Psychotropic drug versus psychotropic drug—update

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Update: Drug-Psychotropic Drug Interactionshis section will appear in the Journal from time to time as new important reports on drug-psychotropic drug interactions are published.ince the authors are not bound by only scientific studies and random control trials, even technical reports from work in progress in

aboratories, case reports, and early observations will be included. We welcome the readership to bring to our attention importantnteractions that we have overlooked and should be considered for citation in this section. It is our hope to move the scope of reporting tonclude technical reports, Food Drug Administration (FDA) communications, laboratory reports, and so forth, and not limit citations onlyo refereed journals. Thus, alerts will be more timely and not delayed by publication schedules.

Psychotropic drug versus psychotropic drug—update

James J. Strain, M.D.a,*, Niem Mu Chiu, M.D.a, Kaiser Sultana, M.D.a,Anwarul Karim, M.D.a, Gina Caliendo, Ph.D., R.Ph.b,

Shawkat Mustafa, M.D.a, Jay J. Strain, M.D.c

aDivision of Behavioral Medicine and Consultation Psychiatry, Mount Sinai School of Medicine, Mount Sinai—NYU Medical Center/Health System, 1Gustave L. Levy Place, New York, NY 10029, USA

bDepartment of Pharmacy, Mount Sinai Hospital, 1 Gustave L. Levy Place, New York, NY 10029, USAcDepartment of Surgery, Eden Hospital, Castro Valley, CA, USA

Received 1 July 2003; accepted 20 August 2003

bstract

Psychotropic drugs are not necessarily the drugs of psychiatry. Seventy percent of antidepressants, and 90% of anxiolytics are prescribedy nonpsychiatric physicians. Since psychotropic medications are so frequently employed by nonpsychiatric physicians, e.g., neurologists,rimary care physicians, internists, and because large numbers of their patients are concurrently on medical drugs for somatic reasons, thenteractions of psychotropic versus medical drugs and psychotropic versus psychotropic drugs as listed below must be understood beforerimary care physicians or psychiatrists prescribe psychotropic medications, especially to the medically ill. Seventy commonly prescribedsychotropic drugs were examined for their interactions with other psychotropic medications using six reference tools: 1) MEDLINEPubMed) employing the first generic psychotropic drug name, the second generic psychotropic drug name, and the term “interaction;” 2)anston’s Drug Interaction Analysis and Management Text (quarterly updated version) [2]; 3) Drug Interactions Facts (Facts andomparisons) (July 2001 quarterly updated version) [3]; 4) Micromedex Drug-dex [4]; 5) American Hospital Formulary Service Drug

nformation [5]; and 6) Food and Drug Administration (MedWatch) (Dear Doctor Letters and new labeling) (www.fed.gov/medwatch for1999, 2000, and 2001). The authors recognized that all of the above sources do not necessarily cover the entire information databaseegarding drug–drug interactions. (Citations regarding children, reports in foreign languages or concerning food, animals, in vitroxperiments, analgesics, and naturalistic—herbal or natural products—treatment interactions were excluded). © 2004 Elsevier Inc. Allights reserved.

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. Introduction

The concomitant use of psychotropic with other psych-tropic medications is ubiquitous in the general hospitaletting, and in ambulatory practice. The aim of this litera-ure drug–drug interaction analysis is to compare the mostommonly prescribed psychotropic medications with othersychotropic drugs and their interactions if they are em-

* Corresponding author. Tel.: �1-212-659-8728; fax: �1-212-369-817.

oE-mail address: [email protected] (J.J. Strain).

163-8343/04/$ – see front matter © 2004 Elsevier Inc. All rights reserved.oi:10.1016/j.genhosppsych.2003.10.001

loyed simultaneously. Furthermore, many of the samerugs are prescribed by other disciplines, e.g., neurology,edicine, geriatrics, but not necessarily for the same disor-

er, e.g., carbamazepine for seizure (neurology) and moodtabilization (psychiatry). Psychiatrists as well as other dis-iplines need to be informed of the potential hazards ofmploying concomitantly diverse psychotropic drugs.

Psychiatrists frequently encounter patients with comor-id psychiatric conditions such as affective disorders orsychosis and delirium and dementia. These patients areften on antidepressants, antipsychotics, mood stabilizers,
r combinations of these categories. This may present a
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88 J.J. Strain et al. / General Hospital Psychiatry 26 (2004) 87–105

hallenge when assessing which psychiatric drugs can besed simultaneously: Which medications are safe to pre-cribe, which combination of psychotropic drugs would behe most effective, and which would necessitate a dosedjustment from that usually prescribed or more carefulonitoring of serum levels than is required if only oneedication is applied at a time.The aim of the study is to describe psychotropic versus

sychotropic adverse drug interactions, enumerate theechanisms of the interactions when possible, and given

he adverse interaction and the degree of its severity, specifyecommended action(s) for the practitioners.

. Methods

The drugs selected for review were from: 1) the Redbookist of the 200 most often prescribed medications in thenited States; 2) those medications most commonly em-loyed by the Division of Behavioral Medicine and Con-ultation Psychiatry, and the Department of PharmacyMount Sinai - NYU Medical Center/Health System) (Table). The disciplines of the investigators were: pharmacy-drug

able 1ommonly prescribed psychotropic medications

mantadine methylphenidatemitriptyline molindonemphetamine nefazodonelprazolam nortriptylinemobarbital olanzapineenztropine oxazepamupropion pargylineuspirone paroxetineutalbital pemolinearbamazepine perphenazinehoral hydrate phenobarbitalhlordiazepoxide quetiapinehlorpromazine risperidoneitalopram sertindolelomipramine sertralinelonazepam sildenafillozapine sodium amytalesipramine tarcineextroamphetamine temazepamiazepam thioridazineiphenhydramine thiothixeneivalproex sodium trazodoneonepenzil tranylcypromineuoxetine triazolamuphenazine trifluoperazineuvoxamine trihexiphenidylabapentin valproic acidaloperidol venlafaxinemipramine zaleplonamotrigine zolpidemithiumorazepamoxapineeprobamate

nformation (G.C.), psychiatry (J.J.S., N.M.C.), 2 research F

ssistants (A.K., K.S.), and a medical programmer (J.J.S.) tonstall the data into a special software program for distribu-ion to consultation—liaison programs throughout the world1].

The search strategy utilized the following indexing sys-ems: 1) MEDLINE (PubMed) employing the first genericsychotropic drug name, the second generic psychotropicrug name, and the term “interaction;” 2) Hanston’s Drugnteraction Analysis and Management Text (quarterly up-ated version) [2]; 3) Drug Interactions Facts (Facts andomparisons) (July 2001 quarterly updated version) [3]; 4)icromedex Drug-dex [4]; 5) American Hospital Formu-

ary Service Drug Information [5]; and 6) Food and Drugdministration (MedWatch) (Dear Doctor Letters and new

abeling) (www.fed.gov/medwatch for (1999, 2000, and001). The authors recognized that all of the above sourceso not necessarily cover the entire information databaseegarding drug–drug interactions. (Citations regarding chil-ren, reports in foreign languages or concerning food, ani-als, in vitro experiments, analgesics, and naturalistic—

erbal or natural products—treatment interactions werexcluded).

Should one utilize the known mechanism(s) of interac-ion and established pharmacokinetics and pharmacolgicrinciples to extrapolate selectively to other drugs in a givenlass for which the given interaction has not been reported?or example, interactions involving SSRIs were generalizedhen the risk for the occurrence of the serotonin syndrome

ould be based on a potential pharmacological interaction.or interactions that were pharmacokinetic in nature, dif-erences in extreme impact were addressed individually.imilarity of action in a particular enzyme system might

ndicate possible interactions. Nefazodone is a known in-ibitor of the cytochrome P3A4 isoenzyme. Yet, its use withisapride was initially not contraindicated. Cisapride is anown and established cytochrome P3A4 substrate thatould produce cardiac arrhythmias and/or death when pre-cribed with cytochrome P3A4 inhibitors. Judicious prac-ice would have questioned the use of nefazodone withisapride despite the lack of a documented interaction.ventually, the prescription of cisapride was officially con-

raindicated with nefazodone.

. Dynamics of drug–drug interaction

Although the dynamics of drug–drug interaction(s) haveeen described before [1], it is important to review themere as the psychotropic drug—psychotropic drug interac-ion summaries which follow are constructed with this al-orithm in mind and a reader may not have access to therevious communication. “It is necessary to determine theircumstances in which drugs might interact, and when thelinical situation would be protective or aversive, by addingr subtracting Drug A to or from Drug B, and vice versa.
or example, if Drug A and Drug B were started simulta-
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89J.J. Strain et al. / General Hospital Psychiatry 26 (2004) 87–105

eously and Drug A had the potential to alter the metabo-ism of Drug B, regularly monitoring the clinical responseay be protective in that the net effect of the interaction

ould be adjusted for as the clinician treated the patientither until improvement or toxicity.

Adding Drug A to Drug B where Drug A alters theetabolism of Drug B, might change (increase/decrease)

he concentration of B, which is already in the patient’system, and initiate an adverse drug response. Before add-ng A, drug B might have been at a stable therapeutic dose.hree situations may prevail: higher serum concentration of, less of B, or thirdly, a pharmacologic or pharmacody-amic interaction with an additive incidence or severity ofn adverse event. On the other hand, adding Drug B to ateady state of Drug A, where Drug A alters the metabolismf Drug B but Drug A is not affected by Drug B, will not beversive, as the clinician may add more or less of Drug B,epending upon the clinical situation. Thus the clinician canompensate for the interaction by adjusting the dose of Drug. An approach to observing drug–drug interactions is toutline Drug A’s impact on Drug B when adding andubtracting one drug to or from the other (see Table 2).

Removing Drug A from Drug B or Drug B from Drug A,here Drug A alters metabolism of Drug B, presents addi-

ional issues: Discontinuing one drug may raise or lower theoncentration of another, may alter the clinical effects of theemaining drug and/or may precipitate toxicity. The practi-ioner needs to assess the clinical effects of the remainingrug during withdrawal of the second drug (see Table 3).

In the appendix describing the drug interactions, thislgorithm is employed to aid the physician when adding oriscontinuing drugs, which are known to have adverse re-ctions.

. Rating system: significance levels

Most rating systems indicate: 1) major significance; 2)

able 2rug interactions: adding drugs

atient is on Add on

(Drug A alters metabolismof Drug B)

B No impact as the effectof A on B will beaccounted for as B isinitiated.

&B “ No action is necessaryif there are no adverseeffects present, thepatient is stable on bothand the interaction isaccounted for.

