Comparison of three methods for identifying medicaldrug–psychotropic drug interactions

James J. Strain, M.D.a,*, Nien-Mu Chiu, M.D.a,b, Matthew Brodsky, M.D.c,Anwarul Karim, M.D.a, Gina Caliendo, Pharm.D., R.Ph.d

aDepartment of Psychiatry, Mount Sinai School of Medicine, New York, NY, 10029 USAbDepartment of Psychiatry, Chang Gung Memorial Hospital, Kaohsiung, Taiwan

cDepartment of Neurology, Mount Sinai School of Medicine, Mount Sinai - NYU Medical Center/Health System, New York, NY, 10029 USAdDepartment of Pharmacy, Mount Sinai Hospital, New York, NY 10029 USA

Abstract

Three methods for examining drug–drug interactions were compared to understand advantages and disadvantages of each:ePocrates;Interact; The Mount Sinai multiple source for the evaluation of drug–drug interactions (MS). ePocrates is a commonly employed softwaresystem utilized in a hand held computer, the PalmPilot.Interact is on a CD-ROM, and promoted by the American Psychiatric AssociationPress. The MS system was developed by the authors and utilizes six separate references sources to ascertain the presence and significanceof drug–drug interactions. Commonly prescribed neurology and psychotropic medication interactions were compared using the threesystems.ePocrates did not list the significance level of the interaction, e.g., (major, moderate, minor), often did not include a mechanismof action, and several commonly employed medications were not included. It did permit examining several drugs at the same time, and waseasily carried on the person of the physician.Interact often contained old references, several drugs were not included, was not adapted toa hand held computer format, and had no update since 1999. The MS system listed level of significance, provided mechanism of action ,and advice to the practitioner including recommendations. It is not portable, requiring a laptop or desk top computer or hard copy, and onlysearches one drug at a time. It is hoped that the advantages of each of these three systems may be incorporated into systems of the future.© 2002 Elsevier Science Inc. All rights reserved.

1. Introduction

Medical drug–psychotropic drug interactions are an im-portant concern in the practice of medicine. The need tohave accessible methods to readily identify potential ad-verse psychotropic–medical drug interactions is essentialfor optimal clinical decision-making. More patients withmedical illness are being evaluated for psychiatric comor-bidity; including the elderly (many of whom are on medi-cations for medical conditions), and those patients on psy-chotropic medication who become acutely or chronicallyphysically ill. This paper compares three drug interactiondatabases: [1]Interact, a commercially available databaseendorsed by the American Psychiatric Association and uti-lized by psychiatrists; [2]ePocrates Rx, a shareware data-

base for Personal Digital Assistants (PDAs) that is com-monly employed by hospital-based physicians; and, [3]Multisource (MS), a comprehensive review approach devel-oped at the Mount Sinai School Medicine, New York City[3–5].

2. Materials and method

A team consisting of a neurologist (MB), and threepsychiatrists (JS, AK, NMC) examined the interactions be-tween 86 neurological drugs and 69 psychotropic drugs(Tables 1 and 2). These were selected from two sources: 1)the Redbook list of the 200 most often prescribed drugs inthe United States [6]; and 2) those drugs most frequentlyemployed by the Departments of Neurology and PharmacyMount Sinai/NYU Medical Center/Health Service.

The first method was to examine the shareware softwareePocrates Rx (version 4.0�1) [1] (www.epocrates.com)(November 27, 2001 update) comparing each of the 86neurological drugs against each of the 69 psychotropic med-

This work has been supported by the Malcolm Gibbs Foundation, Inc.,New York, New York.

* Corresponding author. Tel.:�1-212-659-8728; fax:�1-212-369-6817.

E-mail address: jim_strain@hotmail.com

General Hospital Psychiatry 24 (2002) 311–315

0163-8343/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved.PII: S0163-8343(02)00196-2

ications. The second method for comparison was the soft-ware Interact [2] (available through the American Psychi-atric Press, Washington, D.C.) to evaluate the interactionsamong the same neurological and psychotropic drugs. Theauthors looked for statements of: 1) severity, e.g., severemorbidity or mortality, moderate morbidity, or mild adverseinteractions; 2) the strength of the evidence of the interac-tion (when available) e.g., single case report versus multiplecase reports; 3) the year of the references cited (whenavailable) to support the evidence; 4) whether mechanisms/dynamics of the interaction were specified; and, 5) if rec-ommendations were offered (i.e., clinical implication of theinteractions).

