The medical letter on drugs and therapeutics december 19 2016

EFFECTIVENESS — Antipsychotic drugs are more effective in treating the positive symptoms of schizophrenia agitation, hallucinations, delusions than the negative symptoms apathy, socia

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IN THIS ISSUE

ISSUE

1433

Volume 56

Published by The Medical Letter, Inc • A Nonprofi t Organization

ISSUE No.

1510

on Drugs and Therapeutics

Celecoxib Safety Revisited p 159

Drugs for Psychotic Disorders p 160

159

on Drugs and Therapeutics

Take CME Exams

ISSUE

1433

Volume 56

ISSUE No.

1510 Drugs for Psychotic Disorders p 160

ALSO IN THIS ISSUE

Celecoxib Safety Revisited

▶

The results of a clinical trial (PRECISION)1 comparing

the cardiovascular safety of the COX-2 selective

NSAID celecoxib (Celebrex, and generics) with that

of ibuprofen and naproxen, which are nonselective,

have been described in the lay press in terms that may

overestimate the safety of celecoxib.

NSAID PHARMACOLOGY — NSAIDs inhibit the enzyme

cyclooxygenase (COX), which is required for synthesis

of prostaglandins and thromboxane COX-1 inhibition

blocks the protective effect of prostaglandins on the

gastric mucosa, which can cause gastrointestinal

toxicity, and has an antiplatelet effect that can cause

bleeding COX-2 inhibition produces therapeutic

anti-inflammatory and analgesic effects, but it has effects

on vascular endothelium that can be prothrombotic

Ibuprofen and naproxen inhibit COX-1 more than

COX-2 The COX-2 selective NSAID rofecoxib (Vioxx),

which inhibits COX-2 80 times more than COX-1, was

removed from the market because of cardiovascular

toxicity Celecoxib, which inhibits COX-2 9 times

more than COX-1, also has been associated with an

increased risk of cardiovascular toxicity.2,3

All NSAIDs inhibit renal prostaglandins, decrease

renal blood flow, cause fluid retention, and may cause

hypertension and renal failure, especially in the elderly.4

THE PRECISION TRIAL — A total of 24,081 patients

with osteoarthritis (90%) or rheumatoid arthritis

(10%) and established cardiovascular disease or

increased risk of developing cardiovascular disease

were randomized to receive celecoxib 100 mg twice

daily, ibuprofen 600 mg three times daily, or naproxen

375 mg twice daily; the mean treatment duration was

20.3 months and the mean follow-up period was 34.1

months About 50% of the patients were taking

low-dose aspirin at baseline A primary outcome event

(cardiovascular death, nonfatal myocardial infarction,

or nonfatal stroke) occurred in 188 patients taking celecoxib (2.3%), 201 taking naproxen (2.5%), and 218 taking ibuprofen (2.7%); celecoxib was determined to

be noninferior to both ibuprofen and naproxen with regard to cardiovascular safety.1

SOME LIMITATIONS — By the end of the PRECISION

trial, 68.8% of patients had stopped taking their assigned drug The dosage of celecoxib was limited

to 200 mg per day for patients with osteoarthritis;

as a result, the average daily dose of celecoxib was lower than the doses previously associated with cardiovascular toxicity Increases in the dosage of ibuprofen and naproxen were permitted Ibuprofen and naproxen, but not celecoxib, inhibit aspirin binding to platelet COX-1; thus, the cardioprotective effects of aspirin may have been blunted in patients who were taking ibuprofen or naproxen.5

CONCLUSION — The average dosage of the COX-2

selective NSAID celecoxib (Celebrex, and generics)

used in the PRECISION trial was too low to support the determination that celecoxib is noninferior to ibuprofen and naproxen with regard to cardiovascular safety COX-2 selective NSAIDs cause less gastrointestinal toxicity and bleeding than nonselective NSAIDs, but they may have a prothrombotic effect, and all NSAIDs are nephrotoxic Elderly patients, who are most at risk, should exercise caution in taking any NSAID, includ -ing celecoxib ■