“ A Dose of B may need tobe adjusted as theeffect of A on B isobserved.

oderate significance; and, 3) minor significance. Signifi-

ance level 1 indicates a major contraindication or a drugnteraction that requires very careful monitoring. The clini-ian needs to document why he or she is prescribing thisombination, and the medical necessity to use both drugsoncomitantly only if there is no alternative or the potentialenefit outweighs the risk. Drug combinations producing annteraction with a significance level 1 are combinations thatesult in serious and potentially life threatening adverseffects such as arrhythmia and/or death. Obviously, if thisombination is to be used the drug(s) in question must berescribed with an explanation as to the need for theironcomitant use and cautious monitoring. Documentationf the clinician’s awareness of the potential serious—level—interaction should be accomplished at the time of pre-cribing this potentially dangerous combination. In addition,t is obligatory to communicate to the other health careroviders the potential interactions and adverse outcomeshich they should be on guard to observe. Obviously, theptimum choice, if possible, is to use an alternative medi-ation to avoid significance level 1 interactions.

With significance level 2, the potential interaction mustlso be documented and the clinical outcome(s) must beonitored carefully so that unacceptable, pernicious reac-

ions are halted as soon as possible. If feasible, consider-tion should be given to an alternative agent that does nothare the same interaction potential. It is essential that thelinician document that the potential drug interactions wereonsidered when using this combination. It is also essentialo alert the patient’s health care providers of the potentialnteractions so that they are observed early in their course.

Significance level 3 does not preclude the use of a spe-ific drug, but clinical decision making requires acknowl-dging if the adverse reactions, (e.g., nausea, rash, etc.)ight be precluded by choosing an alternative drug. The

otential interaction and its mechanism(s) needs documen-ation in the patient’s medical chart and the patient’s healthare providers need to be informed.

Another rating system is employed by Drug Interactionacts which utilizes a 5 point significance classificationchema [3]:

1. Avoid combination: risk always outweighs benefit;2. Usually avoid combination: use combination only

able 3rug interactions: removing drugs

atient on Take away

� B (Drug A alters metabolism ofDrug B)

B No change in thedose of A will benecessary.

� B “ A The dose of B mayneed to be altered asthe effect of A on Bdissipates.

under special circumstances;

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3. Minimize risk: take action as necessary to reducerisk;

4. No action needed: risk of adverse outcomes appearssmall; and,

5. No interaction: evidence suggests no interaction.

When data were obtained from Drug Interaction Factshe 5 point scale was converted to the 3 levels of signifi-ance rating system described earlier which is employed inhe appendix.

. Conclusion

We described previously methods to keep abreast ofewly reported drug–drug interactions, and identified in-truments available to accomplish this task [1]. Each monthew drug–drug interactions are described. Psychotropicersus psychotropic drug interactions are less often thoughtf and considered then medical drug - psychotropic drug.his unfolding of knowledge of psychotropic drug–psycho-

ropic drug interactions illustrates the importance of meth-ds of surveillance to ensure that information is current,ccurate, and available. Rosebraught et al. report that med-cal schools and residency programs should provide moreraining on preventing adverse drug reactions [11].

Therefore, the data presented in this paper will be avail-ble on the internet on a Web site (www.microcares.com),nd as a part of the dictionaries in a computerized medicalecord, MICROCARES, which is currently employed byonsultation-Liaison (C-L) psychiatrists at the interface ofedicine and psychiatry in the general acute care inpatient

nd ambulatory setting. This will permit medical students,ouse officers, fellows, and attendings in psychiatry, andrimary care to have immediate access to this essential drugnformation as well as to new drug-drug interactions as theyre discovered and reported through the variety of resourcesescribed above and the safety information maintained byhe pharmaceutical manufacturers

The authors were impressed with the number and sever-ty of drug interactions when 2 or more psychotropic drugsere employed simultaneously. Because many disciplines

mploy psychotropic drugs, the consultation psychiatristay encounter the patient who is already on one or more

sychotropic drugs. The psychiatrist must be aware of psy-hotropic–psychotropic interactions when he or she recom-ends additional psychotropic drugs. (Many of these inter-

ctions were not found on 2 commonly employed softwareystems: Interact and ePocrates [6–8].)

Pharmaceutical companies develop limited drug interac-ion profiles before the introduction of a new medication.reclinical in vitro and clinical studies are the basis for this

nformation. After the introduction of a new drug, additionaltudies are conducted and new drug interaction reports areollected and continuously evaluated. This “from use” data
ffers a valuable insight into level 1, 2, and 3 significant d
nteractions and their frequencies. “From use” data mayrovide early indications of potential drug interactions thatave not been previously identified. After evaluation, re-orts can be the basis for a pharmacokinetic drug–drugnteraction study to determine the significance of a collec-ion of single case reports. A well-designed pharmacoki-etic drug interaction study can confirm the validity of aroup of single case reports. Single case reports wereeighted to be less significant than several case reports with

imilar findings. Well-designed pharmacokinetic studiesemonstrating a significant drug interaction were weightedignificantly higher in our review than single case reports.

Because the patient is the “guinea pig” for reactions notbserved during clinical trials and the FDA approval pro-ess, it is this natural experiment of the patient using a drugver time, using the medication with other drugs, herbalgents, and foods, and in some cases acquiring additionaledical illness, etc., which provide the matrix for the in-

eractions to occur. Such data could compare and counterhat presented in “Prozac Backlash” in which the authorrgues that long term effects of the SSRIs can be injuriouso brain, memory, motor movements functioning, etc [9].he Eli Lilly Co. has use data from over 20 million initialnd renewal prescriptions of fluoxetine (1986-2001) whichight answer some of these questions. They probably can

ever have a definitive statement about all adverse re-ponses, because many are not reported, and many reportedre not necessarily related to the drug or drugs in question.nfortunately, the reports received by the manufactureray be self-report statements not verified by a physician.It would be important to know about the long term use of

edication, gender issues and age considerations. Healthare workers might also know if the frequency of adverseeactions is rare, occasional or frequent. And, such “useata” can illuminate risk characteristics for adverse drugesponders, e.g., the elderly, women, those with heart dis-ase, diabetes, etc., to guide the physician and the patientith regard to the risk versus benefit from combined med-

cation usage.Medical drugs are not tested against psychotropics drugs

efore they are FDA approved. Nor are psychotropics drugsested against other psychotropics medications before theyre approved. Some combinations may not have been used,eported, or catalogued as yet. As one follows the evolutionf antipsychotic medications from reserpine (1940s), chlor-romazine (1950s), haloperidol, fluphenazine, thioridazine1960s), to the atypical antipsychotics (loxapine, risperi-one, olanzapine, quetiapine (1990s), and finally to theatypical atypicals” (ziprasidone, aripiprazole, iloperidone2000) [10], it is understandable that we need to wait andee what happens with these 21st century medications withegard to drug–drug interactions. There has not been suffi-ient time for the “atypical atypicals” to run the “naturalxperiment” and be sufficiently employed by the humanguinea pig” with a variety of medical illnesses, medical
rugs, and psychotropic medications to know their poten-
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ially significant adverse interactions. Finally, chronic med-cation use versus acute concomitantly administered drugsas not been delineated. Clinical trials to determine psych-tropic drug interactions with other psychotropic medica-ions would be unethical and could unnecessarily harm aatient. Drug manufacturers often debate or discount thedverse side effects of their medications [12].

Psychotropic drugs are not necessarily the drugs of psy-hiatry. Seventy percent of antidepressants, and 90% ofnxiolytics are prescribed by non psychiatric physicians.ince psychotropic medications are so frequently employedy non psychiatric physicians, e.g., neurologists, primaryare physicians, internists, and since large numbers of theiratients are concurrently on medical drugs for somatic rea-ons, the interactions listed below must be understood be-ore primary care physicians or psychiatrists prescribe psy-hotropic medications, especially to the medically ill.

cknowledgments

This work was funded by The Malcolm Gibbs Founda-ion, Inc., New York, NY.

The authors would like to acknowledge the most helpfuleview and editorial assistance of Dr. Ron Pies of Mass

ental Health, Boston, Mass in the preparation of thisanuscript.

ppendix 1. Psychotropic and psychotropic drugnteractions

Alprazolam, Midazolam/CarbamazepineSignificance level 2: ModerateAdvice to Practitioner: Carbamazepine can increase the

etabolism of some benzodiazepines (alprazolam and mi-azolam). Interactions of this type may take some time toccur or dissipate. If a patient is on carbamazepine and aenzodiazepine is added, no intervention is required, as theose of the benzodiazepine will be monitored by clinicalfficacy. If a patient is stabilized on the combination, noction is necessary. If a patient is on a benzodiazepine andarbamazepine is added, decreased benzodiazepinie activityay be seen. Increased doses may be needed.Action: Monitor benzodiazepine efficacy and adjust

ose as needed as indicated above. An unaffected ben-odiazepine may also be used.

Alprazolam, Midazolam, Triazolam/Selective Seroto-in Reuptake Inhibitors (SSRI) (Fluoxetine, Fluvox-mine):

Significant level 2: ModerateAdvice to the Practitioner: Fluoxetine and fluvoxamine

nhibit CYP450 3A4 which metabolizes alprazolam, mida-olam, and triazolam. Interactions of this type may take
ome time to onset or dissipate. If a patient is on alprazolam, a
nd any of the above named agents are added, increasedenzodiazepine activity may be seen. If a patient is stabi-ized on the combination, no action is necessary. If a patients on either flouxetine or fluvoxamine and alprazolam, mi-azolam or triazolam is added, no action is necessary, as theose of above benzodiazepine will be determined by clinicalfficacy.

Action: Monitor for signs of benzodiazepines efficacynd adjust dose as indicated above. Consider switchingo a benzodiazepine eliminated by glucoronidationlorazepam, oxazepam, temazepam) and or, an alterna-ive SSRI (paroxetine) may be considered.

Amantadine/Anticholinergics (Benztropine, Trihexy-henidyl)

Significance level 3: MinorAdvice to Practitioner: Amantadine has anticholinergic

ffects. When used with other agents that have anticholin-rgic effects, increased anticholinergic and central nervousystem (CNS) effects may occur. This interaction may be aoncern in patients on high doses of these agents. In aatient on an anticholinergic agent, increased anticholin-rgic effects should be expected when Amantadine is added.o action is necessary if a patient is already maintained on

he 2 agents. If an anticholinergic agent is being added tomantadine, increased anticholinergic effects should be ex-ected.

Action: Consider decreasing the dose of the anticho-inergic agent if side effects become problematic.

Amantadine/ThioridazineSignificance level 3: MinorAdvice to the Practitioner: In elderly patients, with Par-

insonian Syndrome, thioridazine has been associated withncreased tremor when added to Amantadine. This has noteen seen with other phenothiazines. Patients should benformed of this possibility and alternative phenothiazinesr other antipsychotics used if it is problematic.

Action: Educate and monitor patient for increaseremor.

Amantadine/Tricyclic Antidepressants (TCA)Significance level 3: MinorAdvice to the Practitioner: Amantadine has anticholin-

rgic effects. When used with a TCA, especially those withigh anticholinergic effects, increased anticholinergic andffects may occur. This interaction may be a concern inatients on high doses of these agents. In a patient on aCA, increased anticholinergic effects should be expectedhen Amantadine is added. No action is necessary if aatient is already maintained on the 2 agents. If a TCA iseing added to Amantadine, increased anticholinergic ef-ects should be expected.

