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IntroductionA drug-drug interaction (DDI) occurs

when the presence of a coprescribeddrug (the perpetrator) alters the nature,magnitude, or duration of the effect of agiven dose of another drug (the victim).“Altered nature” means that the effectproduced when the two drugs are usedtogether is qualitatively different thanwould be expected when either drug is

used alone. An example is serotoninsyndrome, which consists of markedautonomic instability and can be fatal.This syndrome can occur when a sero-tonin uptake pump inhibitor is used incombination with a monoamine oxi-dase inhibitor (MAOI).1 “Altered magni-tude,” on the other hand, means that thenature of the effect is the same as can bereasonably expected from the victim

drug alone but is either more than orless than what would normally beexpected for the specific dose ingested.“Altered duration” means that thenature of the effect is reasonably thesame as can be expected from the victimdrug alone, but the effect either is short-er or longer lived than would normallybe expected for the dose given.

The goal of this guide is to provide aquick reference for prescribers aboutsome of the major psychiatric DDIs.Furthermore, it presents general con-cepts which can aid prescribers inavoiding untoward DDIs when possibleand quickly recognizing them whenthey occur. This way, corrective stepscan be instituted to minimize the conse-quences. This guide is not intended tobe comprehensive or authoritative.Given the speed with which new drugsare entering the market and new discov-eries about the mechanisms underlyingDDIs are being made, the authors rec-ognize that this educational review, likeall printed material on this topic, willquickly become dated. The authors haveaddressed some of these limitations byproviding the reader with a list of Websites that are more comprehensive andcontinuously updated (Appendices Iand II). This general guide provides anintroduction to the topic and serves as agateway to ready sources of additionalinformation via the Internet.

Both authors maintain Web sites rele-vant to DDIs. Dr. Flockhart’s Web site2

summarizes data on cytochrome P450(CYP) enzymes and the drugs theymetabolize and outlines which drugsinhibit or induce CYP enzymes. Thisinformation can be used to predict andavoid DDIs mediated by this mecha-nism. Dr. Preskorn’s Web site3 providescontent on topics relevant to the

2004 GuidetoPsychiatric Drug InteractionsSheldon H. Preskorn, MD, and David Flockhart, MD, PhD

Dr. Preskorn is professor and chair of the Department of Psychiatry and Behavioral Sciences at the University of Kansas School of Medicine in Wichita.

Dr. Flockhart is professor of medicine, genetics, and pharmacology, and is chief of the Division of Clinical Pharmacology in Wishard Hospital at the IndianaUniversity School of Medicine in Indianapolis.

Disclosure: Dr. Preskorn is a consultant to Abbott, AstraZeneca, Biovail, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, Merck, Organon,Pfizer, Solvay, Somerset, Sumitomo, Wyeth, and Yamanouchi; has served on the speaker’s bureaus of Bristol-Myers Squibb, GlaxoSmithKline, Organon, Pfizer, andWyeth; and has received research support/grants from Aventis, Biovail, Boehringer-Ingelheim, Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Janssen, Lundbeck, E.Merck, Neurosearch, Novartis, Organon, Otsuka, Pfizer, Roche, Solvay, Somerset, and Wyeth. Dr. Flockhart received a research grant from the National Institute ofGeneral Medical Sciences.

Please direct all correspondence to: Sheldon H. Preskorn, MD, University of Kansas School of Medicine, 1010 North Kansas, Witchita, KA 67214; Tel: 316-293-2669;Fax: 316-293-1874; E-mail: [email protected].

Educational ReviewPrimary Psychiatry. 2004;11(2):39-60

39Primary Psychiatry, February 2004

AbstractWhy should physicians be concerned about drug-drug interactions (DDIs)? DDIs

have the potential for causing untoward outcomes, including morbidity and evenmortality for the patient, liability for the prescriber, and increased costs for the health-care system. The risk of unintended and untoward DDIs is increasing in concert withboth the increasing number of pharmaceuticals available and the number of patientson multiple medications. A recent survey found that 10% of all Americans >18 yearsof age were taking five or more prescription medications. Additional studies havefound that patients on psychiatric medications, such as antidepressants, are on moremedications than patients not on psychiatric medication. In addition, medicationsinteract not on the basis of their therapeutic use but on the basis of their pharmaco-dynamics and pharmacokinetics. For these reasons, the prescriber of psychiatric med-ications must consider all of the medications the patient is taking. This educationalreview discusses major pharmacologic principles to guide the safe and effective use ofmultiple medications with a focus on neuropsychiatric medications. It also presentstables outlining major pharmacodynamic and pharmacokinetic mechanisms mediat-ing DDIs relevant to the patient on psychiatric medications.

Focus Points• In a drug-drug interaction (DDI), the presence of a second drug alters the

nature, magnitude, or duration of the effect of a given dose of a first drug.These interactions can be therapeutic or adverse, planned or unintended,but are always determined by the pharmacodynamics and pharmacokinet-ics of the drugs involved rather than their therapeutic indication.

• The risk of unintended and untoward DDIs is increasing in concert withboth the increasing number of pharmaceuticals available and the number ofpatients on multiple medications.

• To avoid adverse DDIs, the prescriber must keep in mind fundamental prin-ciples of pharmacology and good clinical management.

• The prescriber must know all of the medications that the patient is takingand be able to use available knowledge about their pharmacodynamic andpharmacokinetic mechanisms to minimize the risk of untoward DDIs.

Available in Pocket

Reference Format

—pg. 59

safe and effective use of psychiatricmedications. For example, under“Columns, Section 1: Polypharmacology,”Dr. Preskorn presents and discusses reallife case examples of how DDIs presentclinically and the mechanisms responsi-ble for the DDI.4 The authors will refer tothese and other Web sites as a referencefor the reader who wants a more extend-ed discussion of a topic or for those whowant to check for updates after this guidehas been published.

This guide has several other limita-tions, starting with the one imposed byits title: drugs do not interact on thebasis of their therapeutic area (eg, psy-chiatric medications) but instead on thebasis of their pharmacodynamics (ie,their action on the body) and their phar-macokinetics (ie, the actions of the bodyon them, including their absorptionfrom the site of administration, theirdistribution in the body, their metabo-lism, and their elimination).5 For thisreason, the authors acknowledge thelimitations inherent in focusing on ther-apeutic class—even one as broad as psy-chiatric or neuropsychiatric medica-tions. In fact, the authors will reclassifythe drugs principally covered in thisguide into other functional classesbased on their pharmacodynamics andpharmacokinetics, such as CYP enzymesubstrates, inducers, and inhibitors. Thereason for taking this approach is thatthose are mechanisms relevant to clini-cally significant DDIs.

While the focus of this review is prin-cipally on neuropsychiatric medica-tions, the authors will also address theeffects of psychiatric on nonpsychiatricmedications and vice versa whereappropriate when covering DDIs. Theseare most important for the prescriberwho treats patients with conditionsbroadly defined as psychiatric illnesses.With these caveats, this guide will focuson neuropsychiatric medications.

This guide will first review the scopeof the problem, discuss strategies andapproaches to avoiding untoward andunintended DDIs, and then presentsummary figures and tables highlight-ing major DDIs involving psychiatricmedications.

Polypharmacy:The Real Landscape ofClinical Prescribing

Over the last 15 years, prescribers ofpsychiatric medications have been

blessed with an ever-expanding array ofoptions to treat a wide variety of psychi-atric maladies. The explosion in psychi-atric medications began with the intro-duction of fluoxetine (Prozac) in 19886

and is likely to continue and even accel-erate in the future as a result of thehuman genome project and the charac-terization of novel therapeutic targets inthe human brain.

While a blessing in many ways, thisdevelopment poses serious challengesfor practitioners trying to keep abreastof new developments. The prescriberhas more therapeutic options, each withdifferent pharmacodynamics and phar-macokinetics, to understand and weigh.

Over the last several decades, treat-ment has moved from a focus on time-limited therapy (ie, a few weeks) of anacute illness (eg, antibiotics for anacute infection) to preventive or main-tenance therapy for chronic illnessesas diverse as major depressive disorder(MDD), schizophrenia, Alzheimer’sdisease, hypertension, human immun-odeficiency virus infection, and ather-osclerosis. As a result of this change infocus, patients are more likely to be onmore than one medication at the sametime.7-10 In fact, they are likely to accu-mulate preventive therapy as they age,which can often continue for manymonths or years, to perhaps the entireremaining lifespan of the individualonce started. As a result, the potentialfor DDIs increases over the lifespan ofthe individual.

In addition to the above general prin-ciple, patients with psychiatric illnessessuch as MDD are frequently on multipleother medications for a variety of rea-sons, regardless of whether they arebeing seen by a psychiatrist or anothertype of healthcare provider (Table 1).3,11

There are undoubtedly numerous rea-sons for this phenomenon. First, psychi-atric illnesses such as MDD have anincreased frequency in patients withother medical illnesses (Figure 1).12-16

Second, patients with one psychiatricillness are at increased risk for otherpsychiatric disorders.17 Third, patientswith depressive and anxiety disordersare high utilizers of healthcare servicesand thus may be treated symptomatical-ly with other medications.15,18-23

These factors likely help explain whyin 1989 patients seeing a psychiatristwere six times more likely to be on mul-tiple psychiatric medications, compared

with patients seeing a primary carephysician.24 The use of multiple psychi-atric medications has also increased infavor over the last 2 decades, reflectingboth the increased availability of effec-tive medications and the fact that theyhave a more focused pharmacology. Thelatter leads to better tolerability but mayalso limit efficacy and thus require theuse of more medications to optimizepatient outcomes. The use of multiplepsychiatric medications to treat patientsis on the rise; there was a 15-foldincrease in percentage of patients onthree or more psychiatric medicationsbeing seen at the Biological PsychiatryBranch of the National Institute ofMental Health from the early 1970s tothe mid 1990s (Figure 2).25

For all of the above reasons, patientson psychiatric medications are at riskfor DDIs and these DDIs are likely toinvolve more than just two drugs. Thus,the problem may not just be the effect ofdrug A on drug B but this effect in thepresence of drugs C and D as well.

To underscore the complexity of suchDDIs, consider the following questions,which help to illustrate the size of theproblem: (1) In 2003, how many dis-crete chemical entities could a physicianprescribe for his/her patient? (2) Giventhe number of drugs, how many differ-ent combinations (up to five drugs)could the physician prescribe for his/herpatient? (3) The first new drug approvedin 2003 could be prescribed in howmany different combinations (up to fivedrugs), given the number of drugsalready on the market when that newdrug is introduced? (4) On average, howmany new drugs have been introducedto the United States market every yearover the last 3 years?

The answers are: (1) >3,200 differentdrugs; (2) 2.8 x 1015; (3) 4.4 trillion; and (4)approximately 18, or one every 3 weeks.

To further put the numbers in per-spective, consider that 10% of allAmericans >18 years of age were takingfive or more prescription drugs in thelast week. These numbers provide aframe of reference which explains whyunderstanding and minimizing the riskof untoward and unintended DDIs isimportant and daunting.

Drug Interactions andMedication Errors

Given the above numbers, DDIs are,not surprisingly, a serious cause of con-

S.H. Preskorn, D. Flockhart

40 Primary Psychiatry, February 2004

cern for the US healthcare system. Theyare so numerous that the dictum to “dono harm” is seriously challenged. Asillustrated by the answers to the ques-tions above, this situation is in part dueto the large number of new prescriptiondrugs available to prescribers. For med-ical students who graduated from med-ical school in 2001, 115 new prescrip-tion drugs had been approved by theFood and Drug Administration duringthe time they were in medical school.26

In contrast, students graduating in 1973had to contend with only 57 new drugsbeing approved during their four yearsof medical school.26 The number ofdrugs available over the counter hasalso increased.

