Antipsychotics

AntipsychoticsCharacteristics of schizophreniaPrevalence 0.51.0% of populationOnsetPositive features in late adolescence or early adulthoodAspects of cognitive deficits detectable earlier in lifeComorbidityDepression: 3050%Substance abuse: 50%Suicide: 510%Schizophrenia: A Disease with Various AspectsPositive SymptomsDelusionsHallucinationsDisorganized speechCatatoniaNegative SymptomsAffective flatteningAlogiaAvolitionAnhedoniaSocial withdrawalCognitive DeficitsAttentionMemoryExecutive functions(e.g., abstraction)Mood SymptomsDepressionAnxietyAggressionHostilityHopelessnessSuicidalitySocial/OccupationalDysfunctionWorkInterpersonal relationshipsSelf-careInter-relationship between disease factors and drug-induced adverse factors in the burden of schizophreniaInt Clin Psychopharmacol 2005, 20:183198.Adverse effect of antipsychotic drugsRisk of hyperglycemia/ diabetesOther effectsAnticholinergicProlactin elevationQTc prolongationSedationExtrapyramidal symptomsTardive dyskinesiaWeight gainSuicidality DysphoriaDiverse symptoms of schizophreniaPositive symptomsCognitive symptomsNegative symptomsDepression/AnxietyDisease factorsDrug-induced factors4Current therapy issues and unmet clinical needs in the treatment of schizophrenia: a review of the new generation antipsychoticsInternational Clinical Psychopharmacology 2005, 20:183198Treatment Goal of SchizophreniaRapid symptom control

Acute Phase TreatmentStabilization Phase TreatmentMaintenance Phase TreatmentPatient relationshipInsight on medicationRelapse/recurrence preventionAdherenceFunctional recoveryInitiation of therapeutically effective dose No need for initial dose titration for tolerability

Minimal drug-drug interactionProven efficacy and safety

Increased tolerance to occasional missed dosesProven relapse prevention effectImproved PSP

Factors affecting antipsychotic responseReceptor pharmacology(binding capacity)PharmacokineticsPharmacogenetics(CYP450)Patient variablesComorbid condition/polypharmacyThe Dopamine hypothesis of psychosisOveractivity of dopamine neurons in the mesolimbic dopamine pathway may mediate the positive symptoms

Dopamine hypocactivity in mesocortical dopamine pathway may mediate the negative and cognitive symptomsDorsolateral prefrontal cortex negative, cognitive symptomsVentromedial prefrontal cortex negative, affective symptomsBrain dopaminergic tracts

12346 Lateral hypothalamus5 CTZSimplify Neurocircuitry of Dopamine in SchizophreniaDAMesolimbic pathwayHyperdopaminergiaD2Positive symptomsDAMesocortical pathwayHypodopaminergiaD1Negative symptomsCognitive symptomsAffective symptomsLimbicPFCxSOME DEFINITIONSNeuroleptic: synonym for antipsychotic drug; originally indicated drug w/antipsychotic efficacy but with neurologic (extrapyramidal motor) side effectsTypical neuroleptic: older agents fitting this descriptionAtypical neuroleptic: newer agents: antipsychotic efficacy with reduced or no neurologic side effectsAntipsychotic Drugs: Development TimelineMinimal efficacy with regard to positive symptoms in 20-30% of patientsMuch weaker effect on negative symptoms than positive symptomsSignificant parkinsonian symptoms and anticholinergic effects (poor compliance and potentially disabling)Tardive dyskinesia in a minimum of 20% of patients who receive chronic neuroleptic treatment.

