TREATMENT OF INSOMNIA
Ruth Benca, MD, PhD, Professor and Associate Chair, Department of Psychiatry, University of Wisconsin Medical
School, Madison
From the 11th Annual Psychopharmacology Update, presented by the American Psychiatric Association and the
Nevada Psychiatric Association
| Introduction: American Academy of Sleep Medicine Standards of Practice state 1) general health screening always
should include questions about symptoms of insomnia; 2) health practitioners should pay particular attention to special
populations (eg, elderly, women, and patients with comorbidity) at increased risk for sleep problems; Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria for primary insomnia 1)
patient must have difficulty initiating sleep or maintaining sleep, and/or experience nonrestorative sleep, which 2)
causes significant distress or impairment in functioning, and 3) sleep problem is not attributable to another sleep disorder,
medical or psychiatric disorder, or substance use (licit or illicit)
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| Normal sleep: subtypes include rapid eye movement (REM) and non-rapid eye movement (non-REM; consists of
stages 1 and 2 sleep and slow-wave sleep); normal adult enters sleep through non-REM sleep, and at beginning of
night tends to have predominantly slow-wave sleep; as night progresses, periods of REM and non-REM sleep alternate,
with 2 general patterns in which 1) slow-wave predominates in early part of night because it is response to
sleep deprivation or homeostatic sleep drive, and 2) REM sleep episodes become longer and more intense as night
goes on and are driven by circadian clock
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| Insomnia: in characteristic pattern, individual takes longer to fall asleep, has frequent and prolonged arousals during
night, and awakens earlier than intended and cannot go back to sleep; in addition, person experiences general
loss of slow-wave sleep through night; to be considered chronic, individual must have 2 to 4 wk (depending on
criteria set used) of insomnia, but most people have had insomnia for much longer, sometimes for many years,
when they finally seek treatment
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 | Primary insomnia: cannot be accounted for by any other medical or psychiatric disorder; patients usually have
baseline hyperarousal
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| Secondary insomnia: now being thought of more as comorbid insomnia; comprises 80% of cases of chronic insomnia
(unfortunately, most research done in primary insomnia); worsens outcomes of comorbid conditions; predisposes
patients to relapses of comorbid conditions; usually persists after primary medical or psychiatric disorder
treated
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| Differential diagnosis: factors that contribute to insomnia include many medical and psychiatric disorders, circadian
rhythm disorders, medications (prescribed or over-the-counter [OTC]), psychosocial stressors, and poor
sleep hygiene; pain among most common medical disorders that contribute to insomnia (and insomnia shown to
make pain worse); contributory psychiatric medications include newer antidepressants, especially selective serotonin
reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), and stimulants
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| Primary sleep disorders: sleep-phase delay—occurs when individual cannot get to sleep at night and has trouble
awakening next day (common in young adults); exaggerated form of this problem may exist in individuals with bipolar
disorder and in younger people with bipolar tendencies; parasomnias more common in psychiatric patients;
REM sleep-behavior disorder—parasomnia in which patient fails to remain paralyzed during sleep and may act out
dreams or become violent; most antidepressants can precipitate or exacerbate this condition; sleep apnea—1 in 5
patients with sleep apnea has depression, and 1 in 5 patients with depression has sleep apnea; patient with sleep apnea
may present with same vegetative symptoms seen in depression; periodic limb movement disorder and restless
legs syndrome—sleep-related movement disorders that can be precipitated or exacerbated by antidepressants
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| Statistics: 10% to 15% of general population affected by chronic insomnia; 33% to 50% of people with insomnia report
psychiatric diagnosis; vast majority (80%) with major depression report insomnia
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| Diagnostic overlaps: occur between insomnia and psychiatric disorders in general, and between insomnia and mood
and anxiety disorders in particular; patient who meets research diagnostic criteria for primary insomnia also meets criteria
for major depression; speaker speculates on whether insomnia and depression represent diagnostic spectrum
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| Sleep abnormalities in psychiatric patients: psychiatric patients in acute episode of illness subjectively complain
of insomnia; objective evidence of sleep disruption found when they are observed in sleep laboratories, where