An ignorance of important interac-tions threatens trust in physicians andother prescribers. As the number of pre-scribed medications has increased overthe past 20 years, so have the number ofpossible interactions between therapies.These interactions have increased to thepoint where prescribers universally findit impossible to remember all conceiv-able interactions and are forced to relyon electronic media. From 7,000 to asmany as 98,000 deaths are caused byadverse drug events each year, more thanthose caused by smoke inhalation or air-plane accidents, causes of death forwhich the US has generated elaborate,nationwide safety control systems.27

In the same way as it is important todevelop some understanding of why firesoccur and the characteristics of fatal air-plane accidents, the importance to thepublic health of a mechanistic under-standing of adverse drug events, and of asystem to prevent them, cannot beunderstated. DDIs are not the entirecause of adverse drug events, but they area significant contributor, as indicated bythe number of medicines withdrawnfrom the market due to drug interactionsin the last 6 years, and by a growingnumber of significant interactions thatresult from co-medication with herbalnutritional supplements, a market onwhich the US spends more than they doon prescription medicines.28

Lastly, the population is aging. It hasbeen clear for many years that adverseevents experienced by the elderly aremarkedly increased in those who takemore than four medications at once.29

The authors will attempt herein todescribe the principal mechanisms bywhich important DDIs with neuropsychi-

atric drugs occur, and to list those thatare most likely to occur and result in clin-ically significant changes in drug activity.

The convergence of these multiplecomplicating influences makes clearthat the simple medication history thatall physicians are taught to take, consist-ing of the question “What medicationsdo you take and do you have any allergies to drugs?” has not evolved toaccommodate the complexity of these con-cerns. Therefore, the authors have pro-posed a more detailed series of questionsusing the acronym “AVOID” (Table 2).

DDIs are of paramount importance tohealth professionals who practice in thepharmaceutical industry. This is becausethe number of prescription medicinesthat were initially approved by the FDAas safe and effective but which then hadto be removed from the market due tounacceptable DDIs, including terfena-dine, cisapride, astemizole, mibefradil,and, most recently, cerivastatin, is con-siderable.30 The financial impact of suchwithdrawals on companies conservative-ly involves billions of dollars, but theharm to patients may also be substan-tial, especially if, as in the case of theantihistamines, the drug is taken with arelatively minor health complaint andpatients do not expect that they areassuming a risk of sudden cardiac deathby treating their allergies.31

Strategies to MinimizeAdverse Outcomes From Unintended DDIsA Personal Formulary:Concept and Criteria

The value of a personal formulary inan era of polypharmacy and pervasiveand potent marketing cannot beoveremphasized. Although all physi-cians are taught pharmacology in med-ical school, it is clear to anyone who hasbeen out of medical school for >5 yearsthat many, if not most, of the drugs thatare commonly prescribed today werenot available during their training. A personal formulary is the central toolof any prescriber’s armamentarium.Such a formulary should consist of thedrugs that are used virtually every day inthe clinician’s practice; rational prescrib-ing in an era when so many drugs areavailable is close to impossible without it.

A personal formulary basically con-sists of a list of drugs that a particularphysician is intimately familiar with.Inevitably, this list cannot be a large

number of drugs. For the drugs intheir personal formulary, the physicianshould be familiar with generic andbrand names, pharmacokinetics, phar-macodynamics, adverse effects, andpotential DDIs. The physician shouldtruly be an expert on a small numberof medications that he or she usescommonly. A high level of knowledgeabout a few drugs insulates the physi-cian against trivial advertising andprotects one’s patients from prescrib-ing errors. The number of drugs in apersonal formulary will vary, but it isgenerally reasonable for a practicingpsychiatrist, family practitioner, orinternist to have 10–15 such drugs asthe core of his or her personal formu-lary. The essential elements of knowl-edge that the physicians should knowabout each drug in their personal for-mulary is listed in Table 3.

It should not be easy for a drug toenter a personal formulary. Diligentstudy of the drugs in question, carefulevaluation of the literature pertaining tothem, and ongoing checks of new devel-opments should be a routine habit. Ifnothing else, these criteria allow theprescriber a means of focusing his orher attention within the sea of the med-ical literature. Thus, physicians becomereal experts in the use of a small numberof drugs important to their practice. Inthe 21st century, it is not enough to bean excellent diagnostician familiar withthe use of laboratory and proceduraltesting: being expert in treatment is alsorequired, and that requires an intimateknowledge not of all drugs available, butof 10–15 that are commonly used. Thisfoundation of knowledge can then serveas a basis for the evaluation of newdrugs as they appear.Generic Names

At a minimum, a prescriber shouldbe aware of the generic name of a med-ication on their personal formulary,without which it is impossible to searchthe medical literature on it or to recog-nize it on a board exam. As medicinebecomes more international and theworld becomes smaller, the physicianmust be aware that medications havedifferent brand names in differentcountries, and the brand name used inthe US may not be the same as thatused elsewhere (Table 4).32 The use ofthe generic name in prescriptionsallows cheaper generic drugs to be usedwhen they are available. Despite claims

2004 Guide to Psychiatric Drug Interactions


to the contrary, there are only a smallnumber of examples where anapproved generic is not an effectivesubstitute for the brand name drug.

Lastly, persistent confusion over thesimilarity of drug names, either written orspoken, accounts for approximately 25%of all reports to the US PharmacopeiaMedication Errors Reporting Program,and the case for the use of both a genericname and brand name in legible hand-writing on prescriptions is strong. Forexample, confusion has been reportedbetween the antidepressant nefazodone(Serzone) and the antipsychotic quetiap-ine (Seroquel), both of which are avail-able as 100 mg and 200 mg tablets. Theantidepressant paroxetine (Paxil) hasbeen confused with the antiplatelet agentclopidogrel (Plavix).

A list of generic names of psychiatricdrugs used in the US and their brandnames is included in Table 5.33 Althoughmany have made the case that a switchto e-prescribing may obviate this prob-lem, incorrect selection of a drug namefrom a computerized list has alreadybeen shown to be a significant problem;thus there is one more argument makingthe case for routinely using both thegeneric and the brand names as a meansof ensuring quality in prescribing.Adverse Effects

While a large number of possibleadverse effects of any drug may be listedin the label that is available in thePhysicians’ Desk Reference,34 relativelyfew matter to an individual patient. Theprescribing physician is in a uniqueposition to assess which adverse effectsare relevant to which patient throughcareful consideration of both the patientand the medication in question. No oneelse is in this position and many patientsurveys over the years clearly show thatpatients much prefer that their physi-cian acquaint them with the benefitsand side effects of drugs that the physi-cian prescribes.35 That is not to say thatpharmacists and nurses are not alsoimportant to the prescribing process,but instead that physicians have a cen-tral role in the prescribing process thatthey must recognize. Patients expectphysicians to educate them about theirmedications, and greatly appreciatewhen a physician takes time to explainthe side effects of a medicine they haveprescribed.Pharmacokinetics

Prescribers should be aware of the rou-

tinely used doses and the serum half-lifeof the drugs they frequently use. In thecase of psychiatric drugs, they shouldalso be aware of the mechanism ofaction, and of the potency of interactionwith specific receptors (Tables 5–8). Thisbasic information can guide prescribingin a number of valuable ways, particular-ly by making prescribers aware of thepotential DDIs and consequences.

The Therapeutic AllianceA therapeutic alliance is a group of

people who communicate with eachother about an individual patient’s ther-apeutic plan and medications. Even thehighest quality of prescribing cannotpossibly work well if patients are non-compliant, but patients often need helpin maintaining adherence with whatcan be a demanding medication sched-ule. To this end, a therapeutic allianceinvolving the patient and the peoplearound them is nearly always valuable.Family members should often be part ofthe therapeutic alliance, as well as thepharmacist, nurse practitioner, homehealth visitors, and friends (whenappropriate). A system of prescribing, inwhich members of the therapeuticalliance are identified early in a patient’stherapeutic plan and then involved inthe follow-up, is as important as thevaluable practice of routine checks bytelephone or e-mail within a few daysafter a drug is prescribed.

Establishment of aTherapeutic Goal

Any prescription should have a cleartherapeutic goal. It might be reducing aserum low-density lipoprotein or bloodpressure or relieving depression, butregardless of the goal, a clear timeexpectation should be attached to it. Forexample, in the “Plan” section of a med-ical chart, an appropriate entry wouldbe: “Reduction of depressive symptomsby 50% within 3–4 weeks.” The settingof goals is important because it allowsthe iterative optimization of therapy: ifthe goal is not achieved, then it is rea-sonable to have a conversation with thepatient about compliance and sideeffects. The same applies to the treat-ment of psychiatric disorders other thandepressive disorders, as well as nonpsy-chiatric medical illness. Therapeuticgoals should be clearly delineated incharts and communicated to patientsand the care providers that are involved

with each patient.

Conceptual Frameworkfor Prescribing in anEra of PolypharmacyPrinciples of Pharmacology

A DDI occurs when the presence of acoprescribed drug (the perpetrator)alters the nature, magnitude, or dura-tion of the effect of a given dose ofanother drug (the victim). Given thisdefinition, DDIs can clearly be thera-peutic or adverse, intended or unintend-ed, but they are always determined bythe pharmacodynamics and pharmaco-kinetics of the coprescribed drugs.When one drug is used to treat anadverse effect or to boost the therapeu-tic benefit of another drug, the pre-scriber wittingly or unwittingly is maycause therapeutic DDI.36

The focus of this guide, however, is tominimize the risk of an unintended anduntoward DDI and therefore will notconsider therapeutic DDIs.

Given the above, the following twoequations are essential to understand-ing and avoiding DDIs:

Equation 1Effect = affinity x drug level x biological

for and (absorption, varianceintrinsic distribution, (genetics,activity metabolism, age,at a site elimination disease,of action [ADME]) environment

[GADE])Equation 2

drug concentration= dosing rateclearance

Equation 1 presents the three vari-ables that determine the effect a drugwill produce in a patient. First, the drugmust work on a site of action (the firstvariable in Equation 1), which is capableof producing the effect observed. For alldrugs, except anti-infectives, the site ofaction is a human regulatory proteinsuch as a receptor, an enzyme, or anuptake pump. By binding to its target(s),the drug is capable of altering the func-tional status of the target(s) and thusaltering human physiology. The ability ofthe drug to bind to the regulatory pro-tein gives it its potential action (ie, itspharmacodynamics). For the drug toexpress its potential action, it must reachthe target to a sufficient degree to engageit to a physiologically relevant extent.That is the domain of the second vari-



able in Equation 1. Drug concentrationin relation to the drug’s binding-affinityprofile determines what site of action thedrug will bind to and to what degree. Atlow concentrations, the drug will bind toits most potent target. As the concentra-tion increases, the drug will bind moresubstantially to that target until it is sat-urated. It may also begin binding tolower affinity targets when its concen-tration reaches a sufficiently high degreerelative to its binding affinity for a sec-ond target(s).37,38

Equation 2 illustrates that a drug con-centration is a function of the dosingrate the patient is taking relative to theirability to clear the drug. This equationexplains why clearance is as importantas dose in determining the nature, themagnitude, and the duration of a drug’seffect on the patient. Clinical trials arepopulation pharmacokinetic studies inwhich the goal is to determine the usualdose needed for the usual patient (ie,usual clearance) enrolled in the clinicaltrial to achieve a concentration suffi-cient to engage the desired target suffi-ciently to produce the best balancebetween efficacy and safety/tolerability.Thus, the second variable in Equation 1is the drug’s pharmacokinetics (or drugmovement), which has four phasessummarized by the acronym “ADME”:absorption of the drug from the site ofadministration into the body, distribu-tion of the drug to the various compart-ments of the body (eg, plasma, termedthe “central compartment,” and tissues,or “deeper compartments” such as thebrain), metabolism or biotransforma-tion into more polar substances, andfinally, elimination from the body.5

The last variable in Equation 1 is theinterindividual differences amongpatients, which can shift the doseresponse curve making patients eithermore or less sensitive to the effect of thedrug. These differences (ie, biologicalvariance among patients) are summa-rized by the acronym “GADE”: genetics,age, disease, and environment. Theenvironment variable refers to the inter-nal environment of the body, whichincludes other drugs or dietary sub-stances the patient may be taking. Thesefour variables modify the first two vari-ables and thus explain how the magni-tude, duration, or even the nature of theeffect of the drug in a specific patientmay differ from the usual effect pro-duced by a given dose of the drug. Thus,

DDIs occur when one drug (the perpe-trator) changes the effect of a given doseof another drug (the victim) by eitherinteracting with it pharmacodynamical-ly or pharmacokinetically (ie, the firstand second variables in Equation 1).This concept is the essential principleunderlying DDIs and the basis for therest of this guide.3

Can Polypharmacy inPsychiatry Be Rational?

