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Treatment Guidelines

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Treatment Guidelines
from The Medical Letter
Published by The Medical Letter, Inc. 145 Huguenot Street, New Rochelle, NY 10801 A Nonprofit Publication
Volume 11 (Issue 130) June 2013
www.medicalletter.org
Take CME exams

Tables
1. Drugs for Depression
2. SSRI and SNRI Drug Interactions
3. Oral Drugs for Bipolar Disorder
4. Antimanic and Anticonvulsant Drug Interactions
5. Parenteral Antipsychotics
6. Oral Antipsychotics
7. Relative Adverse Effects of Second-Generation
Antipsychotics
8. Second-Generation Antipsychotic Drug Interactions

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Drugs for Psychiatric Disorders


Drugs are not the only treatment for psychiatric illness. Psychotherapy remains an important component
in the management of these disorders, and cognitive
behavioral therapy (CBT) can be used for many of
them as well. Electroconvulsive therapy (ECT) has a
long history of efficacy and safety when drugs are
ineffective or cannot be used.
DRUGS FOR DEPRESSION
Most of the drugs approved by the FDA for treatment
of depression are listed in Table 1. Improvement can
occur within the first 2 weeks of drug therapy, but it
may take 4-8 weeks to achieve substantial benefit.
Antidepressant drugs produce a response in about 5060% of adults with major depression and a remission
in about 30%; with multiple courses and/or multiple
drugs, 80% of patients will eventually respond, at least
temporarily.
SSRIs AND SNRIs Selective serotonin reuptake
inhibitors (SSRIs) are recommended for first-line
treatment of major depression. They are generally
well tolerated and relatively safe. There is no convincing evidence that any one SSRI is more effective
than any other. Fluoxetine is the only SSRI approved
by the FDA for treatment of major depressive
disorder in children and adolescents. Escitalopram,
the active enantiomer of citalopram, is approved for
treatment of depression in adolescents. Serotonin and
norepinephrine reuptake inhibitors (SNRIs) are also
considered a first-line option for treatment of major
depression. It is not clear that they offer any advantage in efficacy over SSRIs.
OTHER DRUGS Bupropion can be used as an
alternative to an SSRI for depressed patients who do
not have severe anxiety. It is activating rather than
sedating and has not been associated with weight gain,

sexual side effects or an increased risk of bleeding.


Mirtazapine may be useful when insomnia is prominent, and its appetite-stimulating and weight-gain-promoting properties may be helpful in depressed patients
with marked anorexia. Trazodone, which is also
sedating, is commonly used in a low dose as an
adjunct to an SSRI in patients with insomnia.1
Vilazodone is an SSRI and partial serotonin 1a receptor agonist; limited data suggest it may be an effective
antidepressant.2
Tricyclic antidepressants (TCAs) and monoamine
oxidase inhibitors (MAOIs) remain valuable alternatives for patients with moderate to severe treatmentresistant depression.
ADVERSE EFFECTS SSRIs Jitteriness and
sleep disturbances can occur during treatment with an
SSRI. Other adverse effects include nausea, diarrhea,
headache, dizziness, fatigue and sexual dysfunction
(including decreased libido, impaired arousal and
anorgasmia). An increase in motor activity is more
common in children. The long-term effects of these
drugs on the growth, personality development and
behavior of children are unknown.
Some patients gain significant amounts of weight
with continued use of an SSRI. SSRIs can cause
hyponatremia, particularly in elderly patients. They
have been associated with a possible increase in the
risk of nonvertebral fractures in older women.3
SSRIs can also increase the risk of bleeding by
inhibiting serotonin uptake by platelets. SSRIs have
a variety of effects on CYP450 isoenzymes and may
interact with many other drugs; these are summarized in Table 2. Citalopram can cause significant QT
interval prolongation.4 Escitalopram may also prolong the QT interval.5

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53

Drugs for Psychiatric Disorders


Table 1. Some Drugs for Depression
Drug
SSRIs
Citalopram generic

Celexa (Forest)
Escitalopram generic
Lexapro (Forest)
Fluoxetine generic

Prozac (Lilly)
delayed release generic
Prozac Weekly
Paroxetine hydrochloride generic
Paxil (GSK)
extended release generic
Paxil CR
Paroxetine mesylate Pexeva (Noven)
Sertraline generic
Zoloft (Pfizer)
SNRIs
Desvenlafaxine succinate Pristiq (Pfizer)
Desvenlafaxine generic (Alembic)
Duloxetine Cymbalta (Lilly)
Venlafaxine generic
extended release generic

Effexor XR (Pfizer)
TCAs
Amitriptyline generic
Desipramine generic
Norpramin (Sanofi)
Imipramine generic
Tofranil (Mallinckrodt)
Imipramine pamoate generic
Tofranil PM
Nortriptyline generic
Pamelor (Mallinckrodt)
MAOIs
Isocarboxazid Marplan (Validus)
Phenelzine generic
Nardil (Pfizer)
Selegiline Emsam (Somerset)
Tranylcypromine generic
Parnate (Covis)
Other
Bupropion generic
Wellbutrin (GSK)
extended release (12 hour) generic
Wellbutrin SR
Aplenzin (Sanofi)
extended release (24 hour) generic
Wellbutrin XL
Forfivo XL (Edgemont)
Mirtazapine generic
Remeron (Organon)
orally disintegrating generic
Remeron SolTab
Nefazodone6 generic
Trazodone generic
extended release Oleptro (Labopharm)
Vilazodone Viibryd (Forest)

Some Available
Formulations

Initial Adult
Dosage1

Usual Adult
Dosage1

10, 20, 40 mg tabs, caps;


40 mg ODT; 10 mg/5mL PO soln
10, 20, 40 mg tabs;
10 mg/5 mL PO soln
5, 10, 20 mg tabs;
5 mg/5 mL PO soln
10, 20, 40 mg caps; 10, 20, 60 mg
tabs; 20 mg/5 mL PO soln
10, 20, 40 mg caps
90 mg cap

20 mg once/d

40 mg once/d3

$4.004
145.00

10 mg once/d

10-20 mg once/d

10-20 mg once/d

20 mg once/d

90 mg 1x/wk

90 mg 1x/wk

20 mg once/d

20 mg once/d

12.5-25 mg once/d

25 mg once/d

10, 20, 30, 40 mg tabs


25, 50, 100, 150, 200 mg tabs;
20 mg/mL PO conc
25, 50, 100 mg tabs;
20 mg/mL PO conc

10 mg once/d
25-50 mg once/d

20 mg once/d
50-100 mg once/d

50, 100 mg ER tabs


50, 100 mg ER tabs
20, 30, 60 mg delayed-release
caps
25, 37.5, 50, 75, 100 mg tabs
37.5, 75, 150 mg caps; 37.5, 75,
150, 225 mg tabs
37.5, 75, 150 mg caps

