CURRENT DRUG THERAPY r i

DAVID J. MUZiNA, M D Clinical implications of developments in pharmacology

Dr. M u z i n a is Chief Resident in t h e
D e p a r t m e n t of Psychiatry at t h e
Cleveland Clinic.

D O N A L D A . M A L O N E , JR., M D
Dr. M a l o n e directs t h e M o o d and A n x i e t y
Disorder Clinic at t h e Cleveland Clinic.

D O N A L D G. ViDT, M D , EDITOR

New antidepressants:
more options for
tailoring treatment
• KEY POINTS: • ABSTRACT: Newer antidepressant drugs cause fewer, less-
The newer antidepressant drugs are severe side effects and therefore usually elicit better patient
not more effective than older ones, but compliance than do older drugs. The newer drugs have slightly
they cause fewer and less-severe side differing mechanisms of action and effects and thus offer
effects and thus are better accepted by additional options for tailoring treatment to the individual
patients.
patient. Yet they are not completely innocuous and can cause
The newer antidepressant drugs have serious drug interactions.
a number of drug interactions. In
particular, nefazodone should not be The introduction of fluoxetine in 1987 marked the beginning of an
given with terfenadine, astemizole, or influx of new drugs that have transformed the medical management of
cisapride because of the danger of depression (TABLE I ) . Although treatment of depressive disorders is still
ventricular arrhythmias. challenging, as it has always been, the newer classes of drugs have spe-
cific advantages. This article reviews the therapeutic considerations
Depressed patients w i t h anxiety or posed by the expanding array of effective psychopharmacological
agitation may be more likely to benefit agents.
from an initial trial of a more sedating
antidepressant such as nefazodone or • DEPRESSION IN PERSPECTIVE
paroxetine.
Depression is common, affecting 5.8% to 19% of people at some point
Patients with depressive symptoms in their lives.1 According to 1990 statistics, depression cost the United
such as lethargy and a m o t i v a t i o n States $12 billion in direct care and more than $31 billion in indirect
may do better w i t h a more activating costs.2 Despite the continuing toll reflected by these data, depression is
antidepressant such as fluoxetine, eminently treatable, with response rates that are not unfavorable in
bupropion, or venlafaxine. comparison to many common medical illnesses.

A range of symptoms
Major depressive disorder is a syndrome characterized by a persistently
depressed and sometimes irritable mood lasting longer than 2 weeks. It
is associated with several neurovegetative symptoms, including anorex-
ia, insomnia, lack of energy, fatigue, lack of interest (anhedonia),
impaired concentration, and guilt. Crying spells, hopelessness, and
helplessness are also common. Suicidal ideation is especially troubling
to patients, families, and clinicians. Psychomotor retardation or agita-

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tion may occur. Significant impairment in anxiety, panic disorders,3 obsessive-compulsive
occupational, physical, or interpersonal func- disorder,4 personality disorders, 5 eating disor-
tion is necessary to diagnose a major depressive ders, 6 chronic pain and headache, 7 and pre-
episode. menstrual dysphoric disorder (formerly pre-
menstrual syndrome). 8 T h e Food and Drug
Blocking serotonin reuptake Administration lists fluoxetine, sertraline, and
Antidepressant medications have been used paroxetine as indicated for treating depression,
extensively for about 4 0 years. Although their fluvoxamine and fluoxetine for treating obses-
exact mechanism of action has not been estab- sive-compulsive disorder, and fluoxetine for
lished, they are thought to work by increasing treating bulimia.
synaptic transmission of various neurotrans- These four drugs do not appear to differ
mitters. Initially, a disorder of norepinephrine clinically in efficacy, onset of action, or side
was presumed responsible for depression, but effects.
attention has shifted to serotonin. Increased
understanding of serotonin has resulted in the Advantages of selective
proliferation of serotonergic medications, serotonin-reuptake inhibitors
commonly called selective serotonin-reuptake T h e S S R I s (and other newer antidepressants)
inhibitors ( S S R I s ) . are no more or less effective than the older
monoamine oxidase inhibitors and tricyclic
• SELECTIVE SEROTONIN-REUPTAKE INHIBITORS antidepressants ("tricyclic" refers to their
chemical structure, containing three carbon
Four S S R I s are currently available: fluoxetine, rings), but they have several advantages.
sertraline, paroxetine, and fluvoxamine Better tolerated. Because they do not sig-
(TABLE 1). These medications are useful for an nificantly affect central neurotransmitters
array of mental illnesses: major depression, other than serotonin, S S R I s cause significant-

