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Prescribing antipsychotics in geriatric patients: Focus on schizophrenia and bipolar disorder
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Martha Sajatovic, MD
Helen C. Kales, MD
Benoit H. Mulsant, MD, MS
 

Antipsychotics are FDA-approved as a primary treatment for schizophrenia and bipolar disorder and as adjunctive therapy for major depressive disorder. In the United States, approximately 26% of antipsychotic prescriptions written for these indications are for individuals age >65.1 Additionally, antipsychotics are widely used to treat behavioral symptoms associated with dementia.1 The rapid expansion of the use of second-generation antipsychotics (SGAs), in particular, has been driven in part by their lower risk for extrapyramidal symptoms (EPS) compared with first-generation antipsychotics (FGAs).1 However, a growing body of data indicates that all antipsychotics have a range of adverse effects in older patients. This focus is critical in light of demographic trends—in the next 10 to 15 years, the population age >60 will grow 3.5 times more rapidly than the general population.2

In this context, psychiatrists need information on the relative risks of antipsychotics for older patients. This 3-part series summarizes findings and recommendations on safety and tolerability when prescribing antipsychotics in older individuals with chronic psychotic disorders, such as schizophrenia, bipolar disorder, depression, and dementia. This review aims to:

  • briefly summarize the major studies and analyses relevant to older patients with these diagnoses
  • provide a summative opinion on safety and tolerability issues in these older adults
  • highlight the gaps in the evidence base and areas that need additional research.

Part 1 focuses on older adults with schizophrenia or bipolar disorder. Subsequent articles will focus on prescribing antipsychotics to older adults with depression and those with dementia.

Schizophrenia

Summary of benefits, place in treatment armamentarium. Individuals with schizophrenia have a shorter life expectancy than that of the general population mostly as a result of suicide and comorbid physical illnesses,3 but the number of patients with schizophrenia age >55 will double over the next 2 decades.4 With aging, both positive and negative symptoms may be a focus of treatment (Table 1).5,6 Antipsychotics are a first-line treatment for older patients with schizophrenia with few medication alternatives.7 Safety risks associated with antipsychotics in older people span a broad spectrum (Table 2).8

Clinical trials. Few studies have evaluated treatment of older adults with schizophrenia.7-13 Two Cochrane reviews found only a handful of randomized controlled trials (RCTs).10,11 The largest RCT was an 8-week prospective, multisite RCT of olanzapine vs risperidone in 175 older adults (age ≥60 years; mean age, 71 years) with schizophrenia.5 Before enrollment, just over one-half (53%) had been treated with FGAs. Both risperidone and olanzapine were flexibly dosed, with a target dose of 3 mg/d for risperidone and 20 mg/d for olanzapine. Median daily doses were 2 mg/d for risperidone and 10 mg/d for olanzapine. Both treatments were associated with symptom improvement, but there was no difference between groups. Approximately 70% of patients in each treatment arm experienced adverse events. The most common adverse effects (similar across groups) were somnolence, insomnia, dizziness, agitation, constipation, headache, and diarrhea. Rates of EPS were lower with both risperidone (9.2% EPS-related adverse effects) and olanzapine (15.9% EPS-related adverse effects) vs patients taking FGAs prior to starting the RCT. Drop-out rates were similar (risperidone, 19.3%; olanzapine, 27.6%). There was greater weight gain with olanzapine vs risperidone (P = .04).5

A 6-week prospective RCT evaluated paliperidone extended-release vs placebo in 114 older adults (age ≥65 years; mean age, 70 years) with schizophrenia.14 There was an optional 24-week extension of open-label treatment with paliperidone. Mean daily dose of paliperidone was 8.4 mg. Efficacy measures did not show consistent statistically significant differences between treatment groups. Discontinuation rates were similar between paliperidone (7%) vs placebo (8%). Serious adverse events occurred in 3% of paliperidone-treated vs 8% of placebo-treated patients. Elevated prolactin levels occurred in one-half of paliperidone-treated patients. There were no prolactin or glucose treatment-related adverse events or significant mean changes in body weight for either paliperidone-treated or placebo-treated patients. Safety findings in the 24-week, open-label extension group were consistent with the RCT results.

Howanitz et al15 conducted a 12-week, prospective RCT that compared clozapine (mean dose, 300 mg/d) with chlorpromazine (mean dose, 600 mg/d) in 42 older adults (mean age, 67 years) with schizophrenia. Drop-out rate prior to 5 weeks was 19% and similar between groups. Common adverse effects included sialorrhea, hematologic abnormalities, sedation, tachycardia, EPS, and weight gain. Although both drugs were effective, more patients taking clozapine had tachycardia and weight gain, while more chlorpromazine patients reported sedation.

There have been other, less rigorous studies.7,8 Most of these studies evaluated risperidone and olanzapine, and most were conducted in “younger” geriatric patients (age <75 years). Although patients who participate in clinical trials may be healthier than “typical” patients, adverse effects such as EPS, sedation, and weight gain were still relatively common in these studies.

 

 

 

Other clinical data. A major consideration in treating older adults with schizophrenia is balancing the need to administer an antipsychotic dose high enough to alleviate psychotic symptoms while minimizing dose-dependent adverse effects. There is a U-shaped relationship between age and vulnerability to antipsychotic adverse effects,16,17 wherein adverse effects are highest at younger and older ages. Evidence supports using the lowest effective antipsychotic dose for geriatric patients with schizophrenia. Positive emission tomography (PET) studies suggest that older patients develop EPS with lower doses despite lower receptor occupancy.17,18 A recent study of 35 older patients (mean age, 60.1 years) with schizophrenia obtained PET, clinical measures, and blood pharmacokinetic measures before and after reduction of risperidone or olanzapine doses.18 A ≥40% reduction in dose was associated with reduced adverse effects, particularly EPS and elevation of prolactin levels. Moreover, the therapeutic window of striatal D2/D3 receptor occupancy appeared to be 50% to 60% in these older patients, compared with 65% to 80% in younger patients.

Long-term risks of antipsychotic treatment across the lifespan are less clear, with evidence suggesting both lower and higher mortality risk.19,20 It is difficult to fully disentangle the long-term risks of antipsychotics from the cumulative effects of lifestyle and comorbidity among individuals who have lived with schizophrenia for decades. Large naturalistic studies that include substantial numbers of older people with schizophrenia might be a way to elicit more information on long-term safety. The Schizophrenia Outpatient Health Outcome (SOHO) study was a large naturalistic trial that recruited >10,000 individuals with schizophrenia in 10 European countries.21 Although the SOHO study found differences between antipsychotics and adverse effects, such as EPS, weight gain, and sexual dysfunction, because the mean age of these patients was approximately 40 years and the follow-up period was only 3 years, it is difficult to draw conclusions that could be relevant to older individuals who have had schizophrenia for decades.

Bipolar Disorder

Summary of benefits, place in treatment armamentarium. Up to 25% of bipolar patients are elderly,22 and that number is projected to increase over the next decade.23 Clinical considerations in older adults with bipolar disorder include medical comorbidity, depression burden, and possible cognitive decline (Table 3).24-27 Along with lithium and mood stabilizers, antipsychotics are a first-line treatment for bipolar disorder.28-30 Most FDA-approved antipsychotics for bipolar disorder are SGAs for bipolar mania. However, olanzapine-fluoxetine combination, quetiapine, and lurasidone are approved for bipolar depression. Aripiprazole, olanzapine, quetiapine, long-acting injectable risperidone, and oral ziprasidone are FDA-approved for longer-term use in adults with bipolar disorder. There are no head-to-head trials of antipsychotics for older persons with bipolar disorder.


Clinical trials: Bipolar depression. A post hoc, secondary analysis of two 8-week, double-blind, randomized, placebo-controlled studies in bipolar depression compared 2 dosages of quetiapine (300 mg/d and 600 mg/d) with placebo in mixed-age patients.31 In a subgroup of 72 patients, ages 55 to 65, remission occurred more often with quetiapine than with placebo. Study discontinuation rates were similar between older people and younger people (age <55 years): quetiapine, 300 mg/d, 29.2%; quetiapine, 600 mg/d, 48.1%; and placebo, 29.6% in older adults, compared with 37.1%, 45.8%, and 38.1%, respectively, in younger adults. In all patients, the most common reason for discontinuation was adverse events with quetiapine and lack of efficacy for placebo. Adverse event rates were similar in older and younger adults. Dry mouth and dizziness were more common in older adults. Proportions of adults experiencing clinically significant weight gain (≥7% of body weight) were 5.3%, 8.3%, and 0% in older adults receiving quetiapine, 300 mg/d, quetiapine, 600 mg/d, and placebo, respectively, compared with 7.2%, 10.1%, and 2.6% in younger adults. EPS and treatment-emergent mania were minimal.

A secondary analysis of mixed-age, RCTs examined response in older adults (age ≥55 years) with bipolar I depression who received lurasidone as monotherapy or adjunctive therapy.32 In the monotherapy study, these patients were randomized to 6 weeks of lurasidone 20 to 60 mg/d, lurasidone 80 to 120 mg/d, or placebo. In the adjunctive therapy study, they were randomized to lurasidone 20 to 120 mg/d or placebo with either lithium or valproate. There were 83 older adults (17.1% of the sample) in the monotherapy study and 53 (15.6%) in the adjunctive therapy study. Mean improvement in depression was significantly higher for both doses of lurasidone monotherapy than placebo. Adjunctive lurasidone was not associated with statistically significant improvement vs placebo. The most frequent adverse events in older patients on lurasidone monotherapy 20 to 60 mg/d or 80 to 120 mg/d were nausea (18.5% and 9.7%, respectively) and somnolence (11.1% and 0%, respectively). Akathisia (9.7%) and insomnia (9.7%) were the most common adverse events in the group receiving 80 to 120 mg/d, with the rate of akathisia exhibiting a dose-related increase. Weight change with lurasidone was similar to placebo, and there were no clinically meaningful group changes in vital signs, electrocardiography, or laboratory parameters.

