©2017 MFMER | slide-1

Psychiatry in Medical Settings Pharmacology Challenges in Consultation Psychiatry

Robert P. Bright, M.D.

©2017 MFMER | slide-2

Disclosure

Relevant Financial Relationships

None

Off-Label/Investigational Uses

The off-label use of antipsychotic medications in the treatment of agitated delirium will be discussed

©2017 MFMER | slide-3

Learning Objectives

• Increased understanding of factors influencing the choice of psychotropic medications in a patient with complex medical co-morbidities

©2017 MFMER | slide-4

Altered Mental Status in a Young Patient with Cancer

• 34 year old SWF diagnosed 6 months ago with aplastic anemia, admitted after BIB EMS to ED for after “found down” outside her apartment by a neighbor. AMS upon arrival to ED.

• Consultation Question: Management of Agitated Delirium

©2017 MFMER | slide-5

History

• Psych Hx: Depression and inpatient treatment for an eating disorder

• Medical Hx:

• Multiple childhood admissions for recurrent pneumonias

• Seen in ED 6 months ago for fatigue – viral syndrome? Pancytopenic. Bone marrow bx: hypocellularity (5%)

©2017 MFMER | slide-6

Exam

• T 38.5. P 112 RR 12 BP 98/62

• Yelling and pulling at restraints, attempting to strike staff, demanding to leave

• Waxing and waning LOC, attention and concentration

• AVH, PI

• Oriented only to self

• Labs: WBC 1.7, Hgb 8.2, Plts 3,000

• ECG: QTc 515 msec

©2017 MFMER | slide-7

Antipsychotics with Higher Risk for Causing QTc Prolongation

• IV Haloperidol > PO or IM

• Ziprasidone

• Chlorpromazine

• Thioridazine

• Droperidol

• Pimozide

• Iloperidone

Resource for Medications to Avoid with Prolonged QTc:

Crediblemeds.org

Credible Meds. Drugs to be avoided by congenital long QT patients. Available at: http://crediblemeds.org; Dietle A, QTC Prolongation With Antidepressants and

Antipsychotics. US Pharm. 2015; 40(11): HS34-HS40

©2017 MFMER | slide-8

Antipsychotics that do not cause QTc Prolongation

• Aripiprazole

• Lurasidone

• Clozapine

• Loxapine

• Brexiprazole

Dietle A, QTC Prolongation With Antidepressants and Antipsychotics. US Pharm. 2015; 40(11): HS34-HS40

©2017 MFMER | slide-9

Management of Psychosis and Agitation in Medically Ill Patients with (or at Risk for) Prolonged QTc

• For patients with risk factors, but no prolonged QT:

• First Tier Choice: Olanzapine po or IM, Aripiprazole po

• Second Tier Choice: Risperidone, Quetiapine, po or IM Haloperidol

• If the QTc is 450 – 499 msec

• Aripiprazole, Olanzapine, Risperidone, Quetiapine

• If the QTc is 500 msec +

• Aripiprazole, Valproate, Trazodone*, Benzodiazepines

Ries, R., & Sayadipour, A. (2014). Management of psychosis and agitation in medical-surgical

patients who have or are at risk for prolonged QT interval. J Psychiatr Pract, 20(5), 338-344. *Teply, R. M., Packard, K. A., White, N. D., Hilleman, D. E., & DiNicolantonio, J. J. (2016).

Treatment of Depression in Patients with Concomitant Cardiac Disease. Prog Cardiovasc Dis, 58(5), 514-528.

©2017 MFMER | slide-10

General Considerations

• If risk factors, baseline and intermittent ECG, Quetiapine and olanzapine – sedating meds may make lower doses possible 1

• Avoid polypharmacy, combination with others that prolong QTc, monitor electrolytes 2

• FDA recommends cardiac monitoring for all patients receiving IV haloperidol 3

1 Beach, S. R., Celano, C. M., Noseworthy, P. A., Januzzi, J. L., & Huffman, J. C. (2013). QTc prolongation, torsades de pointes, and psychotropic medications.

Psychosomatics, 54(1), 1-13. 2 Nielsen, J., Graff, C., Kanters, J. K., Toft, E., Taylor, D., & Meyer, J. M. (2011). Assessing QT interval prolongation and its associated

risks with antipsychotics. CNS Drugs, 25(6), 473-490. 3 US Food and Drug Administration. Information for healthcare professionals: Haloperidol. FDA Alert

2007-9, September 2007 (available at http://www.fda.gov/Drugs/DrugSafety/ucm085203.htm)

©2017 MFMER | slide-11

Antipsychotics that do not cause QTc Prolongation

• Aripiprazole

• Lurasidone

• Clozapine

• Loxapine

• Brexiprazole

Dietle A, QTC Prolongation With Antidepressants and Antipsychotics. US Pharm. 2015; 40(11): HS34-HS40

©2017 MFMER | slide-12

Consult # 2

• Four days later, she has been treated for bacteremia/ sepsis and her mental status has cleared. She is A&O X 4, cooperative and has insight that she was confused. She has reported SI to the staff.

