Antipsychotic medications in primary care:

Balanced information for better care Antipsychotic medications in primary care: Limited benefit, sizable risk

Antipsychotic medications in primary care: Limited benefit, sizeable risk Author: Danielle Scheurer, M.D., M.Sc. Consultants: David Osser, M.D., Jerry Avorn, M.D., Niteesh K. Choudhry, M.D., Ph.D., Michael Fischer, M.D., M.S. Reviewers: Matcheri S. Keshavan, M.D., Marshall Forstein, M.D., Carl Salzman, M.D., Laurie LaRusso, M.S., E.L.S. 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. This material is provided by The Alosa Foundation, a nonprofit organization, which is not affiliated in any way with any pharmaceutical company. None of the authors accepts any personal compensation from any pharmaceutical company. These are general recommendations only; specific clinical decisions should be made by the treating physician based on an individual patient s clinical condition. For more information, visit www.rxfacts.org

ii Antipsychotic medications in primary care: Limited benefits, sizeable risk

Accreditation: The Alosa Foundation Antipsychotic medications in primary care: Limited benefit, sizable risk This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Harvard Medical School and The Alosa Foundation. The Harvard Medical School is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation: The Harvard Medical School designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credit. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Activity Overview: The goal of the educational program is to help practitioners assess the comparative effectiveness and safety of antipsychotic medications (APMs); understand the evidence regarding appropriate therapy; weigh the benefits, risks, and value of treatment options; and improve the quality of prescribing and patient care. In addition to providing this evidence report, the education program uses an innovative approach, academic detailing, one-on-one educational sessions in physicians offices with trained outreach educators (pharmacists, nurses, physicians) who present the educational material interactively. Additionally, reference cards and patient education materials are provided. Target Audience: The educational program is designed for primary care physicians practicing internal medicine, primary care, family practice, and geriatrics, and other health care professionals who deliver primary care. Learning Objectives: Upon completion of this activity, participants will be able to: Demonstrate knowledge of the risks associated with APM use; Consider alternative therapies before starting or continuing an APM in a patient who does not have schizophrenia or bi-polar disorder; Safely initiate APM therapy by first obtaining baseline EKG, serum glucose, lipids, and weight; determining what the target symptoms are; and prescribing the lowest dose for the shortest time possible; Appropriately screen for side effects of APMs. Disclosure Policy: Harvard Medical School (HMS) adheres to all ACCME Essential Areas, Standards, and Policies. It is HMS's policy that those who have influenced the content of a CME activity (e.g. planners, faculty, authors, reviewers and others) disclose all relevant financial relationships with commercial entities so that HMS may identify and resolve any conflicts of interest prior to the activity. These disclosures are provided in the activity materials along with disclosure of any commercial support received for the activity. Antipsychotic medications in primary care: Limited benefits, sizeable risk iii

Additionally, faculty members have been instructed to disclose any limitations of data and unlabeled or investigational uses of products discussed. Disclosures: This material is provided by The Alosa Foundation, a nonprofit organization which is not affiliated in any way with any pharmaceutical company. No commercial support has been received for this activity. None of the planners/authors have any financial relationships to disclose. 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. Faculty and Planners: Jerry Avorn, M.D. is a Professor of Medicine at Harvard Medical School and Chief of the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women's Hospital. An internist, he has worked as a primary care physician and geriatrician and has been studying drug use and its outcomes for over 25 years. Dr. Avorn has no relevant financial relationships to disclose. Niteesh K. Choudhry, M.D., Ph.D. is an Associate Professor of Medicine at Harvard Medical School and a hospitalist at Brigham and Women's Hospital. His research focuses on the use of medications to treat common chronic conditions. Dr. Choudhry has no relevant financial relationships to disclose. Michael Fischer, M.D., M.S. is an Assistant Professor of Medicine at Harvard Medical School and a primary care internist who studies cost-effective drug use in outpatient practices. Dr. Fischer has no relevant financial relationships to disclose. Danielle Scheurer, M.D., M.S.C.R, F.H.M. is an Assistant Professor in Medicine, a hospitalist, and the Medical Director of Quality and Safety at the Medical University of South Carolina. Her research focuses on inpatient internal medicine and the prevention and treatment of nosocomial infections. Dr Scheurer has no relevant financial relationships to disclose. David Osser, M.D. is an Associate Professor of Psychiatry at Harvard Medical School and a psychiatrist at the VA Boston Healthcare System. Dr. Osser has no relevant financial relationships to disclose. Matcheri S. Keshavan, M.D. is the Stanley Cobb Professor of Psychiatry at Harvard Medical School and is on staff at the Beth Israel Deaconess Medical Center. Dr. Keshavan has disclosed grant/research support from Sunovion Pharmaceuticals Inc. Marshall Forstein, M.D. is an Associate Professor of Psychiatry at Harvard Medical School and the Director of Psychiatric Residency Training at the Cambridge Health Alliance Department of Psychiatry/ Harvard Medical School. He has been working clinically and educating medical students and psychiatry residents for over 30 years. He has been engaged in the clinical care and neuropsychiatric aspects of HIV disease since 1981 and teaches nationally on the subject. Dr. Forstein has no relevant financial relationships to disclose. Carl Salzman, M.D., is a Professor of Psychiatry at Harvard Medical School and the author of 300 scientific papers and review articles and 4 books; his seminal textbook "Clinical Geriatric iv Antipsychotic medications in primary care: Limited benefits, sizeable risk

Psychopharmacology" is in its 4th edition. Dr. Salzman is well known as an outstanding teacher of psychiatry and psychopharmacology. Dr. Salzman has no relevant financial relationships to disclose. Laurie LaRusso, M.S., E.L.S. is the Principal of Chestnut Medical Communications where she provides reviews of continuing medical education materials and medical writing services on a wide range of topics. Ms. LaRusso has no relevant financial relationships to disclose. Media used: Printed educational material. Instructions for Participation and Credit: There are no fees to participate in this activity. To receive credit, participants must (1) read the statements on target audience, learning objectives, and disclosures, (2) study the educational activity, and (3) complete the post-test and activity evaluation. To receive AMA PRA Category 1 Credit, participants must receive a minimum score of 60% on the post-test. Tests and evaluations should be submitted to the Alosa Foundation via mail or fax. Mailing address: The Alosa Foundation 699 Boylston Street, Suite 2 Boston, MA 02116 Fax: 857-350-9155 The activity will take approximately 1.25 hours to complete. Activity publication date: April 20, 2012 Termination date: April 20, 2015 Please e-mail any questions to info@alosafoundation.org or call (857) 350-9105. Antipsychotic medications in primary care: Limited benefits, sizeable risk v

Table of Contents Introduction.. 1 Antipsychotic drug types. 3 Antipsychotic drug risks.. 3 Overall side effects by class 3 Weight gain/metabolic syndrome 5 Extrapyramidal symptoms (EPS) 7 Prolactin elevation 9 Anti-cholinergic side effects 9 Q-Tc prolongation 9 Neuroleptic malignant syndrome (NMS) 9 Agranulocytosis 10 Mortality 10 Stroke 11 Seizures 11 Overdose syndromes 11 Clozapine 11 Indications for treatment with antipsychotic medications.. 13 Augment for major depressive disorder (e.g., unipolar disorder) 13 Role of antipsychotics 17 Monotherapy for unipolar depression 19 Psychotic depression 19 Post-traumatic stress disorder (PTSD) 21 Obsessive compulsive disorder (OCD) 22 Behavioral management of dementia syndromes 23 Cost 29 Glossary of acronyms... 30 vi Antipsychotic medications in primary care: Limited benefits, sizeable risk

Appendix 1A: Half life, route, dose, and major drug interactions. 31 Appendix 1B: Major inhibitors and inducers of cytochrome P-450 enzyme times... 32 Appendix 2: Abnormal involuntary movement scale 33 Appendix 3: Black box warning for mortality with antipsychotic drugs 34 References 35 Antipsychotic medications in primary care: Limited benefits, sizeable risk vii

