Polymorphous Polypharmacy

August 22, 2006

What does the term “polypharmacy” actually mean? Dr Pies likens polypharmacy to fire: just as the latter may either heat your house or burn it down, polypharmacy may either help or harm the patient.

August 2006, Vol. XXIII, No. 9

As the old saying goes, “There's polypharmacy, and then again, there's polypharmacy.” Consider, for example, a case that I reviewed recently. This involved an unfortunate woman in her 40s, with a diagnosis of fibromyalgia and major depressive disorder. A psychiatrist and a rheumatologist were treating her conjointly on a regimen of tramadol (Ultram), duloxetine (Cymbalta), paroxetine (Paxil), and trazodone (Desyrel). That's right, 3 serotonergic antidepressants and a synthetic opioid that-guess what?-inhibits reuptake of serotonin, as well as norepinephrine.1 Interestingly, in addition to her primary symptoms (depression, fatigue, and “muscle aches”), the patient was complaining of headaches, anxiety, and insomnia

What went through my mind as I read through the case? First, I wondered if the psychiatrist and the rheumatologist had ever talked to one another-there was no indication of that from the records. Then I wondered if the rheumatologist, who was prescribing the tramadol, was aware that this agent boosts serotonin and that the patient was taking it along with 3 other drugs that can have the same effect. I wondered, as well, if the psychiatrist's differential diagnosis had included serotonin syndrome,2 which not incidentally, can include anxiety and restlessness. I also wondered if the psychiatrist was aware that an anxiogenic metabolite of trazodone, m-chlorophenylpiperazine (mCPP), is metabolized by the cytochrome 2D6 (CYP2D6) system, which is effectively quashed by paroxetine-thereby creating the risk of very high blood levels of mCPP and attendant anxiety. Duloxetine is also metabolized, in part, by CYP2D6, and one would expect that paroxetine would substantially elevate duloxetine blood levels too-bludgeoning this patient's brain with still more serotonin.

Of course, it's easy to sound smug and self-satisfied when you are viewing such a case from the safe perspective of the armchair quarterback-also known professionally as the “consultant.” Indeed, most of us have missed the proverbial boat when it comes to recognizing subtle drug-drug interactions. At the same time, no psychiatrist can ignore the fact that up to 7000 deaths occur annually in the United States from adverse drug reactions (ADRs),3,4 and that these are a major source of both hospitalization and litigation in psychiatry. Many of these ADRs stem from inappropriate polypharmacy.

What does the term “polypharmacy” actually mean? The literature reveals many differing or overlapping definitions. For purposes of this article, polypharmacy is defined as the simultaneous prescribing of any 2 or more medications for (a) the same disorder; or, (b) a symptom shared by comorbid disorders. The first part of this definition is, I trust, self-explanatory. The second part requires a little clarification. In the case of the patient described earlier, fatigue was a prominent complaint. Now, fatigue may be seen as part of a major depressive disorder, but it is also a common finding in patients with fibromyalgia. If the 2 physicians involved in the patient's care had conferred and decided to treat the patient's fatigue with, say, a combination of modafinil (Provigil)5 and bupropion (Wellbutrin),6 they would have engaged in polypharmacy, by my definition. Note that, to this point, I have not defined polypharmacy, per se, as either “good” or “bad.” Indeed, I often draw an analogy between polypharmacy and fire: just as the latter may either heat your house or burn it down, polypharmacy may either help or harm the patient.

Parsing polypharmacy

It might be argued that there are as many types of polypharmacy as there are polypharmacists. Still, clinical experience and the research suggest a typology of sorts. First, I would like to distinguish between active and passive polypharmacy. Active polypharmacy occurs when the clinician is entirely responsible at the outset for whatever medications the patient is taking. Passive polypharmacy occurs when one clinician cooperates with, or does not explicitly alter or oppose, a regimen devised by another clinician. The second scenario is often endemic in state hospital populations: Dr C “inherits” the patient from Dr B, who took over the case from Dr A. The patient came to Dr C already taking 9 psychotropic medications-oh yes, it happens-and Dr C decides, “I'd better not rock the boat-the patient is stable right now and I don't want to jeopardize that.” In rare instances, Dr C may actually be making a prudent decision. In most cases, however, this type of passive (and massive!) polypharmacy represents laziness or inexperience on the part of the clinician.