1 SE Nissen et al Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis N Engl J Med 2016 Nov 13 (epub)

2 JM Wright The double-edged sword of COX-2 selective NSAIDs CMAJ 2002; 167:1131

3 SD Solomon et al Cardiovascular risk associated with cele-coxib in a clinical trial for colorectal adenoma prevention N Engl J Med 2005; 352:1071

4 MA Perazella COX-2 selective inhibitors: analysis of the renal effects Expert Opin Drug Saf 2002; 1:53

5 GA FitzGerald ImPRECISION: Limitations to interpretation of a large randomized clinical trial Circulation 2016 Nov 13 (epub)

The Medical Letter ® Vol 58 (1510) December 19, 2016

Drugs for Psychotic Disorders

▶

Oral antipsychotic drugs used for treatment of

schizophrenia, schizoaffective disorder, delusional

disorder, and other manifestations of psychosis or

mania are listed in Table 1 on page 161 Parenteral

antipsychotic drugs used for treatment of these

disorders are listed in Table 2 on page 162.

EFFECTIVENESS — Antipsychotic drugs are more

effective in treating the positive symptoms of

schizophrenia (agitation, hallucinations, delusions)

than the negative symptoms (apathy, social withdrawal,

blunted affect).1,2

Oral – Second-generation antipsychotics are used

more commonly than less expensive fi rst-generation

drugs, even though controlled trials generally have

failed to demonstrate a clear advantage in effi cacy,

except with clozapine and possibly olanzapine.3

Clozapine is generally considered the most effective

antipsychotic drug for treatment of schizophrenia.4

It has been effective for treatment of psychotic

symptoms that have not responded to other drugs and

has been more effective than other antipsychotics in

decreasing the risk of suicide.5

Olanzapine has been more effective than aripiprazole,

quetiapine, risperidone, or ziprasidone in reducing

psychotic symptoms.6 Risperidone has been more

effective than quetiapine or ziprasidone.7

The more recently approved antipsychotic drugs

paliperidone,8 asenapine,9 iloperidone,10 lurasidone,11

brexpiprazole,12 and cariprazine13 may be effective for

some patients, but their effi cacy and safety relative to

older drugs remain to be established

Parenteral – Short-acting parenteral antipsychotics

can be helpful for acute treatment of agitation

associated with schizophrenia or bipolar 1 mania

Long-acting parenteral antipsychotics generally have

been used in patients with a history of relapse due to

poor adherence to oral maintenance therapy

Long-acting injectable formulations can improve adherence,

hospitalization and relapse rates, and long-term

outcomes for patients with schizophrenia, even though

a benefi t has not been consistently demonstrated in

trials comparing long-acting injectable formulations

with oral formulations.14,15 In one head-to-head trial,

once-monthly paliperidone palmitate was no more

effective than haloperidol decanoate, which costs

much less.16 Data on newer long-acting parenteral

formulations such as paliperidone palmitate 3-month, olanzapine, and aripiprazole are limited.17,18

Inhaled – The fi rst-generation antipsychotic loxapine

is available as an inhalation powder (Adasuve) for acute

treatment of agitation associated with schizophrenia

or bipolar 1 disorder in patients who are able to use

an inhaler and who are not at risk for bronchospasm.19

ADVERSE EFFECTS — Movement disorders, metabolic

effects, and other adverse effects can interfere with patient adherence to antipsychotic drugs

The FDA requires labels of both fi rst- and second-generation antipsychotics to include a boxed warning about an increased risk of death in elderly patients with dementia-related psychosis.20

First-Generation – All fi rst-generation antipsychotics

have been variably associated with sexual dysfunction, hyperprolactinemia, neuroleptic malignant syndrome, extrapyramidal symptoms, akathisia, and tardive dyskinesia The risk of extrapyramidal symptoms and tardive dyskinesia may be minimized if dosing

is targeted to the lowest dose at which mild extrapyramidal motor effects fi rst appear.21

Chlorpromazine commonly causes sedation, postural

hypotension, and weight gain, as well as anticholin-ergic and occasional extrapyramidal adverse effects

