drugs for psychiatric disorders med letter tx 2013

Treatment Guidelinesfrom The Medical Letter

Published by The Medical Letter, Inc. 145 Huguenot Street, New Rochelle, NY 10801 A Nonprofit Publication

FORWARDING OR COPYING IS A VIOLATION OF US AND INTERNATIONAL COPYRIGHT LAWS

The Medical Letter publications are protected by US and international copyright laws.Forwarding, copying or any distribution of this material is prohibited.

Sharing a password with a non-subscriber or otherwise making the contents of this site availableto third parties is strictly prohibited.

By accessing and reading the attached content I agree to comply with US and internationalcopyright laws and these terms and conditions of The Medical Letter, Inc.

For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769

Important Copyright Message

IN THIS ISSUE (starts on next page)

Drugs for Psychiatric Disorders.........................................p 53

53Federal copyright law prohibits unauthorized reproduction by any means and imposes severe fines.

Drugs for Psychiatric Disorders

Tables1. Drugs for Depression Page 542. SSRI and SNRI Drug Interactions Page 553. Oral Drugs for Bipolar Disorder Page 584. Antimanic and Anticonvulsant Drug Interactions Page 595. Parenteral Antipsychotics Page 606. Oral Antipsychotics Page 617. Relative Adverse Effects of Second-Generation Page 62

Antipsychotics8. Second-Generation Antipsychotic Drug Interactions Page 62


Published by The Medical Letter, Inc. 145 Huguenot Street, New Rochelle, NY 10801 A Nonprofit Publication

Volume 11 (Issue 130) June 2013www.medicalletter.orgTake CME exams

Drugs are not the only treatment for psychiatric ill-ness. Psychotherapy remains an important componentin the management of these disorders, and cognitivebehavioral therapy (CBT) can be used for many ofthem as well. Electroconvulsive therapy (ECT) has along history of efficacy and safety when drugs areineffective or cannot be used.

DRUGS FOR DEPRESSION

Most of the drugs approved by the FDA for treatmentof depression are listed in Table 1. Improvement canoccur within the first 2 weeks of drug therapy, but itmay take 4-8 weeks to achieve substantial benefit.Antidepressant drugs produce a response in about 50-60% of adults with major depression and a remissionin about 30%; with multiple courses and/or multipledrugs, 80% of patients will eventually respond, at leasttemporarily.

SSRIs AND SNRIs Selective serotonin reuptakeinhibitors (SSRIs) are recommended for first-linetreatment of major depression. They are generallywell tolerated and relatively safe. There is no con-vincing evidence that any one SSRI is more effectivethan any other. Fluoxetine is the only SSRI approvedby the FDA for treatment of major depressivedisorder in children and adolescents. Escitalopram,the active enantiomer of citalopram, is approved fortreatment of depression in adolescents. Serotonin andnorepinephrine reuptake inhibitors (SNRIs) are alsoconsidered a first-line option for treatment of majordepression. It is not clear that they offer any advan-tage in efficacy over SSRIs.

OTHER DRUGS Bupropion can be used as analternative to an SSRI for depressed patients who donot have severe anxiety. It is activating rather thansedating 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 patientswith marked anorexia. Trazodone, which is alsosedating, is commonly used in a low dose as anadjunct to an SSRI in patients with insomnia.1Vilazodone is an SSRI and partial serotonin 1a recep-tor agonist; limited data suggest it may be an effectiveantidepressant.2

Tricyclic antidepressants (TCAs) and monoamineoxidase inhibitors (MAOIs) remain valuable alterna-tives for patients with moderate to severe treatment-resistant depression.

ADVERSE EFFECTS SSRIs Jitteriness andsleep disturbances can occur during treatment with anSSRI. Other adverse effects include nausea, diarrhea,headache, dizziness, fatigue and sexual dysfunction(including decreased libido, impaired arousal andanorgasmia). An increase in motor activity is morecommon in children. The long-term effects of thesedrugs on the growth, personality development andbehavior of children are unknown.

Some patients gain significant amounts of weightwith continued use of an SSRI. SSRIs can causehyponatremia, particularly in elderly patients. Theyhave been associated with a possible increase in therisk of nonvertebral fractures in older women.3SSRIs can also increase the risk of bleeding byinhibiting serotonin uptake by platelets. SSRIs havea variety of effects on CYP450 isoenzymes and mayinteract with many other drugs; these are summa-rized in Table 2. Citalopram can cause significant QTinterval prolongation.4 Escitalopram may also pro-long the QT interval.5

The Medical Letter publications are protected by US and international copyright laws.Forwarding, copying or any other distribution of this material is strictly prohibited.

For further information call: 800-211-2769


Treatment Guidelines from The Medical Letter Vol. 11 ( Issue 130) June 201354

Some Available Initial Adult Usual AdultDrug Formulations Dosage1 Dosage1 Cost2

SSRIsCitalopram generic 10, 20, 40 mg tabs, caps; 20 mg once/d 40 mg once/d3 $4.004

40 mg ODT; 10 mg/5mL PO solnCelexa (Forest) 10, 20, 40 mg tabs; 145.00

10 mg/5 mL PO solnEscitalopram generic 5, 10, 20 mg tabs; 10 mg once/d 10-20 mg once/d 7.00

Lexapro (Forest) 5 mg/5 mL PO soln 143.00Fluoxetine generic 10, 20, 40 mg caps; 10, 20, 60 mg 10-20 mg once/d 20 mg once/d 4.004

tabs; 20 mg/5 mL PO solnProzac (Lilly) 10, 20, 40 mg caps 211.00

delayed release generic 90 mg cap 90 mg 1x/wk 90 mg 1x/wk 110.00Prozac Weekly 145.00

Paroxetine hydrochloride generic 10, 20, 30, 40 mg tabs; 20 mg once/d 20 mg once/d 4.004Paxil (GSK) 10 mg/5 mL PO susp 121.00

extended release generic 12.5, 25, 37.5 mg tabs 12.5-25 mg once/d 25 mg once/d 91.00Paxil CR 128.00

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

20 mg/mL PO concZoloft (Pfizer) 25, 50, 100 mg tabs; 141.00

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

caps divided bidVenlafaxine 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 240.00150, 225 mg tabs

Effexor XR (Pfizer) 37.5, 75, 150 mg caps 522.00TCAsAmitriptyline generic 10, 25, 50, 75, 100, 150 mg tabs 50-100 mg once/d 150 mg once/d 5.00

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

Norpramin (Sanofi) or divided or divided 205.00Imipramine generic 10, 25, 50 mg tabs 25-50 mg once/d 100-150 mg once/d 20.00

Tofranil (Mallinckrodt) or divided 349.00Imipramine pamoate generic 75, 100, 125, 150 mg caps 75 mg once/d 150 mg once/d 348.00

Tofranil PM or divided 549.00Nortriptyline generic 10, 25, 50, 75 mg caps 75-100 mg once/d 150 mg once/d 14.00

Pamelor (Mallinckrodt) or divided 1399.00MAOIsIsocarboxazid Marplan (Validus) 10 mg tabs 10 mg bid 30-40 mg/d divided 260.00Phenelzine generic 15 mg tabs 15 mg tid 30 mg bid 72.00

Nardil (Pfizer) 132.00Selegiline Emsam (Somerset) 6, 9, 12 mg/24 hr patches 6 mg/24 hr 6, 9, 12 mg/24 hr 594.00Tranylcypromine generic 10 mg tabs 10 mg once/d 20-30 mg bid 323.00

Parnate (Covis) 673.00OtherBupropion generic 75, 100 mg tabs 100 mg bid 100 mg tid 63.00

