of randomized trials with high b errors or consensus of evidence of nonrandomized controlled or concurrent cohort studies), and option (inconclusive or conflicting evidence or conflicting expert opinion).5 Stimulus control was recommended as a generally accepted patient-care strategy in the treatment of chronic insomnia (standard). Progressive muscle relaxation, paradoxical intention, and biofeedback were recommended as guideline strategies. Sleep restriction and multicomponent cognitive therapy were classified as options at that time. More recent reviews, however, advocate for the use of multicomponent cognitive therapy, or cognitive-behavioral therapy (CBT), in both primary and secondary/comorbid insomnias.12,13 In general, patients with chronic insomnia tend to exhibit multiple behaviors that perpetuate their sleep disturbance, including anxiety and hyperarousal,14 maladaptive attitudes about sleep, and disruption of circadian and homeostatic processes that govern sleep. Combination CBTs address all of these factors. Several factors may affect the availability of behavioral treatments, including cost, the need for trained therapists, and difficulties with patient motivation and compliance in some cases. However, it has been estimated that about 70% to 80% of cases of primary insomnia could benefit from nonpharmacologic therapies,7 and as few as 24 sessions can lead to significant improvement.12,15

Sleep Hygiene
Regardless of the cause, treatment of insomnia should always include attention to sleep hygiene. Good sleep habits aim at reinforcing the circadian rhythm with regular bedtimes, waking-up times, and daily exercise. They also help to decrease arousal before bedtime by eliminating various factors (eg, environmental, chemical and cognitive) that may interfere with sleep. Maladaptive sleeprelated behaviors are often present in patients with chronic insomnia and can contribute to or reinforce sleep difficulties. Changing sleep habits may improve sleep-onset insomnia or reduce sleepmaintenance problems; for example, instituting a regular sleepwakefulness schedule was associated with decreased latency to sleep onset and increased sleep efficiency in a sample of college undergraduate students.16 Unfortunately, good sleep hygiene alone does not always lead to significant improvement in sleep. Nevertheless, it is an important starting point for other behavioral treatments, and poor sleep habits will likely decrease the efficacy of pharmacotherapy. Sleep hygiene recommendations are listed in

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Primary Psychiatry: Treatment of Insomnia

Table 2.

Psychological and Behavioral Therapies

Psychological and behavioral therapies often produce reliable and long-lasting improvements in sleep in patients with chronic insomnia. Stimulus control therapy, relaxation training, sleep restriction, and cognitive therapy are different approaches used to eliminate the patients misconceptions about sleep, anxiety, and maladaptive conditioning to the sleep environment. Such misperceptions can cause or exacerbate the insomnia. Multifaceted CBT consists of combining behavioral (stimulus control, sleep restriction), cognitive (cognitive restructuring, paradoxical intention) and educational (sleep hygiene) interventions to treat insomnia. The objective of stimulus control therapy is to reassociate bedtime and the bedroom with rapid onset of sleep. Patients are instructed to go to bed only when sleepy, to use the bed and bedroom only for sleep and sex, to get out of bed when unable to sleep, to arise from bed at a regular time each morning, and to avoid napping during the day. Meta-analyses of studies of nonpharmacologic treatment of insomnia have found that stimulus control reduced objective measures of sleep-onset latency and waking time after sleep onset in subjects with chronic insomnia.9,10 Relaxation training aims at reducing somatic arousal, with progressive muscle relaxation or biofeedback, or cognitive arousal, with imagery training or thought stopping, to promote sleep. Progressive muscle relaxation is the most studied type of relaxation therapy, and has shown to reduce sleep latency and time spent awake after sleep onset, leading to an increase of total sleep time in patients with chronic insomnia.9,10 Individuals with insomnia frequently increase their time in bed in an effort to obtain more sleep. With sleep restriction, the amount of time spent in bed is adjusted to the actual amount of sleep time, with the goal of lowering the chance of fragmented and poor-quality sleep. Sleep restriction also increases homeostatic pressure to sleep by producing partial sleep deprivation. It should therefore be used with caution in patients with bipolar disorder, who can have manic episodes triggered by sleep deprivation, or in those with epilepsy, since sleep deprivation lowers the seizure threshold. Reduction of objective measures of sleep latency and time awake after sleep onset can be achieved with this type of treatment.17 The objective of cognitive restructuring therapy is to replace sleep-related dysfunctional beliefs and unrealistic sleep expectations (eg, if I do not get 8 hours of sleep, I will not be able to function at all) with more adaptive concepts (eg, I am usually able to manage pretty well as long as I get some sleep). There is evidence of positive results when this approach is integrated as part of a multifaceted treatment strategy.18 Paradoxical intention is a cognitive strategy that involves instructing the patient to stay awake and give up trying to fall asleep. Despite reports of sleep latency reduction,19-21 some studies have failed to report significant post-treatment differences between paradoxical intention and placebo or wait-list control condition.22,23