Haloperidol and fluphenazine are less likely to cause

sedation, postural hypotension, anticholinergic effects, or weight gain, but are more likely to cause

extrapyramidal symptoms Perphenazine, loxapine, and molindone are generally less sedating than

chlor-promazine and somewhat less likely than haloperidol and fluphenazine to cause extrapyramidal symptoms

Second-Generation – Second-generation

antipsy-chotics have a relatively lower risk of causing extrapyramidal symptoms and are less likely than fi rst-generation antipsychotics to cause tardive dyskinesia and neuroleptic malignant syndrome, but akathisia

is a persistent problem.22,23 Second-generation

Choice of an Antipsychotic Drug

▶ Clozapine is generally the most effective antipsychotic drug for treatment of schizophrenia, but it is usually reserved for refractory disease because of its adverse effects

▶ Olanzapine may be slightly more effective than other anti-psychotic drugs (except clozapine), but its adverse metabolic effects may make it unacceptable for long-term use

▶ Other second-generation antipsychotics are not clearly more effective than less expensive fi rst-generation drugs, but they are less likely to cause tardive dyskinesia

▶ Long-acting injectable antipsychotics may be useful when adherence is a problem

Table 1 Some Oral Antipsychotics

Some Available Initial Usual Drug Formulations Adult Dosage 1 Adult Dosage 1 Cost 2

First-Generation

Chlorpromazine3 – generic 10, 25, 50, 100, 200 mg tabs 10-50 mg bid 200 mg bid $367.80

Fluphenazine3 – generic 1, 2.5, 5, 10 mg tabs; 2.5-10 mg divided 10 mg once/d 130.60

2.5 mg/5 mL elixir; tid or qid

5 mg/mL conc Haloperidol3 – generic 0.5, 1, 2, 5, 10, 20 mg tabs; 5 mg once/d or divided 5 mg bid 57.50

2 mg/mL conc

divided doses

Thioridazine5 – generic 10, 25, 50, 100 mg tabs 50-100 mg tid 100-200 mg bid 47.00

Second-Generation

Aripiprazole3 – generic 2, 5, 10, 15, 20, 30 mg tabs 10-15 mg once/d 10-30 mg once/d 302.50

orally disintegrating – generic 10, 15 mg ODT 10-15 mg once/d 10-15 mg once/d 919.00

Asenapine – Saphris (Allergan) 2.5, 5, 10 mg sublingual tabs 5 mg bid6 5-10 mg bid6 1006.10

Brexpiprazole – Rexulti 0.25, 0.5, 1, 2, 3, 4 mg tabs 1-4 mg once/d7 2-4 mg once/d 934.70

(Otsuka/Lundbeck)

Cariprazine – Vraylar (Allergan) 1.5, 3, 4.5, 6 mg caps 1.5 mg/d8 1.5-6 mg once/d 1006.10

Clozapine9 – generic 25, 50, 100, 200 mg tabs 12.5 mg once/d or bid 300-900 mg divided 200.70

Lurasidone – Latuda11 20, 40, 60, 80, 120 mg tabs 40 mg once/d 40-160 mg once/d 1013.10

(Sunovion)

Olanzapine3 – generic 2.5, 5, 7.5, 10, 15, 20 mg tabs 5-10 mg once/d 10-20 mg once/d 16.20

(Acadia)

extended release –

Seroquel XR13 50, 150, 200, 300, 400 mg ER tabs 300 mg once/d 400-800 mg once/d 750.00

Risperidone3 – generic 0.25, 0.5, 1, 2, 3, 4 mg tabs; 2 mg once/d or 4-6 mg once/d or 11.20

conc = concentrate; ER = extended release; N.A = cost not available; ODT = orally disintegrating tablet; susp = suspension

1 Initial and usual maintenance dosage for schizophrenia Dosage adjustment may be needed for renal or hepatic impairment.

2 Approximate WAC for 30 days’ treatment with the lowest usual adult dosage WAC = wholesaler acquisition cost or manufacturer’s published price to

wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly

December 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy.

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 respond to other

drugs.

6 Tablet should be placed under the tongue and allowed to dissolve completely Avoid eating or drinking for 10 minutes after administration.

