Evidence-Based Reviews

Prescribing antipsychotics in geriatric patients: Focus on major depressive disorder

Current Psychiatry. 2017 November;16(11):21-27

Benoit H. Mulsant, MD, MS

Helen C. Kales, MD

Martha Sajatovic, MD

New evidence supports augmenting an antidepressant with a low-dose antipsychotic. Second of 3 parts.

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References

1. United Nations. Department of Economic and Social Affairs Population Division. World Population Ageing: 1950-2050. http://www.un.org/esa/population/publications/worldageing19502050. Published 2001. Accessed September 27, 2017.
2. Olfson M, King M, Schoenbaum M. Antipsychotic treatment of adults in the United States. J Clin Psychiatry. 2015;76(10):1346-1353.
3. Sajatovic M, Kales HC, Mulsant BH. Prescribing antipsychotics in geriatric patients: focus on schizophrenia and bipolar disorder. Current Psychiatry. 2017;16(10):20-26,28.
4. Hybels CF, Blazer DG. Epidemiology of late-life mental disorders. Clin Geriatr Med. 2003;19(4):663-696,v.
5. Mulsant BH, Blumberger DM, Ismail Z, et al. A systematic approach to pharmacotherapy for geriatric major depression. Clin Geriatr Med. 2014;30(3):517-534.
6. Mulsant BH, Pollock BG. Psychopharmacology. In: Steffens DC, Blazer DG, Thakur ME, eds. The American Psychiatric Publishing textbook of geriatric psychiatry. 5th ed. Arlington, VA: American Psychiatric Publishing; 2015:527-587.
7. U.S. Food and Drug Administration. Public health advisory. deaths with antipsychotics in elderly patients with behavioral disturbances. https://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm053171. Updated August 16, 2013. Accessed September 27, 2017.
8. Andreescu C, Mulsant BH, Rothschild AJ, et al. Pharmacotherapy of major depression with psychotic features: what is the evidence? Psychiatric Annals. 2006;35(1):31-38.
9. Buchanan D, Tourigny-Rivard MF, Cappeliez P, et al. National guidelines for seniors’ mental health: the assessment and treatment of depression. Canadian Journal of Geriatrics. 2006;9(suppl 2):S52-S58.
10. Canadian Coalition for Senior’s Mental Health. National guidelines for senior’s mental health. The assessment and treatment of depression 2006. http://www.ccsmh.ca/projects/depression. Accessed February 28, 2016.
11. Meyers BS, Flint AJ, Rothschild AJ, et al. A double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo for psychotic depression: the study of pharmacotherapy of psychotic depression (STOP-PD). Arch Gen Psychiatry. 2009;66(8):838-847.
12. Mulsant BH, Sweet RA, Rosen J, et al. A double-blind randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in the treatment of psychotic depression in late life. J Clin Psychiatry. 2001;62(8):597-604.
13. Cakir S, Senkal Z. Atypical antipsychotics as add-on treatment in late-life depression. Clin Interv Aging. 2016;11:1193-1198.
14. Maust DT, Oslin DW, Thase ME. Going beyond antidepressant monotherapy for incomplete response in nonpsychotic late-life depression: a critical review. Am J Geriatr Psychiatry. 2013;21(10):973-986.
15. Patel K, Abdool PS, Rajji TK, et al. Pharmacotherapy of major depression in late life: what is the role of new agents? Expert Opin Pharmacother. 2017;18(6):599-609.
16. Alexopoulos GS, Katz IR, Reynolds CF 3rd, et al. Pharmacotherapy of depression in older patients: a summary of the expert consensus guidelines. J Psychiatr Pract. 2001;7(6):361-376.
17. Cooper C, Katona C, Lyketsos K, et al. A systematic review of treatments for refractory depression in older people. Am J Psychiatry. 2011;168(7):681-688.
18. Rutherford B, Sneed J, Miyazaki M, et al. An open trial of aripiprazole augmentation for SSRI non-remitters with late-life depression. Int J Geriatr Psychiatry. 2007;22(10):986-991.
19. Sheffrin M, Driscoll HC, Lenze EJ, et al. Pilot study of augmentation with aripiprazole for incomplete response in late-life depression: getting to remission. J Clin Psychiatry. 2009;70(2):208-213.
20. Steffens DC, Nelson JC, Eudicone JM, et al. Efficacy and safety of adjunctive aripiprazole in major depressive disorder in older patients: a pooled subpopulation analysis. Int J Geriatr Psychiatry. 2011;26(6):564-572.
21. Lenze EJ, Mulsant BH, Blumberger DM, et al. Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(10011):2404-2412.
22. Deligiannidis KM, Rothschild AJ, Barton BA, et al. A gender analysis of the study of pharmacotherapy of psychotic depression (STOP-PD): gender and age as predictors of response and treatment-associated changes in body mass index and metabolic measures. J Clin Psychiatry. 2013;74(10):1003-1009.
23. Flint AJ, Iaboni A, Mulsant BH, et al. Effect of sertraline on risk of falling in older adults with psychotic depression on olanzapine: results of a randomized placebo-controlled trial. Am J Geriatr Psychiatry. 2014;22(4):332-336.
24. Smith E, Rothschild AJ, Heo M, et al. Weight gain during olanzapine treatment for psychotic depression: effects of dose and age. Int Clin Psychopharmacol. 2008;23(3):130-137.
25. Blumberger DM, Mulsant BH, Kanellopoulos D, et al. The incidence of tardive dyskinesia in the study of pharmacotherapy for psychotic depression. J Clin Psychopharmacol. 2013;33(3):391-397.
26. Alexopoulos GS, Canuso CM, Gharabawi GM, et al. Placebo-controlled study of relapse prevention with risperidone augmentation in older patients with resistant depression. Am J Geriatr Psychiatry. 2008;16(1):21-30.
27. Katila H, Mezhebovsky I, Mulroy A, et al. Randomized, double-blind study of the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in elderly patients with major depressive disorder. Am J Geriatr Psychiatry. 2013;21(8):769-784.
28. Sultana J, Trifiro G. Drug safety warnings: a message in a bottle. J Drug Des Res. 2014;1(1):1004.
29. Flint A, Meyers BS, Rothschild AR, et al; STOP-PD II Study Group. Sustaining remission of psychotic depression: rationale, design and methodology of STOP-PD II. BMC Psychiatry. 2013;13:38.
30. Alexopoulos GS; PROSPECT Group. Interventions for depressed elderly primary care patients. Int J Geriatr Psychiatry. 2001;16(6):553-559.
31. Sajatovic M, Forester BP, Gildengers A, et al. Aging changes and medical complexity in late-life bipolar disorder: emerging research findings that may help advance care. Neuropsychiatry (London). 2013;3(6):621-633.
32. Bigos KL, Bies RR, Pollock BG, et al. Genetic variation in CYP3A43 explains racial difference in olanzapine clearance. Mol Psychiatry. 2011;16(6):620-625.
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The proportion of older adults in the world population is growing rapidly. In the next 10 to 15 years, the population age >60 will grow 3.5 times more rapidly than the general population.¹ As a result, there is an increased urgency in examining benefits vs risks of antipsychotics in older individuals. In a 2010 U.S. nationally representative observational study, antipsychotic use was observed to rise slowly during early and middle adulthood, peaking at approximately age 55, declining slightly between ages 55 and 65, and then rising again after age 65, with >2% of individuals ages 80 to 84 receiving an antipsychotic.² This is likely due to the chronology of psychotic, mood, and neurocognitive disorders across the life span. In this large national study, long-term antipsychotic treatment was common, and older patients were more likely to receive their prescriptions from non-psychiatrist physicians than from psychiatrists.² Among patients receiving an antipsychotic, the proportion of those receiving it for >120 days was 54% for individuals ages 70 to 74; 49% for individuals ages 75 to 79; and 46% for individuals ages 80 to 84.