A small (N = 20) open study found improvement in older adults with bipolar depression with aripiprazole (mean dose, 10.3 mg/d).33 Adverse effects included restlessness and weight gain (n = 3, 9% each), sedation (n = 2, 10%), and drooling and diarrhea/loose stools (n = 1, 5% each). In another small study (N = 15) using asenapine (mean dose, 11.2 mg/d) in mainly older bipolar patients with depression, the most common adverse effects were gastrointestinal (GI) discomfort (n = 5, 33%) and restlessness, tremors, cognitive difficulties, and sluggishness (n = 2, 13% each).34

 

 

 

Clinical trials: Bipolar mania. Researchers conducted a pooled analysis of two 12-week randomized trials comparing quetiapine with placebo in a mixed-age sample with bipolar mania.35 In a subgroup of 59 older patients (mean age, 62.9 years), manic symptoms improved significantly more with quetiapine (modal dose, 550 mg/d) than with placebo. Adverse effects reported by >10% of older patients were dry mouth, somnolence, postural hypotension, insomnia, weight gain, and dizziness. Insomnia was reported by >10% of patients receiving placebo.

In a case series of 11 elderly patients with mania receiving asenapine, Baruch et al36 reported a 63% remission rate. One patient discontinued the study because of a new rash, 1 discontinued after developing peripheral edema, and 3 patients reported mild sedation.

Beyer et al37 reported on a post hoc analysis of 94 older adults (mean age, 57.1 years; range, 50.1 to 74.8 years) with acute bipolar mania receiving olanzapine (n = 47), divalproex (n = 31), or placebo (n = 16) in a pooled olanzapine clinical trials database. Patients receiving olanzapine or divalproex had improvement in mania; those receiving placebo did not improve. Safety findings were comparable with reports in younger patients with mania.

Other clinical data. Adverse effects found in mixed-age samples using secondary analyses of clinical trials need to be interpreted with caution because these types of studies usually exclude individuals with significant medical comorbidity. Medical burden, cognitive impairment, or concomitant medications generally necessitate slower drug titration and lower total daily dosing. For example, a secondary analysis of the U.S. National Institute of Health-funded Systematic Treatment Enhancement Program for Bipolar Disorder study, which had broader inclusion criteria than most clinical trials, reported that, although recovery rates in older adults with bipolar disorder were fairly good (78.5%), lower doses of risperidone were used in older vs younger patients.38

Clinical considerations

Interpretation of the relative risks of antipsychotics in older people must be tempered by the caveat that there is limited high-quality data (Table 4). Antipsychotics are the first-line therapy for older patients with schizophrenia, although their use is supported by a small number of prospective RCTs. SGAs are preferred because of their lower propensity to cause EPS and other motor adverse effects. Older persons with schizophrenia have an EPS threshold lower than younger patients and determining the lowest effective dosage may minimize EPS and cognitive adverse effects. As individuals with long-standing schizophrenia get older, their antipsychotic dosages may need to be reduced, and clinicians need to monitor for adverse effects that are more common among older people, such as tardive dyskinesia and metabolic abnormalities. In healthy, “younger” geriatric patients, monitoring for adverse effects may be similar to monitoring of younger patients. Patients who are older or frail may need more frequent assessment.

Like older adults with schizophrenia, geriatric patients with bipolar disorder have reduced drug tolerability and experience more adverse effects than younger patients. There are no prospective controlled studies that evaluated using antipsychotics in older patients with bipolar disorder. In older bipolar patients, the most problematic adverse effects of antipsychotics are akathisia, parkinsonism, other EPS, sedation and dizziness (which may increase fall risk), and GI discomfort. A key tolerability and safety consideration when treating older adults with bipolar disorder is the role of antipsychotics in relation to the use of lithium and mood stabilizers. Some studies have suggested that lithium has neuroprotective effects when used long-term; however, at least 1 report suggested that long-term antipsychotic treatment may be associated with neurodegeneration.39

The literature does not provide strong evidence on the many clinical variations that we see in routine practice settings, such as combinations of drug treatments or drugs prescribed to patients with specific comorbid conditions. There is a need for large cohort studies that monitor treatment course, medical comorbidity, and prognosis. Additionally, well-designed clinical trials such as the DART-AD, which investigated longer-term trajectories of people with dementia taking antipsychotics, should serve as a model for the type of research that is needed to better understand outcome variability among older people with chronic psychotic or bipolar disorders.40

 

Bottom Line

There is limited data available on the safety and efficacy of antipsychotics in geriatric patients with schizophrenia or bipolar disorder. When dosed appropriately, second-generation antipsychotics are preferred over first-generation antipsychotics in this population because they are less likely to cause extrapyramidal symptoms and other neurologic adverse effects.

Related Resources

  • Desai Ak, Seraji M, Redden M, et al. Schizophrenia in older adults. Current Psychiatry. 2010;9(9):22-28,A.
  • Gareri P, Segura-García C, Manfredi VG, et al. Use of atypical antipsychotics in the elderly: a clinical review. Clin Interv Aging. 2014;9:1363-1373.

Drug Brand Names

Aripiprazole • Abilify, Abilify Maintena
Asenapine • Saphris, Sycrest
Chlorpromazine • Ormazine, Thorazine
Clozapine • Clozaril, FazaClo
Divalproex • Depakote
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Olanzapine • Zyprexa, Zyprexa Relprevv
Olanzapine-Fluoxetine • Symbyax
Paliperidone extended-release • Invega
Quetiapine • Seroquel
Risperidone • Risperdal, Risperdal Consta
Valproate • Depakene
Ziprasidone • Geodon

