Sie sind auf Seite 1von 9

Treatment in Psychiatry

Treatment in Psychiatry begins with a hypothetical case illustrating a problem in current clinical practice. The authors
review current data on prevalence, diagnosis, pathophysiology, and treatment. The article concludes with the authors'
treatment recommendations for cases like the one presented.

Chronic Insomnia

Daniel J. Buysse, M.D. priate? What factors should be consid-


ered in formulating a treatment plan?
What treatments would be appropriate?

Ms. F, a 42-year-old divorced woman,


presents for evaluation of chronic insom-
nia. She complains of difficulty falling Insomnia Definitions
asleep, often 30 minutes or longer, and
“Insomnia” is used to refer to both a symptom and a dis-
difficulty maintaining sleep during the
order. The symptom of insomnia is defined as a subjective
night, with frequent awakenings that of-
complaint of difficulty falling asleep, difficulty staying
ten last 30 minutes or longer. These
symptoms occur nearly every night, with asleep, or poor quality sleep. In DSM-IV-TR (1), insomnia
only one or two “good” n ights per symptoms are included among the diagnostic criteria for
month. She typically goes to bed around several other mental disorders, including major depres-
10:00 p.m. to give herself adequate time sive disorder and generalized anxiety disorder. Insomnia
for sleep, and she gets out of bed around disorders are characterized by insomnia symptoms ac-
7:00 a.m. on work days and as late as companied by significant distress or impairment. In DSM-
9:00 a.m. on weekends. Her nighttime IV-TR the specific diagnosis of primary insomnia is further
sleep problems result in daytime irritabil- defined by a duration of at least 1 month and by symptoms
ity and difficulty focusing and organizing that do not occur exclusively during the course of another
her thoughts, which subjectively impair sleep disorder, mental disorder, or medical disorder or re-
her work as an administrative assistant, sult from use of substances or medications. Finally, DSM-
although her performance evaluations IV-TR includes diagnoses of “secondary” insomnia disor-
have been satisfactory. She says that she ders, that is, insomnia that causes significant distress or
has “no energy for anything extra,” that impairment or warrants independent clinical attention
her house is a mess, and that she rou- but is believed to be directly related to a coexisting mental
tinely declines invitations to join social disorder or medical disorder or to the effects of substances
and even family activities. Her insomnia or medications.
began approximately 5 years ago during Sleep medicine specialists use the International Classi-
a period of increased life stress related to fication of Sleep Disorders, Second Edition (ICSD-2) (2), to
a difficult divorce and a job change. At diagnose sleep disorders. ICSD-2 describes general crite-
that time she was diagnosed with major ria that are common to all insomnia disorders (Table 1) as
depression and was started on a success- well as eight specific insomnia disorders (in addition to
ful trial of escitalopram, which she con- “unspecified” and “not otherwise specified” categories),
tinues at a dose of 10 mg/day. Her cur-
each of which meets the general criteria along with more
rent symptoms are distinct from those
specific diagnostic criteria. For most purposes, the general
that were associated with her episode of
insomnia criteria proposed in ICSD-2 serve as a useful ba-
major depression. She denies pervasive
sis for discussing insomnia as a clinical disorder.
sadness or loss of interest, but she is very
frustrated with her inability to function Other classification schemes for insomnia have also
more effectively, which she attributes to been used. For instance, symptom-based classifications
her insomnia. In fact, she believes that distinguish between sleep-onset and sleep-maintenance
her cognitive difficulties and irritability insomnia. However, longitudinal studies suggest that
are most noticeable after nights of partic- these specific symptoms have limited stability over time
ularly poor sleep. Her medical history is (3); patients who present with sleep-onset insomnia at
unremarkable other than a past history one time may present with frequent awakenings at a later
of Graves’ disease. She has been treated time. Moreover, a majority of patients present with some
with levothyroxine for the past 15 years. combination of symptoms. Duration-based classifications
(acute, short-term, and chronic) have also been suggested
How should Ms. F be evaluated? What (4). Such classifications may provide clues to the cause of
medical testing, if any, would be appro- insomnia. For instance, acute and short-term insomnia

