998
Chapter 29: Psychopharmacological Treatment
trial leading to the approval of the extended-release formulation,
the most common adverse events were somnolence or sedation,
dizziness, constipation, and blurred vision. Surprisingly, only
4 percent of patients in the trazodone group discontinued treat-
ment because of somnolence or sedation.
Nefazodone
Pharmacologic Actions
Nefazodone is rapidly and completely absorbed but is then
extensively metabolized so that the bioavailability of active
compounds is about 20 percent of the oral dose. Its half-life is
2 to 4 hours. Steady-state concentrations of nefazodone and its
principal active metabolite, hydroxynefazodone, are achieved
within 4 to 5 days. Metabolism of nefazodone in elderly per-
sons, especially women, is about half of that seen in younger
persons, so lowered doses are recommended for elderly persons.
An important metabolite of nefazodone is meta-chlorophenylpi-
perazine (mCPP), which has some serotonergic effects and may
cause migraine, anxiety, and weight loss.
Although nefazodone is an inhibitor of serotonin uptake and,
more weakly, of norepinephrine reuptake, its antagonism of
serotonin 5-HT
A
receptors is thought to produce its antianxiety
and antidepressant effects. Nefazodone is also a mild antagonist
of the
a
1
-adrenergic receptors, which predisposes some persons
to orthostatic hypotension but is not sufficiently potent to pro-
duce priapism.
Therapeutic Indications
Nefazodone is effective for the treatment of major depression.
The usual effective dosage is 300 to 600 mg a day. In direct com-
parison with SSRIs, nefazodone is less likely to cause inhibition
of orgasm or decreased sexual desire. Nefazodone is also effec-
tive for treatment of panic disorder and panic with comorbid
depression or depressive symptoms, generalized anxiety disor-
der, and premenstrual dysphoric disorder and for management
of chronic pain. It is not effective for the treatment of OCD.
Nefazodone increases rapid eye movement (REM) sleep and
increases sleep continuity. Nefazodone is also of use in patients
with PTSD and chronic fatigue syndrome. It may also be effec-
tive in patients who have been treatment resistant to other anti-
depressant drugs.
Precautions and Adverse Reactions
The most common reasons for discontinuing nefazodone use
are sedation, nausea, dizziness, insomnia, weakness, and agita-
tion. Many patients report no specific side effect but describe
a vague sense of feeling medicated. Nefazodone also causes
visual trails, in which patients see an afterimage when looking
at moving objects or when moving their heads quickly.
A major safety concern with the use of nefazodone is severe
elevation of hepatic enzymes, and, in some instances, liver fail-
ure. Accordingly, serial hepatic function tests need to be done
when patients are treated with nefazodone. Hepatic effects can
be seen early in treatment and are more likely to develop when
nefazodone is combined with other drugs metabolized in the
liver.
Some patients taking nefazodone may experience a decrease
in blood pressure that can cause episodes of postural hypoten-
sion. Nefazodone should therefore be used with caution by per-
sons with underlying cardiac conditions or history of stroke or
heart attack, dehydration, or hypovolemia or by persons being
treated with antihypertensive medications. Patients switched
from SSRIs to nefazodone may experience an increase in side
effects, possibly because nefazodone does not protect against
SSRI withdrawal symptoms. One of its metabolites, mCPP, may
actually intensify these discontinuation symptoms. Patients have
survived nefazodone overdoses in excess of 10 g, but deaths
have been reported when it has been combined with alcohol.
Nausea, vomiting, and somnolence are the most common signs
of toxicity.
The effects of nefazodone in human mothers are not as well
understood as those of the SSRIs, mainly because of the pau-
city of its clinical use. Nefazodone should therefore be used
during pregnancy only if the potential benefit to the mother out-
weighs the potential risks to the fetus. It is not known whether
nefazodone is excreted in human breast milk. Therefore, it
should be used with caution by lactating mothers. The nefazo-
done dosage should be lowered in persons with severe hepatic
disease, but no adjustment is necessary for persons with renal
disease (Table 29.23-1).
Drug Interactions and Laboratory Interferences
Nefazodone should not be given concomitantly with MAOIs.
In addition, nefazodone has particular drug–drug interactions
with the triazolobenzodiazepines triazolam (Halcion) and
alprazolam (Xanax) because of the inhibition of CYP3A4 by
nefazodone. Potentially elevated levels of each of these drugs
can develop after administration of nefazodone, but the levels
of nefazodone are generally not affected. The dose of triazolam
should be lowered by 75 percent, and the dose of alprazolam
should be lowered by 50 percent when given concomitantly with
nefazodone.
Nefazodone may slow the metabolism of digoxin; therefore,
digoxin levels should be monitored carefully in persons taking
Table 29.23-1
Adverse Reactions Reported with Nefazodone
(300–600 mg a Day)
Reaction
Patients (%)
Headache
36
Dry mouth
25
Somnolence
25
Nausea
22
Dizziness
17
Constipation
14
Insomnia
11
Weakness
11
Lightheadedness
10
Blurred vision
9
Dyspepsia
9
Infection
8
Confusion
7
Scotomata
7