References

1. Alexander GC, Gallagher SA, Mascola A, et al. Increasing off-label use of antipsychotic medications in the United States, 1995-2008. Pharmacoepidemiol Drug Saf. 2011;20(2):177-184.
2. United Nations, Department of Economic and Social Affairs, Population Division. World population ageing: 1950-2050. http://www.un.org/esa/population/publications/worldageing19502050. Accessed September 1, 2017.
3. Lawrence D, Kisely S, Pais J. The epidemiology of excess mortality in people with mental illness. Can J Psychiatry. 2010;55(12):752-760.
4. Cohen CI, Vahia I, Reyes P, et al. Focus on geriatric psychiatry: schizophrenia in later life: clinical symptoms and social well-being. Psychiatr Serv. 2008;59(3):232-234.
5. Jeste DV, Barak Y, Madhusoodanan S, et al. International multisite double-blind trial of the atypical antipsychotics risperidone and olanzapine in 175 elderly patients with chronic schizophrenia. Am J Geriatr Psychiatry. 2003;11(6):638-647.
6. Kalache SM, Mulsant BH, Davies SJ, et al. The impact of aging, cognition, and symptoms on functional competence in individuals with schizophrenia across the lifespan. Schizophr Bull. 2015;41(2):374-381.
7. Suzuki T, Remington G, Uchida H, et al. Management of schizophrenia in late life with antipsychotic medications: a qualitative review. Drugs Aging. 2011;28(12):961-980.
8. Mulsant BH, Pollock BG. Psychopharmacology. In: David C. Steffens DC, Blazer DG, Thakur ME (eds). The American Psychiatric Publishing Textbook of Geriatric Psychiatry, 5th Edition. Arlington, VA: American Psychiatric Publishing; 2015:527-587.
9. Cohen CI, Meesters PD, Zhao J. New perspectives on schizophrenia in later life: implications for treatment, policy, and research. Lancet Psychiatry. 2015;2(4):340-350.
10. Marriott RG, Neil W, Waddingham S. Antipsychotic medication for elderly people with schizophrenia. Cochrane Database Syst Rev. 2006;(1):CD005580.
11. Essali A, Ali G. Antipsychotic drug treatment for elderly people with late-onset schizophrenia. Cochrane Database Syst Rev. 2012(2):CD004162.
12. Scott J, Greenwald BS, Kramer E, et al. Atypical (second generation) antipsychotic treatment response in very late-onset schizophrenia-like psychosis. Int Psychogeriatr. 2011;23(5):742-748.
13. Rado J, Janicak PG. Pharmacological and clinical profile of recently approved second-generation antipsychotics: implications for treatment of schizophrenia in older patients. Drugs Aging. 2012;29(10):783-791.
14. Tzimos A, Samokhvalov V, Kramer M, et al. Safety and tolerability of oral paliperidone extended-release tablets in elderly patients with schizophrenia: a double-blind, placebo-controlled study with six-month open-label extension. Am J Geriatr Psychiatry. 2008;16(1):31-43.
15. Howanitz E, Pardo M, Smelson DA, et al. The efficacy and safety of clozapine versus chlorpromazine in geriatric schizophrenia. J Clin Psychiatry. 1999;60(1):41-44.
16. Sproule BA, Lake J, Mamo DC, et al. Are antipsychotic prescribing patterns different in older and younger adults?: a survey of 1357 psychiatric inpatients in Toronto. Can J Psychiatry. 2010;55(4):248-254.
17. Uchida H, Suzuki T, Mamo DC, et al. Effects of age and age of onset on prescribed antipsychotic dose in schizophrenia spectrum disorders: a survey of 1,418 patients in Japan. Am J Geriatr Psychiatry. 2008;16(7):584-593.
18. Graff-Guerrero A, Rajji TK, Mulsant BH, et al. Evaluation of antipsychotic dose reduction in late-life schizophrenia: a prospective dopamine D2/3 occupancy study. JAMA Psychiatry. 2015;72(9):927-934.
19. Khan A, Schwartz K, Stern C, et al. Mortality risk in patients with schizophrenia participating in premarketing atypical antipsychotic clinical trials. J Clin Psychiatry. 2007;68(12):1828-1833.
20. Weinmann S, Read J, Aderhold V. Influence of antipsychotics on mortality in schizophrenia: a systematic review. Schizophr Res. 2009;113(1):1-11.
21. Novick D, Haro JM, Perrin E, et al. Tolerability of outpatient antipsychotic treatment: 36-month results from the European Schizophrenia Outpatient Health Outcomes (SOHO) study. Eur Neuropsychopharmacol. 2009;19(8):542-550.
22. Sajatovic M, Blow FC, Ignacio RV, et al. Age-related modifiers of clinical presentation and health service use among veterans with bipolar disorder. Psychiatr Serv. 2004;55(9):1014-1021.
23. Jeste DV, Alexopoulos GS, Bartels SJ, et al. Consensus statement on the upcoming crisis in geriatric mental health: research agenda for the next 2 decades. Arch Gen Psychiatry. 1999;56(9):848-853.
24. Sajatovic M, Chen P. Geriatric bipolar disorder. Psychiatr Clin North Am. 2011;34(2):319-333,vii.
25. Sajatovic M, Strejilevich SA, Gildengers AG, et al. A report on older-age bipolar disorder from the International Society for Bipolar Disorders Task Force. Bipolar Disord. 2015;17(7):689-704.
26. Lala SV, Sajatovic M. Medical and psychiatric comorbidities among elderly individuals with bipolar disorder: a literature review. J Geriatr Psychiatry Neurol. 2012;25(1):20-25.
27. Dols A, Rhebergen D, Beekman A, et al. Psychiatric and medical comorbidities: results from a bipolar elderly cohort study. Am J Geriatr Psychiatry. 2014;22(11):1066-1074.
28. Pillarella J, Higashi A, Alexander GC, et al. Trends in use of second-generation antipsychotics for treatment of bipolar disorder in the United States, 1998-2009. Psychiatr Serv. 2012;63(1):83-86.
29. De Fruyt J, Deschepper E, Audenaert K, et al. Second generation antipsychotics in the treatment of bipolar depression: a systematic review and meta-analysis. J Psychopharmacol. 2012;26(5):603-617.
30. Nivoli AM, Murru A, Goikolea JM, et al. New treatment guidelines for acute bipolar mania: a critical review. J Affect Disord. 2012;140(2):125-141.
31. Sajatovic M, Paulsson B. Quetiapine for the treatment of depressive episodes in adults aged 55 to 65 years with bipolar disorder. Paper presented at: American Association of Geriatric Psychiatry Annual Meeting; 2007; New Orleans, LA.
32. Sajatovic M, Forester B, Tsai J, et al. Efficacy and safety of lurasidone in older adults with bipolar depression: analysis of two double-blind, placebo-controlled studies. Paper presented at: American College of Neuropsychopharmacology (ACNP) 53rd Annual Meeting; 2014; Phoenix, AZ.
33. Sajatovic M, Coconcea N, Ignacio RV, et al. Aripiprazole therapy in 20 older adults with bipolar disorder: a 12-week, open-label trial. J Clin Psychiatry. 2008;69(1):41-46.
34. Sajatovic M, Dines P, Fuentes-Casiano E, et al. Asenapine in the treatment of older adults with bipolar disorder. Int J Geriatr Psychiatry. 2015;30(7):710-719.
35. Sajatovic M, Calabrese JR, Mullen J. Quetiapine for the treatment of bipolar mania in older adults. Bipolar Disord. 2008;10(6):662-671.
36. Baruch Y, Tadger S, Plopski I, et al. Asenapine for elderly bipolar manic patients. J Affect Disord. 2013;145(1):130-132.
37. Beyer JL, Siegal A, Kennedy JS. Olanzapine, divalproex and placebo treatment, non-head to head comparisons of older adults acute mania. Paper presented at: 10th Congress of the International Psychogeriatric Association; 2001; Nice, France.
38. Al Jurdi RK, Marangell LB, Petersen NJ, et al. Prescription patterns of psychotropic medications in elderly compared with younger participants who achieved a “recovered” status in the systematic treatment enhancement program for bipolar disorder. Am J Geriatr Psychiatry. 2008;16(11):922-933.
39. Gildengers AG, Chung KH, Huang SH, et al. Neuroprogressive effects of lifetime illness duration in older adults with bipolar disorder. Bipolar Disord. 2014;16(6):617-623.
40. Ballard C, Lana MM, Theodoulou M, et al. A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial). PLoS Med. 2008;5(4):e76.

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Author and Disclosure Information

Martha Sajatovic, MD
Professor of Psychiatry and Professor of Neurology
Department of Psychiatry and Department of Neurology
Case Western Reserve University
University Hospitals Cleveland Medical Center
Cleveland, Ohio

Helen C. Kales, MD
Professor of Psychiatry
Department of Psychiatry
University of Michigan
VA Center for Clinical Management Research
Ann Arbor, Michigan

Benoit H. Mulsant, MD, MS
Professor and Chair
Department of Psychiatry
Senior Scientist
Centre for Addiction and Mental Health
University of Toronto
Toronto, Ontario

Disclosures
Dr. Sajatovic has received research grants from Alkermes, Merck, Janssen, Reuter Foundation, Woodruff Foundation, Reinberger Foundation, National Institutes of Health (NIH), and the Centers for Disease Control and Prevention; has been a consultant to Bracket, Prophase, Otsuka, Sunovion, Supernus and Neurocrine; and has received royalties from Springer Press, Johns Hopkins University Press, Oxford Press, UpToDate, and Lexicomp, and compensation for CME activities from American Physician’s Institute, MCM Education, and CMEology. Dr. Kales reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products. Dr. Mulsant has received research support from Brain Canada, the Centre for Addiction and Mental Health, the Canadian Institutes of Health Research, the NIH, Bristol-Myers Squibb (medications for an NIH-funded clinical trial), Eli Lilly (medications for an NIH-funded clinical trial), and Pfizer (medications for an NIH-funded clinical trial). Within the past 5 years, he also has received travel support from Roche.

Issue
October 2017
Publications
MDedge Psychiatry
Current Psychiatry
Topics
Schizophrenia & Other Psychotic Disorders
Page Number
20-26,28
Sections
Evidence-Based Reviews
Reviews
Author(s)
Martha Sajatovic, MD
Helen C. Kales, MD
Benoit H. Mulsant, MD, MS
Author(s)
Martha Sajatovic, MD
Helen C. Kales, MD
Benoit H. Mulsant, MD, MS
Author and Disclosure Information

Martha Sajatovic, MD
Professor of Psychiatry and Professor of Neurology
Department of Psychiatry and Department of Neurology
Case Western Reserve University
University Hospitals Cleveland Medical Center
Cleveland, Ohio

Helen C. Kales, MD
Professor of Psychiatry
Department of Psychiatry
University of Michigan
VA Center for Clinical Management Research
Ann Arbor, Michigan

Benoit H. Mulsant, MD, MS
Professor and Chair
Department of Psychiatry
Senior Scientist
Centre for Addiction and Mental Health
University of Toronto
Toronto, Ontario

Disclosures
Dr. Sajatovic has received research grants from Alkermes, Merck, Janssen, Reuter Foundation, Woodruff Foundation, Reinberger Foundation, National Institutes of Health (NIH), and the Centers for Disease Control and Prevention; has been a consultant to Bracket, Prophase, Otsuka, Sunovion, Supernus and Neurocrine; and has received royalties from Springer Press, Johns Hopkins University Press, Oxford Press, UpToDate, and Lexicomp, and compensation for CME activities from American Physician’s Institute, MCM Education, and CMEology. Dr. Kales reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products. Dr. Mulsant has received research support from Brain Canada, the Centre for Addiction and Mental Health, the Canadian Institutes of Health Research, the NIH, Bristol-Myers Squibb (medications for an NIH-funded clinical trial), Eli Lilly (medications for an NIH-funded clinical trial), and Pfizer (medications for an NIH-funded clinical trial). Within the past 5 years, he also has received travel support from Roche.

Author and Disclosure Information

Martha Sajatovic, MD
Professor of Psychiatry and Professor of Neurology
Department of Psychiatry and Department of Neurology
Case Western Reserve University
University Hospitals Cleveland Medical Center
Cleveland, Ohio

Helen C. Kales, MD
Professor of Psychiatry
Department of Psychiatry
University of Michigan
VA Center for Clinical Management Research
Ann Arbor, Michigan

Benoit H. Mulsant, MD, MS
Professor and Chair
Department of Psychiatry
Senior Scientist
Centre for Addiction and Mental Health
University of Toronto
Toronto, Ontario

Disclosures
Dr. Sajatovic has received research grants from Alkermes, Merck, Janssen, Reuter Foundation, Woodruff Foundation, Reinberger Foundation, National Institutes of Health (NIH), and the Centers for Disease Control and Prevention; has been a consultant to Bracket, Prophase, Otsuka, Sunovion, Supernus and Neurocrine; and has received royalties from Springer Press, Johns Hopkins University Press, Oxford Press, UpToDate, and Lexicomp, and compensation for CME activities from American Physician’s Institute, MCM Education, and CMEology. Dr. Kales reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products. Dr. Mulsant has received research support from Brain Canada, the Centre for Addiction and Mental Health, the Canadian Institutes of Health Research, the NIH, Bristol-Myers Squibb (medications for an NIH-funded clinical trial), Eli Lilly (medications for an NIH-funded clinical trial), and Pfizer (medications for an NIH-funded clinical trial). Within the past 5 years, he also has received travel support from Roche.