678 ajp.psychiatryonline.org Am J Psychiatry 165:6, June 2008


TREATMENT IN PSYCHIATRY

are more often related to life stresses, acute illnesses, or with insomnia continue to have symptoms after follow-
medications, whereas chronic insomnia is more likely to up periods of 1 year or longer, and most cross-sectional
be related to behavioral factors or the effects of chronic studies of insomnia patients report a duration of several
mental or medical disorders. However, the majority of pa- years (8–10). Although the number of true longitudinal in-
tients in clinical trials and in clinical practice have chronic somnia studies is small, evidence suggests that improve-
symptoms, which is the focus of this review. ment in medical and psychiatric conditions is associated
Distinctions have also been drawn between primary with improvement in insomnia (11). As noted above,
and secondary insomnia disorders. The underlying cross-sectional associations between insomnia and psy-
rationale is that secondary insomnia is caused by another chiatric disorders are strong, but additional evidence sug-
disorder, whereas primary insomnia has no other identi- gests that insomnia is a risk factor for the development of
fiable cause. However, as noted in the 2005 National Insti- psychiatric disorders and for poor outcomes in these dis-
tutes of Health (NIH) State of the Science Conference orders. For instance, approximately a dozen longitudinal
statement on the Manifestations and Management of studies have demonstrated that insomnia is an indepen-
Chronic Insomnia in Adults (5), dent risk factor for subsequent de-
such distinctions may not be velopment of depression (12). This
helpful clinically. Insomnia of-
“Insomnia often runs a chronic relationship has been observed
ten has multiple causes, and dis- from adolescence to later adult-
tinguishing when another con- course. Longitudinal studies hood and is maintained after ad-
dition “causes” insomnia can be suggest that approximately justment for concurrent depressive
d i f f i c u l t . Fo r i n s t a n c e, t h e symptoms. In addition, insomnia is
course of insomnia may not fol- 50% of individuals with one of the most common persis-
low the course of the other dis- insomnia continue to have tent sym pt om s in ind ividu als
order, and the two conditions treated for depression, and its pres-
may require different treat- symptoms after follow-up ence is a risk factor for nonre-
ments. For this reason, the NIH periods of 1 year or longer, and sponse to depression treatment
conference commended the and for recurrence following remis-
term “comorbid insomnia” as a most cross-sectional studies of sion (13–15).
preferable alternative to the insomnia patients report a
term “secondary insomnia.” Evaluation
duration of several years.”
A thorough clinical history is the
Epidemiology co rnerston e of evaluation for
The prevalence of insomnia differs depending on the chronic insomnia (16). The evaluation should focus on the
specific case definition used and the population assessed. description of current symptoms, including not only the
However, whatever definition is used, insomnia remains type of sleep disturbance at night but also sleep habits and
the most prevalent sleep disorder in the population. In- patterns. In particular, the clinician should inquire about
somnia symptoms—that is, the complaint in the absence times of going to bed and getting out of bed, variability in
of specific duration or distress criteria—occur in some sleep timing from day to day, and emotional, cognitive,
30%–40% of adults, and specific insomnia disorders—that and physical states surrounding sleep. Symptoms of other
is, the complaint together with meeting duration and im- specific sleep disorders should also be considered. These
pairment criteria—occur in 5%–10% of adults (6). The lat- include loud snoring and witnessed breathing pauses,
ter is most relevant to clinical practice, since the majority which might suggest sleep apnea, and motor restlessness
of individuals with insomnia symptoms do not present for and involuntary leg movements, which might suggest
medical evaluation or treatment unless they have signifi- restless legs syndrome.
cant distress or impairment. Rates of insomnia are higher Daytime consequences associated with insomnia
in medical and psychiatric care settings than in the gen- should also be evaluated. The most common complaints
eral population. include mood disturbance (typically described as irritabil-
A number of consistent risk factors for insomnia have ity and mood lability, rather than depression or anxiety),
been identified (6, 7). The strongest of these is concurrent fatigue, and complaints of cognitive inefficiency or diffi-
depressive symptoms. Female sex is also consistently asso- culty concentrating. The majority of patients with chronic
ciated with insomnia, with a ratio of approximately 1.4:1. insomnia do not actually complain of daytime sleepiness,
Increasing age, comorbid medical disorders, and comorbid that is, the tendency to fall asleep in inappropriate situa-
psychiatric disorders are other consistent risk factors. Addi- tions. Rather, insomnia appears to be associated with dif-
tional evidence also suggests that being separated or di- ficulty sleeping at any time during the 24-hour day.
vorced, having lower income, lower socioeconomic status, The evaluation of insomnia should also include careful
increased chronic life stress, and black race are also associ- consideration of comorbid psychiatric and medical disor-
ated with insomnia prevalence. ders as well as medications and substances that might in-
Insomnia often runs a chronic course. Longitudinal terfere with sleep (Table 2). Virtually any psychiatric disor-
studies suggest that approximately 50% of individuals der can be associated with insomnia, but depressive and