Action: Use a TCA with lower anticholinergic activityr from another class of antidepressant with Amanta-ine if anticholinergic effects are potentially problem-
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Amitriptyline, Imipramine, Nortriptyline/VerapamilSignificance level 3: MinorAdvice to the Practitioner: A controlled study has shown

hat verapamil decreases amitriptyline, imipramine and nor-riptyline clearance by 25%. The addition of verapamil tomitriptyline, imipramine, or nortriptyline may lead to tox-city (arrythmia, dry mouth sedation, and urinary retention).

hen verapamil is given to a patient stable on amitriptyline,mipramine, or nortriptyline, he or she should be aware ofhese side effects and a lower dose may be indicated. On thether hand, an increase in the dosage of a TCA may beequired if verapamil is discontinued from the combination.

Action: Monitor for anticholinergic effects if vera-amil is added to a patient previously stabilized onmitriptyline, imipramine, or nortriptyline adjust theose (upward) if verapamil is discontinued from combi-ation therapy. Consider an alternative antidepressantther than TCA.

Amphetamine, Dextroamphetamine/Monoamine Ox-dase Inhibitors (MAOI)

Significant level 1: MajorAdvice to the Practitioner: Co-administration of MAOIs

nd psychostimulants, e.g., amphetamine may result in se-ere headache, hypertensive crisis, cardiac arrythmias, chestain, hyperpyrexia and death. If the symptoms are notecognized and correctly treated, death may result. This isecondary to the increased norepinephrine availability.

Action: Combination of these 2 drugs should bevoided. Wait at least 2 weeks after discontinuing anAOI before initiating therapy with amphetamine.ait at least 2 weeks after discontinuing amphetamine

efore initiating therapy with an MAOI.

Amphetamine, Dextroamphetamine/PhenothiazinesSignificant level 1: MajorAdvice to the Practitioner: Co-administration of phe-

othiazines and amphetamine may produce seizures. In ad-ition, amphetamine inhibits the antipsychotic effects ofhlorpromazine and chlorpromazine reverses the anorecticffect of amphetamine. This is because of the antagonisticction of each other.

Action: Concurrent use of a phenothiazine and am-hetamine is not recommended.

Amphetamine, Dextroamphetamine/Tricyclic Antide-ressants (TCAs)

Significant level 2: ModerateAdvice to the Practitioner: Co-administration of TCAs

nd amphetamine, dextroamphetamine or pemoline mayause increased effects of amphetamine, e.g., elevation oflood pressure, arrhythmias and CNS stimulation. This in-eraction is because of the additive effects of these drugs onorepinephrine neurotransmission.

Action: Patients who are on TCAs and amphetamine
ike agents require careful monitoring for hypertension,
rrhythmias and CNS stimulation. Avoid this combina-ion if another option is available.

Benztropine/ClozapineSignificance level 2: ModerateAdvice to the Practitioner: Benztropine has anticholin-

rgic effects. When used with clozapine, increased anticho-inergic and CNS effects may occur. This interaction may be

concern in patients on high doses of these agents. In aatient on clozapine, increased anticholinergic effectshould be expected when benztropine is added. No action isecessary if a patient is already maintained on the 2 agents.f clozapine is being added to benztropine, increased anti-holinergic effects should be expected.

Action: Avoid routine use of benztropine with cloza-ine. Consider atypical antipsychotics with reduced in-idence of extrapyramidal symptoms (EPS) if it is prob-ematic. Combined use should be limited to patients withigns and symptoms of EPS.

Benztropine/HaloperidolSignificance level 2: ModerateAdvice to the Practitioner: Both haloperidol and benz-

ropine have anticholinergic effects. The combination ofaloperidol and other anticholingeric agents have resulted inorsening of schizophrenic symptoms and may increase the

isk of tardive dyskinesias.Action: Avoid routine use of benztropine with halo-

eridol. Consider atypical antipsychotics with reducedncidence of EPS if it is problematic. Combined usehould be limited to patients with signs and symptoms ofPS.

Benztropine/PhenothiazinesSignificance level 2: ModerateBenztropine has anticholinergic effects. When used with

phenothiazine antidepressant, especially those with highnticholinergic effects, increased anticholinergic and CNSffects may occur. This interaction may be a concern inatients on high doses of these agents. In a patient on ahenothiazine, increased anticholinergic effects should bexpected when benztropine is added. No action is necessaryf a patient is already maintained on the 2 agents. If ahenothiazine is being added to benztropine, increased an-icholinergic effects should be expected. Additionally, oralbsorption of the phenothiazine may be decreased. It isnknown if spacing the doses of these agents would dimin-sh this effect, but it is unlikely to have an impact as directnterference with absorption is not postulated to be theechanism.Action: Avoid routine use of benztropine with phe-

othiazines. Consider atypical antipsychotics with re-uced incidence of EPS if it is problematic. Combinedse should be limited to patients with signs and symp-oms of EPS.

Bupropion/Carbamazepine
Significant level 2: Moderate

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Advice to the Practitioner: Carbamazepine can signifi-antly decrease peak bupropion concentrations and areander the plasma concentration-time curve (AUC). Carbam-zepine increases the hepatic metabolism of bupropion viaYP-450 3A4 isoenzyme. If a patient is on bupropion andarbamazepine is added, it may decrease the effectivenessf buproprion. If a patient is on carbamazepine, bupropions added, no action is necessary, as the dose of carbamaza-ine should be determined by the clinical efficacy. If theatient is stabilized on this combination, no action is re-uired.

Action: Patient should be monitored for clinical re-ponse to bupropion. If an interaction is suspected, ad-ust therapy as indicated.

Bupropion/Monoamine Oxidase InhibitorsSignificant level 1: MajorAdvice to the Practitioner: Co-administration of an

AOI and bupropion may result in bupropion toxicity (sei-ures, agitation, psychotic changes). If the symptoms are notecognized and correctly treated, death can result. Theechanism of this interaction has not been delineated.Action: Combination of buspirone and MAOI’s is

ontraindicated. Wait at least 2 weeks after discontinu-ng isocarboxazid before initiating therapy with bupro-ion.

Bupropion/PhenobarbitalSignificant level 2: MildAdvice to the Practitioner: Phenobarbital enhances me-

abolism of buproprion, resulting in decreased concentra-ions. If a patient is stable on the combination, no change inherapy is necessary. If a patient is on phenobarbital andupropion is added, no action is necessary as the dose ofupropion will be determined by clinical response. If aatient is on bupropion and phenbarbital is added, the dosef buproprion may need to be adjusted based on clinicalfficacy or serum levels.

Action: Monitor bupropion efficacy when phenobar-ital is added to bupropion as indicated above.

Buspirone/Selective Serotonin Reuptake InhibitorsSSRI)

Significant level 1: MajorAdvice to the Practitioner: Co-administration of buspi-

one and an SSRI may cause serotonin syndrome, charac-erized by symptoms such as restlessness, myoclonus,hanges in mental status, hyperreflexia, diaphoresis, shiver-ng and tremor. This is secondary to inhibition of buspironeerotonergic effects.

Action: The combination of an SSRI and buspironehould be avoided.

Buspirone/Monoamine Oxidase Inhibitors (MAOI)Significant level 1: MajorAdvice to the Practitioner: Co-administration of an

AOI- and buspirone may result in hypertensive crisis, a
yperserotonergic state characterized by symptoms such as n
ushing, headache and elevation of blood pressure. If theymptoms are not recognized and correctly treated, deathan result. This probably is secondary to increased norepi-ephrine availability.

Action: Combination of buspirone and MAOI’s isontraindicated. Wait at least 2 weeks after discontinu-ng an MAOI before initiating therapy with buspirone.

Buspirone/VerapamilSignificant level 2: ModerateAdvice to the Practitioner: Co-administration of buspi-

one and verapamil has been shown to increase the areander the concentration-time curve (AUC) and the maxi-um concentration of buspirone. Increased buspirone ef-

ects such as sedation may be seen. This is secondary to thenhibition of the CYP450 3A4—mediated first-pass metab-lism of buspirone. If a patient is on buspirone and vera-amil is added, monitor for increased buspirone levels andhe need to decrease the dose of buspirone. If a patient is onerapamil and buspirone is added, no action is necessary, ashe dose of buspirone should be determined by clinicalfficacy.

Action: Monitor patients receiving combination ofuspirone and verapamil for the increased buspironeffects such as sedation. An alternative anxiolytic agentay be used.

Carbamazepine/DonepezilSignificance level 3: MinorAdvice to the Practitioner: Carbamazepine induces the

etabolism of donepezil via induction of the cytochrome450 3A4 and 2D6 isoenzymes. Interactions of this typeay take some time to onset or dissipate. If a patient is on

arbamazepine and donepezil is added, no intervention isequired, as the dose of donepezil will be determined bylinical efficacy. If a patient is stabilized on the combina-ion, no action is necessary. If a patient is on donepezil andarbamazepine is added, decreased donepezil activity maye seen, and increased doses may be needed.

Action: Patients should be monitored for clinical re-ponse to donepezil when carbamazepine is added. Theose of donepezil may need to be adjusted when car-amazepine is added to or removed from the regimen.

Carbamazepine/HaloperidolSignificance level 2: ModerateAdvice to the Practitioner: Carbamazepine induces the

etabolism of haloperidol via the cytochrome P450 3A4nd 2D6 isoenzymes. Interactions of this type may takeome time to onset or dissipate. If a patient is on carbam-zepine and haloperidol is added, no intervention is re-uired, as the dose of haloperidol will be determined bylinical efficacy. If a patient is stabilized on the combina-ion, no action is necessary. If a patient is on haloperidol andarbamazepine is added, decreased haloperidol effective-
ess may be seen, and increased doses may be needed.

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Action: Patients should be monitored for clinical re-ponse to haloperidol when carbamazepine is added. Theose of haloperidol may need to be adjusted when carbam-zepine is added to or removed from the regimen.

Carbamazepine/LithiumSignificance level 2: ModerateAdvice to the Practitioner: The combination of lithium

nd carbamazepine has resulted in neurotoxicity, even withherapeutic concentrations. Reported symptoms include: un-teady gait, truncal tremors, ataxia, horizontal nystagmus,yperflexia, muscle fasiculations, confusion, drowsiness,eakness, lethargy, and coarse tremor. When used together,atients must be educated and closely monitored.

Action: Monitor patients for symptoms listed above ifhe combination is necessary.

