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lation variability in CYP2D6 polymorphisms and activity. 22
Age is associated with decreased metabolic clearance by
CYP3A4 and decreased renal clearance. 18 , 20
CYP3A4 can be induced by drugs such as barbiturates
and tamoxifen, leading to reduced TCA levels; CYP2D6
can be inhibited by drugs such as antipsychotic drugs,
methylphenidate, fluoxetine, and paroxetine, leading to
increased TCA levels. 19 Grapefruit juice is a common if
unsuspected inhibitor of CYP3A4.
Awake
Stage 1/REM
Stage 2
Stage 3/4
Pretreatment
PHARMACODYNAMICS AND RECEPTOR PHARMACOLOGY
Tricyclic antidepressants interact with a variety of neu-
rotransmitter receptors, including serotonin, norepineph-
rine, acetylcholine, and histamine. Effects on sleep
probably represent the combined effects of many of these
actions. Amitriptyline and doxepin inhibit both serotonin
and norepinephrine reuptake transporters, whereas trimip-
ramine has minimal reuptake effects. Tertiary TCAs
including amitriptyline and doxepin have relatively more
pronounced effects on serotonin than on norepinephrine
reuptake, whereas their secondary amine metabolites have
more pronounced effects on norepinephrine reuptake. 19 , 23
After chronic dosing, additional effects on serotonergic
and noradrenergic neurotransmission are also observed:
desensitization of presynaptic 5-HT 1A autoreceptors;
upregulation (sensitization) of postsynaptic 5-HT 1A recep-
tors; and both downregulation and antagonism of postsyn-
aptic 5-HT 2 receptors. 24 At 5-HT 2 receptors, antagonism
of the 5-HT 2C subtype is more strongly associated with
increasing slow-wave sleep compared with 5-HT 2A recep-
tors. 25 The net effect of TCA receptor effects is an enhance-
ment of 5-HT effects in the central nervous system (CNS).
Noradrenergic effects of TCAs include desensitization of
presynaptic alpha 2 autoreceptors and a compensatory
downregulation of postsynaptic beta receptors, 18 with a net
effect of increasing noradrenergic neurotransmission.
TCAs also antagonize peripheral alpha 1 - and alpha 2 -adren-
ergic receptors, which accounts for their cardiovascular
effects.
Sedating TCAs also antagonize M 1 muscarinic cholin-
ergic and H 1 histamine receptors. Amitriptyline is the most
anticholinergic of all antidepressants, and doxepin is a
more potent antihistamine than many drugs marketed as
antihistamines, including diphenhydramine. In the doses
recently approved for treatment of insomnia (3 to 6 mg),
doxepin is relatively selective for H 1 antagonism relative to
serotonergic, adrenergic, and cholinergic effects.
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04:00
06:00
A
Time
Awake
Stage 1\REM
Stage 2
Stage 3/4
On amitriptyline
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B
Time
Figure 43-3 Effects of amitriptyline on EEG sleep in a 54-year-
old depressed woman. A, Baseline sleep histogram during
acute depressive episode showing prolonged sleep latency,
reduced sleep efficiency, and reduced stage 3/4 sleep. B, Sleep
histogram after treatment with amitriptyline for 24 days (final
dose, 200 mg) and remission of symptoms. Compared with
baseline, the histogram during treatment shows reduced sleep
latency, improved sleep efficiency, reduced REM sleep, and
prolonged REM latency.
have little or no effect on sleep onset and continuity mea-
sures in depressed patients. 27 , 35
Doxepin and amitriptyline have consistent effects on
sleep stage architecture, including reductions in rapid eye
movement (REM) sleep percentage and increases in phasic
REM activity and REM sleep latency. 26,28,29,36,37 Trimipra-
mine differs from most TCAs in its effects on REM sleep,
which has been reported to increase, to decrease, or to
remain unchanged during treatment. 28,30,31,34 Doxepin,
amitriptyline, and trimipramine have inconsistent effects
on stage 3/4 NREM, which has been reported to increase
in some studies 37 but not in most others. 28,30,31,33 The effects
of a TCA on PSG sleep are illustrated in Figure 43-3 .
In early studies of insomnia patients, relatively low doses
of doxepin (25 to 50 mg) and trimipramine (50 to 200 mg)
were associated with improved overall subjective sleep
quality and daytime well-being compared with placebo. 33 , 34
PSG effects of doxepin include reduced wakefulness and
sleep latency and increased sleep time and sleep efficiency.38 38
A short-term study of doxepin (1, 3, and 6 mg) in primary
insomnia demonstrated reduced wakefulness after sleep
onset, wake time during sleep, and (at the highest dose)
sleep latency as well as increased sleep time and sleep
efficiency 39,39a Sleep efficiency was increased in each third
of the night and each hour of the night, but with no
demonstrable effect on next-day alertness or psychomotor
EFFECTS ON HUMAN SLEEP
Subjectively, tertiary tricyclic drugs are perceived as sedat-
ing, associated with reports of decreased sleep latency and
wakefulness during the sleep period and improved sleep
quality among depressed patients. Secondary TCAs such
as desipramine are less sedating and may even be subjec-
tively alerting. The polysomnographic (PSG) effects of
sedating TCAs in depression have been studied exten-
sively. Reduced sleep latency, reduced wakefulness during
sleep, and increased sleep efficiency have been reported in
depressed patients treated with amitriptyline, 26-28 doxepin, 29
and trimipramine 30 , 31 and in primary insomnia patients
treated with doxepin 32 , 33 and trimipramine. 34 By contrast,
secondary TCAs such as desipramine and nortriptyline
 
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