The findings from ePocrates Rx and Interact were thenfurther compared with the observations from a comprehen-

sive research review developed from multiple sources (MS)and reported elsewhere in this Journal: Neurology Drug–Psychotropic Drug Update [4]. The six sources employedin that comprehensive MS review were: 1) MEDLINE(PubMed) using the generic neurological drug name, thepsychotropic drug name, and the term “ interaction;” 2)Hanston’s Drug Interaction Analysis and Management Text(quarterly updated version) [7]; 3) Drug Interactions Facts;Facts and Comparisons (updated version) [8]; 4) Microme-dex Drug-dex [9]; 5) American Hospital Formulary ServiceDrug Information [10]; and 6) Food and Drug Administra-tion (medwatch) (Dear Doctor Letters and new labeling)(www.fed.gov/medwatch for (1990 to 2001). (Citations re-garding children, reports in foreign languages or about food,animals, in vitro experiments, analgesics, and naturalistictreatment interactions were excluded). This multiple source(MS) data method also edited out interactions that wereregarded as minimally important, e.g., mild, or even oflesser consequences and, those based on literature that wasseveral years old with out any later report in support of theoriginal occurrence of the interaction. Therefore, many mi-nor interactions that had been reported were eliminated

Table 1Commonly prescribed neurologic medications

AcetazolamideAlprazolamAmantadineAmitriptylineAmobarbitalAspirinAtropineBaclofenBenztropineBotulinum toxinBromocriptineCarbamazepineCarbidopa/LevodopaChloral HydrateChlordiazepoxideClonazepamClonidineClopidogrelClozapineCyclobenzaprineDexamethasoneDiazepamDihydroergotamineDiphenhydramineDipyridamoleDipyridamole/AspirinDomperidoneEntacaponeEthosuximideFelbamateFosphenytoinGabapentinGlatiramer AcetateInterferon beta-1 �Interferon beta-1 �Intravenous ImmunoglobulinLamotrigineLevetiracetamLorazepamMeclizineMephenytoinMethylphenidateMethylprednisolone

MetoclopramideMidazolamModafinilNaratriptanNimodipineNortriptylineOlanzapineOndansetronOxazepamOxcarbazepinePenicillaminePentobarbitalPergolidePerphenazinePhenelzinePhenobarbitalPhenytoinPramipexolePrednisolonePrimidoneProchlorperazinePromethazinePyridostigmineRiluzoleRopiniroleSelegilineSumatriptanTacrineTemazepamTiagabineTiclopidineTizanidineTolcaponeTopiramateTrihexiphenydylValproic AcidVigabatrinWarfarinZaleplonZolmitriptanZolpidemZonisamide

Table 2Commonly prescribed psychotropic medications

AlprazolamAmantadineAmitriptylineAmobarbitalAmphetamineBenztropineBupropionBuspironeButalbitalCarbamazepineChloral hydrateChlordiazepoxideChlorpromazineCitalopramClomipramineClonazepamClozapineDesipramineDextroamphetamineDiazepamDiphenhydramineDivalproex sodiumDonepezilFluoxetineFluphenazineFluvoxamineGabapentinHaloperidolImipramineIsocarboxazidLamotrigineLithium CarbonateLorazepamLoxapineMeprobamate

MirtazapineMesoridazineMethylphenidateMolindoneNefazodoneNortriptylineOlanzapineOxazepamOxcarbazepinePargylineParoxetinePemolinePerphenazinePhenelzinePhenobarbitalPimozideQuetiapineRisperidoneSertralineSildenafilSodium amytalTacrineTemazepamThioridazineThiothixeneTranylcypromineTrazodoneTriazolamTrifluoperazineTrihexiphenidylValproic acidVenlafaxineVerapamilZaleplonZolpidem

312 J.J. Strain et al. / General Hospital Psychiatry 24 (2002) 311–315

from the final group because their clinical significance wasdeemed less important.

This MS method assigned severity on the basis of a threelevel organization [8]:

1. Major: The effects are potentially life-threatening orcapable of causing permanent damage.

2. Moderate: The effects may cause a deterioration in apatient’s status. Additional treatment, hospitalizationor extension of hospital stay may be necessary.

3. Minor: The effects are usually mild; consequencesmay be bothersome or unnoticeable, but should notsignificantly affect the therapeutic outcome. Addi-tional treatment is usually not required [8].