Carbamazepine/Monoamine Oxidase InhibitorsMAOIs)

Significance level 1: MajorAdvice to the Practitioner: Use of carbamazepine with a

AOI is contraindicated by the manufacturer, with a rec-mmendation that at least 14 days elapse between the dis-ontinuation of the MAOI and introduction of carbamaz-pine. Concomitant use has resulted in increased bloodressure, hyperpyrexia, and seizures. However, in refractoryases use of a MAOI with carbamazepine may be employedith appropriate monitoring and patient education.Action: Avoid combination whenever possible. At

east 14 days should elapse after discontinuing a MAOIefore carbamazepine is introduced. If the combination

s essential, closely monitor patient for the signs andymptoms listed above.

Carbamazepine/NefazodoneSignificance level 2: ModerateAdvice to the Practitioner: This combination represents a

omplex interaction. Nefazodone inhibits the metabolism ofarbamazepine via inhibition of the cytochrome P450 3A4soenzyme. However, carbamazepine induces the metabo-ism of nefazodone by cytochrome P450 3A4 induction andas been reported to significantly reduce the serum levels ofefazodone.

Action: Patients should be monitored for clinical re-ponse to both nefazodone and carbamazepine. It isifficult to predict the impact of this combination be-ause of the competitive and divergent effect on the samenzyme system. Monitoring of serum carbamazepineevels is essential when nefazodone is added, discontin-ed, or dose adjusted.

Carbamazepine/OlanzapineSignificance level 2: ModerateAdvice to the Practitioner: Carbamazepine induces the

etabolism of olanzapine via induction of the cytochrome450 1A2 isoenzyme. Interactions of this type may takeome time to onset or dissipate. If a patient is on carbam-
zepine and olanzapine is added, no intervention is required, a
s the dose of olanzapine will be determined by clinicalfficacy. If a patient is stabilized on the combination, noction is necessary. If a patient is on olanzapine and car-amazepine is added, decreased olanzapine activity may beeen, and increased doses may be required.

Action: Patients should be monitored for clinical re-ponse to olanzapine when carbamazepine is added. Theose of olanzapine may need to be adjusted when car-amazepine is added or removed from the regimen.

Carbamazepine/PhenobarbitalSignificance level 2: ModerateAdvice to the Practitioner: Phenobarbital induces

YP450 3A4 that metabolizes carbamazepine. The increasen metabolism significantly reduces plasma concentrationsf carbamazepine. If a patient is on a stabilized dose of bothrugs, no action is necessary. When phenobarbital is addedo carbamazepine monitor patients for increased seizurectivity and increase the carbamazepine dose if necessary.owever, phenobarbital levels are not affected by carbam-

zepine.Action: Monitor for increased seizure activity and

ncrease the dose of carbamazepine if necessary whenhenobarbital is added to carbamazepine.

Carbamazepine/RisperidoneSignificance level 2: ModerateAdvice to the Practitioner: Carbamazepine induces the

etabolism of risperidone via induction of the cytochrome450 2D6 and 3A4 isoenzyme. Risperidone serum levelsill decrease when carbamazepine is added, and have been

eported to double when carbamazepine was discontinued.nteractions of this type may take some time to onset orissipate. If a patient is on carbamazepine and risperidone isdded, no intervention is required, as the dose of risperidoneill be determined by clinical efficacy. If a patient is sta-ilized on the combination, no action is necessary. If aatient is on risperidone and carbamazepine is added, de-reased risperidone activity may be seen, and increasedoses may be needed.

Action: Patients should be monitored for their clini-al response to risperidone when carbamazepine isdded. The dose of risperidone may need to be adjustedhen carbamazepine is added or removed from the

egimen.

Carbamazepine/Selective Serotonin Reuptake Inhib-tors (SSRIs)

Significance level 2: ModerateAdvice to the Practitioner: Carbamazepine levels may be

ncreased by the addition of fluoxetine, fluvoxamine, andertraline. In addition, serum levels of citalopram may beecreased by carbamazepine since it is metabolized by the450 3A4 isoenzyme, which is induced by carbamazepine.aroxetine has not been reported to be affected by carbam-
zepine, and does not itself appear to affect carbamazepine.

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Action: Monitor patient for symptoms of increasedarbamazepine concentration and adjust doses aseeded. If using citalopram, monitor patients for inad-quate therapeutic efficacy and increase dosage ifeeded. Use of paroxetine may be considered.

Carbamazepine/TrazodoneSignificance level 2: ModerateAdvice to the Practitioner: Trazodone inhibits the me-

abolism of carbamazepine via induction of the cytochrome450 3A4 isoenzyme. Carbamazepine clearance may beecreased, resulting in carbamazepine toxicity. Also plasmaevels of trazodone and its active metabolite may be de-reased from enhanced metabolism. Interactions of this typeay take some time to onset or dissipate. If a patient is on

arbamazepine and trazodone is added, increased carbam-zepine concentration and toxicity may be seen. If a patients stabilized on the combination, no action is necessary. If aatient is on trazodone, and carbamazepine is added, noction is necessary as the dose of carbamazepine will beetermined by serum levels and clinical efficacy.

Action: Carbamazepine serum levels should be mon-tored when trazodone is added to or removed fromarbamazepine therapy. Patients should be monitoredor clinical signs and symptoms of carbamazepine tox-city.

Carbamazepine/Tricyclic Antidepressants (TCA)Significance level 2: ModerateAdvice to the Practitioner: Addition of carbamazepine to

TCA has been associated with a significant reduction inerum concentration of the TCA. Reductions have beeneported with amitriptyline, nortriptyline, imipramine, andesipramine. It is believed to be a result of carbamazepinenduced metabolism of TCAs. Interactions of this type mayake some time to onset or dissipate. If a patient is onarbamazepine and TCA is added, no intervention is re-uired, as the dose of TCA will be determined by clinicalfficacy. If a patient is stabilized on the combination, noction is necessary. If a patient is on TCA and carbamaz-pine is added, decreased TCA activity may be seen, andncreased doses may be needed.

Action: Monitor patient for symptoms of decreasedCA concentration and adjust dose as needed. Obtain-

ng serum levels of the TCA may be helpful.

Carbamazepine/VerapamilSignificance level 2: ModerateAdvice to the Practitioner: Co-administration of carbam-

zepine and verapamil has resulted in increased carbamaz-pine levels and toxicity (ataxia, nystagmus, diplopia, head-che, vomiting, apnea, seizures, and coma). The probableechanism is decreased carbamazepine metabolism by ve-

apamil. If the patient were stable on this combination, noction would be necessary. Decrease or increase in carbam-zepine dose may be required when verapamil is adminis-
ered or withdrawn, respectively. p
Action: Reduction in the dose of carbamazepine maye required when verapamil is added, and increasing theose of carbamazepine when verapamil is withdrawnay be necessary.

Clozapine/BenzodiazepinesSignificance level 2: ModerateAdvice to the Practitioner: There have been reports of

ardiorespiratory collapse when benzodiazepines have beensed with clozapine. It is unclear what the mechanism ofhis reaction is and it has been rarely reported.

Action: Monitor patient when this combination issed.

Clozapine/CarbamazepineSignificance level 2: ModerateAdvice to the Practitioner: Both clozapine and carbam-

zepine are associated with agranulocytosis and bone mar-ow suppression. Additionally, carbamazepine is an enzymenducer and may decrease clozapine serum levels. Interac-ions of this type may take some time to onset or dissipate.f a patient is maintained on the combination of carbamaz-pine with clozapine, no action is necessary. If a patient isn carbamazepine and clozapine is added, no action isecessary as the dose of clozapine will be determined byerum levels and clinical response. If a patient is on cloza-ine and carbamazepine is added, clozapine levels and tox-city should be monitored as the metabolism of clozapineill be increased and serum levels may decrease.Action: Use this combination only if necessary, and

hen monitor complete blood counts (CBC) and cloza-ine levels as indicated above.

Clozapine/LithiumSignificance level 2: ModerateAdvice to the Practitioner: When lithium has been added

o antipsychotic agents, encephalopathic symptoms haveccurred. In addition, weakness, dyskinesia, and increasedPS, and brain damage have been reported. Some datauggest that lithium levels�0.5 mEq/L minimize this risk,owever, this has not been fully established. This interac-ion is not commonly seen, and lithium is frequently addedo many antipsychotic agents without any interaction.

Action: When using lithium and clozapine together,onitor patient for weakness, EPS, and encephalopathic

ymptoms.

Clozapine/PhenobarbitalSignificance level 2: ModerateAdvice to the Practitioner: Phenobarbital is an enzyme

nducer and may decrease clozapine serum levels. Interac-ions of this type may take some time to be observed orissipate. If a patient is maintained on the combination ofhenobarbital with clozapine, no action is necessary. If aatient is on phenobarbital and clozapine is added, no actions necessary as the dose of clozapine will be determined byerum levels and clinical response. If a patient is on cloza-
ine and phenobarbital is added, clozapine levels should be

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Action: Monitor clozapine serum levels and responsehen adding or removing phenobarbital from a pa-

ient’s medication regimen.

Clozapine/Selective Serotoin Reuptake InhibitorsSSRIs)

Significance level 2: ModerateAdvice to the Practitioner: Clozapine is hepatically me-

abolized via the cytochrome P450 2D6 and 1A2 pathway.luoxetine and sertraline are inhibitors of the 2D6 enzymend fluvoxamine inhibits the 1A2 enzyme, and they mayncrease clozapine levels resulting in toxicity when used inombination. Interactions of this type may take some time toccur or dissipate. If a patient is maintained on the combi-ation of fluoxetine, sertraline or fluvoxamine, with cloza-ine, no action is necessary. If a patient is on fluoxetine,uvoxamine or sertraline and clozapine is added, no action

s necessary as the dose of clozapine will be determined byerum levels and the clinical response. If a patient is onlozapine and fluoxetine, fluvoxamine or sertraline is added,lozapine levels and toxicity should be monitored as theetabolism of clozapine will be decreased and serum levelsay increase to toxic levels.Action: Monitor patient and clozapine levels as above

ith dose adjustments made as required. Alternatively,aroxetine or citalopram may be used as they are less

ikely to impact the 2D6 or 1A2 enzymes.

Clozapine/VenlafaxineSignificant level 2: ModerateAdvice to the Practitioner: Co-administration of ven-

afaxine and clozapine result in increased serum concentra-ions of both, which are associated with clozapine toxicitye.g., dizziness, sedation, vomiting, hypotension) and ven-afaxine toxicity (e.g., somnolence). This is because of theompetitive inhibition of the metabolism of one another.

Action: Careful monitoring of signs of toxicity of bothrugs is required.

Diazepam/Selective Serotonin Reuptake InhibitorsFluoxetine, Fluvoxamine, Sertraline)

Significance level 2: ModerateAdvice to the Practitioner: Fluoxetine, fluvoxamine, and

ertraline inhibit cytochrome P450 3A4 that metabolizesiazepam. Interactions of this type may take some time toccur or dissipate. If a patient is on diazepam and one ofhese SSRI’s are added, increased benzodiazepine activity

ay be seen. If a patient is stabilized on the combination, noction is necessary. If a patient is on any one the aboveamed SSRI’s and diazepam is added, no action is neces-ary, as the dose of diazepam will be determined by clinicalfficacy.