To be fair, it is extremely frustrating and time-consuming to comb through 12 volumes of clinical records, hoping to sort out the reasons why Mr Jones was started on drug X or drug Y, and how he initially responded to them. And yet, we owe the patient our best efforts in just such a fishing expedition. Sometimes, a call to a knowledgeable family member can save a great deal of time in sorting out these issues.

In a comprehensive document prepared by the National Association of State Mental Health Program Directors (NASMHPD), a useful classification of polypharmacy is presented, emphasizing both the class of agents and the circumstances in which they are used (Table [please see Psychiatric Times, August 2006, p. 54]). However, it is sometimes more useful to “get down to cases” and see how polypharmacy actually plays out in clinical practice.

Rational and irrational polypharmacy
Vignette 1

A 19-year-old man with an acute psychotic episode and marked agitation is given risperidone (Risperdal), 4 mg/d. After 3 days, the patient is somewhat calmer but is still delusional. Haloperidol (Haldol), 5 mg/d, is added. Two days later, the patient complains of severe “shakiness” and shows severe muscular rigidity. He remains delusional.

This vignette is an example of irrational polypharmacy, despite the fact that antipsychotics from 2 different classes were used. It was irrational because there is no reason to expect complete “lysis” of a patient's delusion within just 3 days-notwithstanding some provocative new data suggesting that statistically significant decrements in psychotic symptoms may be seen within a week of initiating antipsychotic treatment.7

The Expert Consensus Guidelines for treatment of schizophrenia8 recommend at least a 3-week trial of an antipsychotic drug before making any major regimen change, and I heartily concur. (In addition, this combination in the vingnette greatly increased the risk of extrapyramidal side effects-a particular concern in young males.)

Vignette 2

A 70-year-old patient with severe depression has been taking fluoxetine (Prozac), 20 mg/d for 6 weeks. There has been only a 30% improvement in symptoms. Rather than try a higher dosage of fluoxetine, the physician adds a tricyclic antidepressant, desipramine (Elavil, others), 125 mg/d (a usual dosage is 75 to 200 mg/d). The patient begins to feel dizzy, weak, and light-headed. An ECG shows evidence of second-degree heart block and the patient's blood pressure is 90/60 mm Hg, with a heart rate of 120 beats per minute. Desipramine blood level test results come back at 350 ng/mL (the putative therapeutic range is about 110 to 160 ng/mL, although this is not well established).

This second vignette is another example of irrational polypharmacy because insufficient attention is paid to adverse drug-drug interactions. Fluoxetine is a potent inhibitor of CYP2D6, the enzyme that metabolizes desipramine, and has evidently caused excessive desipramine blood levels; this, in turn, has led to cardiovascular side effects. Had the doctor used a substantially smaller dose of desipramine (eg, 25 mg), this type of polypharmacy might have been a rational approach-but increasing the fluoxetine dosage probably would have been preferable.

Vignette 3

A 40-year-old man with bipolar depression and psychotic features was given lithium carbonate, 1200 mg/d. His depression improved moderately after about 2 weeks, but he remained delusional. At that time, risperidone, 3 mg/d, was added, with some resolution of the psychosis after about 3 weeks. However, the patient's depression unexpectedly worsened, and he was given lamotrigine (Lamictal) (in addition to his existing regimen), titrated gradually up to 200 mg/d. Ten weeks after onset of the episode, the patient was nearly euthymic and free of psychosis but experienced profound generalized anxiety in anticipation of returning to work. In addition to individual supportive therapy, clonazepam (Xanax, others), 0.5 mg bid, was added to his regimen. He was able to return to work after an additional 3 weeks.