Pharmacologic treatment
The ideal hypnotic medication should be effective at promoting sleep onset, maintaining sleep, improving sleep quality, and improving daytime performance without altering normal sleep architecture or leading to tolerance, withdrawal, or side effects. Although various classes of medications are used in treating insomnia because of their sedative-hypnotic effects (Table 3), the search for the ideal hypnotic has been hampered by our lack of knowledge of the function of sleep at a molecular level.

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Current Food and Drug Administration-approved agents to treat primary insomnia are the benzodiazepinesflurazepam, triazolam, quazepam, estazolam, and temazepamand the nonbenzodiazepine agentszolpidem, zaleplon, and eszopiclone. Unfortunately, with the exception of eszopiclone, these agents are only indicated for the short-term treatment of insomnia, since most have not been evaluated for long-term use in randomized controlled studies. Other medications with sedating properties are also commonly used to treat insomnia, including antidepressants, anticonvulsants, antipsychotics, and various over-the-counter medications. Despite their widespread use, little data on the efficacy of these agents in treating insomnia are available, and they are not approved by the FDA for such use at present.

Benzodiazepine Receptor Agonists

As allosteric modulators of the -aminobutyric acid (GABA)A receptor, benzodiazepine receptor agonists cause neuronal inhibition by facilitating the opening of chloride channels. Their effects on sleep depend on their half-life and, possibly, on receptor subtype selectivity. Benzodiazepines

