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Antipsychotics andAntipsychotics andMood Stabilizers:Mood Stabilizers:

PharmacokineticsPharmacokineticsAdverse EffectsAdverse Effects

Drug InteractionsDrug Interactions

Philip G. Janicak, MDPhilip G. Janicak, MD

Professor of PsychiatryProfessor of Psychiatry

Rush University Medical CenterRush University Medical Center

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GoalsGoals AntipsychoticsAntipsychotics

Diagnostic indicationsDiagnostic indications Classification Classification Relevant PharmacokineticsRelevant Pharmacokinetics Serious Adverse EffectsSerious Adverse Effects Drug InteractionsDrug Interactions

Mood StabilizersMood Stabilizers Diagnostic indicationsDiagnostic indications Classification Classification Relevant PharmacokineticsRelevant Pharmacokinetics Serious Adverse EffectsSerious Adverse Effects Drug InteractionsDrug Interactions

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Antipsychotics:Antipsychotics:Diagnostic IndicationsDiagnostic Indications

PsychiatricPsychiatric SchizophreniaSchizophrenia Schizoaffective disorderSchizoaffective disorder Mood disorders with psychosisMood disorders with psychosis Delusional disorderDelusional disorder

NonpsychiatricNonpsychiatric Dementia/DeliriumDementia/Delirium Psychosis secondary to a non-psychiatric medical disorder Psychosis secondary to a non-psychiatric medical disorder Developmental disability with psychosis and/or aggressionDevelopmental disability with psychosis and/or aggression Tourette’s disorderTourette’s disorder Nausea, vomitingNausea, vomiting

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Positive symptoms:

Delusions*Hallucinations*Disorganized speechCatatonia

Cognitive symptoms:

AttentionMemoryExecutive functions

Moodsymptoms:

DysphoriaSuicidalityHelplessness

Negativesymptoms:

Affective flatteningAlogiaAvolitionAnhedoniaSocial inattentiveness

Occupational

Interpersonal

Self- care

Social

Work

Impact of Schizophrenic Impact of Schizophrenic Symptoms on Overall Symptoms on Overall

FunctioningFunctioning

*Schneiderian First Rank Symptoms4

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Pharmacokinetics of Pharmacokinetics of AntipsychoticsAntipsychotics

ADME profilesADME profiles All are readily absorbedAll are readily absorbed All are metabolized by the hepatic cytochrome All are metabolized by the hepatic cytochrome

P450 systemP450 system prone to drug interactionsprone to drug interactions

TT1/21/2 is generally 20 hours except: is generally 20 hours except: ziprasidone, quetiapine, aripiprazole ziprasidone, quetiapine, aripiprazole

Dosing adjustment in elderly renal and/or Dosing adjustment in elderly renal and/or hepatic impairmenthepatic impairment

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Antipsychotic AgentsAntipsychotic Agents

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Class/Trade Name Generic Name Dosage (average range; PO, qd)

Phenothiazines

Aliphatics

Thorazine Chlorpromazine 100-1000 mg

Sparine Promazine 25-1000 mg

Vesprin Triflupromazine 20-150 mg

Piperidines

Mellaril Thioridazine 30-800 mg

Serentil Mesoridazine 20-200 mg

Quide Piperacetazine 20-160 mg

Piperazines

Stelazine Trifluoperazine 2-60 mg

Prolixin Fluphenzine 5-40 mg

Trilafon Perphenazine 2-60 mg

Tindal Acetophenazine 40-80 mg

Compazine Prochlorperazine 15-125 mg

Thioxanthenes

Navane Thiothixene 6-60 mg

Taractan Chlorprothixene 10-600 mg

Dibenzoxapines

Loxitane Loxapine 20-250 mg

Butyrophenones

Haldol Haloperidol 3-50 mg

Inapsine Droperidol 2.5-10 mg (IM)

Dihydroindolones

Moban Molindone 15-225 mg

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Antipsychotic Agents (con’t)Antipsychotic Agents (con’t)Class/Trade Name Generic Name Dosage (average range; PO, qd)