Am J Psychiatry 165:6, June 2008 ajp.psychiatryonline.org 679


TREATMENT IN PSYCHIATRY

TABLE 1. General Criteria for Insomniaa TABLE 2. Comorbid Psychiatric and Medical Disorders and
A. A complaint of difficulty initiating sleep, difficulty maintaining Medications and Substances That May Interfere With Sleep
sleep, or waking up too early or sleep that is chronically nonrestor- Psychiatric disorders
ative or poor in quality. In children, the sleep difficulty is often re- Mood disorders (major depression, dysthymic disorder, bipolar af-
ported by the caretaker and may consist of observed bedtime resis- fective disorder)
tance or inability to sleep independently. Anxiety disorders (generalized anxiety disorder, panic disorder,
B. The above sleep difficulty often occurs despite adequate opportu- posttraumatic stress disorder)
nity and circumstances for sleep. Psychotic disorders (schizophrenia)
C. At least one of the following forms of daytime impairment related Substance use disorders
to the nighttime sleep difficulty is reported by the patient: Medical disorders and conditions
i. Fatigue or malaise Cardiovascular (congestive heart failure, coronary artery disease)
ii. Attention, concentration, or memory impairment Pulmonary (chronic obstructive pulmonary disease, asthma)
iii. Social or vocational dysfunction or poor school performance Neurologic (stroke, Parkinson’s disease, neuropathy, traumatic
iv. Mood disturbance or irritability brain injury, cerebrovascular disease)
v. Daytime sleepiness Gastrointestinal (gastroesophageal reflux disease)
vi. Motivation, energy, or initiative reduction Renal and genitourinary (chronic renal failure, prostatic hypertro-
vii. Proneness for errors or accidents at work or while driving phy)
viii. Tension, headaches, or gastrointestinal symptoms in response Endocrine and metabolic (diabetes, hyperthyroidism, obesity)
to sleep loss Musculoskeletal (rheumatoid arthritis, osteoarthritis, fibromyalgia)
ix. Concerns or worries about sleep Other (menopause)
a Adapted from the International Classification of Sleep Disorders, Medications and substances
Second Edition (2). Alcohol (acute use, withdrawal)
Caffeine
Nicotine
anxiety disorders are especially common. Likewise, a wide Antidepressants (selective serotonin reuptake inhibitors, serotonin-
range of medical and neurologic conditions can be associ- norepinephrine reuptake inhibitors, atypical antidepressants)
Decongestants (phenylpropanolamine, pseudoephedrine)
ated with insomnia. Particular attention should be given Corticosteroids
to those conditions that are associated with pain, breath- β-Agonist and theophylline-derivative bronchodilators
ing difficulty, and impaired mobility. Medications that af- β-Antagonists
Stimulants
fect any CNS neurotransmitter can be associated with
Statins
insomnia. Common examples include high doses of caf- Dopamine agonists
feine, alcohol, and antidepressants, particularly selective
serotonin reuptake inhibitors, serotonin-norepinephrine
might lead to a central dysregulation of breathing, such as
reuptake inhibitors, and atypical antidepressants.
congestive heart failure and stroke. Insomnia patients
It is often useful to view the insomnia history in terms of with unusual behaviors during sleep, such as violent be-
predisposing, precipitating, and perpetuating factors (17). havior, should also be considered for polysomnography.
These factors can help identify potential causes of insom- Finally, failure to respond to usual insomnia treatments
nia and treatment targets. Predisposing factors include may warrant referral to a sleep specialist and, in some
family/genetic diathesis and chronic mental or medical cases, polysomnography.
disorders that increase the likelihood of insomnia symp-
toms. Precipitating factors are acute events or experiences Differential Diagnosis
that may push vulnerable individuals over the threshold
into acute insomnia. Perpetuating factors include behav- As noted above, distinctions between primary and sec-
ioral patterns (e.g., spending excessive time in bed) and ondary forms of insomnia are of limited clinical utility be-
medical or medication factors that maintain insomnia cause of the difficulty in establishing causality. ICSD-2 lists
symptoms over time. eight specific insomnia diagnoses, each distinguished by
The clinical history can be usefully supplemented by specific clinical features. However, in general practice, it is
collection of a 2-week sleep-wake diary. This is a prospec- most useful to identify an insomnia disorder using the
tive charting of a patient’s actual sleep hours and habits, general criteria listed in Table 1, and then to distinguish
and it can usefully identify variability in sleep patterns and between comorbid and noncomorbid (primary) forms of
specific daytime correlates that may provide targets for insomnia. Common comorbidities, as noted above, in-
subsequent intervention (Figure 1). clude psychiatric disorders, general medical and neuro-
logic disorders, and certain sleep disorders, such as sleep
Specific laboratory testing has limited utility in the diag-
apnea and restless legs syndrome. The importance of
nosis and assessment of insomnia. However, in specific
identifying comorbid insomnia is that it should lead to ap-
situations, general metabolic panels, CBC, or endocrine
propriate treatment of both the insomnia disorder and the
testing (e.g., thyroid hormone) may be useful. Overnight
comorbid conditions. Treatment of primary insomnia, on
sleep studies with polysomnography are not routinely in-
the other hand, focuses only on the sleep problems and
dicated in the evaluation of chronic insomnia. However, in
their daytime correlates.
specific situations, such testing may be useful. For exam-
ple, individuals with a high index of suspicion for sleep ap-
nea should be referred for polysomnographic testing. Risk
Pathophysiology
factors include obesity, loud snoring, witnessed pauses in The etiology and pathophysiology of chronic insomnia
breathing, craniofacial abnormalities, or factors that are unknown. However, converging lines of evidence from

680 ajp.psychiatryonline.org Am J Psychiatry 165:6, June 2008


TREATMENT IN PSYCHIATRY

FIGURE 1. Graphic Sleep Diary of a Patient With Insomniaa

a In a graphic sleep diary, each day is displayed on one horizontal line, with times of day along the horizontal axis. In this example, midnight
is displayed in the middle of the page, and midnight and 8:00 a.m. have been circled. The patient indicates the time of going to bed with a
down arrow, the time of getting out of bed with an up arrow, and estimated actual sleep time with a horizontal line. In the far right column,
the patient rates sleep quality on a scale of 1–10. This example shows day-to-day regularity in times for going to bed and getting up, with
interrupted sleep in between.

