29.23 Nefazodone and Trazodone
999
both medications. Nefazodone also slows the metabolism of
haloperidol (Haldol) so that the dosage of haloperidol should
be reduced in persons taking both medications. Addition of
nefazodone may also exacerbate the adverse effects of lithium
carbonate (Eskalith).
There are no known laboratory interferences associated with
nefazodone.
Dosage and Clinical Guidelines
Nefazodone is available in 50-, 200-, and 250-mg unscored
tablets and 100- and 150-mg scored tablets. The recommended
starting dosage of nefazodone is 100 mg twice a day, but 50 mg
twice a day may be better tolerated, especially by elderly per-
sons. To limit the development of adverse effects, the dosage
should be slowly raised in increments of 100 to 200 mg a day at
intervals of no less than 1 week per increase. The optimal dos-
age is 300 to 600 mg daily in two divided doses. However, some
studies report that nefazodone is effective when taken once a
day, especially at bedtime. Geriatric persons should receive dos-
ages about two-thirds of the usual nongeriatric dosages, with
a maximum of 400 mg a day. Similar to other antidepressants,
clinical benefit of nefazodone usually appears after 2 to 4 weeks
of treatment. Patients with premenstrual syndrome are treated
with a flexible dosage that averages about 250 mg a day.
Trazodone
Pharmacologic Actions
Trazodone is readily absorbed from the GI tract and reaches
peak plasma levels in about 1 hour. It has a half-life of 5 to
9 hours. Trazodone is metabolized in the liver, and 75 percent of
its metabolites are excreted in the urine.
Trazodone is a weak inhibitor of serotonin reuptake and a
potent antagonist of serotonin 5-HT
2A
and 5-HT
2C
receptors.
The active metabolite of trazodone is mCPP, which is an ago-
nist at 5-HT
2C
receptors and has a half-life of 14 hours. mCPP
has been associated with migraine, anxiety, and weight loss.
The adverse effects of trazodone are partially mediated by
a
1
-adrenergic receptor antagonism.
Therapeutic Indications
Depressive Disorders.
The main indication for the use
of trazodone is MDD. There is a clear dose–response relation-
ship, with dosages of 250 to 600 mg a day being necessary for
trazodone to have therapeutic benefit. Trazodone increases total
sleep time, decreases the number and the duration of nighttime
awakenings, and decreases the amount of REM sleep. Unlike
tricyclic drugs, trazodone does not decrease stage 4 sleep. Tra-
zodone is thus useful for depressed persons with anxiety and
insomnia.
Insomnia.
Trazodone is a first-line agent for the treatment
of insomnia because of its marked sedative qualities and favor-
able effects on sleep architecture (see above) combined with its
lack of anticholinergic effects. Trazodone is effective for insom-
nia caused by depression or use of drugs. When used as a hyp-
notic, the usual initial dosage is 25 to 100 mg at bedtime.
Erectile Disorder.
Trazodone is associated with an increased
risk of priapism. Trazodone can potentiate erections resulting
from sexual stimulation. It has thus been used to prolong erectile
time and turgidity in some men with erectile disorder. The dosage
for this indication is 150 to 200 mg a day. Trazodone-triggered
priapism (an erection lasting more than 3 hours with pain) is a
medical emergency. The use of trazodone for treatment of male
erectile dysfunction has diminished considerably since the intro-
duction of phosphodiesterase (PDE)-5 agents (see Chapter 25).
Other Indications.
Trazodone may be useful in low dos-
ages (50 mg a day) for controlling severe agitation in chil-
dren with developmental disabilities and elderly persons with
dementia. At dosages above 250 mg a day, trazodone reduces
the tension and apprehension associated with generalized anx-
iety disorder. It has been used to treat depression in patients
with schizophrenia. Trazodone may have a beneficial effect on
insomnia and nightmares in persons with PTSD.
Precautions and Adverse Reactions
The most common adverse effects associated with trazodone are
sedation, orthostatic hypotension, dizziness, headache, and nau-
sea. Some persons experience dry mouth or gastric irritation.
The drug is not associated with anticholinergic adverse effects,
such as urinary retention, weight gain, and constipation. A few
case reports have noted an association between trazodone and
arrhythmias in persons with preexisting premature ventricular
contractions or mitral valve prolapse. Neutropenia, usually not
of clinical significance, may develop, which should be consid-
ered if persons have fever or sore throat.
Trazodone may cause significant orthostatic hypotension 4
to 6 hours after a dose is taken, especially if taken concurrently
with antihypertensive agents or if a large dose is taken without
food. Administration of trazodone with food slows absorption
and reduces the peak plasma concentration, thus reducing the
risk of orthostatic hypotension.
Because suicide attempts often involve ingestion of sleeping
pills, it is important to be familiar with the symptoms and treat-
ment of trazodone overdose. Patients have survived trazodone
overdoses of more than 9 g. Symptoms of overdose include
lethargy, vomiting, drowsiness, headache, orthostasis, dizzi-
ness, dyspnea, tinnitus, myalgias, tachycardia, incontinence,
shivering, and coma. Treatment consists of emesis or lavage and
supportive care. Forced diuresis may enhance elimination. Treat
hypotension and sedation as appropriate.
Trazodone causes priapism, prolonged erection in the
absence of sexual stimuli, in one of every 10,000 men. Trazo-
done-induced priapism usually appears in the first 4 weeks of
treatment but may occur as late as 18 months into treatment. It
can appear at any dose. In such cases, trazodone use should be
discontinued, and another antidepressant should be used. Pain-
ful erections or erections lasting more than 1 hour are warning
signs that warrant immediate discontinuation of the drug and
medical evaluation. The first step in the emergency management
of priapism is intracavernosal injection of an
a
1
-adrenergic ago-
nist pressor agent, such as metaraminol (Aramine) or epineph-
rine. In about one-third of reported cases, surgical intervention
was required. In some cases, permanent impairment of erectile
function or impotence resulted.