The patient in the third vignette ended up taking 4 psychotropic agents. That may sound like an excessive number of medications, but in this case, the regimen represents quite rational polypharmacy. Each agent was added sequentially, with enough time in between agents to assess response. Each agent was aimed at a specific component of the patient's syndrome (ie, depression, psychosis, or anxiety). Furthermore, each agent represented a different pharmacologic class and mechanism of action. Could the patient have been treated with a more parsimonious regimen-say, clozapine monotherapy? Perhaps. Rational polypharmacy does not always equal optimal pharmacotherapy, but in this case, the regimen used may have provided a better risk-benefit ratio than would clozapine.

Wrapping it up

Psychiatrists should not be afraid to use rational, safe, evidence-based polypharmacy, notwithstanding the often-legitimate concerns of cost cutters, pharmacy review boards, and colleagues. That said, we had better be prepared to explain and even to defend our polypharmacy practices-for medical, economic, and legal reasons. Polypharmacy should always be based on sound medical principles, including:

  • Sequential use of agents rather than “piling on” several drugs at once, with enough time in between to assess drug effects.
  • Discontinuation of ineffective agents rather than passive collusion with previous irrational polypharmacy.
  • Careful assessment of adherence to regimen and adequacy of dosage and blood levels before concluding that a drug isn't working.
  • Careful evaluation of every polypharmacy regimen for risk of drug-drug interactions-and use of appropriate agents to avoid this outcome.
  • Evaluation of the cost-effectiveness and evidence base (especially randomized controlled studies) for a given polypharmacy regimen.
  • Development of outcome measures that enable the clinician to determine whether a second or third agent is actually helping the patient.


Finally, whether prescribing 1 medication or 4, careful discussion with the patient about the risks, benefits, and side effects of the regimen is always a part of good medical practice.

Dr Pies is clinical professor of psychiatry at Tufts University. His most recent books include Creeping Thyme, a collection of poetry (Brandylane Publishing); Zimmerman's Tefillin, a short story collection (PublishAmerica); and Handbook of Essential Psychopharmacology, 2nd edition, from American Psychiatric Publishing.


1. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43:879-923.
2. Mahlberg R, Kunz D, Sasse J, Kirchheiner J. Serotonin syndrome with tramadol and citalopram. Am J Psychiatry. 2004;161:1129.
3. Cozza KL, Armstrong SC, Oesterheld JR. Concise Guide to Drug Interaction Principles for Medical Practice, 2nd ed. Washington, DC: American Psychiatric Press; 2003.
4. Carlat D. Drug-drug interactions you need to know. Carlat Rep. 2003;1:1-3.
5. Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005;66:85-93.
6. Moss EL, Simpson JS, Pelletier G, Forsyth P. An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners. Psychooncology. 2006;15:259-267.
7. Agid O, Seeman P, Kapur S. The “delayed onset” of antipsychotic action-an idea whose time has come and gone. J Psychiatry Neurosci. 2006;31:93-100.
8. Kane JM, Leucht S, Carpenter D, Docherty JP. Expert consensus guideliummary. J Clin Psychiatry. 2003;64:5-19.
9. Honer WG, Thornton AE, Chen EY, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med. 2006;354: 472-482.
10. National Association of State Mental Health Program Directors (NASMHPD). Technical Report on Psychiatric Polypharmacy. Available at: www.nasmhpd.org/general_files/publications/med_directors_pubs/Polypharmacy.PDF. Accessed June 14, 2006.

Recommended for further reading

  • Carlat D. When Molecules Collide. Drug Metabolism in Psychiatry. London: Clearview Publishing; 2005.
  • Ghaemi SN, ed. Polypharmacy in Psychiatry (Medical Psychiatry #17). New York: Marcel Dekker; 2002.