For polypharmacy to be rational, theprescriber in any area of medicine mustbe able to answer the following ques-tions: (1) Why am I using more than onedrug? (2) Do the drugs interact? (3) Ifso, what are the data that support thesafety, tolerability, and efficacy of thecombination?

Table 9 lists five major reasons why aprescriber may use more than one drugto treat a patient.3,36 The first reason isthe most obvious: the patient has morethan one disease process and the pre-scriber must employ one or moreagents for each disease. In this exam-ple, the prescriber is not planning aDDI, though one may occur becausedrugs interact on the basis of the mech-anisms underlying their pharmacody-namics and pharmacokinetics, ratherthan on the basis of their therapeuticindication. For this reason, the pre-scriber of psychiatric medications mustbe aware of and consider all of the med-ications the patient is taking.

The second reason listed in Table 9 isparticularly relevant to psychiatry.3,36

Conditions such as bipolar andschizoaffective disorder have complexsymptom clusters which wax and waneover the course of the illness. Patientswith these illnesses may need differentmedications for different phases of theirillness. While mood stabilizers (eg, lithi-um) are usually the foundation for thetreatment of a patient with bipolar dis-order, at different phases of the illnessthe patient may need to have antide-pressants, antipsychotics, or anxiolyticsadded and may even need treatmentwith more than one mood stabilizer.This is similar to patients with epilepsy,many of whom need to be on more thanone anticonvulsant to achieve optimalcontrol of their seizures.39,40

The remaining reasons listed in Table9 are all based on planned therapeuticDDIs, whether the prescriber thinks inthese terms or not.3,36 When a second

drug diminishes, amplifies, or speedsthe onset of a first drug, that effect is bydefinition a DDI. When using a drug forthese purposes, the ideal situationwould be one in which the pathophysi-ology of the illness and the effects ofeach drug on that pathophysiology areall clearly understood.

An example is Parkinson’s disease, asoutlined in Table 10.3,36 The problem inpsychiatry is that the pathophysiologyof psychiatric illnesses is not well under-stood and thus the effects of the drugson that pathophysiology cannot be wellunderstood. Nevertheless, Table 11 listsa series of features that can be used torationally prescribe treatment with twoor more psychiatric medications togeth-er to accomplish the last three goals list-ed in Table 9.3,4,36

Beyond Psychiatric Drugs to theTotal Therapeutic Regimen

The prescriber of psychiatric medica-tions cannot simply focus on those med-ications but must examine all of themedications the patient is taking,including over-the-counter (OTC) med-ications, illicit substances, herbal prod-ucts, and even dietary substances. Forexample, ibuprofen, an OTC analgesic,can cause serious and even life-threat-ening elevations in lithium levels byaffecting its rate of tubular reabsorp-tion.41 The duration of the effect of illic-it substances can be prolonged bycoprescribed drugs, which inhibit theenzymes responsible for clearing theillicit substance. St. John’s wort is a sub-stantial inducer of CYP 3A and thus canaccelerate the clearance of a number ofco-prescribed medications.42 Smokingcan induce the metabolism of drugssuch as clozapine, which are normallycleared by smoking-inducible CYP1A2.43 Thus, the prescriber must take thewhole patient into consideration whentrying to understand and/or predict theeffect of a treatment regimen involvingmore than one medication.

Special Considerations for HowDDIs Present in Psychiatry

The term DDI frequently conjuresimages of a sudden catastrophic andeven fatal outcome. While such anevent can occur and is obviously impor-tant to prevent, DDIs can present as vir-tually anything, including the worsen-ing of the illness being treated or theemergence of a new illness. For this rea-



son, such “masked” DDIs can ironicallylead to the use of more medications totreat the apparent worsening of the pri-mary condition or to treat the apparentemergence of a new condition.

All drugs, except anti-infectives, aregiven to change human physiology.44

Those changes can present in everyway clinically imaginable. For this rea-son, the prescriber should keep inmind that the patient may not be doingwell because of the medications he isreceiving rather than despite the med-ications he is receiving.42

Understanding and identifying DDIswith psychiatric medications is perhapsmore challenging than in any other areaof medicine. The reason is the complex-ity of the organ they affect and the com-plexity of its output (Table 12).45 Theaverage adult human is composed ofapproximately 10–20 billion cellsarranged in a hierarchal and integratedsystem. Seventy-five neurotransmittershave been identified in the humanbrain. That number may double in thenext 10 years as a result of discoveriesmade possible by the human genomeproject. Every identified neurotransmit-ter has 2–17 receptor subtypes. Thus,the human brain may contain thou-sands of receptors, which are the prima-ry targets of drug action. There are alsodifferent enzymes for the synthesis anddegradation of these neurotransmitters,different uptake pumps, and storagemechanisms. All of these regulatory pro-teins can be the target for drug action.Thus, current drugs may interact phar-macodynamically in ways that are nei-ther understood nor predictable at thepresent time.3 Their detection is depen-dent on the careful assessment at thetime of a medcheck by the prescriber asdiscussed in the next paragraph.

As psychiatric drugs are more ratio-nally developed to affect only the brain,their adverse effects will not be onperipheral systems but on the brain.Thus, the result of psychiatric DDIscould present as changes in mentation,reality testing, emotional control, inter-personal relationships, and memoryfunction. The prescriber of psychiatricmedications must be a good behavioralpharmacologist as well as a good diag-nostician, and must also keep in mindthat changes in these outputs of thehuman brain may be because of themedications that the patient is receivingrather than in spite of them. This dis-

cussion further emphasizes the limita-tions of this guide and of all informationsystems in clinical psychopharmacolo-gy. There is much more that needs to beknown. In the interim, the goal of thisguide is to summarize what is known, toexplain the limits of current knowledge,and to define good clinical practices asthey relate to avoiding untoward DDIs.

Proper Use of TherapeuticDrug Monitoring

Equation 1 illustrates that drug con-centration determines what site(s) ofaction are engaged and to what degree,while Equation 2 illustrates that drugconcentration is the dosing rate dividedby the clearance. By re-arrangingEquation 2, it is clear that:

clearance= dosing rate drug concentration

If the prescriber is confident in thedosing rate (ie, noncompliance is notan issue), then measuring the drugconcentration allows the prescriber toassess the patient’s clearance to deter-mine whether it is usual or unusuallyfast or slow. For example, if the clearance is faster than usual, then thedosing rate must be increased propor-tionately to reach the usual drug con-centration achieved on the usuallyeffective dose; in other words, the usualsite(s) of action must be engaged to theusual degree associated with optimalresponse as determined by the registra-tion trials that lead to the marketing ofthe drug. Thus, the goal of therapeuticdrug monitoring (TDM) is not to simplyknow whether the concentration is ther-apeutic but to know whether thepatient’s ability to clear the drug is usualor not. If not, the results of TDM canprovide a rational basis for determiningwhat sort of an adjustment in the dosingrate must be made to compensate forthe patient’s unusual clearance.

This issue is of critical importancewhen understanding and avoiding unto-ward effects mediated by the co-pre-scription of a drug capable of eitherinducing or inhibiting the enzymesresponsible for the clearance of the vic-tim drug. Induction can increase theclearance of the victim drug such thatits levels fall below what is usually ther-apeutic, resulting in either loss of effica-cy or withdrawal symptoms.46 Inhibitioncan decrease the clearance of the victim

drug such that its levels rise causingconsequences, which may range froman increase in the frequency and severi-ty of dose-dependent adverse effects,such as extrapyramidal side effects inthe case of conventional antipsychoticsto life-threatening toxicity in the case oftricyclic antidepressants.

The logic underlying pharmacokineticinteractions mediated by the inductionor inhibition of CYP enzymes is outlinedin Figure 3.3,32 This logic forms the basisfor the section on CYP enzyme-mediatedDDIs with psychiatric medications.

Time Course of InteractionsDrugs have the potential to interact as

long as they and/or their effects persistin the body. Thus, the potential for aninteraction may persist for days toweeks and even months after one of thedrugs has been discontinued.

This fact is illustrated in Figure 4from a study examining the effect of flu-oxetine on the metabolism of the CYP2D6 model substrate desipramine.47 Inthis study, genotypically normal metab-olizers via CYP 2D6 (>95% of the popu-lation) were first treated withdesipramine 50 mg/day for 7 days toachieve steady-state conditions. On day8, fluoxetine 20 mg was added to theirregimen. Without changing the dose ofdesipramine, its levels increased >4-foldover the next 3 weeks as fluoxetine andits active metabolite, norfluoxetine,accumulated, resulting in the inhibitionof CYP 2D6. The inhibition of CYP 2D6resulted in a reduction in the clearanceof desipramine (Equation 2), hence anincrease in desipramine levels without achange in dose.

On day 28, fluoxetine was discontin-ued but desipramine was continued atthe same dose. Over the next 3 weeks,the desipramine levels fell as fluoxetineand norfluoxetine cleared from the bodyand CYP 2D6 inhibition in parallel wasreversed, leading to an increase indesipramine clearance. Nevertheless,desipramine levels even 3 weeks afterfluoxetine was discontinued were stilldouble what they were before fluoxetinewas added because norfluoxetine wasstill present in the body and still inhibit-ing CYP 2D6-mediated clearance. Thistime course is consistent with the factthat the half-lives of fluoxetine and nor-fluoxetine in young healthy individuals(such as those in this study) are 2–4 daysand 7–15 days, respectively. Of note, the



average half-life of norfluoxetine inhealthy individuals >_65 years of age is 3 weeks; thus it takes an average of 4 months to reach steady-state once thedrug is started in older individuals, and4 months to completely clear once thedrug is discontinued.48

While the study that provided theresults in Figure 4 was about the effect offluoxetine on CYP 2D6,47 it graphicallyillustrates the point that the effect of acoprescribed perpetrator drug (eg, fluox-etine) on the response to the victim drug(eg, desipramine) can continue toincrease for weeks after the perpetratorhas been started and can persist forweeks after the perpetrator has beenstopped. Sometimes that is because theperpetrator has a long residual time inthe body, as in the case of fluoxetine, andsometimes it is because the perpetrator’seffect persists long after it has beencleared. An example of the latter wouldbe the classic MAOIs, which cause irre-versible inhibition of that enzyme; syn-thesis of new enzyme is required torestore usual levels of activity once thatclassic MAOI has been stopped.48,49 Thus,prescribers should wait >_2 weeks afterstopping an irreversible MAOI beforestarting a norepinephrine and serotoninagonist to minimize the risk of a hyper-tensive crisis or a serotonin syndrome,respectively. In a similar way, enzymeinducers have their induction effectimmediately, though the time course forthe maximum effect on increased clear-ance is not achieved until a new steady-state level of enzyme protein has beenproduced as a result of increased proteinsynthesis. For the same reason, theincreased clearance persists for severalweeks after the enzyme inducer has beenstopped.50 These delayed onsets and off-sets are not simply limited to pharmaco-kinetic interactions as witnessed byMAO inhibition (which is a pharmaco-dynamic interaction) but can be appliedto all interactions in which the effect ofthe perpetrator persists for a sustainedperiod after the perpetrator has been dis-continued (eg, receptor supersensitivityor subsensitivity).