Action: Monitor benzodiazepine efficacy and adjust
ose as needed as indicated above. An unaffected ben-
odiazepine or paroxetine may be considered as alter-atives.

Diphenhydramine/Tricyclic Antidepressants (TCA)Significance level 2: ModerateAdvice to the Practitioner: TCAs and diphenhydramine

ave anticholinergic effects. Use of both agents may resultn adynamic ileus, urinary retention, or chronic glaucoma.his may be more problematic in the elderly or in patientsensitive to anticholinergic effects.

Action: In patients where additional anticholinergicffects are undesirable, or in elderly patients, use of aCA with lower anticholinergic activity or an antide-ressant of a different class is recommended.

Haloperidol/Clozapine, OlanzapineSignificant level 2: ModerateAdvice to the Practitioner: Co-administration of haloper-

dol and olanzapine or clozapine may result in increasederum concentration of haloperidol which is associated witharkinsonism symptoms (cogwheel rigidity, unstable gait).aloperidol metabolism is inhibited by clozapine and olan-

apine via CYT P45 2D6. If a patient is on a haloperidol andlozapine or olanzapine is added, monitor for increasedalopreridol levels and the need to decrease the dose ofaloperidol. If a patient is clozapine or olanzapine and aaloperidol is added, no action is necessary, as the dose oflozapine or olanzapine should be determined by clinicalfficacy.

Action: Monitor for extrapyramidal symptoms whenlanzapine or clozapine are added to haloperidol. Mon-tor and adjust the dose of haloperidol if necessary whentarting or stopping clozapine or olanzapine.

Haloperidol/Fluvoxamine, Fluoxetine, Paroxetine,efazodoneSignificant level 2: ModerateAdvice to the Practitioner: Co-administration of haloper-

dol and fluoxetine, fluvoxamine or nefazodone result inncreased serum concentration of haloperidol that is associ-ted with extrapyramidal symptoms, akathisia, tongue stiff-ess and cognitive impairment. The SSRI’s and nefazodonenhibit the metabolism of haloperidol and its clearance. Ifatient is on haloperidol and the above named SSRIs andefazodone are added, increase haloperidol level will beeen. Decreased the dose of haloperidol. If a patient is onSRIs or nefazodone and haloperidol is added, no action isecessary, as the dose of SSRI or nefazodone should beetermined by the clinical efficacy.

Action: Monitor for signs of extrapyramidal symp-oms and also cognitive impairment when using thebove combination. When patients are stabilized on hal-peridol, alter the dose when starting or stopping SSRI’sr nefazodone.

Haloperidol/Phenothiazines
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ction is necessary, as the dose of phenothiazine should beetermined by clinical efficacy.

Action: Monitor the clinical response of the patient toaloperidol when a phenothiazine is started or stopped.

Lamotrigine/Carbamazepine, OxcarbamazepineSignificance level 2: ModerateAdvice to the Practitioner: Concurrent use of lamotrigine

nd carbamazepine can result in a 40% decrease in lam-trigine steady state levels and a doubling of lamotriginelearance leading to a decreased pharmacologic effect ofamotrigine. Reduced lamotrigine efficacy can lead to theoss of seizure control and mood stabilization. The exactechanism is not known, but it maybe because of carbam-

zepine’s potent ability to induce CYP3A4 and other en-ymes in the liver accelerating the metabolism of lam-trigine. Loss of seizure control is more likely to occurhen the initial dose of carbamazepine is high and lam-trigine is added. Oxcarbamazepine has a less pronouncedffect on lamotrigine levels, but the effect is still significant.

Action: Monitor for loss of efficacy. May need toonsider increasing lamotrigine dose and/or decreasinghe carbamazepine/oxcarbamazepine dose.

Lamotrigine/PhenobarbitalSignificance level 2: ModerateAdvice to the Practitioner: The administration of pheno-

arbital significantly decreases the half-life of lamotrigineecause of its ability to induce hepatic enzymes. If a patients on lamotrigine and phenobarbital is added, an increase inamotrigine dose may be necessary. If a patient is on theombination and phenobarbital is discontinued, the lam-trigine dose may need to be decreased. If a patient is onoth drugs and well maintained, no action is necessary.

Action: Monitor for loss of seizure control and theeed to increase or decrease the lamotrigine dose. Whenatients are receiving concurrent therapy and the phe-obarbital dose is decreased or discontinued, monitoratients carefully for lamotrigine toxicity and the needo lower the lamotrigine dose.

Lamotrigine/Valproic AcidSignificance level 2: ModerateAdvice to the Practitioner: Concurrent use of lamotrigine

nd valproic acid can result in a 2-fold increase in theormal half life of lamotrigine with a significant rise inlasma concentrations. The mechanism of interaction is
ompetitive inhibition between lamotrigine and valproic f
cid for hepatic glucuronidation. In addition, use of valproiccid and lamotrigine may increase the risk of severe skineactions such as Stevens-Johnson Syndrome. When addingamotrigine to valproic acid, begin at a lower dose (25 mgod). Target doses are also lower (100-200 mg daily). Whendding valproic acid to lamotrigine, decreasing the lam-trigine dose by 50% has been recommended, and patientshould be monitored for any signs of skin rash.

Action: Use of a lower dose of lamotrigine with val-roic acid is recommended. Patients should contact theirealth care practitioner if a skin rash develops, andractitioners should be advised that the risk of severekin reactions is increased with combination therapy.

Lithium/AntipsychoticsSignificant level 2: ModerateAdvice to the Practitioner: When lithium has been added

o antipsychotic agents, encephalopathic symptoms haveccurred. In addition, weakness, dyskinesia and increasedPS, and brain damage have been reported. Some datauggest that lithium levels �0.5 mEq/L minimize this risk,owever, this has not been fully established. This interac-ion is not commonly seen, and lithium is frequently addedo many antipsychotic agents without any interaction. (Seelso Phenothiazines/Lithium.)

Action: When using lithium and clozapine together,onitor patient for weakness, EPS and encephalopathic

ymptoms.

Lithium/Monoamine Oxidase Inhibitors (MAOI)Significant level 1: MajorAdvice to the Practitioner: Co-administration of an

AOI and lithium may result in neuroleptic malignantyndrome (incoherent speech, reduced consciousness, mus-ular rigidity, nystagmas, hyperreflexia, diaphoresis, shiv-ring, and tremor). If the symptoms are not recognized andorrectly treated, death can result. The mechanism is un-nown.

Action: Combination of these 2 drugs should bevoided. Wait at least 2 weeks after discontinuing MAOIefore initiating therapy with lithium.

Lithium/Tricyclic Antidepressants (TCA)Significant level 2: ModerateAdvice to the Practitioner: The addition of lithium to

atients who are taking TCAs may result in neurotoxicitytremors, ataxia, and seizures) and worsening of the mania.he mechanism is not fully understood, but may be related

o the synergistic interaction between lithium and TCAsimipramine).

Action: Use this combination cautiously. Discontinueither lithium or the TCA if any interaction is suspected.erum lithium levels should be monitored periodicallynd adjust the dose periodically. The clinician may pre-
er to use other antidepressants, e.g., SSRI’s.

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Lithium/VerapamilSignificant level 2: ModerateAdvice to the Practitioner: Co-administration of lithium

nd verapamil may result in the decreased serum concen-ration of lithium that is associated with the worsening ofania. Neurotoxicity and bradycardia may occur when cal-

ium channel blockers are combined with lithium. Thisnteraction is because of the synergistic decrease of theransport of the calcium ion. If a patient is on lithium anderapamil is added, monitor for decreased lithium levels andhe dose of lithium may need to be increased. If verapamils taken away lithium dosage may need to be increased.

Action: Careful monitoring of lithium levels, signs ofania and symptoms of neurotoxicity, and bradycardia

s indicated when verapamil is added or discontinued toithium.

Loxapine/LorazepamSignificant level 2: ModerateAdvice to the Practitioner: Co-administration of loraz-

pam and loxapine may develop severe respiratory depres-ion, stupor and hypotension. The mechanism of action isnknown. If a patient is stabilized on the combination, noction is necessary.

Action: Careful monitoring of patients receiving lox-pine and lorazepam for excessive sedation and respira-ory depression is required.

Nefazodone/BenzodiazepinesSignificant level 2: ModerateAdvice to the Practitioner: Co-administration of nefaz-

done and alprazolam or triazolam may result in increasedlasma concentration of benzodiazepines that are associatedith impaired psychomotor performance and memory. Ne-

azodone inhibits the metabolism of above benzodiazepinesia CYP-450 3A4 isoenzyme. If a patient is stabilized on theombination, no action is necessary. If the patient is onlprazolam or triazolam and the nefazodone is added, in-reased benzodiazepines activity will be seen.

If a patient is on nefazodone and benzodiazepaines isdded, no action is necessary, as the dose of benzodiaz-pines should be determined by clinical efficacy.

Action: Monitor for signs of benzodiazepines efficacynd adjust dose as indicated above. Consider switchingo an unaffected benzodiazepine or, paroxetine may beonsidered as alternatives.

Nefazodone/Monoamine Oxidase Inhibitors (MAOI)Significant level 1: MajorAdvice to the Practitioner: Co-administration of MAOIs

nd nefazodone may result in CNS toxicity or serotoninyndrome, a hyperserotonergic state. If the symptoms areot recognized and correctly treated, death may result. Theechanism is secondary to inhibition of serotonin metabo-

ism by monoamine oxidase. t

Action: Combination of these 2 drugs should bevoided. Wait at least 2 weeks after discontinuing MAOIefore initiating therapy with nefazodone. Wait at leastweeks after discontinuing nefazodone before initiating

herapy with MAOI’s.

Nefazodone/PimozideSignificant level 1: MajorAdvice to the Practitioner: Nefazodone inhibits the me-

abolism of pimozide via the CYP-450 3A4 isoenzyme.o-administration of nefazodone and pimozide result in

ncreased plasma concentration of pimozide which haveeen associated with adverse cardiovascular effects includ-ng QT prolongation, cardiac arrhythmia, torsades deointes, and sudden death.

Action: Because of potential for significant life threat-ning, proarrhythmic effects, concurrent administrationf nefazodone and pimozide is contraindicated.

Nefazodone/Tricyclic Antidepressants (TCA)Significant level 1: MajorAdvice to the Practitioner: Co-administration of TCAs

nd nefazodone may result in serotonin syndrome, a hyper-erotonergic state. If the symptoms are not recognized andorrectly treated, death may result. The mechanism is be-ause of altered serotonin metabolism.

Action: Combination therapy should be avoided.ait at least 2 weeks after discontinuing TCA’s before

nitiating therapy with nefazodone. Wait at least 2 weeksfter discontinuing nefazodone before initiating therapyith TCA’s.

