restrained use of antipsychotic medications · restrained use of antipsychotic medications:...

Restrained use of antipsychotic medications:

Rational management of irrationality

Balanced information for better care

These drugs are commonly prescribed in conditions for which there is little evidence of benefit, but considerable risk of harm.

2 Restrained use of antipsychotic medications: Rational management of irrationality

Year

Antipsychotic medications (APMs) are a mainstay for managing major psychiatric illnesses such as schizophrenia and bipolar disorder, and can do enormous good for patients with these problems.

FIGURE 1. Annual US antipsychotic prescription trends, 1995 to 20081

Olanzapine approved

Clozapine, 1989 Risperidone, 1993

Quetiapine approved

Ziprasidone approved

Aripiprazole approved

Warning: Metabolic side effects (Atypicals)

Paliperidone approved

Black Box Warning (Atypicals)

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

18000

16000

14000

12000

10000

8000

6000

4000

2000

0

Ant

ipsy

chot

ic tr

eatm

ent v

isits

However, in recent years newer agents, the atypical APMs, have been promoted widely for use in very different conditions, for which their efficacy is often not well established. These include the management of patients with Alzheimer’s disease, and as a core treatment for depression (Table 1). Besides their limited efficacy, these drugs can cause weight gain, raise blood sugar, prolong the Q-T interval, and increase cholesterol levels. They also significantly increase the risk of death in older patients.

Atypical Antipsychotics

Typical Antipsychotics

Balanced information to support better care 3

Antipsychotic medications cause important adverse effects:

TABLE 2. Adverse effects of APMs*

TABLE 1. Relative efficacy of APMs, other medications, and non-pharmacologic therapies for selected conditions

Condition Efficacy of APMsEfficacy of other medications

Efficacy of non-drug therapies

Schizophrenia can be useful as adjuncts to APMs

can be useful as adjuncts to APMs

Bipolar illness mood stabilizers are primary and APMs can be adjuncts

can be useful as adjuncts to APMs

Depression SSRIs, bupropion, SNRIs, mirtazapine

psychotherapy, cognitive behavioral therapy, ECT

Dementia SSRIs, trazodone re-orientation, calming techniques

PTSD without psychosis SSRIs, SNRIs psychotherapy

PTSD with psychosis SSRIs, SNRIs psychotherapy

OCD SSRIs, SNRIs psychotherapy

DRUG

haloperidol (Haldol) — ++ + + — — ++ ++

perphenazine (Trilafon) — + — + — — ++ +

clozapine (Clozaril) ++ — + ++ ++ ++ — +

risperidone (Risperdal) + — + — + — ++ +

olanzapine (Zyprexa) ++ — + + — — + +

quetiapine (Seroquel) +§ — ++ + + — — +

aripiprazole (Abilify) + — — — — — — +

ziprasidone (Geodon) — — ++ — — — — +

Weight gain**

& metabolic

effects

Extra py

ramidal

symptoms

QTc prolongatio

n

Sedation

Orthosta

tic

hypotensio

n

Anticholin

ergic

toxici

tyProlacti

n

elevatio

n

1st g

ener

atio

n2n

d ge

nera

tion

(aty

pica

l AP

Ms)

* Authors’ consensus interpretation of pertinent evidence ** For weight gain, ++: 2-3 kg/month +: 1-2 kg/month§ More triglyceride elevation than risperidone and aripiprazole

Death

Evidence of substantial benefit from randomized controlled trials

Evidence of some benefit from small trials or observational studies

Little evidence of benefit


Remission?

Continue treatment

Maximize dose of first agent

Augment with triiodothyronine

Try second line drug (TCA)

Y

Start with SSRI, bupropion, SNRI, or mirtazapine,

4- 6 weeks. Choose agent

based on anticipated side effects

Remission?

Combine venlafaxine + mirtazapine

Try another option above. If all fail to achieve remission, try 1 of 3 additional options, or refer to psychiatrist

Remission?

