The Role of Pharmacogenomics in Bipolar and Other Psychiatric Disorders – Case Studies WithWith aa FocusFocus onon DDIsDDIs Neil B. Sandson, M.D. Director,Director, DivisionDivision ofof EducationEducation andand ResidencyResidency Training;Training; SheppardSheppard PrattPratt HealthHealth SystemSystem Director,Director, PsychopharmacologyPsychopharmacology ConsultationConsultation Service;Service; SheppardSheppard PrattPratt HealthHealth SystemSystem ClinicalClinical AssistantAssistant Professor,Professor, UniversityUniversity ofof MarylandMaryland MedicalMedical School,School, DepartmentDepartment ofof PsychiatryPsychiatry Psychiatric Case Studies -- Organized Pharmacokinetically CarbamazepineCarbamazepine (CBZ)(CBZ) PhenytoinPhenytoin (PHT)(PHT) LithiumLithium LamotrigineLamotrigine ValproateValproate OtherOther anticonvulsantsanticonvulsants AnalgesicAnalgesic agentsagents VariousVarious antidepressantsantidepressants andand antipsychoticantipsychotic agentsagents Non-standard abbreviations CACA == cancercancer CBZCBZ == carbamazepinecarbamazepine DDIDDI == drugdrug--dependentdependent interactioninteraction PgPPgP == PP--glycoproteinglycoprotein PHTPHT == phenytoinphenytoin SJWSJW == St.St. JohnJohn’’ss wortwort VPAVPA == valproicvalproic acidacid 2D6 Vignette SadSad andand SoreSore FluoxetineFluoxetine waswas addedadded toto hydrocodonehydrocodone.. 2D62D6 waswas inhibited.inhibited. HydrocodoneHydrocodone waswas notnot ableable toto bebe metabolizedmetabolized intointo hydromorphonehydromorphone.. LossLoss ofof analgesiaanalgesia resulted.resulted. AnalgesiaAnalgesia returnedreturned withwith removalremoval ofof fluoxetine.fluoxetine. SimilarSimilar issuesissues encounteredencountered withwith codeinecodeine →→ morphinemorphine andand tramadoltramadol →→ M1.M1. 3A4 Vignettes NaturalNatural DisasterDisaster St.St. JohnJohn’’ss wortwort waswas addedadded toto cyclosporincyclosporin inin aa recentrecent heartheart transplanttransplant recipient.recipient. 3A43A4 andand PP--glycoproteinglycoprotein werewere induced.induced. TheThe bloodblood levellevel ofof cyclosporincyclosporin significantlysignificantly decreased.decreased. RejectionRejection ofof thethe donordonor heartheart ensued.ensued. AlthoughAlthough PgPPgP wouldwould notnot bebe involved,involved, thisthis DDIDDI doesdoes occuroccur withwith CBZ,CBZ, PHT,PHT, oror phenobarbitalphenobarbital inin thethe placeplace ofof SJWSJW and/orand/or withwith tacrolimustacrolimus inin thethe placeplace ofof cyclosporincyclosporin.. 3A4 Vignettes ParanoiaParanoia PhenytoinPhenytoin waswas addedadded toto quetiapinequetiapine.. 3A43A4 waswas induced.induced. ThisThis ledled toto aa fivefive--foldfold increaseincrease inin thethe clearanceclearance ofof quetiapinequetiapine withwith aa markedmarked decreasedecrease inin thethe quetiapinequetiapine bloodblood level.level. ThisThis ledled toto aa recurrencerecurrence ofof paranoidparanoid delusionsdelusions andand inpatientinpatient hospitalization.hospitalization. 3A4 Vignettes UnplannedUnplanned ParenthoodParenthood CarbamazepineCarbamazepine waswas addedadded toto OCP.OCP. 3A43A4 waswas induced.induced. TheThe bloodblood levellevel ofof ethinylethinyl estradiolestradiol (EE)(EE) significantlysignificantly decreased.decreased. UnintendedUnintended pregnancypregnancy ensued.ensued. ThisThis couldcould justjust asas easilyeasily havehave happenedhappened withwith thethe additionaddition ofof phenytoin,phenytoin, phenobarbital,phenobarbital, topiramatetopiramate,, oror oxcarbazepineoxcarbazepine toto EE.EE. 3A4 Vignettes BitterBitter FruitFruit GrapefruitGrapefruit juicejuice waswas addedadded toto carbamazepine.carbamazepine. 3A43A4 andand PP--glycoproteinglycoprotein werewere inhibited.inhibited. TheThe bloodblood levellevel ofof carbamazepinecarbamazepine roserose significantly.significantly. Sedation,Sedation, nausea,nausea, andand tremortremor resulted.resulted. ManyMany hospitalshospitals havehave removedremoved grapefruitgrapefruit juicejuice fromfrom theirtheir menusmenus duedue toto thesethese concerns.concerns. 3A4 Vignettes AtaxicAtaxic ErythromycinErythromycin waswas addedadded toto carbamazepine.carbamazepine. 3A43A4 andand PP--glycoproteinglycoprotein werewere inhibited.inhibited. TheThe bloodblood levellevel ofof carbamazepinecarbamazepine (CBZ)(CBZ) roserose significantly.significantly. Sedation,Sedation, ataxia,ataxia, slurredslurred speech,speech, andand jerkingjerking motionsmotions ofof armsarms resulted.resulted. AlthoughAlthough itit waswas notnot aa factorfactor inin thisthis case,case, CBZCBZ’’ss inductioninduction ofof 3A43A4 couldcould wellwell havehave renderedrendered thethe erythromycinerythromycin ineffective.ineffective. 