Wellbutrin (GSK) 266.00extended release (12 hour) generic 100, 150, 200 mg tabs 150 mg once/d 150 mg bid 37.00

Wellbutrin SR 233.00Aplenzin (Sanofi) 174, 348, 522 mg ER tabs 174 mg once/d 348 mg once/d 395.00

extended release (24 hour) generic 150, 300 mg tabs 150 mg once/d 300 mg once/d 38.00Wellbutrin XL 319.00Forfivo XL (Edgemont) 450 mg ER tabs See footnote 5 450 mg once/d 135.00

Mirtazapine generic 7.5, 15, 30, 45 mg tabs 15 mg once/d at hs 30-45 mg once/d 20.00Remeron (Organon) 15, 30, 45 mg tabs 130.00

orally disintegrating generic 15, 30, 45 mg ODT 57.00Remeron SolTab 104.00

Nefazodone6 generic 50, 100, 150, 200, 250 mg tabs 100 mg bid 200 mg bid 35.00Trazodone 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 96.00Vilazodone Viibryd (Forest) 10, 20, 40 mg tabs 10 mg once/d 40 mg once/d 138.00ODT = orally disintegrating tablet; ER = extended-release1. 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, discontinuationsymptoms including nervousness, anxiety, irritability,electric-shock sensations, bouts of crying or tearful-ness, dizziness, lightheadedness, insomnia, confusion,trouble concentrating, nausea and vomiting can occur;these effects are most severe with paroxetine becauseof 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, butcan also include increased sweating, tachycardia and uri-nary retention. Severe discontinuation symptoms canoccur when these drugs are stopped, especially with ven-lafaxine and desvenlafaxine because of their short half-lives. SNRIs can cause a dose-dependent increase inblood pressure; blood pressure should be under controlbefore starting an SNRI and monitored during treatment.False-positive urine immunoassay screening tests forphencyclidine (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 canlead to arrhythmias. TCAs are more dangerous thanSSRIs in overdose.

Adverse effects of MAOIs include sleep disturbance,orthostatic hypotension, sexual dysfunction andweight gain. Interactions with serotonergic drugs,bupropion, sympathomimetics, and tyramine-richfoods 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 2weeks 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 iscontraindicated in patients with eating disordersbecause such patients have a higher incidence ofseizures when treated with bupropion. Mirtazapinecan cause sedation, increased appetite, weight gain,dizziness, dry mouth and constipation; febrile neu-tropenia has occurred rarely.

Vilazodone has an adverse effect profile similar tothat of SSRIs; available evidence is insufficient tosupport claims that it causes less weight gain or lesssexual dysfunction.2 Trazodone can cause drowsi-ness, orthostatic hypotension and priapism.Nefazodone has caused somnolence, dry mouth, nau-sea, dizziness and rarely, hepatic failure requiringliver transplantation, which has led to its withdrawalfrom 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 antidepressantstudies, summarized in the package inserts of thesedrugs, found an increased risk of suicidality in chil-dren, adolescents and young adults (24 years old)being treated with an antidepressant. A recentCochrane review also found that antidepressantsincreased the risk of suicidal ideation and behavior inchildren and adolescents.6 No increase in completedsuicides has been demonstrated (there were no suicidesin the pediatric trails summarized by the FDA), and thesubject continues to be debated. All depressed chil-dren, adolescents and adults, whether they are treatedwith drugs or not, should be monitored for suicidalideation and behavior.

55

Drug CYP450 CommentsCitalopram 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 Low potential for interactions; dose adjustments may be needed with 2C19 inhibitors; may prolong the QT interval

Fluoxetine Metabolized by 2D61 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 occurModerate inhibitor of 2C19

Paroxetine Metabolized by 2D6 May decrease efficacy of tamoxifen; may increase concentrations of 2D6 substrates;Strong inhibitor of 2D6 lower doses of paroxetine may be needed with 2D6 inhibitors

Sertraline Metabolized by 2C19 Low potential for interactionsModerate inhibitor of 2D6

Venlafaxine Metabolized by 2D61 and 3A4 Low potential for interactions; serum concentrations may be increased by 3A4 inhibitorsDesvenlafaxine Metabolized by 3A4 Low potential for interactions; reduce dose of 2D6 substrates if administered with

Weak inhibitor of 2D6 400 mg of desvenlafaxineDuloxetine Metabolized by 1A21 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 2D61. Primary pathway

Table 2. Some SSRI and SNRI Drug Interactions



Serotonin Syndrome All serotonergic drugs cancause serotonin syndrome, a rare but potentially life-threatening condition characterized by altered mentalstatus, fever, tachycardia, hypertension, agitation,tremor, myoclonus, hyperreflexia, ataxia, incoordina-tion, diaphoresis, shivering and gastrointestinal symp-toms. Serotonin syndrome occurs most commonly as aresult of interactions with other drugs.

Because of the risk of serotonin syndrome, serotonergicdrugs 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, andgenerics), tramadol (Ultram, and generics), methadoneand St. Johns wort, may not be recognized as seroton-ergic, but can cause serotonin syndrome when takenconcurrently with an SSRI or SNRI.7

Mania All antidepressants can induce mania, mostoften in patients with bipolar disorder. Patients shouldbe screened for personal or first-degree-relative histo-ry of mania, hypomania or other evidence of bipolardisorder 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 birthand low birth weight.8,9 Taking SSRIs in the thirdtrimester has been associated with a self-limitedneonatal behavioral syndrome, treatment in a neonatalintensive care unit, and a possible risk of persistentpulmonary hypertension.10,11 Paroxetine is classifiedas category D (positive evidence of human fetal risk)for use during pregnancy because of an increased riskof cardiovascular and other malformations in infantsborn to mothers taking it in the first trimester.12 Thesafety of other SSRIs in the first trimester has alsobeen questioned13,14; all except paroxetine are classi-fied as pregnancy category C (adverse fetal effects inanimals or no animal reproductive studies, and noadequate 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 increasein perinatal mortality among a cohort of women treat-ed with SSRIs.17

Pregnancy studies with SNRIs are limited,13 but expo-sure during the third trimester may cause a self-limitedneonatal behavioral syndrome. TCA use in late preg-nancy has been associated with jitteriness and convul-sions in newborns. MAOIs are classified as category Cfor use during pregnancy, but because of the risk of druginteractions or foods causing a hypertensive crisis, some

56

clinicians recommend that they not be used. Data on thesafety 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 retrospectivestudy found delays in sitting and walking (but withinthe normal range) in children exposed to antidepres-sants during pregnancy.18

CHOICE OF DRUGS First-Line An SSRI, anSNRI, bupropion or mirtazapine could be used forfirst-line treatment of major depression, but mostexpert clinicians begin with an SSRI. The choiceamong SSRIs may be determined by adverse effectprofiles and differences in drug interactions. Takingthese and cost into consideration, generic sertraline orgeneric escitalopram would be a reasonable firstchoice for treatment of depression in adults. Genericfluoxetine would be a good choice for treatment ofdepressed children, adolescents or young adults.

Second-Line When patients show little to noresponse to an adequate trial of an SSRI, many clini-cians switch to another antidepressant, combine twoantidepressants of different classes, such as an SSRIand bupropion, or add another drug, such as a second-generation antipsychotic.19 MAOIs should not beadded to an SSRI or SNRI or to another MAOIbecause of the risk of serotonin syndrome.