Article PDF
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Antipsychotics are FDA-approved as a primary treatment for schizophrenia and bipolar disorder and as adjunctive therapy for major depressive disorder. In the United States, approximately 26% of antipsychotic prescriptions written for these indications are for individuals age >65.1 Additionally, antipsychotics are widely used to treat behavioral symptoms associated with dementia.1 The rapid expansion of the use of second-generation antipsychotics (SGAs), in particular, has been driven in part by their lower risk for extrapyramidal symptoms (EPS) compared with first-generation antipsychotics (FGAs).1 However, a growing body of data indicates that all antipsychotics have a range of adverse effects in older patients. This focus is critical in light of demographic trends—in the next 10 to 15 years, the population age >60 will grow 3.5 times more rapidly than the general population.2

In this context, psychiatrists need information on the relative risks of antipsychotics for older patients. This 3-part series summarizes findings and recommendations on safety and tolerability when prescribing antipsychotics in older individuals with chronic psychotic disorders, such as schizophrenia, bipolar disorder, depression, and dementia. This review aims to:

  • briefly summarize the major studies and analyses relevant to older patients with these diagnoses
  • provide a summative opinion on safety and tolerability issues in these older adults
  • highlight the gaps in the evidence base and areas that need additional research.

Part 1 focuses on older adults with schizophrenia or bipolar disorder. Subsequent articles will focus on prescribing antipsychotics to older adults with depression and those with dementia.

Schizophrenia

Summary of benefits, place in treatment armamentarium. Individuals with schizophrenia have a shorter life expectancy than that of the general population mostly as a result of suicide and comorbid physical illnesses,3 but the number of patients with schizophrenia age >55 will double over the next 2 decades.4 With aging, both positive and negative symptoms may be a focus of treatment (Table 1).5,6 Antipsychotics are a first-line treatment for older patients with schizophrenia with few medication alternatives.7 Safety risks associated with antipsychotics in older people span a broad spectrum (Table 2).8

Clinical trials. Few studies have evaluated treatment of older adults with schizophrenia.7-13 Two Cochrane reviews found only a handful of randomized controlled trials (RCTs).10,11 The largest RCT was an 8-week prospective, multisite RCT of olanzapine vs risperidone in 175 older adults (age ≥60 years; mean age, 71 years) with schizophrenia.5 Before enrollment, just over one-half (53%) had been treated with FGAs. Both risperidone and olanzapine were flexibly dosed, with a target dose of 3 mg/d for risperidone and 20 mg/d for olanzapine. Median daily doses were 2 mg/d for risperidone and 10 mg/d for olanzapine. Both treatments were associated with symptom improvement, but there was no difference between groups. Approximately 70% of patients in each treatment arm experienced adverse events. The most common adverse effects (similar across groups) were somnolence, insomnia, dizziness, agitation, constipation, headache, and diarrhea. Rates of EPS were lower with both risperidone (9.2% EPS-related adverse effects) and olanzapine (15.9% EPS-related adverse effects) vs patients taking FGAs prior to starting the RCT. Drop-out rates were similar (risperidone, 19.3%; olanzapine, 27.6%). There was greater weight gain with olanzapine vs risperidone (P = .04).5

A 6-week prospective RCT evaluated paliperidone extended-release vs placebo in 114 older adults (age ≥65 years; mean age, 70 years) with schizophrenia.14 There was an optional 24-week extension of open-label treatment with paliperidone. Mean daily dose of paliperidone was 8.4 mg. Efficacy measures did not show consistent statistically significant differences between treatment groups. Discontinuation rates were similar between paliperidone (7%) vs placebo (8%). Serious adverse events occurred in 3% of paliperidone-treated vs 8% of placebo-treated patients. Elevated prolactin levels occurred in one-half of paliperidone-treated patients. There were no prolactin or glucose treatment-related adverse events or significant mean changes in body weight for either paliperidone-treated or placebo-treated patients. Safety findings in the 24-week, open-label extension group were consistent with the RCT results.

Howanitz et al15 conducted a 12-week, prospective RCT that compared clozapine (mean dose, 300 mg/d) with chlorpromazine (mean dose, 600 mg/d) in 42 older adults (mean age, 67 years) with schizophrenia. Drop-out rate prior to 5 weeks was 19% and similar between groups. Common adverse effects included sialorrhea, hematologic abnormalities, sedation, tachycardia, EPS, and weight gain. Although both drugs were effective, more patients taking clozapine had tachycardia and weight gain, while more chlorpromazine patients reported sedation.

There have been other, less rigorous studies.7,8 Most of these studies evaluated risperidone and olanzapine, and most were conducted in “younger” geriatric patients (age <75 years). Although patients who participate in clinical trials may be healthier than “typical” patients, adverse effects such as EPS, sedation, and weight gain were still relatively common in these studies.

 

 

 

Other clinical data. A major consideration in treating older adults with schizophrenia is balancing the need to administer an antipsychotic dose high enough to alleviate psychotic symptoms while minimizing dose-dependent adverse effects. There is a U-shaped relationship between age and vulnerability to antipsychotic adverse effects,16,17 wherein adverse effects are highest at younger and older ages. Evidence supports using the lowest effective antipsychotic dose for geriatric patients with schizophrenia. Positive emission tomography (PET) studies suggest that older patients develop EPS with lower doses despite lower receptor occupancy.17,18 A recent study of 35 older patients (mean age, 60.1 years) with schizophrenia obtained PET, clinical measures, and blood pharmacokinetic measures before and after reduction of risperidone or olanzapine doses.18 A ≥40% reduction in dose was associated with reduced adverse effects, particularly EPS and elevation of prolactin levels. Moreover, the therapeutic window of striatal D2/D3 receptor occupancy appeared to be 50% to 60% in these older patients, compared with 65% to 80% in younger patients.

Long-term risks of antipsychotic treatment across the lifespan are less clear, with evidence suggesting both lower and higher mortality risk.19,20 It is difficult to fully disentangle the long-term risks of antipsychotics from the cumulative effects of lifestyle and comorbidity among individuals who have lived with schizophrenia for decades. Large naturalistic studies that include substantial numbers of older people with schizophrenia might be a way to elicit more information on long-term safety. The Schizophrenia Outpatient Health Outcome (SOHO) study was a large naturalistic trial that recruited >10,000 individuals with schizophrenia in 10 European countries.21 Although the SOHO study found differences between antipsychotics and adverse effects, such as EPS, weight gain, and sexual dysfunction, because the mean age of these patients was approximately 40 years and the follow-up period was only 3 years, it is difficult to draw conclusions that could be relevant to older individuals who have had schizophrenia for decades.

Bipolar Disorder

Summary of benefits, place in treatment armamentarium. Up to 25% of bipolar patients are elderly,22 and that number is projected to increase over the next decade.23 Clinical considerations in older adults with bipolar disorder include medical comorbidity, depression burden, and possible cognitive decline (Table 3).24-27 Along with lithium and mood stabilizers, antipsychotics are a first-line treatment for bipolar disorder.28-30 Most FDA-approved antipsychotics for bipolar disorder are SGAs for bipolar mania. However, olanzapine-fluoxetine combination, quetiapine, and lurasidone are approved for bipolar depression. Aripiprazole, olanzapine, quetiapine, long-acting injectable risperidone, and oral ziprasidone are FDA-approved for longer-term use in adults with bipolar disorder. There are no head-to-head trials of antipsychotics for older persons with bipolar disorder.


Clinical trials: Bipolar depression. A post hoc, secondary analysis of two 8-week, double-blind, randomized, placebo-controlled studies in bipolar depression compared 2 dosages of quetiapine (300 mg/d and 600 mg/d) with placebo in mixed-age patients.31 In a subgroup of 72 patients, ages 55 to 65, remission occurred more often with quetiapine than with placebo. Study discontinuation rates were similar between older people and younger people (age <55 years): quetiapine, 300 mg/d, 29.2%; quetiapine, 600 mg/d, 48.1%; and placebo, 29.6% in older adults, compared with 37.1%, 45.8%, and 38.1%, respectively, in younger adults. In all patients, the most common reason for discontinuation was adverse events with quetiapine and lack of efficacy for placebo. Adverse event rates were similar in older and younger adults. Dry mouth and dizziness were more common in older adults. Proportions of adults experiencing clinically significant weight gain (≥7% of body weight) were 5.3%, 8.3%, and 0% in older adults receiving quetiapine, 300 mg/d, quetiapine, 600 mg/d, and placebo, respectively, compared with 7.2%, 10.1%, and 2.6% in younger adults. EPS and treatment-emergent mania were minimal.

A secondary analysis of mixed-age, RCTs examined response in older adults (age ≥55 years) with bipolar I depression who received lurasidone as monotherapy or adjunctive therapy.32 In the monotherapy study, these patients were randomized to 6 weeks of lurasidone 20 to 60 mg/d, lurasidone 80 to 120 mg/d, or placebo. In the adjunctive therapy study, they were randomized to lurasidone 20 to 120 mg/d or placebo with either lithium or valproate. There were 83 older adults (17.1% of the sample) in the monotherapy study and 53 (15.6%) in the adjunctive therapy study. Mean improvement in depression was significantly higher for both doses of lurasidone monotherapy than placebo. Adjunctive lurasidone was not associated with statistically significant improvement vs placebo. The most frequent adverse events in older patients on lurasidone monotherapy 20 to 60 mg/d or 80 to 120 mg/d were nausea (18.5% and 9.7%, respectively) and somnolence (11.1% and 0%, respectively). Akathisia (9.7%) and insomnia (9.7%) were the most common adverse events in the group receiving 80 to 120 mg/d, with the rate of akathisia exhibiting a dose-related increase. Weight change with lurasidone was similar to placebo, and there were no clinically meaningful group changes in vital signs, electrocardiography, or laboratory parameters.