7 The recommended starting dosage is 1 mg once daily on days 1-4 The dose should be increased to 2 mg/day on days 5-7 and then to 4 mg/day on day 8.

8 Dosage can be increased to 3 mg/day on day 2.

9 Clozapine can cause seizures and severe neutropenia and should be reserved for patients with schizophrenia who fail to respond to other drugs.

10 Dose should be doubled each day to reach a target of 12-24 mg/day.

11 Must be taken with food (≥350 calories with lurasidone and 500 calories with ziprasidone [K Gandelman et al J Clin Psychiatry 2009; 70:58] to maximize absorption).

12 Only approved for treatment of hallucinations and delusions associated with Parkinson's disease (Med Lett Drugs Ther 2016; 58:74).

13 A 400-mg ER generic formulation has recently been approved, but the cost is not yet available.

The Medical Letter ® Vol 58 (1510) December 19, 2016

Despite its structural similarity to clozapine,

olanzapine is unlikely to cause severe neutropenia

or seizures It does cause weight gain and other metabolic adverse effects, including diabetes mellitus Postural hypotension, somnolence, constipation, hyperlipidemia, dizziness, and akathisia can also occur Increases in serum hepatic transaminases have been reported DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome has been reported rarely with olanzapine.27,28

Adverse effects of risperidone have included

parkinsonism, akathisia, dystonia, insomnia, constipation, dizziness, salivary hypersecretion, weight gain, and prolactin elevation (much more than other second-generation antipsychotics except for paliperidone, which is the active metabolite

of risperidone) At doses >6 mg/day, the risk of extrapyramidal symptoms increases with only a modest increase in effi cacy In addition to prolactin

elevation, adverse effects of paliperidone include

antipsychotics have a higher risk than fi rst-generation

drugs of causing metabolic syndrome, including weight

gain, hyperglycemia, and hyperlipidemia Table 3

(see page 163) lists some adverse effects of

second-generation antipsychotics and the relative likelihood

of their occurrence.

Clozapine causes granulocytopenia in about 1%

of patients; weekly monitoring of blood counts is

required It can also cause orthostatic hypotension,

bradycardia, and syncope Seizures occur in 1-4% of

patients and are dose-related Increased salivation and

enuresis can occur.24 Gastrointestinal hypomotility,

which can be severe and result in toxic megacolon, is

common in patients taking clozapine and can result in

life-threatening complications; prophylactic laxatives

are recommended.25 Weight gain and hyperlipidemia

are also common Myocarditis, which often occurs

within the fi rst few weeks of treatment and is fatal in

up to 50% of cases, has been reported in as many as

0.5-3% of patients.26

Table 2 Some Parenteral Antipsychotics

Drug Some Available Formulations Usual Adult Dosage 1,2 Cost 3

Short-Acting First-Generation

Short-Acting Second-Generation

Long-Acting First-Generation

Fluphenazine decanoate – generic 25 mg/mL vials 12.5-25 mg IM or SC q2-3 wks 137.804

Haloperidol decanoate – generic 50, 100 mg/mL vials, ampules 10-15 times previous daily oral 6.005

Long-Acting Second-Generation

Aripiprazole – Abilify Maintena (Otsuka/Lundbeck) 300, 400 mg prefi lled syringes, vials 400 mg IM once/month 1796.00

Aripiprazole lauroxil – Aristada (Alkermes) 441, 662, 882 mg prefi lled syringes 441-882 mg IM once/month 1087.00

Olanzapine pamoate – Zyprexa Relprevv (Lilly) 210, 300, 405 mg single-use vials 150-300 mg IM q2 wks 842.40

Paliperidone palmitate – Invega Sustenna (Janssen) 39, 78, 117, 156, 234 mg 117-234 mg IM once/month 1095.10

prefi lled syringes

syringes

Risperidone – Risperdal Consta (Janssen) 12.5, 25, 37.5, 50 mg vials 25-50 mg IM q2 wks 794.00

N.A = cost not available

1 Dosage adjustment may be needed for renal or hepatic impairment.

2 Short-acting formulations: single dose for acute agitation; repeat doses may be needed Long-acting formuations: dosage for schizophrenia, based on patient’s stable oral maintenance dosage.