50 mg once/d
50 mg once/d
30-60 mg once/d

10, 25, 50, 75, 100, 150 mg tabs

50-100 mg once/d

10, 25, 50, 75, 100, 150 mg tabs


10, 25, 50 mg tabs

50-100 mg once/d
or divided
25-50 mg once/d

75, 100, 125, 150 mg caps

75 mg once/d

10, 25, 50, 75 mg caps

75-100 mg once/d

10 mg tabs
15 mg tabs

10 mg bid
15 mg tid

30-40 mg/d divided


30 mg bid

6, 9, 12 mg/24 hr patches
10 mg tabs

6 mg/24 hr
10 mg once/d

6, 9, 12 mg/24 hr
20-30 mg bid

75, 100 mg tabs

100 mg bid

100 mg tid

100, 150, 200 mg tabs

150 mg once/d

150 mg bid

174, 348, 522 mg ER tabs


150, 300 mg tabs

174 mg once/d
150 mg once/d

348 mg once/d
300 mg once/d

450 mg ER tabs
7.5, 15, 30, 45 mg tabs
15, 30, 45 mg tabs
15, 30, 45 mg ODT

See footnote 5
15 mg once/d at hs

450 mg once/d
30-45 mg once/d

50, 100, 150, 200, 250 mg tabs


50, 100, 150, 300 mg tabs
150, 300 mg tabs
10, 20, 40 mg tabs

100 mg bid
75 mg bid
150 mg once/d
10 mg once/d

200 mg bid
300 mg divided bid
150-375 mg once/d
40 mg once/d

10, 20, 30, 40 mg tabs;


10 mg/5 mL PO susp
12.5, 25, 37.5 mg tabs

Cost2

7.00
143.00
4.004
211.00
110.00
145.00
4.004
121.00
91.00
128.00
204.00
5.00
141.00

25 mg tid
37.5 mg once/d

50 mg once/d
50 mg once/d
60 mg once/d or
divided bid
75 mg tid
225 mg once/d

161.00
139.00
199.00
64.00
240.00
522.00

150 mg once/d
or divided
150 mg once/d
or divided
100-150 mg once/d
or divided
150 mg once/d
or divided
150 mg once/d
or divided

5.00
151.00
205.00
20.00
349.00
348.00
549.00
14.00
1399.00
260.00
72.00
132.00
594.00
323.00
673.00
63.00
266.00
37.00
233.00
395.00
38.00
319.00
135.00
20.00
130.00
57.00
104.00
35.00
16.00
96.00
138.00

ODT = orally disintegrating tablet; ER = extended-release


1. Dose may need to be adjusted for renal or hepatic impairment or for drug interactions.
2. Approximate wholesale acquisition cost (WAC) for 30 days treatment at the lowest usual daily dosage. $ource Monthly (Selected from FDB MedKnowledge)
May 5, 2013. Reprinted with permission by FDB, Inc. All rights reserved. 2013. www.fdbhealth.com/policies/drug-pricing-policy. Actual retail prices may be higher.
3. The daily dose should not exceed 40 mg (20 mg in patients >60 years old, patients with hepatic impairment and for CYP2C19 poor metabolizers or those taking
a CYP2C19 inhibitor).
4. Cost of generics at some large discount pharmacies.
5. Initiate with another bupropion formulation.
6. Brand name nefazodone was withdrawn from the market due to hepatic toxicity.

54

Treatment Guidelines from The Medical Letter Vol. 11 ( Issue 130) June 2013

Drugs for Psychiatric Disorders

Table 2. Some SSRI and SNRI Drug Interactions


Drug

CYP450

Comments

Citalopram

Metabolized by 2C191 and 3A4

Maximum dose of 20 mg/day in 2C19 poor metabolizers or with inhibitors of 2C19;


higher serum concentrations increase the risk of QT prolongation; avoid use
with other drugs that prolong the QT Interval

Escitalopram

Metabolized by 2C191 and 3A4

Fluoxetine

Metabolized by 2D61 and 2C9


Strong inhibitor of 2D6
Moderate inhibitor of 2C19
Metabolized by 2D6
Strong inhibitor of 2D6
Metabolized by 2C19
Moderate inhibitor of 2D6
Metabolized by 2D61 and 3A4
Metabolized by 3A4
Weak inhibitor of 2D6
Metabolized by 1A21 and 2D6
Moderate inhibitor of 2D6

Low potential for interactions; dose adjustments may be needed with 2C19
inhibitors; may prolong the QT interval
May decrease efficacy of tamoxifen; may increase concentrations of 2D6 substrates;
long half-life is a problem when interactions occur

Paroxetine
Sertraline
Venlafaxine
Desvenlafaxine
Duloxetine

May decrease efficacy of tamoxifen; may increase concentrations of 2D6 substrates;


lower doses of paroxetine may be needed with 2D6 inhibitors
Low potential for interactions
Low potential for interactions; serum concentrations may be increased by 3A4 inhibitors
Low potential for interactions; reduce dose of 2D6 substrates if administered with
400 mg of desvenlafaxine
Avoid strong inhibitors of 1A2; 2D6 inhibitors can increase duloxetine concentrations;
duloxetine increases concentrations of drugs that are substrates of 2D6

1. Primary pathway

When SSRIs are stopped abruptly, discontinuation


symptoms including nervousness, anxiety, irritability,
electric-shock sensations, bouts of crying or tearfulness, dizziness, lightheadedness, insomnia, confusion,
trouble concentrating, nausea and vomiting can occur;
these effects are most severe with paroxetine because
of its short half-life and least likely to occur with fluoxetine because of its long half-life.
SNRIs The adverse effects of venlafaxine, desvenlafaxine and duloxetine are similar to those of SSRIs, but
can also include increased sweating, tachycardia and urinary retention. Severe discontinuation symptoms can
occur when these drugs are stopped, especially with venlafaxine and desvenlafaxine because of their short halflives. SNRIs can cause a dose-dependent increase in
blood pressure; blood pressure should be under control
before starting an SNRI and monitored during treatment.
False-positive urine immunoassay screening tests for
phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine or desvenlafaxine.
Other Drugs TCAs commonly cause anticholinergic effects (urinary retention, constipation, dry mouth,
blurred vision and confusion), orthostatic hypotension, weight gain, sedation and sexual dysfunction.
They can cause cardiac conduction delay, which can
lead to arrhythmias. TCAs are more dangerous than
SSRIs in overdose.
Adverse effects of MAOIs include sleep disturbance,
orthostatic hypotension, sexual dysfunction and
weight gain. Interactions with serotonergic drugs,
bupropion, sympathomimetics, and tyramine-rich
foods can result in serotonin syndrome or a hypertensive crisis, either of which can be fatal. The enzymeinhibiting effects of MAOIs can persist for up to 2
weeks after the drug is stopped.

Bupropion can cause agitation, anxiety, insomnia,


headache, nausea, anorexia and hypersensitivity reactions. Dose-related seizures may occur; the drug is
contraindicated in patients with eating disorders
because such patients have a higher incidence of
seizures when treated with bupropion. Mirtazapine
can cause sedation, increased appetite, weight gain,
dizziness, dry mouth and constipation; febrile neutropenia has occurred rarely.
Vilazodone has an adverse effect profile similar to
that of SSRIs; available evidence is insufficient to
support claims that it causes less weight gain or less
sexual dysfunction.2 Trazodone can cause drowsiness, orthostatic hypotension and priapism.
Nefazodone has caused somnolence, dry mouth, nausea, dizziness and rarely, hepatic failure requiring
liver transplantation, which has led to its withdrawal
from the market in Canada and Europe and discontinuation of the branded version in the US.
Suicidality All antidepressants carry a boxed warning about suicidality (suicidal ideation and behavior).
An FDA analysis of placebo-controlled antidepressant
studies, summarized in the package inserts of these
drugs, found an increased risk of suicidality in children, adolescents and young adults (24 years old)
being treated with an antidepressant. A recent
Cochrane review also found that antidepressants
increased the risk of suicidal ideation and behavior in
children and adolescents.6 No increase in completed
suicides has been demonstrated (there were no suicides
in the pediatric trails summarized by the FDA), and the
subject continues to be debated. All depressed children, adolescents and adults, whether they are treated
with drugs or not, should be monitored for suicidal
ideation and behavior.