In one controlled trial, among patients with majordepressive disorder who had not responded to or couldnot tolerate 12 weeks treatment with the SSRI citalo-pram, switching antidepressants to sustained-releasebupropion, sertraline or extended-release venlafaxineled to remissions in 26%, 27% and 28% of patients,respectively, but the study did not include a placebogroup or one that continued on citalopram.20

Augmentation with antipsychotic drugs may behelpful when the response to antidepressant agents isinadequate, but they can cause adverse effects such asweight gain or akathisia.21,22 Quetiapine and oralaripiprazole 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 iscomplete remission of symptoms; partial response isassociated with an increased risk of relapse. For a firstepisode of depression, many experts recommend thatantidepressant treatment continue at the same dose forat least 6-9 months following remission to consolidaterecovery. For patients with recurrent depressive



episodes, long-term maintenance therapy can reducethe risk of recurrence.

NON-DRUG THERAPY Psychotherapy, particu-larly cognitive behavioral therapy (CBT) and inter-personal therapy (IPT), is an effective treatment fordepression. ECT is highly effective for severe depres-sion, depression with psychosis or bipolar disorder,and depression refractory to drugs23; it can be usedduring pregnancy. Vagus nerve stimulation (VNS)and transcranial magnetic resonance stimulation(TMS) are FDA-approved for treatment-resistantdepression, but a short-term trial of VNS did not finda statistically significant response.24,25 TMS, unlikeECT, does not require anesthesia and does not appearto have cognitive side effects. Studies of TMS havedemonstrated response and remission rates similar tothose of antidepressant medications; it may be a rea-sonable treatment option when patients are unable totolerate or do not respond to antidepressant medica-tions, but it is expensive and time-consuming (3-5times a week for several weeks), and its efficacy hasbeen limited in patients who have not responded tomultiple medications.

DRUGS FOR BIPOLAR DISORDER

Some oral drugs for treatment of bipolar disorder arelisted 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 ofchoice for maintenance treatment of bipolar disorder.Antiepileptic drugs such as valproate and carba-mazepine are also widely used for maintenance despiteevidence suggesting that they are less effective thanlithium in preventing recurrence. The anticonvulsantlamotrigine is especially effective for prevention ofrecurrent depression in bipolar disorder. Maintenancetherapy with lithium alone or in combination with val-proate, carbamazepine or lamotrigine decreases the riskof recurrent manic and depressive episodes.

Second-generation antipsychotics may also beeffective in preventing recurrences of manic anddepressive episodes, especially when taken in combi-nation with lithium. A long-acting form of risperi-done, given intramuscularly every 2 weeks, has beenapproved by the FDA for maintenance treatment andmay be helpful for patients with frequent relapses,especially when adherence is an issue.

TREATMENT OF MANIA For treatment ofmania, lithium, valproate and second-generationantipsychotics have similar efficacy.27 Both lithium

and valproate may take days to weeks to have a fulltherapeutic effect; manic patients often requireadjunctive treatment with an antipsychotic drug ortemporary treatment with a benzodiazepine.

TREATMENT OF DEPRESSION Monotherapywith antidepressant drugs can precipitate mania inpatients with bipolar disorder and is not recommended.For treatment of depression in patients with bipolardisorder, lithium has protective effects against suicideand self-harm.28 The effectiveness of valproate intreating depression in bipolar patients is unclear.29 Theantipsychotic quetiapine or a combination of olanzap-ine and fluoxetine have been shown to be effective intreating depression in bipolar patients. Lamotriginemay also be effective for this indication.

ALTERNATIVES A benzodiazepine such aslorazepam (Ativan, and generics) may be helpful whenan adjunct is needed for insomnia, agitation or anxiety,but bipolar patients are at risk for substance depend-ence. Some clinicians have used clozapine to treatmania resistant to other drugs. ECT is effective fortreatment of both acute mania and acute depressionand may be particularly useful for drug-resistant maniaand in pregnant women.

ADVERSE EFFECTS Nausea and fatigue mayoccur 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 andweight gain may persist for the duration of treatment.Lithium-induced tremors can be treated by reducingthe dosage or adding a beta-blocker such as propra-nolol. Confusion and ataxia can occur. Toxic renaleffects, including tubular lesions, interstitial fibrosisand decreased creatinine clearance, have been reportedwith long-term use of lithium. Nephrogenic diabetesinsipidus can occur; it further increases the risk of lithi-um toxicity, and may be irreversible. Hypothyroidismcan occur with long-term lithium treatment and cancontribute to exacerbations of bipolar illness. Lithiummay cause mild leukocytosis, induce or exacerbatepsoriasis, and cause severe acne, folliculitis, hair lossand other skin reactions. Many commonly used drugs,including most NSAIDs (but not aspirin), ACEinhibitors and diuretics, can increase serum lithiumconcentrations 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, buttremor is less common than with lithium. Reversiblehair loss can occur. Thrombocytopenia may occur andappears to be dose-related. Transient elevations of

57



Some Available Initial Adult Usual AdultDrug Formulations Dosage1 Dosage1 Cost2Antimanic AgentLithium carbonate3,4 generic 150, 300, 600 mg caps; 300 mg tabs; 900-1800 mg 900-1200 mg $15.00

8 mEq/5 mL PO soln5 divided tid or qid divided tid or qidextended release generic 300, 450 mg tabs 900-1800 mg 900-1200 mg 24.00

Lithobid (Noven) 300 mg tab divided bid or tid divided bid or tid 240.00AnticonvulsantsCarbamazepine generic6 100, 200, 300, 400 mg tabs; 200-600 mg 600-1200 mg 9.008

100, 200 mg chewable tabs; divided tid-qid divided bid or tid100 mg/5 mL susp7

Tegretol (Novartis)6 200 mg tabs; 100 mg chewable tabs; 236.00100 mg/5 mL susp7

extended release generic6 100, 200, 400 mg tabs; 200-600 mg 600-1200 mg 89.00100, 200, 300 mg caps divided bid divided bid

Equetro (Validus)3,9 100, 200, 300 mg caps 200 mg bid 138.00Carbatrol (Shire)6 100, 200, 300 mg caps 200-600 mg 106.00Tegretol XR (Novartis)6 100, 200, 400 mg tabs divided bid 120.00

Lamotrigine generic4 25, 100, 150, 200 mg tabs; 25 mg once/d11 200 mg once/d 12.00Lamictal (GSK)4 2, 5, 25 mg chewable tabs10 252.00Lamictal ODT4 25, 50, 100, 200 mg ODT; 248.00

extended release generic6 25, 50, 100, 200, 250, 300 mg tabs 25 mg once/d11 200 mg once/d 350.00Lamictal XR6 416.00

Valproate12Valproic acid generic 250 mg cap; 250 mg/5 mL syrup 250 mg tid 1500-2000 mg 67.00

Depakene6 (Abbott) divided bid 607.00delayed release Stavzor3(Noven) 125, 250, 500 mg caps 750 mg/d divided 227.00

Divalproex sodium generic 125, 250, 500 mg tabs 750 mg/d divided 29.00Depakote3 (Abbott) 214.00Depakote Sprinkle6 125 mg cap 479.00

extended release Depakote ER 3 250, 500 mg tabs 25 mg/kg once/d13 25-40 mg/kg once/d13 412.00Second-Generation AntipsychoticsAripiprazole3,4,9 Abilify (BMS/Otsuka) 2, 5, 10, 15, 20, 30 mg tabs; 15 mg once/d 15-30 mg once/d 669.00

1 mg/mL soln14,15Abilify Discmelt 10,15 mg ODT 797.00

Asenapine Saphris (Merck)3,9 5, 10 mg sublingual tabs 10 mg bid 5-10 mg bid 690.00Olanzapine3,4,9 generic 2.5, 5, 7.5, 10, 15, 20 mg tabs15 10-15 mg once/d 5-20 mg once/d 29.00