psychological and physiological studies suggest that some relaxation approaches, and multimodal cognitive-behav-
form of “hyperarousal” is common to many individuals ioral treatment for insomnia (20). The general features of
with insomnia (18). The cognitive and affective hyper- these treatments are summarized in Table 3. Qualitative
arousal in insomnia has been demonstrated with both and quantitative analyses of treatment studies using these
symptom reports and results of experimental cognitive techniques have indicated robust treatment effects on a
paradigms. Physiological indicators of increased arousal variety of self-report sleep outcome measures and a
include elevated cortisol/ACTH in the evening hours, in- smaller number of objective sleep outcome measures us-
creased heart rate and alterations in heart rate variability, ing polysomnography (21). Published treatment manuals
and increased whole body metabolic rate. EEG markers of and self-help books describe the specific techniques for
increased arousal include increased activity in frequency these treatments, which are simple enough to implement
ranges from 16 to 50 Hz. Evidence from positron emission in routine clinical practice (22–25).
tomography (PET) studies also supports the hypothesis of The various psychological and behavioral treatments
hyperarousal: individuals with primary insomnia have el- for insomnia share several common elements that have
evated whole brain metabolism during both sleep and been combined into briefer forms of treatment. Common
wakefulness and regional activation in affective and
elements to many of these treatments include 1) educa-
arousal centers during non-REM sleep (19).
tion regarding sleep, sleep needs, and physiological regu-
lation of sleep; 2) the establishing of more regular sleep
Psychological and Behavioral Treatment hours, with particular emphasis on the time of arising in
Both psychological-behavioral treatments and pharma- the morning; 3) limitation of time in bed to more closely
cologic treatments have demonstrated efficacy in the match the individual’s actual sleep hours; 4) reinforce-
treatment of chronic insomnia. A variety of psychological ment of the bed and bedroom as a stimulus for sleep
and behavioral techniques have been evaluated in well- rather than for wakefulness and frustration about sleep.
designed controlled clinical trials. Specific techniques in- The mechanisms of psychological-behavioral treatments
clude sleep restriction therapy, stimulus control therapy, are unknown, but these common elements suggest the

Am J Psychiatry 165:6, June 2008 ajp.psychiatryonline.org 681


TREATMENT IN PSYCHIATRY

TABLE 3. Psychological and Behavioral Treatments for In- peutic index. Approved BzRAs include a set of drugs that
somniaa are true benzodiazepines as defined by their chemical
Technique and Aim structure and a set of drugs that are not benzodiazepines
Sleep hygiene education but appear to share a common mechanism of action.
Promotion of behaviors that improve sleep; limitation of behaviors
that interfere with sleep. Specific instructions include getting reg-
BzRAs act at a specific recognition site on γ-aminobutyric
ular exercise, limiting caffeine and alcohol consumption, main- acid type A (GABAA) receptors in the CNS; this recognition
taining a regular sleep-wake schedule, and avoiding naps. site is distinct from the GABA recognition site itself (26).
Stimulus control therapy Benzodiazepines have affinity for several subtypes of
A set of behavioral interventions that promote associative condi-
tioning between the sleep environment and sleepiness. Patients GABAA receptors, which are defined by the specific com-
are instructed to use the bed only for sleep (and sex); not to go to position of five protein subunits. Some nonbenzodiaz-
bed unless sleepy; to get out of bed and engage in other low- epine BzRAs have greater selectivity for GABA receptors
stimulation activities if awake and unable to sleep during the
containing an alpha1 protein subunit. The sedating and
night and to return to bed only when sleepy; to maintain a regu-
lar wake-up time regardless of sleep duration; and to avoid nap- amnestic effects of BzRAs both appear to be related to af-
ping. finity for alpha1-containing GABAA receptors, but the clin-
Sleep restriction therapy ical significance of drug specificity in vivo is uncertain.
Sleep practices that increase duration of wakefulness and “sleep
drive” to facilitate the ability to sleep. A sleep diary is used to de- BzRAs differ from each other mainly in terms of phar-
termine actual sleep time, time in bed, and “sleep efficiency” macokinetic properties, and particularly in terminal elim-
([sleep time ÷ time in bed] × 100). Time in bed is decreased to ination half-life (Table 4). Available agents have terminal
match actual sleep time and is increased by 15–30 minutes only
when sleep efficiency exceeds 85% for a week. Patients are also elimination half-lives ranging from 1 to 120 hours. The du-
prohibited from napping and are instructed to maintain a regu- ration of action of a drug is most strongly, although not ex-
lar wake time. clusively, related to half-life. Therefore, selection of a par-
Cognitive behavior therapy for insomnia
ticular drug often depends on the ideal duration of action
Identification, challenge, and replacement of dysfunctional beliefs
and attitudes regarding sleep and sleep loss. These beliefs in- for a particular patient, rather than on any specific distinc-
crease arousal and tension, which in turn impede sleep and rein- tions between drugs.
force the dysfunctional beliefs. Cognitive techniques are most of-
BzRA drugs as a class reduce sleep onset latency and in-
ten combined with stimulus control and sleep restriction therapy
(see above). crease total sleep time; depending on the specific pharma-
Relaxation training cokinetics of the drug in question, decreased wakefulness
Training in techniques that decrease waking arousal and facilitate after sleep onset may also result. Qualitative and quantita-
sleep at night, based on the premise that muscular tension and
cognitive arousal are incompatible with sleep. Specific tech- tive analyses of clinical trials with BzRAs demonstrate
niques include progressive muscle relaxation, guided imagery, their efficacy as judged by self-report and objective out-
and abdominal breathing. Patients should practice to proficiency comes (29, 30). However, as is the case with psychological
during waking hours before using relaxation techniques at bed- and behavioral treatments, few studies have paid atten-
time.
a tion to functional outcomes or to the broader insomnia
Drawn from references 20, 21, 23, and 25.
syndrome.
BzRAs also share a similar set of adverse effects, which
potential importance of augmenting homeostatic sleep
include anterograde amnesia, postural instability, and
drive, providing regular sleep-wake (and dark-light) cues
sleepiness (16, 31). The presence of such side effects may
for the circadian timing system, and reducing cognitive-
be related to the specific drug’s half-life; impaired memory
affective arousal.
and daytime sedation are more likely with agents having
Psychological-behavioral treatments for chronic insom-
long half-lives. A range of more serious behavioral adverse
nia may be provided by psychologists and other behav-
consequences, including sleep-related eating, sexual be-
ioral medicine specialists with adequate training. In addi-
havior, and even driving, have been reported anecdotally
tion, certification in behavioral sleep medicine is provided
and in the lay press. Although most of these reports have
by the American Academy of Sleep Medicine. More basic
occurred in association with zolpidem, which is the most
forms of psychological-behavioral treatments may be pro-
widely prescribed drug in this class, it seems likely that
vided by other health professionals, including nurses as
similar adverse effects are possible with any agent in this
well as physicians.
class.
BzRAs may also be associated with rebound insomnia,
Pharmacologic Treatment
withdrawal, tolerance, and dependence (16, 31). Rebound
Numerous prescription and nonprescription agents insomnia has been demonstrated predominantly with
have been used to treat insomnia. Agents currently ap- short-acting drugs, and it can be minimized by gradual
proved by the U.S. Food and Drug Administration (FDA) dose tapering and even by alternate-day dosing after the
for treatment of insomnia include eight benzodiazepine dose has been reduced. Withdrawal symptoms can also be
receptor agonists (BzRAs) and one melatonin receptor ag- minimized by dose and frequency tapering. Abuse of BzRA
onist. Although several barbiturate and miscellaneous drugs as agents of first choice is not common. However,
nonbarbiturate drugs (e.g., chloral hydrate, ethchlor- individuals who abuse these drugs commonly abuse other
vynol) are also approved as sedative-hypnotics, they are substances, and the use of higher-than-prescribed doses
not recommended for clinical use given their low thera- or requests for early prescription refills should raise con-