Treatment Guidelines from The Medical Letter Vol. 11 ( Issue 130) June 2013

55

Drugs for Psychiatric Disorders

Serotonin Syndrome All serotonergic drugs can


cause serotonin syndrome, a rare but potentially lifethreatening condition characterized by altered mental
status, fever, tachycardia, hypertension, agitation,
tremor, myoclonus, hyperreflexia, ataxia, incoordination, diaphoresis, shivering and gastrointestinal symptoms. Serotonin syndrome occurs most commonly as a
result of interactions with other drugs.
Because of the risk of serotonin syndrome, serotonergic
drugs and MAOIs should not be used together or within 2 weeks of each other. Some drugs with MAOI activity, such as the antimicrobial agent linezolid (Zyvox),
and some serotonergic drugs, such as the cough suppressant dextromethorphan, sumatriptan (Imitrex, and
generics), tramadol (Ultram, and generics), methadone
and St. Johns wort, may not be recognized as serotonergic, but can cause serotonin syndrome when taken
concurrently with an SSRI or SNRI.7
Mania All antidepressants can induce mania, most
often in patients with bipolar disorder. Patients should
be screened for personal or first-degree-relative history of mania, hypomania or other evidence of bipolar
disorder before starting antidepressant therapy.

clinicians recommend that they not be used. Data on the


safety of other classes of antidepressants during pregnancy are lacking.
Data on long-term behavioral effects of in utero antidepressant exposure are limited; one retrospective
study found delays in sitting and walking (but within
the normal range) in children exposed to antidepressants during pregnancy.18
CHOICE OF DRUGS First-Line An SSRI, an
SNRI, bupropion or mirtazapine could be used for
first-line treatment of major depression, but most
expert clinicians begin with an SSRI. The choice
among SSRIs may be determined by adverse effect
profiles and differences in drug interactions. Taking
these and cost into consideration, generic sertraline or
generic escitalopram would be a reasonable first
choice for treatment of depression in adults. Generic
fluoxetine would be a good choice for treatment of
depressed children, adolescents or young adults.
Second-Line When patients show little to no
response to an adequate trial of an SSRI, many clinicians switch to another antidepressant, combine two
antidepressants of different classes, such as an SSRI
and bupropion, or add another drug, such as a secondgeneration antipsychotic.19 MAOIs should not be
added to an SSRI or SNRI or to another MAOI
because of the risk of serotonin syndrome.

PREGNANCY Both untreated maternal depression and use of SSRIs in pregnancy have been associated with delayed fetal development, preterm birth
and low birth weight.8,9 Taking SSRIs in the third
trimester has been associated with a self-limited
neonatal behavioral syndrome, treatment in a neonatal
intensive care unit, and a possible risk of persistent
pulmonary hypertension.10,11 Paroxetine is classified
as category D (positive evidence of human fetal risk)
for use during pregnancy because of an increased risk
of cardiovascular and other malformations in infants
born to mothers taking it in the first trimester.12 The
safety of other SSRIs in the first trimester has also
been questioned13,14; all except paroxetine are classified as pregnancy category C (adverse fetal effects in
animals or no animal reproductive studies, and no
adequate human studies). Overall, the risk of congenital malformations after taking an SSRI during pregnancy appears to be very low.15,16 One study that controlled for maternal characteristics found no increase
in perinatal mortality among a cohort of women treated with SSRIs.17

Augmentation with antipsychotic drugs may be


helpful when the response to antidepressant agents is
inadequate, but they can cause adverse effects such as
weight gain or akathisia.21,22 Quetiapine and oral
aripiprazole are FDA-approved for adjunctive treatment of major depressive disorder. A fixed-dose combination of olanzapine and fluoxetine is FDAapproved for treatment-resistant depression.

Pregnancy studies with SNRIs are limited,13 but exposure during the third trimester may cause a self-limited
neonatal behavioral syndrome. TCA use in late pregnancy has been associated with jitteriness and convulsions in newborns. MAOIs are classified as category C
for use during pregnancy, but because of the risk of drug
interactions or foods causing a hypertensive crisis, some

Maintenance The goal of antidepressant treatment is


complete remission of symptoms; partial response is
associated with an increased risk of relapse. For a first
episode of depression, many experts recommend that
antidepressant treatment continue at the same dose for
at least 6-9 months following remission to consolidate
recovery. For patients with recurrent depressive

56

In one controlled trial, among patients with major


depressive disorder who had not responded to or could
not tolerate 12 weeks treatment with the SSRI citalopram, switching antidepressants to sustained-release
bupropion, sertraline or extended-release venlafaxine
led to remissions in 26%, 27% and 28% of patients,
respectively, but the study did not include a placebo
group or one that continued on citalopram.20

Treatment Guidelines from The Medical Letter Vol. 11 ( Issue 130) June 2013

Drugs for Psychiatric Disorders

episodes, long-term maintenance therapy can reduce


the risk of recurrence.
NON-DRUG THERAPY Psychotherapy, particularly cognitive behavioral therapy (CBT) and interpersonal therapy (IPT), is an effective treatment for
depression. ECT is highly effective for severe depression, depression with psychosis or bipolar disorder,
and depression refractory to drugs23; it can be used
during pregnancy. Vagus nerve stimulation (VNS)
and transcranial magnetic resonance stimulation
(TMS) are FDA-approved for treatment-resistant
depression, but a short-term trial of VNS did not find
a statistically significant response.24,25 TMS, unlike
ECT, does not require anesthesia and does not appear
to have cognitive side effects. Studies of TMS have
demonstrated response and remission rates similar to
those of antidepressant medications; it may be a reasonable treatment option when patients are unable to
tolerate or do not respond to antidepressant medications, but it is expensive and time-consuming (3-5
times a week for several weeks), and its efficacy has
been limited in patients who have not responded to
multiple medications.
DRUGS FOR BIPOLAR DISORDER
Some oral drugs for treatment of bipolar disorder are
listed in Table 3 on the next page. Even with maintenance treatment, recurrences of manic or (more frequently) depressive episodes are common.26
MAINTENANCE Lithium is generally the drug of
choice for maintenance treatment of bipolar disorder.
Antiepileptic drugs such as valproate and carbamazepine are also widely used for maintenance despite
evidence suggesting that they are less effective than
lithium in preventing recurrence. The anticonvulsant
lamotrigine is especially effective for prevention of
recurrent depression in bipolar disorder. Maintenance
therapy with lithium alone or in combination with valproate, carbamazepine or lamotrigine decreases the risk
of recurrent manic and depressive episodes.
Second-generation antipsychotics may also be
effective in preventing recurrences of manic and
depressive episodes, especially when taken in combination with lithium. A long-acting form of risperidone, given intramuscularly every 2 weeks, has been
approved by the FDA for maintenance treatment and
may be helpful for patients with frequent relapses,
especially when adherence is an issue.
TREATMENT OF MANIA For treatment of
mania, lithium, valproate and second-generation
antipsychotics have similar efficacy.27 Both lithium