Olanzapine/FluvoxamineSignificance level 2: ModerateAdvice to the Practitioner: Concurrent use of olanzapine

nd fluvoxamine may cause an increase in olanzapine lev-ls. Fluvoxamine inhibits P450 1A2 isoenzyme that is par-ially responsible for olanzapine metabolism. Monitor forncreased olanzapine adverse reactions (tachycardia, ortho-tatic hypertension, seizures). If a patient is on olanzapinend fluvoxamine is added, monitor for increased olanzapineevels and the need to decrease the dose of olanzapine. If aatient is stabilized on the combination, no action is neces-ary. If a patient is on the combination and fluvoxamine isiscontinued, monitor for decreased olanzapine efficacy anddjust the dose as needed.

Action: Monitor for olanzapine efficacy and adjustose as needed.

Oxazepam/PhenobarbitalSignificance level 2: ModerateAdvice to the Practitioner: Concurrent use of oxazepam

nd phenobarbital results in a shortened elimination half-lifend higher clearance of oxazepam. The mechanism of ac-ion is enhanced activity of glycuronyl transferase activity.f phenobarbital is added to oxazepam it may be necessaryo increase the dose of oxazepam. If a patient is stabilized on
he combination no action is necessary.

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Action: Increased dosage of oxazepam may be neededf phenobarbital is added, or use an unaffected benzo-iazepine.

Paroxetine/NefazodoneSignificant level 1: MajorAdvice to the Practitioner: Co-administration of parox-

tine and nefazodone may result in CNS toxicity or seroto-in syndrome, a hyperserotonergic state characterized byymptoms such as restlessness, myoclonus, changes in men-al status, hyperreflexia, diaphoresis, shivering, and tremor.he mechanism is because of inhibition of serotonin re-ptake.

Action: Combination of these 2 drugs should bevoided. Wait at least 7 days after discontinuing nefaz-done before initiating therapy with paroxetine.

Phenobarbital/ClonazepamSignificance level 2: ModerateAdvice to the Practitioner: Concurrent use of phenobar-

ital and clonazepam decreases the steady state plasmaoncentration of clonazepam. If a patient is on a stabilizedose of both drugs, no action is necessary. When phenobar-ital is added to clonazepam there may be a loss of efficacynd a dosage adjustment may be needed. If phenobarbital isithdrawn from the combination there may be an increase

n clonazepam levels and side effects. Dose adjustment maye necessary. The addition of clonazepam to phenobarbitaloes not effect phenobarbital plasma concentrations.

Action: Monitor patients for decreased efficacy oflonazepam if phenobarbital is added and increasedlonazepam levels if phenobarbital is withdrawn. Dos-ge adjustments may be necessary.

Phenobarbital/HaloperidolSignificance level 2: ModerateAdvice to the Practitioner: Phenobarbital induces en-

yme stimulation that can significantly lower haloperidollood levels. When phenobarbital is added to haloperidol,atients experience a decrease in plasma concentrations.hen adding phenobarbital to haloperidol, patients should

e monitored for decreased efficacy and lower plasma levelsf haloperidol. The dose of haloperidol may need to bencreased when phenobarbital is given. When patients re-eive concurrent therapy and the dose of phenobarbital isecreased or discontinued, monitor patients for increasedaloperidol levels and the need for a decreased dose.

Action: Monitor patients for increased or decreasedaloperidol levels depending upon the addition or dis-ontinuation of phenobarbital.

Phenobarbital/Monoamine Oxidase Inhibitors (MAOI)Significance level 2: ModerateAdvice to the Practitioner: MAOIs may inhibit the me-

abolism of phenobarbital resulting in a prolonged effect ofhenobarbital. Hypotension, increased CNS and respiratoryffects may be observed. When an MAOI is added to phe-
obarbital, consider the need to decrease the phenobarbital n
ose. In patients receiving concurrent therapy, if the MAOIose is lowered or discontinued, consider increasing theose of phenobarbital.

Action: Monitor patients for increased or decreasedhenobarbital levels depending on the addition or dis-ontinuation of the MAOI.

Phenobarbital/ParoxetineSignificance level 3: MinorAdvice to the Practitioner: Phenobarbital induces hepatic

soenzymes that may decrease serum concentrations of par-xetine. If a patient is maintained on the combination ofhenobarbital with paroxetine, no action is necessary. Ifhenobarbital is added to paroxetine, monitor the patient forecreased paroxetine efficacy and the need to increase thearoxetine dose.

Action: Monitor paroxetine efficacy and adjust theose as indicated above.

Phenobarbital/ThioridazineSignificance level 2: ModerateAdvice to the Practitioner: Concomitant administration

as resulted in reports of decreased effectiveness of both phe-obarbital and thioridazine. In addition, phenobarbital mayecrease thioridazine levels because of the induction of hepaticnzymes. Patients should be monitored for decreased therapeu-ic effects for one or both drugs when adding one to the other.f a patient is maintained on the combination no action isecessary, but if one drug is discontinued the patient should beonitored for increase levels and adverse reactions.Action: Monitor patients for increased or decreased

rug effects of both drugs when changing therapy ordding either agent.

Phenobarbital/Tricyclic Antidepressants (TCA)Significance level 2:ModerateAdvice to the Practitioner: Tricyclic antidepressants have

een reported to reduce seizure threshold resulting in possibleoss of seizure control. When adding a TCA to phenobarbital,atients should be monitored closely for loss of seizure control.n increase in phenobarbital dose may be necessary. If a TCA

s discontinued from combination therapy, monitor patients forncreased phenobarbital adverse reactions and the need to de-rease the dose of phenobarbital. In combination, additive CNSnd respiratory depressant effects are also possible, resulting inhe need to adjust the dose of one or both drugs. It has beeneported that phenobarbital may stimulate the metabolism ofCA resulting in decreased serum levels of the TCA and their

herapeutic effectiveness. When adding phenobarbital to aCA, it may be necessary to increase the TCA dose to main-

ain therapeutic levels. If phenobarbital is discontinued fromombination therapy, it may be necessary to decrease the TCAose.

Action: Monitor patients for reduced seizure control,NS and respiratory depressant effects, and changes inCA levels and efficacy. Dosage adjustments may be
ecessary.

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Phenobarbital/Valproic AcidSignificance level 2:moderateAdvice to the Practitioner: Concomitant administration

f phenobarbital and valproic acid results in the inhibitionf phenobarbital metabolism and increased serum levels ofhenobarbital. Patients should be monitored for serum lev-ls and signs of phenobarbital toxicity. When adding val-roic acid to phenobarbital it may be necessary to decreasehe phenobarbital dose. If a patient is on the combinationnd valproic acid is discontinued phenobarbital levels mayecrease requiring a dose adjustment. Concurrent phenobar-ial and valproic acid therapy shortens the serum half-life ofalproate because of hepatic enzyme induction. This resultsn a 10% increase in valproic acid clearance.

Action: Monitor patients for changes in phenobarbi-al serum concentration when adding or discontinuingalproic acid. Concurrent use may also increases val-roic acid clearance. Adjust doses accordingly.

Phenobarbital/VerapamilSignificance level 3: MinorAdvice to the Practitioner: Concurrent use of oral phe-

obarbital resulted in a significant decrease in the concen-ration of verapamil. A possible mechanism is the increasen first pass hepatic metabolism of verapamil by phenobar-ital. If phenobarbital is added to verapamil, the amounts ofhe latter may need to be increased to maintain an optimumffect; and, a higher dose of verapamil may be requiredhen it is added to a patient currently taking phenobarbital.Action: An increase of dose of verapamil may be

equired in a previously stabilized patient when pheno-arital is added; the verapamil dose should be adjusteddecreased) when phenobarbital is withdrawn from theombination.

Phenothiazines/LithiumSignificant level 2: ModerateAdvice to the Practitioner: When lithium has been added

o antipsychotic agents, encephalopathic symptoms haveccurred. In addition, weakness, dyskinesia and increasedPS, and brain damage have been reported. Some datauggest that lithium levels �0.5 mEq/L minimize this risk,owever, this has not been fully established. This interac-ion is not commonly seen, and lithium is frequently addedo many antipsychotic agents without any interaction.

Action: When using lithium and a phenothiazine to-ether, monitor patient for weakness, EPS, and en-ephalopathic symptoms.

Phenothiazines/PimozideSignificant level 1: MajorAdvice to the Practitioner: Combination of a phenothi-

zine and pimozide is associated with adverse cardiovascu-ar effects including QT prolongation, cardiac arrythmia,orsades de pointes, and sudden death. This can be second-
ry to possible additive prolongation of the QTc interval. p
Action: The concurrent administration of a phenothi-zine and pimozide is contraindicated.

Phenothiazines/PropranololSignificant level 1: MajorAdvice to the Practitioner: Co-administration of pro-

ranolol and a phenothiazine may cause increased risk ofhenothiazinetoxicity, e.g., QT prologation, torsades deointes, cardiac arrest. The mechanism of action is a resultf the inhibition of phenothiazine metabolism via CYP450D6 isoenzyme.

Action: Concurrent administration of phenothiazinesnd propranolol is contraindicated because of potentialife-threatening cardiac arrythmias.

Phenothiazines/Selective Serotonin Reuptake Inhibi-ors (SSRI)

Significant level 2: ModerateAdvice to the Practitioner: Co-administration of phe-

othiazines and SSRIs results in increased phenothiazineslasma levels which may cause adverse effects, e.g., exces-ive sedation, extrapyramidal symptoms, impaired psy-homotor performance and memory. This is secondary tohe decreased metabolism of the phenothiazines via thenhibition of CYP450 2D6 isoenzyme. Not all SSRIs inhibitYP 2D6 to the same extent. If a patient is on a phenothi-zine and an SSRI is added, monitor for increased phenothi-zine levels and the need to decrease the dose of phenothi-zine. If a patient is on an SSRI and a phenothiazine isdded, no action is necessary, as the dose of the phenothi-zine will be determined by clinical efficacy.

Action: Carefully observe the clinical response whenn SSRI is used in combination with a phenothiazine asndicated above.

Phenothiazines/Tricyclic Antidepressants (TCA)Significant level 2: MildAdvice to the Practitioner: Co-administration of phe-

othiazines and TCAs may result in an increase in anticho-inergic effects (dry mouth, urinary retention, sedation).

Action: Careful monitoring of potential side effects isequired for patients receiving phenothiazines andCAs

Pimozide/Tricyclic Antidepressants (TCA)Significant level 1: MajorAdvice to the Practitioner: The concurrent administra-

ion of pimozide and tricyclic antidepressants results in thencreased risk of cardiotoxicity (QT prolongation, torsadese pointes, cardiac arrests). This is secondary to the additiveffects on QT interval.

Action: Concurrent administration of TCA andimozide is contraindicated.