682 ajp.psychiatryonline.org Am J Psychiatry 165:6, June 2008


TREATMENT IN PSYCHIATRY

TABLE 4. Pharmacokinetic Properties of Hypnotic Drugs Approved by the U.S. Food and Drug Administrationa
Elimination Half-Life in Young
Drug Peak Time (Hours) Adults (Hours) Typical Adult Dose (mg)
Benzodiazepine receptor agonists
Zaleplon 1 1 5–20
Zolpidem 1.6 2.5–2.8 5–10b
Eszopiclone 1 5–6 1–3
Triazolam 1–2 1.5–5.5 0.125–0.50
Temazepam 1.2–1.6 3.5–18.4 7.5–30
Estazolamc 2 8–28 0.5–2
Quazepamc 1–3 47–100 7.5–15
Flurazepamc 0.5–13.6 2–100 15–30
Melatonin receptor agonists
Ramelteon 0.75 0.8–2.6 8
Other drugs not approved as hypnotics
Doxepin 0.5–1 18–37 10–150
Amitriptyline 3–4 21–31 25–150
Diphenhydramine 2–3 8–9 25–50
Trazodone 1–2 5–9 25–150
a Drawn from references 27 and 28. The pharmacokinetic values listed are approximate values in young adults.
b Zolpidem is also available in a modified-release formulation, for which the typical adult dose is 6.25–12.5 mg.
c Values reflect parent drug and active metabolite.

cern. Hypnotic dependence has both physiological and concerns are raised by the use of sedating antipsychotic
psychological determinants. Physiological aspects of de- drugs, which may have metabolic and neurologic side ef-
pendence are related to the discontinuation effects noted fects. Therefore, their use for treatment of sleep distur-
above. Psychological aspects of dependence are related to bance is recommended only in cases of insomnia that is
the fear or belief that good sleep will not be possible with- comorbid with psychiatric disorders that independently
out medications. This may lead some individuals to con- warrant their use, such as severe bipolar disorder.
tinue taking medications for extended periods, even in the Alcohol and antihistamines are the most commonly
absence of clear therapeutic benefits. used self-treatments for insomnia. Alcohol may help pro-
BzRAs have also been shown to be useful for individuals mote sleep initially, but it disrupts sleep for the remainder
with comorbid insomnia, including those with comorbid of the night and raises the additional issues associated
depression (32). They also reduce insomnia in perimeno- with chronic alcohol use. Very little evidence is available
pausal women with hot flashes (33). Both nightly dosing supporting the efficacy or safety of diphenhydramine or
and intermittent (e.g., three times per week) dosing have other antihistamines for the treatment of insomnia. In ad-
been shown to be efficacious (34). Although most clinical dition, their anticholinergic properties raise safety ques-
trials have been conducted for 1 week or less, recent evi- tions, particularly in older people. Finally, naturopathic
dence from double-blind studies shows continued evi- remedies such as valerian (37) have been assessed in some
dence for efficacy for up to 6 months of nightly use (35). clinical trials. However, substantial difficulties arise in the
One melatonin receptor agonist, ramelteon, has been standardization of these products, and their overall effi-
shown to be efficacious for treatment of insomnia (36). Its cacy is marginal at best.
primary effect appears to be on sleep onset latency, with
little effect on wakefulness during the middle of the night. Treatment Implementation
Its side effect profile appears to be relatively benign, al-
though increased blood levels have been observed in older Before initiating any treatment, the clinician should de-
adults, and some hormonal alterations (e.g., reduced test- termine whether the patient’s insomnia symptoms war-
osterone) have been observed. rant treatment, as indicated by the severity of sleep symp-
A wide variety of drugs that have not been approved by toms, daytime symptoms, and distress. Reasonable
the FDA for the treatment of insomnia have been used in treatment goals should also be discussed. For instance,
clinical practice. These include sedating antidepressant patients should recognize that some degree of night-to-
drugs, sedating antipsychotic drugs, and sedating anti- night variability in sleep quality is natural and may be ex-
convulsant drugs, often used in low doses. Small clinical perienced even after treatment. Their sleep problems
trials have supported the efficacy of low doses of traz- should become more manageable with treatment, how-
odone and sedating tricyclic drugs for treatment of insom- ever, and their daytime function can improve. Treatment
nia (16). Their role in the routine treatment of chronic in- outcomes should focus not only on the quantitative sleep
somnia has not been defined, but they are likely to be parameters, such as sleep latency, wakefulness after sleep
most useful in patients who have a history of substance onset, and sleep duration, but also on qualitative aspects
use and those who have a contraindication or poor re- of the individual’s sleep and daytime function.
sponse to BzRAs. Important side effects of these drugs in- Psychological and behavioral treatments are appropri-
clude orthostatic hypotension and anticholinergic effects, ate in almost all cases of chronic insomnia. A simplified
which are of particular concern in the elderly. Even greater approach focusing on education and behavioral princi-