and valproate may take days to weeks to have a full


therapeutic effect; manic patients often require
adjunctive treatment with an antipsychotic drug or
temporary treatment with a benzodiazepine.
TREATMENT OF DEPRESSION Monotherapy
with antidepressant drugs can precipitate mania in
patients with bipolar disorder and is not recommended.
For treatment of depression in patients with bipolar
disorder, lithium has protective effects against suicide
and self-harm.28 The effectiveness of valproate in
treating depression in bipolar patients is unclear.29 The
antipsychotic quetiapine or a combination of olanzapine and fluoxetine have been shown to be effective in
treating depression in bipolar patients. Lamotrigine
may also be effective for this indication.
ALTERNATIVES A benzodiazepine such as
lorazepam (Ativan, and generics) may be helpful when
an adjunct is needed for insomnia, agitation or anxiety,
but bipolar patients are at risk for substance dependence. Some clinicians have used clozapine to treat
mania resistant to other drugs. ECT is effective for
treatment of both acute mania and acute depression
and may be particularly useful for drug-resistant mania
and in pregnant women.
ADVERSE EFFECTS Nausea and fatigue may
occur in the first days to weeks of treatment with lithium, even when serum concentrations are in the recommended range. Tremor, thirst, polyuria, edema and
weight gain may persist for the duration of treatment.
Lithium-induced tremors can be treated by reducing
the dosage or adding a beta-blocker such as propranolol. Confusion and ataxia can occur. Toxic renal
effects, including tubular lesions, interstitial fibrosis
and decreased creatinine clearance, have been reported
with long-term use of lithium. Nephrogenic diabetes
insipidus can occur; it further increases the risk of lithium toxicity, and may be irreversible. Hypothyroidism
can occur with long-term lithium treatment and can
contribute to exacerbations of bipolar illness. Lithium
may cause mild leukocytosis, induce or exacerbate
psoriasis, and cause severe acne, folliculitis, hair loss
and other skin reactions. Many commonly used drugs,
including most NSAIDs (but not aspirin), ACE
inhibitors and diuretics, can increase serum lithium
concentrations and should be avoided if possible.
Other medications, including theophylline and caffeine, can lower serum lithium concentrations.
Adverse effects of valproate include somnolence,
fatigue, weight gain, nausea, diarrhea and tremor, but
tremor is less common than with lithium. Reversible
hair loss can occur. Thrombocytopenia may occur and
appears to be dose-related. Transient elevations of

Treatment Guidelines from The Medical Letter Vol. 11 ( Issue 130) June 2013

57

Drugs for Psychiatric Disorders


Table 3. Some Oral Drugs for Bipolar Disorder
Drug

Some Available
Formulations

Initial Adult
Dosage1

Usual Adult
Dosage1

150, 300, 600 mg caps; 300 mg tabs;


8 mEq/5 mL PO soln5
300, 450 mg tabs
300 mg tab

900-1800 mg
divided tid or qid
900-1800 mg
divided bid or tid

900-1200 mg
divided tid or qid
900-1200 mg
divided bid or tid

100, 200, 300, 400 mg tabs;


100, 200 mg chewable tabs;
100 mg/5 mL susp7
200 mg tabs; 100 mg chewable tabs;
100 mg/5 mL susp7
100, 200, 400 mg tabs;
100, 200, 300 mg caps
100, 200, 300 mg caps
100, 200, 300 mg caps
100, 200, 400 mg tabs
25, 100, 150, 200 mg tabs;
2, 5, 25 mg chewable tabs10
25, 50, 100, 200 mg ODT;
25, 50, 100, 200, 250, 300 mg tabs

200-600 mg
divided tid-qid

600-1200 mg
divided bid or tid

Cost2

Antimanic Agent
Lithium carbonate3,4 generic
extended release generic
Lithobid (Noven)
Anticonvulsants
Carbamazepine generic6

Tegretol (Novartis)6
extended release generic6

Equetro (Validus)3,9
Carbatrol (Shire)6
Tegretol XR (Novartis)6
Lamotrigine generic4
Lamictal (GSK)4
Lamictal ODT4
extended release generic6
Lamictal XR6
Valproate12
Valproic acid generic
Depakene6 (Abbott)
delayed release Stavzor3(Noven)
Divalproex sodium generic
Depakote3 (Abbott)
Depakote Sprinkle6
extended release Depakote ER 3
Second-Generation Antipsychotics
Aripiprazole3,4,9 Abilify (BMS/Otsuka)
Abilify Discmelt
Asenapine Saphris (Merck)3,9
Olanzapine3,4,9 generic
Zyprexa (Lilly)
orally disintegrating generic
Zyprexa Zydis
Quetiapine generic
Seroquel (AstraZeneca)3,4,16
extended release Seroquel XR3,4,9,16
Risperidone3,9 generic
Risperdal (Janssen)
orally disintegrating generic
Risperdal M-Tab
Ziprasidone generic
Geodon (Pfizer)3,4,9
Combination
Olanzapine/fluoxetine16 generic
Symbyax (Lilly)

$15.00
24.00
240.00
9.008

236.00
200-600 mg
divided bid
200 mg bid
200-600 mg
divided bid
25 mg once/d11

200 mg once/d

25 mg once/d11

200 mg once/d

250 mg cap; 250 mg/5 mL syrup

250 mg tid

1500-2000 mg
divided bid

125, 250, 500 mg caps


125, 250, 500 mg tabs

750 mg/d divided


750 mg/d divided

125 mg cap
250, 500 mg tabs

25 mg/kg once/d13

67.00
607.00
227.00
29.00
214.00
479.00
25-40 mg/kg once/d13 412.00

15 mg once/d

15-30 mg once/d

10 mg bid
10-15 mg once/d

5-10 mg bid
5-20 mg once/d

50-100 mg once/d
or divided bid
50-300 mg once/d
2-3 mg once/d

300-800 mg
divided bid
300-800 mg once/d
4-6 mg once/d

40 mg bid

40-80 mg bid

6/25 mg once in
the evening

6/25-12/50 mg once 348.00


in the evening
402.00

2, 5, 10, 15, 20, 30 mg tabs;


1 mg/mL soln14,15
10,15 mg ODT
5, 10 mg sublingual tabs
2.5, 5, 7.5, 10, 15, 20 mg tabs15

600-1200 mg
divided bid

5, 10, 15, 20 mg ODT


25, 50, 100, 150 200, 300, 400 mg tabs
25, 50, 100, 200, 300, 400 mg tabs
50, 150, 200, 300, 400 mg tabs
0.25, 0.5, 1, 2, 3, 4 mg tabs;
1 mg/mL soln17
0.25, 0.5, 1, 2, 3, 4 mg ODT
0.5, 1, 2, 3, 4 mg ODT
20, 40, 60, 80 mg caps

3/25, 6/25, 6/50, 12/25, 12/50 mg


caps

89.00
138.00
106.00
120.00
12.00
252.00
248.00
350.00
416.00

669.00
797.00
690.00
29.00
367.00
226.00
397.00
89.00
754.00
497.00
38.00
513.00
373.00
616.00
237.00
543.00