A small (N = 20) open study found improvement in older adults with bipolar depression with aripiprazole (mean dose, 10.3 mg/d).33 Adverse effects included restlessness and weight gain (n = 3, 9% each), sedation (n = 2, 10%), and drooling and diarrhea/loose stools (n = 1, 5% each). In another small study (N = 15) using asenapine (mean dose, 11.2 mg/d) in mainly older bipolar patients with depression, the most common adverse effects were gastrointestinal (GI) discomfort (n = 5, 33%) and restlessness, tremors, cognitive difficulties, and sluggishness (n = 2, 13% each).34

 

 

 

Clinical trials: Bipolar mania. Researchers conducted a pooled analysis of two 12-week randomized trials comparing quetiapine with placebo in a mixed-age sample with bipolar mania.35 In a subgroup of 59 older patients (mean age, 62.9 years), manic symptoms improved significantly more with quetiapine (modal dose, 550 mg/d) than with placebo. Adverse effects reported by >10% of older patients were dry mouth, somnolence, postural hypotension, insomnia, weight gain, and dizziness. Insomnia was reported by >10% of patients receiving placebo.

In a case series of 11 elderly patients with mania receiving asenapine, Baruch et al36 reported a 63% remission rate. One patient discontinued the study because of a new rash, 1 discontinued after developing peripheral edema, and 3 patients reported mild sedation.

Beyer et al37 reported on a post hoc analysis of 94 older adults (mean age, 57.1 years; range, 50.1 to 74.8 years) with acute bipolar mania receiving olanzapine (n = 47), divalproex (n = 31), or placebo (n = 16) in a pooled olanzapine clinical trials database. Patients receiving olanzapine or divalproex had improvement in mania; those receiving placebo did not improve. Safety findings were comparable with reports in younger patients with mania.

Other clinical data. Adverse effects found in mixed-age samples using secondary analyses of clinical trials need to be interpreted with caution because these types of studies usually exclude individuals with significant medical comorbidity. Medical burden, cognitive impairment, or concomitant medications generally necessitate slower drug titration and lower total daily dosing. For example, a secondary analysis of the U.S. National Institute of Health-funded Systematic Treatment Enhancement Program for Bipolar Disorder study, which had broader inclusion criteria than most clinical trials, reported that, although recovery rates in older adults with bipolar disorder were fairly good (78.5%), lower doses of risperidone were used in older vs younger patients.38

Clinical considerations

Interpretation of the relative risks of antipsychotics in older people must be tempered by the caveat that there is limited high-quality data (Table 4). Antipsychotics are the first-line therapy for older patients with schizophrenia, although their use is supported by a small number of prospective RCTs. SGAs are preferred because of their lower propensity to cause EPS and other motor adverse effects. Older persons with schizophrenia have an EPS threshold lower than younger patients and determining the lowest effective dosage may minimize EPS and cognitive adverse effects. As individuals with long-standing schizophrenia get older, their antipsychotic dosages may need to be reduced, and clinicians need to monitor for adverse effects that are more common among older people, such as tardive dyskinesia and metabolic abnormalities. In healthy, “younger” geriatric patients, monitoring for adverse effects may be similar to monitoring of younger patients. Patients who are older or frail may need more frequent assessment.

Like older adults with schizophrenia, geriatric patients with bipolar disorder have reduced drug tolerability and experience more adverse effects than younger patients. There are no prospective controlled studies that evaluated using antipsychotics in older patients with bipolar disorder. In older bipolar patients, the most problematic adverse effects of antipsychotics are akathisia, parkinsonism, other EPS, sedation and dizziness (which may increase fall risk), and GI discomfort. A key tolerability and safety consideration when treating older adults with bipolar disorder is the role of antipsychotics in relation to the use of lithium and mood stabilizers. Some studies have suggested that lithium has neuroprotective effects when used long-term; however, at least 1 report suggested that long-term antipsychotic treatment may be associated with neurodegeneration.39

The literature does not provide strong evidence on the many clinical variations that we see in routine practice settings, such as combinations of drug treatments or drugs prescribed to patients with specific comorbid conditions. There is a need for large cohort studies that monitor treatment course, medical comorbidity, and prognosis. Additionally, well-designed clinical trials such as the DART-AD, which investigated longer-term trajectories of people with dementia taking antipsychotics, should serve as a model for the type of research that is needed to better understand outcome variability among older people with chronic psychotic or bipolar disorders.40

 

Bottom Line

There is limited data available on the safety and efficacy of antipsychotics in geriatric patients with schizophrenia or bipolar disorder. When dosed appropriately, second-generation antipsychotics are preferred over first-generation antipsychotics in this population because they are less likely to cause extrapyramidal symptoms and other neurologic adverse effects.

Related Resources

  • Desai Ak, Seraji M, Redden M, et al. Schizophrenia in older adults. Current Psychiatry. 2010;9(9):22-28,A.
  • Gareri P, Segura-García C, Manfredi VG, et al. Use of atypical antipsychotics in the elderly: a clinical review. Clin Interv Aging. 2014;9:1363-1373.

Drug Brand Names

Aripiprazole • Abilify, Abilify Maintena
Asenapine • Saphris, Sycrest
Chlorpromazine • Ormazine, Thorazine
Clozapine • Clozaril, FazaClo
Divalproex • Depakote
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Olanzapine • Zyprexa, Zyprexa Relprevv
Olanzapine-Fluoxetine • Symbyax
Paliperidone extended-release • Invega
Quetiapine • Seroquel
Risperidone • Risperdal, Risperdal Consta
Valproate • Depakene
Ziprasidone • Geodon

 

Antipsychotics are FDA-approved as a primary treatment for schizophrenia and bipolar disorder and as adjunctive therapy for major depressive disorder. In the United States, approximately 26% of antipsychotic prescriptions written for these indications are for individuals age >65.1 Additionally, antipsychotics are widely used to treat behavioral symptoms associated with dementia.1 The rapid expansion of the use of second-generation antipsychotics (SGAs), in particular, has been driven in part by their lower risk for extrapyramidal symptoms (EPS) compared with first-generation antipsychotics (FGAs).1 However, a growing body of data indicates that all antipsychotics have a range of adverse effects in older patients. This focus is critical in light of demographic trends—in the next 10 to 15 years, the population age >60 will grow 3.5 times more rapidly than the general population.2

In this context, psychiatrists need information on the relative risks of antipsychotics for older patients. This 3-part series summarizes findings and recommendations on safety and tolerability when prescribing antipsychotics in older individuals with chronic psychotic disorders, such as schizophrenia, bipolar disorder, depression, and dementia. This review aims to:

  • briefly summarize the major studies and analyses relevant to older patients with these diagnoses
  • provide a summative opinion on safety and tolerability issues in these older adults
  • highlight the gaps in the evidence base and areas that need additional research.

Part 1 focuses on older adults with schizophrenia or bipolar disorder. Subsequent articles will focus on prescribing antipsychotics to older adults with depression and those with dementia.

Schizophrenia

Summary of benefits, place in treatment armamentarium. Individuals with schizophrenia have a shorter life expectancy than that of the general population mostly as a result of suicide and comorbid physical illnesses,3 but the number of patients with schizophrenia age >55 will double over the next 2 decades.4 With aging, both positive and negative symptoms may be a focus of treatment (Table 1).5,6 Antipsychotics are a first-line treatment for older patients with schizophrenia with few medication alternatives.7 Safety risks associated with antipsychotics in older people span a broad spectrum (Table 2).8

Clinical trials. Few studies have evaluated treatment of older adults with schizophrenia.7-13 Two Cochrane reviews found only a handful of randomized controlled trials (RCTs).10,11 The largest RCT was an 8-week prospective, multisite RCT of olanzapine vs risperidone in 175 older adults (age ≥60 years; mean age, 71 years) with schizophrenia.5 Before enrollment, just over one-half (53%) had been treated with FGAs. Both risperidone and olanzapine were flexibly dosed, with a target dose of 3 mg/d for risperidone and 20 mg/d for olanzapine. Median daily doses were 2 mg/d for risperidone and 10 mg/d for olanzapine. Both treatments were associated with symptom improvement, but there was no difference between groups. Approximately 70% of patients in each treatment arm experienced adverse events. The most common adverse effects (similar across groups) were somnolence, insomnia, dizziness, agitation, constipation, headache, and diarrhea. Rates of EPS were lower with both risperidone (9.2% EPS-related adverse effects) and olanzapine (15.9% EPS-related adverse effects) vs patients taking FGAs prior to starting the RCT. Drop-out rates were similar (risperidone, 19.3%; olanzapine, 27.6%). There was greater weight gain with olanzapine vs risperidone (P = .04).5

A 6-week prospective RCT evaluated paliperidone extended-release vs placebo in 114 older adults (age ≥65 years; mean age, 70 years) with schizophrenia.14 There was an optional 24-week extension of open-label treatment with paliperidone. Mean daily dose of paliperidone was 8.4 mg. Efficacy measures did not show consistent statistically significant differences between treatment groups. Discontinuation rates were similar between paliperidone (7%) vs placebo (8%). Serious adverse events occurred in 3% of paliperidone-treated vs 8% of placebo-treated patients. Elevated prolactin levels occurred in one-half of paliperidone-treated patients. There were no prolactin or glucose treatment-related adverse events or significant mean changes in body weight for either paliperidone-treated or placebo-treated patients. Safety findings in the 24-week, open-label extension group were consistent with the RCT results.