Quetiapine/BarbiturateSignificant level 3: MinorAdvice to the Practitioner: Co-administration of quetia-

ine and barbiturate may result in decreased quetiapine

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erum concentrations. The mechanism of this drug interac-ion is unknown. If a patient is on the combination andtable, no action is required. Caution should be used whendding barbiturate as quetiapine efficacy can be decreased.hen adding quetiapine to barbiturate monitor for the clin-

cal effects of quetiapine.Action: When co-administering quetiapine and bar-

iturate, monitor patients for quetiapine efficacy. Anncrease in quetiapine dose may be necessary.

Quetiapine/CarbamazepineSignificant level 3: MinorAdvice to the Practitioner: Co-administration of quetia-

ine and carbamazepine may result in decreased quetiapineerum concentrations. The mechanism of this drug interac-ion is unknown. If a patient is on the combination andtable, no action is required. Caution should be used whendding carbamazepine as quetiapine efficacy can be de-reased. When adding quetiapine to carbamazepine monitoror the clinical effects of quetiapine.

Action: When co-administering quetiapine and car-amazepine, monitor patients for quetiapine efficacy.n increase in quetiapine dose may be necessary.

Quetiapine/LorazepamSignificance level 3: MinorAdvice to the Practitioner: Co-administration of quetia-

ine and lorazepam decreased the mean oral clearance oforazepam resulting in increased lorazepam serum con-entrations. The mechanism of this drug interaction isnknown. Caution should be used when adding quetiap-ne to lorazepam. If a patient is on the combinationnd stable, no action is required. When adding lorazepamo quetiapine monitor for the clinical efficacy of loraz-pam.

Action: When co-administering quetiapine and loraz-pam, monitor patients for excessive lorazepam adverseffects including sedation, dizziness, and ataxia.

Quetiapine/ThioridazineSignificance level 2: ModerateAdvice to the Practitioner: Co-administration of quetia-

ine and thioridazine increased the oral clearance ofuetiapine resulting in decreased quetiapine serum con-entrations, which is associated with its decreased effec-iveness. The mechanism of this drug interaction is un-nown. If a patient is on the combination and stable, noction is required. Caution should be used when addinghioridazine as quetiapine efficacy can be decreased.

hen adding quetiapine to thioridazine monitor for thelinical affects of quetiapine.

Action: When co-administering quetiapine and thio-idazine, monitor patients for quetiapine efficacy. Anncrease in quetiapine dose may be necessary.

Risperidone/Selective Serotonin Reuptake InhibitorsSSRI)

Significant level 2: Moderate m

Advice to the Practitioner: Co-administration of ris-eridone and an SSRI may result in serotonin syndromehypertension, hyperthermia, myoclonus, mentalhanges). The mechanism of this drug interaction is un-nown. Clinicians should be aware of the increased riskf serotonin syndrome in patients receiving potent sero-onergic agents.

Action: When co-administering an SSRI and risperi-one, monitor patients for excessive adverse effects likeerotonin toxicity. Alternative agents should be em-loyed if possible.

Risperidone/SSRIs—Fluvoxamine, FluoxetineSignificant level 2: ModerateAdvice to the Practitioner: Co-administration of risperi-

one and fluvoxamine or fluoxetine may increase serumoncentrations of risperidone. Fluvoxamine and fluoxetinenhibit cytochome P450 2D6 and 3A4, isoenzymes partiallyesponsible for risperidone metabolism. This may result inisperidone toxicity.

Action: Concurrent administration of risperidonend fluvoxamine or fluoxetine should be avoided.

Selegiline/Monoamine Oxidase-A Inhibitors (MAO-AI)Significance level 1: MajorAdvice to the Practitioner: Concurrent use of selegiline

a selective MAO-B inhibitor) and a monoamine oxidase-Anhibitor antidepressant is potentially hazardous and mayesult in synergistic pharmacologic effects leading toxcessive monoamine oxidase inhibition causing hyperten-ive crisis, fever, marked sweating, tremor, excitation, sei-ures, delirium, coma and circulatory collapse. This is par-icularly more likely to occur if the dose of selegilinexceeds 10 mg daily, above which dose the drug cannhibit the MAO-A enzyme and acts as a nonselective

AO inhibitor. If the patient is stable on the combination,o action is needed. Caution should be used, however,hen adding selegiline to an MAO-AI or an MAO-AI to

elegiline as both drugs potentiate inhibition of monoaminexidase.

Action: Closely monitor patients for adverse effects ofynergistic monoamine oxidase inhibition if concurrentse is necessary. Severe adverse interactions may occurhypertensive crisis, fever, marked sweating, tremor, ex-itation, seizures, delirium, coma, and circulatory col-apse).

Selegiline/Selective Serotonin Reuptake InhibitorsSSRI), nefazodone, venlafaxine, buspirone

Significance level 1: MajorAdvice to the Practitioner: Concurrent use of selegiline

a selective MAO-B inhibitor) and an SSRI or a serotoninffinity antidepressant is potentially hazardous and mayesult in synergistic pharmacologic effects leading toxcessive serotonergic stimulation causing serotonin syn-rome (hypertension, hyperthermia, myoclonus and
ental status changes). This is particularly more likely to

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ccur if the dose of selegiline exceeds 10 mg daily, abovehich dose the drug can inhibit the MAO-A enzyme andcts as a nonselective MAO inhibitor. If the patient istable on the combination, no action is needed. Cautionhould be used, however, when adding selegiline to an SSRIr an SSRI to selegiline as both drugs potentiate serotoninffects.

Action: Closely monitor patients for adverse serotoner-ic effects if concurrent use is necessary. Severe interac-ions—the serotonin syndrome could occur (hypertension,yperthermia, myoclonus, and mental status changes).

Selegiline/Tricyclic Antidepressants (TCA)Significance level 1: MajorAdvice to the Practitioner: Concurrent use of selegiline

a selective MAO-B inhibitor) and a TCA antidepressant isotentially hazardous and may result in synergistic pharma-ologic effects leading to excessive serotonergic stimulationausing the serotonin syndrome (hypertension, hyperther-ia, myoclonus and mental status changes). This is partic-larly more likely to occur if the dose of selegiline ex-eeds 10 mg daily, above which dose the drug can inhibithe MAO-A enzyme and acts as a nonselective MAOnhibitor. If the patient is stable on the combination, noction is needed. Caution should be used, however, whendding selegiline to a TCA or TCA to selegiline as bothrugs potentiate serotonin effects.

Action: Closely monitor patients for adverse seroto-ergic effects if concurrent use is necessary. Severe in-eractions—the serotonin syndrome could occur (hyper-ension, hyperthermia, myoclonus, and mental statushanges).

Selective Serotonin Reuptake Inhibitors (SSRI)/Lith-um

Significant level 1: MajorAdvice to the Practitioner: Concurrent use of lithium and

SRIs may increase lithium levels and cause neurotoxicity,erotonin syndrome, somnolence, and mania. The exactechanism is not known. Caution should be taken when

sing this combination. If a patient is stabilized on theombination, no action is necessary.

Action: Monitor signs of lithium toxicity with con-omitant therapy; dosage adjustment may be necessary.erum lithium levels should also be considered with theddition of an SSRI and periodically throughout ther-py to assure stability.

Selective Serotonin Reuptake Inhibitors (SSRI)/onoamine oxidase inhibitors (MAOI)Significant level 1: MajorAdvice to the Practitioner: Co-administration of an

AOI and an SSRI may result in CNS toxicity or serotoninyndrome, a hyperserotonergic state characterized by symp-oms such as restlessness, myoclonus, changes in mentaltatus, hyperreflexia, diaphoresis, shivering, and tremor. If
he symptoms are not recognized and correctly treated, a
eath may result. The mechanism is because of inhibition oferotonin metabolism by monoamine oxidase.

Action: Combination of these 2 drugs should bevoided. Wait at least 2 weeks after discontinuing MAOIefore initiating therapy with SSRIs. Wait at least 2eeks after discontinuing SSRIs before initiating ther-py with MAOI.

Selective Serotonin Reuptake Inhibitors (SSRI)/Pro-ranolol

Significant level 2: ModerateAdvice to the Practitioner: Co-administration of pro-

ranolol and some SSRIs (fluoxetine, fluvoxamine, sertra-ine) may significantly increase serum concentration of pro-ranolol levels. This is because of their inhibition ofropranolol metabolism via CYP2D6. Elevated propranololerum concentrations may be associated with an increasedisk of bradycardia and hypotension, and chest pain. If aatient is on propranolol and a SSRI is added, monitor forncreased propranolol levels and the need to decrease theose of propranolol. If a patient is on any one of the aboveamed SSRI’s and a propranolol is added, no action isecessary, as the dose of benzodiazepines should be deter-ined by clinical efficacy.Action: Carefully monitor heart rate and blood pres-

ure. The propranolol dose may need to be reduced ifradycardia or hypotension develop. Alternatively, usef atenolol, a �-blocker which does not undergo hepaticetabolism may be considered.

Tacrine/FluvoxamineSignificance level 3: MinorAdvice to the Practitioner: Two studies involving

ealthy volunteers and using a single dose of tacrine foundhat fluvoxamine inhibited the metabolism of tacrine caus-ng an increase in its plasma concentration and 3 of itsetabolites. The probable mechanism is inhibition of CYP

A2 isoenzymes by fluvoxamine.Action: Although the exact clinical implications of

his drug interaction are uncertain, patients receivingoncurrent tacrine and fluvoxamine should be moni-ored for excessive tacrine adverse effects (includingholinergic effects) and liver function tests monitoredor hepatotoxicity.

Tacrine/HaloperidolSignificance level 3: MinorAdvice to the Practitioner: Concurrent use of tacrine and

aloperidol has resulted in Parkinsonian syndrome in 2eparate case reports. The mechanism is thought to be aynergistic effect of these drugs resulting in an increase incetylcholine activity in the striatal region of the brain. Thedverse effects of akinesia, shuffling gait, masked facies,lurred speech, lead-pipe rigidity, and/or cogwheel signs arehought to be caused by this increase in acetylcholine ac-ivity. If patients are on the combination and stable, no
ction is necessary. As both drugs increase acetylcholine

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Action: Monitor patients closely for the signs andymptoms of Parkinsonian syndrome when adding ei-her tacrine to haloperidol or haloperidol to tacrine.

Trazodone/Barbiturate and other sedativesSignificant level 3: MinorAdvice to the Practitioner: Co-administration of traz-

done and sedatives resulting in sedative potentiation. Theechanism of this drug interaction is unknown. If a patient

s on the combination and stable, no action is required.aution should be used when adding barbiturates to traz-done.

Action: The dose of barbiturates should be reducedhen co-administered with trazodone.

Trazodone/HaloperidolSignificant level 2: ModerateAdvice to the Practitioner: Co-administration of traz-

done and haloperidol may result in an increase level of thective metabolite of trazodone, m-chlorophenylpiperazinem-CPP). The interaction is a result of the inhibition ofYP450 2D6 metabolism of m-CPP by haloperidol. If pa-

ient is on trazodone and haloperidol is added the dosage ofhe former may be decreased. If haloperidol is discontinued,he latter’s dosage may need to be increased. The addition ofrazodone to haloperidol does not change its plasma con-entration.