How to Avoid DDIsTable 13 summarizes the major prin-

ciples relevant for minimizing the riskof DDIs. Next, the major tables for sum-marizing knowledge relevant to avoid-ing pharmacodynamic and pharmaco-kinetic DDIs are provided.

Pharmacodynamic DDIsDrugs are approved and generally con-

sidered from the perspective of theirtherapeutic use; however, they interacton the basis of their pharmacodynamicsand pharmacokinetics. They also are fre-quently used for reasons other than theirinitial labeled indication. For example,most selective serotonin reuptakeinhibitors were initially approved asantidepressants but several have subse-quently gained approved labeling for thetreatment of a variety of anxiety disor-ders. In a similar way, a number of atyp-ical antipsychotics are seeking approvalas mood stabilizers. In recognition ofthese facts, the tables in this guide out-lining DDIs will consider these drugs interms of their pharmacodynamics andpharmacokinetics rather than in termsof their labeled therapeutic indication.

Table 5 lists the neuropsychiatricmedications to be covered in this guideby their principal mechanism of action.Table 1451 enumerates the pharmacody-namically mediated DDIs that can occurfor each mechanism of action listed inTable 5. Using these tables together, thereader can determine the potential DDIsthat can occur when any drug in Table 5is used with a drug having a mechanismthat interacts with its mechanism ofaction (Table 11).32,51

A number of neuropsychiatric med-ications including tertiary amine tri-cyclic antidepressants and atypicalantipsychotics affect more than onemechanism of action under clinicallyrelevant dosing conditions. For this rea-son, Tables 6–8 have been developed toshow the relative effect of the most com-monly used neuropsychiatric medica-tion with multiple mechanisms ofaction.34,52-56 In these tables, the mostpotent binding site of the drug wasassigned the value of 1 and its relativebinding affinity for other targets wasexpressed as its binding affinity for thattarget divided by its binding affinity forits most potent target. The resultingratio reflects the increase in concentra-tion needed for the drug to affect its lesspotent target in relationship to its mostpotent target. For example, quetiapinebinds most avidly to the α1 adrenergicreceptor and binds almost as avidly tothe H1 receptor, but requires a 23-foldincrease in dose to bind to thedopamine D2 receptor (Table 6). Thatexplains why low doses of quetiapinecan be used for sedative effects but

why higher doses are needed forantipsychotic efficacy. For the samereason, quetiapine can have the samepharmacodynamic DDIs as otherpotent histamine H1 receptor antago-nists even though those other drugsmight not have any efficacy as anantipsychotic medication.

The reader can use Tables 6–8 todetermine how a multiple mechanismof action drug may carry the potentialfor interacting pharmacodynamicallyby a mechanism other than its majorpresumed therapeutic mechanism (aslisted in Table 5) and have an approxi-mate understanding of the relative like-lihood of such an interaction based onits relative binding affinity for sec-ondary targets in relationship to thedose that is being used and the concen-tration which is likely being achievedin the patient. The reader can also usethis information to determine whetherhe or she might wish to employ TDM tofurther establish the actual concentra-tions being achieved in their specificpatient and relate that to both relativebinding affinity for its multiple targetsas well as relative to the concentrationusually achieved on the dose beingused. The clinician could use TDM todetermine whether his or her specificpatient has unusually fast or slowclearance relative to the usual clear-ance found in the registration trialsand whether the patient is developingconcentrations comparable to or con-centrations much higher or lower thanthose found in registration trials.

Pharmacokinetic TablesThese tables outline potential CYP

enzyme-mediated DDIs. Parenthetically,CYP-mediated DDIs are the most com-mon, clinically meaningful type of phar-macokinetic DDIs. Table 15 lists whichCYP enzymes metabolize which drugsand which drugs inhibit or induce spe-cific CYP enzymes. Using these tablesand the logic outlined in Figure 3, thereader can predict the major potentialCYP enzyme-mediated DDIs.3,32

Pharmacokinetic DrugInteractions That Are NotMetabolism-Based

This guide restricted its discussionof pharmacokinetic DDIs to thosemediated by CYP enzymes because oftheir clinical relevance. Nevertheless,there are other possible pharmacoki-



netic DDIs (Table 16)57 worth brieflymentioning as follows: the chelation ofdrugs in the gastrointestinal tract byiron salts prescribed to treat anemia orby antacids with high aluminum con-tent; interactions that occur prior tothe administration of intravenous (IV)drugs due to the incompatibility of IVsolutions; interaction with secretingdrug transporters that line the renaltubules and the blood-brain barrier(eg, lithium intoxication due to coad-ministration with ibuprofen and possi-bly other nonsteroidal anti-inflamma-tory drugs); and nutritional interac-tions that deplete the co-factorsrequired for the phase II metabolismof some drugs (ie, reduced acetylationand glycosylation due to persistenthypoglycemia or clinically significantmalnutrition).58

Important to note is that thesemechanisms do not include proteinbinding (or “bumping”) interactions inwhich a perpetrator displaces a victimdrug from serum proteins such asalbumin or α-acid glycoprotein. Thismechanism virtually never mediates aDDI of clinical significance, althoughit is well ensconced in the literatureand the minds of physicians. Thismechanism is virtually never clinicallysignificant because the resultingincreased free drug persists for a veryshort and clinically insignificant peri-od before the access of the same freedrug to elimination mechanisms, suchas enzymes transporters, reduces thefree concentration to a new equilibri-um very close to the original.59

AppendicesAppendix I lists Web sites that the read-

er can use to find additional informa-tion.2,3,60-64 Web sites have the advantage ofbeing regularly updated so that the infor-mation will stay current even after thisguide has been published. Appendix IIlists software packages65-69 and the currentlimitations of such software.

One major limitation is that thereare no standard guidelines for produc-ing such drug alert systems in terms ofwhat constitutes sufficient evidence tolist an interaction as possible. Thus,software packages can either be overlyconservative and can list interactionsbased on theory rather than fact orbased on a single case report of dubi-ous validity. This, in turn, can cause a

high rate of situation, false positivealerts which can again lead the pre-scriber to ignore the system (ie, “theboy who cried wolf”).

Other systems may require that aformal study be conducted showingthat the interaction occurs; they do notgeneralize the interaction to otherdrugs with the same mechanism. Thissituation leads to false negatives. Anexample of the latter would be a sys-tem that reports that fluoxetine ele-vates the level of desipramine on thebasis of the study illustrated in Figure4 but does not warn about bupropion,which, at a dose of 300 mg/day,inhibits CYP 2D6 to a degree compara-ble to that of fluoxetine 20 mg/day.34

Most drug alert systems only consid-er the effect of drug A on drug B,whereas many patients are on multipledrugs that may interact in complexways. An example would be a patientwho is taking a drug equally cleared byCYP 2D6 and CYP 3A. That patientmay not be at substantial risk for toxi-city when treated with either a CYP2D6 or CYP 3A inhibitor alone butmay be if treated with both inhibitorsat the same time.4 Most systems focuson pharmacodynamic or pharmacoki-netic DDIs as if they were mutuallyexclusive, when in fact both can occursimultaneously and hence amplifyeach other.4,70

Current DDI alert systems may alertbut provide little or no guidance aboutwhat the prescriber can do to mini-mize risk of the interactions, such asfinding a substitute for either the per-petrator or the victim drug, adjustingthe dosage of the victim drug (in thecase of CYP enzyme mediated DDI), orspecially monitoring the treatment byusing, for example, TDM or electrocar-diograms.

However, the greatest limitation isknowledge. While there are 2,800 tril-lion possible combinations of up tofive drugs using the number of drugsin the 2003 Physicians’ DeskReference,34 there are <700 formal DDIstudies published, and virtually all ofthose are constrained to the effect ofone drug on another drug. In fact, vir-tually all clinically significant DDIswere first discovered by astute andconscientious clinicians who pub-lished their findings as case reports inmedical literature. Those reports

served as a stimulus for scientificstudy, which uncovered the pharmaco-logic basis for the interactions andthus led to generalizable knowledge.For this reason, the authors encouragethe readers to write up their cases andpublish them in the medical literature,as well as to use the adverse drug reac-tion reporting system developed by theFDA (Table 18).

Given the above limitations, soft-ware packages do not replace the edu-cated, astute, and conscientious pre-scriber who remains the major safe-guard against the occurrence of seri-ous untoward interactions. Theauthors hope that this guide can serveas an aid to these prescribers in pro-viding safe and effective treatment fortheir patients.

ConclusionDDIs are common, important, and

growing in frequency in concert withboth the increasing number of pharmaceuticals available and thenumber of patients on multiple med-ications. Each year more medicationsare added to the available armamen-tarium. There is an increasing use ofmultiple medications to treat patients,particularly as the focus of treatmenthas shifted from short-term therapy ofacute illnesses (eg, bacterial infec-tions) to chronic treatment and/or prevention of long-term illnesses (eg, schizophrenia and Alzheimer’s dis-ease, respectively).

To avoid unintended and untowardDDIs, the prescriber must understandfundamental principles of pharmacol-ogy and good clinical management.The prescriber must have knowledgeof the pharmacodynamic and pharma-cokinetics of the drugs that his or herpatients are taking. This educationalreview has addressed these principlesand presented tables summarizing themajor pharmacodynamic and pharma-cokinetic interactions affecting and/orcaused by commonly used neuropsy-chiatric medications. Additionally,appendices were provided listing Websites, books, and cards containingadditional information on specificDDIs. In addition, these Web sites areupdated on a regular basis so that thereader can stay informed of the rapiddevelopments in knowledge concern-ing DDIs. PP





Table 1What Percentage of Patients on Antidepressants Have the Potentialto Experience a DDI as a Function of Treatment Setting?3,9,11

Number of Only on On Antidepressants and Clinical Setting Patients Antidepressants (%) >_3 Other Medications (%)Primary care 2,045 28 34Psychiatry clinic 224 29 30VA Medical Center and clinics 1,076 7 68HIV clinic 66 2 77DDI=drug drug interaction; VA=Veterans Administration; HIV=human immunodeficiency virus.

Preskorn SH. Outpatient Management of Depression: A Guide for the Practitioner. Caddo, Ok: Professional Communications, Inc; 1999. Reprinted withpermission. ©Preskorn.

Preskorn SH, Flockhart D. Primary Psychiatry. Vol 11, No 2. 2004.

Figure 1Prevalence of Depression in Chronic Disease12-16

PD=Parkinson’s disease; CVA=cerebrovascular accident; CAD=coronaryartery disease; MI=myocardial infarction; HIV=human immunodeficiencyvirus; AD=Alzheimer’s disease.


Figure 2Increasing Use of Polypharmacy*at the NIMHBiological Psychiatry Branch Between 1974 and199525

*>_3 medications at the time of discharge.NIMH=National Institute of Mental Health.


1974-79

4540353025201510

50

1980-84 1985-89 1990-95

Percentage of patients

Figure 3How Knowledge of CYP Enzymes Will SimplifyUnderstanding of Pharmacokinetic Interactions3,32

Drug A affects* CYP enzyme X

CYP enzyme X metabolizes B, C, D, E

Therefore, Drug A affects* B, C, D, E

*Could be inhibition or inductionCYP=cytochrome P450.

Preskorn SH. Clinical Pharmacology of Selective Serotonin Reuptake Inhibitors. 1sted. Caddo, Ok: Professional Communications, Inc; 1996:234-236. Reprinted withpermission. ©Preskorn.


