Drugs for psychiatric disorders

Data on long-term behavioral effects of in utero anti-depressant exposure are limited; one retrospective study found delays in sitting and walking but within the normal range in childre

Treatment Guidelines

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IN THIS ISSUE (starts on next page)

Drugs for Psychiatric Disorders p 53

Drugs for Psychiatric Disorders

Tables

4 Antimanic and Anticonvulsant Drug Interactions Page 59

7 Relative Adverse Effects of Second-Generation Page 62 Antipsychotics

8 Second-Generation Antipsychotic Drug Interactions Page 62

Treatment Guidelines

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

Drugs are not the only treatment for psychiatric

ill-ness 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

50-60% 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

con-vincing 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

advan-tage 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

promi-nent, and its appetite-stimulating and weight-gain-pro-moting 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

recep-tor agonist; limited data suggest it may be an effective antidepressant.2

Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) remain valuable

alterna-tives for patients with moderate to severe treatment-resistant 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 summa-rized in Table 2 Citalopram can cause significant QT interval prolongation.4 Escitalopram may also pro-long the QT interval.5

For further information call: 800-211-2769

Related article(s) since publication

Some Available Initial Adult Usual Adult

SSRIs

Citalopram – generic 10, 20, 40 mg tabs, caps; 20 mg once/d 40 mg once/d 3 $4.00 4

40 mg ODT; 10 mg/5mL PO soln

10 mg/5 mL PO soln Escitalopram – generic 5, 10, 20 mg tabs; 10 mg once/d 10-20 mg once/d 7.00

Fluoxetine – generic 10, 20, 40 mg caps; 10, 20, 60 mg 10-20 mg once/d 20 mg once/d 4.00 4

tabs; 20 mg/5 mL PO soln

Paroxetine hydrochloride – generic 10, 20, 30, 40 mg tabs; 20 mg once/d 20 mg once/d 4.00 4

extended release – generic 12.5, 25, 37.5 mg tabs 12.5-25 mg once/d 25 mg once/d 91.00

Paroxetine mesylate – Pexeva (Noven) 10, 20, 30, 40 mg tabs 10 mg once/d 20 mg once/d 204.00 Sertraline – generic 25, 50, 100, 150, 200 mg tabs; 25-50 mg once/d 50-100 mg once/d 5.00

20 mg/mL PO conc

20 mg/mL PO conc

SNRIs

Desvenlafaxine succinate – Pristiq (Pfizer) 50, 100 mg ER tabs 50 mg once/d 50 mg once/d 161.00 Desvenlafaxine – generic (Alembic) 50, 100 mg ER tabs 50 mg once/d 50 mg once/d 139.00 Duloxetine – Cymbalta (Lilly) 20, 30, 60 mg delayed-release 30-60 mg once/d 60 mg once/d or 199.00

Venlafaxine – generic 25, 37.5, 50, 75, 100 mg tabs 25 mg tid 75 mg tid 64.00 extended release – generic 37.5, 75, 150 mg caps; 37.5, 75, 37.5 mg once/d 225 mg once/d 240.00

150, 225 mg tabs

TCAs

Amitriptyline – generic 10, 25, 50, 75, 100, 150 mg tabs 50-100 mg once/d 150 mg once/d 5.00

or divided Desipramine – generic 10, 25, 50, 75, 100, 150 mg tabs 50-100 mg once/d 150 mg once/d 151.00

Imipramine – generic 10, 25, 50 mg tabs 25-50 mg once/d 100-150 mg once/d 20.00

Imipramine pamoate – generic 75, 100, 125, 150 mg caps 75 mg once/d 150 mg once/d 348.00

Nortriptyline – generic 10, 25, 50, 75 mg caps 75-100 mg once/d 150 mg once/d 14.00