At least as effective as typical neuroleptics with regard to positive symptomsMore effective than typical agents with regard to negative symptomsMuch lower incidence of parkinsonian symptoms and anticholinergic effects than typical agentsTD does occur but at much lower incidenceElevated risk of metabolic side effects

NEUROLEPTICSTYPICAL NEUROLEPTICS:PHENOTHIAZINES:Chlorpromazine (Thorazine )Thioridazine (Mellaril )Fluphenazine (Prolixin )THIOXANTHENEThiothixene (Navane )OTHERHaloperidol (Haldol )

NEUROLEPTICSATYPICAL NEUROLEPTICS:Risperidone (Risperdal ; most frequently prescribed in U.S.)Clozapine (Clozaril )Olanzapine (Zyprexa )Quetiapine (Seroquel )

Therapeutic effects from D2 receptor blockadeAmelioration of the positive signs, symptoms of psychosis, manic symptoms, aggressive behaviorsAntiemetic effect

Modified J Clin Psychiatry 1999;60(suppl 10):514.Adverse effects from D2 receptor blockadeExtrapyramidal symptom (EPS)Acute; akathisia, acute dystonia, parkinsonismLate; tardive dyskinesia

Endocrine effects: prolactin elevation

Weight gain due to increase feeding

Modified J Clin Psychiatry 1999;60(suppl 10):514.Binding affinities of chlorpromazine and haloperidol for various receptor

J Psychiatr Pract 2005;11:25861.Higher potencyHigher EPSLower anticholinergic effectLower potencyLow EPSHigher anticholinergic effectHaloperidolFluphenazineTrifluoperazineThioxanthinePerphenazinePimozideChlorpromazineThioridazineMesoridazineRational explanations for SDA therapeutic effectsTherapeutic effects D2-receptor blockade in the mesolimbic pathway to reduce positive symptomsEnhanced dopamine release and 5-HT2A receptor blockade in the mesocortical pathway to reduce negative symptoms

Side-effect profile5-HT2A antagonism in the nigrostriatal pathway reduces EPS and tardive dyskinesia5-HT2A antagonism in the tuberoinfundibular pathway reduces hyperprolactinemia

DAD1D2Caudate/putamenNormal functionSunstantia nigra pars compacta5-HT2A-5-HTRaphe5-HTTRole of 5-HT in Nigrostriatal Dopaminergic SynapseNigrostriatal tractDAD1D2Caudate/putamenEPS5-HT2A-5-HTRaphe5-HTTRole of 5-HT in Nigrostriatal Dopaminergic SynapseNigrostriatal tractHaloperidolSunstantia nigra pars compactaDAD1D2Caudate/putamenLess EPS5-HT2A-5-HTRaphe5-HTTRole of 5-HT in Nigrostriatal Dopaminergic SynapseNigrostriatal tractSDASunstantia nigra pars compacta Modified from Clin Ther 2004;26:649-66All values are reported as Ki (nM).Receptor affinities of selected atypical antipsychotics Receptor HAL CLOZ OLAN RIS QUET ZIP ARI D2 0.7 126 11 4 160 5 0.45 (partial)5-HT1A 2600 875 >7100 210 >830 3 4.4 (partial)5-HT2A 45 16 4 0.5 295 0.4 3.4 5-HT2C 1500 16 23 25 1500 1 15 1 6 7 19 0.7 7 10 57 2 360 8 230 3 87 H1 440 6 7 20 11 47 61 M1>1500 1.9 1.9 >10,000 120 >1,000 >10,000 GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICSThe older, typical neuroleptics are effective antipsychotic agents with neurologic side effects involving the extrapyramidal motor system. Typical neuroleptics block the dopamine-2 receptor.

GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICSTypical neuroleptics do not produce a general depression of the CNS, e.g. respiratory depression

Abuse, addiction, physical dependence do not develop to typical neuroleptics.GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICSTypical neuroleptics are generally more effective against positive (active) symptoms of schizophrenia than the negative (passive) symptoms.Positive/active symptoms include thought disturbances, delusions, hallucinations

Negative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech. impaired personal hygiene

THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICSAll appear equally effective; choice usually based on tolerability of side effectsMost common are haloperidol, chlorpromazine and thioridazineLatency to beneficial effects; 4-6 week delay until full response is common70-80% of patients respond, but 30-40% show only partial response THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS (Continued)Relapse, recurrence of symptoms is common ( approx. 50% within two years).