Figure 4Time Course: Effect of Fluoxetine on CYP 2D6 FunctionUsing Desipramine as the Probe Drug47

CYP=cytochrome P450; PK=pharmacokinetics; Flx=Fluoxetine.

Preskorn SH, Alderman J, Chung M, Harrison W, Messig M, Harris S.Pharmacokinetics of desipramine co-administered with sertraline orfluoxetine.J Clin Psychopharmacol. 1994;2:90-98. Adapted with permission. ©Preskorn.


7 8 14 21 28 35 42 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63

1901801701601501401301201101009080706050403020100

Study Day

De

sipra

min

e P

lasm

a L

eve

l (n

g/m

L)

Fix Start Fix Stop

Fluoxetine Group (N=9)

ActualPredicted from Day 7 PK Data

PD

10

20

30

40

50

60

0

Pre

vela

nce

Pe

rce

nt (

%)

Cancer Diabetes CVA CAD MI HIV AD

Table 2The “AVOID” Method for Assessment of Current MedicationsAllergies: Are there any medicines we should not give you for any reason?

Vitamins and Herbs: Do you take any herbal medicines?

OTC: Do you take any over-the-counter medicines?

Interactions: Use a database to check for interactions.

Dependence: Are there any medicines that you feel we should not discontinue?




Table 3Personal Formulary: Essential Elements of Knowledge for Each Drug


Dosage Forms• Know the dosage forms available for the drugs posted

Pharmacokinetic Data• Enzymes or transporters responsible for elimination• Half-life and effect of renal or liver disease• Pharmacokinetic variability in ethnic groups

Pharmacodynamic Data• Receptor affinity and specificity relative to other drugs • Clinically important side effects

Clinical Trial data• An ongoing familiarity with all major clinical trials and studies

Table 4Examples of SSRIs With Different Brand Names Throughout the World32

Country Citalopram Fluoxetine Fluvoxamine Paroxetine SertralineArgentina NA Animex-On, NA Aropax Zoloft

Equilibrane,Foxetin, Neupax,

SauratAustralia NA Prozac 20 NA Aropax ZoloftAustria Seropram Fluctine Floxyfral Seroxat TresleenBelgium Cipramil Prozac Floxyfal Aropax, Seroxat ZoloftCanada NA Prozac Luvox Paxil ZoloftDenmark Cipramil Fontex, Fonzac Fevarin Seroxat ZoloftFinland Cipramil Fontex, Fonzac Fevarin Seroxat ZoloftFrance Cipramil Prozac Floxyfral Deroxat ZoloftGermany Saroten Fluctin Fevarin Seroxat, Tagonis ZoloftGreece Seropram Flonital, Fluxadir Dumyrox Seroxat NA

Ladose, OrthonItaly NA Fluxeren, Prozac Dumirox, Sereupin, Serad, Tatig,

Fevarin, Seroxat ZoloftMaveral

Mexico NA Fluoxac, Prozac NA Aropax, Paxil AltrulineNetherlands NA Prozac Fevarin Seroxat ZoloftNorway Cipramil Fontex Fevarin Seroxat ZoloftPortugal NA Digassim, Dumyrox NA NA

Nodepe, Prozac,Psipax, Tuneluz

South Africa Cipramil Prozac Luvox Aropax 20 ZoloftSpain NA Adofen, Prozac, Dumirox Frosinor, Motivan, Aramis,

Reneuron Seroxat BesitranSweden Cipramil NA Fevarin Seroxat ZoloftSwitzerland Seropram Fluctine Floxyfral Deroxat Gladem,

ZoloftTurkey NA Depreks, Prozac Faverin NA LustralUnited Kingdom NA Prozac Faverin NA LustralUnited States Celexa Prozac Luvox Paxil ZoloftSSRIs=selective serotonin reuptake inhibitors; NA=not available at the time of original publication.

Preskorn SH. Clinical Pharmacology of Selective Serotonin Reuptake Inhibitors. 1st ed. Caddo, Ok: Professional Communications, Inc; 1996:234-236. Adapted withpermission. ©Preskorn.


Table 5Classification of Neuropsychiatric Medications Based on Their Principle Mechanism of Action33

AcetylcholineMuscarinic Acetylcholine Receptor AntagonismAtropine Glycopyrrolate (eg, Robinul) Procyclidine (Kemadrin)Belladonna Mepenzolate (Cantil) Propanthethine (eg, Pro-Banthine)Benztropine (Cogentin) Methscopolamine (Pamine) Scopolamine (eg, Sopace)Biperiden (Akineton) Orphenadrine (eg, Norflex) Trihexyphenidyl (Artane)Clidinium (Quarzan) Oxybutynin (eg, Ditropan)Dicyclomine (eg, Bentyl)

Also includes: a number of low-potency phenothiazines (see the class labeled “5-HT2A, D2, and Multiple Other ReceptorAntagonism”), a number of tertiary amine TCAs and related antidepressants (see the class labeled “Dual Norepinephrine andSerotonin (NE >5-HT) Uptake Pump Inhibition Plus Other Actions”), clozapine, olanzapine, and protriptyline.



Table 5 (cont)Classification of Neuropsychiatric Medications Based on Their Principle Mechanism of Action33

Cholinesterase Inhibition Donepezil (Aricept) Galantamine (Reminyl) Rivastigmine (Exelon)

Biogenine Amines (Effects on NE, D, 5-HT)Catechol-O-methyltransferase InhibitionEntacapone (Comtan) Tolcapone (Tasmar)

Monoamine Oxidase InhibitionIsocarboxazid (Marplan) Selegiline (Eldepryl) Tranylcypromine (Parnate)Phenelzine (Nardil)

Biogenic Amine ReleaseAmphetamines Dextroamphetamine (eg, Dexedrine) Methylphenidate (eg, Ritalin)Benzphetamine (Didrex) Diethylpropion (eg, Tenuate) Phendimetrazine (eg, Prelu-2)Bupropion (Wellbutrin, Zyban)* Methamphetamine (eg, Desoxyn) Phentermine (eg, Ionamin)

Classically NE>D>5-HT, but rank order of effects on these neurotransmitters may vary amongst the different drugs in this class.

DopamineDopamine Agonism (General)Levodopa (dopamine precursor, component of Sinemet)

D2 AgonismBromocriptine (+ partial D1 agonism) (Parlodel) Pramipexole (+ D3 agonism but no D1 activity) (Mirapex)Pergolide (+ D1 agonism) (Permax) Ropinirole (+ D3 agonism but no D1 activity) (Requip)

Uptake InhibitionAmantadine (Symmetrel) Cocaine

Dopa Decarboxylase InhibitorsCarbidopa (component of Sinemet)

Selective D2 Receptor Antagonism

Fluphenazine (eg, Prolixin)† Pimozide (Orap) Trifluoperazine (eg, Stelazine)Haloperidol (eg, Haldol)‡ Piperazine (Entacyl)Perphenazine (eg, Trilafon)

D2 Receptor Partial Agonism

Aripiprazole (Abilify)‡

D2 Receptor Antagonism Plus Multiple Other EffectsSee class labeled “5-HT2A, D2, and 5-HT2A, D2, and Multiple Other Receptor Antagonism.”

EthanolSolubilizes electrically excitable membranes

GABABarbiturates (enhance the binding of GABA to GABAA receptors and promote rather than displace the binding of benzodiazepines)Amobarbital (Amytal) Betharbital Primidone (Mysoline)Butabital (eg, Butisol) Pentobarbital (eg, Nembutal) Secobarbital (Seconal)

Barbiturate-Like DrugsChloral hydrate (eg, Aquachloral) Ethchlorvynol (Placidyl)

Benzodiazepine Binding Site AgonismAlprazolam (eg, Xanax) Estazolam (eg, ProSom) Prazepam (Centrax)Chlordiazepoxide (eg, Librium) Flurazepam (eg, Dalmane) Quazepam (Doral)Clonazepam (eg, Klonopin) Halazepam (Paxipam) Temazepam (eg, Restoril)Clorazepate (eg, Tranxene) Lorazepam (eg, Ativan) Triazolam (eg, Halcion)Diazepam (eg, Valium) Midazolam (eg, Versed) Zolpidem (Ambien)




Benzodiazepine-Like DrugsMeprobamate (eg, Miltown)

GABA Transaminase Inhibition and Stimulation of Glutaminic Acid DecarboxylaseDivalproex sodium (Depakote) Valproic acid (Depakene) Valproate sodium (Depacon)

Promotion of Nonvesicular Release of GABAGabapentin (Neurontin)

HerbalsGinkgo biloba Ginseng St. John’s wort

HistamineCentrally Active H1 AntagonismChlorpheniramine Ciphenhydramine (Benadryl) Hydroxyzine (Atarax)Cyclobenezaprine (Flexeril)

Also includes: a number of low-potency phenothiazines (see the class labeled “5-HT2A, D2, and Multiple Other Receptor Antagonism”), a num-ber of tertiary amine tricyclic and related antidepressants (see the class labeled “Dual Norepinephrine and Serotonin (NE >5-HT) Uptake PumpInhibition Plus Other Actions”), clozapine, olanzapine, maprotiline, mirtazapine, nefazodone, and quetiapine.

Ion Channel InhibitionCarbamazepine (eg, Tegretol) slows the recovery of voltage-activated Na+ channelsDantrolene (Dantrium) interferes with the release of Ca++ from sacroplasmic reticulumFelbamate (Felbatol) inhibits N-methyl-D-aspartate–evoked responses and potentiates GABA-evoked responsesLithium (eg, Eskalith) substitutes for multiple ionsLamotrigine (Lamictal) see carbamazapine plus inhibition of glutamate releaseMephentyoin (Mesantonin) slows recovery of voltage-activated Na+ channelsPhentyoin (eg, Dilantin) slows recovery of voltage-activated Na+ channelsTopiramate (Topamax) reduces voltage-gated Na+ currents, enhances postsynaptic GABAA receptor currents, and

limits activation of AMPA-kainate subtypes of the glutamate receptorOther CNS drugs with potentially clinically relevant effects on ion channels at usual concentrations include: a number of low poten-cy phenothiazines (see the class labeled “5-HT2A and D2 Antagonists With Other Effects”), a number of tertiary amine tricyclic andrelated antidepressants (see the class labeled “Serotonin and Norepinephrine Reuptake Inhibition With Other Effects”), clozapine,pimozide, and ziprasidone. Thioridazine has a black box warning, possibly because of such effects.

Norepinephrineα1 Antagonism

This mechanism is not known to mediate any desired CNS effect, thus no neuropsychiatric medications were developed tohave this specific mechanism of action. Nevertheless, several neuropsychiatric medications do achieve concentrationsunder clinically relevant dosing conditions, which block this receptor. These medications include: amitriptyline, chlorpro-mazine, clozapine, quetiapine, nefazodone, risperidone, thioridazine, and trazodone.