Combine SSRI + bupropion

Augment with buspirone

Switch to another first line agent

N

FIGURE 2. Pharmacologic management of depression2-5

Antipsychotic medications and depressionGiven their risks, these drugs should not be used for most patients to manage depression resistant to conventional antidepressant therapy.2

Then, treat with non-pharmacologic therapy (psychotherapy, or cognitive behavioral therapy), first line antidepressants, or both. ECT can be useful in some non-responsive patients, especially the elderly.

The algorithm below depicts several first, second, and third line treatments for depression, all of which are safer than use of an APM.2-5 SGAs are not recommended at any time because of tardive dyskinesia risk (see next page for explanation).

First, make sure the patient actually has depression, based on DSM-IV criteria:2

N

N

Either 1 or 2 of the following must be present: plus, these other symptoms to make a total of 5:

depressed mood markedly diminished interest or pleasure

change in sleep or appetite/weight decreased energy thoughts of worthlessness/guilt, or death/suicide psychomotor retardation or agitation poor concentration

The patient must have these symptoms most of the day, nearly every day, for >2 weeks.

Y

Y


Aripiprazole, quetiapine, and olanzapine (in combination with fluoxetine) are FDA approved for depression therapy augmentation, but should be used when other augmentation strategies have failed.

—There is robust evidence for mild efficacy for these SGAs (number needed to treat for improvement of 9) but the side effects, especially weight gain, are much more significant than with the other recommended augmentation strategies.7-8

APMs are not FDA approved for monotherapy in depression.

In patients with psychotic depression (that is, with disruptive or dangerous delusions or hallucinations), an antipsychotic can be combined with an antidepressant.6

FIGURE 3. Management of depression with psychotic features6

Symptoms improved?

Continue treatment

Switch to other combination

Symptoms improved?

Continue treatment

Refer to psychiatrist

Continue treatment

Symptoms improved?

SSRI OR TCA

SSRI + antipsychotic OR

TCA + antipsychotic

Psychosis disruptive or dangerous

Psychosis not disruptive or dangerous, or patient unwilling

to take antipsychotic

NN

N

YY

Y

Reconsider antipsychotic

6 Restrained use of antipsychotic medications: Rational management of irrationality6

In older patients with dementia, the use of antipsychotic medications increases the relative risk of death by 70%.9

The risks of APMs often outweigh their benefits, especially when used for non-severe problems. In a randomized trial, only 20-30% of patients had improvement in symptoms when treated with an antipsychotic drug for dementia symptoms.10

It has been estimated that for every 100 patients with dementia treated with an antipsychotic medication, only 9 to 25 patients will benefit and 1 will die.10-11

Despite their risks, antipsychotic medications are often used loosely in patients with dementia to manage a wide variety of behaviors, including wandering, socially inappropriate interactions, and difficulty sleeping. Many nursing home patients with dementia are prescribed APMs without a clear indication.

All APMs carry a black box warning about the risk of death:9

WARNING: Increased Mortality in Elderly Patients With Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

The risk of death in drug-treated patients is 1.6–1.7 times that of placebo-treated patients.

Rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Most deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Treatment with conventional antipsychotic drugs also increases mortality.

FIGURE 4. Information from FDA Black Box Warning that appears on labeling for all antipsychotic medications9


If these drugs must be used to manage agitation or aggressive behavior:

identify the target behaviors being treated

start at a low dose

reassess regularly — to gauge the response of the targeted symptoms — to monitor for side effects

use for the shortest time possible.

A systematic review found some APMs work better than others in patients with dementia with aggressive behavior requiring APM use:13

* Measured by BEHAVE-AD, BPRS, or NPI: www.assessmentpsychology.com/geriatricscales.htm This review did not find any studies with ziprasidone for dementia-related symptoms.