Noncompliance is common.

Adverse effects are common. GENERAL CHARACTERISTICS OF ATYPICAL NEUROLEPTICSEffective antipsychotic agents with greatly reduced or absent EPS, esp. reduced Parkinsonism and tardive dyskinesiaAll atypical neuroleptics block dopamine and serotonin receptors; other neurochemical effects differAre effective against positive and negative symptoms of schizophrenia; and in patients refractory to typical neurolepticsEffects of blockade of neuroreceptors ReceptorsEffects of blockadeD2Anipsychotic, antimanic, antiaggressive, EPS/akathisia, tardive dyskinesia, increase prolactin, weight gain5-HT1AAnxiolytic, antidepressant, anti-EPS/akathisia5-HT2AAnti-EPS/akathisia, possible antipsychotics, improve REM sleep5-HT2CPossible increased appetite/weightModified from J Clin Psychiatry 2008;69[suppl4]:26-36.Effects of blockade of neuroreceptors ReceptorsEffects of blockade1Postural hypotension, dizziness, syncope, nasal congestion 2Antidepressive effect, increase alertness, increase blood pressureH1Anxiolytic, sedation, weight gain, potentiate CNS depressant drugModified from J Clin Psychiatry 2008;69[suppl4]:26-36.Effects of blockade of neuroreceptors ReceptorsEffects of blockadeM1 (central)Memory dysfunction, delirium, confusion, sedation, REM sleep disturbance , anti-EPSM2, M3(peripheral)Blurred vision, attack or exacerbation of narrow-angle glaucoma, dry mouth, sinus tachycardia, constipation, urinary retention, interfere pancreatic insulin releaseModified from J Clin Psychiatry 2008;69[suppl4]:26-36.Impact of receptor binding affinity on clinical responses of antipsychotics Modified from Clin Ther 2004;26:649-66All values are reported as Ki (nM).Receptor affinities of selected atypical antipsychotics: Potential riskReceptor HAL CLOZ OLAN RIS QUET ZIP ARI D2 0.7 126 11 4 160 5 0.45 (partial)5-HT1A 2600 875 >7100 210 >830 3 4.4 (partial)5-HT2A 45 16 4 0.5 295 0.4 3.4 5-HT2C 1500 16 23 25 1500 1 15 1 6 7 19 0.7 7 10 57 2 360 8 230 3 87 H1 440 6 7 20 11 47 61 M1>1500 1.9 1.9 >10,000 120 >1,000 >10,000 Orthostatic hypotensionAnticholinergicsSedation, weight gainEPS risk and hyperprolactinemia Modified from Clin Ther 2004;26:649-66Receptor affinities of selected atypical antipsychotics: Potential BenefitReceptor HAL CLOZ OLAN RIS QUET ZIP ARI D2 0.7 126 11 4 160 5 0.45 (partial)5-HT1A 2600 875 >7100 210 >830 3 4.4 (partial)5-HT2A 45 16 4 0.5 295 0.4 3.4 5-HT2C 1500 16 23 25 1500 1 15 1 6 7 19 0.7 7 10 57 2 360 8 230 3 87 H1 440 6 7 20 11 47 61 M1>1500 1.9 1.9 >10,000 120 >1,000 >10,000 PD psychosisBPSD, autismSedative actionAll values are reported as Ki (nM).Sleep quality improvementAlleviate EPS risk*Receptor activity measured as inhibition of forskolin-induced cAMP accumulation in CHO cells transfected with human D2L DNA.Adapted from Burris et al. J Pharmacol Exp Ther. 2002;302:381.050100Drug ConcentrationMaximum DA Response (%)*Dopamine100 nM Dopamine+ Haloperidol100 nM Dopamine+ AripiprazoleAripiprazole10-1010-910-810-710-610-5Aripiprazole Activity at Cloned Human D2 ReceptorsHaloperidol Full Receptor ActivityPartialReceptor Activity(Modulated) No Receptor Activity(Blocked)

37Paliperidone vs RisperidonePaliperidone is active metabolite of risperidone via metabolism by CYP2D6.