TABLE 1
NEW ANTIDEPRESSANT DOSING INFORMATION

Drug Dosage Usual Geriatric Tablet Half- Dosing

range dose dose strengths life schedule
(mg/day) (mg/day) (mg/day)* (mg) (hours)

Selective serotonin-
reuptake inhibitors

Fluoxetine 10-80 20 10-20 10,20t 84 Daily

(Prozac)
Sertraline 50-200 100 50 50,100 26 Daily
(Zoloft)
Paroxetine 20-50 20 10-20 20,30 21 Daily
(Paxil)
Fluvoxamine 50-300 100 50-100 50,100 15 Daily or twice daily
(Luvox)

Other, related agents

Venlafaxine 75-375 150-225 75-150 25,37.5,50,75,101 4-10 Twice or three times daily
(Effexor)
Bupropion 150-450 300 150-300 75,100 8-24 Twice or three times daily
(Wellbutrin)
Nefazodone 300-600 400-500 300-500 100,150,200,250 4-8 Twice a day
(Serzone)
'Geriatric dose should not be determined by age alone. Patients of advanced age, ie, > 65 years, who also
have concomitant medical illness of significant degree, should be considered candidates for lower starting doses.
t A l s o available as liquid 20 mg/5 cc

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 ANTIDEPRESSANTS MUZINA AND MALONE

I TABLE 2
I In most cases these side effects are self-lim-
iting and transient, occurring during the first
ANTIDEPRESSANT DRUG INTERACTIONS 1 to 2 weeks of therapy and then subsiding.
Treatment includes decreasing the antidepres-
Antidepressant Liver isoenzyme Drug actions Drug actions may be
inhibited increased increased sant dosage if therapeutically possible.
Starting at a low dose and increasing it slowly
Fluvoxamine 1A2 Caffeine Phenacetin can prevent these effects for most patients.
Theophylline Qastrointestinal disturbances. In our
Tricyclic antidepressants
experience, constipation is more frequent
Haloperidol
with paroxetine than with other SSRIs, and
Fluvoxamine 2C9 Diazepam Tricyclic antidepressants loose stools are more frequent with sertraline.
Fluoxetine Phenytoin Warfarin Antidiarrheals and antiemetics can be tried
Sertraline Tolbutamide for severe cases during the early part of treat-
ment.
Fluoxetine 2C19 Diazepam
Sertraline Tricyclic antidepressants Central nervous system effects.
Omeprazole Fluoxetine seems to cause more activation (ie,
Propranolol central nervous system stimulation, which
individual patients may experience as anxiety
Paroxetine 2D6 Tricyclic antidepressants Antipsychotics
Fluoxetine Antiarrhythmics (type 1C)
or agitation) than do the other SSRIs.
Antiarrhythmics
Sertraline Haloperidol Opiates Insomnia often can be relieved by adding
Fluvoxamine Clozapine Beta blockers a low dose of a sedating antidepressant such as
Selective serotonin- Vinblastine trazodone 50 to 100 mg at bedtime. If a
reuptake inhibitors Dextromethorphan patient takes his or her SSRI at bedtime, tak-
3A4
ing it in the morning instead may relieve the
Nefazodone Astemizole Benzodiazepines
Sertraline Terfenadine Calcium channel blockers sleep problem.
Fluoxetine Cisapride Sexual dysfunction typically involves
Fluvoxamine Midazolam delayed orgasm and decreased libido in both
Alprazolam men and women. The problem sometimes
Carbamazepine
persists after the SSRI is reduced in dosage or
stopped, but it may resolve if the dosage is
reduced and, in some cases, if the antihista-
ly fewer anticholinergic, antihistaminic, and mine cyproheptadine is added. This agent has
antiadrenergic side effects. Consequently, they serotonin antagonist activity; the dosage is 4 to
are better tolerated, and patients comply with 16 mg 1 or 2 hours before anticipated sexual
taking them better. activity. 10
Easier to titrate. Because the starting Other effects. Since SSRIs primarily act
dosage for newer agents is frequently effective, on serotonergic receptors, they have essential-
one need not escalate the dosage over several ly no cardiotoxic effects, unlike tricyclic anti-
weeks as with most older agents. depressants, which can have a quinidine-like
Safer. Overdoses of tricyclic antidepres- effect. A few, rare cases of bradycardia have
sants can be fatal, whereas SSRIs are unlikely been reported with fluoxetine. Paroxetine has
to cause significant morbidity or mortality if weak anticholinergic properties and can some-
overdosage occurs. times cause bothersome dry mouth, constipa-
tion, and dizziness.
Side effects of SSRIs
Characteristic adverse effects of SSRIs include Pharmacokinetics of SSRIs
gastrointestinal disturbances (nausea, vomit- The SSRIs differ in their pharmacokinetic and
ing, diarrhea), central nervous system effects pharmacodynamic profiles. For example,
(headache, insomnia, agitation), sexual dys- paroxetine, sertraline, and fluvoxamine have
function, and tremor.9 half-lives of approximately 24 hours and