MAOIs

Isocarboxazid – Marplan (Validus) 10 mg tabs 10 mg bid 30-40 mg/d divided 260.00

Selegiline – Emsam (Somerset) 6, 9, 12 mg/24 hr patches 6 mg/24 hr 6, 9, 12 mg/24 hr 594.00

Other

extended release (12 hour) – generic 100, 150, 200 mg tabs 150 mg once/d 150 mg bid 37.00

extended release (24 hour) – generic 150, 300 mg tabs 150 mg once/d 300 mg once/d 38.00

Mirtazapine – generic 7.5, 15, 30, 45 mg tabs 15 mg once/d at hs 30-45 mg once/d 20.00

Nefazodone 6 – generic 50, 100, 150, 200, 250 mg tabs 100 mg bid 200 mg bid 35.00 Trazodone – generic 50, 100, 150, 300 mg tabs 75 mg bid 300 mg divided bid 16.00 extended release – Oleptro (Labopharm) 150, 300 mg tabs 150 mg once/d 150-375 mg once/d 96.00 Vilazodone – Viibryd (Forest) 10, 20, 40 mg tabs 10 mg once/d 40 mg once/d 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.

Table 1 Some Drugs for Depression

When SSRIs are stopped abruptly, discontinuation

symptoms including nervousness, anxiety, irritability,

electric-shock sensations, bouts of crying or

tearful-ness, dizzitearful-ness, lightheadedtearful-ness, 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

flu-oxetine because of its long half-life

SNRIs – The adverse effects of venlafaxine,

desven-lafaxine and duloxetine are similar to those of SSRIs, but

can also include increased sweating, tachycardia and

uri-nary retention Severe discontinuation symptoms can

occur when these drugs are stopped, especially with

ven-lafaxine and desvenven-lafaxine because of their short

half-lives 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

report-ed in patients taking venlafaxine or desvenlafaxine

Other Drugs – TCAs commonly cause

anticholiner-gic effects (urinary retention, constipation, dry mouth,

blurred vision and confusion), orthostatic

hypoten-sion, 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

hyperten-sive crisis, either of which can be fatal The

enzyme-inhibiting 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 reac-tions 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 neu-tropenia 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

drowsi-ness, orthostatic hypotension and priapism

Nefazodone has caused somnolence, dry mouth,

nau-sea, dizziness and rarely, hepatic failure requiring liver transplantation, which has led to its withdrawal from the market in Canada and Europe and discontin-uation of the branded version in the US

Suicidality – All antidepressants carry a boxed

warn-ing 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 chil-dren, 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 trials summarized by the FDA), and the subject continues to be debated All depressed chil-dren, adolescents and adults, whether they are treated with drugs or not, should be monitored for suicidal ideation and behavior

Citalopram Metabolized by 2C19 1 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 2C19 1 and 3A4 Low potential for interactions; dose adjustments may be needed with 2C19

inhibitors; may prolong the QT interval Fluoxetine Metabolized by 2D6 1 and 2C9 May decrease efficacy of tamoxifen; may increase concentrations of 2D6 substrates;

Strong inhibitor of 2D6 long half-life is a problem when interactions occur Moderate inhibitor of 2C19

Strong inhibitor of 2D6 lower doses of paroxetine may be needed with 2D6 inhibitors

Moderate inhibitor of 2D6 Venlafaxine Metabolized by 2D6 1 and 3A4 Low potential for interactions; serum concentrations may be increased by 3A4 inhibitors Desvenlafaxine Metabolized by 3A4 Low potential for interactions; reduce dose of 2D6 substrates if administered with

Duloxetine Metabolized by 1A2 1 and 2D6 Avoid strong inhibitors of 1A2; 2D6 inhibitors can increase duloxetine concentrations;

Moderate inhibitor of 2D6 duloxetine increases concentrations of drugs that are substrates of 2D6