α2 AgonismClonidine (eg, Catapres)

Uptake Pump InhibitionAtomoxetine (Strattera) Maprotoline (eg, Ludiomil)* Protriptyline (eg, Vivactil)*Cocaine Nortriptyline (eg, Pamelor)* Reboxetine (Vespar)*§

Desipramine (eg, Norpramin)* Phentermine (eg, Ionamine)

Dual Norepinephrine and Serotonin (NE >5-HT) Uptake Pump Inhibition Plus Other ActionsAmitriptyline (eg, Elavil)* Clomipramine (eg, Anafril)* Imipramine (eg, Tofranil)*Amoxapine (eg, Ascendin)* Doxepin (eg, Sinequan)* Trimipramine (eg, Surmontil)*

Opiate ReceptorAlfentanil (Alfental) Hydromorphine (eg, Dilaudid) Oxycodone (Roxicodone)Buprenorphine (Buprenex) Meperidine (eg, Demerol) Pentazocine (eg, Talwin)Codeine Methadone (eg, Dolophine) Prophyphene (eg, Darvon)Fentanyl (eg, Sublimaze) Nalbuphine (eg, Nubain) Tramadol (Ultram)Hydrocodone (eg, Vicodin) Opium (eg, Paregoric)

Serotonin5-HT1A Partial Agonism




Buspirone (eg, Buspirone)

5-HT1B/D AgonismErgotamine (eg, Ergomar) Naratriptan (Amege) Rizatriptan (Maxalt)Dihyrdoergotamine (D.H.E. 45) Sumitriptan (Imitrex) Zolmitriptan (Zomig)

5-HT2 Receptor AntagonismCyproheptadine (Periactin) Mirtazapine (Remeron)* Trazodone (eg, Desyrel)*Methysergide (Sansert) Nefazodone (Serzone)*

5-HT2A and D2 Receptor Antagonism

Olanzapine (Zyprexa)‡ Risperidone (Risperdal)‡ Ziprasidone (Geodon)‡

5-HT2A, D2, and Multiple Other Receptor Antagonism

Chlorpromazine (eg, Thorazine)† Prochlorperazine (eg, Compazine) Propiomazine (Largon)Clozapine (eg, Clozaril)‡ Promazine (eg, Sparine) Thiethylperazine (Torecan)Loxapine (eg, Loxitane)† Promethazine (eg, Phenergan) Thioridazine (eg, Mellaril)†

Mesoridazine (eg, Serentil)

Serotonin Uptake InhibitionDexfenfluramine (Redux) Fluvoxamine (eg, Luvox) Paroxetine (Paxil)Fenfluramine (Pondimin)

Selective Serotonin Uptake InhibitionCitalopram (Celexa)* Paroxetine (Paxil)* Fluvoxamine (eg, Luvox)*Fluoxetine (eg, Prozac)* Escitalopram (Lexapro)* Sertraline (Zoloft)*

Dual Serotonin and Norepinephrine (5-HT>NE) Uptake Pump InhibitionSibutramine (Meridia) Venlafaxine (Effexor)*

* See Table 8 for relative effects on neuroreceptors.† See Table 7 for relative effects on neuroreceptors.‡ See Table 6 for relative effects on neuroreceptors.§ Not available in the United States. 5-HT=serotonin; D=dopamine; NE=norepinephrine; TCAs=trycyclic antidepressants; GABA=γ-aminobutyric acid; Na=sodium; Ca=calcium; H=histamine;CNS=central nervous system.

Preskorn SH. Classification of neuropsychiatric medications by principle mechanism of action: a meaningful way to anticipate pharmacodynamically medi-ated drug interactions. J Psychiatr Pract. 2003;5:376-383. Reprinted with permission. ©Preskorn.Preskorn SH, Flockhart D. Primary Psychiatry. Vol 11, No 2. 2004.

Table 6Relative Binding Affinity* of Selected Antipsychotics for Specific Neuroreceptors†33,34,51-54

Agent D1 D2 D3 D4 5-HT1A 5-HT2A 5-HT2C α1 H1 M1

Aripiprazole 780 1‡ 2 129 5 10 44 138 180 >1,000Clozapine 45 66 250 18 460 8 8 4 3 1Haloperidol 300 1 3 4 >1,000 64 >10,000 9 629 >2,000Olanzapine 16 6 25 24 >5,000 2 12 9 4 1Quetiapine 65 23 49 230 400 42 214 1 2 17Risperidone 614 6 14 13 300 1 36 1 29 >10,000Ziprasidone >1,000 13 18 80 8 1 2.5 28 125 >1,000

* Relative binding affinity=

† In this table, the most potent site of action for a specific drug is arbitrarily given a value of 1 so that the drug’s affinity for all other sites can beexpressed in relationship to its most potent site of action. The actual affinity in nanomolar concentration for its most potent site of action for each ofthe drugs listed above are as follows: aripiprazole D2 (0.34), clozapine M1 (1.9), haloperidol D2 (0.7), olanzapine M1 (1.9), quetiapine α1 (7), risperidoneα1 (0.7), ziprasidone 5-HT2A (0.7).

‡ Partial agonist at D2 receptor where others in this table are full antagonists.

D=dopamine; 5-HT=serotonin; H=histamine; M=muscarine.

Preskorn SH. Classification of neuropsychiatric medications by principle mechanism of action: a meaningful way to anticipate pharmacodynamically medi-ated drug interactions. J Psychiatr Pract. 2003;5:376-383. Reprinted with permission. ©Preskorn.


binding affinity for secondary sites of actionbinding affinity for most potent site of action


Table 7Relative Binding Affinity* of Selected Antipsychotics for Specific Neuroreceptors†33,34,51-54

Agent D2 5-HT2A α1 α2 H1 M1

Chlorpromazine 13 1 2 546 6 50Cis-Thiothixene 1 289 24 444 13 >1,000Fluphenazine 1 24 11 >1,000 26 >1,000Loxapine 12 1 20 >1,000 4 331Thioridazine 5 4 1 167 3 3

* Relative binding affinity=

† In this table, the most potent site of action for a specific drug is arbitrarily given a value of 1 so that the drug’s affinity for all other sites can beexpressed in relationship to its most potent site of action. The actual affinity in nanomolar concentration for its most potent site of action for each of thedrugs listed above are as follows: chlorpromazine 5-HT2A (1.41), cis-thiothixenc D2 (0.45), fluphenazine D2 (0.8), loxapine 5-HT2A (1.37), thioridazine α1 (5).

D=dopamine; 5-HT=serotonin; H=histamine; M=muscarine.

Preskorn SH. Classification of neuropsychiatric medications by principle mechanism of action: a meaningful way to anticipate pharmacodynamically medi-ated drug interactions. J Psychiatr Pract. 2003;5:376-383. Reprinted with permission. ©Preskorn.


binding affinity for secondary sites of actionbinding affinity for most potent site of action

Table 8Relative Binding Affinity* of Specific Antidepressants to Specific Neurotransporters and Neuroreceptors†33,55,56

SET NET DAT H1 M1 α1 α2 D2 5-HT2A

Tertiary amine TCAsAmitriptyline 4 34 >1,000 1 16 25 827 910 27Amoxapine 57 16 >1,000 24 970 49 >1,000 17 1Chlorimipramine 1 133 >1,000 113 133 138 >1,000 679 97Doxepin 280 124 >1,000 1 350 100 >1,000 >1,000 105Imipramine 1 26 >1,000 8 65 65 >1,000 >1,000 55Trimipramine 552 >1,000 >1,000 1 218 88 >1,000 661 119

Secondary Amine TCAsDesipramine 21 1 >1,000 132 235 156 >1,000 >1,000 333Maprotiline >1,000 6 500 1 278 45 >1,000 172 60Nortriptyline 4 1 261 2 34 14 575 277 10Protriptyline 14 1 >1,000 18 18 92 >1,000 >1,000 47

SSRIsCitalopram 1 >1,000 >1,000 410 >1,000 >1,000 >1,000 NA >1,000Escitalopram 1 >1,000 >1,000 >1,000 >1,000 >1,000 >1,000 NA NAFluoxetine 1 293 >1,000 >1,000 >1,000 >1,000 >1,000 >1,000 250Fluvoxamine 1 584 >1,000 >1,000 >1,000 >1,000 >1,000 NA >1,000Paroxetine 1 320 >1,000 >1,000 860 >1,000 >1,000 >1,000 >1,000Sertraline 1 >1,000 85 >1,000 >1,000 >1,000 >1,000 >1,000 >1,000

SNRIsMilnacipran 1 9 >1,000 >1,000 >1,000 >1,000 NA NA 917Reboxetine 8 1 >1,000 44 933 >1,000 NA NA 875Venlafaxine 1 117 991 >1,000 >1,000 >1,000 >1,000 >1,000 >1,000

5-HT2A Inhibition and Weak SerotoninNefazodone 60 107 107 6 >1,000 8 >1,000 273 1Trazodone 21 >1,000 929 45 >1,000 5 65 500 1

Specific Histamine, Serotonin, and Norepinephrine Receptor AntagonistMirtazapine >1,000 >1,000 >1,000 1 >1,000 >1,000 986 >1,000 115

Dopamine and Norepinephrine Reuptake InhibitionBupropion 17 100 1 13 90 9 158 396 173

* Relative binding affinity =† In this table, the most potent site of action for a specific drug is arbitrarily given a value of 1 so that the drug’s affinity for all other sites can beexpressed in relationship to its most potent site of action. The actual affinity in nanomolar concentration for its most potent site of action for each ofthe drugs listed above are as follows: amitriptyline H (1), amoxapine 5-HT2 (1), bupropion (526), citalopram SET (1.16), chlorimipramine SET (0.28),desipramine NET (0.83), doxepin H (0.24), fluoxetine SET (0.83), fluvoxamine SET (2.22), imipramine SET (1.41), maprotiline H1 (2), milnacipran SET (9), mir-tazapine H1 (0.14), nefazodone 5-HT2A (3.33), nortriptyline NET (4.35), paroxetine SET (0.13), protriptyline NET (1.41), reboxetine NET (7), sertraline SET(0.29), trazodone 5-HT2A (7.7), trimipramine H1 (0.27), venlafaxine SET (9.1).

SET=serotonin transporter; NET=norepinephrine transporter; H=histamine; M=muscarine; D=dopamine; 5-HT=serotonin; TCAs=tricyclic antidepressants;SSRIs=selective serotonin reuptake inhibitors; NA=not available; SNRIs=selective norepinephrine reuptake inhibitors.

Preskorn SH. Classification of neuropsychiatric medications by principle mechanism of action: a meaningful way to anticipate pharmacodynamically medi-ated drug interactions. J Psychiatr Pract. 2003;5:376-383. Reprinted with permission. ©Preskorn.Preskorn SH, Flockhart D. Primary Psychiatry. Vol 11, No 2. 2004.

binding affinity for most potent site of action

binding affinity for secondary sites of action


Table 9Five Reasons for Polypharmacy3,36

1. To treat a concomitant disorder 4. To boost or augment the desired effect2. To treat an intervening phase of the illness 5. To speed the onset of the desired effect3. To treat an adverse effect

Preskorn SH, Lacey R. Polypharmacy: When is it rational? J Pract Psychiatr Behav Health. 1995;1:92-98. Reprinted with permission. ©Preskorn.


Table 12Complexity of the Human Brain45

•10–20 billion cells •Enzymes (synthesis, degradation) •Second messenger systems•75 known neurotransmitters •2–17 receptor subtypes •Ion channels•300 putative neurotransmitters •Transport mechanisms, storage and release

Preskorn SH. The human genome project and drug discovery in psychiatry: identifying novel targets. J Psychiatr Pract. 2001;2:133-140. ©Preskorn.Preskorn SH, Flockhart D. Primary Psychiatry. Vol 11, No 2. 2004.

