Case Studies Bipolar and Other Psychiatric Disorders

8/12/2019 Case Studies Bipolar and Other Psychiatric Disorders

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Neil B. Sandson, M.D.

Director, Division of Education andDirector, Division of Education andResidency Training; Sheppard Pratt HealthResidency Training; Sheppard Pratt HealthSystemSystem

Director, Psychopharmacology ConsultationDirector, Psychopharmacology ConsultationService; Sheppard Pratt Health SystemService; Sheppard Pratt Health System

Clinical Assistant Professor, University ofClinical Assistant Professor, University ofMaryland Medical School, Department ofMaryland Medical School, Department ofPsychiatryPsychiatry


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Psychiatric Case Studies --Organized Pharmacokinetically

CarbamazepineCarbamazepine

PhenytoinPhenytoin

LithiumLithium

LamotrigineLamotrigine

ValproateValproate

Other anticonvulsantsOther anticonvulsantsAnalgesic agentsAnalgesic agents

Various antidepressants and antipsychotic agentsVarious antidepressants and antipsychotic agents


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2D6 VignetteSad and SoreSad and Sore

Fluoxetine was added toFluoxetine was added to hydrocodonehydrocodone ..2D6 was inhibited.2D6 was inhibited.

HydrocodoneHydrocodone was not able to be metabolizedwas not able to be metabolizedintointo hydromorphonehydromorphone ..Loss of analgesia resulted.Loss of analgesia resulted.Analgesia returned with removal of fluoxetine.Analgesia returned with removal of fluoxetine.Similar issues encountered with codeineSimilar issues encountered with codeine morphine andmorphine and tramadoltramadol M1.M1.


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3A4 VignettesNatural DisasterNatural Disaster

St. JohnsSt. Johns wortwort was added towas added to cyclosporincyclosporin in ain arecent heart transplant recipient.recent heart transplant recipient.

3A4 and P3A4 and P --glycoprotein were induced.glycoprotein were induced.The blood level ofThe blood level of cyclosporincyclosporin significantlysignificantlydecreased.decreased.

Rejection of the donor heart ensued.Rejection of the donor heart ensued.AlthoughAlthough PgPPgP would not be involved, this DDIwould not be involved, this DDIdoes occur with CBZ, PHT, ordoes occur with CBZ, PHT, or phenobarbital phenobarbital ininthe place of SJW and/or withthe place of SJW and/or with tacrolimustacrolimus in thein the

place of place of cyclosporincyclosporin ..


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3A4 Vignettes

ParanoiaParanoiaPhenytoin was added toPhenytoin was added to quetiapinequetiapine ..3A4 was induced.3A4 was induced.This led to a fivefold increase in theThis led to a fivefold increase in theclearance ofclearance of quetiapinequetiapine with a markedwith a marked

decrease in thedecrease in the quetiapinequetiapine blood level. blood level.This led to a recurrence of paranoidThis led to a recurrence of paranoiddelusions and inpatient hospitalization.delusions and inpatient hospitalization.


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3A4 VignettesUnplanned ParenthoodUnplanned Parenthood

CarbamazepineCarbamazepine was added to OCP.was added to OCP.3A4 was induced.3A4 was induced.

The blood level ofThe blood level of ethinylethinyl estradiolestradiol (EE)(EE)significantly decreased.significantly decreased.Unintended pregnancy ensued.Unintended pregnancy ensued.This could just as easily have happened withThis could just as easily have happened withthe addition of phenytoin,the addition of phenytoin, phenobarbital phenobarbital ,,topiramatetopiramate , or, or oxcarbazepineoxcarbazepine to EE.to EE.


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3A4 VignettesAtaxicAtaxic

Erythromycin was added toErythromycin was added to carbamazepinecarbamazepine ..3A4 and P3A4 and P --glycoprotein were inhibited.glycoprotein were inhibited.

The blood level ofThe blood level of carbamazepinecarbamazepine roserosesignificantly.significantly.Sedation, ataxia, slurred speech, and jerkingSedation, ataxia, slurred speech, and jerkingmotions of arms resulted.motions of arms resulted.Although it was not a factor in this case,Although it was not a factor in this case, CBZsCBZsinduction of 3A4 could well have rendered theinduction of 3A4 could well have rendered theerythromycin ineffective.erythromycin ineffective.


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3A4 VignettesGradual WithdrawalGradual Withdrawal

CarbamazepineCarbamazepine was added to chronicwas added to chronicmethadone.methadone.