3A4 Vignettes GradualGradual WithdrawalWithdrawal CarbamazepineCarbamazepine waswas addedadded toto chronicchronic methadone.methadone. 3A43A4 waswas induced.induced. TheThe bloodblood levellevel ofof methadonemethadone decreaseddecreased significantlysignificantly (by(by aboutabout 60%).60%). OpioidOpioid withdrawalwithdrawal resulted.resulted. ThisThis couldcould alsoalso havehave occurredoccurred ifif PHTPHT oror phenobarbitalphenobarbital waswas addedadded toto methadone.methadone. 3A4 Vignettes InhibitorInhibitor InductionInduction St.St. JohnJohn’’ss WortWort waswas addedadded toto indinavirindinavir.. 3A43A4 andand PP--glycoproteinglycoprotein werewere induced.induced. TheThe bloodblood levellevel ofof indinavirindinavir decreaseddecreased significantly.significantly. AnAn abruptabrupt dropdrop inin thethe CD4CD4 countcount resulted.resulted. TheThe successsuccess ofof HAARTHAART maymay bebe jeopardizedjeopardized byby thethe additionaddition ofof 3A43A4 inducersinducers (CBZ,(CBZ, PHT,PHT, phenobarbital,phenobarbital, etc.)etc.) ifif thisthis effecteffect isis notnot anticipatedanticipated andand compensatedcompensated for.for. 3A4 Vignettes GradualGradual WithdrawalWithdrawal IIII CarbamazepineCarbamazepine (CBZ)(CBZ) waswas addedadded toto alprazolamalprazolam.. 3A43A4 waswas induced.induced. TheThe bloodblood levellevel ofof alprazolamalprazolam decreaseddecreased significantly.significantly. Again,Again, thisthis maymay occuroccur withwith otherother 3A43A4 inducersinducers (PHT,(PHT, phenobarbital,phenobarbital, etc.).etc.). 3A4 Vignettes CholesterolCholesterol 451451 PhenytoinPhenytoin waswas addedadded toto atorvastatinatorvastatin.. 3A43A4 waswas induced.induced. TheThe bloodblood levellevel ofof atorvastatinatorvastatin decreaseddecreased significantly,significantly, leadingleading toto anan increaseincrease inin cholesterolcholesterol level.level. 1A2 and Phase II Vignette ConspiracyConspiracy TheoryTheory CarbamazepineCarbamazepine waswas addedadded toto olanzapineolanzapine.. 1A21A2 andand UGTUGT 1A41A4 werewere induced.induced. TheThe bloodblood levellevel ofof olanzapineolanzapine decreaseddecreased significantlysignificantly (roughly(roughly 40%).40%). ThisThis resultedresulted inin aa recurrencerecurrence ofof psychoticpsychotic symptoms.symptoms. 2C9/2C19 Vignettes NystagmusNystagmus FluoxetineFluoxetine waswas addedadded toto phenytoin.phenytoin. 2C92C9 andand 2C192C19 (and(and PgPPgP)) werewere inhibited.inhibited. TheThe phenytoinphenytoin bloodblood levellevel significantlysignificantly increasedincreased (by(by almostalmost 100%),100%), resultingresulting inin sedation,sedation, vertigo,vertigo, andand nystagnusnystagnus.. ThisThis DDIDDI isis eveneven moremore markedmarked whenwhen fluvoxaminefluvoxamine isis addedadded toto PHT.PHT. 2C9/2C19 Vignettes DoubleDouble FaultFault FluconazoleFluconazole waswas addedadded toto phenytoinphenytoin (PHT)(PHT) 2C92C9 waswas inhibited.inhibited. TheThe bloodblood levellevel ofof PHTPHT roserose significantly,significantly, producingproducing nausea,nausea, slurredslurred speech,speech, andand incoordinationincoordination.. FluconazoleFluconazole cancan alsoalso increaseincrease CBZCBZ levels,levels, althoughalthough thisthis isis likelylikely moremore attributableattributable toto itsits moderatemoderate inhibitioninhibition ofof 3A43A4 thanthan itsits potentpotent inhibitioninhibition ofof 2C9.2C9. 2C9/2C19 Vignettes FromFrom HeartbreakHeartbreak toto HeartburnHeartburn OmeprazoleOmeprazole waswas addedadded toto PHT.PHT. 2C192C19 andand PP--glycoproteinglycoprotein werewere inhibited.inhibited. TheThe bloodblood levellevel ofof PHTPHT roserose significantly,significantly, producingproducing moderatemoderate PHTPHT toxicitytoxicity symptoms.symptoms. 2C9/2C19 Vignettes JustJust DessertsDesserts ValproateValproate waswas addedadded toto glipizideglipizide.. 2C92C9 waswas inhibited.inhibited. TheThe bloodblood levellevel ofof glipizideglipizide significantlysignificantly increased.increased. ThisThis causedcaused aa decreasedecrease inin thethe patientpatient’’ss serumserum glucoseglucose (51(51 mg/dL)mg/dL) withwith accompanyingaccompanying c/oc/o dizziness,dizziness, sweating,sweating, anxiety,anxiety, andand tachycardiatachycardia (110(110 beats/min).beats/min). 2C9/2C19 Vignettes SensitiveSensitive TopiramateTopiramate waswas addedadded toto phenytoinphenytoin (PHT).(PHT). 2C192C19 waswas inhibited.inhibited. TheThe bloodblood levellevel ofof PHTPHT increasedincreased significantlysignificantly (nearly(nearly 50%),50%), leadingleading toto ataxiaataxia andand drowsiness.drowsiness. AlthoughAlthough thisthis diddid notnot comecome toto lightlight inin thisthis case,case, PHTPHT’’ss inductioninduction ofof phasephase