High affinity for D2, 5-HT2A, 1 and 2 receptors

Very low affinity for M1 as same as as risperidone

Expert Opin Drug Saf. 2007 ;6(6):651-62.

Pharmacokinetics differences of risperidone and paliperidoneRisperidonePaliperidoneTmax1-2 hr (risperidone)3 hr (paliperidone in CYP2D6 EM)17 hr (paliperidone in CYP2D6 PM)1-2 Hr (IR form)24 hr (ER form)T1/23 hr23 hr (IR and ER form)Elimination pathwayCYP2D6 to paliperidone (major)CYP3A4 (minor)CYP3A4 to (minor) inactive metabolite and >80% found in urine and 60%unchangedAdverse Effect Profile of AntipsychoticsPast Areas of ConcernCurrent Medical RealitiesShift in Risk Perception of Antipsychotics SedationWeight GainInsulin ResistanceCHDHyper-lipidemiaWeight GainDiabetesProlactinInsulin ResistanceSedationHyperlipidemiaCoronary HeartDiseaseTardive DyskinesiaTDProlactin41DOPAMINE-2 receptor blockade in meso-limbic and meso-cortical systems for antipsychotic effect.

DOPAMINE-2 receptor blockade in basal ganglia (nigro-striatal system) for EPS

DOPAMINE-2 receptor supersensitivity in nigrostriatal system for tardive dyskinesiaLONG TERM EFFECTS OF D2 RECEPTOR BLOCKADE:Dopamine neurons reduce activity.Postsynaptic D-2 receptor numbers increase (compensatory response).When D2 blockade is reduced, DA neurons resume firing and stimulate increased number of receptors >> hyper-dopamine state >> tardive dyskinesia ADVERSE EFFECTS OF TYPICAL NEUROLEPTICSAnticholinergic (antimuscarinic) side effects:Dry mouth, blurred vision, tachycardia, constipation, urinary retention, impotence

ADVERSE EFFECTS OF TYPICAL NEUROLEPTICSAntiadrenergic (Alpha-1) side effects:Orthostatic hypotension w/ reflex tachycardiasedation

ADVERSE EFFECTS OF TYPICAL NEUROLEPTICSAntihistamine effect: sedation, weight gain

D2 Blocking-related Side EffectsSpectrum of EPS

Late onsetAcute onsetAcute dystonia

Relationship between clinical effectiveness, EPS and D2 receptor occupancy

Threshold for EPSThreshold for antipsychotic efficacy80%

Medication used to treat EPSAm J Health-Sys Pharm 1997;54:2461-77.

Association of medication, target dose, and likelihood of treatment-emergent EPS

J Psychiatric Pract 2007;13:1324.Tardive dyskinesia (TD)TD is a latent extrapyramidal effect generally not occurring for months or years, occur in 20% patient treated with antipsychotic.

It is characterized by abnormal movements that can occur in any part of the body, including faces, tongue, shoulders, hips, extremities, fingers, and toesProminent Feature of TDLingual-facial hyperkinesiasChewing movementsSmacking and licking of the lipsSucking movementsTongue movements within the oral cavityTongue protrusionTongue tremor with mouth openMyokemic movements (worm-like movement on the surface of the tongue)BlinkingGrotesque grimaces and spastic facial distortionsNeck and trunk movementsSpasmodic torticollisRetrocollisTorsion movements of the trunkAxial hyperkinesia (hip-rocking)Choreoathetoid movements of the extremities

Neuroleptic malignant syndromeNMS is an uncommon but serious and potentially fatal complication of therapy

It is a syndrome of EPS, hyperthermia, altered consciousness, and autonomic changes (tachycardia, unstable BP, incontinence)

ManagementDiscontinuation of the antipsychotic agentsSupportive therapyBromocriptine may be benificial

The onset is sudden and recovery may take 5-10 days after discontinuation of the agent