3A4 was induced.3A4 was induced.The blood level of methadone decreasedThe blood level of methadone decreasedsignificantly (by about 60%).significantly (by about 60%).

OpioidOpioid withdrawal resulted.withdrawal resulted.This could also have occurred if PHT orThis could also have occurred if PHT or

phenobarbital phenobarbital was added to methadone.was added to methadone.


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3A4 VignettesInhibitor InductionInhibitor Induction

SJW was added toSJW was added to indinavir indinavir ..3A4 and P3A4 and P --glycoprotein were induced.glycoprotein were induced.

The blood level ofThe blood level of indinavir indinavir decreaseddecreasedsignificantly.significantly.An abrupt drop in the CD4 count resulted.An abrupt drop in the CD4 count resulted.

The success of HAART may be jeopardized byThe success of HAART may be jeopardized bythe addition of 3A4 inducers (CBZ, PHT,the addition of 3A4 inducers (CBZ, PHT,

phenobarbital phenobarbital , etc.) if this effect is not, etc.) if this effect is notanticipated and compensated for.anticipated and compensated for.


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3A4 Vignettes

Gradual Withdrawal IIGradual Withdrawal IICarbamazepineCarbamazepine was added towas added to alprazolamalprazolam ..

3A4 was induced.3A4 was induced.

The blood level ofThe blood level of alprazolamalprazolam decreaseddecreasedsignificantly.significantly.

Again, this may occur with other 3A4Again, this may occur with other 3A4inducers (PHT, Phenobarbital, etc.).inducers (PHT, Phenobarbital, etc.).


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3A4 Vignettes

Cholesterol 451Cholesterol 451Phenytoin was added toPhenytoin was added to atorvastatinatorvastatin ..

3A4 was induced.3A4 was induced.

The blood level ofThe blood level of atorvastatinatorvastatin decreaseddecreasedsignificantly, leading to an increase insignificantly, leading to an increase incholesterol level.cholesterol level.


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1A2 and Phase II Vignette

Conspiracy TheoryConspiracy TheoryCarbamazepineCarbamazepine was added towas added to olanzapineolanzapine ..

1A2 and UGT 1A4 were induced.1A2 and UGT 1A4 were induced.

The blood level ofThe blood level of olanzapineolanzapine decreaseddecreasedsignificantly (roughly 40%).significantly (roughly 40%).

This resulted in a recurrence of psychoticThis resulted in a recurrence of psychoticsymptoms.symptoms.


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2C9/2C19 VignettesNystagmusNystagmus

Fluoxetine was added to phenytoin.Fluoxetine was added to phenytoin.2C9 and 2C19 (and2C9 and 2C19 (and PgPPgP ) were inhibited.) were inhibited.The phenytoin blood level significantlyThe phenytoin blood level significantlyincreased (by almost 100%), resulting inincreased (by almost 100%), resulting in

sedation, vertigo, andsedation, vertigo, and nystagnusnystagnus ..This DDI is even more marked whenThis DDI is even more marked whenfluvoxaminefluvoxamine is added to PHT.is added to PHT.


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2C9/2C19 VignettesDouble FaultDouble Fault

FluconazoleFluconazole was added to phenytoinwas added to phenytoin2C9 was inhibited.2C9 was inhibited.

The blood level of PHT rose significantly,The blood level of PHT rose significantly, producing nausea, slurred speech, and producing nausea, slurred speech, andincoordinationincoordination ..

FluconazoleFluconazole can also increase CBZ levels,can also increase CBZ levels,although this is likely more attributable to itsalthough this is likely more attributable to itsmoderate inhibition of 3A4 than its potentmoderate inhibition of 3A4 than its potent

inhibition of 2C9.inhibition of 2C9.


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2C9/2C19 Vignettes

From Heartbreak to HeartburnFrom Heartbreak to HeartburnOmeprazole was added to PHT.Omeprazole was added to PHT.

2C19 and P2C19 and P --glycoprotein were inhibited.glycoprotein were inhibited.

The blood level of PHT roseThe blood level of PHT rosesignificantly, producing moderate PHTsignificantly, producing moderate PHTtoxicity symptoms.toxicity symptoms.


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2C9/2C19 VignettesSensitiveSensitive

TopiramateTopiramate was added to phenytoin.was added to phenytoin.2C19 was inhibited.2C19 was inhibited.

