Download PAROXETINE Paxil NEFAZODONE Serzone

A NTIDEPRESSANTS
NEFAZODONE
453
Serzone
Pharmacology. Nefazodone is a postsynaptic serotonin 5-HT2A antagonist and
presynaptic serotonin reuptake inhibitor. These two serotonergic effects make it
different from SSRIs and TCAs.153–156 (See Antidepressants Comparison Chart.)
Administration and Adult Dosage. PO for depression 100 mg bid initially (50 mg
bid in the elderly), increasing q 4–7 days to the effective dosage range of 150–
300 mg bid. After initial dosage titration, once-daily bedtime administration is
preferred to minimize daytime sedation.157
Dosage Forms. Tab 50, 100, 150, 200, 250 mg.
Pharmacokinetics. Nefazodone has an oral bioavailability of about 20%. Singledose studies in the elderly have shown a 100% larger AUC; with multiple doses,
the AUC differences decreased to 10–20% above those in younger populations. It
is >99% protein bound and extensively metabolized, with a dose-dependent elimination half-life of about 1–2.3 hr in young patients, modestly prolonged in the
elderly, and 2–3 times longer in hepatic disease. The major active metabolite,
hydroxynefazodone, has a half-life of 1.2–1.6 hr in young and elderly patients,
increasing to 2–4 hr with hepatic disease. Renal impairment does not markedly
affect nefazodone pharmacokinetics.
Adverse Reactions. Although chemically similar to trazodone, it causes less sedation and orthostatic hypotension, and its lower -adrenergic blockade makes
priapism much less likely (no cases reported). Frequent adverse effects include sedation, dry mouth, nausea, and dizziness. Unlike SSRIs, nefazodone’s effects on
sexual function, agitation, tremor, insomnia, and weight are no different from
placebo.
Drug Interactions. Nefazodone is a potent inhibitor of the CYP3A4 isoenzyme
and a weak inhibitor of the CYP2D6 isoenzyme. Drug interactions of particular
concern include the triazolobenzodiazepines (ie, alprazolam, triazolam, midazolam). A 1- to 2-week washout period is recommended when converting a patient
to or from a MAOI and nefazodone.
PAROXETINE
Paxil
Pharmacology. Paroxetine is a highly selective and potent inhibitor of serotonin
reuptake (an SSRI) similar to fluoxetine.126,158–164 (See Antidepressants Comparison Chart.)
Administration and Adult Dosage. PO for depression 20 mg/day; a few patients
require 30–50 mg/day for full efficacy. PO for social anxiety disorder and panic
disorder 10 mg/day initially; usual maintenance dosage is 20–60 mg/day. PO for
OCD 20 mg/day initially; maintenance dosage is 40 mg/day to a maximum of
60 mg/day, preferably as a single dose in the morning or evening. The starting
dosage for all uses in elderly patients and those with marked renal or hepatic impairment is 10 mg/day. For the elderly or those with severe renal or hepatic impairment, the maximum dosage is 40 mg/day.
Dosage Forms. Tab 10, 20, 30, 40 mg; SR Tab 12.5, 25 mg; Susp 2 mg/mL.
454
C ENTRAL N ERVOUS S YSTEM D RUGS
Pharmacokinetics. Paroxetine is completely orally bioavailable; protein binding
is 93–95%. Unlike fluoxetine, paroxetine is metabolized to inactive metabolites
and has an elimination half-life of 24 hr.
Adverse Reactions. Paroxetine causes the typical SSRI adverse effects of nausea,
sexual dysfunction, and headache but is more likely to cause sedation than insomnia and can cause more delay of orgasm or ejaculation and more impotence than
other SSRIs.165 Like the other SSRIs, it is much safer in overdose than TCAs.
Drug Interactions. Paroxetine is a potent inhibitor of CYP2D6, so most other antidepressants, antipsychotics, -blockers, and type Ic antiarrhythmics can have increased serum levels and adverse effects when paroxetine is combined with these
drugs. Do not use paroxetine within 14 days of using an MAOI.
REBOXETINE (Investigational—Pharmacia)
Vestra
Pharmacology. Reboxetine is the first in a new class of selective norepinephrine
reuptake inhibitors with no affinity for serotonin or dopamine reuptake sites. It has
negligible affinity for muscarinic, histaminic, or adrenergic receptors. This noradrenergic mechanism for antidepressant efficacy is similar to TCAs such as desipramine without the potential for appreciable adverse anticholinergic, cardiovascular, and sedative effects. It has efficacy for major depression equal to fluoxetine
and desipramine.166,167 (See Antidepressants Comparison Chart.)
Administration and Adult Dosage. PO for depression 8–10 mg/day given bid,
4–6 mg/day given bid in the elderly.
Dosage Forms. Tab 4 mg (investigational).
