Psychotropic Medications:

Uses and Misuses

John Spollen, MD

Vice Chair for Education

Department of Psychiatry, UAMS

spollenjohnj@uams.edu

Antidepressants and Antipsychotics:

“Is that medication harming my

patient?”

John Spollen, MD

Vice Chair for Education

Department of Psychiatry, UAMS

spollenjohnj@uams.edu

Objectives

Participants will be able to:

• Identify which antidepressants and antipsychotics are associated with significant QT prolongation.

• Identify which antipsychotics are most likely to cause movement disorder side effects.

• Identify which antipsychotics are most likely to cause weight gain and worsen diabetes and hyperlipidemia.

Agenda

• QTc Issues with antidepressants and antipsychotics

• Review recent meta-analysis of antipsychotic adverse effects

• Update on pharmacologic management of agitation due to

▫ Delirium

▫ Dementia

Case 1

• CW is a 66yo female admitted for pneumonia. EKG on admission shows QTc of 505. She is prescribed sertraline, mirtazapine and aripiprazole for major depression with psychotic features.

• Did any of these psychotropic medications likely contribute to her long QT?

History: Cardiac Issues with Psychotropics

• 1963: Thioridazine hydrochloride (Mellaril): its effect on the electrocardiogram and a report of two fatalities with electrocardiographic abnormalities. Can Med Assoc J.

• 1964: Ventricular tachycardia associated with administration of thioridazine hydrochloride (Mellaril): report of a case with a favourable outcome. Can Med Assoc J.

• 1964: The effect of phenothiazines on the ECG. Can Med Assoc J.

• How long until 1st FDA warnings on Mellaril:

▫ July 7, 2000!

History: Cardiac Issues with Psychotropics

• Fowler NO, McCall D, Chou TC, et al. Electrocardiographic changes and cardiac arrhythmias in patients receiving psychotropic drugs. Am J Cardiol. 1976;37:223-230.

▫ “Major cardiac arrhythmias are a potential hazard in patients without heart disease who are receiving customary therapeutic doses of psychotropic drugs. ”

QT issues with Antipsychotics (APs)

• Known since the 1960’s▫ In the day of only high risk for toxicity psychotropic

medications (TCAs, MAOIs, 1st Generation APs), maybe got less attention than deserved

• Almost all antipsychotics effectively block the hERGchannel in a dose-dependent manner1

• FDA warnings, and some removals from the marketplace, started in the early 2000’s

1Silvestre JS and Prous JR. Methods Find Exp Clin Pharmacol 2007, 29(7): 457

FDA Warnings for QTC Issues with APs

• 7/2000: Thioridazine

▫ Withdrawn from market in 2005

• 9/2000: Mesoridazine

▫ Withdrawn from market in 2004

• 12/2001: Droperidol

▫ “Deaths associated with QT prolongation and torsades de pointes”

Haloperidol and FDA Warning

• September 2007 FDA announced▫ “Higher doses and intravenous administration of

haloperidol appear to be associated with a higher risk of QT prolongation and TdP.”

▫ “Because of this risk of TdP and QT prolongation, ECG monitoring is recommended if haloperidol is given intravenously.”

APs in Dementia Warnings

• 11/2005: Increased mortality in patients with dementia-related psychosis (for “2nd Gen APs”)

▫ “Patients with dementia-related psychosis treated with atypical (second generation) antipsychotic medications are at an increased risk of death compared to placebo”

• 6/2008: Added conventional APs to Dementia-related psychosis warning

▫ “Both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis.”

Citalopram and FDA Warnings

• August 2011 FDA announced

▫ “Citalopram causes dose-dependent QT interval prolongation. Citalopram should no longer be prescribed at doses greater than 40 mg per day.”

• March 2012 FDA further restricted the max dose to 20 mg for some patients including >60yo and if used with cytochrome P450 2C19 inhibitors

▫ Common 2C19 inhibitors include PPIs and ticlodipine

• Citalopram was the most widely prescribed AD in the US in 2011 with 37.8 million prescriptions

Citalopram and FDA Warnings

• Warnings based on unpublished crossover RCT study of 119 patients

▫ Citalopram QTc prolongation 20mg - 8.5ms 40mg* - 12.6ms 60mg - 18.5ms

▫ Escitalopram 10mg - 4.5ms 20mg* - 6.6ms 30mg - 10.7ms

*Estimate based on the relationship between citalopram/escitalopram blood concentrations and QT interval

QT prolongation with Antidepressant Use

• Review of 38,397 patients prescribed an AD from 1990-2011 with available EKG

• ADs included all major SSRIs, venlafaxine, doluxetine, bupropion, nortriptyline and amitriptyline

▫ Added methadone for “assay sensitivity”

• QT prolongation found for citalopram, escitalopram, amitriptyline and methadone but not for others

▫ Bupropion associated with QT shortening

Castro VM, et al. BMJ. 2013 Jan 29;346:f288.