This 3-part review summarizes findings and risk–benefit considerations when prescribing antipsychotics to older individuals. Part 1 focused on those with chronic psychotic disorders, such as schizophrenia or bipolar disorder,³and part 3 will cover patients with dementia. This review (part 2) aims to:

briefly summarize the results of randomized controlled trials (RCTs) of second-generation antipsychotics (SGAs) and other major studies and analyses in older patients with major depressive disorder (MDD)
provide a summative opinion on the relative risks and benefits associated with using antipsychotics in older adults with MDD
highlight the gaps in the evidence base and areas that need additional research.

Summary of benefits, place in treatment armamentarium

The prevalence of MDD and clinically significant depressive symptoms in communitydwelling older adults is 3% to 4% and 15%, respectively, and as high as 16% and 50%, respectively, in nursing home residents.⁴ Because late-life depression is associated with suffering, disability, and excessive mortality, it needs to be recognized and treated aggressively.⁵ Antidepressants are the mainstay of pharmacotherapy for late-life depression. Guidelines and expert opinion informed by the current evidence recommend using selective serotonin reuptake inhibitors, such as escitalopram or sertraline, as a first-line treatment; serotonin norepinephrine reuptake inhibitors, such as duloxetine or venlafaxine, as a second-line treatment; and other antidepressants, such as bupropion or nortriptyline, as a third-line treatment.^5,6 However, antipsychotics also have a role in treating late-life depression.

Over the past decade, several antipsychotics have been FDA-approved for treating MDD: aripiprazole and brexpiprazole as adjunctive treatment of MDD in adults; olanzapine-fluoxetine combination for acute and maintenance treatment of treatment-resistant depression in adults and geriatric adults; and quetiapine extended-release (XR) as monotherapy for MDD in adults and as adjunctive treatment of MDD in adults and geriatric adults who have had an inadequate response to antidepressants alone (Table 1). However, “black-box” warnings for all first-generation antipsychotics (FGAs) and SGAs alert clinicians that these medications have been associated with serious adverse events in older adults with dementia, including “deaths […] due to heart-related events (eg, heart failure, sudden death) or infections (mostly pneumonia),” with 15 of 17 placebo-controlled trials showing a higher number of deaths with an antipsychotic compared with placebo.⁷ Although similar controlled data on the mortality risk of antipsychotics in older adults with mood disorders do not exist, most experts limit their use to 2 groups of older patients: those with MDD and psychotic features (“psychotic depression”) and those with treatment-resistant depression.

Data from several rigorously conducted RCTs support using an antidepressant plus an FGA or SGA as first-line pharmacotherapy in younger and older patients with “psychotic depression.”^8-12 SGAs also can be used as augmenting agents when there is only a partial response to antidepressants.^13-15 In this situation, guidelines and experts favor an augmentation strategy over switching to another antidepressant.^5,9,10,16 Until recently, most published pharmacologic trials for late-life treatment-resistant depression supported using lithium to augment antidepressants.^14,17 However, because several antipsychotics are now FDA-approved for treating MDD, and in light of positive findings from several studies relevant to older patients,^18-21 many experts now support using SGAs to augment antidepressants in older patients with nonpsychotic depression.^5,15

References

The art of psychopharmacology: Avoiding medication changes and slowing down

Prescribing antipsychotics in geriatric patients: Focus on major depressive disorder

References

Summary of benefits, place in treatment armamentarium

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