Pharmacokinetics. Reboxetine is rapidly absorbed. Metabolism occurs through
three oxidative pathways: hydroxylation, dealkylation, and oxidation. The
CYP450 isoenzymes responsible for metabolism have not been identified, and the
degree of activity of the metabolites is unknown. Reboxetine has no inhibitory effect on CYP450 isoenzymes. Elimination half-life is 13 hr.166
Adverse Reactions. The most common adverse effects include dry mouth, constipation, increased sweating, insomnia, and urinary hesitancy, which are greater than
placebo, but less frequent than imipramine. These “anticholinergic-like” effects are
believed to result from increased norepinephrine levels. Side effects commonly associated with serotonin reuptake inhibitors such as nausea, anxiety or agitation, and
daytime somnolence were no more common with reboxetine than with placebo.167
No information is available regarding reboxetine overdose in humans.
SERTRALINE
Zoloft
Pharmacology. Sertraline is an SSRI similar to fluoxetine, which indirectly results in a downregulation of -adrenergic receptors. It has no clinically important
effect on noradrenergic or histamine receptors and no effect on MAO. It lacks
stimulant, cardiovascular, anticholinergic, and convulsant effects. Sertraline has
antidepressant effects equal to TCAs and fluoxetine and might have anorectic effects and efficacy in OCD.130,168–170 (See Antidepressants Comparison Chart.)
Administration and Adult Dosage. PO for depression, panic disorder, OCD, and
posttraumatic stress disorder 50 mg/day initially, increasing if necessary at weekly
intervals to a maximum of 200 mg/day in a single dose in the morning or evening.
A NTIDEPRESSANTS
455
Dosage Forms. Tab 25, 50, 100 mg; Soln 20 mg/mL.
Pharmacokinetics. Sertraline has an oral bioavailability of 36%, and, when it is
taken with food, peak serum concentrations and bioavailability increase by 30–40%.
Peak serum concentrations are reached in 6–8 hr. Sertraline concentrations in breast
milk are the lowest of the SSRIs and produce minimal serum levels in the breast-fed
infant.171 Its primary metabolite is N-desmethylsertraline, which has 5–10 times less
activity than sertraline as an SSRI and has no demonstrated antidepressant activity.
Cl is decreased by up to 40% in the elderly. Steady-state half-life is 27 hr.
Adverse Reactions. Frequent adverse effects include nausea, diarrhea, ejaculatory
delay, tremor, and increased sweating. It causes less agitation, anxiety, and insomnia than fluoxetine and is a less potent inhibitor of the CYP2D6 isoenzyme at a
dosage of 50 mg/day. Use with caution in patients with renal or hepatic impairment
and do not use it within 14 days of using an MAOI. SIADH has been reported.172
VENLAFAXINE
Effexor
Pharmacology. Venlafaxine is a potent reuptake inhibitor of serotonin and norepinephrine, like many TCAs, but lacks effects on muscarinic, -adrenergic, or
histamine receptors.173–176 (See Antidepressants Comparison Chart.)
Administration and Adult Dosage. PO for depression (immediate-release) 75
mg bid or tid initially, increasing q 4–7 days to an effective antidepressant dosage
of 225–375 mg/day in 2 or 3 divided doses; (sustained-release) 75 mg once daily
initially, increasing in increments of up to 75 mg/day at intervals of 4 or more
days to a maximum of 225 mg/day. The sustained-release preparation does not reduce side effects but allows once-daily administration. PO for generalized anxiety disorder 75–225 mg/day in 2–3 divided doses. Patients with renal impairment
or on hemodialysis require a 25–50% dosage reduction.
Dosage Forms. Tab 25, 37.5, 50, 75, 100 mg; SR Cap 37.5, 75, 150 mg (Effexor
XR).
Pharmacokinetics. Venlafaxine is well absorbed orally; food has no effect on absorption. Serum concentrations in elderly patients are no different from those in
younger patients. Unlike SSRIs, venlafaxine has minimal protein binding
(27–30%). It undergoes extensive hepatic metabolism. Venlafaxine has an elimination half-life of 5 hr, and one major active metabolite has an 11-hr half-life.
Venlafaxine exhibits linear pharmacokinetics over the recommended dosage
range, and steady state is reached in 3 days.
Adverse Reactions. Frequent adverse effects include expected serotonin-related
effects (eg, nausea, headache, insomnia or somnolence, and sexual dysfunction).
At higher dosages (375 mg/day), venlafaxine is unique in causing a consistent but
mild elevation in diastolic blood pressure (6 mm Hg). Regular blood pressure
monitoring is required for all patients.
Drug Interactions. Venlafaxine is not a potent inhibitor of the cytochrome P450
enzyme system, making it different from most of the SSRIs. Avoid it in patients
who have received an MAOI within the past 14 days.
