SchizophreniaSchizophrenia

Paul M. MoranPaul M. MoranMaverick MillerMaverick Miller

Leslie RadkaLeslie RadkaJennifer SchmidJennifer Schmid

Michael BallMichael BallCheryl RosarioCheryl Rosario

BackgroundBackground

1% Prevalence1% Prevalence 10-15% take their own lives10-15% take their own lives

Within first 10yrs of diagnosisWithin first 10yrs of diagnosis OnsetOnset

Late teens to early 20’sLate teens to early 20’s Early treatments relied on AntipsychoticsEarly treatments relied on Antipsychotics

There were however many adverse effectsThere were however many adverse effects Early 1990’s pharmacological breakthroughs Early 1990’s pharmacological breakthroughs

allowed for a more functioning lifestyle in allowed for a more functioning lifestyle in societysociety

BackgroundBackground

It is believed that Schizophrenia must be It is believed that Schizophrenia must be treated in a multifaceted treatmenttreated in a multifaceted treatment While medication is the first line treatment While medication is the first line treatment

counseling, social and family services should counseling, social and family services should be provided for proper treatment of patientsbe provided for proper treatment of patients

Further developments in pharmacological Further developments in pharmacological treatments should increase functioning of treatments should increase functioning of patients in society by reducing side patients in society by reducing side effects with more selective drugseffects with more selective drugs

EtiologyEtiology

Schizophrenia is a misregulation of Schizophrenia is a misregulation of information in the braininformation in the brain Many different NT pathways are Many different NT pathways are

hypothesized to be involved in the hypothesized to be involved in the biological basis of the disorderbiological basis of the disorder

Genetics may be an important roleGenetics may be an important role The environment may trigger a possible The environment may trigger a possible

genetic predispositiongenetic predisposition

EtiologyEtiology

Despite years of research there is no Despite years of research there is no consensus on a single etiology for consensus on a single etiology for this disorderthis disorder

SymptomsSymptoms

Schizophrenia has been broken down into Schizophrenia has been broken down into two sets of symptomstwo sets of symptoms Positive and NegativePositive and Negative

Positive SymptomsPositive Symptoms HallucinationsHallucinations DelusionsDelusions Disorganized Speech, Behavior and MovementsDisorganized Speech, Behavior and Movements Increase in goal directed activityIncrease in goal directed activity Illogical thoughtsIllogical thoughts

Negative SymptomsNegative Symptoms

Blunted AffectBlunted Affect Impaired emotional responsivenessImpaired emotional responsiveness ApathyApathy Loss of motivation and interestLoss of motivation and interest Social withdrawalSocial withdrawal

Atypical vs TraditionalAtypical vs Traditional

Traditional Antipsychotics only Traditional Antipsychotics only alleviate the positive symptomsalleviate the positive symptoms

Atypical drugs however treat both Atypical drugs however treat both the positive and negative symptomsthe positive and negative symptoms Lower extrapyrimidal effects Lower extrapyrimidal effects Act on 5HT2 as well as D2Act on 5HT2 as well as D2 More expensiveMore expensive

Role of DopamineRole of Dopamine

Original theory proposed that an over Original theory proposed that an over activation of DA led to schizophrenic activation of DA led to schizophrenic symptomssymptoms

More recently it has been More recently it has been hypothesized that hypothesized that Positive symptoms are caused by an over Positive symptoms are caused by an over

activation of specific DA pathwaysactivation of specific DA pathways Negative symptoms arise from and under Negative symptoms arise from and under

activation of different DA pathwaysactivation of different DA pathways

Role of Dopamine Role of Dopamine

DA subtypesDA subtypes DA1 receptorsDA1 receptors

DA1, D1BDA1, D1B DA2 receptorsDA2 receptors

D2, D3 and D4D2, D3 and D4 DA1 and DA2 exert opposite actions on DA1 and DA2 exert opposite actions on

intracellular mechanismsintracellular mechanisms Traditional view of antipsychotics were that Traditional view of antipsychotics were that

they antagonize D2 and D4 receptorsthey antagonize D2 and D4 receptors The problem with these drugs were that they caused The problem with these drugs were that they caused

Parkinson like symptoms, tardive dyskinesias and Parkinson like symptoms, tardive dyskinesias and may worsen negative symptomsmay worsen negative symptoms

