Polypharmacy has been met with challenges because many practicing clinical guidelines and treatment algorithms prefer a monotherapy approach.
The pharmacological management of psychiatric disorders has been revolutionized since chlorpromazine became available in 1955. Newer psychotropics have added years to the life of people suffering with mental illness, and they have enhanced the quality of life for patients. Psychopharmacology is responsible for the reduction in duration of inpatient care, and it has helped to provide recovery to millions of patients discriminated against because of the stigma of mental disorders. However, polypharmacy has been met with challenges because many practicing clinical guidelines and treatment algorithms prefer a monotherapy approach.
The challenge of polypharmacy is not only in clinical practice but also in the evidence for its effects. Poly-pharmacy in psychiatry is often a clinical need that reflects a clinician’s frustration. The main indication of polypharmacy remains nonresponse to monotherapy and persisting symptoms. These symptoms are seen in the domain of persistent positive, negative, cognitive, affective, or anxiety/phobias.
The prescribing of polypharmacy continues despite the evidence that monotherapy often works and non-drug therapies may be preferred options. Psychosocial interventions are seldom used because they are not easily accessible, and such limitations make it necessary to prescribe more medication in a hope to obtain symptom remission. In the presence of clear clinical evidence of serious adverse effects due to multiple medications, one argument in decision making is the effectiveness of polypharmacy in improving the outcomes for patients.1
When using polypharmacy, it is important to address adherence issues and to educate patients and their families. In doing so, medication dosages, the possible adverse effects of the medications, and drug-drug interactions are explained. Despite all the difficulties and complexities associated with polypharmacy, there has been an exponential rise in its use (based on clinical communication and experience sharing with colleagues). The primary reason for this is the advent of psychopharmacology that is receptor specific-based rather than a disorder-based medication.2
Although polypharmacy is often used in the management of psychiatric disorders, there is very poor awareness of its efficacy. In some situations, polypharmacy also lacks respect and acceptability. This arises out of the fact that most reputed textbooks and clinical guidelines advocate monotherapy and a single drug at high doses rather than clinical practice scenario where multiple drugs targeted at specific symptoms are prescribed.
There is a need for polypharmacy that is rational and judicious. Despite its limitations and lack of consensus, polypharmacy does improve overall outcomes for patients.3 The National Association of State Mental Health Programme Directors (NASMHPD) provides classification of polypharmacy (Table 1).4
Is there evidence to substantiate polypharmacy?
One of the major fallacies of poly-pharmacy is the lack of randomized controlled trials and an evidence base that can help clinicians decide what combinations and medications will work for psychiatry. Many reviews of polypharmacy look at drug combinations that are used in the treatment of schizophrenia and depression.5 Certain combinations are mentioned; however, none has been found to be superior to another. Moreover, because there are huge differences in prescribing styles among clinicians, there are many variations in the combinations of drugs prescribed. It is often construed that polypharmacy is more calculated scientific guesswork than evidence-based treatment.6
It is important to remember that each prescribed drug has clear indications, has well-defined therapeutic goals, and as far as possible is evidence based. Clinicians need to evaluate whether polypharmacy enhances clinical outcomes or whether it promotes adverse effects. This is even more important when patients already on polypharmacy are shifted to a new combination of drugs and when patients are shifted from mono-
therapy to polypharmacy.7
The STAR*D and CATIE trials have focused on combination therapy but despite elaborate methodology and painstaking research, they have failed to elucidate what drug combination works in either depression or schizophrenia.8,9 Most of the combinations used in polypharmacy are based on the clinical judgment and experience of the treating psychiatrist and their experience with individual patients rather than clinical studies.
Mr VD, aged 40 years, has a diagnosis of schizophrenia. He is being treated daily with 15-mg olanzapine in divided doses, 30-mg mirtazapine at night, and 300-mg clozapine at night. He also receives 10-mg zolpidem because of sleep disturbances. He was treated in the past with risperidone and haloperidol, but the drugs had to be withdrawn because of extrapyramidal reactions when he was initially started on these drugs. During his last relapse, Mr VD received clozapine during his inpatient stay. He had a 90% improvement in symptoms with clozapine.
After drinking alcohol at a family function, he became drowsy and started convulsing. He was taken to a nearby hospital and admitted in an intensive care unit; he died later that night due to seizure-related complications. The emergency physician was unable to ascertain which medication may have caused the seizures. The hospital did not have the facility for clozapine monitoring, and patient records were not available.
This raises several questions about prescribing patterns. Despite strict guidelines about clozapine, its use remains fairly complex in many countries. Was clozapine alone responsible for seizures or was this an additive effect of the various drugs prescribed with clozapine? Would clozapine do better as monotherapy of 300 to 400 mg with a response of 60% to 70% compared with polypharmacy that showed an improvement of 90% but may have additively caused seizures? Emergency physicians may not be aware of the adverse effects of psychiatric drugs, and in this case no serum clozapine levels were checked to determine whether clozapine toxicity resulted in the seizures. Polypharmacy, while viable in improving the quality of life, may have additive adverse effects that may go undetected when the patient presents to the emergency department.
Does polypharmacy enhance clinical outcomes?