ODT = orally disintegrating tablet


1. Dose for maintenance. Dosage may need to be adjusted for renal or hepatic impairment or when used concomitantly with lithium, valproate or carbamazepine.
2. Approximate wholesale acquisition cost (WAC) for 30 days treatment with tabs or caps for a 70-kg patient at the lowest usual daily dosage. $ource Monthly
(Selected from FDB MedKnowledge) May 5, 2013. Reprinted with permission by FDB, Inc. All rights reserved. 2013. www.fdbhealth.com/policies/drug-pricingpolicy. Actual retail prices may be higher.
3. FDA-approved for mania.
4. FDA-approved for maintenance treatment of bipolar disorder.
5. Available as lithium citrate.
6. Not FDA-approved for bipolar disorder.
7. Patients on conventional tablets can be switched to the suspension on a mg-per-mg basis, but in smaller, more frequent doses.
8. Cost using 200-mg tablets.
9. FDA-approved for mixed episode.
10. Chewable tablets should be administered whole. If necessary, the dose should be rounded down to the nearest whole tablet.
11. For monotherapy, titrate to a goal of 200 mg/day as follows: 25 mg/day for 2 weeks, then 50 mg/day for 2 weeks, then 100 mg/day for 1 week, then 200 mg/day.
12. Also available in an IV formulation as valproate sodium (Depacon, and generics).
13. When switching from Depakote to Depakote ER, the dosage may need to be increased 8-20% to maintain serum concentrations.
14. Aripiprazole PO solution should be given at the same dose (mg per mg) as the tablets, except that when patients receive the 30-mg tablet, 25 mg of the solution should be used.
15. Also available for rapid intramuscular injection for agitation associated with bipolar mania.
16. FDA-approved for depressive episode with bipolar disorder.
17. Also available as a long-acting injectable for maintenance treatment of bipolar disorder.

58

Treatment Guidelines from The Medical Letter Vol. 11 ( Issue 130) June 2013

Drugs for Psychiatric Disorders

hepatic transaminases are common; fatal hepatotoxicity has occurred rarely, particularly in young children
and with use of multiple anticonvulsants. Polycystic
ovary syndrome has been reported. Rare idiosyncratic
reactions include hemorrhagic pancreatitis, hyperammonemic encephalopathy and agranulocytosis.
Adverse effects of carbamazepine include rash, dizziness, diplopia, nausea, somnolence, headache, hyponatremia, elevated transaminases and, rarely, StevensJohnson syndrome, agranulocytosis and aplastic anemia. Han Chinese may have a ten-fold increased risk
of Stevens-Johnson syndrome because of genetic vulnerability.30 Eosinophilia and hepatic toxicity
(DRESS Syndrome) have been reported.31 Because
of the many drug interactions that occur with carbamazepine, oxcarbazepine, which causes less induction
of hepatic enzymes, may be used instead.

Liver function and complete blood counts should be


monitored in patients taking valproate. Complete
blood counts should be monitored in patients taking
carbamazepine.
PREGNANCY Lithium use during pregnancy has
been associated with congenital cardiac abnormalities;
the absolute risk is low. High neonatal lithium concentrations are a risk factor for lower Apgar scores, longer
hospital stays, and reversible neurologic toxicity; the
risk could be minimized or avoided by withholding
maternal lithium for 24 hours before delivery.
Valproate taken during pregnancy can cause neonatal
toxicity, neural tube defects, cardiac and other major
teratogenic effects, and adverse effects on neurocognitive development with measurable impairment of IQ.33
Unless there is no alternative, it should not be used
during pregnancy.

Adverse effects of lamotrigine include nausea, dizziness and somnolence. About 10% of patients develop
mild rash; severe, life-threatening rash, including
Stevens-Johnson syndrome and toxic epidermal
necrolysis, has occured rarely. Very gradual up-titration of the dose may minimize the risk of rash.32

Carbamazepine is not recommended for use during pregnancy, unless no alternatives exist, because of an increased
risk of major malformations, including neural tube
defects, low birth weight, and fetal and neonatal vitamin K
deficiency, which can lead to neonatal hemorrhage.

Second-generation antipsychotics can cause somnolence, weight gain, diabetes, extrapyramidal symptoms, QT prolongation and elevated prolactin levels
(see Table 7).

Data on use of lamotrigine during pregnancy are


inconsistent; it appears to have a lower risk of adverse
fetal outcomes than valproate or carbamazepine, but
midline clefts have been reported.

MONITORING Lithium has a narrow therapeutic


window and requires careful monitoring. Serum lithium concentrations should be monitored every three
months (every 6-12 months in a stable patient) to
maintain serum concentrations within the therapeutic
range and avoid toxicity. Concentrations should be
measured about 12 hours after the last dose. For acute
treatment, target serum concentrations are 0.8 to 1.2
mEq/L. For maintenance, serum concentrations should
be between 0.6 and 1.0 mEq/L. Thyroid and renal
function should be monitored at baseline and every six
months. In addition to laboratory monitoring, patients
should be monitored for clinical signs of toxicity such
as vomiting, diarrhea, tremor, lethargy, slurred speech
and weakness.

Data on use of second-generation antipsychotics during pregnancy are limited; increased birth weight has
been reported.34
CHOICE OF DRUGS Lithium is generally the
drug of choice for maintenance treatment of bipolar
disorder. Lamotrigine may be used to prevent recurrent depressive episodes. Lithium, valproate, and second-generation antipsychotics are similarly effective
for treatment of mania. Quetiapine or a combination
of olanzapine and fluoxetine are effective for treatment of depression in patients with bipolar disorder.
Lamotrigine may also be effective for treatment of
bipolar depression.

Table 4. Some Antimanic and Anticonvulsant Drug Interactions


Drug

Comments

Carbamazepine

Carbamazepine is a strong inducer of multiple hepatic enzymes, including 3A4; increase in dosage of 3A4
substrates may be required. It is also a 3A4 substrate; dosage adjustments may be required with strong 3A4
inducers and inhibitors.
Diuretics, ACE inhibitors, and NSAIDs (except aspirin) reduce renal clearance of lithium; reduce dosage of
lithium. Carbamazepine increases the risk of neurotoxicity; a reduction in dosage of lithium may be required.
Valproate is a moderate inhibitor of 2C9; reduction in dosage of 2C9 substrates may be required. Phenytoin,
carbamazepine, phenobarbital, and rifampin increase renal clearance of valproate; increase dosage of
proate. Use with lamotrigine increases the risk of Stevens-Johnson syndrome; reduce dosage of lamotrigine.

Lithium
Valproate

Treatment Guidelines from The Medical Letter Vol. 11 ( Issue 130) June 2013

59

Drugs for Psychiatric Disorders

PSYCHOTIC DISORDERS
The oral antipsychotic drugs used for treatment of schizophrenia, schizoaffective disorder, delusional disorder
and other manifestations of psychosis or mania are listed
in Table 6. Adverse effects such as movement disorders
and metabolic effects, cost, and lack of access to nonpharmacological services (rehabilitation, psychotherapy,
education and intensive case management) can interfere
with patient adherence to these medications.
EFFECTIVENESS Antipsychotic drugs are generally more effective for treating the positive symptoms
of schizophrenia (agitation, hallucinations and delusions) than the negative symptoms (apathy, social
withdrawal and blunted affect).35 Some symptoms of
schizophrenia and acute psychoses may improve rapidly after treatment with antipsychotic drugs, but chronic
schizophrenia usually takes many weeks to respond;
some patients may continue to improve for months.
Maintenance treatment with antipsychotic medications
reduces relapse rates in schizophrenia.36
Oral Second-generation antipsychotics are now used
more commonly than first-generation drugs, even
though controlled trials have failed to demonstrate a
clear advantage in efficacy with the newer drugs,
except for clozapine and possibly olanzapine.37,38
Clozapine can be effective for treatment of psychotic
symptoms in patients who have not responded to other
drugs. It also appears to be more effective than other
antipsychotics in decreasing the risk of suicide.39,40
Olanzapine appears to be more effective than aripiprazole, quetiapine, risperidone and ziprasidone in reducing psychotic symptoms.41
The more recently FDA-approved antipsychotic drugs
asenapine,42 iloperidone43 and lurasidone44 may be
effective for some patients, but their efficacy and safety relative to other drugs in the class remain to be
established.
Parenteral The long-acting parenteral antipsychotics listed in Table 5 are generally used in patients
with a history of relapse due to poor adherence to oral
maintenance therapy. Data on the newer long-acting
parenteral formulations such as paliperidone, olanzapine and aripiprazole are limited. Short-acting parenteral antipsychotics can be helpful for rapid treatment of
acute psychotic agitation or mania.45
Inhaled The first-generation antipsychotic loxapine
has been approved by the FDA as a powder for oral
inhalation (Adasuve) for acute treatment of agitation
associated with bipolar disorder or schizophrenia.