Mean (SD) corrected QT (QTc) interval recorded on electrocardiogram 14–90 days after

prescription of antidepressant or methadone, by drug dose.

Castro V M et al. BMJ 2013;346:bmj.f288

QT Prolongation with SSRIs

• Meta-analysis of 4292 patients from 25 datasets

▫ Citalopram (10.58ms), escitalopram (7.27 ms) and sertraline (3.0ms) has statistically significant QTcprolongation

▫ Fluoxetine and paroxetine had no significant QTc effect

Beach SR et al., JClinPsych 2014;75(5):e441-e449

Antidepressant QTc Reviews

• Of SSRIs▫ Citalopram highest risk, followed by escitalopram

▫ Fluoxetine and sertraline are low risk and paroxetine is the lowest risk

▫ In post ACS patients, fluoxetine, sertraline and even escitalopram did not show QTc prolongation

• Of other newer ADs▫ Relatively limited data, but all seem low risk in usual

dosing range

▫ Venlafaxine or bupropion may lengthen QT in overdoses

Funk KA, Bostwick JR. Ann Pharmacother. 2013 Oct;47(10):1330-41.

Jasiak NM, Bostwick JR. Ann Pharmacother. 2014 Dec;48(12):1620-8.

Arguments vs FDA warnings for citalopram

• Strident article arguing FDA QTc concerns of citalopram have been overstated

• Reviewed all published cases of TdP within 20-60mg/d range and found all had other major risk factors

• Pointed out several “unintended consequences” of the FDA warnings

Vieweg WV et al. Am J Med. 2012;125:859-868.

• Large VA cohort study of depressed patients treated with citalpram (618,450) or sertraline (365,898)

▫ Citalopram daily doses >40 mg were associated with lower risks of ventricular arrhythmia, all-cause mortality, and noncardiac mortality

▫ No increased risks of cardiac mortality were found Ventricular arrhythmia risk actually decreased with

higher dose of citalopram and sertraline!

Zivin K et al. Am J Psychiatry 2013; 170:642–650.

Arguments vs FDA warnings for citalopram

Low dosages for citalopram and sertraline were 1–20 mg/day and 1–50 mg/day, respectively; medium dosages were 21–40 mg/day and 51–100 mg/day, respectively; and high dosages were >40 mg/day and >100 mg/day, respectively.

Clinical and Mortality Outcomes for Veterans Health Administration Patients With Depression

Treated With Citalopram or Sertraline (2004–2009): Zivin K et al. Am J Psychiatry 2013; 170:642–650

Pfizer 054 Study

A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition.

Harrigan EP, et al. J Clin Psychopharm. 24(1):62-9, 2004 Feb.

QTc prolongation

Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013;

382: 951–62

**

* *Not available in US

Clinical Management of the Risk of

Arrhythmia Induced by Psychotropics

• Recently published expert consensus guidelines for management from a group from Danish cardiac and psychiatric societies

• Reviewed data from FDA, EU’s equivalent, Maudsleyguidelines, AzCERT and Micromedex

• Rated risk by drug and provided algorithm for reducing risks including workup, if needed

Fanoe S et al. Eur Heart J 2014;35:1306-1315 AzCERT: Arizona Center on Education and Research on Therapeutics

An algorithm for lowering the risk of cardiac arrhythmia during treatment with psychotropic medications.