Howanitz et al15 conducted a 12-week, prospective RCT that compared clozapine (mean dose, 300 mg/d) with chlorpromazine (mean dose, 600 mg/d) in 42 older adults (mean age, 67 years) with schizophrenia. Drop-out rate prior to 5 weeks was 19% and similar between groups. Common adverse effects included sialorrhea, hematologic abnormalities, sedation, tachycardia, EPS, and weight gain. Although both drugs were effective, more patients taking clozapine had tachycardia and weight gain, while more chlorpromazine patients reported sedation.

There have been other, less rigorous studies.7,8 Most of these studies evaluated risperidone and olanzapine, and most were conducted in “younger” geriatric patients (age <75 years). Although patients who participate in clinical trials may be healthier than “typical” patients, adverse effects such as EPS, sedation, and weight gain were still relatively common in these studies.

 

 

 

Other clinical data. A major consideration in treating older adults with schizophrenia is balancing the need to administer an antipsychotic dose high enough to alleviate psychotic symptoms while minimizing dose-dependent adverse effects. There is a U-shaped relationship between age and vulnerability to antipsychotic adverse effects,16,17 wherein adverse effects are highest at younger and older ages. Evidence supports using the lowest effective antipsychotic dose for geriatric patients with schizophrenia. Positive emission tomography (PET) studies suggest that older patients develop EPS with lower doses despite lower receptor occupancy.17,18 A recent study of 35 older patients (mean age, 60.1 years) with schizophrenia obtained PET, clinical measures, and blood pharmacokinetic measures before and after reduction of risperidone or olanzapine doses.18 A ≥40% reduction in dose was associated with reduced adverse effects, particularly EPS and elevation of prolactin levels. Moreover, the therapeutic window of striatal D2/D3 receptor occupancy appeared to be 50% to 60% in these older patients, compared with 65% to 80% in younger patients.

Long-term risks of antipsychotic treatment across the lifespan are less clear, with evidence suggesting both lower and higher mortality risk.19,20 It is difficult to fully disentangle the long-term risks of antipsychotics from the cumulative effects of lifestyle and comorbidity among individuals who have lived with schizophrenia for decades. Large naturalistic studies that include substantial numbers of older people with schizophrenia might be a way to elicit more information on long-term safety. The Schizophrenia Outpatient Health Outcome (SOHO) study was a large naturalistic trial that recruited >10,000 individuals with schizophrenia in 10 European countries.21 Although the SOHO study found differences between antipsychotics and adverse effects, such as EPS, weight gain, and sexual dysfunction, because the mean age of these patients was approximately 40 years and the follow-up period was only 3 years, it is difficult to draw conclusions that could be relevant to older individuals who have had schizophrenia for decades.

Bipolar Disorder

Summary of benefits, place in treatment armamentarium. Up to 25% of bipolar patients are elderly,22 and that number is projected to increase over the next decade.23 Clinical considerations in older adults with bipolar disorder include medical comorbidity, depression burden, and possible cognitive decline (Table 3).24-27 Along with lithium and mood stabilizers, antipsychotics are a first-line treatment for bipolar disorder.28-30 Most FDA-approved antipsychotics for bipolar disorder are SGAs for bipolar mania. However, olanzapine-fluoxetine combination, quetiapine, and lurasidone are approved for bipolar depression. Aripiprazole, olanzapine, quetiapine, long-acting injectable risperidone, and oral ziprasidone are FDA-approved for longer-term use in adults with bipolar disorder. There are no head-to-head trials of antipsychotics for older persons with bipolar disorder.


Clinical trials: Bipolar depression. A post hoc, secondary analysis of two 8-week, double-blind, randomized, placebo-controlled studies in bipolar depression compared 2 dosages of quetiapine (300 mg/d and 600 mg/d) with placebo in mixed-age patients.31 In a subgroup of 72 patients, ages 55 to 65, remission occurred more often with quetiapine than with placebo. Study discontinuation rates were similar between older people and younger people (age <55 years): quetiapine, 300 mg/d, 29.2%; quetiapine, 600 mg/d, 48.1%; and placebo, 29.6% in older adults, compared with 37.1%, 45.8%, and 38.1%, respectively, in younger adults. In all patients, the most common reason for discontinuation was adverse events with quetiapine and lack of efficacy for placebo. Adverse event rates were similar in older and younger adults. Dry mouth and dizziness were more common in older adults. Proportions of adults experiencing clinically significant weight gain (≥7% of body weight) were 5.3%, 8.3%, and 0% in older adults receiving quetiapine, 300 mg/d, quetiapine, 600 mg/d, and placebo, respectively, compared with 7.2%, 10.1%, and 2.6% in younger adults. EPS and treatment-emergent mania were minimal.

A secondary analysis of mixed-age, RCTs examined response in older adults (age ≥55 years) with bipolar I depression who received lurasidone as monotherapy or adjunctive therapy.32 In the monotherapy study, these patients were randomized to 6 weeks of lurasidone 20 to 60 mg/d, lurasidone 80 to 120 mg/d, or placebo. In the adjunctive therapy study, they were randomized to lurasidone 20 to 120 mg/d or placebo with either lithium or valproate. There were 83 older adults (17.1% of the sample) in the monotherapy study and 53 (15.6%) in the adjunctive therapy study. Mean improvement in depression was significantly higher for both doses of lurasidone monotherapy than placebo. Adjunctive lurasidone was not associated with statistically significant improvement vs placebo. The most frequent adverse events in older patients on lurasidone monotherapy 20 to 60 mg/d or 80 to 120 mg/d were nausea (18.5% and 9.7%, respectively) and somnolence (11.1% and 0%, respectively). Akathisia (9.7%) and insomnia (9.7%) were the most common adverse events in the group receiving 80 to 120 mg/d, with the rate of akathisia exhibiting a dose-related increase. Weight change with lurasidone was similar to placebo, and there were no clinically meaningful group changes in vital signs, electrocardiography, or laboratory parameters.

A small (N = 20) open study found improvement in older adults with bipolar depression with aripiprazole (mean dose, 10.3 mg/d).33 Adverse effects included restlessness and weight gain (n = 3, 9% each), sedation (n = 2, 10%), and drooling and diarrhea/loose stools (n = 1, 5% each). In another small study (N = 15) using asenapine (mean dose, 11.2 mg/d) in mainly older bipolar patients with depression, the most common adverse effects were gastrointestinal (GI) discomfort (n = 5, 33%) and restlessness, tremors, cognitive difficulties, and sluggishness (n = 2, 13% each).34

 

 

 

Clinical trials: Bipolar mania. Researchers conducted a pooled analysis of two 12-week randomized trials comparing quetiapine with placebo in a mixed-age sample with bipolar mania.35 In a subgroup of 59 older patients (mean age, 62.9 years), manic symptoms improved significantly more with quetiapine (modal dose, 550 mg/d) than with placebo. Adverse effects reported by >10% of older patients were dry mouth, somnolence, postural hypotension, insomnia, weight gain, and dizziness. Insomnia was reported by >10% of patients receiving placebo.

In a case series of 11 elderly patients with mania receiving asenapine, Baruch et al36 reported a 63% remission rate. One patient discontinued the study because of a new rash, 1 discontinued after developing peripheral edema, and 3 patients reported mild sedation.

Beyer et al37 reported on a post hoc analysis of 94 older adults (mean age, 57.1 years; range, 50.1 to 74.8 years) with acute bipolar mania receiving olanzapine (n = 47), divalproex (n = 31), or placebo (n = 16) in a pooled olanzapine clinical trials database. Patients receiving olanzapine or divalproex had improvement in mania; those receiving placebo did not improve. Safety findings were comparable with reports in younger patients with mania.

Other clinical data. Adverse effects found in mixed-age samples using secondary analyses of clinical trials need to be interpreted with caution because these types of studies usually exclude individuals with significant medical comorbidity. Medical burden, cognitive impairment, or concomitant medications generally necessitate slower drug titration and lower total daily dosing. For example, a secondary analysis of the U.S. National Institute of Health-funded Systematic Treatment Enhancement Program for Bipolar Disorder study, which had broader inclusion criteria than most clinical trials, reported that, although recovery rates in older adults with bipolar disorder were fairly good (78.5%), lower doses of risperidone were used in older vs younger patients.38

Clinical considerations

Interpretation of the relative risks of antipsychotics in older people must be tempered by the caveat that there is limited high-quality data (Table 4). Antipsychotics are the first-line therapy for older patients with schizophrenia, although their use is supported by a small number of prospective RCTs. SGAs are preferred because of their lower propensity to cause EPS and other motor adverse effects. Older persons with schizophrenia have an EPS threshold lower than younger patients and determining the lowest effective dosage may minimize EPS and cognitive adverse effects. As individuals with long-standing schizophrenia get older, their antipsychotic dosages may need to be reduced, and clinicians need to monitor for adverse effects that are more common among older people, such as tardive dyskinesia and metabolic abnormalities. In healthy, “younger” geriatric patients, monitoring for adverse effects may be similar to monitoring of younger patients. Patients who are older or frail may need more frequent assessment.