Simplified Pathophysiology of Neuroleptic Malignant Syndrome (NMS)

Am J Psychiatry 2007;164:870-876.Spectrum-based concept of NMS

J Am Acad Child Adolesc Psychiatry 1992;31:11614.Proposed Treatment Algorithm for NMS Spectrum-Related Symptoms

Am J Psychiatry 2007;164:870-876.Hyperprolactinemia: possible signs and symptoms

J Clin Psychopharmacol 2007;27:639661.Osteoporosis60Clinical Implications of Antipsychotic-InducedHyperprolactinemia in Patients With SchizophreniaSpectrum or Bipolar Spectrum DisordersRecent Developments and Current PerspectivesMean Plasma Prolactin Level Changes Over 24 Hours in 18 Patients After Taking Clozapine, Olanzapine, or Risperidone and in Five of the Same Patients After Not Taking the Drugs

Am J Psychiatry 2002; 159:133135Effects of Antipsychotics on Prolactin Levels

J Clin Psychopharmacol 2007;27:639661.SedationReceptor blocking properties that affect arousal and sleep stagesBlocking of H1 sedationBlocking of M1 sedation, REM sleep interference Blocking of 1, 2, 5-HT2A promote cholinergic pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT) firing REM sleep improvement

Clin Ther 2004;26:649-66All values are reported as Ki (nM).Receptor affinities of selected atypical antipsychotics Receptor HAL CLOZ RIS OLAN QUET ZIP ARI D1 210 85 460 31 455 525 265 D2 0.7 126 4 11 160 5 0.45 (partial)D3 2 473 10 49 340 7 0.8 D4 3 35 9 27 1600 32 44 5-HT1A 2600 875 210 >7100 >830 3 4.4 (partial)5-HT2A 45 16 0.5 4 295 0.4 3.4 5-HT2C 1500 16 25 23 1500 1 15 1 6 7 0.7 19 7 10 57 2 360 8 3 230 87 H1 440 6 20 7 11 47 61 M1>1500 1.9 >10,000 1.9 120 >1,000 >10,000 Sedation

J Clin Psychiatry 2008;69 Suppl 1:18-31.Obesity and metabolic syndromesClinical issues of weight gain and antipsychoticsNot everyone gains weightDifficult to predict who will have weight gainMultifactorial etiologyNot dose related ADR.Start in first few weeksReach plateau between 3 months to 1 year

Mean weight gain during treatment withantipsychotic drugs.CNS Drugs 2005; 19 (Suppl. 1): 193.

Mechanisms of antipsychotic-induced weight gain and metabolic abnormalitiesInterfere feeding behavior by blocking many neuroreceptorFeeding centerLateral hypothalamus (DA D2)Ventromedial hypothalamus (5-HT 5-HT2A, 5-HT2C)Satiety centerParaventricular nuclei (NE 1, , Histamine H1)Interfere pancreatic insulin release Pancreas (ACh M3 )