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achieve a steady state within the first week of quently if they take an SSRI, especially early
treatment. They also lack clinically significant on in SSRI treatment, as the interaction can
metabolites. prolong the prothrombin time. Lower doses of
In contrast, fluoxetine may take more warfarin may be necessary. Fluoxetine has
than 3 weeks to achieve a steady state, owing been reported to increase bleeding times
to prolonged elimination of its primary and through decreased granular storage of sero-
active metabolite, norfluoxetine. This is a tonin in platelets. For this reason, some clini-
potential disadvantage of fluoxetine because it cians recommend checking bleeding times
takes longer to clear; however, an advantage before surgery in patients taking SSRIs. 1 2
may be that patients can miss doses occasion-
ally without deleterious effects. Dosage and administration of SSRIs
Starting dosage. In most cases, the usual
Drug interactions with SSRIs starting dosage is therapeutic and does not
A major concern with SSRIs is their drug need to be increased. Some patients with sig-
interactions, as they inhibit the hepatic nificant anxiety may do better with lower ini-
cytochrome systems responsible for metaboliz- tial dosages, ie, fluoxetine 10 mg/day, as these
ing many other agents. There are 34 lower dosages may be less likely to produce side
cytochrome P450 isoenzymes, and antidepres- effects and exacerbate their anxiety. In these
sants can inhibit five of them (1A2, 2C9, anxious patients, the dosage can slowly be
2C19, 2D6, and 3A4), potentiating or pro- increased to the usual dosage. In a few cases,
longing the action of the drugs these enzymes dosages greater than the usual starting dosage
inhibit (TABLE 2). Drug interactions are particu- may be required.
larly important in medically ill patients, who The effective starting dosage for fluoxetine
frequently take several other essential medica- is 20 mg/day, for sertraline 50 mg/day, and for
tions. 11 paroxetine 20 mg/day. Fluvoxamine can be
hihibition of the P 4 5 0 - 2 D 6 isoenzyme started at 50 mg at bedtime and increased safe-
system can increase levels of: ly in the first week to 50 mg twice a day.
• Tricyclic antidepressants Dosage schedule. Most recommendations
• Antipsychotics favor giving fluoxetine, sertraline, and paroxe-
• Beta blockers tine once a day, in the morning, with food, to
• Antiarrhythmics minimize gastrointestinal side effects. Twice-a- Because the
• Opiates day dosage can be helpful for patients with starting dosage
• Vinblastine prolonged gastrointestinal side effects. for newer agents
• Dextromethorphan Titration should be conservative. Liver is frequently
A small percentage of persons genetically disease slows SSRI metabolism and generally
effective, one
lack this enzyme because of genetic polymor- warrants lower dosages. Renal impairment
phism, making them even more susceptible to slows metabolism less than liver disease, but in need not
drug interactions. In these "poor metabolizers," severe cases of renal impairment lower dosages escalate the
any additional reduction of enzyme action by are probably indicated. Elderly patients also dosage over
inhibitory drugs such as antidepressants can may need lower dosages, as they may be more several weeks
significantly increase the concentration of the susceptible to side effects, including tremor, as with most
poorly metabolized drug to toxic levels. anxiety, restlessness, and insomnia.
older agents.
Of the SSRIs, paroxetine is the most
potent inhibitor of this enzyme, and fluvoxam- How long to treat?
ine the weakest. As with all antidepressants, depressed mood
Inhibition of other cytochrome systems does not improve immediately with SSRI ther-
can increase the action of: apy, sometimes taking take 3 to 6 weeks or
• Warfarin longer to improve. Neurovegetative symptoms
• Nonsteroidal anti-inflammatory drugs such as disturbances of sleep, appetite, and
• Phenytoin energy may respond sooner. After 6 to 8 weeks,
• Calcium-channel blockers a partial response may signal the need to
• Ketoconazole increase the dosage; lack of response may indi-
• Terfenadine cate the need to change to another class of
Prolonged prothrombin time. Patients antidepressant.
receiving anticoagulant therapy should have If successful, antidepressant therapy
their prothrombin times checked more fre- should continue for at least 6 months. Patients