Zyprexa (Lilly) 367.00orally disintegrating generic 5, 10, 15, 20 mg ODT 226.00

Zyprexa Zydis 397.00Quetiapine generic 25, 50, 100, 150 200, 300, 400 mg tabs 50-100 mg once/d 300-800 mg 89.00

Seroquel (AstraZeneca)3,4,16 25, 50, 100, 200, 300, 400 mg tabs or divided bid divided bid 754.00extended release Seroquel XR3,4,9,16 50, 150, 200, 300, 400 mg tabs 50-300 mg once/d 300-800 mg once/d 497.00

Risperidone3,9 generic 0.25, 0.5, 1, 2, 3, 4 mg tabs; 2-3 mg once/d 4-6 mg once/d 38.00Risperdal (Janssen) 1 mg/mL soln17 513.00

orally disintegrating generic 0.25, 0.5, 1, 2, 3, 4 mg ODT 373.00Risperdal M-Tab 0.5, 1, 2, 3, 4 mg ODT 616.00

Ziprasidone generic 20, 40, 60, 80 mg caps 40 mg bid 40-80 mg bid 237.00Geodon (Pfizer)3,4,9 543.00

CombinationOlanzapine/fluoxetine16 generic 3/25, 6/25, 6/50, 12/25, 12/50 mg 6/25 mg once in 6/25-12/50 mg once 348.00

Symbyax (Lilly) caps the evening in the evening 402.00ODT = orally disintegrating tablet1. 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 childrenand with use of multiple anticonvulsants. Polycysticovary syndrome has been reported. Rare idiosyncraticreactions 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 riskof Stevens-Johnson syndrome because of genetic vul-nerability.30 Eosinophilia and hepatic toxicity(DRESS Syndrome) have been reported.31 Becauseof the many drug interactions that occur with carba-mazepine, oxcarbazepine, which causes less inductionof hepatic enzymes, may be used instead.

Adverse effects of lamotrigine include nausea, dizzi-ness and somnolence. About 10% of patients developmild rash; severe, life-threatening rash, includingStevens-Johnson syndrome and toxic epidermalnecrolysis, 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 therapeuticwindow and requires careful monitoring. Serum lithi-um concentrations should be monitored every threemonths (every 6-12 months in a stable patient) tomaintain serum concentrations within the therapeuticrange and avoid toxicity. Concentrations should bemeasured about 12 hours after the last dose. For acutetreatment, target serum concentrations are 0.8 to 1.2mEq/L. For maintenance, serum concentrations shouldbe between 0.6 and 1.0 mEq/L. Thyroid and renalfunction should be monitored at baseline and every sixmonths. In addition to laboratory monitoring, patientsshould be monitored for clinical signs of toxicity suchas vomiting, diarrhea, tremor, lethargy, slurred speechand weakness.

Liver function and complete blood counts should bemonitored in patients taking valproate. Completeblood counts should be monitored in patients takingcarbamazepine.

PREGNANCY Lithium use during pregnancy hasbeen associated with congenital cardiac abnormalities;the absolute risk is low. High neonatal lithium concen-trations are a risk factor for lower Apgar scores, longerhospital stays, and reversible neurologic toxicity; therisk could be minimized or avoided by withholdingmaternal lithium for 24 hours before delivery.

Valproate taken during pregnancy can cause neonataltoxicity, neural tube defects, cardiac and other majorteratogenic effects, and adverse effects on neurocogni-tive development with measurable impairment of IQ.33Unless there is no alternative, it should not be usedduring pregnancy.

Carbamazepine is not recommended for use during preg-nancy, unless no alternatives exist, because of an increasedrisk of major malformations, including neural tubedefects, low birth weight, and fetal and neonatal vitamin Kdeficiency, which can lead to neonatal hemorrhage.

Data on use of lamotrigine during pregnancy areinconsistent; it appears to have a lower risk of adversefetal outcomes than valproate or carbamazepine, butmidline clefts have been reported.

Data on use of second-generation antipsychotics dur-ing pregnancy are limited; increased birth weight hasbeen reported.34

CHOICE OF DRUGS Lithium is generally thedrug of choice for maintenance treatment of bipolardisorder. Lamotrigine may be used to prevent recur-rent depressive episodes. Lithium, valproate, and sec-ond-generation antipsychotics are similarly effectivefor treatment of mania. Quetiapine or a combinationof olanzapine and fluoxetine are effective for treat-ment of depression in patients with bipolar disorder.Lamotrigine may also be effective for treatment ofbipolar depression.

59

Drug CommentsCarbamazepine 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 3A4inducers 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 disorderand other manifestations of psychosis or mania are listedin Table 6. Adverse effects such as movement disordersand metabolic effects, cost, and lack of access to non-pharmacological services (rehabilitation, psychotherapy,education and intensive case management) can interferewith patient adherence to these medications.

EFFECTIVENESS Antipsychotic drugs are gener-ally more effective for treating the positive symptomsof schizophrenia (agitation, hallucinations and delu-sions) than the negative symptoms (apathy, socialwithdrawal and blunted affect).35 Some symptoms ofschizophrenia and acute psychoses may improve rapid-ly after treatment with antipsychotic drugs, but chronicschizophrenia usually takes many weeks to respond;some patients may continue to improve for months.Maintenance treatment with antipsychotic medicationsreduces relapse rates in schizophrenia.36

Oral Second-generation antipsychotics are now usedmore commonly than first-generation drugs, eventhough controlled trials have failed to demonstrate aclear advantage in efficacy with the newer drugs,except for clozapine and possibly olanzapine.37,38

Clozapine can be effective for treatment of psychoticsymptoms in patients who have not responded to otherdrugs. It also appears to be more effective than otherantipsychotics in decreasing the risk of suicide.39,40Olanzapine appears to be more effective than aripipra-zole, quetiapine, risperidone and ziprasidone in reduc-ing psychotic symptoms.41

The more recently FDA-approved antipsychotic drugsasenapine,42 iloperidone43 and lurasidone44 may beeffective for some patients, but their efficacy and safe-ty relative to other drugs in the class remain to beestablished.

Parenteral The long-acting parenteral antipsy-chotics listed in Table 5 are generally used in patientswith a history of relapse due to poor adherence to oralmaintenance therapy. Data on the newer long-actingparenteral formulations such as paliperidone, olanzap-ine and aripiprazole are limited. Short-acting parenter-al antipsychotics can be helpful for rapid treatment ofacute psychotic agitation or mania.45

Inhaled The first-generation antipsychotic loxapinehas been approved by the FDA as a powder for oralinhalation (Adasuve) for acute treatment of agitationassociated with bipolar disorder or schizophrenia.

60

ADVERSE EFFECTS First-Generation Allfirst-generation antipsychotic drugs have been associ-ated with sexual dysfunction, hyperprolactinemia, neu-roleptic malignant syndrome and tardive dyskinesia.The risk of extrapyramidal symptoms and tardivedyskinesia with the first-generation agents may beminimized if dosing is targeted to the lowest dose atwhich fine, rather than coarse, extrapyramidal motoreffects first appear.46

Chlorpromazine commonly causes sedation, posturalhypotension and weight gain, as well as anticholiner-gic and occasional extrapyramidal adverse effects.Haloperidol and fluphenazine are less likely to causesedation, postural hypotension or anticholinergiceffects, but typically cause extrapyramidal symptoms.

