Healthcare and Medicine Reference
In-Depth Information
with amoxapine. There are no studies objectively measur-
ing sleepiness. Minimal data suggest little cognitive impair-
ment with maprotiline.
15
In healthy individuals, mianserin
impaired driving and tracking performance as well as reac-
tion time and other psychomotor measures.
12
,
44
Agomela-
tine, recently approved for treatment of depression in
Europe, is a potent agonist at both melatonin MT
1
and
MT
2
receptors as well as an antagonist at serotonergic
5-HT
2C
receptors. Limited non-placebo-controlled PSG
data in depressed patients showed increases in sleep efi-
ciency and SWS without effects on REM sleep compared
with baseline.
59
but insomnia has also been reported. Among the older
drugs, chlorpromazine and thioridazine appear to be more
sedating than haloperidol. Clozapine is even more sedating
than these drugs (with transient sedation reported by 54%
of patients, persistent sedation by 46%, and sedation
requiring drug discontinuation by 24%)
66
; aripiprazole is
the least sedating. Whereas ziprasidone and quetiapine
would be expected to be sedating given their pharmaco-
logic proiles, they appear less sedating than other drugs,
possibly because of their short half-lives. Insomnia occurs
at variable rates with these drugs. Although the mechanism
is not clear, options include 5-HT
1A
receptor agonism and
restless legs symptoms secondary to dopaminergic antago-
nism.
64
Restless legs syndrome symptoms have been
reported as case reports for olanzapine, risperidone, que-
tiapine, and clozapine.
67
There are few double-blind placebo-controlled PSG
studies of antipsychotics in healthy normals and none in
schizophrenia patients. Small-sample controlled studies
indicate that olanzapine, quetiapine, and ziprasidone
decrease sleep latency and improve sleep continuity.
64,67,68
Uncontrolled studies suggest that clozapine, haloperidol,
and risperidone also improve sleep.
69
REM suppression is
variable, whereas increased SWS is typical, except for
quetiapine.
64
,
67
There are no MSLT or other studies that objectively
evaluate daytime sleepiness.
Although antipsychotics cause cognitive impairment in
healthy subjects,
70
these drugs may have no negative effects
in patient populations.
71
Some of the newer drugs, in par-
ticular, appear to be more likely to improve cognitive func-
tion in patients despite significant sedation.65
65
LITHIUM
Lithium, which is used primarily in the treatment of
manic-depressive illness, is subjectively associated with
improved nocturnal sleep and increased daytime sleepi-
ness, at least initially.
60
Sleep disturbance is a prominent
feature of mania and similar polysomnographically to that
observed in major depression.
61
In healthy volunteers,
lithium increases SWS and decreases REM sleep
62
; it pro-
duces cognitive and psychomotor deicits, including pro-
longed reaction times, decreased vigilance, and impairment
of semantic reasoning.
61
Similar deicits have been shown
in psychiatric patients taking lithium for periods ranging
from 2 weeks to longer than 3 months,
63
although it is
difficult to determine whether the deficits seen in the
patient population are caused by the medication or the
psychiatric illness. Degree of cognitive deficit increases
with age, severity of disease, and lithium concentration.
Antipsychotic Drugs
Table 46-2
summarizes the effects of antipsychotic drugs
on sleep and waking behavior. Sedating drugs used as hyp-
notics (olanzapine, quetiapine) are covered more fully in
Chapter 43.
Antipsychotic drugs have complex pharmacologic pro-
iles. Their antipsychotic effects are thought to be medi-
ated primarily by antagonism of dopamine D
2
receptors in
the mesolimbic dopamine pathway.
64
These drugs also
block dopamine receptors in other neural pathways,
leading to unwanted effects such as anhedonia, extrapyra-
midal symptoms, and hyperprolactinemia, which are com-
monly seen with the older or “typical” antipsychotics (e.g.,
chlorpromazine, haloperidol, thioridazine). These effects
are decreased with the newer or “atypical” antipsychotic
drugs, which in addition to blockade of dopamine recep-
tors also antagonize serotonin receptors (especially
5-HT
2A
), have the ability to dissociate from D
2
receptors,
may have partial agonist activity at D
2
receptors, or may
act as partial agonists at serotonin 5-HT
1A
receptors.
50
These drugs differ in their specificity for dopamine D
2
versus D
1
receptors and also differ in the degree to which
they block muscarinic cholinergic, histamine, and alpha-
adrenergic receptors (see
Table 46-2
).
65
Sedation is more
likely in drugs with relatively more potent antagonism of
histamine, alpha-adrenergic, or 5-HT
2
receptors com-
pared with antagonism of dopamine receptors.
66
Patients with schizophrenia commonly have insomnia
and circadian rhythm disturbances as well as cognitive
impairment, complicating evaluation of the effects of anti-
psychotic medications. Sedation is a common side effect,
Anxiolytic Drugs
The primary drugs used in the treatment of anxiety disor-
ders include antidepressants (particularly SSRIs and
SNRIs), benzodiazepines, and buspirone, a 5-HT
1A
recep-
tor partial agonist. Antiepileptics and atypical antipsychot-
ics are also sometimes used. Prazosin, an antihypertensive
with alpha
1
-adrenergic antagonism, has been used to treat
nightmares in posttraumatic stress disorder.
72
Antidepres-
sants, antiepileptics, and antipsychotics are covered else-
where in this chapter. Benzodiazepines approved for
treatment of anxiety disorders (e.g., alprazolam, clonaze-
pam, diazepam, lorazepam) have pharmacologic profiles
similar to those of benzodiazepines used to treat insomnia
and thus similar side effects. Given that these drugs
enhance GABA at the GABA
A
receptor, their most common
side effect is sedation.
60
In nonanxious subjects, daytime
administration of alprazolam and diazepam produced
decreased sleep latencies as measured by MSLT on both
day 1 and day 7 of treatment, with alprazolam producing
greater sleepiness than diazepam on the first day of treat-
ment.
73
Performance impairment, including impairment of
actual driving performance,
74
is common with benzodiaz-
epines in studies of normal subjects and patient groups for
treatment periods of up to 3 weeks, particularly at higher
doses. Well-controlled studies are needed to determine
whether longer term use of benzodiazepine anxiolytics
results in tolerance to these performance-impairing effects
and whether there are differential effects between younger
and older individuals.