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 ANTIDEPRESSANTS MUZINA AND MALONE ri

with severe or recurrent depression should epinephrine. 14 Considered an "atypical" anti-

probably keep taking medication longer, in depressant, it generates a different spectrum of
some cases for life. neurochemical effects than do other antide-
pressants. This distinctive mechanism of
• VENLAFAXINE action makes it particularly useful for patients
who do not respond to other antidepressant
Venlafaxine strongly inhibits reuptake of both medications.
serotonin and norepinephrine. Early data sug- Structurally similar to some ampheta-
gest it has a more rapid onset of action than mines, bupropion can be useful as a stimulat-
other antidepressants, and greater efficacy in ing antidepressant in atypical and melancholic
cases resistant to other drugs. However, these depressions. (Amphetamines such as
findings are preliminary.13 methylphenidate have been used for treating
depression with particularly anergic features,
Side effects of venlafaxine ie, after a stroke.) A recent study of bupropion
Venlafaxine's side effects are similar to those of for treating attention-deficit disorder in chil-
SSRIs and include nausea, nervousness, dren and adults was promising.15
sweating, dizziness, and dry mouth. Sexual
dysfunction has been reported but may be less Side effects of bupropion
common. Bupropion's side-effect profile is similar to that
Nausea can be quite troublesome; there- of SSRIs; however, it does not appear to cause
fore, low initial doses are encouraged. sexual dysfunction. It has no significant car-
Hypertension is a potentially serious side diotoxic effects, so it is useful in medically ill
effect. Lower dosages can minimize this effect, and cardiac patients. Hypertension is an
A major concern since diastolic blood pressure increases by unlikely adverse effect but is more likely to
with SSRIs is more than 10 mm Hg in only about 5 % of occur in patients with preexisting hyperten-
their drug inter- patients taking less than 200 mg/day, but 13% sion than in those without it.
actions, as they of those taking more than 300 mg/day. Seizures have been reported with bupropi-
on therapy.16 However, the incidence of
inhibit
Dosage and administration of venlafaxine seizures during bupropion therapy is compara-
the hepatic Venlafaxine has a much shorter half-life than ble to that of other antidepressants if patients
cytochrome sys- SSRIs ( 4 - 1 0 hours), necessitating two or three with risk factors for seizures are excluded.
tems responsible doses per day. The recommended dosage is 75 Therefore, patients with epilepsy, alcoholism,
for metabolizing to 375 mg/day in divided doses. A starting benzodiazepine dependence, eating disorders,
many other dosage of 25 to 37.5 mg once or twice a day is or history of head trauma should receive other
reasonable. antidepressants.
agents.
Although metabolized by the liver, ven-
lafaxine does not greatly inhibit the Dosage and administration of bupropion
cytochrome P450-2D6 enzyme system. Its use Bupropion's elimination half-life ranges from 8
in patients with liver or kidney disease should to 24 hours; therefore, it is usually given twice
be guided by caution, with lower starting or three times a day. The starting dosage is 75
dosages and conservative titration. or 100 mg twice a day and can be safely
increased to 75 or 100 mg three times a day;
• BUPROPION the recommended dosage is 300 mg/day. The
therapeutic dosage range is 150 to 450 mg/day
Bupropion, a monocyclic (one carbon ring) in divided doses.
antidepressant, was introduced in 1989. Its Doses must be limited to 150 mg and sepa-
mechanism of action is poorly understood, but rated by at least 4 hours. More than 450 mg/day
it is thought to act primarily by blocking reup- should be avoided to minimize seizure risk.
take of dopamine and, to a lesser extent, nor-