• Consultation Question: Evaluate for depression

©2017 MFMER | slide-13

History and ROS

• FHx: Depression in 3 maternal relatives. No bipolar illness or psychosis

• Psych Hx: No suicide attempts, mania, psychosis, SIB. Inpatient X 2 for depression and anorexia nervosa, binge-eating/ purging type. No h/o mania/ hypomania

• Social History:

• No EtOH, rx or illicit substance abuse hx.

©2017 MFMER | slide-14

Exam

• PHQ -9 = 27

• Depressed mood, hopeless re her prognosis and future, feels helpless and unworthy of treatment, no appetite, anergic, no motivation, hypersomnia, no libido, can’t concentrate. No psychosis.

• + SI with plan to ingest “poison”

• Affect: tearful, distraught, depressed

©2017 MFMER | slide-15

What’s All the Fuss?

• SSRI’s are associated with a dose-dependent MODEST (+6.10 msec), but statistically significant, increase in QTc interval compared with placebo

Beach, S. R., Kostis, W. J., Celano, C. M., Januzzi, J. L., Ruskin, J. N., Noseworthy, P. A., & Huffman, J. C. (2014). Meta-analysis of selective serotonin

reuptake inhibitor-associated QTc prolongation. J Clin Psychiatry, 75(5), e441-449.

©2017 MFMER | slide-16

What’s All the Fuss?

• “A comprehensive review of the published literature has concluded that there is little evidence that psychotropic drug – associated QTc interval prolongation by itself is sufficient to predict TdP.”

• At least one additional risk factor in 92% of cases

• In TdP cases

• 20% had QTc < 500 msec

• 75% at therapeutic drug doses Hasnain, M., & Vieweg, W. V. (2014). QTc interval prolongation and torsade de

pointes associated with second-generation antipsychotics and antidepressants: a comprehensive review. CNS Drugs, 28(10), 887-920.

©2017 MFMER | slide-17

Other Risk Factors

• Congenital Prolonged QTc

• Female

• Hypomagnesemia

• Hypokalemia

• Bradycardia

• Recent MI

• Co-administered QTc-prolonging meds

Beach, S. R., Celano, C. M., Noseworthy, P. A., Januzzi, J. L., & Huffman, J. C. (2013). QTc prolongation, torsades de pointes, and psychotropic medications.

Psychosomatics, 54(1), 1-13.

©2017 MFMER | slide-18

Antidepressants with Higher Risk for Causing QTc Prolongation

• Amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline

• Citalopram, escitalopram, fluoxetine, paroxetine, sertraline

• Mirtazapine, trazodone, venlafaxine

Credible Meds. Drugs to be avoided by congenital long QT patients. Available at: http://crediblemeds.org; Dietle A, QTC Prolongation With Antidepressants and Antipsychotics. US Pharm. 2015; 40(11): HS34-HS40

©2017 MFMER | slide-19

Antidepressants and QTc

• No QTc Prolongation:

• Cymbalta (duloxetine)

• Pristiq (desvenlafaxine)

• Fetzima (levomilnacipran)

• No clinically significant QTc Prolongation at Therapeutic Doses:

• Viibryd (vilazodone)

• Desyrel (trazodone)

• Wellbutrin (bupropion)

• Trintellix (vortioxetine)

Dietle A, QTC Prolongation With Antidepressants and Antipsychotics. US Pharm. 2015; 40(11): HS34-HS40

©2017 MFMER | slide-20

Which would be the SAFEST antipsychotic medication for the management of her agitation?

1. Intravenous haloperidol

2. Oral quetiapine

3. Intramuscular olanzapine

4. Oral aripiprazole

5. Oral risperidone

©2017 MFMER | slide-21

What would be the SAFEST antidepressant choice?

1. Sertraline

2. Nortriptyline

3. Desvenlafaxine

4. Mirtazapine

5. Bupropion

©2017 MFMER | slide-22

©2017 MFMER | slide-23

Low-dose IV Haloperidol in the ICU

• 34 patients. Baseline QTc < 500 msec. Delirium, in ICU. Other risk factors not excluded.

• 1 mg IV q6h vs placebo, double blind. Telemetry + q 12h ECG.

• No significant difference in average rate of change of QTc over time, proportion of patients who developed QTc prolongation (8/34 H vs 14/34 P), a QTc > 500 msec (4/34 H vs 3/34 P) or increase QTc by > 60 msec 6/34 H vs 14/34 P)

• Need to study larger numbers and higher doses Duprey, M. S., Al-Qadheeb, N., Roberts, R., Skrobik, Y., Schumaker, G., & Devlin, J. W. (2016). The use of low-dose IV haloperidol is not associated with QTc prolongation: post hoc analysis of

a randomized, placebo-controlled trial. Intensive Care Med.

©2017 MFMER | slide-24

Saphris (asenapine): Sublingual

• Mild effect on QTc, comparable to quetiapine

• 2 to 5 msec compared to placebo. No QTc increases ≥60 msec , no prolongation to QTc to ≥500 msec.

• 10 mg SL acute agitation in ER. Well tolerated. NNT comparable to IM ziprasidone 10-20 mg, IM olanzapine 10 mg, IM aripiprazole 9.75 mg, haloperidol 6.5 – 7.5 mg, IM lorazepam 2 mg

Citrome, L. (2014). Asenapine review, part II: clinical efficacy, safety and tolerability. Expert Opin Drug Saf, 13(6), 803-830.