The blood level of PHT increased significantlyThe blood level of PHT increased significantly(nearly 50%), leading to ataxia and drowsiness.(nearly 50%), leading to ataxia and drowsiness.Although this did not come to light in this case,Although this did not come to light in this case,

PHTsPHTs induction of phase II enzymes is likelyinduction of phase II enzymes is likelyresponsible for the roughly 50% decreases inresponsible for the roughly 50% decreases intopiramatetopiramate levels that occur with thislevels that occur with this

combination.combination.


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2B6 VignetteOptimizationOptimization

Phenytoin was added to the regimen of a patientPhenytoin was added to the regimen of a patientwithwith nonseminomatousnonseminomatous testicular CA due totesticular CA due tonew onset seizures.new onset seizures.After two unsuccessful courses ofAfter two unsuccessful courses ofchemotherapy, his third course, which includedchemotherapy, his third course, which includedifosfamideifosfamide , was successful., was successful.It is possible thatIt is possible that PHTsPHTs induction of 2B6 led toinduction of 2B6 led tomore conversion of the pseudomore conversion of the pseudo -- prodrug prodrug

ifosfamideifosfamide into its more active metabolite.into its more active metabolite.


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Non-P450 VignetteDisplacedDisplaced

Daily ASA was added to VPADaily ASA was added to VPAASA both inhibitedASA both inhibited --oxidation and displacedoxidation and displaced

VPA fromVPA from plasma protein binding sites. plasma protein binding sites.This led to only a modest increase in the totalThis led to only a modest increase in the totalVPA level, but a roughly 150% increase in theVPA level, but a roughly 150% increase in the

free VPA level.free VPA level.The patient experienced sudden onset of severeThe patient experienced sudden onset of severefatigue, sedation, andfatigue, sedation, and incoordinationincoordination ..


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Complex P450 VignettesVertigoVertigo

CBZ was added toCBZ was added to phenobarbital phenobarbital ..1A2, 3A4, and 2C8/9 were induced by1A2, 3A4, and 2C8/9 were induced by

phenobarbital phenobarbital ..The level of CBZ dropped and theThe level of CBZ dropped and the

phenobarbital phenobarbital level remained unchanged.level remained unchanged.The patient experienced mild sedation butThe patient experienced mild sedation butsignificant vertigo.significant vertigo.


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Complex P450 VignettesVertigo (cont.)Vertigo (cont.)

These sideThese side --effects may have beeneffects may have beenattributable to aattributable to a pharmacodynamic pharmacodynamicsynergy, but another possibility is thatsynergy, but another possibility is that

phenobarbitals phenobarbitals induction of 3A4 led toinduction of 3A4 led to

increased production of CBZincreased production of CBZ --10,1110,11 --epoxide.epoxide.


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Complex P450 VignettesRisky RegimenRisky Regimen

CarbamazepineCarbamazepine was added towas added to valproatevalproate ..CBZ induced phase II enzymes, leading to aCBZ induced phase II enzymes, leading to a

roughly 60% decrease in VPA levels.roughly 60% decrease in VPA levels.Also,Also, CBZsCBZs induction of (probably) 2C9 led toinduction of (probably) 2C9 led toincreased production of theincreased production of the hepatotoxichepatotoxic 44--eneene --

valproate metabolite.valproate metabolite.VPAsVPAs inhibition ofinhibition of epoxideepoxide hydrolasehydrolase led toled toincreased levels of CBZincreased levels of CBZ --10,1110,11 --epoxide.epoxide.


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Complex P450 VignettesRisky Regimen (cont.)Risky Regimen (cont.)

Results:Results:

Increased lethargy and irritabilityIncreased lethargy and irritability

Unsteady gaitUnsteady gait

First grand mal seizure in two yearsFirst grand mal seizure in two years


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Complex P450 VignettesHighHigh --LowLow

PhenytoinPhenytoin was added towas added to valproatevalproate

VPA both inhibited 2C9 and displacedVPA both inhibited 2C9 and displacedPHT from plasma protein binding sites,PHT from plasma protein binding sites,thus increasing the total PHT level, with athus increasing the total PHT level, with a

disproportionate increase in the freedisproportionate increase in the freeconcentration of PHT.concentration of PHT.


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Complex P450 VignettesHighHigh --Low (cont.)Low (cont.)

PHT induced 2C9/19 and phase IIPHT induced 2C9/19 and phase IIenzymes, leading to:enzymes, leading to:

A decrease in the VPA level, andA decrease in the VPA level, and

Increased production of theIncreased production of thehepatotoxichepatotoxic 44--eneene --valproatevalproatemetabolite.metabolite.