Table 11Criteria for Rational Copharmacy in Psychiatry3,36

1. Knowledge that the combination has a positive effect on the pathophysiology or pathoetiology of the disorder2. Convincing evidence that the combination is more effective, including more cost-effective, than monodrug therapy3. The combination should not pose significantly greater safety or tolerability risks than monotherapy

-Drugs should not have narrow therapeutic indices-Drugs should not have poor tolerability profiles

4. Drugs should not interact both pharmacokinetically and pharmacodynamically5. Drugs should have mechanisms of action that are likely to interact in a way that augments response6. Drugs should have only one mechanism of action7. Drugs should not have a broad-acting mechanism of action8. Drugs should not have the same mechanism of action9. Drugs should not have opposing mechanisms of action10. Each drug should have simple metabolism11. Each drug should have an intermediate half-life12. Each drug should have linear pharmacokinetics



Table 10Parkinson’s Disease as a Model of Rational Copharmacy3,36

Treatment Effect (Type of Interaction)L-Dopa Increase synthesis of central dopamine (PK)L-Dopa+carbidopa (Sinemet) Carbidopa inhibits peripheral decarboxylase to reduce the dose of L-

dopa needed to increase synthesis of central dopamine (PK)L-Dopa/carbidopa+dopamine reuptake inhibitor Second drug potentiates the effect of released central dopamine (PK)(eg, bupropion, amantadine)L-Dopa/cardibopa+L-deprenyl L-deprenyl increases synthesis of central dopamine and block its

degradation (PK)L-Dopa/carbidopa+bromocriptine Bromocriptine and related D2 agonists potentiate central dopamine

agonism by addition of direct dopamine agonist (PD)PK=pharmacokinetic; PD=pharmacodynamic; D=dopamine.



Table 13Summary of Major Principles to Avoid Adverse Drug-Drug Interactions*• Be aware and follow good clinical practice • Anticipation and prevention• Avoid multiple-target medications that affect nonessential targets -highly potent inducer/inhibitor• Use logic rather than memorization or denial -narrow therapeutic index of victim• Use available literature and software • When possible, choose low-risk perpetrators• When in doubt, start low and go slow • When possible, choose victims with multiple parallel pathways• Monitor for adverse outcome* The adverse effects of many psychotropic medications can mimic the illness being treated. Hence, patients may not be doing well because of their

drug treatment rather than in spite of it.

©Preskorn.Preskorn SH, Flockhart D. Primary Psychiatry. Vol 11, No 2. 2004.



Table 14Major Pharmacodynamic Drug-Drug Interactions Based on Mechanism of Action51

Acetylcholine

Muscarinic Acetylcholine Receptor Antagonism•Mitigates and can even fully reverse the extrapyramidal symptoms caused by excessive D2 blockade•Can block the memory-enhancing effects of cholinesterase inhibitors in dementing illnesses, such as Alzheimer’s disease•Decreases gastric empyting, thus decreasing the absorption of acetaminophen

Cholinesterase Inhibition•Opposite consequences to muscarinic acetylcholine receptor antagonism (see above)

Biogenine Amine (Effects on D, NE, and 5-HT)

Catechol-O-methyltransferase Inhibition•Potentiate the effects of other drugs increasing the synaptic concentration of D, NE, and 5-HT.•Could theoretically increase the likelihood and severity of hypertensive crisis and serotonin syndrome•Antagonize the effects of drugs that block specific D, NE, and 5-HT receptors

Monoamine Oxidase Inhibition •Potentiate the effects of other drugs increasing the synaptic concentration of D, NE, and 5-HT. Known to cause the hyper-

tensive crisis and the serotonin syndrome when used in combination with drugs which have agonistic effects on central NEand 5-HT systems

•Augment and prolong the efficacy of dopamine agonists for the treatment of Parkinson’s disease•Can increase the likelihood and severity of dyskinesia, hyperactivity, and hyperkinesias, and psychosis and hyperactivity

induced by dopamine agonists•Antagonize the effects of drugs that block specific D, NE, and 5-HT receptors

Release•Can amplify the effects of other drugs increasing the synaptic concentration of D, NE, and 5-HT. Known to cause the hyper-

tensive crisis and the serotonin syndrome when used in combination with drugs, which have agonistic effects on central nor-epinephrine and serotonin systems

•Augment and prolong the efficacy of dopamine agonists for the treatment of Parkinson’s disease•Can increase the likelihood and severity of dyskinesia, hyperactivity, hyperkinesia, and psychosis induced by dopamine agonists•Antagonize the effects of drugs that block specific D, NE, and 5-HT receptors

Dopamine

Dopamine Agonism (General)•Can ameliorate Parkinson’s disease•Can cause dyskinesia, hyperactivity, hyperkinesia, and psychosis•Above effects can be augmented by other dopamine agonists and blocked by dopamine antagonists

D2 Agonism•Can ameliorate Parkinson’s disease•Can cause dyskinesia, hyperactivity, hyperkinesia, and psychosis•Can aggravate dyskinesias in conditions such as Huntington’s disease•Above effects can be augmented by other dopamine agonists and blocked by dopamine antagonists

Uptake Inhibition•Can ameliorate Parkinson’s disease•Can cause dyskinesia, hyperactivity, hyperkinesia, and psychosis•Above effects can be augmented by other dopamine agonists and blocked by dopamine antagonists

Dopa Decarboxylase Inhibition•Decrease the peripheral conversion of L-dopa to dopamine and thus increase its availability to the brain increasing its net

central dopamine agonistic effects

Selective D2 Receptor Antagonism•Can cause extrapyramidal symptoms, including Parkinsonism•Can aggravate Parkinson’s disease•Can reduce dyskinesias in conditions such as Huntington’s disease and reduce psychosis seen in a number of other illnesses•Can reverse hyperactivity and hyperkinesias caused by dopamine agonists



Table 14 (cont)Major Pharmacodynamic Drug-Drug Interactions Based on Mechanism of Action51

D2 Receptor Partial Agonism•Reduced risk of extrapyramidal symptoms, including Parkinsonism•Reduced risk of aggravating Parkinson’s disease and bradykinesia seen in other dementing illnesses such as Alzheimer’s disease•Could have variable effects on dyskinesias in conditions such as Huntington’s disease•Can reduce psychosis seen in a number of illnesses•Should reduce the hyperactivity and hyperkinesias caused by dopamine agonists

Ethanol

The central nervous system impairment caused by ethanol can be enhanced by a number of different mechanistic classesof drugs including drugs which promote GABA in the brain, drugs which block central H1 receptors, and opiates.

GABA

Barbiturates Barbiturate-Like DrugsBenzodiazepine Binding Site AgonismBenzodiazepine-Like DrugsGABA Transaminase Inhibition and Stimulation of Glutaminic Acid DecarboxylasePromotion of Nonvesicular Release of GABAThe central nervous system impairment caused by the above direct and indirect GABA agonists can be enhanced by eachother and by a number of different mechanistic classes of drugs including drugs which block central H1 receptors, ethanol,and opiates.

Histamine

Central Active H1 AntagonismThe sedation caused by central H1 antagonism can be amplified by:•Drugs that promote GABA in the brain•Ethanol•Opiates

Ion Channel Inhibition

•There is a concern that the effect of drugs which inhibit ion channel function may have additive or synergistic effects in termsof prolonging intracardiac conduction and/or causing seizures. These theoretical interactions have not been formally test-ed with psychiatric medications due to the potential risk involved but have led in some instances to class labeling warningagainst such combined use principally on the basis of the theoretical concern.

Norepinephrine

α1 Antagonism•This mechanism can cause decreased peripheral arterial resistance leading to hypotension particularly orthostatic hypoten-

sion. Thus, neuropsychiatric medications with this mechanism of action can amplify the blood pressure lowering effects of anumber of antihypertensive medications including α2 agonists, angiotension-converting enzyme inhibitors, β-blockers, calci-um channel inhibitors, and diuretics.

α2 Agonism•This mechanism decreases central NE outflow and was initially used to treat hypertension. Rapid reversal of this effect either

by abruptly stopping drugs such as clonidine or by administering an α2 antagonist can cause clinically serious hypertensiverebound. Mirtazapine is an α2-adrenegic antagonist.

•By decreasing NE outflow, α2-adrenergic agonists would be expected to antagonize the effects of neuropsychiatric med-ications that block NE uptake pumps and MAOIs.

Norepinephrine Uptake Pump Inhibition•The effect of these drugs would be reduced by α2-adrenergic agonists (eg, clonidine) and would be amplified enhanced

by α2-adrenergic antagonists (eg, mirtazapine).•This mechanism can cause generally modest blood pressure elevations through enhancing sympathetic vascular tone. This

effect would modestly antagonize the effects of a variety of blood pressure lowering agents.•This mechanism can amplify the effect of MAOIs by increasing the duration of NE in the synaptic cleft while the MAOIs

increase the intracytoplasmic stores of NE available for release when the adrenergic neurons fire.



Table 14 (cont)Major Pharmacodynamic Drug-Drug Interactions Based on Mechanism of Action51

Norepinephrine and Serotonin (NE>5-HT) Uptake Pump Inhibition•These drugs carry with them the potential for combined interactions associated with either of these mechanisms. The rela-

tive magnitude of the interaction mediated by each mechanism would be a function of the concentration of the drug andthus the degree of specific uptake inhibition that is achieved.

Dual Norepinephrine and Serotonin (NE>5-HT) Uptake Pump Inhibition Plus Other Actions•These drugs would have the potential interactions mediated by each of the individual mechanisms. The relative magnitude

of the interaction mediated by each mechanism would be a function of the concentration of the drug and thus the degreeto which each mechanism is affected. Refer to tables on relative binding affinity and refer to each section on each mech-anism for the potential interactions that could occur.

Opiate Receptor Agonism

The decreased central nervous system arousal, particularly respiratory depression, caused by opiates can be amplified by:•Drugs which promote GABA in the brain•Drugs which block central H1 receptors

Serotonin

5-HT1A Partial AgonismThe pharmacology of these drugs is complicated. These receptors exist both presynaptically and postsynaptically.Presynaptically, they are analogous to the α2-adrenergic receptor as a feedback mechanism. Postsynaptically, they serve aneffector mechanism. In addition, the effect of these drugs is dependent on the intrasynaptic concentration of serotonin. Atlow concentrations, they act as a 5-HT1A agonist to diminish serotonin outflow. At high serotonin concentrations, they act asa 5-HT1A antagonist. Thus, they can theoretically interact in complex and even paradoxical ways with other serotonin activedrugs. They can therefore:•Amplify the effects of serotonin uptake pump inhibitors in theory, and thus have been used as an augmenting strategy for

antidepressant response, but the only large clinical trial was not supportive of this concept.•For the same reason, there is a theoretical risk of serotonin syndrome when combined with serotonin uptake pump inhibitors

and/or MAOIs.

5-HT1B/D Agonism•There is a theoretical risk of serotonin syndrome when combined with other serotonin agonists, such as serotonin uptake

pump inhibitors and MAOIs but little journal data to support this concern.

5-HT2 Receptor Antagonism•Serotonin agonism at this receptor may be responsible for the disruption of sleep that can be caused by serotonin uptake

pump inhibitors. Trazodone blocks this receptor and is commonly used to treat the insomnia associated with serotonin uptakepump inhibitors.

5-HT2A and D2 Receptor Antagonism •These drugs have the potential for interactions mediated by either of these mechanisms.

5-HT2A, D2, and Multiple Other Receptor Antagonism •These drugs have the potential for interactions mediated by all of these mechanisms.

Serotonin Uptake Inhibition•The effects of these drugs can be substantially amplified by MAOIs up to and including fulminant and fatal serotonin syndromes.

Serotonin syndrome is a theorectical risk when combined with 5-HT1A partial agonists and 5-HT1B/D agonists.•Lithium, by facilitating the neuronal release of serotonin, can enhance the serotonin agonism produced by serotonin uptake

pump inhibitors. Since serotonin is an inhibitory neurotransmitter for dopamine cell firing, this mechanism may account for theincreased tremors that can occur with the combined use of lithium and a serotonin uptake pump inhibitor.

Selective Serotonin Uptake InhibitionSee “Serotonin Uptake Inhibition”

Dual Serotonin and Norepinephrine (5-HT>NE) Uptake Pump InhibitionSee “Serotonin and Norepinephrine Uptake Pump Inhibition”

D=dopamine; NE=norepinephrine; 5-HT=serotonin; GABA=γ-aminobutyric acid; H=histamine; MAOIs=monoamine oxydase inhibitors.