Action: Careful monitoring of m-CPP level is sug-ested.

Trazodone/Selective Serotonin Reuptake InhibitorsSSRI)

Significant level 2: ModerateAdvice to the Practitioner: Co-administration of traz-

done and an SSRI may increase the plasma concentrationf trazodone. The mechanism of this drug interaction isossibly because of inhibition of the hepatic metabolism ofrazodone. There is also a possibility of serotonin syndrome.razodone probably should be used with caution in patients

eceiving any SSRI or other serotonergic agent.Action: Trazodone plasma levels should be monitored

hen it is added to an SSRI. Patients should be moni-ored for clinical signs and symptoms of serotonin syn-rome.

Tricyclic Antidepressants (TCA)/BupropionSignificant level 2: ModerateAdvice to the Practitioner: Bupropion causes increase

lasma concentration of TCAs, producing an increase inharmacologic and adverse effects. This is because of thenhibition of TCA metabolism by bupropion via CYT P450D6 isoenzyme. If a patient is on TCA and bupropion isdded, serum concentrations of the TCA may be increased.f a patient is on bupropion and a TCA is added, no action
s necessary, as the dose of TCAs should be determined by b
he clinical efficacy. If the patient is stabilized on thisombination, no action is required.

Action: Patient should be observed for clinical re-ponse of TCAs when bupropion therapy is started ortopped.

Tricyclic Antidepressants (TCA)/Monoamine Oxi-ase Inhibitors (MAOI)

Significant level 1: MajorAdvice to the Practitioner: Co-administration of MAOI

nd TCAs may result in CNS toxicity or serotonin syn-rome, a hyperserotonergic state characterized by symp-oms such as restlessness, myoclonus, changes in mentaltatus, hyperreflexia, diaphoresis, shivering, and tremor. Ifhe symptoms are not recognized and correctly treated,eath may result. The mechanism is from altered catechol-mine uptake and metabolism.

Action: Combination of these 2 drugs should bevoided. Wait at least 2 weeks after discontinuing anAOI before initiating therapy with TCA’s. Wait at

east 2 weeks after discontinuing TCA’s before initiatingherapy with an MAOI.

Tricyclic Antidepressants (TCA)/Selective Serotonineuptake Inhibitors (SSRI)Significance level 2: ModerateAdvice to the Practitioner: Concurrent use of a TCA and

SRI can significantly increase the plasma levels of theCA. Elevated nortriptyline levels can lead to increasedigns of nortriptyline toxicity (urinary retention, dry mouth,edation). Most SSRIs are inhibitors of the cyctochrome450 2D6 leading to increased nortriptyline levels. Fluox-tine and paroxetine are potent inhibitors of P450 2D6,ertraline to a lesser degree. When a SSRI inhibitor thatignificantly inhibits 2D6 is added to a TCA, monitor forCA toxicity and the need to decrease the TCA dose. Whendministered together and the SSRI is discontinued, monitoror decreased plasma TCA levels and the need to increasehe TCA dose. Plasma concentrations of the TCA should beonitored. No action is necessary, if the patient is alreadyaintained successfully on the 2 drugs.Action: Monitor tricyclic blood levels, for signs of

CA toxicity or decreased TCA efficacy when adding oriscontinuing a SSRI regimen. Consider a dosage ad-ustment.

Valproic acid/Benzodiazepines (Diazepam, Loraz-pam)

Significant level 3: MinorAdvice to the Practitioner: Co-administration of valproic

cid and diazepam or lorazepam may result in increasedenzodiazepine effects. It is thought that metabolism oforazepam is inhibited by valproic acid, and that diazepams displaced from its protein binding sites by valproic acid.f a patient is on valproic acid and lorazepam or diazepamre added, there is no need to alter therapy as the dose of the
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Action: Monitor for signs of excessive sedation whendded valproic acid to lorazepam or diazepam. Use of anlternative benzodiazepine may also be considered.

Valproic Acid (VPA)/CarbamazapineSignificant level 2: ModerateAdvice to the Practitioner: Co-administration of carbam-

zepine (CBZ) and VPA will increase the clearance ofalproic acid and decrease VPA levels. Valproic acid mayncrease the concentration of the active metabolite of CBZ,hich may result in toxicity, e.g., ataxia, nystagmus, dip-

opia, headache, seizure, coma. In addition, valproic acidisplaces carbamazepine from its protein binding site. If aatient is on carbamazepine and valproic acid is added,onitor for increased levels of the active metabolite of

arbamazepineand for signs and symptoms of toxicity. If aatient is on valproic acid and carbamazepine is added,onitor valproic acid levels and increase the dose of val-

roic acid as needed.Action: Carefully monitor both valproic acid and

arbamazepine serum concentrations when using theombination.

Venlafaxine/BupropionSignificant level 3: MinorAdvice to the Practitioner: Co-administration of bupro-

ion and venlafaxine may result in increased velafaxineevels.

Action: Patients receiving venlafaxine and bupropionhould be monitored for velafaxine toxicities.

Venlafaxine/Monoamine Oxidase Inhibitors (MAOI)Significant level 1: MajorAdvice to the Practitioner: Co-administration of MAOI

nd venlafaxine may result in CNS toxicity or serotoninyndrome, a hyperserotonergic state characterized by symp-oms such as restlessness, myoclonus, changes in mentaltatus, hyperreflexia, diaphoresis, shivering, and tremor. Ifhe symptoms are not recognized and correctly treated,eath may result. The mechanism is from the inhibition oferotonin metabolism by monoamine oxidase.

Action: Combination of these 2 drugs should bevoided. Wait at least 2 weeks after discontinuing anAOI before initiating therapy with venlafaxine. Wait

t least 2 weeks after discontinuing venlafaxine beforenitiating therapy with an MAOI.

Venlafaxine/Selective Serotonin Reuptake InhibitorsSSRIs)

Significant level 1: MajorAdvice to the Practitioner: Co-administration of an SSRI

nd venlafaxine may result in CNS toxicity or serotoninyndrome. If the symptoms are not recognized and correctlyreated, death may result. The mechanism is from altered
erotonin metabolism. t
Action: Combination of these 2 drugs should bevoided. Wait at least 2 weeks after discontinuing aSRI before initiating therapy with venlafaxine. Wait at

east 2 weeks after discontinuing venlafaxine before ini-iating therapy with a SSRI.

Venlafaxine/PhenobarbitalSignificant level 2: ModerateAdvice to the Practitioner: Co-administration of ven-

afaxine and phenobarbital may result in the decreased ven-afaxine serum concentrations and thereby may reduce itsfficacy. The mechanism is from the phenobarbital’s en-ancing metabolism of venlafaxine via CYT P45 2D6soenzyme.

Action: Careful monitoring of venlafaxine efficacyhould be measured when this combination is used. Dosedjustment is necessary when Phenobarbital is added tor withdrawn from the combination.

Venlafaxine/PhenothiazinesSignificant level 2: ModerateAdvice to the Practitioner: Co-administration of a phe-

othiazine and venlafaxine may cause neuroleptic malig-ant syndrome (profuse sweating, anxiety, tremor, rigidity,nd hypertention). This is because of dopamine-inhibitionffect of venlafaxine that augments dopamine-receptor in-ibition by phenothiazines.

Action: Monitor patients receiving venlafaxine and ahenothiazine regarding neuroleptic malignant syn-rome, which can be manifested as profuse sweating,

ncreased heart rate, tremor, rigidity, and increasedlood pressure.

Venlafaxine/Tricyclic Antidepressants (TCA)Significant level 1: MajorAdvice to the Practitioner: Co-administration of a TCA

nd venlafaxine may precipitate the serotonin syndrome anday cause increase concentration of both amitriptyline and

enlafaxine. Venlafaxine is a weak inhibitor of CYP2D6, inddition to being metabolized by this enzyme and TCA isetabolized by CYP2D6 isoenzyme as well. Both agents

ompetitively inhibit the metabolism of each others andoth are serotonergic.

Action: Monitor patients receiving concurrent TCAsnd venlafaxine for signs of TCA toxicity and venlafax-ne toxicity. Doses of either or both drugs may need to beeduced.

Verapamil/�-blockersSignificant level 2: ModerateAdvice to the Practitioner: �-blockers and verapamil

ave negative inotropic effects, slow AV conduction,nd potentiate hypotention, bradycardia, congestiveeart failure, and conduction abnormalities. This is sec-ndary to decreased metabolism of beta blockers thatesults in deleterious cardiac effects. These agents aresed together frequently for the management of hyper-
ension.

s

acta

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Action: Combination of verapamil and beta blockershould be done cautiously.

Ziprasidone/PimozideSignificant level 1: MajorAdvice to the Practitioner: Combination of ziprasidone

nd pimozide have been associated with adverse cardiovas-ular effects including QT prolongation, cardiac arrhythmia,orsades de pointes, and sudden death. This can be second-ry to possible additive prolongation of the QTc interval.

Action: Concurrent administration of ziprasidonend pimozide is contraindicated.

eferences

[1] Strain JJ, Caliendo G, Alexis JD, Lowe RS, Karim A, Loigman M.Part II: Cardiac drug and psychotropic drug interactions: significanceand recommendations. Gen Hosp Psychiatry 1999;21:408–29.

[2] Hansten PD, Horn JR, Koda-Kimble MA, Young LY, eds. Drug

Interactions and Analysis and Management. Facts and Comparisons.St. Louis, MO: Quarterly Update, 2000.

[3] Tatro DS, ed. Drug Interaction Facts. St Louis: Facts and Compari-sons, Quarterly Update, 1999.

[4] Micromedex Drugdex, Micromedex, Vol. 97. Englewood, NJ, 2000.[5] McEvoy GK, ed. American Hospital Formulary Service Drug Infor-

mation. Bethesda, MD: American Society of Health System Pharma-cists, 2000.

[6] Goldman LS. Interact: psychotropic drug interactions. Washington,DC: American Psychiatric Press Inc., 1999.

[7] ePocrates Rx, Clinical Drug Database. Copyright epocrates Inc.http://www. jobs@ePocrates, 2000.

[8] Strain JJ, Chiu NM, Brodsky M, Karim A. Comparison of threemethods for identifying medical drug—psychotropic drug interac-tions. Gen Hosp Psychiatry 2002;24:311–316.

[9] Glenmullen J. Prozac backlash. New York: Simon and Schuster,2000.

10] Lieberman J. Treating psychotic disorders: what is the state of the art?New Orleans, LA: American Psychiatric Association Annual Meet-ing, May, 2001.

11] Rosebraught CJ, Honig PK, Yasuda SU, et al. Clin Pharmacol Ther-apeutics 2002;71(1):4-10.

12] Drug makers go to war over side-effect claims. Psychiatric News,August 2001.

Documents

Psychotropic drug versus psychotropic drug—update