Introduction The first antipsychotic medications (APMs) were introduced to the US market in the early 1950 s. These first generation drugs were used primarily to treat psychiatric conditions such as schizophrenia, and remained the main APMs used until the second generation drugs, often known as atypical antipsychotics, were introduced in the mid-1990 s, starting with clozapine in 1989, then risperidone in 1994. Aggressive promotion has caused the atypical APMs to be widely used for common conditions, including managing behavioral symptoms in elderly patients with cognitive impairment, depression, posttraumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). Primary care doctors prescribe 20% of all APMs in the US. 1 Figure 1: Antipsychotic medication prescriptions written by specialty (top) and by indication in primary care (bottom) 2, 3 Neurology 2% Primary care physician 20% All others 9% Psychiatry 69% All others 25% Schizophrenia 23% Anxiety 6% Bipolar 12% Dementia 16% Depression 18% Antipsychotic medications in primary care: Limited benefits, sizeable risk 1

The use of APMs by primary care doctors grew 18% from 1996 to 2001, and accounted for >4 million prescriptions in 2001. 2, 3 As a class, antipsychotics rank 5 th in US medication expenditure, with spending in 2010 reaching over $16 billion, $6 billion of which is estimated to be prescribed for off-label conditions for which they may not even be effective (see below). The APMs most commonly used for off-label conditions include risperidone, quetiapine, and olanzapine. 4, 5 Figure 2: Growth of antipsychotic volume in primary care, 1996 to 2001 2, 3 Total Prescription Volume (millions) 4.5 4 3.5 3 2.5 2 1.5 1 0.5 1996-2001: +18% -2.7% +2.0% +2.7% +4.8% +10.6% 0 1996 1997 1998 1999 2000 2001 As shown in Figure 1, some primary care doctors need to manage advanced psychiatric diseases, such as schizophrenia and bipolar disease, especially in areas with limited access to specialists. About 15% of patients with schizophrenia are seen exclusively by primary care doctors. 3, 6 In addition, side effects of APMs are commonly managed by primary care doctors, even if the antipsychotic drug is prescribed by a psychiatric specialist. In this environment, primary care doctors need to have an advanced understanding of the indications, efficacy, and risk profiles of each of these drugs, as they differ in their side effect profiles, drug interactions, dosing, cost and need for adjustments with renal or hepatic insufficiency. For each condition for which an antipsychotic medication is being considered, the benefit and risk of each drug needs to be carefully considered. The risks of these drugs are substantial, and some are life threatening. For advanced debilitating psychiatric diseases such as schizophrenia or bipolar disease, the benefits of these drugs often outweigh the risks. But for less debilitating diseases, such as behavioral management in dementia, or uncomplicated depression, the risks of these drugs often outweigh their modest benefits. This evidence document will review the risk profiles of each of these drugs, then discuss the efficacy of these drugs by condition (e.g. depression, dementia, etc). For each condition, an algorithm of treatment options will be presented (where appropriate), to help support clinicians in deciding when antipsychotic drug use is reasonable. The newest second generation antipsychotic drugs (e.g. asenapine, iloperidone, 2 Antipsychotic medications in primary care: Limited benefits, sizeable risk

and paliperidone) have not been studied adequately in any of these conditions, so discussion of these agents in primary care is limited at this time. APMs cannot be assumed to have a class effect in terms of efficacy or safety, so should not be used for off-label conditions at present. In addition, clozapine is on a restricted distribution program in the US, based on the severity of its side effects, and so will also have a limited role in the primary care setting. Bottom line: Antipsychotics are commonly prescribed by primary care doctors, necessitating a firm understanding of their indications, efficacy, and risks. Antipsychotic drug types The antipsychotic medications are generally divided into first and second generation drugs, known as conventional and atypical, respectively. All of these drugs share the common characteristic of binding to dopamine 2 (D2) receptors in several areas of the brain. The affinity of binding to D2 receptors is related to the antipsychotic potency of the drug. 1 Each drug is unique in its binding patterns and binding affinity to various neurotransmitter receptors. A detailed table of each agent, with half-life, onset of action, route of administration, starting and maximum recommended doses, and major drug interactions is presented in Appendix 1. Bottom line: Antipsychotics are categorized into first generation and second generation drugs (e.g., conventional and atypical ) but each drug is unique, with different constellations of neurochemical affinities leading to a variety of side effect profiles. Antipsychotic drug risks Overall side effects by class: For each of these drugs, there is a fine balance between efficacy and adverse effects. For example, it is estimated that 65% occupancy of the D2 receptors is needed for antipsychotic effects, but 80% occupancy results in extrapyramidal symptoms. 7 Each individual drug s side effect profile differs by the affinity to other neuronal receptors, including acetylcholine, alpha-1, histamine, cardiac, and serotonin receptors. The table below briefly outlines side effects associated with blocking of these other receptors. Antipsychotic medications in primary care: Limited benefits, sizeable risk 3

Table 1: Typical side effects associated with blocking of non-dopamine neuronal receptors Receptor type Muscarinic acetylcholine receptors Alpha-1 adrenergic receptors Histamine receptors Cardiac receptors Serotonin receptors Side effect profile Anti-cholinergic effects: Dry mouth and skin Blurry vision Tachycardia Sedation Constipation Urinary retention Angle closure glaucoma Orthostatic hypotension Reflex tachycardia Miosis Nasal congestion Sedation Hypotension Appetite stimulation Q-Tc interval prolongation Torsades de pointes QRS prolongation Headache Agitation Nausea Diarrhea As a class, the first generation agents are more likely to produce extrapyramidal side effects (EPS) that can perfectly mimic Parkinson s Disease, while second generation agents are more likely to produce weight gain and metabolic side effects. However, each agent differs in the side effects it can cause, so lumping agents by generation to predict side effect profiles should not be done. One unique agent, aripiprazole, is a partial dopamine agonist (post-synaptic) and dopamine antagonist (pre-synaptic). This reduces dopamine synthesis and release, resulting in a dopamine stabilizing effect (blunting excess activity and augmenting deficient activity), and little to no EPS. It also has a low affinity for the other neuronal receptors, giving it a more favorable side effect profile. The overall side effect profile among the most commonly used antipsychotic drugs is outlined in Table 2. 4 Antipsychotic medications in primary care: Limited benefits, sizeable risk

Table 2: Adverse effects of APMs* Drug Weight gain** & metabolic effects Extra pyramidal symptoms QTc prolongation Sedation Orthostatic hypotension Anticholinergic toxicity Prolactin elevation Death First generation (typical APMs) haloperidol (Haldol) perphenazine (Trilafon) Second generation (atypical APMs) clozapine (Clozaril) risperidone (Risperdal) olanzapine (Zyprexa) quetiapine (Seroquel) aripiprazole (Abilify) ziprasidone (Geodon) - ++ + + - - ++ ++ - + - + - - ++ ++ ++ - + ++ ++ ++ - + + + + - + - ++ + ++ - + + - - + + ++ - ++ + + - - + + - - - - - - + - - ++ - - - - + * Authors consensus interpretation of pertinent evidence ** For weight gain, ++: equals 2-3 kg/month +: equals 1-2 kg/month More triglyceride elevation than risperidone and apriprazole Bottom line: The first generation APMs are limited primarily by extrapyramidal side effects, and the second generation by weight gain and metabolic side effects. Each drug varies slightly in its other side effects, based on binding to other neuronal receptors. Weight gain/metabolic syndrome: Weight gain and derangement in glucose and lipid metabolism occur much more frequently with the second generation agents, and vary by specific drug. Most weight gain in clinical trials occurs during the first 3 months of treatment. In a randomized clinical trial of antipsychotic-naïve patients, after about 3 months of treatment, mean changes in weight and lipids are outlined in Table 3. 8 Antipsychotic medications in primary care: Limited benefits, sizeable risk 5