Dibenzodiazepines

Clozaril Clozapine 100-900 mg

Benzisoxazole

Risperdal

Invega

Risperidone

Paliperidone

2-10 mg

3-12 mg

Thienobenzodiazepines

Zyprexa Olanzapine 5-20 mg

Dibenzothiazepines

Seroquel Quetiapine 75-750 mg

Benzisothiazolyls

Geodon Ziprasidone 40-160 mg

Quinolinones

Abilify Aripiprazole 10-30 mg

Diphenytbutyrylpiperidines

Semap Penfluridol 100 mg/wk

Orap Pimozide 1-10 mg© Janicak 7

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EPS*EPS* HPDLHPDL CLOZCLOZ RISPRISP OLZOLZ QTPQTP ZIPZIP ARIPARIP

NeurologicalNeurological ++++++ 00 ++ 0/+0/+ 00 0/+0/+ 0/+0/+

Weight gain/ Weight gain/ EndocrineEndocrine

++ ++++++ ++++ ++++++ ++++ 0/+0/+ 0/+0/+

AnticholinergicAnticholinergic 00 ++++++ 0/+0/+ +/+++/++ 0/+0/+ 0/+0/+ 00

HematologicalHematological 00 ++++++ 00 00 00 00 00

CardiovascularCardiovascular ++ 0/+0/+ ++ ++ ++ ++++ 00

ProlactinProlactin ++++ 0/+0/+ ++++++ 0/+0/+ 0/+0/+ 0/+0/+ 00

SedationSedation ++ ++++++ ++ +/+++/++ ++++ ++++ ++

PALIPALI

++

++++

0/+0/+

00

++

++++++

++

Adapted from Masand PS et al. Handbook of Psychiatry in Primary Care. 1998.

Antipsychotics:Antipsychotics:Adverse Effect ProfilesAdverse Effect Profiles

*At appropriate doses; 0 = none; + = mild; ++ = moderate; +++ = substantial*At appropriate doses; 0 = none; + = mild; ++ = moderate; +++ = substantial

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Maximum Minimum

HIGH POTENCY RISPERIDONE OLANZAPINE CLOZAPINEFGAs PALIPERIDONE ZIPRASIDONE

(DOSE-RELATED) QUETIAPINE ARIPIPRAZOLE*

ADVERSE EFFECTS OF ANTIPSYCHOTICSADVERSE EFFECTS OF ANTIPSYCHOTICS

Acute EPSAcute EPS

*Based on clinical trial data

• Psuedoparkinsonism

• Dystonia

• Akathisia

• Tardive Dyskinesia

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Dementia PatientsDementia Patients RisksRisks

Mortality rateMortality rate CVA in 4% vs 2%CVA in 4% vs 2% Risks may be Risks may be

higher for all APshigher for all APs

RecommendationsRecommendations Avoid in those with Avoid in those with

vascular dementiavascular dementia Avoid with TIA, Avoid with TIA,

hypertension, Afibhypertension, Afib Use low doses Use low doses

Monitor for Monitor for hypotension, hypotension, sedation, EPSsedation, EPS

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Weight Gain: OverviewWeight Gain: Overview General populationGeneral population

Increased morbidity and mortalityIncreased morbidity and mortality StigmatizationStigmatization Major mental disordersMajor mental disorders

This This adverse effect adverse effect is more common with someis more common with some recent recent antipsychoticsantipsychotics

Recognized problem since chlorpromazineRecognized problem since chlorpromazine PolypharmacyPolypharmacy may contribute may contribute

Divalproex sodiumDivalproex sodium LithiumLithium AntidepressantsAntidepressants AntipsychoticsAntipsychotics

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The Metabolic SyndromeThe Metabolic Syndrome

Insulin Insulin resistanceresistance HyperinsulinemiaHyperinsulinemia Decreased Decreased beta cellbeta cell function function Postprandial Postprandial hyperglycemiahyperglycemia

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SGAs and Metabolic SGAs and Metabolic AbnormalitiesAbnormalities

+ = increase effect; - = no effect; D = discrepant results.*Newer drugs with limited long-term data.Diabetes Care. 2004.

Risk for Worsening Drug Weight Gain Diabetes Lipid Profile

Clozapine +++ + +

Olanzapine +++ + +

Risperidone ++ D D

Quetiapine ++ D D

Aripiprazole* +/- - -

Ziprasidone* +/- - -

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Baseline MonitoringBaseline Monitoring

HistoryHistory (personal or family) of obesity, (personal or family) of obesity, diabetes, dyslipidemia, hypertension, CVDdiabetes, dyslipidemia, hypertension, CVD

BMIBMI WaistWaist circumference circumference Blood pressureBlood pressure Fasting Fasting lipid profilelipid profile Fasting plasma Fasting plasma glucoseglucose

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Anticholinergic EffectsAnticholinergic Effects

Most common with:Most common with: ClozapineClozapine OlanzapineOlanzapine QuetiapineQuetiapine Low-potency FGAsLow-potency FGAs

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HematologicalHematological

Clozapine-induced agranulocytosisClozapine-induced agranulocytosis ManagementManagement

Stop agentStop agent

Reverse isolation; supportive Reverse isolation; supportive measures measures

GSCF (filgastrim)GSCF (filgastrim) Rechallenging strategies Rechallenging strategies

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CardiovascularCardiovascular

Related to both Related to both alphaalpha11 adrenergic adrenergic and and

muscarinicmuscarinic effects effects HypotensionHypotension TachycardiaTachycardia

MyocarditisMyocarditis ArrhythmogenicArrhythmogenic potential possible with all potential possible with all

antipsychoticsantipsychotics

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Royal College of Psychiatrists. 1997.