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456
ANTIDEPRESSANTS COMPARISON CHARTa
THERAPEUTIC
SERUM LEVELS
(µG/L)
Sedation
15–45
b
Moderate
None
None
300–450
b
None
None
None
300–600
b
Low
Low
Low
Tab 15 mg.
45–90
b
Moderate
Low
Very High
Tab 10 mg.
30–60
b
Low
Low
Very High
8–10
b
Very Low
Low
Very Low
DOSAGE
FORMS
RELATIVE FREQUENCY OF SIDE EFFECTS
Anticholinergic
Orthostatic Hypotension
α2-ADRENERGIC BLOCKERS
Tab (conventional and
rapidly dissolving) 15,
30, 45 mg.
2:00 PM
Mirtazapine
Remeron
CHLOROPROPIOPHENONES
Tab 75, 100 mg
SR Tab 100, 150 mg.
Page 456
Bupropion
Wellbutrin
Zyban
DIBENZOXAZEPINESc
Amoxapine
Asendin
Various
Tab 25, 50, 100,
150 mg.
MONOAMINE OXIDASE INHIBITORS (MAOIs)
Phenelzine
Nardil
Tranylcypromine
Parnate
MORPHOLINES
Reboxetine
Vestra
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USUAL DAILY ADULT
DOSAGE RANGE (MG)
CLASS
AND DRUG
(continued )
5.qxd
ANTIDEPRESSANTS COMPARISON CHARTa (continued )
DOSAGE
FORMS
USUAL DAILY ADULT
DOSAGE RANGE (MG)
THERAPEUTIC
SERUM LEVELS
(µG/L)
RELATIVE FREQUENCY OF SIDE EFFECTS
Sedation
Anticholinergic
Orthostatic Hypotension
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)
Tab 20, 40 mg
Soln 2 mg/mL.
20–60
b
Very Low
Very Low
None
Fluoxetine
Prozac
Cap, Tab 10, 20, 40 mg
SR Cap 90 mg
Soln 4 mg/mL
Tab 10 mg.
10–80
b
None
Very Low
None
Fluvoxamine
Luvox
Tab 25, 50, 100 mg.
100–300d
b
None
None
None
Paroxetine
Paxil
Tab 10, 20, 30, 40 mg
SR Tab 12.5, 25 mg
Susp 2 mg/mL.
20–50
b
Low
Low
Very Low
Sertraline
Zoloft
Tab 25, 50, 100 mg
Soln 20 mg/mL.
50–200
b
None
None
None
2:00 PM
Citalopram
Celexa
Tab 25, 37.5, 50,
75, 100 mg
SR Cap 37.5, 75, 150 mg.
225–375
b
Very Low
Very Low
Very Low
Tab 25, 50, 75 mg.
150–225
200–300b
Moderate
Moderate
Moderate
TETRACYCLICS c
457
Maprotiline
Ludiomil
Various
(continued )
Page 457
SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs)
Venlafaxine
Effexor
Effexor XR
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CLASS
AND DRUG
5.qxd
458
ANTIDEPRESSANTS COMPARISON CHARTa (continued )
DOSAGE
FORMS
USUAL DAILY ADULT
DOSAGE RANGE (MG)
THERAPEUTIC
SERUM LEVELS
(µG/L)
RELATIVE FREQUENCY OF SIDE EFFECTS
Sedation
Anticholinergic
Orthostatic Hypotension
TRIAZOLOPYRIDINES
Tab 50, 100, 150,
300 mg.
50–100 (hypnotic)
200–400
(antidepressant)
b
High
Very Low
High
Nefazodone
Serzone
Tab 50, 100, 150,
200, 250 mg.
300–600
b
Moderate
Very low
Moderate
Amitriptyline
Elavil
Various
Tab 10, 25, 50,
75, 100, 150 mg
Inj 10 mg/mL.
150–300
75–175e
High
High
High
Clomipramine
Anafranil
Various
Cap 25, 50, 75 mg.
100–250d
100–150f
b
High
High
High
Desipramine
Norpramin
Various
Tab 10, 25, 50,
75, 100, 150 mg.
150–300
100–160
Low
Low
Moderate
Doxepin
Adapin
Sinequan
Various
Cap 10, 25, 50,
75, 100, 150 mg
Soln 10 mg/mL.
150–300
110–250e
High
Moderate
High
2:00 PM
Trazodone
Desyrel
Various
8/13/2001
CLASS
AND DRUG
Page 458
TRICYCLICS (TCAs)d
(continued )
5.qxd
ANTIDEPRESSANTS COMPARISON CHARTa (continued )
DOSAGE
FORMS
USUAL DAILY ADULT
DOSAGE RANGE (MG)
THERAPEUTIC
SERUM LEVELS
(MG/L)
RELATIVE FREQUENCY OF SIDE EFFECTS
Sedation
Anticholinergic
Orthostatic Hypotension
150–300
>200e
Moderate
Moderate
High
Nortriptyline
Aventyl
Pamelor
Various
Cap 10, 25, 50,
75 mg
Soln 2 mg/mL.