Am J Psychiatry 165:6, June 2008 ajp.psychiatryonline.org 683


TREATMENT IN PSYCHIATRY

ples, as outlined above, may result in substantial improve- function tests, which showed normal T4,
ment in some cases. Referral to individuals with specific T3, and thyroid-stimulating hormone lev-
training in behavioral sleep medicine or the use of cogni- els. Given that Ms. F’s insomnia had a
tive-behavioral approaches may also be appropriate. course independent of her prior major
Pharmacologic treatment may be appropriate when the depression, a diagnosis of primary in-
insomnia causes significant symptoms, distress, or im- somnia was made. Initial discussion with
the patient focused on sleep education,
pairment. Medication effects and side effects should be
including the need for an adequate dura-
discussed with the patient. In most cases, initial treatment
tion of wakefulness each day to promote
with a short-acting BzRA is a reasonable first step. De-
sleep drive at night. The variability of the
pending on initial treatment response, a second BzRA with
patient’s sleep hours and her excessively
either a shorter or longer half-life may be tried. In the
long time in bed were also discussed. A
event of nonresponse, or in the case of individuals with a
treatment plan was agreed upon using
history of substance abuse, a trial of a sedating antidepres- the four general rules discussed above,
sant at a low dose may be a reasonable approach. based on sleep restriction and stimulus
control principles; the patient was given
Unresolved Issues a “prescription” of going to bed at 11:00
p.m. and getting out of bed no later than
Although a great deal has been learned about the epide-
6:00 a.m. each day. She was also asked to
miology, pathophysiology, and treatment of chronic in- keep a sleep diary. At follow-up 4 weeks
somnia, other questions remain to be answered. First, the later, the sleep diary showed improved
optimal method of combining behavioral and pharmaco- consolidation of her nighttime sleep, al-
logic treatments remains to be determined. Some evi- though Ms. F still felt tired during the day.
dence suggests that psychological-behavioral treatment She thought that her cognitive function
alone may provide superior long-term outcomes, but the was mildly improved. A trial of a short-
combination may provide better short-term outcomes acting hypnotic, zolpidem, was then initi-
(38). A second unresolved issue is the length of treatment, ated, with the patient maintaining the
particularly pharmacologic treatment. Although previous same sleep hours. Subsequent follow-up
assumptions about a rapid development of tolerance have in another month demonstrated further
not been borne out in recent double-blind placebo-con- improvements in sleep consolidation at
trolled studies, it is a common clinical observation that night, but with some feelings of morning
patients say the drug is “no longer working.” In addition, sedation, occurring approximately three
discontinuation of long-term treatment with hypnotics nights out of the week. The patient felt
often results in further improvements in sleep (39). Third, more in control of her sleep problem. It
the benefits of intermittent or as-needed medication use, was agreed that intermittent use of zol-
as opposed to nightly treatment, remain to be defined. Fi- pidem might be appropriate. Thus, the
nally, it has not been clearly demonstrated whether treat- patient began a trial of zolpidem inter-
ing insomnia leads to consistent improvements in comor- mittently, while maintaining attention to
her sleep behaviors. She was advised to
bid conditions or other more general aspects of daytime
use her medication if she had several bad
functioning. Early evidence suggests that treatment of in-
nights in a row, if she felt particularly
somnia may improve outcomes of comorbid depression
stressed, or if she needed the certainty of
(40, 41), but further controlled trials are needed.
consolidated sleep before important ac-
tivities the following day. Several months
Summary and Recommendations later, she reported general improvement
in her sleep, to a tolerable level. Her
Chronic insomnia should be carefully evaluated, begin-
mood also remained stable, with no evi-
ning with a thorough clinical history, including sleep hab-
dence of reemergence of depression.
its and patterns. The possibility of other sleep disorders,
comorbidity with another medical or psychiatric disorder,
and effects of substances and medications should be con-
sidered in patients with insomnia. Treatments for insom-
nia include psychological and behavior treatments and
pharmacotherapy, which can be used in combination. Received Jan. 25, 2008; revision received March 16, 2008; accepted
March 16, 2008 (doi: 10.1176/appi.ajp.2008.08010129). From the
Department of Psychiatry, University of Pittsburgh School of Medi-
cine. Address correspondence and reprint requests to Dr. Buysse, De-
partment of Psychiatry, 3811 O’Hara St., Pittsburgh, PA 15213;
buyssedj@upmc.edu (e-mail).
Ms. F’s physician ordered further medical Dr. Buysse serves as a consultant to Actelion, Avena, Cephalon, Eli
testing, including assessment of thyroid Lilly, GlaxoSmithKline, Merck, Neurocrine, Neurogen, Pfizer,