QTc prolongation

Ventricular fibrillation(sudden death)

Rarely

Rarely

(syncope)

Torsade de pointes arrhythmia

Potential Consequences of Potential Consequences of QTc Interval ProlongationQTc Interval Prolongation

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QT intervalQT interval

Time between onset Time between onset of depolarization and of depolarization and repolarizationrepolarization

Affected by diet, Affected by diet, alcohol intake, time of alcohol intake, time of day, heart rateday, heart rate

Usually corrected for Usually corrected for heart rate = QTcheart rate = QTc

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Antipsychotics:Antipsychotics:Drug InteractionsDrug Interactions

PharmacodynamicPharmacodynamic AnticholinergicAnticholinergic HypotensionHypotension

PharmacokineticPharmacokinetic P450 inhibition (quinidine)P450 inhibition (quinidine) P450 induction (carbamazepine)P450 induction (carbamazepine)

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Bipolar Disorder:Bipolar Disorder:Symptom DomainsSymptom Domains

ManiaManiaEuphoriaEuphoriaGrandiosityGrandiosityPressured speechPressured speechImpulsivityImpulsivityExcessive libidoExcessive libidoRecklessnessRecklessnessDiminished need for sleepDiminished need for sleep

DepressionDepressionDepressionDepressionAnxietyAnxietyIrritabilityIrritabilityHostilityHostilityViolence or suicideViolence or suicide

Manic, depressed or mixed

Psychosis•Delusions•Hallucinations•Sensory hyperactivity

Cognition•Racing thoughts•Distractability•Poor insight•Disorganization•Inattentiveness•Confusion

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Lithium* (A, M)

Anticonvulsants

Valproate* (A)

Lamotrigine* (M)

Carbamazepine (A)

Oxcarbazepine*

Topiramate

Gabapentin

Psychotherapy

Cognitive behavioral therapy Marital/family counseling

Interpersonal therapy Group therapy

Pharmacological/Somatic

Antidepressants; OLZ/FLU* (D)

Quetiapine* (D)

Electroconvulsive therapy

Possibly:» Bright light therapy» Transcranial magnetic stimulation » Vagal nerve stimulation» Sleep deprivation

Mood Disorders:Mood Disorders:Therapeutic OptionsTherapeutic Options

First generation antipsychotics

Second generation antipsychotics

Clozapine

Olanzapine* (A, M)

Risperidone* (A)

Quetiapine* (A)

Ziprasidone* (A)

Aripiprazole* (A)

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Mood Stabilizer PharmacokineticsMood Stabilizer Pharmacokinetics

DrugDrug Desired Desired CpCp

DistributioDistributionn

MetabolisMetabolismm

EliminatioEliminationn

LithiumLithium 0.6-1.0 0.6-1.0

mEq/LmEq/L

No PBNo PBkidneys, kidneys, thyroidthyroid

NoneNone Renally,Renally,

18-20 18-20 hourshours

CBZCBZ 6-12 6-12 mcg/mlmcg/ml

CompleteComplete Hepatic,Hepatic,

autoinducautoinducerer

10,1110,11 epoxide epoxide

15-28 15-28 hourshours

VPAVPA 50-120 50-120

mcg/mlmcg/ml

Rapid in Rapid in

CNSCNS

Hepatic, Hepatic,

Inhibitor or Inhibitor or

InducerInducer

8-17 8-17 hourshours

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LITHIUMLITHIUM

Narrow therapeutic indexNarrow therapeutic index Slow Slow onset of actiononset of action Numerous Numerous adverse effectsadverse effects

DISADVANTAGES

BIPOLAR DISORDERBIPOLAR DISORDER

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Factors Affecting Lithium CpFactors Affecting Lithium Cp

Impaired Renal FunctionImpaired Renal Function PregnancyPregnancy Sodium balanceSodium balance MedicationsMedications

Diuretics Diuretics → Na depletion → Li reabsorption→ Na depletion → Li reabsorption Caffeine Caffeine ↓ lithium levels↓ lithium levels ACE Inhibitors → ↓ GFR → increase Li ACE Inhibitors → ↓ GFR → increase Li

concentrationconcentration

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Lithium: Adverse EffectsLithium: Adverse EffectsOrgan SystemOrgan System Clinical PresentationClinical Presentation CommentsComments