Although in Interact the degree of severity was graded inan inverse fashion to that of the MS system, e.g., 1�minor,2�moderate, and 3�major, Interact’s rating system wasmade concordant with that of the MS system for this studyto permit comparisons.

3. Results

Interact did not contain 31 of the neurological drugsunder investigation (Table 3) and did not list three of thepsychotropic medications: sildenafil, oxcarbazepine, zale-plon. ePocrates Rx did not include 4 neurological drugs:botulinum toxin, iv immunoglobulin, vigabatrin, mirtazap-ine and domperidone; and six psychotropic medications:butalbital, isocarboxazid, meprobamate, mirtazepine, pargy-line and sodium amytal. Even with these omissions theauthors were able to query for over 3249 and 4749 druginteraction possibilities, respectively, for neurology–psy-chotropic drug interactions in the Interact and ePocrates Rxsystems.

It is important to note that neurology listed 29 psycho-tropic medications as drugs they also commonly use in theirspecialty so that these medications appear in the most com-monly prescribed drugs of both disciplines (Table 4).

Of 5499 drug comparisons the number of drug interac-tions found were: ePocrates Rx - N�1006; (18.3%) Interact- N�713 (14.7%); and those reported in MS after editing bythe authors - N�380(6.9%). (See Methods for exclusioncriteria of interactions).

ePocrates Rx did not include information regarding theseverity of the adverse interaction so this component couldnot be compared with Interact and the MS systems whichdid describe severity and at three levels 1�major, 2�mod-erate, 3�minor. The number of drug interactions accordingto severity ratings in Interact were: 1�134, 2�240, 3�339.Those in the MS severity ratings were: 1�37, 2�279,3�64. In a comparison of MS and Interact by severity,Interact missed or decreased the severity rating in 20 (54%)of the 37 MS systems most serious interactions - severity 1interactions. In the Interact system comparing the severity 1interactions of MS, three had no interaction listed, 5 and 5were labeled severity level 2 and 3 respectively, and 7 drugswere not in the system. However, Interact found manyinteractions of severity 1,2,3, not reported by the MS for-mat: 82, 171, 232, respectively (N�485).

With regard to interactions by degree of severity levelsdescribed in the Interact system, ePocrates Rx did not list330 interactions: 25 (level 1), 113 (level 2), and 192 (level3). With regard to interactions by degree of severity levelsdescribed in the MS system ePocrates Rx omitted 178drug–drug interactions: 3 (level 1), 141 (level 2), and 34(level 3). At the same time ePocrates Rx noted 859 inter-actions that MS did not report.

4. Conclusions

It is essential to have some database system available atthe patient’s side—point of case—to reliably assess drug–drug adverse interactions, to know the severity of the inter-action, e.g., could it be life threatening or impair end organfunctioning. Although many systems, texts, articles, jour-nals have described such interactions, no system seemed to

Table 3Neurologic drugs not found in Interact

AtropineBotulinum toxinClopidogrelCyclobenzaprineDihydroergotamineDipyridamoleDipyridamole/AspirinDomperidoneEntacaponeFosphenytoinGlatiramer acetateInterferon beta-1 �Interferon beta-1 �Intravenous ImmunoglobulinLevetiracetamMeclizine

MephenytoinMethylprednisoloneModafinilNimodipineOndansetronOxcarbazepinePenicillaminePrednisoloneProchlorperazinePromethazinePyridostigmineRiluzoleVigabatrinZaleplonZonisamide

Table 4Psychotropic drugs used by neurology and psychiatry

AlprazolamAmantadineAmitriptylineAmobarbitalBenztropineCarbamazepineChloral hydrateChlordiazepoxideClonazepamClozapineDiazepamDiphenhydramineGabapentinLamotrigineLorazepam

MethylphenidateNortriptylineOlanzapineOxazepamOxcarbazepinePerphenazinePhenelzinePhenobarbitalTacrineTemazepamTrihexiphenidylValproic acidZaleplonZolpidem

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combine pertinent background sources into one clinicallyuseful approach that would reflect up to date information, anassessment of severity of the interaction, mechanism for theinteraction, and recommendations or actions for the clini-cian to take. Some systems like MicroMedex are so com-prehensive and include so many interactions that at onehospital the Department of Pharmacy removed this from thehospital computer system and turned to the assistance of adrug information officer [9]. House officers were over-loaded by the information provided and had difficulty sep-arating the “wheat from the chaff.” This is why an attemptwas made in the MS system to edit and select the mostimportant and life threatening interactions and keep theobservations to a manageable number.