Table 3: Mean changes in weight and lipids in antipsychotic-naïve patients, from start to 3 months of treatment Drug Weight gain (kg) Total cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) olanzapine 8.5 (p<0.001) 16 (p<0.001) 12 (p=0.004) 24 (p=0.002) quetiapine 6.1 (p<0.001) 9 (p=0.05) 4 (p value NS) 37 (p=0.01) risperidone 5.3 (p<0.001) 4 (p value NS) <1 (p value NS) 10 (p=0.04) aripiprazole 4.4 (p<0.001) 4 (p value NS) 7 (p=0.05) <1 (p value NS) NS = not significant Metabolic and weight effects were most notable for olanzapine and quetiapine, and least notable for risperidone and aripiprazole. Patterns of insulin resistance were also similar, highest in olanzapine. These metabolic effects are independent of weight gain, and can also cause unfavorable changes in triglycerides and serum cholesterol levels. A large randomized trial (CATIE trial) in patients with schizophrenia (also duration ~3 months) found similar trends in weight gain and metabolic side effects among the agents studied, with the most unfavorable metabolic effects seen with olanzapine and quetiapine (Figure 3). 9 Figure 3: Mean change in cholesterol, triglycerides, and blood sugar, by agent 9 50 40 30 20 10 0 mean change in cholesterol mean change in triglycerides mean change in blood sugar -10-20 -30 olanzapine quetiapine risperidone ziprasidone 6 Antipsychotic medications in primary care: Limited benefits, sizeable risk

Based on these trials and others, the American Diabetes Association and American Psychiatry Association endorse the following screening protocol for all patients being initiated on a second generation antipsychotics. 10 Figure 4: Guidelines for screening patients on antipsychotic medications Personal/family history Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually X X Every 5 years Weight (BMI) X X X X X Waist circumference X X Blood pressure X X X Fasting plasma glucose Fasting lipid profile X X X X X X *More frequent assessments may be warranted based on clinical status For those patients that need an APM, and in whom weight gain is desirable, risperidone will induce weight gain with the least amount of other metabolic side effects (changes in insulin resistance or lipid profiles) and would be a reasonable choice for that particular patient type. For more information on the diagnosis and management of diabetes and hyperlipidemia, see the IDIS evidence documents on diabetes and lipid lowering therapy at www.rxfacts.org. Bottom line: Weight gain is common with the second generation antipsychotics, but is most significant with olanzapine and quetiapine (in that order), and less significant with risperidone, aripiprazole, and ziprasidone. Similarly, the risk of diabetes and lipid derangements is most common with olanzapine and quetiapine, is intermediate for risperidone and aripiprazole, and is minimal for ziprasidone. Screening for weight, blood sugar, and lipids should be done regularly for all patients taking any APM. Extrapyramidal symptoms (EPS): Extrapyramidal symptoms (EPS) refer to involuntary movements, including dystonia, akathisia, and Parkinsonian symptoms, and tardive dyskinesia. The reversible motor syndromes include dystonia, akathisia, and the Parkinsonian symptoms (such as tremor, rigidity, and bradykinesia). All of these motor syndromes occur less commonly with the second generation than the first generation agents, and all appear to be dose-related (making it imperative to use the lowest effective dose of the drug). Tardive dyskinesia (TD) is a hyperkinetic choreoathetotic movement disorder. It may manifest as involuntary thrusting movements of the tongue or other facial muscles, or as asymmetric jerking or Antipsychotic medications in primary care: Limited benefits, sizeable risk 7

writhing (athetosis) that usually occurs with prolonged use of APMs. Tardive indicates a delay in manifestations. TD can be irreversible even after discontinuation of the drug. The overall prevalence of TD in patients on antipsychotics is ~20%. The annual incidence of TD is: 11, 12 3-5% for first generation agents <1% for second generation agents 13 TD usually occurs after long term exposure (e.g. 3-6 months), and is more likely to occur with the 1, 14 following risk factors: Older age Female gender Diabetes Higher dose and duration of drug Patients with EPS (especially parkinsonism) Example videos of these involuntary movements can be viewed at the following YouTube links. Table 4: Video examples of typical motor symptoms associated with antipsychotic drugs Type of motor symptom Video link Dystonia www.youtube.com/watch?v=gjiy1rdzpp8 15 Akathisia www.youtube.com/watch?v=psxzucnli6q 16 Tardive dyskinesia www.youtube.com/watch?v=flwzqbjs8fi 17 Acute EPS (such as dystonia) can be managed with anticholinergic agents (e.g. diphenhydramine or benztropine), though these can cause their own anti-cholinergic side effects, especially in the elderly. Otherwise, EPS onset can be reduced by avoiding first generation agents, and using the lowest dose possible for the shortest treatment course indicated. Patients should be screened for EPS at every visit, including asking if they have noticed any symptoms, and by observing the patient while sitting still, focusing on the face, arms, and legs. Patients and caregivers can also be shown videos of motor symptoms, so they can be aware of what to look for between clinic visits. The Abnormal Involuntary Movement Scale score can also be used to more objectively assess the patient s motor side effects, and can be found at www.cqaimh.org/pdf/tool_aims.pdf; it is attached in Appendix 3. Bottom line: Reversible (e.g. dystonia, akathisia, and parkinsonian symptoms) and irreversible (tardive dyskinesia) EPS occur more commonly with first generation APMs, but can also occur with second generation drugs; the risks are related to dose and duration. Patients should be screened for extrapyramidal symptoms at every clinic visit. Avoiding first generation drugs and using the lowest dose for the shortest time possible can reduce the risk of EPS. 8 Antipsychotic medications in primary care: Limited benefits, sizeable risk

Prolactin elevation: Prolactin elevation primarily occurs with the first generation agents, risperidone, and olanzapine (at doses >20 mg/day) (Table 2). Patients on these agents should be screened for symptoms (e.g. gynecomastia, galactorrhea, amenorrhea, or sexual dysfunction), but should not be screened by lab testing if they do not have symptoms. For those that experience symptoms that are troublesome, the dose can be reduced, the agent can be switched (especially if the patient is taking a first generation drug, risperidone, or olanzapine>20mg/day), or a dopamine agonist can be added (such as amantadine or bromocriptine). 1 If symptoms persist, or the prolactin level (if checked) is >100 mcg/l, referral to an endocrinologist may be warranted. Pituitary prolactinomas have been described in patients on antipsychotics, and have resolved after discontinuation of the drug. 1 Bottom line: Screen patients taking first generation APMs, risperidone, or olanzapine >20 mg/day for symptoms of hyperprolactemia. Anti-cholinergic side effects: Anti-cholinergic side effects from antipsychotic medications occur almost exclusively with the older first generation drugs (e.g.chlorpropamine, but not haloperidol) and clozapine (Table 2), and include the symptoms listed in Table 1. 1 Q-Tc prolongation: Prolongation of the cardiac Q-Tc interval occurs with most of the second generation drugs, most often with quetiapine and ziprasidone and the least with aripiprazole; the risk with haloperidol is increased with intravenous or intramuscular administration. 18 Patients started on an APM should have an initial EKG; for those with a baseline prolonged Q-Tc who require an APM, consider an agent with minimal or no Q-T prolongation (Table 2), and avoid all other drugs that prolong the Q-Tc interval. 1 A list of drugs that can prolong the Q-T interval is available at www.qtdrugs.org. Acute prolongation of Q-Tc should be managed with cardiac monitoring and correction of any electrolyte disturbances (e.g. hypokalemia or hypomagnesemia). Torsades de pointes is a medical emergency, and should be managed with magnesium sulfate, overdrive pacing, isoproterenol, or cardioversion. Bottom line: Prolongation of the cardiac Q-T interval occurs primarily with quetiapine and ziprasidone, and least with aripiprazole (Table 2). Baseline EKG monitoring is warranted with these agents and avoidance of other Q-T prolonging agents is prudent with all APMs. Neuroleptic malignant syndrome (NMS): NMS is a clinical syndrome characterized by fever, rigidity, dysautonomia, and mental status changes; it is typically caused by first generation agents (less commonly with the second generation agents), and is a potentially life-threatening emergency. It occurs in 1-3% of patients taking neuroleptics. Symptoms typically develop within the first 2 weeks of taking the medication, after dose changes, or after switching agents, but can occur at any time. It is more common with first generation agents and after intravenous administration, and risk increases with dose. 19 In a large case series, most patients developed mental Antipsychotic medications in primary care: Limited benefits, sizeable risk 9