684 ajp.psychiatryonline.org Am J Psychiatry 165:6, June 2008


TREATMENT IN PSYCHIATRY

Respironics, Sanofi-Aventis, Sepracor, Servier, Somnus Therapeutics, icine: Basic Science, Technical Considerations, and Clinical
StressEraser, Takeda, and Transcept Pharmaceuticals. Aspects. Edited by Chokroverty S. Boston, Butterworth-Heine-
Supported by National Institute of Aging grant AG-20677 and NIMH mann, 1999, pp 385–416
grant MH-24652.
18. Perlis ML, Smith MT, Pigeon WR: Etiology and pathophysiology
of insomnia, in Principles and Practice of Sleep Medicine. Ed-
ited by Kryger MH, Roth T, Dement WC. Philadelphia, Elsevier
References Saunders, 2005, pp 714–725
19. Nofzinger EA, Buysse DJ, Germain A, Price JC, Miewald JM,
1. American Psychiatric Association: Diagnostic and Statistical
Kupfer DJ: Functional neuroimaging evidence for hyperarousal
Manual of Mental Disorders, 4th ed, Text Revision. Washington,
in insomnia. Am J Psychiatry 2004; 161:2126–2129
DC, American Psychiatric Association, 2000
20. Morin CM: Psychological and behavioral treatments for pri-
2. American Academy of Sleep Medicine: The International Clas-
mary insomnia, in Principles and Practice of Sleep Medicine.
sification of Sleep Disorders, 2nd ed: Diagnostic and Coding
Edited by Kryger MH, Roth T, Dement WC . Philadelphia,
Manual. Westchester, Ill, American Academy of Sleep Medicine,
Elsevier Saunders, 2005, pp 726–737
2005
3. Hohagen F, Kappler C, Schramm E, Riemann D, Weyerer S: 21. Morin CM, Bootzin RR, Buysse DJ, Edinger JD, Espie CA, Lich-
Sleep onset insomnia, sleep maintaining insomnia, and insom- stein KL: Psychological and behavioral treatment of insomnia:
nia with early morning awakening: temporal stability of sub- an update of recent evidence (1998–2004). Sleep 2006; 29:
types in a longitudinal study on general practice attenders. 1398–1414
Sleep 1994; 17:551–554 22. Glovinsky P, Spielman A: The Insomnia Answer: A Personalized
4. National Institutes of Health: Drugs and Insomnia: The Use of Program for Identifying and Overcoming the Three Types of In-
Medications to Promote Sleep: NIH Consensus Development somnia. New York, Perigee Books, 2006
Conference. National Institutes of Health Consensus Develop- 23. Morin CM: Insomnia: Psychological Assessment and Manage-
ment Conference Summary 1984; 4:1–19 ment. New York, Guilford, 1993
5. National Institutes of Health State of the Science Conference 24. Morin CM, Espie CA: Insomnia: A Clinical Guide to Assessment
Statement on Manifestations and Management of Chronic In- and Treatment. New York, Kluwer Academic/Plenum Publish-
somnia in Adults, June 13–15, 2005. Sleep 2005; 28:1049–1057 ers, 2003
6. Ohayon MM: Epidemiology of insomnia: what we know and 25. Perlis ML, Smith MT, Jungquist C, Posner D: Cognitive Behav-
what we still need to learn. Sleep Med Rev 2002; 6:97–111 ioral Treatment of Insomnia: A Session-by-Session Guide. New
7. Buysse DJ, Germain A, Moul DE: Diagnosis, epidemiology, and York, Springer-Verlag, 2005
consequences of insomnia. Prim Psychiatry 2005; 12:37–44 26. Bateson AN: The benzodiazepine site of the GABAA receptor:
8. Buysse DJ, Angst J, Gamma A, Ajdacic V, Eich D, Rössler W: Prev- an old target with new potential? Sleep Med 2004; 5(suppl 1):
alence, course, and comorbidity of insomnia and depression S9–S15
in young adults. Sleep 2008; 31:473–480 27. Drug Facts and Comparisons: Pocket Version 2008. Baltimore,
9. Foley DJ, Monjan A, Simonsick EM, Wallace RB, Blazer DG: Inci- Lippincott Williams & Wilkins, 2007
dence and remission of insomnia among elderly adults: an ep- 28. Brunton LL, Lazo JS, Parker KL: Goodman & Gilman’s The Phar-
idemiologic study of 6,800 persons over three years. Sleep macological Basis of Therapeutics, 11th ed. New York,
1999; 22(suppl 2):S366–S372 McGraw-Hill, 2006
10. Moul DE, Nofzinger EA, Pilkonis PA, Houck PR, Miewald JM, 29. Nowell PD, Mazumdar S, Buysse DJ, Dew MA, Reynolds CF,
Buysse DJ: Symptom reports in severe chronic insomnia. Sleep Kupfer DJ: Benzodiazepines and zolpidem for chronic insom-
2002; 25:553–563 nia: a meta-analysis of treatment efficacy. JAMA 1997; 278:
11. Katz DA, McHorney CA: Clinical correlates of insomnia in pa- 2170–2177
tients with chronic illness. Arch Intern Med 1998; 158:1099– 30. Smith MT, Perlis ML, Park A, Smith MS, Pennington J, Giles DE,
1107 Buysse DJ: Comparative meta-analysis of pharmacotherapy
12. Perlis ML, Smith LJ, Lyness JM, Matteson SR, Pigeon WR, and behavior therapy for persistent insomnia. Am J Psychiatry
Jungquist CR, Tu X: Insomnia as a risk factor for onset of de- 2002; 159:5–11
pression in the elderly. Behav Sleep Med 2006; 4:104–113 31. Walsh JK, Roehrs T, Roth T: Pharmacologic treatment of pri-
13. Buysse DJ, Tu XM, Cherry CR, Begley AE, Kowalski J, Kupfer DJ, mary insomnia, in Principles and Practice of Sleep Medicine.
Frank E: Pretreatment REM sleep and subjective sleep quality Edited by Kryger MH, Roth T, Dement WC . Philadelphia,
distinguish depressed psychotherapy remitters and nonremit- Elsevier Saunders, 2005, pp 748–760
ters. Biol Psychiatry 1999; 45:205–213 32. Fava M, McCall WV, Krystal A, Wessel T, Rubens R, Caron J, Am-
14. Nierenberg AA, Keefe BR, Leslie VC, Alpert JE, Pava JA, Wor- ato D, Roth T: Eszopiclone co-administered with fluoxetine in
thington JJ, Rosenbaum JF, Fava M: Residual symptoms in de- patients with insomnia coexisting with major depressive disor-
pressed patients who respond acutely to fluoxetine. J Clin Psy- der. Biol Psychiatry 2006; 59:1052–1060
chiatry 1999; 60:221–225 33. Dorsey CM, Lee KA, Scharf MB: Effect of zolpidem on sleep in
15. Reynolds CF III, Frank E, Houck PR, Mazumdar S, Dew MA, women with perimenopausal and postmenopausal insomnia:
Cornes C, Buysse DJ, Begley A, Kupfer DJ: Which elderly pa- a 4-week randomized, multicenter, double-blind, placebo-con-
tients with remitted depression remain well with continued in- trolled study. Clin Ther 2004; 26:1578–1586
terpersonal psychotherapy after discontinuation of antidepres- 34. Perlis ML, McCall WV, Krystal AD, Walsh JK: Long-term, non-
sant medication? Am J Psychiatry 1997; 154:958–962 nightly administration of zolpidem in the treatment of pa-
16. Buysse DJ, Germain A, Moul D, Nofzinger EA: Insomnia, in Sleep tients with primary insomnia. J Clin Psychiatry 2004; 65:1128–
Disorders and Psychiatry. Edited by Buysse DJ. Review of Psy- 1137
chia, vol 24. Arlington, Va, American Psychiatric Publishing, 35. Krystal AD, Walsh JK, Laska E, Caron J, Amato DA, Wessel TC,
2005, pp 29–75 Roth T: Sustained efficacy of eszopiclone over 6 months of
17. Spielman AJ, Anderson MW: The clinical interview and treat- nightly treatment: results of a randomized, double-blind, pla-
ment planning as a guide to understanding the nature of in- cebo-controlled study in adults with chronic insomnia. Sleep
somnia: the CCNY Insomnia Interview, in Sleep Disorders Med- 2003; 26:793–799