Perphenazine and loxapine are generally less sedat-ing than chlorpromazine and somewhat less likely thanhaloperidol or fluphenazine to cause extrapyramidalsymptoms.Table 5. Some Parenteral AntipsychoticsDrug Usual Adult Dosage Cost2

Long-Acting1First-GenerationFluphenazine decanoate 12.5-25 mg IM $108.003

generic q2-3 wksHaloperidol decanoate 10-15 times previous

generic daily oral dose IM 32.004Haldol (Janssen) q4 wks 119.00

Second-GenerationAripiprazole 400 mg IM once/month 1450.00

Abilify Maintena (Otsuka/Lundbeck)

Olanzapine pamoate 150-300 mg IM q2 wks 795.00Zyprexa Relprevv (Lilly) or 300-405 mg IM q4 wks

Paliperidone palmitate 117-234 mg IM q4 wks 859.00Invega Sustenna (Janssen)

Risperidone 25-50 mg IM q2 wks 573.00Risperdal Consta (Janssen)

Short-Acting5First-GenerationChlorpromazine generic 25 mg IM 16.00Droperidol generic 2.5-5 mg IM 2.00Fluphenazine hydrochloride 1.25 mg IM 6.00

genericHaloperidol lactate generic 2-5 mg IM 2.00

Haldol (Janssen) 6.00Second-GenerationAripiprazole Abilify 9.75 mg IM 21.00

(BMS/Otsuka)Olanzapine generic 5-10 mg IM 16.00

Zyprexa (Lilly) 20.00Ziprasidone Geodon (Pfizer) 10-20 mg IM 9.001. Dosage for schizophrenia, based on patients stable oral maintenance dosage.2. Approximate wholesale acquisition cost (WAC) for 4 weeks or 1 months 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 fromFDB 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 extrapyramidaleffects, and are probably less likely than first-genera-tion antipsychotics to cause tardive dyskinesia andneuroleptic malignant syndrome.47 Some second-gen-eration drugs (particularly clozapine, olanzapine andquetiapine) cause more weight gain than others. The

FDA requires the manufacturers of all second-genera-tion antipsychotics to include product-label warningsabout hyperglycemia and diabetes, even though therisks are not equivalent for all drugs in the class, andabout an increased risk of death among elderly patientswith dementia.48 Table 7 lists some relative adverseeffects of second-generation antipsychotics.

61

Table 6. Oral AntipsychoticsSome Available Initial Usual

Drug Oral Formulations Adult Dosage Adult Dosage1 Cost2

First-GenerationChlorpromazine3 generic 10, 25, 50, 100, 200 mg tabs 10-50 mg bid 200 mg bid $140.00Fluphenazine3 generic 1, 2.5, 5, 10 mg tabs; 2.5-5 mg divided 10 mg once/d 11.00

2.5 mg/5 mL elixir; q6-8h5 mg/mL conc

Haloperidol3 generic 0.5, 1, 2, 5, 10, 20 mg tabs; 5 mg once/d or divided 5 mg bid 14.002 mg/mL soln

Loxapine4 generic 5, 10, 25, 50 mg caps 10 mg bid 60-100 mg in 2-4 129.00Loxitane (Watson) 5, 10 mg caps divided doses 371.00

Perphenazine generic 2, 4, 8, 16 mg tabs 4 mg tid 24 mg in divided 139.00doses

Thioridazine5 generic 10, 25, 50, 100 mg tabs 50-100 mg tid 100-200 mg bid 24.00Thiothixene generic 1, 2, 5, 10 mg caps 2 mg tid 10 mg bid 26.00Trifluoperazine generic 1, 2, 5, 10 mg tabs 2-5 mg bid 10 mg bid 57.00Second-Generation Aripiprazole3 Abilify 2, 5, 10, 15, 20, 30 mg tabs; 10-15 mg once/d 10-30 mg once/d 669.00

(BMS/Otsuka) 1 mg/mL soln6orally disintegrating

Abilify Discmelt 10, 15 mg ODT 10-15 mg once/d 10-15 mg once/d 797.00Asenapine Saphris (Merck) 5, 10 mg sublingual tabs 5 mg bid 5-10 mg bid 690.00Clozapine7 generic 25, 50, 100, 200 mg tabs 12.5-25 mg bid 100-300 mg tid 218.00

Clozaril (Novartis) 25, 100 mg tabs 812.00orally disintegrating generic 12.5, 25, 100 mg ODT 589.00

FazaClo (Jazz) 12.5, 25, 100, 150, 200 mg ODT 783.00Iloperidone 1, 2, 4, 6, 8, 10, 12 mg tabs 1 mg bid 6-12 mg bid

Fanapt (Novartis) 697.00Lurasidone Latuda 20, 40, 80, 120 mg tabs 40 mg once/d 40-160 mg once/d 553.00

(Sunovion)Olanzapine3 generic 2.5, 5, 7.5, 10, 15, 20 mg tabs 5-10 mg once/d 10-20 mg once/d 23.00

Zyprexa (Lilly) 553.00orally disintegrating generic 5, 10, 15, 20 mg ODT 340.00

Zyprexa Zydis 583.00Paliperidone3 1.5, 3, 6, 9 mg ER tabs 6 mg once/d 6-12 mg once/d

Invega (Janssen) 604.00Quetiapine generic 25, 50, 100, 200, 300, 25 mg bid 300-800 mg in 2 or 3 72.00

Seroquel (AstraZeneca) 400 mg tabs divided doses 600.00extended release

Seroquel XR 50, 150, 200, 300, 400 mg tabs 300 mg once/d 400-800 mg once/d 585.00Risperidone3 generic 0.25, 0.5, 1, 2, 3, 4 mg tabs; 2 mg once/d or 4-8 mg once/d 42.00

Risperdal (Janssen) 1 mg/mL soln divided bid 513.00orally disintegrating generic 0.25, 0.5, 1, 2, 3, 4 mg ODT 362.00

Risperdal M-TAB 0.5, 1, 2, 3, 4 mg ODT 616.00Ziprasidone generic 20, 40, 60, 80 mg caps 20-40 mg bid 60-80 mg bid 292.00

Geodon3 (Pfizer) 659.00ODT = orally disintegrating tablet1. 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 retailprices 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.



Clozapine causes granulocytopenia or agranulocytosisin about 1% of patients, requiring weekly monitoringof blood counts. Seizures occur in 1-4% of patients andare dose-related. Increased salivation and enuresisoccur at higher doses. Gastrointestinal hypomotility,which can be severe, marked sedation, diabetes,weight gain and hyperlipidemia are common withclozapine.49 Myocarditis, often occurring within thefirst few weeks of treatment and sometimes fatal, hasbeen reported.50

Despite its structural similarity to clozapine, olanzapineis much less likely to cause agranulocytosis or seizures.It does cause weight gain and other metabolic effects,including diabetes mellitus. Postural hypotension, som-nolence, constipation, hyperlipidemia, dizziness andakathisia can also occur. Increases in serum hepatictransaminases have been reported.

The most common adverse effects of risperidone arepostural hypotension, insomnia, constipation, dizzi-ness, prolactin elevation, hyperglycemia and weightgain. At doses higher than 6 mg/day, the risk ofextrapyramidal symptoms increases without an addi-tional increase in efficacy. The adverse effect profile ofpaliperidone (9-hydroxyrisperidone) resembles thatof its parent compound risperidone, includingextrapyramidal symptoms, prolactin elevation, nausea,somnolence, dizziness, tachycardia and QT intervalprolongation.51

62

Quetiapine commonly causes somnolence, dizziness,constipation, postural hypotension, hyperglycemia andweight gain. Though mentioned in the drugs packageinsert with a recommendation for twice-yearly ophthal-mologic monitoring, clinical use of quetiapine proba-bly does not cause cataract formation.52

Ziprasidone seldom causes significant weight gain,hyperlipidemia or hyperglycemia. Its adverse effectshave included mild to moderate somnolence, prolon-gation of the QT interval, extrapyramidal symptoms inabout 5% of patients and, occasionally, paradoxicalexcitement.