status changes first, followed by rigidity, hyperthermia, and then autonomic dysfunction. 20 Treatment consists of stopping the drug, and administering supportive treatment in a hospitalized setting, including anti-pyretics, fluids, and either dantrolene or bromocriptine. Mortality at one point was ~12%, but most cases now resolve with supportive care within 1-2 weeks. Resumption of antipsychotic drugs should be done with caution, but if required, should be initiated with a low-potency agent at a low-dose, with careful monitoring for symptom recurrence. 21 Bottom line: NMS is an unusual but potentially fatal complication associated most commonly with the first generation agents. Symptoms typically include mental status changes, rigidity, hyperthermia, and autonomic dysfunction. Immediately administer supportive care in an acute care setting. If APMs must be restarted, do so very cautiously. Agranulocytosis: This side effect is primarily limited to the agent clozapine. Due to this risk and other troublesome side effects, the drug is on a restricted distribution program in the US (see below section on clozapine ). Mortality: The risk of death is higher among patients with dementia who use an antipsychotic drug versus those who do not, with cause of death primarily cardiac events or stroke. The use of these agents in demented populations has been associated with a 60% to 70% increased risk of death, leading to the addition of a black box warning to both first and second generation APMs. 22 A large meta-analysis of randomized trials found a 54% increased risk of death in patients only on the drug for a short time (e.g. 8-12 weeks). 23 This mortality risk differs by type of antipsychotic. Evaluation of a large cohort of outpatient Veterans Affairs patients with dementia found, after adjusting for why the patient was on the antipsychotic, the risk of death (using risperidone as the referent) was: Higher with haloperidol (relative risk 1.5, 95% CI 1.4 to 1.7) Equivalent with olanzapine (relative risk 0.9, 95% CI 0.9 to 1.1) Lowest with quetiapine (relative risk 0.7, 95% CI 0.7 to 0.8) There is also a higher and dose dependent - risk of sudden cardiac death in patients prescribed antipsychotics. This risk is twice as high as for non-users (rate ratio 2.0, 95% CI 1.7 to 2.3), with no significant difference in risk between the first and second generation agents. 24 The risk of mortality for all agents was highest in the first 30 to 120 days of use. 25 These trials included in the FDA black box warning found an absolute difference in death of 1.9% (4.5% in APM group versus 2.6% in the placebo group), yielding a number needed to harm of 53. That means: For every 53 patients treated, one will die (who would not have died on placebo). However, more sobering, since the efficacy of antipsychotics is only modest in patients with dementia (more below), it is also estimated: For every 9-25 patients that benefit from antipsychotics, one will die. 23 10 Antipsychotic medications in primary care: Limited benefits, sizeable risk

Bottom line: The use of antipsychotic drugs in patients with dementia is associated with a 60% to 70% increased relative risk of mortality, which is highest in the first 30-120 days of use, as reflected in a black box warning for all APMs. It is estimated that one patient will die from antipsychotic use, for every 9-25 patients that benefit. Stroke: Data on the risk of stroke with antipsychotics have been conflicting. Two recent large cohort studies 26, 27 comparing users with non-users with dementia syndromes did not find an increased risk of stroke. while a self-controlled case series from a research database found the risk of stroke was 1.7 times higher during exposed times (e.g. when a patient was on an APM) compared to unexposed times. 28 Seizures: The risk of seizures is highest with clozapine (more below), olanzapine, and quetiapine, and is minimal with the other second generation agents. Overdose syndromes: The risk of intentional or accidental overdose of antipsychotics depends on the type of antipsychotic, and the degree to which the agent blocks other neuronal receptors (Table 1). In 2009, first generation antipsychotics were implicated in 4,700 calls to poison control centers in the US. 29 Most antipsychotic drugs are rapidly absorbed, with a short time to peak clinical effect (e.g. hours), although anti-cholinergic effects (e.g. delayed gastric emptying) can delay peak effect. Once absorbed, they diffuse into lipophilic tissues and have a large volume of distribution. The signs and symptoms of overdose are variable, and can mimic overdose of many agents (e.g. tricyclics, benzodiazepines, muscle relaxants) but are rarely fatal. Generally, overdose is managed with individualized supportive care, with no specific antidote available. Activated charcoal should be considered for all suspected overdoses. Given the large volume of distribution and high protein binding of these drugs, hemodialysis is not helpful to remove the drug. Bottom line: Intentional or accidental overdose of antipsychotics produce variable clinical syndromes, which are rarely fatal, and generally managed conservatively with supportive care. Clozapine: Clozapine is a second generation antipsychotic that is currently on a restricted distribution program in the US, due to the risk of significant side effects. However, it is also the most effective antipsychotic drug for use in treatment-resistant schizophrenia, and for suicidality. 30 Therefore, although primary care doctors will be unlikely to prescribe the drug, they need to be able to help psychiatrists manage the side effects of the drug. Dosing Clozapine is usually initiated at 12.5 mg (once or twice a day) and increased up to the usual effective dose (300-400 mg/day). Blood levels (if checked) should be between >350-450 ng/ml. Much higher Antipsychotic medications in primary care: Limited benefits, sizeable risk 11

doses and higher serum levels are associated with markedly increased risk of side effects (e.g. seizures), usually at levels of around 600 ng/ml. If the drug is interrupted for any reason for 48 hours, it should be resumed at the starting dose (not resumed at the current dose). Initial work-up As with other antipsychotics, patients should have an initial: History (including family history of obesity, diabetes, lipid problems) Exam (including BMI, waist circumference, and blood pressure) Labs (including fasting glucose and lipid panel) EKG In addition, patients starting clozapine should have a complete blood count (CBC), liver function tests, and urinalysis. 30. Baseline white blood cell count must be 3,500, and absolute neutrophil count (ANC) 2,000 to begin the drug. CBC monitoring should then be done: 30 Weekly for 6 months, then Bi-weekly for 6 months, then Q4 weeks thereafter About 1% of patients on clozapine will experience agranulocytosis, most of which occurs within the first 6 months of treatment (defined as WBC<2,000 or ANC <1,000). 31 This can happen quickly and requires immediate discontinuation of the drug. After is has occurred, the drug can never be restarted. About 2.7% of patients on clozapine will develop mild neutropenia, which requires careful monitoring, but does not necessarily require drug discontinuation. Other clozapine side effects In addition to the side effects for other second-generation antipsychotics (e.g. weight gain and metabolic side effects) there are additional troublesome side effects that occur more commonly with clozapine than others. Seizures occur in 1-2% of patients on low dose (<300 mg), 3-4% of patients on moderate dose (300-600 mg), and 5% of patients on high dose (>600 mg) clozapine. If a seizure occurs, the dose should be cut in half, and an anti-seizure medication should be added (valproate is preferred). Myocarditis and cardiomyopathy are infrequent but potentially fatal complications, the former usually occurs within the first month of treatment, the latter within the first year (median 9 months). 31 Constipation occurs in ~15% of patients, persists throughout treatment, and can be associated with ileus, obstruction, ischemia, or megacolon. Patients should be monitored closely for this side effect and managed with bulk laxatives, hydration, fiber supplements, and stool softeners. 31 Sedation occurs in ~40% of patients, but subsides over time, and can respond to reassurance and daytime caffeine Hypersalivation occurs in ~30% of patients, and can be significantly bothersome, causing day and nighttime drooling. If severe, medical therapies include glycopyrrolate, pirenzepine, transdermal hyoscine, intranasal ipratropium, or sublingual atropine. 31 12 Antipsychotic medications in primary care: Limited benefits, sizeable risk