AtropineOlanzapineClozapineZiprasidoneRisperidoneHaloperidolDiabetes 2005; 54:15521558. Clin Ther 2004;26:649-66All values are reported as Ki (nM).Receptor affinities of selected atypical antipsychotics Receptor HAL CLOZ RIS OLAN QUET ZIP ARI D1 210 85 460 31 455 525 265 D2 0.7 126 4 11 160 5 0.45 (partial)D3 2 473 10 49 340 7 0.8 D4 3 35 9 27 1600 32 44 5-HT1A 2600 875 210 >7100 >830 3 4.4 (partial)5-HT2A 45 16 0.5 4 295 0.4 3.4 5-HT2C 1500 16 25 23 1500 1 15 1 6 7 0.7 19 7 10 57 2 360 8 3 230 87 H1 440 6 20 7 11 47 61 M1>1500 1.9 >10,000 1.9 120 >1,000 >10,000 Olanzapine-Associated Weight Gain Plateaus After First 39 Weeks of TreatmentKinon BJ, et al. J Clin Psychiatry 2001;62:92-100WeekMean Weight Change (kg) up to 3 yearsOLZ (N=573)HAL (N=103) -8 -6 -4 -2 0 2 4 6 8 0 20 40 60 80 100 120 140 160Patients Observed for 39 Weeks or More;Double-blind and open-label olanzapine.LOCF; Median = 2.5 YearsWeight gain by olanzapine is not dose dependent (5-20 mg dose range).73Weight gain during long-term olanzapine treatment was investigated in a large cohort of subjects from the olanzapine clinical trial database. This study was the largest controlled psychopharmacologic trial ever conducted, involving nearly 2000 patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder. In these studies, olanzapine was evaluated in doses ranging from 5-20 mg/day and was compared with haloperidol (5-20 mg/day), the most commonly used conventional antipsychotic drug for the treatment of schizophrenia. The study consisted of a six-week acute phase followed by an extension phase to 52 weeks.This analysis retrospectively examined 573 patients receiving olanzapine and 103 patients receiving haloperidol for 39 weeks or more from a study of 1996 patients randomly assigned 2:1 to either olanzapine, 5 to 20 mg/day, or haloperidol, 5 to 20 mg/day. After 6 weeks of acute therapy, patients continued for 1 year or more with either double-blind or open-label olanzapine therapy or double-blind haloperidol therapy. Patients were studied to about three years of treatment. Results indicate that the rate of weight gain changed dramatically over time. The most rapid rate of weight increase occurred early on, within approximately the initial 12 weeks of olanzapine treatment.Weight gain during long-term olanzapine treatment then began to plateau at approximately 39 weeks of treatment, a timepoint after which no further significant pair-wise differences in weight change data were seen. Weight change experienced during haloperidol treatment remained significantly below that of olanzapine at all timepoints. The relatively rapid onset of weight gain suggests the importance of early intervention for weight gain mitigation. The data suggest that patients treated with olanzapine tend to be at progressively lower risk for further weight gain as they continue into maintenance pharmacotherapy.

Why Less weight gain in quetiapine, ziprasidone and aripiprazole?QuetiapineNorquetiapine inhibit norepinephrine reuptake transporter

AripiprazoleLow affinity H1, 5-HT2CPartial D2 agonistZiprasidoneModerate affinity for a1Low affinity H1Full 5-HT1A agonist Inhibit 5-HT/NA reuptake transporter

Metabolic Abnormalities

Clin Psy 2007;68(Suppl 7):27-33.Monitoring protocol for patients on SDAsBaseline4 weeks 8 weeks 12 weeks Quarterly Annually Every 5 years Personal/family history ()Weight (BMI) ()()Waist circumference ()()()()()Blood pressure ()()() ()Fasting plasma glucose ()() () ()Fasting lipid profile () ()() Diabetes Care 2004; 27(2): 596-601.Other Adverse effectsQTC interval prolongationThioridazine, ziprasidoneAgranulocytosisClozapineEpileptogenicClozapineRetinitis pigmentosaThioridazine > 800 mg/dayIncidence of categorical increases in QTc (Bazett correction)

There is a consensus that a QTc interval of >500ms, or an absolute in-crease of 60ms compared with drug-free baseline, puts a patient at significant risk of torsade depointes, ventricular fibrillation and sudden deathClozapine safety issuesClozapine is one of the atypical agents that is EPS/TD free, as same as quetiapineHowever, clozapine is still reserved as last-line therapy because of its increased incidence of agranulocytosis, myocarditis/cardiomyopathy, and convulsion and the need for frequent monitoring

Clozapine safety issuesSeizure risk1-2% and increase to 3-5% if dose is greater than 600 mg/day.Agranulocytosis1% in general95% cases in first 6 m, peak in 4-18 week CBC weekly

Management of clozapine-induced agranulocytosisUSNew patients: weekly blood countsTwice weekly monitoring: WBC 3000-3500 and ANC >1500Temporary discontinuation: WBC 2000-3000 and/or ANC 1000-1500Permanent discontinuation: WBC