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• NEFAZODONE Therefore, its coadministration in patients
taking nefazodone may lead to increased seda-
Introduced in the United States in 1995, nefa- tion and respiratory depression, especially in
zodone is clinically effective and well tolerat- the elderly.
ed. It has a unique pharmacologic profile: like
SSRIs, it inhibits presynaptic reuptake of sero- Dosage and administration of nefazodone
tonin, but it also antagonizes postsynaptic Nefazodone has a relatively short elimination
serotonin receptors and weakly inhibits presy- half-life, suggesting it should be given in fre-
naptic norepinephrine reuptake. 17 quent doses; however, twice-a-day dosing
seems to be adequate. The recommended start-
Side effects of nefazodone ing dosage is 100 mg twice a day, with an effec-
The most common adverse effects of nefa- tive therapeutic dosage being 300 to 600 mg
zodone are dry mouth, somnolence, dizziness, per day. Weekly adjustments in dosage may be
and nausea. 18 Although structurally similar to needed during the initial weeks of therapy.
the older antidepressant trazodone, nefa-
zodone causes minimal orthostatic changes • TOWARD A RATIONAL, TAILORED APPROACH
and less sedation. No cases of priapism (a noto-
rious side effect of trazodone) have been Newer agents such as SSRIs, venlafaxine,
reported with nefazodone therapy. Sexual dys- bupropion, and nefazodone are excellent
function appears much less common with options that are usually tried before traditional
nefazodone than with SSRIs. antidepressants such as tricyclics because of
proven efficacy and fewer and less bothersome
Drug interactions with nefazodone side effects. Because of the distinctive pharma-
Several unique drug interactions can occur cologic differences among these drugs, clini-
with nefazodone. cians can better tailor antidepressant regimens
Alprazolam and triazolam levels can for individual patients and their particular
increase in patients taking nefazodone. symptoms.
Terfenadine or astemizole should not be For example, depressed patients with anx-
given with nefazodone, because nefazodone, iety or agitation may be more likely to benefit
like ketoconazole, inhibits cytochrome P450- from an initial trial of a more sedating antide-
354, which metabolizes these drugs. T h e pressant such as nefazodone or paroxetine. On As with all antide-
resulting increased concentrations of these the other hand, patients with depressive pressants,
antihistamines can lead to potentially fatal symptoms such as lethargy and amotivation depressed mood
ventricular arrhythmias of the torsade de may do better with a more activating antide- does not improve
pointes type. 19 pressant such as fluoxetine, bupropion, or
immediately with
Cisapride is also metabolized by P450- venlafaxine.
3A4, and, given with nefazodone can also Nevertheless, older medications such as SSRI therapy,
cause tachycardia and torsade de points. 20 tricyclic antidepressants continue to be useful. sometimes taking
Venlafaxine and tricyclic antidepressants are Tricyclics such as amitriptyline and nortripty- 3 to 6 weeks or
much less likely to inhibit P450-3A4 and are line can alleviate not only depression but also longer to improve.
better options for patients who need to take insomnia and pain. However, the low dosages
one of these antihistamines or cisapride.19 commonly used for insomnia (ie, amitriptyline
Midazolam, often used intravenously for 25 mg at bedtime) may not be high enough for
sedation in procedures such as colonoscopy, is treating depression—and higher doses increase
also metabolized via the 3 A 4 pathway. the incidence of side effects. •

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