Aripiprazole can cause anxiety, headache, nausea,constipation, lightheadedness, agitation and akathisia.It has a lower risk of hyperlipidemia, hyperglycemia orhyperprolactinemia compared to most second-genera-tion antipsychotics.53 It appears to cause less weightgain than most other second-generation antipsychotics.

The most commonly reported adverse effects of ase-napine are insomnia, somnolence, nausea, vomitingand weight gain.54 Iloperidone causes orthostatichypotension, QT interval prolongation, dizziness, som-nolence, dry mouth and weight gain, but is relativelyfree of extrapyramidal effects.55 Lurasidone can causeakathisia, nausea, extrapyramidal symptoms, agitationand somnolence, but does not appear to increaseweight.56

Weight Extrapyramidal QTc ElevatedDrug Diabetes Gain Symptoms Prolongation ProlactinAripiprazole +/ + ++ +/ +/Asenapine* + ++ ++ + ++Clozapine ++++ ++++ +/ + +/Iloperidone* ++ ++ +/ ++ +/Lurasidone* +/ +/ ++ +/ +/Olanzapine ++++ ++++ + + +Paliperidone ++ +++ ++ + +++Quetiapine ++ +++ +/ + +/Risperidone ++ +++ +++ + +++Ziprasidone +/ +/ + ++ +*Limited experience

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

Drug Metabolism by CYP/P-gp CommentsAripiprazole 3A4, 2D6 Dose adjustments required with strong 3A4 or 2D6 inhibitors and with 3A4 inducersAsenapine 1A2 Low potential for interactionsClozapine 1A2, 3A4, 2D6, 2C19 Many interactions, primarily with 1A2 inhibitors and inducersIloperidone 3A4, 2D6 Dose adjustments required with strong 3A4 or 2D6 inhibitorsLurasidone 3A4 Contraindicated with strong 3A4 inducers and inhibitors; dose adjustments required

with moderate 3A4 inhibitorsOlanzapine 1A2, 2D6 and P-gp Low potential for interactions; serum concentrations altered by strong 1A2 inhibitors

or inducersPaliperidone 2D6, P-gp Low potential for interactionsQuetiapine 3A4 Dose adjustments required with strong 3A4 inducers and inhibitorsRisperidone 3A4, 2D6 and P-gp Dose adjustments required with 3A4 or 2D6 inhibitors and 3A4 inducersZiprasidone 3A4 Serum concentrations modestly effected by 3A4 inhibitors and inducers

Table 8. Some Second-Generation Antipsychotic Drug Interactions



PREGNANCY Data on use of antipsychotic drugsduring pregnancy are limited. None have been provento be teratogenic. Chlorpromazine was once used totreat morning sickness, apparently without teratogene-sis. Only clozapine and lurasidone are classified as cat-egory B for use during pregnancy (no human data; ani-mal data suggest no risk); all the other antipsychoticsare category C (adverse effects in animals or no animalreproductive studies, and no adequate studies inhumans). The risks of hyperglycemia and weight gainare greater with the second-generation antipsychotics,which have been associated with high birth weight andbabies that are large for gestational age.34

CHOICE OF DRUGS Clozapine is the most effec-tive antipsychotic drug, but it should be reserved forrefractory disease because of its potential for serioushematologic toxicity and strict monitoring require-ments. Olanzapine may have some slight advantagesover other drugs in efficacy, but its adverse effects onweight and metabolism may be unacceptable for long-term use. Other second-generation antipsychotics arenot clearly more effective than first-generation drugs,but they have a lower risk of tardive dyskinesia. Somepatients who do not respond to one antipsychotic mayrespond to another. Long-acting injectable antipsy-chotics may be useful when adherence is a problem.

1. Extended-release trazodone (Oleptro) for depression. Med Lett DrugsTher 2010; 52:91.

2. Vilazodone (Viibryd) a new antidepressant. Med Lett Drugs Ther2011; 53:53.

3. V Rabenda et al. Risk of nonvertebral fractures among elderly post-menopausal women using antidepressants. Bone 2012; 51:674.

4. Citalopram (Celexa) and QT-interval prolongation. Med Lett DrugsTher 2012; 54:71.

5. VM Castro et al. QT interval and antidepressant use: a cross sectionalstudy of electronic health records. BMJ 2013; 346:f288.

6. SE Hetrick et al. Newer generation antidepressants for depressive dis-orders in children and adolescents. Cochrane Database Syst Rev 2012;(11):CD004851.

7. EW Boyer and M Shannon. The serotonin syndrome. N Engl J Med2005; 352:1112.

8. KL Wisner et al. Major depression and antidepressant treatment: impacton pregnancy and neonatal outcomes. Am J Psychiatry 2009; 166:557.

9. N Lund et al. Selective serotonin reuptake inhibitor exposure in uteroand pregnancy outcomes. Arch Pediatr Adolesc Med 2009; 163:949.

10. S Gentile. On categorizing gestational, birth, and neonatal complica-tions following late pregnancy exposure to antidepressants: the prenatalantidepressant exposure syndrome. CNS Spectr 2010; 15:167.

11. CD Chambers et al. Selective serotonin-reuptake inhibitors and risk ofpersistent pulmonary hypertension of the newborn. N Engl J Med 2006;354:579.

12. A Brard et al. Paroxetine use during pregnancy and perinatal outcomesincluding types of cardiac malformations in Quebec and France: A shortcommunication. Curr Drug Saf 2012; 7:207.

13. A Einarson et al. Incidence of major malformations in infants followingantidepressant exposure in pregnancy: results of a large prospectivecohort study. Can J Psychiatry 2009; 54:242.

14. M Tuccori et al. Use of selective serotonin reuptake inhibitors duringpregnancy and risk of major and cardiovascular malformations: anupdate. Postgrad Med 2010; 122:49.

15. S Alwan et al. Use of selective serotonin-reuptake inhibitors in preg-nancy and the risk of birth defects. N Engl J Med 2007; 356:2684.

16. C Louik et al. First-trimester use of selective serotonin-reuptakeinhibitors and the risk of birth defects. N Engl J Med 2007; 356:2675.

17. O Stephansson et al. Selective serotonin reuptake inhibitors during preg-nancy and risk of stillbirth and infant mortality. JAMA 2013; 309:48.

18. LH Pedersen et al. Fetal exposure to antidepressants and normal mile-stone development at 6 and 19 months of age. Pediatrics 2010; 125:e600(epub Feb 22).

19. KR Connolly and ME Thase. If at first you dont succeed: a review ofthe evidence for antidepressant augmentation, combination and switch-ing strategies. Drugs 2011; 71:43.

20. AJ Rush et al. Bupropion-SR, sertraline, or venlafaxine-XR after failureof SSRIs for depression. N Engl J Med 2006; 354:1231.

21. Adjunctive antipsychotics for major depression. Med Lett Drugs Ther2011; 53:74.

22. BM Wright et al. Augmentation with atypical antipsychotics for depres-sion: a review of evidence-based support from the medical literature.Pharmacotherapy 2013; 33:344.

23. PE Holtzheimer and HS Mayberg. Neuromodulation for treatment-resistant depression. F1000 Med Rep 2012; 4:22.

24. Repetitive transcranial magnetic stimulation (TMS) for medication-resistant depression. Med Lett Drugs Ther 2009; 51:12.

