Tackling polypharmacy in psychiatry

While “polypharmacy” eludes an easy definition, many pharmacists are keenly aware of its prevalence, especially in the field of psychiatry. Close to 60% of patients in an American national ambulatory survey were prescribed two or more psychotropic medications in 2005, a sharp rise from the 42.6% seen in 1996.1 Similarly, the percentage of patients prescribed three or more psychotropic medications increased from 16.9% in 1996, to 33.2% in 2005.1For the purpose of this column, we will consider polypharmacy as the use of two or more medications to treat the same psychiatric condition. Some combinations are supported by evidence, such as the addition of certain atypical antipsychotics to an antidepressant for treatment of major depressive disorder. However, many other combinations are not strongly grounded in evidence and may even put patients at risk of drug interactions and additional side effect burden with uncertain clinical benefit.2,3 With that in mind, why is polypharmacy in psychiatry so common?Rational vs. irrational polypharmacyPolypharmacy in psychiatry can be conceptualized as “rational” and “irrational.” Rational polypharmacy involves the use of multiple medications in evidence-based augmentation or combination strategies, as highlighted with the example of combining an antidepressant with an atypical antipsychotic for the treatment of major depressive disorder. This is often done when the patient shows only a partial response to monotherapy, with the hope of achieving a more complete and robust resolution of symptoms. There are many other examples of this in psychiatry, with the combinations proven to be safe and effective in clinical trials and research.2-7The use of polypharmacy may be especially prevalent in psychiatry given the unfortunately low rate of efficacy for many first-line medications. For example, 63.2% of patients in the landmark STAR*D trial did not achieve remission after receiving citalopram monotherapy for major depressive disorder.8 Similarly, 23.7% of patients discontinued their first- or second-generation antipsychotic medication in the CATIE trial due to a lack of efficacy for treatment of schizophrenia.9 With such high percentages of patients not responding to monotherapy, it is easy to see why clinicians often turn to polypharmacy in hopes of helping patients achieve some relief of their symptoms, especially in treatment-refractory cases.Unfortunately, this can occasionally lead to irrational polypharmacy, or the use of multiple psychotropic medications that are redundant, antagonistic or deleterious. Many pharmacists can surely recall cases of this in their practice. A classic example is the use of multiple different benzodiazepines, which not only serves no benefit from an efficacy standpoint, but can potentially lead to additive sedation and increased risks of falls and overdose.10 Other irrational polypharmacy may initially appear rational, such as the addition of low-dose quetiapine for insomnia to an already well-established antipsychotic treatment. But this combination ultimately has the same increased risk of adverse effects and lack of compelling evidence seen in irrational polypharmacy. It is the pharmacist’s responsibility to identify irrational polypharmacy and work towards “rationalizing” the patient’s medication regimen.Rationalizing polypharmacyCan I simplify the regimen? This is the question every pharmacist should be asking when a patient visits the pharmacy with an overwhelming laundry list of psychotropic medications. Are all medications indicated? Are the combinations being used evidence-based or guideline recommended? Is the original condition still part of the picture? If the answer to any of these questions is “no,” further examination may be warranted, with consideration given to deprescribing in collaboration with the patient and the care team.Harnessing certain medications that can be used for multiple indications may also be of benefit. In other words, assess whether you can “kill two birds with one stone.” For instance, in the case where quetiapine is added for insomnia in a patient with a well-established antipsychotic regimen, it may be worthwhile exploring the possibility of optimizing quetiapine to antipsychotic doses in order to establish quetiapine monotherapy in place of the existing dual antipsychotic therapy. Similarly, the use of pregabalin or duloxetine may be of benefit in patients who suffer from comorbid general anxiety disorder and neuropathic pain.11-13It is important to remember, polypharmacy does not hasten the therapeutic response.14 Instead, a thorough assessment of whether there have been optimal trials of monotherapy, at adequate doses and adequate durations, should be completed prior to considering polypharmacy. The use of objective measures of outcomes, such as validated rating scales, can also be of benefit. Often, the patient may be the last to recognize improvements in their symptoms subjectively, when objective rating scales indicate therapeutic benefits. Ensuring adequate monotherapy trials can help limit polypharmacy from being inadvertently prescribed.SummaryPolypharmacy in psychiatry is commonplace. The use of rational polypharmacy is evidence-based and may be of benefit in certain clinical scenarios. However, it is important for pharmacists to identify irrational polypharmacy in psychiatry, and actively engage the patient and care team in rationalizing the medication regimen to optimize both efficacy and safety outcomes for the patient.Sunny Wang is a clinical pharmacist and Pharmacy Education Coordinator at the Centre for Addiction and Mental Health (CAMH) in Toronto. His clinical work is currently with the inpatient Crisis and Critical Care Unit, serving a diverse population of patients with acute psychiatric and substance use disorders. In addition to his role as Education Coordinator at CAMH, Wang is involved as a Clinical Instructor at the Leslie Dan Faculty of Pharmacy and serves as an Expert Hub Member for the Addiction Medicine and Psychosocial Interventions Program with Project ECHO.References:Mojtabai R, Olfson M. National trends in psychotropic medication polypharmacy in office-based psychiatry. Arch Gen Psychiatry 2010;67(1):26-36. doi: 10.1001/archgenpsychiatry.2009.175.Canadian Network for Mood and Anxiety Treatments (CANMAT). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: Section 3. Pharmacological treatments: CANMAT; 2016. (accessed March 5, 2024).Zhou X, Keitner GI, Qin B, et al. Atypical antipsychotic augmentation for treatment-resistant depression: a systematic review and network meta-analysis. Int J Neuropsychopharmacol 2015;18(11):pyv060. doi: 10.1093/ijnp/pyv060.Canadian Network for Mood and Anxiety Treatments (CANMAT). Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder: CANMAT; 2018. (accessed March 5, 2024).Ogawa Y, Tajika A, Takeshima N, et al. Mood stabilizers and antipsychotics for acute mania: a systematic review and meta- analysis of combination/augmentation therapy versus monotherapy. CNS Drugs 2014;28:989-1003.Reischies FM, Hartikainen J, Berghoefer A. Initial lithium and valproate combination therapy in acute mania. Neuropsychobiology 2002;46:22‐7.Blier P, Ward HE, Tremblay P, et al. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. Am J Psychiatry 2010;167(3):281-8. doi: 10.1176/appi.ajp.2009.09020186.Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006;163(11):1905-17. doi: 10.1176/ajp.2006.163.11.1905.Lieberman JA, Stroup TS, McEvoy JP, et al; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353(12):1209-23. doi: 10.1056/NEJMoa051688. Erratum in: N Engl J Med 2010;363(11):1092-3. PMID: 16172203.Canadian Pharmacists Association. Choosing Wisely Canada. Six tests and treatments to question. Last updated September 2023. (accessed March 5, 2024).Katzman MA, Bleau P, Blier P, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry 2014; S1. (accessed March 5, 2024).Eli Lilly. Duloxetine product monograph. Toronto, ON; March 25, 2021. Accessed electronically via Compendium of Pharmaceuticals and Specialties (accessed February 8, 2024).Upjohn Canada ULC. Pregabalin product monograph. Etobicoke, ON; May 11, 2020. Accessed electronically via Compendium of Pharmaceuticals and Specialties (accessed February 8, 2024).Rush AJ, Trivedi MH, Stewart JW, et al. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry 2011;168(7):689-701. doi: 10.1176/appi.ajp.2011.10111645.

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Tackling polypharmacy in psychiatry

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Sunny Wang

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