3 Approximate WAC for 4 weeks’ or 1 month’s treatment with the lowest usual adult dosage for long-acting, or cost of a single injection of the lowest usual

dosage for short-acting WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly December 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy.

4 Cost of one 5-mL vial.

5 Cost of a 100-mg dose.

6 Cost of one 410-mg syringe.

Aripiprazole can cause anxiety, headache, nausea,

constipation, lightheadedness, agitation, and aka thisia It is less likely than most second-generation antipsychotics to cause hyper lipidemia, hyperglycemia, weight gain, and hyperprolactin-emia.32 Impulse-control problems, such as compulsive eating, shopping, and sexual activity, have been reported rarely.33

Asenapine can cause insomnia, somnolence, nausea,

vom iting, and weight gain.34

In published studies to date, brexpiprazole has been

associated with fewer clinically relevant adverse effects than other antipsychotics; insomnia, weight gain, headache, and agitation have been reported.12,35

Cariprazine can cause akathisia, extrapyramidal

symptoms, tremor, and small changes in meta -bolic parameters.36

extrapyramidal symptoms, nausea, somnolence,

dizzi-ness, tachycardia, and QT interval prolongation.

Quetiapine commonly causes somnolence, dizziness,

constipation, postural hypotension, hyperglycemia,

and weight gain Although its package insert

recommends twice-yearly ophthalmologic monitoring,

clinical use of quetiapine probably does not cause

cataract formation.29

Ziprasidone seldom causes signifi cant weight

gain, hyperlipidemia, or hyperglycemia Its adverse

effects have included mild to moderate

somno-lence, extrapyramidal symptoms and, occasionally,

paradoxical excitement Prolongation of the QT

interval has been reported, but a postmarketing

trial in >18,000 patients did not fi nd an increase in

cardiac deaths with ziprasidone compared to

olanzapine.30 DRESS syndrome has been reported

rarely with ziprasidone.31

Table 3 Some Relative Adverse Effects of Second-Generation Antipsychotics

Extrapyramidal QTc Interval Elevated Drug Diabetes Weight Gain Symptoms Prolongation Prolactin

* Limited experience

Table 4 Some Drug Interactions with Second-Generation Antipsychotics 1

Drug Metabolism/Transport Comments

Aripiprazole 3A4, 2D6 Dose adjustments required with strong 3A4 or 2D6 inhibitors and with strong 3A4 inducers

Brexpiprazole 3A4, 2D6 Dose adjustments required with strong or moderate 3A4 or 2D6 inhibitors and with strong

3A4 inducers Cariprazine 3A4, 2D6 Dose adjustments required with strong 3A4 inhibitors; concurrent use with 3A4 inducers is

not recommended Clozapine 1A2, 3A4, 2D6, 2C19 Many interactions, primarily with 1A2 inhibitors and inducers; concurrent use with

strong 3A4 inducers is not recommended Iloperidone 3A4, 2D6 Dose adjustments required with strong 3A4 or 2D6 inhibitors

Lurasidone 3A4 Contraindicated with strong 3A4 inducers and inhibitors; dose adjustments required

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

or inducers Paliperidone 3A4, 2D6, P-gp Dose adjustments may be necessary with strong 3A4/P-gp inducers

Quetiapine 3A4 Dose adjustments required with strong 3A4 inducers and inhibitors

Risperidone 3A4, 2D6, P-gp Dose adjustments required with 3A4 or 2D6 inhibitors and 3A4 inducers

Ziprasidone 3A4 Serum concentrations modestly affected by 3A4 inhibitors and inducers

1 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2016 Aug 2 (epub) Available at secure.medicalletter.org/downloads/

CYP_PGP_Tables.pdf Accessed December 8, 2016.