Tachycardia is dose related and occurs in up to 50% of patients, with a mean increase of 10-15 beats per minute. If it causes symptoms or is >120, the dose may need to be decreased, caffeine should be reduced, or a beta blocker should be initiated. Hypotension/dizziness occurs in ~20% of patient, usually at initiation or dose increases. It can be managed by slower dose titrations, support hose, and hydration. Obsessive compulsive symptoms occur in ~10% of patients and may respond to lowering the dose. 31 Summary of Risks Antipsychotic drugs are associated with many unfavorable side effects. The most common side effects, particularly weight gain and metabolic derangements, occur with olanzapine and quetiapine; therefore these agents should rarely be used as first line agents for any condition. The most favorable side effect profiles exist for aripiprazole, ziprasidone, and risperidone. There is little long term information available at this time on the newer second generation antipsychotic agents (paliperidone, eglurasidone, asenapine, iloperidone), but none appear to be appreciably safer than commonly used agents. Clozapine, which is on a restricted distribution program in the US, can cause agranulcytosis. However, it is a very effective antipsychotic drug, and must be used in treatment-resistant cases, so that primary care doctors must be experienced at managing its risks. Indications for treatment with antipsychotic medications Augmentation for major depressive disorder (e.g., unipolar depression): Diagnosis Major depressive disorder is defined by a depressive episode with duration of over 2 weeks, a change from the patient s baseline, and significant distress or functional impairment. It is characterized by 5 or more cardinal symptoms, at least one of which must be depressed mood or anhedonia, present most of the day nearly every day: 32 Antipsychotic medications in primary care: Limited benefits, sizeable risk 13

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 much have these symptoms more of the day, nearly every day, for >2 weeks. change in sleep or appetite/weight decreased energy thoughts of worthlessness/guilt, or death/suicide psychometer retardation or agitation poor concentration Non-pharmacologic therapy Major depression is commonly treated with a combination of non-pharmacologic and drug treatments. Non-pharmacologic treatments include: psychodynamic psychotherapy cognitive-behavioral therapy interpersonal psychotherapy electroconvulsive therapy (ECT) All of these require referral to a specialist, and may not be readily available, but can be very effective, alone or combined with pharmacologic therapy. For a full discussion of non-pharmacologic therapies for major depression, see the evidence document on depression at www.rxfacts.org. Pharmacologic therapy A list of the major classes of antidepressants is listed in Table 4. Both the American Psychiatry Association and the Veterans Affairs Department of Defense guidelines for the treatment of patients with major depression acknowledge there is no good evidence for treatment superiority of one class over 33, 34 another, and that depression treatment should usually be based on the following factors: patient preference nature of prior response to medication (if any have been tried in the past) safety, tolerability, anticipated side effects (Table 4) comorbid psychiatric and medical conditions potential drug interactions half-life cost Based on efficacy, side effects profiles, and cost, first line therapies include selective serotonin reuptake inhibitors (SSRIs), bupropion, serotonin norepinephrine reuptake inhibitors (SNRIs), and mirtazapine 35, 33 (Table 5). 14 Antipsychotic medications in primary care: Limited benefits, sizeable risk

Table 5: Major classes of antidepressants and mechanism of action Drug Class Mechanism of action Examples (Brand name) Major side effects First line Selective serotonin reuptake inhibitors (SSRIs) Selectively inhibit the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane sertraline (Zoloft) fluoxetine (Prozac) paroxetine (Paxil) citalopram (Celexa) escitalopram (Lexapro) Sexual side effects Weight gain (most with paroxetine) QTc prolongation (citalopram) Dopaminenorepinephrine reuptake inhibitors Inhibit dopamine reuptake with some effect on norepinephrine bupropion (Wellbutrin) Insomnia Constipation Cannot use with history of seizures or eating disorders (bulimia/anorexia) Serotonin norepinephrine reuptake inhibitors (SNRIs) Inhibit reuptake of both serotonin and norepinephrine; weakly inhibit dopamine reuptake venlafaxine (Effexor) duloxetine (Cymbalta) Sedation Insomnia Noradrenergic and specific serotonergic antidepressant Block presynaptic central alpha 2 - adrenergic autoreceptors, resulting in increased neuro transmission of noradrenaline and serotonin; also block post-synaptic 5HT 2 and 5HT 3 receptors mirtazapine (Remeron) Sedation Dry mouth Weight gain Second line Serotonin modulators Selective inhibitor of serotonin reuptake; also acts as a 5HT 2 antagonist trazodone (Desyrel) trazodone ER (Oleptro) Sedation Dry mouth Orthostasis Tricyclic antidepressants (TCAs) Inhibit reuptake of norepinephrine and serotonin into presynaptic terminals amitriptyline (Elavil) imipramine (Tofranil) nortriptyline (Pamelor) desipramine (Norpramin) Anticholinergic side effects Cannot use with cardiac conditions Monoamine oxidase inhibitors (MAOIs) Competitively inhibit monoamine oxidase; agents in the class differ in their reversibility and their activity against MAOa and MOAb phenelzine (Nardil) tranylcypromine (Parnate) Sedation Insomnia Weight gain Orthostasis Cannot use with tyraminecontaining food/drink Antipsychotic medications in primary care: Limited benefits, sizeable risk 15

Within the first week of starting an antidepressant, the patient should follow up to assess response, adherence, and any side effects. 36 After a 4-6 week treatment trial, patients should be reassessed to determine their response to treatment. Generally patients are categorized as: no response (<50% reduction in their symptoms), OR partial response (some response, but <50% reduction in their symptoms) OR remission ( 50% reduction in symptoms) Unfortunately, only ~40% of depressed patients will have symptom remission with the first antidepressant initiated. 37 Partial or no response is more common in patients with worse initial symptoms, and those for whom the depression has been chronic or recurrent. For patients who do not have symptom remission, adherence to their medication should always be determined, in a non-judgmental and non-threatening manner. Ongoing social stressors should be assessed as well, including financial difficulties, marital discord, chronic physical pain, or alcohol/substance abuse. Side effects to inquire about include sexual side effects, such as loss of libido, failure to get an erection, etc. Undiagnosed bipolar disorder should also be considered, which would warrant referral to a specialist for treatment (see sidebar on bipolar). Bipolar disorder is characterized by distinct episodes of both major depression and episodes of mania (or hypomania) lasting days to weeks, which may or may not have obvious precipitants for the mood change. Features helpful in distinguishing bipolar disorder include: Family history of bipolar disease Personal or family history of suicidality or substance abuse Sudden onset of depression Earlier age onset (adolescence, versus third decade of life for major depression) Initial doses of the antidepressant can be increased until the maximum dose is reached, the patient experiences intolerable side effects, or a remission is achieved. For those who do not respond to, or experience intolerable side effects with the first agent tried, another agent from the same class, or another first line agent can be tried next. For patients needing combination therapy, combining agents from different first line classes can be very effective, the most well studied of which is a combination of SSRI + bupropion. In patients with concomitant anxiety, augmenting with buspirone is very effective. 33 Other adjuvants non-antidepressant adjuvants can be added to first line agents in refractory depression, including lithium, and triiodothyronine. Patients should also be considered for referral for non-pharmacologic therapies, which can often be as effective as first-line antidepressants for remission. A summary algorithm for treatment of major depression is outlined in Figure 5. 16 Antipsychotic medications in primary care: Limited benefits, sizeable risk

Figure 5: Pharmacologic management of depression 33-35 Role of antipsychotics: For patients who require additional augmentation treatment (e.g. after all the options listed above have been depleted), there may be a role for the use of antipsychotics in those with continued DSM-IV criteria for major depressive disorder. As with any chronic condition, the risks of the drugs should be carefully considered before initiating, and strong consideration should be given to referral to a psychiatrist, if available. Antipsychotic medications in primary care: Limited benefits, sizeable risk 17