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Complex P450 VignettesHighHigh --Low (cont.)Low (cont.)

Results:Results:Acutely, moderate sedation and twitchingAcutely, moderate sedation and twitching

eyeballseyeballsTwo weeks later, a recurrence of maniaTwo weeks later, a recurrence of maniaVPA level had declined from 105VPA level had declined from 105 g/mLg/mL toto

6262 g/mLg/mL , while the PHT level had, while the PHT level hadincreased from 17increased from 17 g/mLg/mL to 23to 23 g/mLg/mL (no(nofree levels were obtained).free levels were obtained).


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Phase II VignettesContraceptive ConvulsionContraceptive Convulsion

An OCP was added toAn OCP was added to lamotriginelamotrigine (which was(which was being used as an anticonvulsant). being used as an anticonvulsant).

EE induced the production of glucuronidationEE induced the production of glucuronidationenzyme 1A4, which metabolizesenzyme 1A4, which metabolizes lamotriginelamotrigine ..The blood level ofThe blood level of lamotriginelamotrigine decreaseddecreased

significantly, producing a grand mal seizure.significantly, producing a grand mal seizure.CBZ, PHT,CBZ, PHT, phenobarbital phenobarbital , and, and oxcarbazepineoxcarbazepine(more weakly) also induce the metabolism of(more weakly) also induce the metabolism of

lamotriginelamotrigine ..


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Phase II VignettesRash Decision (I)Rash Decision (I)

This same patient doubled herThis same patient doubled her lamotriginelamotrigine dosedoseto compensate for the EE, and remainedto compensate for the EE, and remainedseizureseizure --free for years.free for years.EE was then discontinued due to DVT.EE was then discontinued due to DVT.A reversal of induction of glucuronidationA reversal of induction of glucuronidation

enzyme 1A4 occurred.enzyme 1A4 occurred.This led to a rapid increase in theThis led to a rapid increase in the lamotriginelamotrigine blood level, resulting in a drug rash. blood level, resulting in a drug rash.


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Phase II VignettesRash Decision(II)Rash Decision(II)

DivalproexDivalproex was added towas added to lamotriginelamotrigine ..

Glucuronidation enzyme 1A4 was inhibited.Glucuronidation enzyme 1A4 was inhibited.

The blood level ofThe blood level of lamotriginelamotrigine roserosesignificantly and rapidly.significantly and rapidly.

A drug rash ensued.A drug rash ensued.

The addition of sertraline toThe addition of sertraline to lamotriginelamotrigine cancanalso doublealso double lamotriginelamotrigine blood levels. blood levels.


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Lithium VignetteThe TremulousThe Tremulous TriathleteTriathlete

IndomethacinIndomethacin was added to lithium.was added to lithium.

Inhibition of prostaglandin synthesisInhibition of prostaglandin synthesisinterfered with the excretion of lithium.interfered with the excretion of lithium.

The lithium level increased significantlyThe lithium level increased significantly(about 50% in this case), resulting in(about 50% in this case), resulting in

polyuria polyuria , feeling spacey, and tremor., feeling spacey, and tremor.


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Lithium DDIsLithium levels are decreased by:Lithium levels are decreased by:

XanthinesXanthines (incl. Caffeine) and osmotic(incl. Caffeine) and osmoticdiureticsdiuretics

Loop diuretics produce little or no change inLoop diuretics produce little or no change inlithium levelslithium levels inconsistent andinconsistent and

unpredictable.unpredictable.


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P-glycoprotein VignettesStuporStupor

Omeprazole was added toOmeprazole was added to carbamazepinecarbamazepine ..

Omeprazole inhibited POmeprazole inhibited P --glycoprotein function.glycoprotein function.

More absorption ofMore absorption of carbamazepinecarbamazepine resulted.resulted.The blood level ofThe blood level of carbamazepinecarbamazepine increasedincreasedsignificantly.significantly.

Frank delirium ensued.Frank delirium ensued.


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P-glycoprotein VignettesFlaggelatedFlaggelated

MetronidazoleMetronidazole was added towas added to carbamazepinecarbamazepine ..Indirect evidence leads me to believe thatIndirect evidence leads me to believe thatmetronidazolemetronidazole is a Pis a P --glycoprotein inhibitor,glycoprotein inhibitor,which would thus yield increased absorption ofwhich would thus yield increased absorption ofcarbamazepinecarbamazepine ..