1 Primary pathway

Table 2 Some SSRI and SNRI Drug Interactions

Serotonin Syndrome – All serotonergic drugs can

cause serotonin syndrome, a rare but potentially

life-threatening condition characterized by altered mental

status, fever, tachycardia, hypertension, agitation,

tremor, myoclonus, hyperreflexia, ataxia,

incoordina-tion, diaphoresis, shivering and gastrointestinal

symp-toms 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

with-in 2 weeks of each other Some drugs with MAOI

activ-ity, such as the antimicrobial agent linezolid (Zyvox),

and some serotonergic drugs, such as the cough

sup-pressant dextromethorphan, sumatriptan (Imitrex, and

generics), tramadol (Ultram, and generics), methadone

and St John’s wort, may not be recognized as

seroton-ergic, 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

histo-ry of mania, hypomania or other evidence of bipolar

disorder before starting antidepressant therapy

PREGNANCY — Both untreated maternal

depres-sion and use of SSRIs in pregnancy have been

associ-ated 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

classi-fied as pregnancy category C (adverse fetal effects in

animals or no animal reproductive studies, and no

adequate human studies) Overall, the risk of

congen-ital malformations after taking an SSRI during

preg-nancy appears to be very low.15,16 One study that

con-trolled for maternal characteristics found no increase

in perinatal mortality among a cohort of women

treat-ed with SSRIs.17

Pregnancy studies with SNRIs are limited,13but

expo-sure during the third trimester may cause a self-limited

neonatal behavioral syndrome TCA use in late

preg-nancy has been associated with jitteriness and

convul-sions 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

clinicians recommend that they not be used Data on the safety of other classes of antidepressants during preg-nancy are lacking

Data on long-term behavioral effects of in utero

anti-depressant exposure are limited; one retrospective study found delays in sitting and walking (but within the normal range) in children exposed to antidepres-sants 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 clini-cians switch to another antidepressant, combine two antidepressants of different classes, such as an SSRI and bupropion, or add another drug, such as a second-generation antipsychotic.19 MAOIs should not be added to an SSRI or SNRI or to another MAOI because of the risk of serotonin syndrome

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

citalo-pram, 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

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

treat-ment of major depressive disorder A fixed-dose

com-bination of olanzapine and fluoxetine is

FDA-approved for treatment-resistant depression

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

episodes, long-term maintenance therapy can reduce

the risk of recurrence

NON-DRUG THERAPY — Psychotherapy,

particu-larly cognitive behavioral therapy (CBT) and

inter-personal therapy (IPT), is an effective treatment for

depression ECT is highly effective for severe

depres-sion, 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

rea-sonable treatment option when patients are unable to

tolerate or do not respond to antidepressant

medica-tions, 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

mainte-nance treatment, recurrences of manic or (more

fre-quently) 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

carba-mazepine 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

val-proate, 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

combi-nation with lithium A long-acting form of

risperi-done, 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 olanzap-ine and fluoxetolanzap-ine 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

depend-ence 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

lithi-um, even when serum concentrations are in the

rec-ommended 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 propra-nolol 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

lithi-um 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 caf-feine, 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

Some Available Initial Adult Usual Adult

Antimanic Agent

Anticonvulsants

100 mg/5 mL susp 7

100 mg/5 mL susp 7

Valproate 12

Second-Generation Antipsychotics

1 mg/mL soln 14,15

Combination

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-pricing-policy 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 solu-tion 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.

Table 3 Some Oral Drugs for Bipolar Disorder

hepatic transaminases are common; fatal

hepatotoxic-ity 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,

hyperam-monemic encephalopathy and agranulocytosis

Adverse effects of carbamazepine include rash,

dizzi-ness, diplopia, nausea, somnolence, headache,

hypona-tremia, elevated transaminases and, rarely,

Stevens-Johnson syndrome, agranulocytosis and aplastic

ane-mia Han Chinese may have a ten-fold increased risk

of Stevens-Johnson syndrome because of genetic

vul-nerability.30 Eosinophilia and hepatic toxicity

(“DRESS Syndrome”) have been reported.31 Because

of the many drug interactions that occur with

carba-mazepine, oxcarbazepine, which causes less induction

of hepatic enzymes, may be used instead

Adverse effects of lamotrigine include nausea,

dizzi-ness 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-titra-tion of the dose may minimize the risk of rash.32