The efficacy of an antipsychotic augmentation strategy was evaluated in a large meta-analysis of 16 randomized trials with 3,480 participants. The study calculated the efficacy of aripiprazole, olanzapine, quetiapine, or risperidone, all compared to placebo, in inducing a remission or any response (improvement in depression rating scale 50%) in patients who had failed antidepressant monotherapy. Remission occurred in: 31% of antipsychotic group 17% of placebo group Odds ratio of remission with APM=2.0 (95% CI 1.7 to 2.4, p<0.0001) Any response (at least 50% improvement in depression rating scale) occurred in: 44% of antipsychotic group 30% of placebo group Odds ratio of any response with APM=1.7 (95% CI 1.5 to 2.0, p<0.00001) There were no significant differences in remission or response between the agents, indicating they are likely all equally effective, although there are no head-to-head randomized trials of these agents. Of note, discontinuation rates due to adverse events were significantly higher with APMs than with placebo (OR 3.9, 95% CI 2.7 to 5.7, p<0.0001). 38 The mean doses of these second generation agents used for augmentation therapy was lower than doses used for other serious psychiatric disease (e.g. schizophrenia). Average doses from these trials are listed in Table 6. Other second generation agents have not been studied in randomized placebo controlled trials, and none of the second generation agents have been compared to other augmentation treatments (e.g. lithium, triiodothyronine, or other antidepressant agents). Table 6: Mean starting and final doses of antipsychotics used for augmentation therapy in depression Drug Mean starting dose Mean final dose aripiprazole* 5 mg 11 mg olanzapine** 6 mg 9 mg quetiapine* 150 mg 182 mg risperidone 0.25 mg 1.5 mg * FDA approved for depression augmentation ** FDA approved for depression augmentation with fluoxetine (e.g. Symbyax) Bottom line: For major depression resistant to multiple first and second line antidepressants, augmentation with an antipsychotic may increase the rate of remission. None of the antipsychotics appear to be any better than another in inducing remission of depression when used as augmentation. When considering safety and cost, antipsychotics should generally not be used in the primary care setting for treatment resistant major depressive disorder, and strong consideration should be given to referral to a psychiatrist. 18 Antipsychotic medications in primary care: Limited benefits, sizeable risk

Monotherapy for unipolar depression: Antipsychotics do not have a role as monotherapy in unipolar depression. Although some studies of APMs found a marginal benefit in monotherapy (outlined in Table 7 below), the FDA has not approved these agents for monotherapy, based on the safety issues raised above. Table 7: Randomized controlled trials of quetiapine for monotherapy in unipolar depression Drugs studied (dose) Trial duration Number Remission rates Response rates Withdrawal rates# quetiapine (50, 150, or 300 mg) Placebo 39 6 week 723 No difference 43% (50 mg)* 51% (150 mg)* 45% (300 mg)* 30% (placebo) 9% (50 mg) 15% (150 mg) 18% (300 mg) 8% (placebo) quetiapine (150 or 300 mg) duloxetine (60 mg) Placebo 40 6 week 612 32% (300 mg)** 27% (150 mg)^ 32% (duloxetine)** 20% (placebo) N/A 15% (150 mg) 20% (300 mg) 13% (duloxetine) 4% (placebo) quetiapine (150-300 mg) Placebo 41 8 week 310 35% (quetiapine)^ 25% (placebo) 62% (quetiapine)** 48% (placebo) 10% (quetiapine) 3% (placebo) *p<0.01 versus placebo **p<0.05 versus placebo ^p value not significant versus placebo # p-value for withdrawal rates not reported in any of these studies Psychotic depression: Diagnosis Major depression with psychotic features is a sub-type of depression characterized by symptoms of delusions (false fixed beliefs) and/or hallucinations (false sensory perceptions). This type of depressive disorder is more severe, and is more likely to lead to hospitalization and suicidal ideation/attempts. Patients with severe symptoms or suicidal ideation should be referred urgently to a psychiatrist, as outpatient therapy may not be appropriate, and early ECT may be needed. 42 Antipsychotic medications in primary care: Limited benefits, sizeable risk 19

Role for antipsychotics For patients stable enough for outpatient treatment, most should be initially treated with a combination of antidepressant and antipsychotic, as endorsed by the American Psychiatric Association. 33 First line antidepressant combinations for psychotic depression can include either a tricyclic antidepressant (TCA) or a selective serotonin reuptake inhibitor (SSRI), combined with an antipsychotic. For those who do not respond to the first combination, switch to the other combination (if appropriate for the patient). If providers or patients prefer to avoid an antipsychotic as first line therapy, patients can first be tried on monotherapy with a TCA or SSRI, but if they fail to respond to monotherapy, antipsychotic treatment should be reconsidered. There is no evidence that any one antipsychotic is better than another in the treatment of psychotic depression; the only second generation drug that has been studied in a placebo controlled randomized trial is olanzapine. 42 Therefore, the side effect profiles of the second generation drug should dominate the decision for which antipsychotic is the most appropriate for the patient being treated. If the patient fails to respond to any of these treatments, referral to a psychiatrist is very appropriate, for consideration for ECT or lithium treatment. An outpatient treatment algorithm for psychotic depression is outlined in Figure 6 below. 42 Figure 6: Management of depression with psychotic features 20 Antipsychotic medications in primary care: Limited benefits, sizeable risk

Post-traumatic stress disorder (PTSD): Diagnosis PTSD is a potentially debilitating disorder that can occurs after a traumatic event. It is most commonly described in veterans of war, but is also present in those experiencing non-war events, and has an estimated prevalence of 7% of Americans. 43 The clinical syndrome is characterized by four clusters of symptoms: Re-experiencing the trauma (with intrusive thoughts, nightmares, or flashbacks) Emotional numbing Avoidance behaviors Persistent hyperarousal and mood symptoms (depression, irritability, anger) Treatment of sleep disturbances in PTSD Sleep disturbance is a major contributor to PTSD symptoms, which usually manifests as difficulty with sleep initiation and/or sleep latency, and/or difficulty with nightmares and/or nocturnal hyperarousal. 44 There is evidence from randomized controlled trials that prazosin (an alpha-1 agent that crosses the blood brain barrier) is particularly effective in improving sleep disturbance symptoms in patients with PTSD, including sleep initiation/latency and nightmares/hyperarousal. 45-47 It these clinical trials, prazosin was initiated at low dose (1 mg) and titrated up ~1 mg every 3-7 days, for a maximum dose ~10 mg in men and ~3 mg in women. For patients who continue to have difficulty with sleep initiation, trazodone is an antidepressant with sedating properties that can improve sleep difficulties in those with PTSD. 44 For a full discussion of insomnia, including non-pharmacologic and pharmacologic management, see the evidence document on insomnia at www.rxfacts.org. Role for antipsychotics For patients with continued PTSD symptoms after sleep management, SSRIs are a first line treatment. A Cochrane meta-analysis of 7 trials found those treated with an SSRI were much more likely to improve symptoms (based on the CAPS, or clinician administered PTSD scale) versus placebo (relative risk 1.6, 95% CI 1.4 to 1.8). 48 Although less well studied, SNRI s are reasonable second line options for PTSD; two randomized placebo controlled trials found venlafaxine (an SNRI) was significantly more likely to 49, 50 induce remission than placebo. For patients with continued PTSD symptoms despite the above treatment, and who have psychotic features (e.g. hallucinations or delusions), an antipsychotic can be an appropriate next choice. The psychotic symptoms can be related to initial trauma (such as hearing screams or visualizing an aggressor), or can be unrelated to the trauma, and do not always occur during flashbacks. The only antipsychotic that has been evaluated in randomized placebo controlled trials is risperidone, which was found to significantly improve psychotic symptoms in both military and civilian PTSD patients, but does not benefit PTSD patients without psychosis. 51, 52 Open label trials have found symptom improvement with 44, 53, 54 olanzapine and quetiapine Antipsychotics should generally not be used to treat PTSD in the primary care setting; some specialists may treat resistant patients with antipsychotic augmentation, but the evidence does not currently support Antipsychotic medications in primary care: Limited benefits, sizeable risk 21