Like older adults with schizophrenia, geriatric patients with bipolar disorder have reduced drug tolerability and experience more adverse effects than younger patients. There are no prospective controlled studies that evaluated using antipsychotics in older patients with bipolar disorder. In older bipolar patients, the most problematic adverse effects of antipsychotics are akathisia, parkinsonism, other EPS, sedation and dizziness (which may increase fall risk), and GI discomfort. A key tolerability and safety consideration when treating older adults with bipolar disorder is the role of antipsychotics in relation to the use of lithium and mood stabilizers. Some studies have suggested that lithium has neuroprotective effects when used long-term; however, at least 1 report suggested that long-term antipsychotic treatment may be associated with neurodegeneration.39

The literature does not provide strong evidence on the many clinical variations that we see in routine practice settings, such as combinations of drug treatments or drugs prescribed to patients with specific comorbid conditions. There is a need for large cohort studies that monitor treatment course, medical comorbidity, and prognosis. Additionally, well-designed clinical trials such as the DART-AD, which investigated longer-term trajectories of people with dementia taking antipsychotics, should serve as a model for the type of research that is needed to better understand outcome variability among older people with chronic psychotic or bipolar disorders.40

 

Bottom Line

There is limited data available on the safety and efficacy of antipsychotics in geriatric patients with schizophrenia or bipolar disorder. When dosed appropriately, second-generation antipsychotics are preferred over first-generation antipsychotics in this population because they are less likely to cause extrapyramidal symptoms and other neurologic adverse effects.

Related Resources

  • Desai Ak, Seraji M, Redden M, et al. Schizophrenia in older adults. Current Psychiatry. 2010;9(9):22-28,A.
  • Gareri P, Segura-García C, Manfredi VG, et al. Use of atypical antipsychotics in the elderly: a clinical review. Clin Interv Aging. 2014;9:1363-1373.

Drug Brand Names

Aripiprazole • Abilify, Abilify Maintena
Asenapine • Saphris, Sycrest
Chlorpromazine • Ormazine, Thorazine
Clozapine • Clozaril, FazaClo
Divalproex • Depakote
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Olanzapine • Zyprexa, Zyprexa Relprevv
Olanzapine-Fluoxetine • Symbyax
Paliperidone extended-release • Invega
Quetiapine • Seroquel
Risperidone • Risperdal, Risperdal Consta
Valproate • Depakene
Ziprasidone • Geodon

References

1. Alexander GC, Gallagher SA, Mascola A, et al. Increasing off-label use of antipsychotic medications in the United States, 1995-2008. Pharmacoepidemiol Drug Saf. 2011;20(2):177-184.
2. United Nations, Department of Economic and Social Affairs, Population Division. World population ageing: 1950-2050. http://www.un.org/esa/population/publications/worldageing19502050. Accessed September 1, 2017.
3. Lawrence D, Kisely S, Pais J. The epidemiology of excess mortality in people with mental illness. Can J Psychiatry. 2010;55(12):752-760.
4. Cohen CI, Vahia I, Reyes P, et al. Focus on geriatric psychiatry: schizophrenia in later life: clinical symptoms and social well-being. Psychiatr Serv. 2008;59(3):232-234.
5. Jeste DV, Barak Y, Madhusoodanan S, et al. International multisite double-blind trial of the atypical antipsychotics risperidone and olanzapine in 175 elderly patients with chronic schizophrenia. Am J Geriatr Psychiatry. 2003;11(6):638-647.
6. Kalache SM, Mulsant BH, Davies SJ, et al. The impact of aging, cognition, and symptoms on functional competence in individuals with schizophrenia across the lifespan. Schizophr Bull. 2015;41(2):374-381.
7. Suzuki T, Remington G, Uchida H, et al. Management of schizophrenia in late life with antipsychotic medications: a qualitative review. Drugs Aging. 2011;28(12):961-980.
8. Mulsant BH, Pollock BG. Psychopharmacology. In: David C. Steffens DC, Blazer DG, Thakur ME (eds). The American Psychiatric Publishing Textbook of Geriatric Psychiatry, 5th Edition. Arlington, VA: American Psychiatric Publishing; 2015:527-587.
9. Cohen CI, Meesters PD, Zhao J. New perspectives on schizophrenia in later life: implications for treatment, policy, and research. Lancet Psychiatry. 2015;2(4):340-350.
10. Marriott RG, Neil W, Waddingham S. Antipsychotic medication for elderly people with schizophrenia. Cochrane Database Syst Rev. 2006;(1):CD005580.
11. Essali A, Ali G. Antipsychotic drug treatment for elderly people with late-onset schizophrenia. Cochrane Database Syst Rev. 2012(2):CD004162.
12. Scott J, Greenwald BS, Kramer E, et al. Atypical (second generation) antipsychotic treatment response in very late-onset schizophrenia-like psychosis. Int Psychogeriatr. 2011;23(5):742-748.
13. Rado J, Janicak PG. Pharmacological and clinical profile of recently approved second-generation antipsychotics: implications for treatment of schizophrenia in older patients. Drugs Aging. 2012;29(10):783-791.
14. Tzimos A, Samokhvalov V, Kramer M, et al. Safety and tolerability of oral paliperidone extended-release tablets in elderly patients with schizophrenia: a double-blind, placebo-controlled study with six-month open-label extension. Am J Geriatr Psychiatry. 2008;16(1):31-43.
15. Howanitz E, Pardo M, Smelson DA, et al. The efficacy and safety of clozapine versus chlorpromazine in geriatric schizophrenia. J Clin Psychiatry. 1999;60(1):41-44.
16. Sproule BA, Lake J, Mamo DC, et al. Are antipsychotic prescribing patterns different in older and younger adults?: a survey of 1357 psychiatric inpatients in Toronto. Can J Psychiatry. 2010;55(4):248-254.
17. Uchida H, Suzuki T, Mamo DC, et al. Effects of age and age of onset on prescribed antipsychotic dose in schizophrenia spectrum disorders: a survey of 1,418 patients in Japan. Am J Geriatr Psychiatry. 2008;16(7):584-593.
18. Graff-Guerrero A, Rajji TK, Mulsant BH, et al. Evaluation of antipsychotic dose reduction in late-life schizophrenia: a prospective dopamine D2/3 occupancy study. JAMA Psychiatry. 2015;72(9):927-934.
19. Khan A, Schwartz K, Stern C, et al. Mortality risk in patients with schizophrenia participating in premarketing atypical antipsychotic clinical trials. J Clin Psychiatry. 2007;68(12):1828-1833.
20. Weinmann S, Read J, Aderhold V. Influence of antipsychotics on mortality in schizophrenia: a systematic review. Schizophr Res. 2009;113(1):1-11.
21. Novick D, Haro JM, Perrin E, et al. Tolerability of outpatient antipsychotic treatment: 36-month results from the European Schizophrenia Outpatient Health Outcomes (SOHO) study. Eur Neuropsychopharmacol. 2009;19(8):542-550.
22. Sajatovic M, Blow FC, Ignacio RV, et al. Age-related modifiers of clinical presentation and health service use among veterans with bipolar disorder. Psychiatr Serv. 2004;55(9):1014-1021.
23. Jeste DV, Alexopoulos GS, Bartels SJ, et al. Consensus statement on the upcoming crisis in geriatric mental health: research agenda for the next 2 decades. Arch Gen Psychiatry. 1999;56(9):848-853.
24. Sajatovic M, Chen P. Geriatric bipolar disorder. Psychiatr Clin North Am. 2011;34(2):319-333,vii.
25. Sajatovic M, Strejilevich SA, Gildengers AG, et al. A report on older-age bipolar disorder from the International Society for Bipolar Disorders Task Force. Bipolar Disord. 2015;17(7):689-704.
26. Lala SV, Sajatovic M. Medical and psychiatric comorbidities among elderly individuals with bipolar disorder: a literature review. J Geriatr Psychiatry Neurol. 2012;25(1):20-25.
27. Dols A, Rhebergen D, Beekman A, et al. Psychiatric and medical comorbidities: results from a bipolar elderly cohort study. Am J Geriatr Psychiatry. 2014;22(11):1066-1074.
28. Pillarella J, Higashi A, Alexander GC, et al. Trends in use of second-generation antipsychotics for treatment of bipolar disorder in the United States, 1998-2009. Psychiatr Serv. 2012;63(1):83-86.
29. De Fruyt J, Deschepper E, Audenaert K, et al. Second generation antipsychotics in the treatment of bipolar depression: a systematic review and meta-analysis. J Psychopharmacol. 2012;26(5):603-617.
30. Nivoli AM, Murru A, Goikolea JM, et al. New treatment guidelines for acute bipolar mania: a critical review. J Affect Disord. 2012;140(2):125-141.
31. Sajatovic M, Paulsson B. Quetiapine for the treatment of depressive episodes in adults aged 55 to 65 years with bipolar disorder. Paper presented at: American Association of Geriatric Psychiatry Annual Meeting; 2007; New Orleans, LA.
32. Sajatovic M, Forester B, Tsai J, et al. Efficacy and safety of lurasidone in older adults with bipolar depression: analysis of two double-blind, placebo-controlled studies. Paper presented at: American College of Neuropsychopharmacology (ACNP) 53rd Annual Meeting; 2014; Phoenix, AZ.
33. Sajatovic M, Coconcea N, Ignacio RV, et al. Aripiprazole therapy in 20 older adults with bipolar disorder: a 12-week, open-label trial. J Clin Psychiatry. 2008;69(1):41-46.
34. Sajatovic M, Dines P, Fuentes-Casiano E, et al. Asenapine in the treatment of older adults with bipolar disorder. Int J Geriatr Psychiatry. 2015;30(7):710-719.
35. Sajatovic M, Calabrese JR, Mullen J. Quetiapine for the treatment of bipolar mania in older adults. Bipolar Disord. 2008;10(6):662-671.
36. Baruch Y, Tadger S, Plopski I, et al. Asenapine for elderly bipolar manic patients. J Affect Disord. 2013;145(1):130-132.
37. Beyer JL, Siegal A, Kennedy JS. Olanzapine, divalproex and placebo treatment, non-head to head comparisons of older adults acute mania. Paper presented at: 10th Congress of the International Psychogeriatric Association; 2001; Nice, France.
38. Al Jurdi RK, Marangell LB, Petersen NJ, et al. Prescription patterns of psychotropic medications in elderly compared with younger participants who achieved a “recovered” status in the systematic treatment enhancement program for bipolar disorder. Am J Geriatr Psychiatry. 2008;16(11):922-933.
39. Gildengers AG, Chung KH, Huang SH, et al. Neuroprogressive effects of lifetime illness duration in older adults with bipolar disorder. Bipolar Disord. 2014;16(6):617-623.
40. Ballard C, Lana MM, Theodoulou M, et al. A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial). PLoS Med. 2008;5(4):e76.