100–200
50–150
Moderate
Moderate
Low
Protriptyline
Vivactil
Various
Tab 5, 10 mg.
30–60
70–260b
Very Low
Moderate
Moderate
Trimipramine
Surmontil
Cap 25, 50, 100 mg.
150–300
b
Moderate
Moderate
High
459
a
Antidepressants with serotonergic activity (SSRIs, nefazodone, venlafaxine, and mirtazapine) have established efficacy for many indications other than depression. Some have received approval from the Food and Drug Administration for generalized anxiety disorder, bulimia nervosa, obsessive-compulsive disorder, social phobia, panic disorder, posttraumatic stress disorder,
and premenstrual dysphoric disorder. Effective doses for major depression for most patients are in the low to moderate ranges listed, which is also true for generalized anxiety disorder, social
phobia, panic disorder, and premenstrual dysphoric disorder. The middle to high end of the listed dosage ranges is usually necessary for efficacy when treating bulimia nervosa, obsessivecompulsive disorder, and posttraumatic stress disorder.180
b
Not well established.
c
Amoxapine, maprotiline, and the tricyclic antidepressants are categorized together as heterocyclic antidepressants because their therapeutic and side effect profiles are similar.
d
For obsessive-compulsive disorder.
e
Includes active metabolites.
f
Major depression.
From references 106, 112, 122, 126, 127, 140, 141, 145, 146, 148, 153, 159, 160, 175, and 177–179.
Page 459
Tab 10, 25, 50 mg
Cap (as pamoate)
75, 100, 125,
150 mg.
2:00 PM
Imipramine
Tofranil
Janimine
Various
8/13/2001
CLASS
AND DRUG
460
C ENTRAL N ERVOUS S YSTEM D RUGS
Antipsychotic Drugs
Class Instructions. Antipsychotics. This drug can cause drowsiness. Until the
extent of this effect is known, use caution when driving, operating machinery, or
performing other tasks requiring mental alertness. Avoid excessive concurrent use
of alcohol or other drugs that cause drowsiness.
Missed Doses. If you miss a dose, take it as soon as you remember. If it is almost
time for your next dose, skip it and resume your normal schedule. Do not double
doses.
ANTIPSYCHOTIC DRUGS
Pharmacology. Antipsychotic efficacy is most likely related to blockade of postsynaptic dopaminergic receptors in the mesolimbic and prefrontal cortexes of the
brain, although other neurotransmitter systems also are involved.181
Administration and Adult Dosage. (See Antipsychotic Drugs Comparison Chart
for oral dosage ranges.) Initiate therapy with divided doses until therapeutic
dosage is found; then, for most patients, once-daily hs administration is preferred.
For maintenance, decrease acute dosage by 25% q 3 months, with a target maintenance dosage being 50–67% of the acute treatment dosage.182 Recent concern has
focused on the need to establish a minimum effective dosage for antipsychotic
drugs, and treatment regimens at the low end of the dosage range are preferred.
Oral dosages of high-potency antipsychotics (eg, fluphenazine, haloperidol) in
the range of 5–20 mg/day are better tolerated and equal in efficacy to dosages
>20 mg/day.183 Most patients can be given a maintenance dosage of 50% the acute
dosage by the end of 1 yr, although 10–15% of chronically ill patients require a
maintenance dosage >15 mg/day of haloperidol or its equivalent.184,185 For manic
episodes, no additional benefit is achieved with dosages >10 mg/day of haloperidol.186 Mesoridazine and thioridazine are indicated only in patients who fail with
other drugs because of inefficacy or intolerable side effects.
Special Populations. Pediatric Dosage. As with adults, dosage is determined primarily by titration to individual response. No precise dosage range exists, but in
general the initial dosage is lower and increased more gradually in children.
Geriatric Dosage. Initial dosage is 20–25% of the dosage used in younger adults.
Typical starting dosages in the elderly are haloperidol 0.5–2 mg/day. Dosage adjustments also must be done more slowly than in younger adults.187
Other Conditions. Dosages in the lower range are sufficient for most elderly patients, and the rate of dosage titration is slower.
Dosage Forms. (See Antipsychotic Drugs Comparison Chart.)
Patient Instructions. (See Antipsychotics Class Instructions.) These drugs usually take several weeks for clinical response and up to 8 weeks for full therapeutic
response.
Pharmacokinetics. Onset and Duration. Onset of antipsychotic activity is variable, with noticeable response requiring days to weeks.
Serum Levels. Correlation of serum levels with clinical response is not consistently established. The best evidence exists for haloperidol, with serum concen-