©Preskorn.




Table 15Drugs Categorized as Specific CYP Enzyme Substrates, Inhibitors, or Inducers to Permit Prediction of CYP-Mediated Drug-Drug Interactions2

1A2 SubstratesAmitriptyline (Elavil, Endep) Haloperidol (Haldol)Clomipramine (Anafril) Imipramine N-DeMe (Tofranil)Clozapine (Clozaril) Olanzapine (Zyprexa)Cyclobenzaprine Riluzole (Rilutek)

(Cyclobenz, Flexeril) Tacrine (Cognex)Fluvoxamine (Luvox) Zolmitriptan (Zomig)

Relative Effect at1A2 Inhibitors Usual Therapeutic DoseAmiodarone (Cordarone, Pacerone) +++Cimetidine (Tagamet) +Fluoroquinolones +Fluvoxamine (Luvox) +Methoxsalen (Oxsoralen-Ultra, Uvadex) +Ticlopidine (Ticlid) ++

1A2 InducersBroccoli ~Brussel sprouts ~Char-grilled meat ~Methyl cholanthrene ~Modafinil (Provigil) +Mafcillin (Nafcil, Unipen) +β-naphthoflavone +Omeprazole (Prilosec) +Tobacco ~

2B6 SubstratesBupropion (Wellbutrin, Zyban) Methadone (Dolophine)Efavirenz (Sustiva)

Relative Effect at2B6 Inhibitors Usual Therapeutic DoseThiotepa (Thioplex) +++Ticlopidine (Ticlid) ++

2B6 InducersPhenobarbital (Phenob) ++Rifampin (Rifadin, Rifamate, Rimactane) ++

2C19 SubstratesAntiepilepticsAmitriptyline (Elavil, Endep) R-mephobarbital Citalopram (Celexa) (Mebaral)Clomipramine (Anafranil) MoclobemideDiazepam Nelfinavir (Viracept)

(Diastat, Dizac, Valium) Nilutamide (Niladron)Hexobarbital PhenobarbitoneImipramine N-DeME (Tonfanil) Phenytoin(O) (Dilantin)S-mephenytoin (Mesantoin) Primidone (Mysoline)

Relative Effect at2C19 Inhibitors Usual Therapeutic DoseCimetidine (Tagamet) +Felbamate (Felbatol) +Fluoxetine (Prozac, Sarafem) ++Fluvoxamine (Luvox) +++Indomethacin (Indocin) +Ketoconazole (Nizoral) ++Lansoprazole (Prevacid) ++++Omeprazole (Prilosec) +++Paroxetine (Asimia, Paxil) +++Probenicid (Colbenemid, Probene) +Ticlopidine (Ticlid) +++Topiramate (Topamax) ++

Relative Effect at2C19 Inducers Usual Therapeutic DoseCarbamazepine ++

(Carbatrol, Epital, Tegretol)Norethindrone +

(Brevicon, Norinyl, Ortho-Novum)NOT pentobarbital ~

(Nembutal, Pentobarb)Prednisone (Deltasone, +

Liquid Pred, Orasone, Sterapred)Rifampin (Rifadin, ++

Rifamate, Rimactane)

2C9 SubstratesAmitriptyline (Elavil, Endep) Phenytoin (Dilantin)Fluoxetine (Prozac, Sarafem) S-warfarin (Coumadin)

Relative Effect at2C9 Inhibitors Usual Therapeutic DoseAmiodarone (Cordarone, Pacerone) +++Fluconazole (Diflucan) ++Fluvastatin (Lescol) ++Fluvoxamine (Luvox) +Isoniazid (Rifater, Nydrazid) +Lovastatin (Altocor, Mevacor) +++Paroxetine (Paxil, Asimia) ++Phenylbutazone +Probenicid (Colbenemid, Probene) ++Sertraline (Zoloft) +++Sulfamethoxazole (Bactrim, Bethaprim, +++

Cotrim, Septra, Sulfatrim, Trimeth-Sulfa, Gantanol)

Sulfaphenazole +Teniposide (Vumon) +++Trimethoprim (Trimeth-Sulfa, Proloprim, +

Trimpex, Polytrim)Zafirlukast (Accolate) ++

2C9 InducersRifampin (Rifadin, Rimactane, Rifamate) ++Secobarbital (Seconal, Tuinal) ++

2D6 SubstratesAntidepressantsAmitriptyline (Elavil, Endep) Imipramine (Tonfanil)Clomipramine (Anafril) Nortriptyline (Pamelor)Desipramine (Norpramin) Paroxetine (Paxil, Asimia)

AntipsychoticsAripiprazole (Abilify) Risperidone (Risperdal)Haloperidol (Haldol) Thioridazine (Mellaril)Perphenazine (Trilafon)

AmphetaminesChlorpheniramine Methoxyamphetamine

(Chlor-Trimeton, Efidac) MinaprineChlorpromazine (Thorazine) Nortriptyline (Pamelor)Codeine QuanoxanDexfenfluramine (Redux) SparteineFluoxetine (Prozac, Sarafem) Tramadol (Ultram, Ultracet)Fluvoxamine (Luvox) Venlafaxine (Effexor)Metoclopramide (Reglan,

Metoclopram)



Table 15 (cont)Drugs Categorized as Specific CYP Enzyme Substrates, Inhibitors, or Inducers to Permit Prediction of CYPMediated Drug-Drug Interactions2

2D6 InhibitorsAmiodarone (Cordarone, Pacerone) +++Bupropion (Wellbutrin, Zyban) +++Celecoxib (Celbrex) ++Chlorpromazine (Thorazine) +++Chlorpheniramine (Chlor-Trimeton, Efidac) +Cimetidine (Tagamet) +Citalopram (Celexa) +Clomipramine (Anafril) +Escitalopram (Lexapro) +Fluoxetine (Prozac, Sarafem) +++Red-haloperidol (Haldol) ++Levomepromazine ++Methadone (Dolophine) ++Metoclopramide (Metoclopram, Reglan) +Mibefradil (Posicor) +Moclobemide (Manerix) +Paroxetine (Paxil, Asimia) +++Quinidine (Quinaglute, Cardioquin, Quinidex) +++Ranitidine (Tritec, Zantac) +Sertraline (Zoloft) +Terbinafine (Lamisil) ++

2E1 SubstratesAcetaminophen (Tylenol, etc)Chlorzoxazone (Paraflex, Parafon Forte)

Relative Effect at2E1 Inhibitors Usual Therapeutic DoseDiethyl-dithiocarbamate +++Disulfiram (Antabuse) +++

2E1 InducersEthanol (Dehydrated alcohol) ++Isoniazid (Nydrazid, Rifater) ++

3A4, 3A5, 3A7 SubstratesBenzodiazepinesAlprazolam (Xanax) Midazolam (Versed)Diazepam (Diastat, Dizac, Valium) Triazolam (Halcion)

AntihistaminesAstemizole (Hismanal)Chlorpheniramine (Chlor-Trimeton, Efidac)Terfenidine (Seldane)

MiscellaneousAlfentanyl (Alfenta) DextromethorphanAripiprazole (Abilify) (Benylin DM, Delsym, Buspirone (Buspar) Touro DM, Tussi Org)Codeine-N-demethylation Donepezil (Aricept)

Miscellaneous (cont)Eplerenone (Inspra) Pimozide (Orap)Fentanyl (Actiq, Duragesic, Quetiapine (Seroquel) Sublimaze) Trazodone (Desyrel)

Haloperidol (Haldol) Zaleplon (Sonata)Methadone (Dolophine) Ziprasidone (Geodon)Nefazodone (Serzone) (minor pathway)Ondansetron (Zofran) Zolpidem (Ambien)O-desmethylvenlafaxine (major metabolite ofvenlafaxine)

Relative Effect at3A4,5,7 Inhibitors Usual Therapeutic DoseHIV AntiviralsAmiodarone (Cordarone, Pacerone) +++NOT azithromycin (Zithromax) ~Cimetidine (Tagamet) +++Clarithromycin (Biaxin) +++Delaviridine (Rescriptor) ++Diltiazem (Cartia, Cardizem, Dilacor, ++

Diltiazem, Taztia, Tiamate, Tiazac)Erythromycin (Emgel) ++Fluconazole (Diflucan) ++Fluvoxamine (Luvox) ++Gestodene ++Grapefruit juice +++Indinavir (Crixivan) ++Itraconazole (Sporanox) +++Ketoconazole (Nizoral) +++Nefazodone (Serzone) +++Nelfinavir (Viracept) ++Norfloxacin (Chibroxin, Noroxin) +Norfluoxetine ++Ritonavir (Norvir) +++Saquinavir (Fortovase, Invirase) +Verapamil (Calan, Covera, Isoptin) +++

3A4,5,7 InducersHIV AntiviralsBarbiturates ++Carbamazepine (Carbatrol, Epital, Tegretol) ++Efavirenz (Sustiva) ++Modafinil (Provigil) +Nevirapine (Viramune) ++Phenobarbital (Phenob) ++Phenytoin (Dilantin) ++Rifabutin (Mycobutin) ++Rifampin (Rifadin, Rifamate, Rimactane) ++St. John’s wort (Hypericum perforatum) ++

CYP=cytochrome P450; DDIs=drug-drug interactions; HIV=human immunodeficiency virus.

Inhibition variable: +=<2–fold increase plasma drug levels; ++=>2–4–fold; +++=>4–fold.

Induction variable: ~=usual clearance; +=<2 usual clearance; ++=>2 usual clearance




Table 18Reporting Adverse Drug ReactionsMedWatch: 1-800-FDA-1088, Fax: 1-800-FDA-0178Report online at: www.fda.gov/medwatch Practitioner reporting online at: www.usp.orgFDA=Food and Drug Administration.


Table 16Potential Mechanisms Underlying Pharmacokinetic Drug-Drug Interactions57

• Protein binding* • Phase I enzymes • Phase II enzymes • ABC transporters • Nuclear receptors-CYPs and nonCYPs

*Although firmly entrenched in the minds of physicians, this mechanism rarely mediates clinically significantly as explained in the text.

ABC=ATP-binding casette; CYPs=cytochrome P450.


Table 17Limitations of Current Software Packages3

• May not be mechanism based • Limited knowledge base• Generally only a binary system • Generally either PD or PK but not the interaction of PD and PK• An alert rather than an information system • Little reference base in the literaturePD=pharmacodynamic; PK=pharmacokinetic.

©Preskorn.


Appendix IICurrent Drug Drug Interactions Software Packages65-69

•Drug facts and comparisons •Epocrates •Hansten’s•Mhc.com/Cytochromes •MicromedexPreskorn SH, Flockhart D. Primary Psychiatry. Vol 11, No 2. 2004.

Appendix IWeb Sites* for Additional Information2,3,60-64

Description Web sitePsychiatric Drug Interactions http://www.preskorn.comCytochrome P450 Interactions http://www.drug-interactions.comFDA Food and Drug Interactions http://vm.cfsan.fda.gov/~lrd/fdinter.htmlHerbal Interactions http://www.personalhealthzone.com/herbsafety.htmlHIV Drug Interactions http://www.hiv-druginteractions.org/HIV Drug Interactions http://www.projinf.org/fs/drugin.htmlGrapefruit Juice – Drug Interactions http://www.powernetdesign.com/grapefruit/

* While there are a large number of unreferenced Web sites available on the Internet, all of the sites in this table contain direct references or links to peer-reviewed medical literature.

FDA=Food and Drug Administration; HIV=human-immunodeficiency virus.


To receive a complimentary pocket reference guide version of this educational review, please e-mail your request to:

[email protected] or fax it to (212) 328-0600.



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at et primary psychiatry ... · terization of novel therapeutic targets in the human brain. while a...

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