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Benzodiazepines were the most commonly used hypnotic medications prior to the development of the nonbenzodiazepine agents. They reduce sleep latency, increase stage 2 sleep, decrease slow-wave sleep (SWS), prolong rapid eye movement (REM) latency, and may produce mild REM sleep suppression.24 Flurazepam, quazepam, and estazolam are longer acting and have been shown to decrease wake time after sleep onset and the number of awakenings in subjective and objective studies.25-29 However, their longer effect may also explain the association with next-day sedation and impaired cognitive and psychomotor functioning.30 Temazepam has been reported to reduce objective measures of sleep latency and may improve sleep maintenance.31-33 Temazepam has also been associated with next-day sedation and impairment of memory and cognition.34 Triazolam has a shorter half-life and, although effective in reducing latency to sleep onset, has not consistently been shown to improve sleep maintenance.31,33,35 Benzodiazepines can cause respiratory depression, due to their muscle relaxant effects. Flurazepam has been reported to increase the number and duration of apneic episodes, as well as increasing the degree of oxygen desaturation.36 Other concerns related to use of benzodiazepines include the risk of developing tolerance and withdrawal effects (including rebound insomnia). Despite the potential of physical dependence at therapeutic doses with long-term use, the risks of benzodiazepines for chronic treatment of insomnia may be overestimated.37 Other Benzodiazepine-Receptor Agonists Recently, agonists of the benzodiazepine receptor that have chemical structures different from benzodiazepines have been developed. In contrast to the benzodiazepines that bind nonselectively to all GABAA subtypes, these newer agents tend to show relative specificity for one or more of the GABAA subtypes. They may cause less rebound insomnia, abuse potential, or respiratory depression than benzodiazepines when given at recommended therapeutic doses. This is possibly related to their shorter half-lives and receptor binding specificities.24 Zolpidem, zaleplon, and eszopiclone are currently approved by the FDA for treatment of insomnia. Zolpidem, a selective agonist of the type 1 GABAA subunit (BZ1), is primarily effective for treating sleep-onset insomnia rather than for improving sleep maintenance later in the night, which is probably related to its relatively short half-life. It has been shown to improve subjective measures of sleep, as well as objective measures of sleep latency.38-41 The improvement in sleep efficiency appears to be related to the reduction in sleep latency. Unlike the benzodiazepines, therapeutic doses of zolpidem do not appear to alter normal sleep architecture. Specifically, the SWS and REM sleep suppression typically seen with benzodiazepines have not been reported with zolpidem use. An advantage of zolpidem is that subjective residual next-day effects seem to be minimal.41-43 However, actual benefits on next-day cognitive, psychomotor, and subjective well-being have not been clearly demonstrated yet.44,45 Zolpidem also has fewer drug-drug interactions than benzodiazepines, possibly because the latter are metabolized by several cytochrome P450 (CYP) isozymes, whereas zolpidem is metabolized primarily by the CYP isoenzyme 3A4. A general consideration in using hypnotics in the elderly is the risk of falls. A retrospective case-control study showed an association between the use of zolpidem in the elderly and a higher risk of hip fractures,46 although long-acting benzodiazepines are more likely associated with falls and hip fractures than shorter-acting agents.47 The clinician must also consider that untreated insomnia in the elderly may also represent a risk for falls, as sleep problems in this population are independently associated with an increased risk of falls.48 Zaleplon, another agent with specificity for the BZ1 receptor, has the shortest half-life of currentlyavailable hypnotics and is primarily used for sleep induction.49,50 Its next-day side effects and residual sedation are minimal.51,52 In fact, its short half-life allows it to be used during the night for sleep initiation, if there are at least 4 hours of time in bed remaining. The recommended 10-mg dose taken at sleep onset has not shown to increase subjective total sleep time or decrease the number of awakenings, but doses of 20 mg have been reported to increase sleep duration and reduce the number of awakenings.49,50 However, side effects associated with the use of the 20-mg dose are not well known at this time. Like zolpidem, zaleplon does not appear to alter normal sleep architecture.43,53

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Eszopiclone, with a half-life of five to six hours,54 binds GABAA receptor complexes at domains near the benzodiazepine receptor. It was recently approved by the FDA for treatment of sleep onset and sleep maintenance insomnia and is the first hypnotic agent for which a long-term, randomized, double-blind, placebo controlled study has been performed. As a result, it is the only currently available hypnotic without a short-term treatment indication. Patients with chronic primary insomnia treated with eszopiclone for 6 months showed a significant reduction of time to sleep onset, as well as reduction of wakefulness time after sleep onset and a decreased number of awakenings.55 Sleep quality and improvement of daytime alertness, sense of well-being, and daytime ability to function also improved. Its longer half-life likely accounts for its more consistent effects in improving sleep maintenance. No evidence of significant tolerance or residual next-day sedation was reported.55 A recent 6-week, placebocontrolled study showed that eszopiclone significantly improved sleep latency, sleep efficiency, and total sleep time in subjects with chronic insomnia. The most common side effect was unpleasant taste.56 As with benzodiazepines, zolpidem, zaleplon, and eszopiclone should be used with caution in patients taking other central nervous system depressants.