In actuality, this combination did produceIn actuality, this combination did producenotable ataxia and delirium. Anotable ataxia and delirium. A carbamazepinecarbamazepinelevel was 27 micrograms/ml (therapeutic rangelevel was 27 micrograms/ml (therapeutic range= 4= 4 --12 micrograms/ml).12 micrograms/ml).


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Take-home messagesPreferentially use safer psychoactive agents.Preferentially use safer psychoactive agents.

AntidepressantsAntidepressantscitalopramcitalopram ((Celexa)/escitalopramCelexa)/escitalopram ((LexaproLexapro ))

mirtazepinemirtazepine ((RemeronRemeron ))venlafaxine (venlafaxine ( Effexor Effexor ))

AnxiolyticsAnxiolytics

lorazepamlorazepam ((AtivanAtivan ))oxazepamoxazepam ((SeraxSerax ))

clonazepamclonazepam ((KlonopinKlonopin ))


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Take-home messagesAntipsychoticsAntipsychotics

Beware of 1A2 effects, especially inductionBeware of 1A2 effects, especially inductionthrough smokingthrough smoking ---- applies toapplies to typicalstypicals ,,olanzapineolanzapine , and, and clozapineclozapine ..Beware of 3A4 inhibition and inductionBeware of 3A4 inhibition and induction ----applies toapplies to aripiprazolearipiprazole , RISP, and, RISP, and quetiapinequetiapine ..

Mood stabilizersMood stabilizersMany (but not all) of these are inducers,Many (but not all) of these are inducers,which can undermine the efficacy of otherwhich can undermine the efficacy of other

agents.agents.


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Take-home messagesPreferentially use safer somatic agents.Preferentially use safer somatic agents.

pravastatin pravastatin

azithromycinazithromycin

HH--2 blockers2 blockers other thanother than cimetidine.cimetidine.


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Take home messagesKeep reliable references and otherKeep reliable references and otherinformation sources close at hand.information sources close at hand.

Drug Interaction Principles for MedicalDrug Interaction Principles for MedicalPractice: Cytochrome P450s,Practice: Cytochrome P450s, UGTsUGTs , P, P --GlycoproteinsGlycoproteins , by Kelly, by Kelly CozzaCozza , M.D.,, M.D.,

Scott Armstrong, M.D., and JessicaScott Armstrong, M.D., and JessicaOesterheldOesterheld , M.D., M.D.


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Take home messagesDrug Interactions Casebook: TheDrug Interactions Casebook: TheCytochrome P450 System and Beyond,Cytochrome P450 System and Beyond,

by Neil by Neil SandsonSandson , M.D., M.D.

Dr.Dr. OesterheldsOesterhelds site is at:site is at:http://www.mhc.com/Cytochromeshttp://www.mhc.com/Cytochromes

Pub med is at:Pub med is at:http://http:// www.ncbi.nlm.nih.gov/pubmedwww.ncbi.nlm.nih.gov/pubmed
http://www.mhc.com/Cytochromeshttp://www.mhc.com/Cytochromeshttp://www.mhc.com/Cytochromes


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Take home messagesDr.Dr. FlockhartsFlockharts site is at:site is at: www.drugwww.drug --interactions.cominteractions.com (hyperlinks to pub med).(hyperlinks to pub med).The Physicians Desk Reference online is at:The Physicians Desk Reference online is at:

www.pdr.netwww.pdr.netExisting drug interaction programs (Existing drug interaction programs ( ePocratesePocrates ,,ePocratesePocrates RxProRxPro , MICROMEDEX, etc.) are not, MICROMEDEX, etc.) are not

great (in my humble opinion), but they are agreat (in my humble opinion), but they are agood deal better than nothing.good deal better than nothing.
http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/http://www.drug-interactions.com/


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Take-home messagesMost importantly, listen to the patient.Most importantly, listen to the patient.

Unless they are notoriously unreliable, theirUnless they are notoriously unreliable, theirreports of difficulties are much morereports of difficulties are much morevaluable and accurate than what littlevaluable and accurate than what littleunderstanding we have about how our drugsunderstanding we have about how our drugs

work, how they fail, and how they interactwork, how they fail, and how they interactwith other drugs.with other drugs.


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Take-home messagesGood luck, and may all your interactions beGood luck, and may all your interactions be

benign. benign.

Case Studies Bipolar and Other Psychiatric Disorders

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