Polypharmacy is paramount when treating comorbid psychiatric disorders (eg, depression and panic disorder; ADHD and enuresis).10 In polypharmacy we may use multiple drugs prescribed at lower to normal doses rather than one drug at a higher dose. Various neurotransmitters are implicated in psychiatric disorders and polypharmacy can target several receptor sites allowing multiple symptom recovery and quicker improvement.11
Treatment adherence is another area of difficulty in patients who have serious mental illness. Many patients may have poor access to care. The issues related to polypharmacy are not only academic but also social, administrative, and political.12 The evidence base that polypharmacy improves clinical outcomes is very small and is addressed in only a few studies (Table 2).
The need for rational polypharmacy
When clozapine was re-introduced in developing countries, psychiatrists working in communities faced difficulties-facilities for blood monitoring were not available and if available, patients were nonadherent. This led to many psychiatrists prescribing clozapine in combination with other drugs without blood monitoring; other psychiatrists did not use the drug, thus depriving patients of possible better outcomes.13
There is a need for proper clinical titration, sound treatment algorithms, and well-defined protocols to effectively reduce irrational polypharmacy. An important clinical issue is when a patient on multiple drugs presents to a psychiatrist who wants to change the prescriptions to another multiple-drug combination. It is important that certain drugs from the previous prescriptions be retained so that a switch can be made.14 Tapering medication must be done at a gradual rate while closely monitoring for withdrawal/rebounding symptoms. When changing a medication, it is wise to switch the medication with one that has a similar half-life to enhance continuity of action.
Conclusions and recommendations
We are clearly living in an era where polypharmacy is necessary and where monotherapy often provides insufficient symptom improvement. The dilemma is the number of overwhelming drug possibilities available and the need to be aware of the right permutations and combinations. This perplexing decision is left to the clinician where rational prescribing is needed. Clinicians must regularly review scientific journals, clinical trial data, research on drug safety, latest neurobiological research, and update their knowledge of drug interactions to enable them to become scientific yet judicious, rational polypharmacy users. The most important point is the decision of whether to opt for polypharmacy or stick to monotherapy. Psychiatrists who prescribe multiple drugs may see better results; they may see an increase in adverse effects but have better clinical outcomes compared with monotherapy.
Dr Shrivastava is Professor Emeritus of Psychiatry and Adjunct Scientist, Lawson Health Research Centre, Western University, London, Ontario, Canada; Dr De Sousa is Consultant Psychiatrist, Desousa Foundation, Mumbai, India; and Ms Lodha is Research Assistant, Desousa Foundation, Mumbai. The authors report no conflicts of interest concerning the subject matter of this article.
1. Preskorn SH, Lacey RL. Polypharmacy: when is it rational ? J Psychiatr Pract. 2007;13:97-105.
2. Evers K. Personalized medicine in psychiatry: ethical challenges and opportunities. Dial Clin Neurosci. 2009;11:427-434.
3. Baker JA, Lovell K, Harris N. Mental health professionals’ psychotropic pro re nata (prn) medication practices in acute inpatient mental health care: a qualitative study. Gen Hosp Psychiatry. 2007;29:163-168.
4. Medical Directors Council and State Medicaid Directors. National Association of State Mental Health Program Directors: Technical Report on Psychiatric Polypharmacy. Alexandria, Virginia; 2001.
5. Freudenreich O, Kontos N, Querques J. Psychiatric polypharmacy: a clinical approach based on etiology and differential diagnosis. Harv Rev Psychiatry. 2012;20:79-85.
6. Freudenreich O, Goff DC. Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatr Scand. 2002;106:323-330.
7. Ito H, Koyama A, Higuchi T. Polypharmacy and excessive dosing: psychiatrists’ perceptions of antipsychotic drug prescription. Br J Psychiatry. 2005;187:243-247.
8. Gaynes BN, Warden D, Trivedi MH, et al. What did STAR* D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr Serv. 2009;60:1439-1445.
9. Stroup TS, McEvoy JP, Swartz MS, et al. The National Institute of Mental Health clinical antipsychotic trials of intervention effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophr Bull. 2003;29:15-31.
10. Kennedy NB, Procyshyn RM. Rational antipsychotic polypharmacy. Can J Clin Pharmacol. 2000;7:155-159.
11. Kukreja S, Kalra G, Shah N, Shrivastava A. Polypharmacy in psychiatry: a review. Mens Sana Monogr. 2013;11:82-99.
12. Werder SF, Preskorn SH. Managing polypharmacy: walking the fine line between help and harm. Curr Psychiatry. 2003;2:24-36.
13. Shrivastava A, Shah N. Prescribing practices of clozapine in India: results of a opinion survey of psychiatrists. Indian J Psychiatry. 2009;51:225-226.
14. Ghaemi SN. Polypharmacy in Psychiatry. New York: Marcel Dekker; 2002.
15. Fleischhacker WW, Uchida H. Critical review of anti-psychotic polypharmacy in the treatment of schizophrenia. Int J Neuropsychopharmacol. 2014;17:1083-1093.
16. Tiihonen J, Suokas JT, Suvisaari JM, et al. Poly-pharmacy with antipsychotics, antidepressants, or benzodiazepines and mortality in schizophrenia. Arch Gen Psychiatry. 2012;69:476-483.
17. Thase ME. Antidepressant combinations: cutting edge psychopharmacology or passing fad? Curr Psychiatr Rep. 2013;15:403-410.
18. Sarkar S. Psychiatric polypharmacy, etiology, and potential consequences. Curr Psychopharmacol. 2017;6:12-26.