The Medical Letter ® Vol 58 (1510) December 19, 2016

Iloperidone can cause orthostatic hypotension,

QT interval prolongation, dizziness, somnolence,

dry mouth, and weight gain, but is relatively free of

extrapyramidal effects, including akathisia.37

Lurasidone can cause akathisia, nausea, extrapyramidal

symptoms, and somnolence, but is among the least

likely to be associated with weight gain.38

PREGNANCY — Data on use of antipsychotic drugs

during pregnancy are limited39; none have been

proven to be teratogenic Chlorpromazine was once

used to treat morning sickness, apparently without

teratogenesis Neonates exposed to antipsychotic

drugs in the third trimester of pregnancy are at risk for

extrapyramidal and withdrawal symptoms following

delivery The risks of hyperglycemia and weight gain

are greater with second-generation antipsychotics,

which have been associated with high birth weight and

babies that are large for gestational age.40 ■

1 P Fusar-Poli et al Treatments of negative symptoms in

schizo-phrenia: meta-analysis of 168 randomized placebo-controlled

trials Schizophr Bull 2015; 41:892

2 HJ Möller and P Czobor Pharmacological treatment of negative

symptoms in schizophrenia Eur Arch Psychiatry Clin Neurosci

2015; 265:567

3 S Leucht et al Second-generation versus fi rst-generation

an-tipsychotic drugs for schizophrenia: a meta-analysis Lancet

2009; 373:31

4 TS Stroup et al Comparative effectiveness of clozapine and

standard antipsychotic treatment in adults with schizophrenia

Am J Psychiatry 2016; 173:166

5 HY Meltzer et al Clozapine treatment for suicidality in

schizo-phrenia: International Suicide Prevention Trial (InterSePT) Arch

Gen Psychiatry 2003; 60:82

6 K Komossa et al Olanzapine versus other atypical

antipsy-chotics for schizophrenia Cochrane Database Syst Rev 2010;

3:CD006654

7 TS Stroup et al Effectiveness of olanzapine, quetiapine,

risperi-done, and ziprasidone in patients with chronic schizophrenia

following discontinuation of a previous atypical antipsychotic

Am J Psychiatry 2006; 163:611

8 Paliperidone (Invega) for schizophrenia Med Lett Drugs Ther

2007; 49:21

9 C Orr et al Asenapine for the treatment of psychotic disorders:

a systematic review and meta-analysis Can J Psychiatry 2016

Aug 1 (epub)

10 Iloperidone (Fanapt) - another second-generation

antipsychot-ic Med Lett Drugs Ther 2010; 52:13

11 Lurasidone (Latuda) for schizophrenia Med Lett Drugs Ther

2011; 53:13

12 Brexpiprazole (Rexulti) for schizophrenia and depression Med

Lett Drugs Ther 2015; 57:116

13 Cariprazine (Vraylar) for schizophrenia and bipolar I disorder

Med Lett Drugs Ther 2016; 58:51

14 RA Rosenheck et al Long-acting risperidone and oral

antipsy-chotics in unstable schizophrenia N Engl J Med 2011; 364:842

15 PF Buckley et al Comparison of SGA oral medications and a

long-acting injectable SGA: the PROACTIVE study Schizophr

Bull 2015; 41:449

16 JP McEvoy et al Effectiveness of paliperidone palmitate vs

haloperidol decanoate for maintenance treatment of

schizo-phrenia: a randomized clinical trial JAMA 2014; 311:1978

17 Two long-acting injectable antipsychotics for schizophrenia

Med Lett Drugs Ther 2015; 57:152

18 R Emsley et al Long-acting injectable antipsychotics in early psy-chosis: a literature review Early Interv Psychiatry 2013; 7:247

19 Inhaled loxapine (Adasuve) for acute agitation Med Lett Drugs Ther 2014; 56:31

20 R Liperoti et al All-cause mortality associated with atypical and conventional antipsychotics among nursing home residents with dementia: a retrospective cohort study J Clin Psychiatry 2009; 70:1340

21 O Freudenreich and JP McEvoy Optimizing outcome with antipsy-chotic treatment in fi rst-episode schizophrenia: balancing effi cacy and side effects Clin Schizophr Relat Psychoses 2012; 6:115