this practice in the primary care setting. 55 An outpatient treatment algorithm for PTSD is outlined in Figure 7 below, based on the latest available clinical evidence. 44 Figure 7: Management of post-traumatic stress disorder Bottom line: PTSD treatment should first address sleep disturbances; for those with continued symptoms, an SSRI is usually first-line therapy. For patients with continued symptoms with psychotic features, risperidone can be considered, along with referral to a psychiatric specialist. Obsessive compulsive disorder (OCD): OCD is characterized by intrusive, recurrent thoughts or images or impulses that can result in compulsive acts, in an attempt to relieve the intrusions. Pharmacologic treatment and role for antipsychotics SSRI s are also first line therapy for patients with OCD. A Cochrane meta-analysis of 17 studies with 3,097 participants found those treated with an SSRI were much more likely to experience a clinical response versus placebo (relative risk 1.8, 95% CI 1.6 to 2.2). There was no significant difference among any of the SSRIs compared, indicating equivalent efficacy. 56 Although less well studied, SNRI s are 22 Antipsychotic medications in primary care: Limited benefits, sizeable risk

reasonable second line options for OCD; a randomized trial found venlafaxine to be equivalent in efficacy to paroxetine (an SSRI) for relieving OCD symptoms. 57 Treatment should begin with a medium-dose SSRI for 8-12 weeks, then increased to the maximum dose for 8-12 weeks (in those who do not respond to a medium dose). Patients with OCD often require the maximum doses of SSRIs. SSRIs that have been FDA approved for OCD include: fluoxetine fluvoxamine sertraline For those who fail to improve despite maximum doses, two options include: 1) Switch to another SSRI or an SNRI 2) Refer to a psychiatrist. An SSRI blood level can also be checked in patients on maximum doses, as patients differ in SSRI metabolism rates. For patients on the maximum recommended dose, with inadequate blood levels, the SSRI dose can be increased above the maximal recommended dose. In patients who fail to respond to an SSRI or SNRI, most will benefit from referral to a psychiatrist for a detailed evaluation to confirm the diagnosis. Psychiatric specialists may use antipsychotics for OCD as augmentation of first-line therapy. A meta-analysis of 9 trials with 278 participants found SSRI + antipsychotic had a higher rate of response than SSRI + placebo (32% versus 11%; measured by the Yale Brown Obsessive Compulsive Scale, Y-BOCS). The most beneficial response was seen in those with co-morbid tics. 58 The only second generation antipsychotic found to be beneficial was risperidone, although observational studies have found benefit with aripiprazole (which has a better safety profile than risperidone). However, a more recent randomized trial failed to find a benefit from antipsychotic augmentation. 59 Given that the benefit of antipsychotics in OCD is controversial, referral to a psychiatrist is highly recommended for those that fail to improve on SSRIs or SNRIs. Bottom line: Treatment of OCD should first be an SSRI, or as a second-line treatment, an SNRI. Augmentation with risperidone or aripiprazole should be reserved for those with an inadequate response, but referral to a psychiatrist is highly recommended. Behavioral management of dementia syndromes: Background Antipsychotics are often used in the behavioral management of patients with dementia, and are prescribed in up to 15% of nursing home patients. 60 Although data on safety problems with these agents has accumulated in the last 10 years, their ongoing use is likely related to the high level of their promotion, even for off-label uses, the growing number of patients with dementia, the need for behavioral management of many of these patients, and the lack of safe and effective alternatives. None of the antipsychotics are FDA approved for behavioral management of patients with dementia syndromes, based on limited efficacy and risk of harm (agents studied are in Table 9). As noted in the section on risk of antipsychotics, the use of these agents in older patients with cognitive impairment has been associated with a 60% to 70% increased risk of death, leading to the addition of a Antipsychotic medications in primary care: Limited benefits, sizeable risk 23

black box warning to all of these APMs (both first and second generation agents, Appendix 3). 22 For a full discussion of dementia syndromes, including the diagnosis and management, see the evidence document on cognitive impairment at www.rxfacts.org. Types of behaviors Dementia syndromes in the elderly can be accompanied by a number of behavioral manifestations which range from those that can endanger the patient and others to those that are merely annoying: Agitation, aggression Delusions, hallucinations Wandering Depression Sleep disturbance One or more of these symptoms is present in about two-thirds of patients with dementia, and are four times more common in those with dementia than elderly without dementia. The prevalence of symptoms increases with the severity of the dementia. 61 Any time a new symptom presents, the patient should be evaluated for a medical illness or medication side effect that may be causing the symptom. This should include a thorough history, physical exam, and focused diagnostic testing (where relevant) to determine if there is a reversible trigger underlying the new symptom. For example, agitated behavior can accompany delirium, an acute confusional state which itself can be the result of a new-onset medical condition. Making the correct diagnosis can be challenging if the patient s cognitive impairment is severe enough that he or she cannot provide an adequate history or cooperate fully with a physical exam. However, treating a reversible medical problem can be much more effective and safe than simply sedating the patient with an APM. Such reversible causes of new-onset behavioral disorders in the elderly can include: Acute infection (e.g., urinary tract infection, sepsis) Hypoxia (e.g., congestive heart failure, pneumonia, anemia due to g.i. hemorrhage) Pain (e.g., vertebral or hip fracture, acute abdomen) Medication side effect The assessment of new-onset behavioral symptoms in an older patient with cognitive impairment must start with an assessment of these and other reversible causes, including a history from the patient or caregivers, physical examination, and basic laboratory tests (including CBC, glucose, electrolytes, and BUN/creatinine, as well as more specific tests suggested by the initial evaluation). If no reversible medical cause can be found, the new symptom may be attributable to the dementia syndrome itself. Non-pharmacologic behavioral treatments Agitation, aggression, and wandering should first be managed with behavioral interventions, including reorientation strategies, calming techniques, and 24-hour supervision. Randomized controlled trials have found the following calming techniques can be effective in reducing agitation and aggression. Exercise therapy 62 Music therapy 63 Massage therapy 64 Person-centered bathing 65 Aromatherapy 66-68 24 Antipsychotic medications in primary care: Limited benefits, sizeable risk

Vision and hearing deficits can increase fearfulness, anxiety, and agitation, so patients should be assessed for these deficits, and corrected if present (with glasses, hearing aids, etc.). Other environmental factors can increase agitation including: Temperature (too hot or too cold) Noise (in or outside the home) Lighting (too much or too little) Unfamiliarity (new people, new furniture, new surroundings) Disrupted routines Needing assistance but not know how to ask (toileting, bathing) Education, support, and resources can help the patient and family understand and cope with the behavioral disturbances that commonly accompany dementia syndromes. The Alzheimer s Disease Education and Referral (ADEAR) Center provides information on behaviorally managing cognitive and behavioral problems, which can be found at www.nia.nih.gov/alzheimers, toll free at 800-438-4380, or by email: adear@nia.nih.gov. The National Institute of Aging also provides a number of valuable resources that address many aspects of caring for patients with cognitive decline, including driving, legal and financial planning, and home safety, including: 69 Understanding Alzheimer s Disease Older drivers Legal and financial planning for people with Alzheimer s disease Home safety for people with Alzheimer s Disease The Alzheimer s Association is also a valuable resource center for those caregivers seeking advice on how to manage disturbing behaviors, including access to licensed social workers (call 1-866-AFA-8484), household strategies to improve home safety, support groups and discussion boards, and a free subscription to the quarterly magazine Advantage. These are all available at www.alzfdn.org. Another organization, Children of Aging Parents (CAPS), provides many online resources including respite care services, long term care services, and online and local support groups, available at www.caps4caregivers.org (or 1800-227-7294). For more information on the behavioral management of cognitive impairment in the elderly, see the evidence document on cognitive impairment at www.rxfacts.org. Pharmacologic management Although the data are limited, a number of pharmacologic therapies have some efficacy in treating the behavioral manifestations of dementia syndromes. Some consideration should be given to these therapeutic options, before resorting to antipsychotic therapies. SSRIs A Cochrane review found that antidepressants (primarily SSRIs) were significantly better than placebo in reducing mean agitation scores in patients with dementia syndromes (reduced in the treatment group by ~1 point on a 7-point scale). 70 Another randomized trial compared citalopram to risperidone in reducing agitation and psychosis in dementia patients, and found no difference in efficacy between the two Antipsychotic medications in primary care: Limited benefits, sizeable risk 25