ePocrates Rx included no severity ratings making thesignificance of the interaction less obvious to the clinicianand thus limited its use in clinical decision-making. TheInteract author did not state how he arrived at the degree ofseverity and used his own system with the lesser numberhaving the least significance. This is in contrast to most ofthe systems we encountered and those commonly employedby Departments of Pharmacies in general hospitals. The MSsystem applied the standard system based on the criteriadescribed in the methods section.

With regard to references, ePocrates Rx did not includethem, and Interact had many citations often in excess of 10years old (Table 5). What made these old references ofconcern is that often there was no later report of such aninteraction. And, many of these references were a singlecase report. Should such limited evidence support the in-clusion of an interaction?

ePocrates Rx had limited statements of mechanisms forthe interaction as did Interact, making them less pedagog-ically useful to medical students, residents, fellows and eventhose at the attending level. The MS system attempted tosupply a substantive mechanism statement for explanatoryand teaching purposes.

With regard to recommendations for action, both eP-ocrates Rx and Interact were again quite limited. In the MSsystem the authors strove for a specific and concrete actionstatement to assist the clinician in decision making.

Of the drugs selected for study Interact had the largestnumber of drugs not in the system - 31 neurological drugsand 3 psychotropic medications. This could partly be ex-plained by the fact that the publication date was 1999 and nonew update is in press. Similarly with ePocrates Rx four ofthe neurological drugs and 6 of the psychotropic medica-tions were not in the shareware software. It would be im-portant to know how drugs are selected to be included forthese two common software databases. The Redbook is anational resource for the most commonly prescribed drugsin the United States and is one standard on which drugsshould be included in drug interaction databases [6]. Withthe MS system all drugs were located and examined. For themissing drugs in ePocrates Rx and Interact, it would benecessary for the user to go to other sources, e.g., a drug

information officer or some text like Drugs InteractionFacts (quarterly updated version) [8], that contained all thedrugs that had been selected for study.

ePocrates Rx provided by far the greatest number ofdrug-drug interactions. In this regard, it may be consideredthe most sensitive database of the three and thus advanta-geous for those with less clinical experience, such as med-ical students or residents. Such a large number of citedinteractions, however, can cause greater confusion if manyare of minor clinical consequences, especially since theseverity of the interaction that is essential for clinical deci-sion making is not described in ePocrates Rx.

An important advantage of the ePocrates Rx software isthat it is stored in a hand held computer (e.g., Palm PilotTM,

HandspringTM Visor, etc.), which can be available at thepatient’s side where ever the clinical encounter takes place.Currently, Interact and the MS system require a laptop, or adesktop computer because the databases are on floppys orCDs. (Of course they can be printed and available in a hard

Table 5Reference years for Interact citations compared with Mount SinaiInteraction Severity Level

Year Not in MountSinai System

Mount SinaiSeverity Level

Total

1 2 3

-(No year cited)- 2 21968 1 4 51969 1 5 61970 4 5 91972 11 5 161973 6 61975 10 2 121976 3 31977 1 11979 2 21980 15 4 8 271981 33 15 481982 4 41983 1 11984 3 3 61985 93 26 17 1361986 7 2 91987 83 4 871988 5 2 2 91989 2 21990 28 5 9 4 461991 10 5 151992 11 4 5 201993 4 2 61994 4 8 121995 47 4 10 4 651996 25 15 1 411997 48 27 1 761998 22 9 9 1 41No Interaction in

Interaction SystemN � 4634

10 116 26 4786

Total 4634 485 37 279 64 5499

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copy form which the clinicians would need to carry withthem. ePocrates Rx easy accessibility, and portability makeit one of the most frequently employed of the drug - druginteractional software databases. Another advantage whichePocrates Rx provides is the power to check the interactionsof up to 30 drugs simultaneously, referred to as “Multi-Check” . Finally, the AutoUpdate feature that is part of theePocrates Rx system, ensures that physicians are kept up todate on new reports of drug–drug interactions, as well asnew medications as they become available. It is important tomention that other “on line” resources that examine thecytochrome drug–drug interactions or potential interactionsexist: David Flockhart’s web site is such an example (http://medicine.iupui.edu/Flockhart). The MS system has pro-vided an update of its cardiac drug–psychotropic drug re-view [11].