Drug and starting dose

aripiprazole (5mg)

olanzapine (1.25mg)

quetiapine (12.5mg)

risperidone (0.25mg)

Overall symptoms*

Psychosis

Agitation

TABLE 3. Relative efficacy of APMs in treatment of dementia-related behaviors13

FIGURE 5. Percentage of nursing home patients with dementia prescribed an APM, by type of behavioral symptom12

60%

40%

20%

0%with aggressive

behavioral problems

with non-aggressive behavioral problems

with no behavioral problems

Moderate-high evidence Mixed results Low or very low evidence

51%

40%

23%


Given the lack of benefit and substantial risks of APMs in older patients, whenever circumstances permit first try non-pharmacologic behavioral treatments. If these fail, medications can be added to manage severe persistent behavioral symptoms that present a real risk to the patient or others:

FIGURE 6. Treatment algorithm for behavioral symptoms of dementia13-15

Dementia with no aggression

Attempt these non-drug approaches in all dementia patients with behavioral symptoms:

gently remind of person, place, time Supervise: provide companionship and observation

offer exercise, music, massage, aromatherapy address temperature, lighting, hunger, thirst

reduce noise, correct hearing/vision

Dementia with mild aggression

Dementia with severe aggression

No additional medications needed

Non-APM medications: SSRI, trazadone,

memantine

APM medications: risperidone aripiprazole


Post-traumatic stress disorder: For PTSD, first treat any sleep disturbance (algorithm below), then prescribe an SSRI.16

Sertraline and Paroxetine are the only FDA-approved medications for PTSD. Of the two, paroxetine has the better evidence-base, but also more side effects such as weight gain and sexual dysfunction.

Resort to antipsychotic medications for PTSD patients with psychotic symptoms that persist on SSRIs, as depicted below:16

Antipsychotic drugs in other conditionsThese drugs may be of use in some patients with post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD), but usually after other therapies (including psychotherapy) have been tried.

Obsessive-compulsive disorder:First treat with an SSRI (most OCD patients will need maximum or higher doses); if poor response, try another SSRI.17

Continued symptoms may require an antipsychotic medication (risperidone is the most effective in OCD). Patients whose symptoms are severe enough to require consideration of an APM are likely to need the care of a psychiatrist.

FIGURE 7. Management of post-traumatic stress disorder16

SSRI

Continued PTSD symptoms?

With psychosis: add antipsychotic (risperidone best)

Without psychosis: try 2nd SSRI, SNRI,

or mirtazapine

Continue treatment

Sleep disturbed?

Continued PTSD symptoms?

Nightmares/ hyperarousal:

prazosin

Sleep initiation: trazodone

Both: prazosin then trazodone

N

N

N

Y

Y

Y

10 Restrained use of antipsychotic medications: Rational management of irrationality10

Screening and monitoring are necessaryWhatever the indication, all patients prescribed an APM will require a number of screening tests both at baseline and at regular intervals, to monitor adverse effects.18

TABLE 4. Monitoring adverse effects in patients taking APMs

Adverse effect What to assessScreening: at baseline, and then:

Metabolic effects

overall weight gain weight and BMI monthly x 3, then quarterly

central weight gain waist circumference annually

diabetes fasting glucose, or HgbA1c 3 months, then annually

hyperlipidemia fasting lipid profile 3 months, then every 5 years or less

Neurologic effects

extrapyramidal symptoms involuntary movements every visit

sedation daytime somnolence every visit

Cardiovascular effects

QT prolongation QT interval on EKG with addition of other QT prolonging drugs*

orthostatic hypotension dizziness or BP drop with standing

every visit

Other effects

prolactin elevation galactorrhea, amenorrhea, sexual dysfunction, gynecomastia

every visit

anticholinergic toxicity blurry vision, dry mouth, sedation, urinary retention, constipation

every visit

* A list of QT prolonging drugs can be found at: www.qtdrugs.org


CostAll second generation antipsychotics are expensive.

Antipsychotics are the 5th most costly medication class in the U.S., with annual spending of >$16 billion.19 Even with low doses or generics, the monthly cost of all these agents may be unaffordable for many patients.

