Medicating Distress.

Chlorpromazine hydrochloride first became available in Europe and theUnited States in the early 1950s. A large, doubleblind, placebo-controlled trial thatwas conductedwithin the US Veterans Affairs system and included nearly 700 patients (allmenaged≤50years) helped establish its efficacy for treating schizophrenia.1 Theuseof chlorpromazine is creditedwith largedecreases inpsychiatric inpatientpopulationsaroundthe world, aswell as prompting awidespread search for other antipsychotic drugs. However, before the study on schizophrenia was published in 1960,1 advertisementsmarketing chlorpromazine (as Thorazine) appeared in the late 1950s for a host of indications andpopulations, ranging from“prompt control of senile agitation” (featuring a whitehaired oldermanwielding an upraised cane) to “prompt control of nausea and vomiting in children” (with a child leaning over a sink) to “relief from the suffering and mental anguishofcancer.”Butwhystopthere?Advertisementsalsotouted Thorazine for the treatment of arthritis, acute alcoholism, and the “psychic stress” of severe asthma. For all varieties of distress, apparently chlorpromazine and similar antipsychotic drugs were the solution. By 1990,more than40antipsychotic drugshadbeenmarketed worldwide,2 although the indications for use had been narrowed since the 1950s. Although severe asthma is not a common reason for use of antipsychotic drugs in 2016, they are still used forperceivedbenefit in reducing“psychic stress” or distress. As such, antipsychotic drugs have a long history of use for treating delirium associated with severe or terminalmedical illness, althoughrigorousevidencesupporting this use is sparse.3 In this issueof JAMAInternalMedicine,Agarand colleagues4 provide critical evidence to help guide the use of antipsychotic drugs for delirium in patients receiving palliative care. The short answer is: don’t. Thestudytargetedsymptomsofdeliriumthatareassociated withdistress: inappropriatebehavior, inappropriatecommunication, and illusionsorhallucinations.Haloperidol and risperidonewerenotonlynotbetter thanplacebobut thesesymptoms actuallyworsenedinpatientsrandomizedtoreceivetheantipsychoticdrugs,while thepatients’overalldeliriumalsoworsened. Aswouldbeexpected,patientsreceivingtheantipsychoticdrugs experiencedmoreextrapyramidaleffects.Perhapsmostconcerning,median time to survivalwas shorter forpatients takingantipsychotic drugs, and these patients were approximately 1.5 timesmore likely todie.This finding is remarkable inaplacebocontrolled trial inwhichpatients received just 6doses of study medication(orplacebo) in72hours.Hopefully, thestudybyAgar et al4will help convincehealth careprofessionals that, inusing antipsychotic drugs to treat delirium in terminally ill patients, notonlyare theynot reducingdistressbut theyare in factworsening patients’ symptoms. What happens nowwith the use of antipsychotic drugs in this patient population? It may be useful to consider the use of antipsychotic drugs in patients with dementia as a potential guide. The advertisement for Thorazine with the whitehaired gentleman wielding a cane illustrates that, since their development, antipsychotic drugshavebeen seenasuseful to treat the distressing behavioral and psychological symptoms of dementia (BPSD). However, as manufacturers sought approval to use the newer atypical antipsychotic drugs specifically fordistressingBPSD, it becameclear that theiruse caused an increased risk of death relative toplacebo.5 In 2005, theUS Food andDrug Administration issued a black boxwarning regarding the increased risk ofmortality associatedwith theuse of atypical antipsychotic drugs to treat BPSD. Although the use of atypical antipsychotic drugs did decrease after this warning was issued, the use of conventional antipsychoticdrugs,whichhadbeendecliningupto thatpoint, plateaued. Inaddition, theuseofotherpsychotropicdrugs that werenot antipsychotics,witheven less evidenceofbenefit but lacking definitive evidence of harms, grew.6 And today, despitemore thanadecadeof evidence about theharmsofusing antipsychotic drugs to treat distressing BPSD, their use persists, alongwith theuseofotherpsychotropicdrugswithminimal evidence of benefit. Although nonpharmacologic (better termed ecobiopsychosocial) management of BPSD is promoted as first-line treatment instead ofmedication by nearly every expert group, such strategies lack an industry behind themtopromote andprofit fromtheir implementation in realworld practice. Ideally, the studybyAgar et al4will be immediately translated into practice, with a marked drop in the use of antipsychotic drugs for delirium in patients receiving palliative care. As the authors note, there are other means of reducing distress in thesepatients, beginningwith identifyingdelirium, reversing precipitants of delirium, and providing supportive interventions.7 But the experience with the use of antipsychotic drugs in dementia, where there are many evidencebased, ecobiopsychosocial interventions forpatients andcaregivers, suggests that this change in practice is unlikely.8 Such alternatives can be time-consuming and are not incentivized in the current reimbursement systems in theUnitedStates.As a result, for physicians andother prescribing clinicians, all too often the desire to reduce patient distress is reduced to writing a prescription for a sedating psychotropic medication. How will this practice change for patients with delirium, dementia, or both?First, cliniciansmust recognize the real potential harms towhich they expose their patients by prescribing antipsychotics. And not only harms from medicationassociated adverse effects or events but, for patients with delirium who are receiving palliative care, actually worsening thepatientdistress forwhich theantipsychotic isbeingprescribed. Second, health care professionals should recognize Related article Medicating Distress Invited Commentary