References

1. Alexander GC, Gallagher SA, Mascola A, et al. Increasing off-label use of antipsychotic medications in the United States, 1995-2008. Pharmacoepidemiol Drug Saf. 2011;20(2):177-184.
2. United Nations, Department of Economic and Social Affairs, Population Division. World population ageing: 1950-2050. http://www.un.org/esa/population/publications/worldageing19502050. Accessed September 1, 2017.
3. Lawrence D, Kisely S, Pais J. The epidemiology of excess mortality in people with mental illness. Can J Psychiatry. 2010;55(12):752-760.
4. Cohen CI, Vahia I, Reyes P, et al. Focus on geriatric psychiatry: schizophrenia in later life: clinical symptoms and social well-being. Psychiatr Serv. 2008;59(3):232-234.
5. Jeste DV, Barak Y, Madhusoodanan S, et al. International multisite double-blind trial of the atypical antipsychotics risperidone and olanzapine in 175 elderly patients with chronic schizophrenia. Am J Geriatr Psychiatry. 2003;11(6):638-647.
6. Kalache SM, Mulsant BH, Davies SJ, et al. The impact of aging, cognition, and symptoms on functional competence in individuals with schizophrenia across the lifespan. Schizophr Bull. 2015;41(2):374-381.
7. Suzuki T, Remington G, Uchida H, et al. Management of schizophrenia in late life with antipsychotic medications: a qualitative review. Drugs Aging. 2011;28(12):961-980.
8. Mulsant BH, Pollock BG. Psychopharmacology. In: David C. Steffens DC, Blazer DG, Thakur ME (eds). The American Psychiatric Publishing Textbook of Geriatric Psychiatry, 5th Edition. Arlington, VA: American Psychiatric Publishing; 2015:527-587.
9. Cohen CI, Meesters PD, Zhao J. New perspectives on schizophrenia in later life: implications for treatment, policy, and research. Lancet Psychiatry. 2015;2(4):340-350.
10. Marriott RG, Neil W, Waddingham S. Antipsychotic medication for elderly people with schizophrenia. Cochrane Database Syst Rev. 2006;(1):CD005580.
11. Essali A, Ali G. Antipsychotic drug treatment for elderly people with late-onset schizophrenia. Cochrane Database Syst Rev. 2012(2):CD004162.
12. Scott J, Greenwald BS, Kramer E, et al. Atypical (second generation) antipsychotic treatment response in very late-onset schizophrenia-like psychosis. Int Psychogeriatr. 2011;23(5):742-748.
13. Rado J, Janicak PG. Pharmacological and clinical profile of recently approved second-generation antipsychotics: implications for treatment of schizophrenia in older patients. Drugs Aging. 2012;29(10):783-791.
14. Tzimos A, Samokhvalov V, Kramer M, et al. Safety and tolerability of oral paliperidone extended-release tablets in elderly patients with schizophrenia: a double-blind, placebo-controlled study with six-month open-label extension. Am J Geriatr Psychiatry. 2008;16(1):31-43.
15. Howanitz E, Pardo M, Smelson DA, et al. The efficacy and safety of clozapine versus chlorpromazine in geriatric schizophrenia. J Clin Psychiatry. 1999;60(1):41-44.
16. Sproule BA, Lake J, Mamo DC, et al. Are antipsychotic prescribing patterns different in older and younger adults?: a survey of 1357 psychiatric inpatients in Toronto. Can J Psychiatry. 2010;55(4):248-254.
17. Uchida H, Suzuki T, Mamo DC, et al. Effects of age and age of onset on prescribed antipsychotic dose in schizophrenia spectrum disorders: a survey of 1,418 patients in Japan. Am J Geriatr Psychiatry. 2008;16(7):584-593.
18. Graff-Guerrero A, Rajji TK, Mulsant BH, et al. Evaluation of antipsychotic dose reduction in late-life schizophrenia: a prospective dopamine D2/3 occupancy study. JAMA Psychiatry. 2015;72(9):927-934.
19. Khan A, Schwartz K, Stern C, et al. Mortality risk in patients with schizophrenia participating in premarketing atypical antipsychotic clinical trials. J Clin Psychiatry. 2007;68(12):1828-1833.
20. Weinmann S, Read J, Aderhold V. Influence of antipsychotics on mortality in schizophrenia: a systematic review. Schizophr Res. 2009;113(1):1-11.
21. Novick D, Haro JM, Perrin E, et al. Tolerability of outpatient antipsychotic treatment: 36-month results from the European Schizophrenia Outpatient Health Outcomes (SOHO) study. Eur Neuropsychopharmacol. 2009;19(8):542-550.
22. Sajatovic M, Blow FC, Ignacio RV, et al. Age-related modifiers of clinical presentation and health service use among veterans with bipolar disorder. Psychiatr Serv. 2004;55(9):1014-1021.
23. Jeste DV, Alexopoulos GS, Bartels SJ, et al. Consensus statement on the upcoming crisis in geriatric mental health: research agenda for the next 2 decades. Arch Gen Psychiatry. 1999;56(9):848-853.
24. Sajatovic M, Chen P. Geriatric bipolar disorder. Psychiatr Clin North Am. 2011;34(2):319-333,vii.
25. Sajatovic M, Strejilevich SA, Gildengers AG, et al. A report on older-age bipolar disorder from the International Society for Bipolar Disorders Task Force. Bipolar Disord. 2015;17(7):689-704.
26. Lala SV, Sajatovic M. Medical and psychiatric comorbidities among elderly individuals with bipolar disorder: a literature review. J Geriatr Psychiatry Neurol. 2012;25(1):20-25.
27. Dols A, Rhebergen D, Beekman A, et al. Psychiatric and medical comorbidities: results from a bipolar elderly cohort study. Am J Geriatr Psychiatry. 2014;22(11):1066-1074.
28. Pillarella J, Higashi A, Alexander GC, et al. Trends in use of second-generation antipsychotics for treatment of bipolar disorder in the United States, 1998-2009. Psychiatr Serv. 2012;63(1):83-86.
29. De Fruyt J, Deschepper E, Audenaert K, et al. Second generation antipsychotics in the treatment of bipolar depression: a systematic review and meta-analysis. J Psychopharmacol. 2012;26(5):603-617.
30. Nivoli AM, Murru A, Goikolea JM, et al. New treatment guidelines for acute bipolar mania: a critical review. J Affect Disord. 2012;140(2):125-141.
31. Sajatovic M, Paulsson B. Quetiapine for the treatment of depressive episodes in adults aged 55 to 65 years with bipolar disorder. Paper presented at: American Association of Geriatric Psychiatry Annual Meeting; 2007; New Orleans, LA.
32. Sajatovic M, Forester B, Tsai J, et al. Efficacy and safety of lurasidone in older adults with bipolar depression: analysis of two double-blind, placebo-controlled studies. Paper presented at: American College of Neuropsychopharmacology (ACNP) 53rd Annual Meeting; 2014; Phoenix, AZ.
33. Sajatovic M, Coconcea N, Ignacio RV, et al. Aripiprazole therapy in 20 older adults with bipolar disorder: a 12-week, open-label trial. J Clin Psychiatry. 2008;69(1):41-46.
34. Sajatovic M, Dines P, Fuentes-Casiano E, et al. Asenapine in the treatment of older adults with bipolar disorder. Int J Geriatr Psychiatry. 2015;30(7):710-719.
35. Sajatovic M, Calabrese JR, Mullen J. Quetiapine for the treatment of bipolar mania in older adults. Bipolar Disord. 2008;10(6):662-671.
36. Baruch Y, Tadger S, Plopski I, et al. Asenapine for elderly bipolar manic patients. J Affect Disord. 2013;145(1):130-132.
37. Beyer JL, Siegal A, Kennedy JS. Olanzapine, divalproex and placebo treatment, non-head to head comparisons of older adults acute mania. Paper presented at: 10th Congress of the International Psychogeriatric Association; 2001; Nice, France.
38. Al Jurdi RK, Marangell LB, Petersen NJ, et al. Prescription patterns of psychotropic medications in elderly compared with younger participants who achieved a “recovered” status in the systematic treatment enhancement program for bipolar disorder. Am J Geriatr Psychiatry. 2008;16(11):922-933.
39. Gildengers AG, Chung KH, Huang SH, et al. Neuroprogressive effects of lifetime illness duration in older adults with bipolar disorder. Bipolar Disord. 2014;16(6):617-623.
40. Ballard C, Lana MM, Theodoulou M, et al. A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial). PLoS Med. 2008;5(4):e76.

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Prescribing antipsychotics in geriatric patients: Focus on schizophrenia and bipolar disorder
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