60

ADVERSE EFFECTS First-Generation All


first-generation antipsychotic drugs have been associated with sexual dysfunction, hyperprolactinemia, neuroleptic malignant syndrome and tardive dyskinesia.
The risk of extrapyramidal symptoms and tardive
dyskinesia with the first-generation agents may be
minimized if dosing is targeted to the lowest dose at
which fine, rather than coarse, extrapyramidal motor
effects first appear.46
Chlorpromazine commonly causes sedation, postural
hypotension and weight gain, as well as anticholinergic and occasional extrapyramidal adverse effects.
Haloperidol and fluphenazine are less likely to cause
sedation, postural hypotension or anticholinergic
effects, but typically cause extrapyramidal symptoms.
Perphenazine and loxapine are generally less sedating than chlorpromazine and somewhat less likely than
haloperidol or fluphenazine to cause extrapyramidal
symptoms.
Table 5. Some Parenteral Antipsychotics
Drug

Usual Adult Dosage

Cost2

12.5-25 mg IM
q2-3 wks
10-15 times previous
daily oral dose IM
q4 wks

$108.003

Long-Acting1
First-Generation
Fluphenazine decanoate
generic
Haloperidol decanoate
generic
Haldol (Janssen)
Second-Generation
Aripiprazole
Abilify Maintena
(Otsuka/Lundbeck)
Olanzapine pamoate
Zyprexa Relprevv (Lilly)
Paliperidone palmitate
Invega Sustenna (Janssen)
Risperidone
Risperdal Consta (Janssen)
Short-Acting5
First-Generation
Chlorpromazine generic
Droperidol generic
Fluphenazine hydrochloride
generic
Haloperidol lactate generic
Haldol (Janssen)
Second-Generation
Aripiprazole Abilify
(BMS/Otsuka)
Olanzapine generic
Zyprexa (Lilly)
Ziprasidone Geodon (Pfizer)

32.004
119.00

400 mg IM once/month 1450.00

150-300 mg IM q2 wks
795.00
or 300-405 mg IM q4 wks
117-234 mg IM q4 wks
859.00
25-50 mg IM q2 wks

25 mg IM
2.5-5 mg IM
1.25 mg IM

573.00

16.00
2.00
6.00

2-5 mg IM

2.00
6.00

9.75 mg IM

21.00

5-10 mg IM

16.00
20.00
9.00

10-20 mg IM

1. Dosage for schizophrenia, based on patients stable oral maintenance dosage.


2. Approximate wholesale acquisition cost (WAC) for 4 weeks or 1 months treatment with the lowest usual adult dosage for long-acting, or cost of a single injection of the lowest usual dose for short-acting. $ource Monthly (Selected from
FDB MedKnowledge) May 5, 2013. Reprinted with permission by FDB, Inc.
All rights reserved. 2013. www.fdbhealth.com/policies/drug-pricing-policy.
Actual retail prices may be higher.
3. Cost of one 5-mL vial.
4. Cost of 100-mg dose.
5. Single dose for acute agitation; repeat doses may be needed.

Treatment Guidelines from The Medical Letter Vol. 11 ( Issue 130) June 2013

Drugs for Psychiatric Disorders


Table 6. Oral Antipsychotics
Some Available
Oral Formulations

Initial
Adult Dosage

Usual
Adult Dosage1

10-50 mg bid
2.5-5 mg divided
q6-8h

200 mg bid
10 mg once/d

5 mg once/d or divided

5 mg bid

Loxapine4 generic
Loxitane (Watson)
Perphenazine generic

10, 25, 50, 100, 200 mg tabs


1, 2.5, 5, 10 mg tabs;
2.5 mg/5 mL elixir;
5 mg/mL conc
0.5, 1, 2, 5, 10, 20 mg tabs;
2 mg/mL soln
5, 10, 25, 50 mg caps
5, 10 mg caps
2, 4, 8, 16 mg tabs

10 mg bid

129.00
371.00
139.00

Thioridazine5 generic
Thiothixene generic
Trifluoperazine generic

10, 25, 50, 100 mg tabs


1, 2, 5, 10 mg caps
1, 2, 5, 10 mg tabs

50-100 mg tid
2 mg tid
2-5 mg bid

60-100 mg in 2-4
divided doses
24 mg in divided
doses
100-200 mg bid
10 mg bid
10 mg bid

2, 5, 10, 15, 20, 30 mg tabs;


1 mg/mL soln6

10-15 mg once/d

10-30 mg once/d

669.00

10, 15 mg ODT
5, 10 mg sublingual tabs
25, 50, 100, 200 mg tabs
25, 100 mg tabs
12.5, 25, 100 mg ODT
12.5, 25, 100, 150, 200 mg ODT
1, 2, 4, 6, 8, 10, 12 mg tabs

10-15 mg once/d
5 mg bid
12.5-25 mg bid

10-15 mg once/d
5-10 mg bid
100-300 mg tid

797.00
690.00
218.00
812.00
589.00
783.00

1 mg bid

6-12 mg bid

20, 40, 80, 120 mg tabs

40 mg once/d

40-160 mg once/d

2.5, 5, 7.5, 10, 15, 20 mg tabs

5-10 mg once/d

10-20 mg once/d

1.5, 3, 6, 9 mg ER tabs

6 mg once/d

6-12 mg once/d

25, 50, 100, 200, 300,


400 mg tabs

25 mg bid

300-800 mg in 2 or 3
divided doses

50, 150, 200, 300, 400 mg tabs


0.25, 0.5, 1, 2, 3, 4 mg tabs;
1 mg/mL soln
0.25, 0.5, 1, 2, 3, 4 mg ODT
0.5, 1, 2, 3, 4 mg ODT
20, 40, 60, 80 mg caps

300 mg once/d
2 mg once/d or
divided bid

400-800 mg once/d
4-8 mg once/d

20-40 mg bid

60-80 mg bid

Drug

Cost2

First-Generation
Chlorpromazine3 generic
Fluphenazine3 generic

Haloperidol3 generic

Second-Generation
Aripiprazole3 Abilify
(BMS/Otsuka)
orally disintegrating
Abilify Discmelt
Asenapine Saphris (Merck)
Clozapine7 generic
Clozaril (Novartis)
orally disintegrating generic
FazaClo (Jazz)
Iloperidone
Fanapt (Novartis)
Lurasidone Latuda
(Sunovion)
Olanzapine3 generic
Zyprexa (Lilly)
orally disintegrating generic
Zyprexa Zydis
Paliperidone3
Invega (Janssen)
Quetiapine generic
Seroquel (AstraZeneca)
extended release
Seroquel XR
Risperidone3 generic
Risperdal (Janssen)
orally disintegrating generic
Risperdal M-TAB
Ziprasidone generic
Geodon3 (Pfizer)