Listed doses reflect dosing equivalents, and are not recommended starting doses in the elderly. Drug prices obtained from drugstore.com

FIGURE 8. Monthly cost of antipsychotic medications based on defined daily dose from the World Health Organization

References:(1) Alexander GC, Gallagher SA, Mascola A, Moloney RM, Stafford RS. Increasing off-label use of antipsychotic medications in the United States, 1995-2008. Pharmacoepidemiology and Drug Safety. Feb 2011; 20(2):177-184. (2) American Psychiatric Association. Treatment of patients with major depressive disorder. 2010; http://www.psychiatryonline.org/guidelines.aspx (3) Rush AJ, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med, 2006; 354:1231-42. (4) Zimmerman M, Posternak MA, Attiullah N, et al. Why isn’t bupropion the most frequently prescribed antidepressant? The Journal of Clinical Psychiatry. May 2005; 66(5):603-610. (5) VA-DOD. Management of major depressive disorder (MDD). 2009; http://www.healthquality.va.gov/mdd/mdd_sum09_c.pdf (6) Hamoda HM, and Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An update on psychotic depression. Harvard Review of Psychiatry. 2008; 16(4):235-247. (7) Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. American Journal of Psychiatry. 2009; 166:980-991. (8) Correll CU, Manu P, Olshanskiy V, et al. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. Journal of the American Medical Association. 2009; 302:1765-73. (9) FDA. Public Health Advisory: Deaths with antipsychotics in elderly patients with behavioral disturbances. 2008; www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm124830.htm (10) Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med. Oct 12 2006; 355(15):1525-1538. (11) Schneider, LS et al. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005; 294:1934-1943. (12) Crystal S, Olfson M, Huang C, Pincus H, and Gerhard T. Broadened use of atypical antipsychotics: Safety, effectiveness, and policy challenges. Health Affairs. 2009; 28(5):w770-w781. (13) AHRQ. Off label use of atypical antipsychotics. 2011; http://www.effectivehealthcare.ahrq.gov/ehc/products/150/786/CER43_Off-Label-Antipsychotics_execsumm_20110928.pdf (14) Henry G, et al. Am J Alz Dis and Other Dementias. 2011; 26:169. (15) Wilcock GK, Ballard CG, Cooper JA, and Loft H. Memantine for agitation/aggression and psychosis in moderately severe to severe Alzheimer’s disease: A pooled analysis of 3 studies. The Journal of Clinical Psychiatry. Mar 2008; 69(3):341-348. (16) Stein DJ. Pharmacotherapy for post traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2006; CD002795. (17) Soomro GM. Selective serotonin reuptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD). Cochrane Database Syst Rev. 2008; CD001765. (18) Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004; 27(2):596-601. (19) Primary care companion. Use of antipsychotics in primary care. J Clin Psychiatry. 2003; 5(suppl 3):3-8.

Additional references documenting these recommendations are provided in the evidence document accompanying this material, also available at www.RxFacts.org.

0 200 400 600 800

haloperidol (generic)

perphenazine (generic)

aripiprazole (Abilify)

olanzapine (generic)

olanzapine (Zyprexa)

quetiapine XR (Seroquel XR)

quetiapine (Seroquel)

risperidone (generic)

risperidone (Risperdal)

ziprasidone (Geodon) $332

$473

$200

$576

$511

$624

$380

$560

$108

$36

The Independent Drug Information Service (IDIS) is supported by the PACE Program of the Department of Aging of the Commonwealth of Pennsylvania, and the Washington D.C. Department of Health. Additional support is provided by the Rx Foundation.

This material is provided by The Alosa Foundation, a nonprofit education organization which is not affiliated in any way with any pharmaceutical company.

This material was produced by Danielle Scheurer, M.D., M.Sc., S.F.H.M., Assistant Professor of Medicine, Medical University of South Carolina; David N. Osser, M.D., Associate Professor of Psychiatry, Harvard Medical School and VA Boston Healthcare System; Niteesh K. Choudhry, M.D., Ph.D., Associate Professor of Medicine, Harvard Medical School; Michael A. Fischer, M.D., M.S., Assistant Professor of Medicine, Harvard Medical School; Jerry Avorn, M.D., Professor of Medicine, Harvard Medical School. Drs. Avorn, Choudhry, and Fischer are all physicians at the Brigham and Women’s Hospital in Boston. Dr. Scheurer is a physician at the Medical University of South Carolina. None of the authors accepts any personal compensation from any drug company.

©2012 The Alosa Foundation

These are general recommendations only; specific clinical decisions should be made by the treating physician based on an individual patient’s clinical condition.

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