CardiovascularCardiovascular ECG changesECG changes T wave suppression, delayed or irregular rhythm, increase in PVCsT wave suppression, delayed or irregular rhythm, increase in PVCs

Sick sinus node syndrome (SSNS)Sick sinus node syndrome (SSNS)

MyocarditisMyocarditis

DermatologicDermatologic AcneAcne

PsoriasisPsoriasis

RashesRashes

WorsensWorsens

Treatment-refractory worseningTreatment-refractory worsening

Maculopapular and follicularMaculopapular and follicular

EndocrineEndocrine Hypothyroid stateHypothyroid state About 5% goiter; about 4% clinically significant hypothyroidismAbout 5% goiter; about 4% clinically significant hypothyroidism

Hyperparathyroid stateHyperparathyroid state Clinically nonsignificantClinically nonsignificant

Fetus (teratogenic)Fetus (teratogenic) Tricuspid valve malformationTricuspid valve malformation

Atrial septal defectAtrial septal defect

Ebstein’s anomalyEbstein’s anomaly

GastrointestinalGastrointestinal AnorexiaAnorexia

Nausea (10-30%)Nausea (10-30%)

VomitingVomiting

Diarrhea (5-20%)Diarrhea (5-20%)

Usually early in treatment and usually transient; may be early sign Usually early in treatment and usually transient; may be early sign of toxicityof toxicity

Slow release preparations may helpSlow release preparations may help

HematologicalHematological GranulocytosisGranulocytosis May be useful in disorders such as Felty’s syndrome, iatrogenic May be useful in disorders such as Felty’s syndrome, iatrogenic neutropenia. May counter CBZ-induced leukopenianeutropenia. May counter CBZ-induced leukopenia

RenalRenal Polyuria-polydipsia Polyuria-polydipsia (Nephrogenic diabetes (Nephrogenic diabetes insipidus)insipidus)

May be an indication of morphologic changesMay be an indication of morphologic changes

Requires adequate hydrationRequires adequate hydration

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Neurological Neurological Cognitive; tremorsCognitive; tremors

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Anticonvulsants for Mood DisordersAnticonvulsants for Mood Disorders

Valproate (VPA)Valproate (VPA)

Lamotrigine (LTG)Lamotrigine (LTG)

Carbamazepine (CBZ)Carbamazepine (CBZ)

OxcarbazepineOxcarbazepine

Gabapentin (GBN)Gabapentin (GBN)

Topiramate (TOP)Topiramate (TOP)

OthersOthers

BIPOLAR DISORDERBIPOLAR DISORDER

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VALPROATEVALPROATE

Adverse effectsAdverse effects Weight gainWeight gain TremorsTremors HyperammonemiaHyperammonemia PCOS (?)PCOS (?)

DISADVANTAGES

BIPOLAR DISORDERBIPOLAR DISORDER

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PancreatitisPancreatitis

HepatotoxicityHepatotoxicity

TeratogenicityTeratogenicity

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Valproic Acid Valproic Acid PharmacokineticsPharmacokinetics

Usually inhibits hepatic metabolismUsually inhibits hepatic metabolism Occasionally induces hepatic metabolismOccasionally induces hepatic metabolism

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CBZ PharmacokineticsCBZ Pharmacokinetics

Oxidation to CBZ-10,11-epoxideOxidation to CBZ-10,11-epoxide Potent enzyme inducerPotent enzyme inducer

antidepressants, anticonvulsants, antidepressants, anticonvulsants, antipsychoticsantipsychotics

AutoinductionAutoinduction serum level should stabilize within 4 weeksserum level should stabilize within 4 weeks

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Carbamazepine MetabolismCarbamazepine Metabolism

10,11 epoxide metabolite10,11 epoxide metabolite

CarbamazepineCarbamazepine

Further metabolismFurther metabolism

→→ ToxicityToxicity

XXValproic acidValproic acid

oxidationoxidation

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LAMOTRIGINELAMOTRIGINE

Slow titration to avoid rashSlow titration to avoid rash Adverse effectsAdverse effects

Serious rashesSerious rashes SJSSJS TENTEN

BIPOLAR DISORDERBIPOLAR DISORDER

DISADVANTAGES

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GoalsGoals AntipsychoticsAntipsychotics

Diagnostic indicationsDiagnostic indications Classification Classification Relevant PharmacokineticsRelevant Pharmacokinetics Serious Adverse EffectsSerious Adverse Effects Drug InteractionsDrug Interactions

Mood StabilizersMood Stabilizers Diagnostic indicationsDiagnostic indications Classification Classification Relevant PharmacokineticsRelevant Pharmacokinetics Serious Adverse EffectsSerious Adverse Effects Drug InteractionsDrug Interactions

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