Second-generation antipsychotics can cause

somno-lence, weight gain, diabetes, extrapyramidal

symp-toms, QT prolongation and elevated prolactin levels

(see Table 7)

MONITORING — Lithium has a narrow therapeutic

window and requires careful monitoring Serum

lithi-um 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

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 concen-trations 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 neurocogni-tive development with measurable impairment of IQ.33

Unless there is no alternative, it should not be used during pregnancy

Carbamazepine is not recommended for use during

preg-nancy, 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

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

Data on use of second-generation antipsychotics

dur-ing 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 recur-rent depressive episodes Lithium, valproate, and sec-ond-generation antipsychotics are similarly effective

for treatment of mania Quetiapine or a combination

of olanzapine and fluoxetine are effective for

treat-ment of depression in patients with bipolar disorder.

Lamotrigine may also be effective for treatment of bipolar depression

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.

Lithium 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 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.

Table 4 Some Antimanic and Anticonvulsant Drug Interactions

PSYCHOTIC DISORDERS

The oral antipsychotic drugs used for treatment of

schiz-ophrenia, 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

non-pharmacological services (rehabilitation, psychotherapy,

education and intensive case management) can interfere

with patient adherence to these medications

EFFECTIVENESS — Antipsychotic drugs are

gener-ally more effective for treating the “positive symptoms”

of schizophrenia (agitation, hallucinations and

delu-sions) than the “negative symptoms” (apathy, social

withdrawal and blunted affect).35 Some symptoms of

schizophrenia and acute psychoses may improve

rapid-ly 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

aripipra-zole, quetiapine, risperidone and ziprasidone in

reduc-ing 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

safe-ty relative to other drugs in the class remain to be

established

Parenteral – The long-acting parenteral

antipsy-chotics 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,

olanzap-ine and aripiprazole are limited Short-acting

parenter-al 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

ADVERSE EFFECTS — First-Generation – All

first-generation antipsychotic drugs have been associ-ated with sexual dysfunction, hyperprolactinemia, neu-roleptic 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 anticholiner-gic 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

sedat-ing than chlorpromazine and somewhat less likely than haloperidol or fluphenazine to cause extrapyramidal symptoms

Table 5 Some Parenteral Antipsychotics

Long-Acting 1

First-Generation

Haloperidol decanoate – 10-15 times previous

Second-Generation

Abilify Maintena (Otsuka/Lundbeck)

Zyprexa Relprevv (Lilly) or 300-405 mg IM q4 wks

Invega Sustenna (Janssen)

Risperdal Consta (Janssen)

Short-Acting 5

First-Generation

generic

Second-Generation

(BMS/Otsuka)

1 Dosage for schizophrenia, based on patient’s stable oral maintenance dosage.

2 Approximate wholesale acquisition cost (WAC) for 4 weeks’ or 1 month’s treat-ment with the lowest usual adult dosage for long-acting, or cost of a single injec-tion 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.

Second-Generation – Second-generation

antipsy-chotics have a relatively low risk of extrapyramidal

effects, and are probably less likely than

first-genera-tion antipsychotics to cause tardive dyskinesia and

neuroleptic malignant syndrome.47 Some

second-gen-eration drugs (particularly clozapine, olanzapine and

quetiapine) cause more weight gain than others The

FDA requires the manufacturers of all second-genera-tion 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

Table 6 Oral Antipsychotics

First-Generation

5 mg/mL conc

2 mg/mL soln

doses

Second-Generation

orally disintegrating –

(Sunovion)

extended release –

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 solu-tion 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.