Fanoe S et al. Eur Heart J 2014;35:1306-1315Published on behalf of the European Society of Cardiology. All rights reserved. © The Author

2014. For permissions please email: journals.permissions@oup.com

“A” level (no “heart check-ups”) Medications

• APs▫ Aripiprazole

▫ Olanzapine

▫ Perphenazine▫ (not enough data yet on lurasidone to say OK)

• ADs▫ Most SSRIs (fluoxetine, paroxetine, sertraline)

▫ Duloxetine, bupropion, mirtazapine

▫ So, only B (“need check-up”) of newer ADs were: citalopram, escitalopram and venlafaxine

Fanoe S et al. Eur Heart J 2014;35:1306-1315

Other Adverse Effects of Antipsychotic

Medications

•A “cut to the chase” on

▫ Most effective antipsychotic medication

▫ Metabolic side effects

▫ Motor side effects

▫ Prolactin elevation

Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-

treatments meta-analysis. Lancet 2013; 382: 951–62

Comparative Efficacy for Schizophrenia

Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-

treatments meta-analysis. Lancet 2013; 382: 951–62

EPS vs. Metabolic Risks: Dones vs. the Pines

• Metabolic risk usually worse with “pine” drugs▫ Clozapine and olanzapine easily the worst

▫ Quetiapine next worst, and often very bad for triglycerides

▫ Risperidone mid-level risk, much lower than “pines”

▫ Aripiprazole, ziprasidone and lurazisdone the least risk

• EPS risk the opposite; worse with “done/ole’s” ▫ No risk with clozapine and quetiapine, very low with

olanzapine unless very high doses

▫ Aripirazole and ziprasidone can cause EPS and seem especially bad for akathisia

▫ Paliperidone and lurasidone appear high risk in RCTs

▫ Risperidone risk dose dependent and only at >6mg/d

Weight Gain

EPS (Dystonias, Parkinsonism, Akathisia)

Prolactin Increases

EPS vs. Metabolic Risks: Dones vs. the Pines

• Metabolic risk usually worse with “pine” drugs▫ Clozapine and olanzapine easily the worst

▫ Quetiapine next worst, and often very bad for triglycerides

▫ Risperidone mid-level risk, much lower than “pines”

▫ Aripiprazole, ziprasidone and lurazisdone the least risk

• EPS risk the opposite; worse with “done/ole’s” ▫ No risk with clozapine and quetiapine, very low with

olanzapine unless very high doses

▫ Aripiprazole and ziprasidone can cause EPS and seem especially bad for akathisia

▫ Paliperidone and lurasidone appear high risk in RCTs

▫ Risperidone risk dose dependent and only at >6mg/d

Quick Update on Related Psychiatry

Consult Recommendations

•Delirium

•Dementia with agitation/”behavioral disturbance”

Pharmacologic Management of Agitation

Due to Delirium• Haloperidol still considered by most experts to be first line agent

for management of agitation in delirium – but not FDA approved

• Reasons it is first line: ▫ Extensive history of use▫ Minimal anticholinergic side effects▫ No active metabolites▫ Can be administered IV – possibly less extrapyramidal side effects (EPS)

when given IV ▫ Less sedation than most other neuroleptics/ benzodiazepines ▫ Rare CV side effects

Prolonged QT interval, especially if IV, and may lead to torsades TdP usually seen only high doses (>35mg/day) Obtain baseline ECG and monitor QTc interval

FDA guidelines only require checking ECG if using IV

Pharmacologic Management of

Agitation Due to Delirium

• Can start with prn but if being used frequently consider adding low dose standing order:

o Haloperidol 0.5-1 mg po qd - q4 hr up to 10 mg/d (best to stay below 4-5 mg/d if patient is over 65)

o Quetiapine 12.5-25 mg po qd - q 4hr up to 150 mg/d (best choice for Parkinson’s or Lewy Body dementia; more sedating than haloperidol/risperidone)

o Risperidone 0.25-0.5 mg po qd- q 4hr up to 2 mg/d

o Olanzapine 2.5-5 mg po qd - q 4hr up to 10 mg/d

• Baseline and repeat EKG - for QT interval

Pharmacologic Management of Agitation

in Dementia

• Antipsychotics used for years but

▫ Not effective in large RCTs

▫ Death rate is 1.5-2x placebo rate in RCTs

• Citalopram recently shown to be moderately effective

▫ Reduced agitation and caregiver stress

• And (mostly) well tolerated

▫ QTc prolongation of 18ms was noted

▫ Mild worsening of cognition (1 point on MMSE)

Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA.

2014 Feb 19;311(7):682-91.

Pharmacologic Management of Agitation

in Dementia

• How to use this?

▫ Use escitalopram 5-10mg daily

~½ the QTc prolongation, no FDA warnings

Essentially same active chemical

▫ Expect other SSRIs would work as well

Use low dose sertraline 25-50mg

Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA.

2014 Feb 19;311(7):682-91.

Questions?