they show reductions in total sleep time, worse sleep efficiency, and longer time to fall asleep (ie, prolonged sleep
latency); compared to controls, patients with mood disorders and those with insomnia show robust decrements in
slow-wave sleep; of patients with insomnia, 75% have primary or secondary diagnosis of insomnia-related psychiatric
disorder; 50% to 69% of insomnia patients in primary care have psychiatric disorder; in patients with major
depression, sleep disturbance tends to persist after treatment of depression; “furthermore, not only is sleep [disturbance]
the last symptom to go, it tends to be the first symptom to appear”; in multiple studies, people with insomnia
tend to develop depression later, sometimes as long as 20 yr later
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| Management of insomnia: treat any underlying causes and/or comorbid conditions; promote good sleep habits;
consider cognitive behavioral therapy (CBT); consider medications to improve sleep
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| CBT: advantages—effects long lasting (may be superior to medications because of this); no risk for rebound insomnia
or substance dependence; disadvantages—delayed onset; requires commitment on part of patient and therapist;
therapist must have time and expertise to teach techniques; patient must have resources to obtain this form of
therapy and incentive to practice techniques regularly
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| Pharmacotherapy: advantages—rapid onset of clinical benefits; minimal time investment by patient and therapist;
disadvantages—clinical benefit may end when drug stopped; risks for substance dependence and rebound insomnia
(ie, insomnia worse than it was initially, with patient experiencing more sleep disturbance than he or she
had before starting medication)
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| Combination therapy: may be ideal; provides durability of behavioral therapy with rapid effectiveness of pharmacotherapy;
however, some patients will not practice behavioral techniques when medications available
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| Behavioral interventions: change maladaptive sleep habits (“and people who have long-standing insomnia generally
develop maladaptive habits”); decrease arousal; change beliefs and attitudes about sleep; adopt practices that
improve sleep
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| Self-medication: most common substance used is alcohol; self-medication may be risk factor for substance abuse
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| OTC medications: sedating antihistamine—most common active ingredient in OTC medications; OTC medications
may be effective for mild transient insomnia; produce hangover effect in 10% to 25% of users; adverse effects include
cognitive impairment, anticholinergic effects, and daytime sleepiness; may have paradoxic effect and be agitating
in children and elderly persons; habitual users may develop tolerance to diphenhydramine; herbal
preparations—widely used to treat insomnia, but little data available (literature inconsistent, and randomized
controlled trials lacking); not approved by Food and Drug Administration (FDA) for treatment of insomnia; kava-
kava (Piper methysticum) has potential to cause liver damage; melatonin—best-studied OTC preparation; may
affect circadian clock; some studies suggest it has phase-shifting properties (thereby helping people with circadian-rhythm
disorders or jet lag); some studies suggest it promotes sleep, others say it does not; potential side effects
include vasoactive effects (eg, constriction of cardiac vessels); lack of standardization and FDA regulation
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| Benzodiazepine receptor agonists (BzRAs): until recently, all FDA-approved medications for sleep acted on γ-
aminobutyric acid-A (GABA A) receptors; traditional benzodiazepines bind to all GABA A receptors “across
the board”; nonbenzodiazepines are variably selective to subtypes of GABA A receptors
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| Benzodiazepines: FDA-approved agents range from ultra-short–acting agents to long-acting; in general, have longest
durations of action and longest half-lives at benzodiazepine receptor; some of longest acting agents have active
metabolites, leading to potential for adverse effects, especially residual daytime sedation; some potential for
tolerance, withdrawal, or abuse, but these concerns mostly in patients with history of or potential for substance
abuse; benzodiazepines affect sleep architecture, in particular suppressing slow-wave sleep; may also have some
tendency to suppress REM sleep
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| Non-benzodiazepines that are also BzRAs: include zaleplon (Sonata), zolpidem (Ambien), zolpidem modified release
(MR; Ambien CR), and eszopiclone (Lunesta); although zolpidem and zolpidem MR have similar half-
lives, zolpidem MR has longer duration of action; BzRAs appear to have fewer side effects than benzodiazepines;
