Restrained use of antipsychotic medications:

Transcription

1 Balanced information for better care Restrained use of antipsychotic medications: Rational management of irrationality These drugs are commonly prescribed in conditions for which there is little evidence of benefit, but considerable risk of harm.

2 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 Antipsychotic treatment visits Clozapine, 1989 Risperidone, 1993 Olanzapine approved Quetiapine approved Aripiprazole approved Ziprasidone approved Warning: Metabolic side effects (Atypicals) Black Box Warning (Atypicals) Paliperidone approved ear Atypical Antipsychotics Typical Antipsychotics 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. 2 Restrained use of antipsychotic medications: Rational management of irrationality

3 TABLE 1. Relative efficacy of APMs, other medications, and non-pharmacologic therapies for selected conditions Condition Efficacy of APMs Efficacy of other medications Efficacy of non-drug therapies Schizophrenia Bipolar illness Depression can be useful as adjuncts to APMs mood stabilizers are primary and APMs can be adjuncts SSRIs, bupropion, SRIs, mirtazapine can be useful as adjuncts to APMs can be useful as adjuncts to APMs psychotherapy, cognitive behavioral therapy, ECT Dementia SSRIs, trazodone re-orientation, calming techniques PTSD without psychosis SSRIs, SRIs psychotherapy PTSD with psychosis SSRIs, SRIs psychotherapy OCD SSRIs, SRIs psychotherapy Evidence of substantial benefit from randomized controlled trials Evidence of some benefit from small trials or observational studies Little evidence of benefit Antipsychotic medications cause important adverse effects: TABLE 2. Adverse effects of APMs* 1st generation 2nd generation (atypical APMs) DRUG Weight gain** & metabolic effects Extra pyramidal symptoms QTc prolongation Sedation Orthostatic hypotension Anticholinergic toxicity Prolactin elevation haloperidol (Haldol) perphenazine (Trilafon) clozapine (Clozaril) risperidone (Risperdal) olanzapine (Zyprexa) quetiapine (Seroquel) aripiprazole (Abilify) + + ziprasidone (Geodon) ++ + * 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 Balanced information to support better care 3

4 Antipsychotic medications and depression Given their risks, these drugs should not be used for most patients to manage depression resistant to conventional antidepressant therapy. 2 First, make sure the patient actually has depression, based on DSM-IV criteria: 2 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 The patient must have these symptoms most of the day, nearly every day, for >2 weeks. change in sleep or appetite/weight decreased energy thoughts of worthlessness/guilt, or death/suicide psychomotor retardation or agitation poor concentration 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). FIGURE 2. Pharmacologic management of depression 2-5 Start with SSRI, bupropion, SRI, or mirtazapine, 4-6 weeks. Choose agent based on anticipated side effects Remission? Maximize dose of first agent Remission? Continue treatment Combine SSRI + bupropion Augment with buspirone Switch to another first line agent Remission? Try another option above. If all fail to achieve remission, try 1 of 3 additional options, or refer to psychiatrist Augment with triiodothyronine Try second line drug (TCA) Combine venlafaxine + mirtazapine 4 Restrained use of antipsychotic medications: Rational management of irrationality

5 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 features 6 Psychosis disruptive or dangerous Psychosis not disruptive or dangerous, or patient unwilling to take antipsychotic SSRI + antipsychotic OR TCA + antipsychotic SSRI OR TCA Symptoms improved? Symptoms improved? Continue treatment Continue treatment Switch to other combination Reconsider antipsychotic Symptoms improved? Continue treatment Refer to psychiatrist Balanced information to support better care 5

6 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 All APMs carry a black box warning about the risk of death: 9 FIGURE 4. Information from FDA Black Box Warning that appears on labeling for all antipsychotic medications 9 WARIG: 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 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. 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 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. 6 Restrained use of antipsychotic medications: Rational management of irrationality