22 S Ryu et al Tardive dyskinesia and tardive dystonia with second-generation antipsychotics in non-elderly schizophrenic patients unexposed to fi rst-generation antipsychotics: a cross-sectional and retrospective study J Clin Psychopharmacol 2015; 35:13

23 A O’Brien Comparing the risk of tardive dyskinesia in older adults with fi rst-generation and second-generation antipsy-chotics: a systematic review and meta-analysis Int J Geriatr Psychiatry 2016; 31:683

24 J Fitzsimons et al A review of clozapine safety Expert Opin Drug Saf 2005; 4:731

25 S Every-Palmer et al Clozapine-treated patients have marked gastrointestinal hypomotility, the probable basis of life-threat-ening gastrointestinal complications: a cross-sectional study EBioMedicine 2016; 5:125

26 SC Cook et al Clozapine-induced myocarditis: prevention and considerations in rechallenge Psychosomatics 2015; 56:685

27 FDA Drug Safety Communication: FDA warns about rare but serious skin reactions with mental health drug olanzapine (Zyprexa, Zyprexa Zydis, Zyprexa Relprevv, and Symbyax) Available at: www.fda.gov/Drugs/DrugSafety/ucm499441 Ac-cessed December 8, 2016

28 TJ Bommersbach et al Management of psychotropic drug-induced DRESS syndrome: a systematic review Mayo Clin Proc 2016; 91:787

29 AM Laties et al Cataractogenic potential of quetiapine versus risperidone in the long-term treatment of patients with schizo-phrenia or schizoaffective disorder: a randomized, open-label, ophthalmologist-masked, flexible-dose, non-inferiority trial J Psychopharmacol 2015; 29:69

30 BL Strom et al Comparative mortality associated with ziprasi-done and olanzapine in real-world use among 18,154 patients with schizophrenia: The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) Am J Psychiatry 2011; 168:193

31 VC Chan et al US Food and Drug Administration warning about the risk of drug reaction with eosinophilia and systemic symp-toms with ziprasidone J Clin Psychiatry 2015; 76:e1138

32 CU Pae A review of the safety and tolerability of aripiprazole Expert Opin Drug Saf 2009; 8:373

33 FDA Drug Safety Communication: FDA warns about new im-pulse-control problems associated with mental health drug aripiprazole (Abilify, Abilify Maintena, Aristada) Available at: www.fda.gov/Drugs/DrugSafety/ucm498662.htm Accessed December 8, 2016

34 J Weber and PL McCormack Asenapine CNS Drugs 2009; 23:781

35 JM Kane et al Overview of short- and long-term tolerabil-ity and safety of brexpiprazole in patients with schizophrenia Schizophr Res 2016; 174:93

36 JM Kane et al Effi cacy and safety of cariprazine in acute exac-erbation of schizophrenia: results from an international, Phase III clinical trial J Clin Psychopharmacol 2015; 35:367

37 JM Kane et al Long-term effi cacy and safety of iloperidone: results from 3 clinical trials for the treatment of schizophrenia

J Clin Psychopharmacol 2008; 28(2 Suppl 1):S29

38 R Musil et al Weight gain and antipsychotics: a drug safety review Expert Opin Drug Saf 2015; 14:73

39 KF Huybrechts et al Antipsychotic use in pregnancy and the risk for congential malformations JAMA Psychiatry 2016; 73:938

40 S Gentile Antipsychotic therapy during early and late pregnancy A systematic review Schizophr Bull 2010; 36:518

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

1 Discuss the results and limitations of the PRECISON trial evaluating the cardiovascular safety of the COX-2 selective NSAID celecoxib (Celebrex, and generics).

2 Discuss the pharmacologic options available for treatment of psychotic disorders and compare them based on their effi cacy, dosage and administration, potential adverse effects, and drug interactions.

