How to make polypharmacy more rational? Jl psychopharmacology.Dec.2012


Polypharmacy is common in psychiatric practice .The poor rates of remission from available treatments is one major reason for this. One third of patients with depression do not achieve remission even after multiple trials (STAR.D).In bipolar disorder,nearly half of the patients did not achieve recovery while on expert treatment for 2 yrs (STEP.BD). In CATIE study  quarter of the patients discontinued antipsychotics due to lack of efficacy in Phase 1, with 44% doing same in Phase 2.

Evidence based guidelines  are not applicable for most of the very treatment resistant mental disorders as most research findings are not generalisable to this group.Daniel Zigman and Pierre Blier  provide a useful frame work to avoid irrational polypharmacy in this group of patients.

1. Pharmacodynamic redundancy:

Additional benefit is unlikely if the second drug added has the same mechanism of action.  ie adding another SSRI to one SSRI or use of multiple benzodiazepines at the same time is unlikely to have any  additional benefit. In the case of medications acting on multiple sites, adding another one which is already covered by first one may not be useful. Eg:  adding SSRI,while on SNRI, is unlikely to be useful. Mirtazapine and antidepressant doses of quetiapine act on similar sites so combining may not give any advantage . Buspirone’s action (5HT 1a agonism)  is covered by  aripiprazole, quetiapine, asenapine, clozapine, and vilazodone . Combining two antipsychotics will not yield greater antipsychotic effects than a single adequately dosed drug, though clozapine in combination with other antipsychotics might be different.If combining antipsychotics, it should be as part of time limited trials.

2.Pharmacodynamic  interactions:   

Eg: Methyl phenidate ( stimulant) would not improve symptoms  if patients are on  antipsychotic  for other reasons. Antipsychotics with less D2 affinity may not block the action of stimulants.

3.Pharmacokinetic interactions:

 Eg: Carbamazepine,  modafinil, phenytoin, and St. John’s wort  cause clinically significant induction of CYP3A4 .Quetiapine levels will be markedly reduced if patient is on any  of these medications. Lamotrigine can reduce quetiapine levels.

4.Inadequate dosing:

Tricyclic antidepressants, lithium, and anticonvulsants are particularly prone to be used at sub-therapeutic doses .Plasma Drug monitoring is an option in some SNRIs may  be under-dosed for treatment-resistant depression and chronic pain, i.e. nor adrenergic re uptake inhibition may not occur at doses below 225 mg of venlafaxine  and  120 mg of duloxetine.

5.Regular assessments/review: Check whether the response to added agent is placebo response or not. Review necessity of each medication at regular intervals . Consider  whether residual symptoms are resulting from existing meds e.g.. SSRI induced apathy or  antipsychotic induced akathisia.

Conclusions: Polypharmacy is common in resistant disorders. Consideration to above principles would help to make it more rational.

Summary of the article:

framework to avoid irrational polypharmacy in psychiatry.Zigman D, Blier P.J Psychopharmacol. 2012 Dec;26(12):1507-11

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