Psychotropic Medications:
Uses and Misuses
John Spollen, MD
Vice Chair for Education
Department of Psychiatry, UAMS
Antidepressants and Antipsychotics:
“Is that medication harming my
patient?”
John Spollen, MD
Vice Chair for Education
Department of Psychiatry, UAMS
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▫ Withdrawn from market in 2005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: [email protected]
“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?