3 Determine the most appropriate therapy given the clinical presentation of an individual patient with schizophrenia.

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Issue 1510 Questions

(Correspond to questions #121-130 in Comprehensive Exam #75, available January 2017)

6 A 37-year-old man with schizophrenia and bronchial asthma was well-controlled for many years on oral haloperidol It has recently become more diffi cult for his caretaker to persuade him

to take the drug Which of the following would be a reasonable choice of therapy for this patient?

a clozapine

b a benzodiazepine

c haloperidol decanoate

d loxapine inhalation powder

7 The labels of both fi rst- and second-generation antipsychotics include a boxed warning about the risk of:

a tardive dyskinesia in young patients

b DRESS syndrome

c neuroleptic malignant syndrome

d death in elderly patients with dementia-related psychosis

8 Clozapine can cause:

a granulocytopenia b.gastrointestinal hypomotility

c myocarditis

d all of the above

9 A 26-year-old woman with schizophrenia has been taking risperidone for the past 3 years She has responded to treatment, but has gained about 40 pounds since starting the drug You are considering switching her to lurasidone Which

of the following statements about the use of risperidone and lurasidone is true?

a risperidone is an older drug with a longer record of safety

b lurasidone is less likely to cause diabetes than risperidone

c among all the drugs in this class, lurasidone is among those least likely to cause weight gain

d all of the above

10 The second-generation antipsychotics most likely to cause weight gain and diabetes are:

a quetiapine and risperidone

b risperidone and paliperidone

c clozapine and olanzapine

d iloperidone and quetiapine

Celecoxib Safety Revisited

1 Nonselective NSAIDs such as naproxen can cause:

a gastrointestinal toxicity

b bleeding

c fluid retention

d all of the above

2 The PRECISION trial found that celecoxib was noninferior

to ibuprofen and naproxen with regard to cardiovascular

safety, but:

a it was a retrospective trial with confounding factors

b the average daily dose of celecoxib was lower than the

doses previously associated with cardiovascular toxicity

c none of the drugs were superior in effi cacy to placebo

d all of the above

Drugs for Psychotic Disorders

3 In comparing fi rst- and second-generation antipsychotic drugs,

which of the following is true?

a fi rst-generation drugs are less likely to cause tardive

dyskinesia

b controlled trials generally have found second-generation

drugs more effective

c second-generation drugs are more expensive

d all of the above

4 Which antipsychotic drug is generally considered the most

effective for treatment of schizophrenia?

a clozapine

b olanzapine

c risperidone

d haloperidol

5 Second-generation antipsychotics are more likely than fi

rst-generation drugs to cause:

a anticholinergic effects

b metabolic syndrome

c extrapyramidal symptoms

d all of the above

ACPE UPN: Per Issue Exam: 0379-0000-16-510-H01-P; Release: December 19, Expire: December 19, 2017 Comprehensive Exam 75: 0379-0000-17-075-H01-P; Release: January 2017, Expire: January 2018

PRESIDENT: Mark Abramowicz, M.D.; VICE PRESIDENT AND EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR IN CHIEF: Jean-Marie Pflomm,

Pharm.D.; ASSOCIATE EDITORS: Susan M Daron, Pharm.D., Amy Faucard, MLS, Corinne Z Morrison, Pharm.D., Michael P Viscusi, 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 Surgeons; Vanessa K Dalton, M.D., M.P.H., University of Michigan Medical School;

Eric J Epstein, M.D., Albert Einstein College of Medicine; Jane P Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; David N Juurlink, BPhm, M.D., Ph.D.,

Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; Franco M Muggia, M.D., New York University Medical Center; Sandip K Mukherjee,

M.D., F.A.C.C., Yale School of Medicine; Dan M Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K Schaefer, M.D., M.P.H., Harvard Medical School; F Estelle

R Simons, M.D., University of Manitoba; Neal H Steigbigel, M.D., New York University School of Medicine; Arthur M F Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell

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Founded in 1959 by Arthur Kallet and Harold Aaron, M.D.

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edito-rial process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical tedito-rials, and on the opinions of its consultants The Medical Letter, Inc does not sell advertising or receive any commercial support No part of the material may be reproduced or transmitted by any process in whole or in part without prior permission in writing The editors do not warrant that all the material in this publication is accurate and complete in every respect The editors shall not be held responsible for any damage resulting from any error, inaccuracy, or omission.

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