Antidepressants
Despite the paucity of research on their effectiveness in insomnia and the lack of FDA approval for this indication, antidepressants are commonly used to treat insomnia complaints.57 In contrast to benzodiazepine receptor agonists, antidepressants are non-scheduled drugs and clinicians are usually more familiar with their long-term prescription. Furthermore, given the strong association between depression and insomnia,58 the use of an antidepressant may be perceived as treating both the sleep condition, as well as the underlying problem. Doses of antidepressants generally used to treat insomnia are often lower than those found to be effective in treating depression. Mechanisms that may explain the sedating effect of antidepressants include histamine (H)1, serotonin type 2 (5-HT2) receptor antagonism, and possibly 1-adrenergic receptor antagonism. Tricyclic antidepressants continue to be used for insomnia, despite their relatively unfavorable sideeffect profile. A study of 40 patients with primary insomnia treated with 2550 mg of doxepin showed short (1 night) and medium term (28 nights) improvement of objectively measured sleep efficiency, total sleep time, wake time after sleep onset, and stage 2 sleep percentages. A subjective improvement of sleep quality and next-day functioning was also reported by patients in this study.59 The use of tricyclic antidepressants should be monitored closely because of the potential for anticholinergic side effects (arrhythmias, orthostatic hypotension, constipation, urinary retention, cognitive deficits), and interactions with other drugs metabolized by the liver. Furthermore, abrupt withdrawal can cause rebound insomnia, including prominent REM sleep rebound, as many of these agents produce significant REM sleep suppression, making them problematic for use on an as-needed basis. Trazodone, the most widely-prescribed antidepressant for insomnia, is another low-cost antidepressant with low abuse potential compared with benzodiazepine receptor agonists.60 Despite its frequent use, relatively little is known about its efficacy in primary insomnia because trazodone studies have usually been conducted in small samples of depressed patients for no longer than 8 weeks.61,62 There is evidence of improvement of sleep latency, sleep efficiency, total sleep time, and wakefulness during sleep associated with trazodone in older insomnia subjects63 and patients with depression.64 In terms of sleep architecture, trazodone has been associated with increase of SWS64 and minimal suppression of REM sleep.63 Trazodone is known to cause next-day sedation and it can possibly cause tolerance and rebound insomnia after discontinuation.42,63 Nevertheless, trazodone may be beneficial for treating insomnia associated with depression,24 or in patients with histories of substance abuse, who should not take benzodiazepine receptor agonists. Paroxetine and mirtazapine are also used to treat insomnia, particularly in patients with depression. A small study (n=15) of paroxetine for treatment of primary insomnia showed a subjective improvement of sleep quality, but no increased sleep quantity.65 Effects of mirtazapine on sleep in patients with insomnia and depression include reduced sleep latency, increased sleep efficiency, and increased total sleep.66,67 Selective serotonin reuptake inhibitors (SSRIs), in general, tend to disrupt sleep,68 suggesting that their subjective efficacy may be related to improving depressive symptomatology.

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Antipsychotics
Most antipsychotic drugs can produce sedation as a side effect, particularly the low-potency neuroleptics such as chlorpromazine. Some of the atypical antipsychotics, such as clozapine, risperidone, olanzapine, and quetiapine, are also known to promote sleep and have been useful for treatment of insomnia in psychiatric patients, including those with psychotic disorders, bipolar disorders or dementia. Olanzapine has been reported to prolong REM sleep latency, increase SWS, improve sleep continuity measures and subjective sleep quality, and decrease REM sleep in studies of healthy subjects.69 Reduction of sleep stage 1 with increases of sleep stage 2 and SWS was reported in a study of 20 schizophrenic patients.70 The use of atypical antipsychotics in primary insomnia is usually not recommended, due to the high prevalence of unwanted side effects, including daytime sedation, weight gain, extrapyramidal symptoms, and the risk of neuroleptic malignant syndrome. A possible association between the use of atypical antipsychotics and cerebrovascular adverse events has also been reported.71 The FDA recently ordered black-box warnings noting that treatment of behavioral disorders in elderly dementia patients with atypical (second generation) antipsychotics is associated with increased mortality.72