It is hoped that the advantages and disadvantages of threedrug–drug interaction approaches would advance the devel-opment of these systems in the future. Each has advantagesand disadvantages and the goal would be to have the mostcomprehensive, accessible, easily updatable, recently refer-enced, and with pedagogic tools supplied to explain themechanisms of the interaction as an important learningdevice for the physician.

It is the findings of this paper that important systems areunder development and perhaps the advantages of all mightone day be combined in an inexpensive hand held devicethat could be easily updated and serve as a clinical decisionand teaching tool. As the medical information databasedoubles every five and half years [12], and the drug infor-mation is one of the most rapidly changing domains, it isessential to have on the physician’s person in the clinicalsetting a device that would allow immediate access, severityratings, recent references, mechanisms of action, essentialrecommendations, a complete drug list within a specialty,and easily facilitated down loads, as currently used in manyof the antivirus programs. This is especially important forthe consultation–liaison psychiatrist or the consultant neu-rologist who could be asked to see any patient, with anyillness, and who could be on any drug in the pharmacopoeia.

The task of the consultation–liaison psychiatrist and con-sultant neurologist is foreboding, as he/she must go from thedomain of psychiatry and neurology to the many domains ofmedicine and surgery. Not only are the complications of theillnesses and their end organ effects difficult to know andcomprehend, but the variety of medicines’ drugs, and thentheir interaction with psychiatry’s and neurology’s pharma-ceutical arsenal imposes an enormous task and expectation.The world of the new technologies—as adumbrated in thispaper—may be an important beginning to cope with thisoverwhelming information demand.

References

[1] ePocrates Rx, Clinical Drug Database, Copyright epocrates Inc, 2000.[2] Goldman LS. Interact: Psychotropic Drug Interactions. American

Psychiatric Press, Inc., Washington, D.C., 1999.[3] Strain JJ, Caliendo G, Alexis JD, Lowe RS, III, Karim A, Loigman

M. Part II: cardiac drug, and psychotroic drug interactions. Signifi-cance and recommendations. Gen Hosp Psychiatry 1999;21:408–29.

[4] Strain JJ, Karim A, Caliendo G, Brodsky M, Himelien C, Lowe III,RS. Neurologic drugs–psychotropic drugs update. Significance, andRecommendations. Gen Hosp Psychiatry 2002;5:290–310.

[5] Strain JJ, Caliendo G, Himelein C. Using computer databases topredict, and avoid drug-drug interactions in the cancer patient requir-ing psychotropics. Psychopharmacology Special Edition. Psy-chooncology 1998;7:321–32.

[6] Redbook. Medical Economics Company, Inc., Montvale, NJ 2000:07645–1742.

[7] Hansten PD, Horn JR, Koda-Kimble MA, Young LY, editors. Druginteractions, and analysis, and management. Facts and comparisons.St Louis, MO, 2000. Quarterly Update.

[8] Tatro DS, editor. Drug interaction facts. St Louis: Facts and compar-isons, 1998. Quarterly Update 1999.

[9] Micromedex Drugdex, Micromedex, Volume 97, Englewood, NewJersey, 2000.

[10] McEvoy GK, editor. American Hospital Formulary Service DrugInformation 2000. American Society of Health System Pharmacists.Bethesda, MD.

[11] Strain JJ, Karim A, Caliendo G, Alexis J, Lowe, III, RS, Fuster V.Cardiac drug–psychotropic drug update. Gen Hosp Psychiatry 2002;5:283–90.

[12] Piemme TE. Computer-assisted learning, and evaluation in medicine.JAMA 1988;260(3):367–72.

Table 6Comparison of three drug-drug interaction systems

MS Interact ePocrates RX

Severity of interaction specified

ReferencesInclusiveness of drugs studiedMechanism of drug-drug interactions.Clinical recommendationsEase of accessibility

Severity level determined bydefined clinical parametersUpdatedAll availableDetailedDetailedRequires laptop or hard copy

Severity levels withoutdescription of criteriaMany not currentMany missingFrequently missingRarely mentionedRequires laptop or hard copy

Not provided

No references providedMany missingNo mechanisms includedVaguePDA application

315J.J. Strain et al. / General Hospital Psychiatry 24 (2002) 311–315