less likely to produce withdrawal symptoms; preserve sleep architecture; have relatively rapid onset of
action; doses must be reduced in elderly
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| Ramelteon (Rozerem): acts on melatonin type 1 and type 2 receptors in brain, principally in suprachiasmatic nucleus;
does not have binding affinity for peripheral melatonin receptors, which may eliminate some melatonin side
effects; does not act on benzodiazepine receptors; shows no potential for abuse or dependence; no limitation on
length of use; no dose adjustments needed across clinical populations; reduces sleep latency; cannot be given to patient
who takes fluoxetine because fluoxetine increases level of ramelteon
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| Other classes of drugs used for insomnia: general considerations—not approved by FDA for treatment of insomnia;
lack of short- or long-term efficacy data; no direct evidence to show lack of tolerance or rebound insomnia;
some anecdotal reports of less efficacy than BzRAs; all have potential side effects; antidepressants may be
used to treat both insomnia and depression
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| Antidepressants: in 2002, trazodone was antidepressant most commonly used for insomnia; nefazodone used infrequently
because of potential liver damage; advantages—low potential for abuse; disadvantages—may be less effective
than BzRAs; side effects include daytime sedation, weight gain, extrapyramidal effects, and metabolic
abnormalities; may cause toxicity in overdose; many do not have same safety profiles as hypnotics in overdose; in
patients with bipolar disorder, most antidepressants can cause switch into mania; may precipitate other sleep disorders,
such as movement disorders during sleep; agents that have potent REM-sleep–suppressing effects can cause
rebound insomnia on withdrawal
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| Atypical antipsychotics: advantages—anxiolytic; mood stabilizing in bipolar disorder; low potential for abuse;
disadvantages—may be less effective than BzRAs; potential side effects include weight gain, daytime sedation,
extrapyramidal effects, metabolic abnormalities, and sudden death in elderly patients
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| Anticonvulsants: advantages—seem to enhance slow-wave sleep (clinical significance unknown); some increase
GABA transmission; low potential for abuse; disadvantages—may not be as effective as BzRAs; potential side effects
include weight gain and daytime sedation
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| On horizon: indiplon (α1 selective agent; will be available in immediate-release and extended-release formulations);
agomelatine (melatonin receptor agonist with 5-HT2C properties); GABA receptor agents (eg, gaboxadol, pregabalin,
tiagabine); 5-HT2A antagonists (eg, eplivanserin)
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| National Institutes of Health state-of-the-science summary: many medications used for insomnia have not
been evaluated for long-term use; many drugs commonly used for insomnia not approved for this use and their efficacy
not proven; newer BzRAs appear to have fewer and less severe adverse effects than benzodiazepines, but require
further evaluation; CBT effective, unlikely to have adverse effects, and may provide long-lasting benefits;
more practitioners need to practice CBT
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| What happens when ramelteon is coadministered with fluvoxamine? levels of ramelteon increase up to 160-fold;
ramelteon proven safe at 20 times recommended dose; however, assessments of neuroendocrine side effects of
ramelteon have been done only at normal doses, so unknown whether increased levels have adverse effect on reproductive
hormones
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| Some patients who take eszopiclone (Lunesta) complain of metallic taste in mouth; is this side effect temporary? in
most people, metallic taste goes away after patient has eaten something or brushed teeth, but may persist in some
patients, requiring change to another medication
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| Some nursing homes forbid use of benzodiazepines and BzRAs because they may cause falls in elderly patients;
what to do? controversial whether hypnotics cause falls in elderly, but insomnia does have increased risk; educate
nursing home on how to do risk-benefit analysis
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| Is trazodone safe in patients with bipolar disorder? speaker discourages using it in this population because it is
known to trigger manic episodes; use only with extreme caution
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| Can trazodone be used in higher doses for insomnia? yes, but higher doses increase potential for hangover
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Suggested Reading
Benca RM et al: Special considerations in insomnia diagnosis and management: depressed, elderly, and chronic
pain populations. J Clin Psychiatry 65(Suppl 8):26, 2004; Benca RM: Consequences of insomnia and its therapies.