Anticonvulsants
Some anticonvulsant medications have sedating effects, presumably related to potentiation of GABA neurotransmission. These include gabapentin, tiagabine, and benzodiazepines.73 Although it has not been specifically studied for treatment of insomnia, gabapentin has been reported to decrease awakenings in stage 1 sleep, increase REM sleep, and SWS percentage in patients with epilepsy.74 A small (n=10) double-blind, placebo-controlled study, assessing the effect of a single 5-mg dose of tiagabine in elderly subjects showed that it significantly increased sleep efficiency, decreased wakefulness, and increased SWS activity.75 However, the FDA recently issued a warning regarding an increased risk of seizures in patients without epilepsy when treated with tiagabine, discouraging off-label use of this drug. Clonazepam, a benzodiazepine anticonvulsant, has a half-life longer than the benzodiazepines described above, and is commonly used to treat insomnia in patients with associated periodic limb movements, restless legs syndrome, or REM sleep behavior disorder. Tolerance has been reported as mild and infrequent with chronic use.37

Over-the-Counter Medications
The active ingredients in most over-the-counter sleeping pills are sedating antihistamines, usually diphenhydramine. These agents are antagonists of H1 receptors. Results of a placebo-controlled study showed that a 50-mg bedtime dose of diphenhydramine improved sleep latency.76 There are no controlled studies demonstrating objective efficacy of diphehydramine for longer than 3 weeks in the treatment of insomnia. A recent study suggested that tolerance to its sedating effects could occur within a few days.77 Antihistamines can cause next-day sedation,76 and impaired cognitive and psychomotor functioning.78 Melatonin is a hormone normally secreted at night and considered to regulate sleep. It binds to specific receptor subtypes MT1 and MT2, activating inhibitory G-protein pathways.79 Melatonin has been shown to reduce sleep latency,80,81 but has not consistently been found to increase total sleep time.82 Persistent improvement of sleep latency and efficiency over a 2-month period of administration of 1 mg of sustained release melatonin in elderly patients suggested lack of tolerance.80 Melatonin also has a chronobiotic effect and, is therefore, used to treat insomnia in patients with circadian rhythm problems. Valerian is an herbal product that has been associated with subjective improvement of sleep latency, total sleep time, and sleep quality. Further research is needed to determine its mechanism of action, objective effects on sleep, and safety. Case reports have associated its use with the development of hepatotoxicity and next-day sedation.83

Newer Agents
New hypnotic agents will likely be released soon in the United States. Indiplon is a nonbenzodiazepine BZ1 receptor agonist with hypnotic properties, currently in clinical development. Its immediate-release form has been shown to improve objective and patient-reported measures of sleep onset over a 5-week period.84 The modified-release form improved subjective measures of time to sleep onset, total sleep time, and waking time after sleep onset in adult patients with insomnia in a 2-week study.85 Ramelteon
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is an MT1 melatonin receptor agonist currently under investigation for the treatment of insomnia. Its site of action (MT1 receptors are located in the suprachiasmatic nucleus) suggests it may have an effect on circadian regulation as well.

Pediatric Population
Insomnia is also a common problem in children and adolescents. Delayed sleep onset and disruptive nighttime awakenings have been reported in 25% to 50% of preschool-aged children.86,87 A communitybased survey, showed that sleep onset delays and nighttime awakening were present in 11% of 5-yearold and 7% of 12-year-old children.88 Insomnia is also commonly comorbid with psychiatric problems in pediatric patients; for example 10% of a population sample of adolescents complained of difficulty falling asleep as well as symptoms of anxiety, depression, inattention, and conduct problems.89

