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In-Depth Information
particularly for patients with a sleep-related breathing dis-
order or a history of alcohol or drug abuse.
Use of melatonin as an adjunct treatment for residual
insomnia has been the subject of investigational study.
Melatonin is the principal hormone produced by the pineal
gland. Because disturbed patterns of melatonin secretion
have been associated with insomnia, patterns of melatonin
secretion have been examined in medication-free schizo-
phrenic patients. In certain studies, the nighttime peak in
melatonin secretion was blunted, and normalization of
melatonin levels did not occur following clinical improve-
ment with antipsychotic-treatment. 86 , 87 Subsequent studies
tested the effect of exogenous melatonin on residual
insomnia in antipsychotic-treated schizophrenic patients.
Melatonin replacement was associated with improved
sleep maintenance measured by actigraphy 88 and by
self-report. 89
The prevalence of sleep-disordered breathing (SDB), such
as obstructive sleep apnea (OSA), in antipsychotic-naive
schizophrenic patients has not been established. Antipsy-
chotic-treated schizophrenic patients who have volun-
teered for research protocols have demonstrated a high
prevalence rate for SDB, with reported estimates of 17%, 80
19%, 94 and 48%. 81 These studies varied in terms of sample
size, age, sex, type of antipsychotic, and measurement
instrument (PSG, oximetry, and ambulatory apnea monitor
In contrast, among schizophrenic patients referred to a
sleep clinic for a suspected sleep disorder, more than 46%
had a respiratory disturbance index greater than 10 events
per hour; the mean respiratory disturbance index was 64.8
events per hour (Video 131-1). 95 In this study, the most
powerful predictor of OSAS was obesity. Weight gain has
long been a reported side effect of antipsychotic treatment,
but as discussed previously, weight gain secondary to the
use of the atypical antipsychotics has been associated with
greater rates of morbid obesity and the development of
moderate to severe SDB. 96
Daytime somnolence is a relatively common side effect
of antipsychotic treatment, but clinicians must consider
the possibility of comorbid SDB for schizophrenic patients
who have a history of obesity or who have gained weight
secondary to antipsychotic treatment. Schizophrenic
patients with comorbid SDB can be treated effectively with
nasal continuous positive airway pressure and can demon-
strate relatively good compliance and significant clinical
improvement. 97 , 98
The CATIE study 64 also reported rates of antipsychotic-
related somnolence. Rates of somnolence in antipsychotic-
treated schizophrenic patients ranged from 24% to 31%.
Somnolence in antipsychotic-treated schizophrenic
patients may be a side effect of antipsychotic treatment, or
it may be symptomatic of a sleep disorder such as a sleep-
related breathing disorder enhanced by, or induced by,
antipsychotic treatment.
Among first-generation antipsychotics, sedation is a side
effect associated with high-milligram, low-potency agents
such as chlorpromazine. In contrast, the low-milligram,
high-potency agents such as haloperidol have lower seda-
tion rates. Among second-generation antipsychotics, clo-
zapine and olanzapine are the most sedating. The remaining
atypical agents have lower rates of sedation. Sedation rates
also reflect the half-life of the agent as well as dosing levels.
Clinicians typically address excessive antipsychotic-related
sedation by changing antipsychotic agents or reducing
Investigational studies have examined the effect of
modafinil as an adjunct to antipsychotic treatment.
Modafinil is a wake-promoting agent whose mechanism
of action remains unclear. Its primary FDA-approved
target is the excessive daytime sleepiness associated with
narcolepsy. However, modafinil may improve excessive
daytime sleepiness in a variety of off-label conditions such
as antipsychotic-induced daytime somnolence. Case
studies 90 and an open-label pilot study 91 have shown that
modafinil can increase wake time, reduce total sleep time,
and ameliorate fatigue in antipsychotic-treated schizo-
phrenic patients. However, a randomized, double-blind,
placebo-controlled trial of modafinil as an adjunct to anti-
psychotic treatment reported only a nonsignificant trend
toward less nighttime and daytime sleep time. 92 Taken
together, these studies suggest that modafinil may be ben-
eficial in countering somnolence in some antipsychotic-
treated schizophrenic patients. However, off-label use of
modafinil as an adjunct to antipsychotic treatment in
schizophrenia needs further study, particularly because
stimulant drugs run the risk of exacerbating psychosis in
patients with schizophrenia. 93
First-generation antipsychotics, particularly in combina-
tion with lithium 99 can induce somnambulism. Sleepwalk-
ing also has been documented in patients treated with
second-generation agents such as olanzapine. 100 Because
sleepwalking is associated with impaired arousal from
SWS, patients treated with lithium and olanzapine may
develop somnambulism because these agents have been
credited with SWS enhancement. It has been reported that
clonazepam may be a treatment option for antipsychotic-
induced somnambulism 101 but with the same caveats as
those noted for hypnotic use. Another parasomnia, sleep-
related eating disorder, may be induced by antipsychotics
such as haloperidol, 102 olanzapine, 103 and risperidone. 104
Treatment options for sleep-related eating disorders might
include topiramate, a selective serotonin reuptake inhibi-
tor, or a sedative agent.
One of the ongoing controversies is the diagnostic speci-
ficity of sleep abnormalities. Although a range of abnor-
malities is observed in schizophrenia, they lack diagnostic
specificity. Long sleep-onset latencies and other sleep
maintenance abnormalities found in schizophrenia are
observed in primary insomnia as well as in psychotic
depression. Sleep-onset REM periods and SWS deficits
are also observed in depressive illness.
A goal less ambitious than establishing diagnostic speci-
ficity is to find a brain abnormality that would reliably
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