treatments, but a significantly higher rate of withdrawals due to adverse events among the risperidone group. 71 Trazodone Two small trials, included in a Cochrane review, found that trazodone was as effective as haloperidol in reducing agitation, with no difference in adverse event rates. However, these trials were limited by small sample sizes. Prazosin Prazosin is an alpha-1 antagonist used primarily in the treatment of benign prostatic hypertrophy and (rarely) hypertension. The drug also antagonizes norepinephrine release in the central nervous system, postulated as a mechanism by which it can reduce agitation and aggression in dementia patients. A small placebo controlled study of prazosin found that those in the prazosin group had significantly more improvement in two agitation rating scales, with no differences between the groups in blood pressure or adverse events (at a mean dose of 6 mg). 72 Memantine Memantine is an NMDA receptor antagonist, which is used to prevent the progression of cognitive decline in Alzheimer s dementia. A retrospective pooled analysis of randomized controlled trials found memantine use was associated with a higher percentage of patients having some improvement in agitation / aggression, compared to placebo (56% versus 44% improved at 12 weeks in treatment versus placebo group, respectively). 73 However, this medication is expensive and can cause side effects in some patients. A full discussion of the efficacy and safety of memantine in Alzheimer s disease can be found at www.rxfacts.org. Benzodiazepines Benzodiazepines should generally not be used for agitation or aggression in the elderly demented patient. Only one randomized trial found both ativan and olanzapine were better than placebo at reducing short term agitation in demented elderly, but the effects were short acting in the ativan group. Given the side effects and risk of physical dependence with regular use, benzodiazepines should be reserved for acute, severe agitation / aggression unresponsive to other agents. 74 Role of antipsychotics The threshold for using antipsychotics in older patients with cognitive impairment and behavioral symptoms should be based on the specific expected benefits (reduction of one or more identified and targeted symptoms) and the expected risks. APMs should be considered only after behavioral therapies have been tried, and other less risky pharmacologic agents have been considered and/or used. As mentioned above, most dementia patients will exhibit disruptive behavioral symptoms during the course of their disease, some of which will be psychotic symptoms. Of the psychotic symptoms, delusions are more common than hallucinations in dementia patients, and hallucinations are usually visual, but can be auditory. If these psychotic symptoms are not disruptive, dangerous, or distressing to the patient or caregiver, then medication therapy is clearly not warranted. However, for those delusions or hallucinations that are frightening or dangerous, the risks and benefits of antipsychotics should be discussed with the caregiver. 26 Antipsychotic medications in primary care: Limited benefits, sizeable risk

Unfortunately, the efficacy of antipsychotics in improving agitation and psychosis are modest at best. Two separate systematic reviews of randomized controlled trials both found that of all the agents studied, risperidone and olanzapine had the best evidence for efficacy, but the behavioral improvements were only modest. 75, 76 A subsequent large trial randomized 421 outpatients with Alzheimer s and psychosis, agitation, or aggression to olanzapine, quetiapine, risperidone, or placebo. Minimal or greater improvement in symptoms was not significantly different among any of the groups compared to placebo. However, treatment discontinuation due to adverse events was significantly worse in all the antipsychotic groups, compared to placebo (Table 8). 77 Table 8: Efficacy and tolerability of antipsychotics in behavioral treatment of dementia symptoms Drug % improvement in symptom scale % treatment discontinuation olanzapine 32% 24% quetiapine 26% 16% risperidone 29% 18% placebo 21% (p=0.22 for trend) 5% (p=0.009 for trend) Therefore, 70-80% of patients with dementia will not derive a significant behavioral benefit from the use of an antipsychotic medication. And keeping in mind the risks of APMs, the FDA black box warning concluded from randomized controlled trials, over ~10 weeks of treatment, the risk of death is 4.5% in dementia patients on an antipsychotic drug and 2.6% in those dementia patients not on an antipsychotic drug. In summary, weighing the risk and benefit: for ~every 53 dementia patients that are treated with the drug, one will die 22 for ~every 9-25 dementia patients that will benefit from the drug, one will die 23 However, some dementia patients will have severely disruptive or dangerous behavioral disturbances that do not respond to first line, safer therapies. In those situations, where a provider and family have depleted other options, and after they have had an open discussion of the risks associated with antipsychotics, the choice of antipsychotic should be based on understanding which agents have some evidence of efficacy. A recent systematic review by the Agency for Healthcare Research and Quality (AHRQ) found the following relative strength of evidence of efficacy for second generation antipsychotics in dementia syndromes (Table 9). 78 Antipsychotic medications in primary care: Limited benefits, sizeable risk 27

Table 9: Relative efficacy of APMs in treatment of dementia-related behaviors 78 Drug and starting dose aripiprazole olanzapine quetiapine risperidone (5 mg) (1.25 mg) (12.5 mg) (0.25 mg) Overall symptoms* Psychosis Agitation Green moderate to high evidence; Yellow: mixed results; Red: low or very low evidence *Overall symptoms measured by BEHAVE-AD, BPRS, or NPI, all of which are further described at: http://www.assessmentpsychology.com/geriatricscales.htm This review did not find any studies with ziprasidone for dementia-related symptoms. The CATIE-AD trial found the symptoms most likely to respond to an APM are anger, aggression, and paranoia, but not overall functioning or quality of life. 79 In addition, the CATIE-AD trial found caregivers of patients treated with APMs had lower scores of burden (rated by the Burden Interview and NPI Caregiver Distress scales) than those caregivers of patients on placebo. Therefore, even in the face of high risk, some patients and their caregivers may derive an overall benefit from the use of APMs. 80 If an antipsychotic is initiated, very low doses should be used (Table 10). One randomized trial found that low dose antipsychotics were better than placebo at managing aggression, but that increasing doses escalated adverse events (primarily somnolence and falls). 81 Table 10: Starting and maximum doses of antipsychotics in elderly with dementia syndromes Drug Starting dose Maximum dose aripiprazole 5 mg 15 mg olanzapine 1.25 mg-5 mg 10 mg quetiapine 12.5 mg-50 mg 300 mg risperidone 0.25 mg-1 mg 2 mg ziprasidone Unknown unknown Bottom line: Antipsychotic drugs should be used for behavioral management of dementia syndromes only after all non-pharmacologic modalities have been exhausted. If an APM is indicated, the best evidence of efficacy is with aripiprazole, olanzapine, and risperidone (depending on the symptom being targeted). None are FDA-approved for this indication, and the benefits of treating the symptom should outweigh the well-established risks, including mortality. 82 Patients with dementia requiring antipsychotics may benefit from referral to a psychiatrist. 28 Antipsychotic medications in primary care: Limited benefits, sizeable risk

Cost 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) $360 apriprazole (Ability) $560 perphenazine (generic) haloperidol (generic) $108 $36 $0 $100 $200 $300 $400 $500 $600 $700 List doses reflect dosing equivalents, and are not recommended starting doses in the elderly. Drug prices obtained from Drugstore.com. Antipsychotic medications in primary care: Limited benefits, sizeable risk 29