Behavioral Treatment
Like in adults, clinicians should determine if the difficulties with sleep onset, sleep maintenance, or nonrestorative sleep represent primary or secondary insomnia. Behavioral factors commonly precipitate or complicate the course of insomnia in children and adolescents. Children who learn to self-soothe and fall asleep on their own are less likely to struggle initiating sleep or returning to sleep. Parental behavior often plays a role in the development of sleep problems in children as well. Insomnia is more likely to develop when parents become over-involved in the childs sleep.90 Participation of the parents in the implementation of behavioral treatment interventions is therefore indicated. A behavioral strategy that has been shown to be effective to treat sleep-onset insomnia and bedtime resistance in young children is gradual extinction,91 which involves parents putting the child to bed and ignoring the childs protests, except for issues of safety. Parents should, for example, briefly check on the child without excessive negative or positive feedback to the child, after an initial delay of 35 minutes. This delay is then prolonged gradually to 1520 minutes until the child falls asleep and the sequence is repeated for subsequent arousals.92 Allowing the child to go to bed later, at a time when rapid sleep onset is likely, and gradually moving bedtime earlier until the desired sleep onset time is achieved (fading), may also be effective.93 Adolescents can benefit from cognitive restructuring therapy and other behavioral interventions used in adults as listed in Table 2. A particular problem in adolescents is sleep phase delay, in which they fall asleep much later than the desired bedtime and have difficulty awakening in the morning. Although this may present as a complaint of insomnia, it is a circadian rhythm disorder that tends to respond to aggressive behavioral treatments specifically designed to realign sleep with the desired schedule. Good sleep hygiene, rigid adherence to the schedule, and avoidance of exposure to bright light in the evening are essential.94 Hypnotic medications alone are generally not helpful in treating phase delay.95

Pharmacologic Treatment
Despite the lack of clinical studies investigating the efficacy and tolerability of medications to treat insomnia in children, several agents are commonly used, particularly in children with concomitant psychiatric disorders.92 Antihistamines, like diphenhydramine, at a dose of 1mg/kg can reduce sleep latency and number of awakenings,96 but can also lead to paradoxical activation in some children.97 Clonidine is an a-adrenergic agonist antihypertensive agent that has been found to cause sedation, and may be helpful in treating insomnia in children with attention-deficit/hyperactivity disorder.98 Melatonin is frequently used in children with developmental disorders and irregular sleep-wake patterns, despite limited evidence of efficacy; significant improvements, if present, are generally related to reduced latency of sleep onset.99 Melatonin has also been reported to be helpful in sleep-onset insomnia in nonneurologically impaired children.100 Partial arousals and enuresis are often treated with tricyclic antidepressants, particularly imipramine.101 Peripheral anticholinergic effects appear to be the mechanism implicated in the improvement of enuresis.102 Benzodiazepines decrease the frequency of arousals that occur during the night,92 but are generally not recommended in children due to their risk of inducing tolerance, rebound insomnia, and paradoxical activation. Clinicians need to carefully and individually assess risks and benefits of benzodiazepine use in

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young patients. For instance, low doses of clonazepam (0.250.5 mg at bedtime) may be helpful to treat parasomnias that put children at risk of hurting themselves, but side effects may be more harmful to children than the original condition in some cases.

Conclusion
In general, the treatment of patients with insomnia begins with careful determination of all possible factors affecting sleep initiation or sleep maintenance. In addition to treating comorbid medical and psychiatric conditions, multimodal treatment strategies (eg, sleep hygiene, behavioral therapies, medications) are often necessary for patients with secondary insomnia. The presence of psychiatric disorders or other associated sleep disorders may direct the choice of other medications such as antidepressants, antipsychotic, or anticonvulsant drugs that may also help promote sleep. PP

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Dr. Infante is assistant professor of psychiatry and Dr. Benca is professor of psychiatry at the University of Wisconsin Psychiatric Institute and Clinics in Madison. Disclosure: Dr. Infante reports no affiliations with or financial interest in any organization that may pose a conflict of interest. Dr. Benca is a consultant to and/or on the speakers bureaus of King, Neurocrine/ Pfizer, Sanofi-Aventis, Sepracor, Takeda, and Wyeth. Please direct all correspondence to: Ruth M. Benca, MD, PhD, University of Wisconsin Psychiatric Institute and Clinics, 6001 Research Park Blvd, Madison, WI 53719; Tel: 608-263-6162; Fax: 608-2652953; E-mail: rmbenca@facstaff.wisc.edu.

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