J Clin Psychiatry 62(Suppl 10):33, 2001; Benca RM: Diagnosis and treatment of chronic insomnia: a review. Psychiatr
Serv 56:332, 2005; Brzezinski A et al: Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med
Rev 9:41, 2005; Chesson A Jr et al: Practice parameters for the evaluation of chronic insomnia. An American
Academy of Sleep Medicine report. Standards of Practice Committee of the American Academy of Sleep Medicine.
Sleep 23:237, 2000; Hajak G: Insomnia in primary care. Sleep 23(Suppl 3):S54, 2000; Karam-Hage M, Brower
KJ: Open pilot study of gabapentin versus trazodone to treat insomnia in alcoholic outpatients. Psychiatry Clin Neurosci
57:542, 2005; Kato K et al: Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor
agonist. Neuropharmacology 48:301, 2005; Katz DA, McHorney CA: Clinical correlates of insomnia in
patients with chronic illness. Arch Intern Med 158:1099, 1998; Katz DA, McHorney CA: The relationship between
insomnia and health-related quality of life in patients with chronic illness. J Fam Pract 51:229, 2002; Lippmann
S et al: Insomnia: therapeutic approach. South Med J 94:866, 2001; Mendelson WB et al: The treatment
of chronic insomnia: drug indications, chronic use and abuse liability. Summary of a 2001 New Clinical Drug Evaluation
Unit meeting symposium. Sleep Med Rev 8:7, 2004; Morin CM et al: Residual symptoms in depressed patients
who respond acutely to fluoxetine. J Clin Psychiatry 60:221, 1999; Peterson MJ, Benca RM: Sleep in
mood disorders. Psychiatr Clin North Am 29:1009, 2006; Ringdahl EN et al: Treatment of primary insomnia. J
Am Board Fam Pract 17:212, 2004; Roth T et al: Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist,
reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep
28:303, 2005; Sateia MJ, Nowell PD: Insomnia. Lancet 364:1959, 2004; Sharpley AL et al: Olanzapine increases
slow-wave sleep: evidence for blockade of central 5-HT(2C) receptors in vivo. Biol Psychiatry 47:468, 2000;
Shochat T et al: Insomnia in primary care patients. Sleep 22(Suppl 2):S359, 1999; Smith MT et al: Comparative
meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. Am J Psychiatry 159:5, 2002;
Walsh JK: Drugs used to treat insomnia in 2002: regulatory-based rather than evidence-based medicine. Sleep
27:1441, 2004.
Educational Objectives
| The goal of this program is to improve the treatment of insomnia in patients with psychiatric comorbidity. After hearing
and assimilating this program, the clinician will be better able to:
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| 1. Implement the American Academy of Sleep Medicine Standards of Practice in the treatment of insomnia.
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| 2. Distinguish primary from secondary insomnia.
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| 3. Discuss the ramifications of sleep abnormalities in psychiatric patients.
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| 4. Compare and contrast the advantages and disadvantages of cognitive behavioral therapy and pharmacotherapy
in the treatment of insomnia.
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| 5. Evaluate medications currently used for the treatment of insomnia.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, the Audio-Digest Foundation requires all faculty members
to disclose relevant financial relationships within the past 12 months that might create any personal conflict of
interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care
education and not a proprietary business or commercial interest. For this program, Dr. Benca reported that she is a
consultant for, or on the advisory board of, King, Neurocrine/Pfizer, Sanofi-Aventis, Sepracor, and Takeda, and is on
the Speakers’ Bureaus of all the above and Wyeth.
Acknowledgements
Dr. Benca was recorded at the 11th Annual Psychopharmacology Update, held February 16-19, 2006, in Las Vegas,
NV, and sponsored by the American Psychiatric Association and the Nevada Psychiatric Association. The Audio-Digest
Foundation thanks Dr. Benca and the sponsors for their cooperation in the production of this program.
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