25. Vagus nerve stimulation for depression. Med Lett Drugs Ther 2005;47:50.

26. JR Geddes and DJ Miklowitz. Treatment of bipolar disorder. Lancet2013; 381:1672.

27. ME Thase and T Denko. Pharmacotherapy of mood disorders. AnnuRev Clin Psychol 2008; 4:53.

28. L Tondo and RJ Baldessarini. Long-term lithium treatment in the pre-vention of suicidal behavior in bipolar disorder patients. EpidemiolPsychiatr Soc 2009; 18:179.

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 syndromeinduced by carbamazepine in Southern Han Chinese: genetic markersbesides B*1502? Basic Chem Pharmacol Toxicol 2012; 111:58.

31. P Cacoub et al. The DRESS syndrome: a literature review. Am J Med2011; 124:588.

32. SH Joe et al. Feasibility of a slower lamotrigine titration schedule forbipolar depression: a naturalistic study. Int Clin Psychopharmacol 2009;24:105.

33. FDA Drug Safety Communication: valproate anti-seizure products con-traindicated for migraine prevention in pregnant women due to decreased IQscores 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 sys-tematic 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 forschizophrenia. Cochrane Database Syst Rev 2012; 5:CD008016.

37. S Leucht et al. Second-generation versus first-generation antipsychoticdrugs for schizophrenia: a meta-analysis. Lancet 2009; 373:31.

38. L Hartling et al. Antipsychotics in adults with schizophrenia: compara-tive effectiveness of first-generation versus second-generation medica-tions: a systematic review and meta-analysis. Ann Intern Med2012;157:498.

39. HY Meltzer et al. Clozapine treatment for suicidality in schizophrenia:International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry2003; 60:82.

40. J Tiihonen et al. 11-year follow-up of mortality in patients with schizo-phrenia: 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 second-generation antipsychotics in the treatment of schizophrenia. Am JPsychiatry 2009; 166:152.

42. Asenapine (Saphris) sublingual tablets for schizophrenia and bipolar

63



disorder. Med Lett Drugs Ther 2010; 52:9.43. Iloperidone (Fanapt) - another second-generation antipsychotic. Med

Lett Drugs Ther 2010; 52:13.44. Lurasidone (Latuda) for schizophrenia. Med Lett Drugs Ther 2011;

53:13.45. R Emsley et al. Long-acting injectable antipsychotics in early psy-

chosis: a literature review. Early Interv Psychiatry Jan 2013 (epubahead of print).

46. O Freudenreich and JP McEvoy. Optimizing outcome with antipsy-chotic treatment in first-episode schizophrenia: balancing efficacy andside effects. Clin Schizophr Relat Psychoses 2012; 6:115.

47. CU Correll and EM Schenk. Tardive dyskinesia and new antipsy-chotics. Curr Opin Psychiatry 2008; 21:151.

48 R Liperoti et al. All-cause mortality associated with atypical and con-ventional 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 Saf2005; 4:731.

50. KJ Ronaldson et al. Clinical course and analysis of ten fatal cases ofclozapine-induced myocarditis and comparison with 66 survivingcases. Schizophr Res 2011; 128:161.

51. R Emsley et al. Efficacy and safety of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data fromthree 52-week open-label studies. Int Clin Psychopharmacol 2008;23:343.

52. FW Fraunfelder. Twice-yearly exams unnecessary for patients takingquetiapine. Am J Ophthalmol. 2004; 138:870.

53. CU Pae. A review of the safety and tolerability of aripiprazole. ExpertOpin Drug Saf 2009; 8:373.

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 ClinPsychopharmacol 2008; 28(2 Suppl 1):S29.

56. L Citrome. Lurasidone for schizophrenia: a review of the efficacy andsafety profile for this newly approved second-generation antipsychotic.Int J Clin Pract. 2011; 65:189.

Subscriptions (US):1 year - $98; 2 years - $189; 3 years - $279. $49/yr. for students,interns, residents and fellows in theUS and Canada.

E-mail site license inquiries to:[email protected] or call800-211-2769 x315.Special fees for bulk subscriptions.Special classroom rates are avail-able. Back issues are $12 each.Major credit cards accepted.

Copyright and Disclaimer: The Medical Letter is an independent nonprofit organ-ization that provides healthcare professionals with unbiased drug prescribing rec-ommendations. The editorial process used for its publications relies on a review ofpublished and unpublished literature, with an emphasis on controlled clinical trials,and on the opinions of its consultants.The Medical Letter is supported solely by sub-scription fees and accepts no advertising, grants or donations.

No part of the material may be reproduced or transmitted by any process in whole orin part without prior permission in writing.The editors do not warrant that all the mate-rial in this publication is accurate and complete in every respect.The editors shall notbe held responsible for any damage resulting from any error, inaccuracy or omission.

Subscription ServicesMailing Address:The Medical Letter, Inc.145 Huguenot Street, Ste 312 New Rochelle, NY 10801-7537

Customer Service:Call: 800-211-2769 or 914-235-0500Fax: 914-632-1733Web Site: www.medicalletter.orgE-mail: [email protected]

Permissions:To reproduce any portion of this issue, please e-mail your request to:[email protected]

Subscriptions (US):1 year - $98; 2 years - $189; 3 years - $279. $49/yr. for students,interns, residents and fellows in theUS and Canada.

E-mail site license inquiries to:[email protected] or call800-211-2769 x315.Special fees for bulk subscriptions.Special classroom rates are avail-able. Back issues are $12 each.Major credit cards accepted.

Copyright 2012. ISSN 1541-2792


EDITOR IN CHIEF: Mark Abramowicz, M.D.EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical

SchoolEDITOR: Jean-Marie Pflomm, Pharm.D.ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D.,

Corinne Z. Morrison, Pharm.D.CONSULTING EDITORS: Brinda M. Shah, Pharm.D., F. Peter Swanson, M.D.CONTRIBUTING EDITORS:Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and SurgeonsVanessa K. Dalton, M.D., M.P.H., University of Michigan Medical SchoolEric J. Epstein, M.D., Albert Einstein College of MedicineJane P. Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of MedicineJules Hirsch, M.D., Rockefeller UniversityDavid N. Juurlink, BPhm, M.D., PhD, Sunnybrook Health Sciences CentreRichard B. Kim, M.D., University of Western Ontario Hans Meinertz, M.D., University Hospital, Copenhagen Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of MedicineDan M. Roden, M.D., Vanderbilt University School of Medicine Esperance A. K. Schaefer, M.D., M.P.H., Harvard Medical SchoolF. Estelle R. Simons, M.D., University of Manitoba Neal H. Steigbigel, M.D., New York University School of MedicineArthur M.F.Yee, M.D., Ph.D., F.A.C.R, Weill Medical College of Cornell UniversitySENIOR ASSOCIATE EDITORS: Donna Goodstein, Amy FaucardASSOCIATE EDITOR: Cynthia Macapagal CoveyEDITORIAL FELLOW: Jennifer Y. Lin, M.D., Harvard Medical SchoolMANAGING EDITOR: Susie WongASSISTANT MANAGING EDITOR: Liz DonohuePRODUCTION COORDINATOR: Cheryl BrownEXECUTIVE DIRECTOR OF SALES: Gene CarbonaFULFILLMENT AND SYSTEMS MANAGER: Cristine RomatowskiDIRECTOR OF MARKETING COMMUNICATIONS: Joanne F. ValentinoVICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy

Founded in 1959 byArthur Kallet and Harold Aaron, M.D.

Correction: Drugs for Pain (Treat Guidel Med Lett2013; 11:31)In Table 1 on pages 32 and 33 the price for IV ibuprofen(Caldolor) has been revised.