4 mg tid

5, 10, 15, 20 mg ODT

$140.00
11.00

14.00

24.00
26.00
57.00

697.00
553.00
23.00
553.00
340.00
583.00
604.00
72.00
600.00
585.00
42.00
513.00
362.00
616.00
292.00
659.00

ODT = orally disintegrating tablet


1. Usual oral maintenance dosage for schizophrenia.
2. Approximate wholesale acquisition cost (WAC) for 30 days treatment with the lowest usual daily dosage. $ource Monthly (Selected from FDB
MedKnowledge) May 5, 2013. Reprinted with permission by FDB, Inc. All rights reserved. 2013. www.fdbhealth.com/policies/drug-pricing-policy. Actual retail
prices may be higher.
3. Also available parenterally.
4. Also available as a powder for oral inhalation (Adasuve) for acute treatment of agitation associated with schizophrenia or bipolar disorder in adults.
5. Thioridazine is associated with dose-related prolongation of the QTc interval and should be reserved for schizophrenic patients who fail to resond to other drugs.
6. Aripiprazole PO solution should be given at the same dose, mg per mg, as the tablets, except that when patients receive the 30-mg tablet, 25 mg of the solution should be used.
7. Clozapine is associated with seizures and agranulocytosis and should be reserved for schizophrenic patients who fail to respond to other drugs.

Second-Generation Second-generation antipsychotics have a relatively low risk of extrapyramidal


effects, and are probably less likely than first-generation antipsychotics to cause tardive dyskinesia and
neuroleptic malignant syndrome.47 Some second-generation drugs (particularly clozapine, olanzapine and
quetiapine) cause more weight gain than others. The

FDA requires the manufacturers of all second-generation antipsychotics to include product-label warnings
about hyperglycemia and diabetes, even though the
risks are not equivalent for all drugs in the class, and
about an increased risk of death among elderly patients
with dementia.48 Table 7 lists some relative adverse
effects of second-generation antipsychotics.

Treatment Guidelines from The Medical Letter Vol. 11 ( Issue 130) June 2013

61

Drugs for Psychiatric Disorders


Table 7. Some Relative Adverse Effects of Second-Generation Antipsychotics
Drug

Diabetes

Weight
Gain

Extrapyramidal
Symptoms

QTc
Prolongation

Elevated
Prolactin

Aripiprazole
Asenapine*
Clozapine
Iloperidone*
Lurasidone*
Olanzapine
Paliperidone
Quetiapine
Risperidone
Ziprasidone

+/
+
++++
++
+/
++++
++
++
++
+/

+
++
++++
++
+/
++++
+++
+++
+++
+/

++
++
+/
+/
++
+
++
+/
+++
+

+/
+
+
++
+/
+
+
+
+
++

+/
++
+/
+/
+/
+
+++
+/
+++
+

*Limited experience

Clozapine causes granulocytopenia or agranulocytosis


in about 1% of patients, requiring weekly monitoring
of blood counts. Seizures occur in 1-4% of patients and
are dose-related. Increased salivation and enuresis
occur at higher doses. Gastrointestinal hypomotility,
which can be severe, marked sedation, diabetes,
weight gain and hyperlipidemia are common with
clozapine.49 Myocarditis, often occurring within the
first few weeks of treatment and sometimes fatal, has
been reported.50
Despite its structural similarity to clozapine, olanzapine
is much less likely to cause agranulocytosis or seizures.
It does cause weight gain and other metabolic effects,
including diabetes mellitus. Postural hypotension, somnolence, constipation, hyperlipidemia, dizziness and
akathisia can also occur. Increases in serum hepatic
transaminases have been reported.
The most common adverse effects of risperidone are
postural hypotension, insomnia, constipation, dizziness, prolactin elevation, hyperglycemia and weight
gain. At doses higher than 6 mg/day, the risk of
extrapyramidal symptoms increases without an additional increase in efficacy. The adverse effect profile of
paliperidone (9-hydroxyrisperidone) resembles that
of its parent compound risperidone, including
extrapyramidal symptoms, prolactin elevation, nausea,
somnolence, dizziness, tachycardia and QT interval
prolongation.51

Quetiapine commonly causes somnolence, dizziness,


constipation, postural hypotension, hyperglycemia and
weight gain. Though mentioned in the drugs package
insert with a recommendation for twice-yearly ophthalmologic monitoring, clinical use of quetiapine probably does not cause cataract formation.52
Ziprasidone seldom causes significant weight gain,
hyperlipidemia or hyperglycemia. Its adverse effects
have included mild to moderate somnolence, prolongation of the QT interval, extrapyramidal symptoms in
about 5% of patients and, occasionally, paradoxical
excitement.
Aripiprazole can cause anxiety, headache, nausea,
constipation, lightheadedness, agitation and akathisia.
It has a lower risk of hyperlipidemia, hyperglycemia or
hyperprolactinemia compared to most second-generation antipsychotics.53 It appears to cause less weight
gain than most other second-generation antipsychotics.
The most commonly reported adverse effects of asenapine are insomnia, somnolence, nausea, vomiting
and weight gain.54 Iloperidone causes orthostatic
hypotension, QT interval prolongation, dizziness, somnolence, dry mouth and weight gain, but is relatively
free of extrapyramidal effects.55 Lurasidone can cause
akathisia, nausea, extrapyramidal symptoms, agitation
and somnolence, but does not appear to increase
weight.56

Table 8. Some Second-Generation Antipsychotic Drug Interactions


Drug

Metabolism by CYP/P-gp

Comments

Aripiprazole
Asenapine
Clozapine
Iloperidone
Lurasidone

3A4, 2D6
1A2
1A2, 3A4, 2D6, 2C19
3A4, 2D6
3A4

Olanzapine

1A2, 2D6 and P-gp

Paliperidone
Quetiapine
Risperidone
Ziprasidone

2D6, P-gp
3A4
3A4, 2D6 and P-gp
3A4

Dose adjustments required with strong 3A4 or 2D6 inhibitors and with 3A4 inducers
Low potential for interactions
Many interactions, primarily with 1A2 inhibitors and inducers
Dose adjustments required with strong 3A4 or 2D6 inhibitors
Contraindicated with strong 3A4 inducers and inhibitors; dose adjustments required
with moderate 3A4 inhibitors
Low potential for interactions; serum concentrations altered by strong 1A2 inhibitors
or inducers
Low potential for interactions
Dose adjustments required with strong 3A4 inducers and inhibitors
Dose adjustments required with 3A4 or 2D6 inhibitors and 3A4 inducers
Serum concentrations modestly effected by 3A4 inhibitors and inducers