Am J Psychiatry 165:6, June 2008 ajp.psychiatryonline.org 685


TREATMENT IN PSYCHIATRY

36. Erman M, Seiden D, Zammit G, Sainati S, Zhang J: An efficacy, and cognitive behavior therapy to facilitate benzodiazepine
safety, and dose-response study of ramelteon in patients with discontinuation in older adults with chronic insomnia. Am J
chronic primary insomnia. Sleep Med 2006; 7:17–24 Psychiatry 2004; 161:332–342
37. Taibi DM, Landis CA, Petry H, Vitiello MV: A systematic review 40. Krystal A, Fava M, Rubens R, Wessel T, Caron J, Wilson P, Roth T,
of valerian as a sleep aid: safe but not effective. Sleep Med Rev McCall WV: Evaluation of eszopiclone discontinuation after co-
2007; 11:209–230 therapy with fluoxetine for insomnia with coexisting depres-
38. Morin CM, Wooten V: Psychological and pharmacological ap- sion. J Clin Sleep Med 2007; 3:48–55
proaches to treating insomnia: critical issues in assessing their 41. Smith MT, Huang MI, Manber R: Cognitive behavior therapy for
separate and combined effects. Clin Psychol Rev 1996; 16:521– chronic insomnia occurring within the context of medical and
542 psychiatric disorders. Clin Psychol Rev 2005; 25:559–592
39. Morin CM, Bastien C, Guay B, Radouco-Thomas M, Leblanc J,
Vallières A: Randomized clinical trial of supervised tapering

686 ajp.psychiatryonline.org Am J Psychiatry 165:6, June 2008