Coming Soon in Treatment Guidelines:Drugs for Bacterial Infections July 2013Drugs for Atrial Fibrillation August 2013

Follow us on Twitter @MedicalLetter


Free Individual Exams - Free to active subscribers of Treatment Guidelines from The Medical Letter. Answer 12 questions per issue and submit answers online. Earnup to 2 credits/exam.Paid Individual Exams - Available to non-subscribers. Answer 12 questions per issue and submit answers online. Earn up to 2 credits/exam. $12/exam.ACCREDITATION INFORMATION:ACCME: The Medical Letter is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The MedicalLetter Inc. designates this enduring material for a maximum of 2 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with theextent of their participation in the activity. This CME activity was planned and produced in accordance with the ACCME Essentials and Policies.

AAFP: This enduring material activity, Treatment Guidelines from the Medical Letter Continuing Medical Education Program, has been reviewed and is acceptable forup to 15 Prescribed credits by the American Academy of Family Physicians. AAFP certification begins January 1, 2013. Term of approval is for one year from this date.Each issue is approved for 1.25 Prescribed credits. Credit may be claimed for one year from the date of each issue. Physicians should claim only the credit commen-surate with the extent of their participation in the activity.

ACPE: The Medical Letter is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This exam is acceptable for 2.0 hour(s) of knowledge-based continuing education credit (0.2 CEU).

AANP and AAPA: The American Academy of Nurse Practitioners (AANP) and the American Academy of Physician Assistants (AAPA) accept AMA Category 1Credit for the Physicians Recognition Award from organizations accredited by the ACCME.

AOA: This activity, being ACCME (AMA) approved, is acceptable for Category 2-B credit by the American Osteopathic Association (AOA).Physician Assistants: The National Commission on Certification of Physician Assistants (NCCPA) accepts AMA PRA Category 1 Credit(s) from organiza-tions accredited by ACCME. NCCPA also accepts AAFP Prescribed credits for recertification. Treatment Guidelines is accredited by both ACCME and AAFP.

Physicians in Canada: Members of The College of Family Physicians of Canada residing in the US are eligible to receive Mainpro-M1 credits (equivalent to AAFPPrescribed credits), and members residing in Canada are eligible to receive Mainpro-M2 credits due to a reciprocal agreement with the American Academy of FamilyPhysicians. Treatment Guidelines CME activities are eligible for either Section 2 or Section 4 (when creating a personal learning project) in the Maintenance ofCertification Program of the Royal College of Physicians and Surgeons of Canada (RCPSC).Physicians, nurse practitioners, pharmacists and physician assistants may earn 2 credits with this exam.

MISSION:The mission of The Medical Letter's Continuing Medical Education Program is to support the professional development of healthcare professionals including physi-cians, nurse practitioners, pharmacists and physician assistants by providing independent, unbiased drug information and prescribing recommendations that are freeof industry influence. The program content includes current information and unbiased reviews of FDA-approved and off-label uses of drugs, their mechanisms of action,clinical trials, dosage and administration, adverse effects and drug interactions. The Medical Letter delivers educational content in the form of self-study material.

The expected outcome of the CME Program is to increase the participants ability to know, or apply knowledge into practice after assimilating, information presentedin materials contained in Treatment Guidelines.

The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities. The Medical Letter aims to be aleader in supporting the professional development of healthcare professionals through Core Competencies by providing continuing medical education that is unbiasedand free of industry influence. The Medical Letter is supported solely by subscription fees and accepts no advertising, grants or donations.

GOAL:Through this program, The Medical Letter expects to provide the healthcare community with unbiased, reliable and timely educational content that they will use tomake independent and informed therapeutic choices in their practice.

LEARNING OBJECTIVES:The objective of this activity is to meet the need of healthcare professionals for unbiased, reliable and timely information on treatment of major diseases. The MedicalLetter expects to provide the healthcare community with educational content that they will use to make independent and informed therapeutic choices in their practice.Participants will be able to select and prescribe, or confirm the appropriateness of the prescribed usage of the drugs and other therapeutic modalities discussed inTreatment Guidelines with specific attention to clinical evidence of effectiveness, adverse effects and patient management.

Upon completion of this program, the participant will be able to:

1. Explain the current approach to the management of patients with psychiatric disorders.2. Discuss the pharmacologic agents available for treatment of depression, bipolar disorder and psychosis and compare them based on their efficacy, dosage

and administration, potential adverse effects and drug interactions.3. Determine the most appropriate therapy given the clinical presentation of an individual patient.

Privacy and Confidentiality: The Medical Letter guarantees our firm commitment to your privacy. We do not sell any of your information. Secure server software (SSL)is used for commerce transactions through VeriSign, Inc. No credit card information is stored.

IT Requirements: Windows 98/NT/2000/XP/Vista/7/8, Pentium+ processor, Mac OS X+ w/ compatible process; Microsoft IE 6.0+, Mozilla Firefox 2.0+ or any othercompatible Web browser. Dial-up/high-speed connection.

Have any questions? Call us at 800-211-2769 or 914-235-0500 or e-mail us at: [email protected]

Treatment Guidelines:Online Continuing Medical EducationUp to 24 credits included with your subscription

medicalletter.org/cme

Choose CME from Treatment Guidelines from The Medical Letter and earn up to 24 Category 1 Credits per year:

Questions start on next page


1. First-line treatments for major depression include:a. SSRIsb. SNRIsc. bupropiond. all of the above

2. The only SSRI FDA-approved for treatment of major depressivedisorder in children is:

a. sertralineb. fluoxetinec. citalopramd. paroxetine

3. A 33-year-old woman with depression has been taking paroxetine.She is considering becoming pregnant. Which of the following couldyou tell her about treatment of depression during pregnancy?

a. paroxetine is classified as category D for use during preg-nancy

b. untreated depression has not been associated with pretermbirth

c. all antidepressants are classified as category A for use dur-ing pregnancy

d. all of the above

4. The antidepressant least likely to cause sexual side effects is:a. bupropionb. fluoxetinec. amitriptylined. venlafaxine

5. The drug of choice for maintenance treatment of bipolar disorderis:

a. sertralineb. lithiumc. carbamazepined. lorazepam

6. A 64-year-old otherwise healthy woman with bipolar disorder hashad multiple relapses because she forgets to take her daily dosesof quetiapine. Which of the following long-acting injectableantipsychotics is FDA-approved for maintenance treatment ofbipolar disorder?

a. olanzapineb. aripiprazolec. risperidoned. paliperidone

7. Which of the following drugs is not recommended as monotherapyfor maintenance treatment of bipolar disorder?

a. lithiumb. lamotriginec. risperidoned. citalopram

8. A higher incidence of Stevens-Johnson syndrome has beenreported in some patients of Asian ancestry taking:

a. carbamazepineb. olanzapinec. aripiprazoled. lithium

9. Negative symptoms of schizophrenia include:a. apathyb. social withdrawalc. blunted affectd. all of the above

10. All second-generation antipsychotics have a FDA-required warn-ing label about:

a. thrombocytopeniab. hyperglycemiac. gastrointestinal bleedingd. hypotension

11. A 19-year-old woman newly diagnosed with schizophrenia is veryconcerned about possible weight gain associated with antipsy-chotic treatment. Which of the following might be a good option forher?

a. clozapineb. ziprasidonec. quetiapined. olanzapine

12. Which of the following antipsychotics is thought to be the mosteffective in preventing suicide and may be effective in patientswho have not responded to other antipsychotics?

a. haloperidolb. clozapinec. lurasidoned. loxapine

DO NOT FAX OR MAIL THIS EXAMTo take CME exams and earn credit, go to:

medicalletter.org/CMEstatus

Issue 130 Questions

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

drugs for psychiatric disorders med letter tx 2013

Documents