62

Treatment Guidelines from The Medical Letter Vol. 11 ( Issue 130) June 2013

Drugs for Psychiatric Disorders

PREGNANCY Data on use of antipsychotic drugs


during pregnancy are limited. None have been proven
to be teratogenic. Chlorpromazine was once used to
treat morning sickness, apparently without teratogenesis. Only clozapine and lurasidone are classified as category B for use during pregnancy (no human data; animal data suggest no risk); all the other antipsychotics
are category C (adverse effects in animals or no animal
reproductive studies, and no adequate studies in
humans). The risks of hyperglycemia and weight gain
are greater with the second-generation antipsychotics,
which have been associated with high birth weight and
babies that are large for gestational age.34
CHOICE OF DRUGS Clozapine is the most effective antipsychotic drug, but it should be reserved for
refractory disease because of its potential for serious
hematologic toxicity and strict monitoring requirements. Olanzapine may have some slight advantages
over other drugs in efficacy, but its adverse effects on
weight and metabolism may be unacceptable for longterm use. Other second-generation antipsychotics are
not clearly more effective than first-generation drugs,
but they have a lower risk of tardive dyskinesia. Some
patients who do not respond to one antipsychotic may
respond to another. Long-acting injectable antipsychotics may be useful when adherence is a problem.
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29. LA Smith et al. Valproate for the treatment of acute bipolar depression:
systematic review and meta-analysis. J Affect Disord 2010; 122:1.
30. YW Shi et al. Association between HLA and Stevens-Johnson syndrome
induced by carbamazepine in Southern Han Chinese: genetic markers
besides B*1502? Basic Chem Pharmacol Toxicol 2012; 111:58.
31. P Cacoub et al. The DRESS syndrome: a literature review. Am J Med
2011; 124:588.
32. SH Joe et al. Feasibility of a slower lamotrigine titration schedule for
bipolar depression: a naturalistic study. Int Clin Psychopharmacol 2009;
24:105.
33. FDA Drug Safety Communication: valproate anti-seizure products contraindicated for migraine prevention in pregnant women due to decreased IQ
scores in exposed children. Available at www.fda.gov/Drugs/DrugSafety
/ucm350684.htm. Accessed May 12, 2013.
34. S Gentile. Antipsychotic therapy during early and late pregnancy. A systematic review. Schizophr Bull 2010; 36:518.
35. RJ Baldessarini. Chemotherapy in Psychiatry, third edition. New York:
Springer Press 2013.
36. S Leucht et al. Maintenance treatment with antipsychotic drugs for
schizophrenia. Cochrane Database Syst Rev 2012; 5:CD008016.
37. S Leucht et al. Second-generation versus first-generation antipsychotic
drugs for schizophrenia: a meta-analysis. Lancet 2009; 373:31.
38. L Hartling et al. Antipsychotics in adults with schizophrenia: comparative effectiveness of first-generation versus second-generation medications: a systematic review and meta-analysis. Ann Intern Med
2012;157:498.
39. HY Meltzer et al. Clozapine treatment for suicidality in schizophrenia:
International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry
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40. J Tiihonen et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009;
374:620.
41. S Leucht et al. A meta-analysis of head-to-head comparisons of secondgeneration antipsychotics in the treatment of schizophrenia. Am J
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Treatment Guidelines from The Medical Letter Vol. 11 ( Issue 130) June 2013

63

Drugs for Psychiatric Disorders


disorder. Med Lett Drugs Ther 2010; 52:9.
43. Iloperidone (Fanapt) - another second-generation antipsychotic. Med
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44. Lurasidone (Latuda) for schizophrenia. Med Lett Drugs Ther 2011;
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45. R Emsley et al. Long-acting injectable antipsychotics in early psychosis: a literature review. Early Interv Psychiatry Jan 2013 (epub
ahead of print).
46. O Freudenreich and JP McEvoy. Optimizing outcome with antipsychotic treatment in first-episode schizophrenia: balancing efficacy and
side effects. Clin Schizophr Relat Psychoses 2012; 6:115.
47. CU Correll and EM Schenk. Tardive dyskinesia and new antipsychotics. Curr Opin Psychiatry 2008; 21:151.
48 R Liperoti et al. All-cause mortality associated with atypical and conventional antipsychotics among nursing home residents with dementia:
a retrospective cohort study. J Clin Psychiatry 2009; 70:1340.
49. J Fitzsimons et al. A review of clozapine safety. Expert Opin Drug Saf
2005; 4:731.
50. KJ Ronaldson et al. Clinical course and analysis of ten fatal cases of
clozapine-induced myocarditis and comparison with 66 surviving
cases. Schizophr Res 2011; 128:161.
51. R Emsley et al. Efficacy and safety of oral paliperidone extendedrelease tablets in the treatment of acute schizophrenia: pooled data from
three 52-week open-label studies. Int Clin Psychopharmacol 2008;
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52. FW Fraunfelder. Twice-yearly exams unnecessary for patients taking
quetiapine. Am J Ophthalmol. 2004; 138:870.
53. CU Pae. A review of the safety and tolerability of aripiprazole. Expert
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54. J Weber and PL McCormack. Asenapine. CNS Drugs 2009; 23:781.
55. JM Kane et al. Long-term efficacy and safety of iloperidone: results
from 3 clinical trials for the treatment of schizophrenia. J Clin
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56. L Citrome. Lurasidone for schizophrenia: a review of the efficacy and
safety profile for this newly approved second-generation antipsychotic.
Int J Clin Pract. 2011; 65:189.

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Correction: Drugs for Pain (Treat Guidel Med Lett


2013; 11:31)
In Table 1 on pages 32 and 33 the price for IV ibuprofen
(Caldolor) has been revised.

64

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Issue 130 Questions


1. First-line treatments for major depression include:
a. SSRIs
b. SNRIs
c. bupropion
d. all of the above
2. The only SSRI FDA-approved for treatment of major depressive
disorder in children is:
a. sertraline
b. fluoxetine
c. citalopram
d. paroxetine
3. A 33-year-old woman with depression has been taking paroxetine.
She is considering becoming pregnant. Which of the following could
you tell her about treatment of depression during pregnancy?
a. paroxetine is classified as category D for use during pregnancy
b. untreated depression has not been associated with preterm
birth
c. all antidepressants are classified as category A for use during pregnancy
d. all of the above
4. The antidepressant least likely to cause sexual side effects is:
a. bupropion
b. fluoxetine
c. amitriptyline
d. venlafaxine
5. The drug of choice for maintenance treatment of bipolar disorder
is:
a. sertraline
b. lithium
c. carbamazepine
d. lorazepam
6. A 64-year-old otherwise healthy woman with bipolar disorder has
had multiple relapses because she forgets to take her daily doses
of quetiapine. Which of the following long-acting injectable
antipsychotics is FDA-approved for maintenance treatment of
bipolar disorder?
a. olanzapine
b. aripiprazole
c. risperidone
d. paliperidone

7. Which of the following drugs is not recommended as monotherapy


for maintenance treatment of bipolar disorder?
a. lithium
b. lamotrigine
c. risperidone
d. citalopram
8. A higher incidence of Stevens-Johnson syndrome has been
reported in some patients of Asian ancestry taking:
a. carbamazepine
b. olanzapine
c. aripiprazole
d. lithium
9. Negative symptoms of schizophrenia include:
a. apathy
b. social withdrawal
c. blunted affect
d. all of the above
10. All second-generation antipsychotics have a FDA-required warning label about:
a. thrombocytopenia
b. hyperglycemia
c. gastrointestinal bleeding
d. hypotension
11. A 19-year-old woman newly diagnosed with schizophrenia is very
concerned about possible weight gain associated with antipsychotic treatment. Which of the following might be a good option for
her?
a. clozapine
b. ziprasidone
c. quetiapine
d. olanzapine
12. Which of the following antipsychotics is thought to be the most
effective in preventing suicide and may be effective in patients
who have not responded to other antipsychotics?
a. haloperidol
b. clozapine
c. lurasidone
d. loxapine

ACPE UPN: 0379-0000-13-130-H01-P; Release: May 2013, Expire: May 2014

Treatment Guidelines from The Medical Letter Vol. 11 ( Issue 130) June 2013