7 FIGURE 5. Percentage of nursing home patients with dementia prescribed an APM, by type of behavioral symptom 12 60% 40% 51% 40% 20% 23% 0% with aggressive behavioral problems with non-aggressive behavioral problems with no behavioral problems 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 TABLE 3. Relative efficacy of APMs in treatment of dementia-related behaviors 13 Drug and starting dose aripiprazole (5mg) olanzapine (1.25mg) quetiapine (12.5mg) risperidone (0.25mg) Overall symptoms* Psychosis Agitation Moderate-high evidence Mixed results Low or very low evidence * Measured by BEHAVE-AD, BPRS, or PI: This review did not find any studies with ziprasidone for dementia-related symptoms. Balanced information to support better care 7

8 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 dementia 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 no aggression Dementia with mild aggression Dementia with severe aggression o additional medications needed on-apm medications: SSRI, trazadone, memantine APM medications: risperidone aripiprazole 8 Restrained use of antipsychotic medications: Rational management of irrationality

9 Antipsychotic drugs in other conditions These 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. 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 FIGURE 7. Management of post-traumatic stress disorder 16 Sleep disturbed? ightmares/ hyperarousal: prazosin Sleep initiation: trazodone Both: prazosin then trazodone Continued PTSD symptoms? SSRI Continue treatment Continued PTSD symptoms? Without psychosis: try 2nd SSRI, SRI, or mirtazapine With psychosis: add antipsychotic (risperidone best) 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. Balanced information to support better care 9

10 Screening and monitoring are necessary Whatever 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 Metabolic effects What to assess Screening: at baseline, and then: 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 eurologic 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 Other effects prolactin elevation anticholinergic toxicity dizziness or BP drop with standing galactorrhea, amenorrhea, sexual dysfunction, gynecomastia blurry vision, dry mouth, sedation, urinary retention, constipation every visit every visit every visit * A list of QT prolonging drugs can be found at: 10 Restrained use of antipsychotic medications: Rational management of irrationality

11 Cost All 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. FIGURE 8. Monthly cost of antipsychotic medications based on defined daily dose from the World Health Organization ziprasidone (Geodon) $332 risperidone (Risperdal) $473 risperidone (generic) $200 quetiapine (Seroquel) $576 quetiapine XR (Seroquel XR) $511 olanzapine (Zyprexa) $624 olanzapine (generic) $380 aripiprazole (Abilify) $560 perphenazine (generic) $108 haloperidol (generic) $ Listed doses reflect dosing equivalents, and are not recommended starting doses in the elderly. Drug prices obtained from drugstore.com References: (1) Alexander GC, Gallagher SA, Mascola A, Moloney RM, Stafford RS. Increasing off-label use of antipsychotic medications in the United States, Pharmacoepidemiology and Drug Safety. Feb 2011; 20(2): (2) American Psychiatric Association. Treatment of patients with major depressive disorder. 2010; (3) Rush AJ, et al. Bupropion-SR, sertraline, or venlafaxine-xr after failure of SSRIs for depression. Engl J Med, 2006; 354: (4) Zimmerman M, Posternak MA, Attiullah, et al. Why isn t bupropion the most frequently prescribed antidepressant? The Journal of Clinical Psychiatry. May 2005; 66(5): (5) VA-DOD. Management of major depressive disorder (MDD). 2009; (6) Hamoda HM, and Osser D. The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An update on psychotic depression. Harvard Review of Psychiatry. 2008; 16(4): (7) elson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. American Journal of Psychiatry. 2009; 166: (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: (9) FDA. Public Health Advisory: Deaths with antipsychotics in elderly patients with behavioral disturbances. 2008; ucm htm (10) Schneider LS, Tariot P, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer s disease. Engl J Med. Oct ; 355(15): (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: (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; Antipsychotics_execsumm_ 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): (16) Stein DJ. Pharmacotherapy for post traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2006; CD (17) Soomro GM. Selective serotonin reuptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD). Cochrane Database Syst Rev. 2008; CD (18) Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004; 27(2): (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 Balanced information to support better care 11

12 About this publication These are general recommendations only; specific clinical decisions should be made by the treating physician based on an individual patient s clinical condition. 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. Osser, M.D., Associate Professor of Psychiatry, Harvard Medical School and VA Boston Healthcare System; iteesh 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. one of the authors accepts any personal compensation from any drug company The Alosa Foundation