Atypical AntipsychoticsAtypical Antipsychotics

There is no agreement on what biological There is no agreement on what biological actions define atypical antipsychoticsactions define atypical antipsychotics

These drugs are thought to block D2 These drugs are thought to block D2 receptors receptors

Have a possible effect on D1, 5HT2 or Have a possible effect on D1, 5HT2 or adrenergic receptor blockadeadrenergic receptor blockade

Some are thought to effect D3 and D4Some are thought to effect D3 and D4 Problem with atypicals is that their action Problem with atypicals is that their action

on D2 receptors also may cause side on D2 receptors also may cause side effects involving movement disorderseffects involving movement disorders

Serotonin InvolvementSerotonin Involvement

Observations of psychedelic drugs Observations of psychedelic drugs psilocybin and LSD psilocybin and LSD Cause a state similar to schizophreniaCause a state similar to schizophrenia These drugs are 5-HT agonistThese drugs are 5-HT agonist 5-HT antagonism may have therapeutic 5-HT antagonism may have therapeutic

efficacyefficacy

Serotonin InvolvementSerotonin Involvement

Serotonin’s exact mechanisms of action Serotonin’s exact mechanisms of action are unclearare unclear

Autopsy results show reduced 5HT2 Autopsy results show reduced 5HT2 receptors in the prefrontal cortexreceptors in the prefrontal cortex

PET studies of living schizophrenics have PET studies of living schizophrenics have not confirmed these findingsnot confirmed these findings

Studies show a possibility of serotonin-Studies show a possibility of serotonin-glutamate interactionglutamate interaction Drug-induced serotonin blocking limits Drug-induced serotonin blocking limits

glutamate releaseglutamate release

Glutamate HypothesisGlutamate Hypothesis

NMDA over activity leads to an NMDA over activity leads to an excessive excitatory excessive excitatory neurotransmission in the fontal neurotransmission in the fontal cortexcortex

This damages cortical neurons which This damages cortical neurons which causes degenerationcauses degeneration

Summary of TheoriesSummary of Theories

Overall Overall DA is considered to be involved with the DA is considered to be involved with the

positive symptoms positive symptoms Glutamate is considered to be involved Glutamate is considered to be involved

with the negative symptomswith the negative symptoms

Drug ClassificationsDrug Classifications

Standard, classical, traditionalStandard, classical, traditional Phenothiazines are the prototypical agentsPhenothiazines are the prototypical agents

New generation or atypical New generation or atypical Clozapine, risperidone, olanzapine, sertindole, Clozapine, risperidone, olanzapine, sertindole,

quetiapine and ziprazadonequetiapine and ziprazadone AdvantagesAdvantages

Theputically effective without causing neuroplectic Theputically effective without causing neuroplectic syndromesyndrome

Help relive negative symptoms and cognitive Help relive negative symptoms and cognitive dysfunctionsdysfunctions

PhenothiazinesPhenothiazines

Widely usedWidely used Least expensiveLeast expensive

PharmacokineticsPharmacokinetics

Absorbed unpredictably and erratically through Absorbed unpredictably and erratically through the GI tractthe GI tract Dose decisions commonly made by trial and errorDose decisions commonly made by trial and error

Oral is still most common Oral is still most common Rapid distributed once in bloodstreamRapid distributed once in bloodstream 24-48hr half life24-48hr half life Slowly metabolized in liverSlowly metabolized in liver Bind extensively to tissueBind extensively to tissue

Causing slow eliminationCausing slow elimination May be responsible for slow rate of reoccurrence of May be responsible for slow rate of reoccurrence of

psychotic episodespsychotic episodes

Pharmacological EffectsPharmacological Effects

Blocks D2 receptorsBlocks D2 receptors Ach, 5HT, Histamine and NE Ach, 5HT, Histamine and NE

receptorsreceptors Limbic system Limbic system Brain StemBrain Stem Basal GangliaBasal Ganglia Hypothalamus-PituitaryHypothalamus-Pituitary

Side Effects and ToxicitySide Effects and Toxicity

High Potency PhenothiazapinesHigh Potency Phenothiazapines Fluphenazine, Trifluphenazine, PerphenazineFluphenazine, Trifluphenazine, Perphenazine Cause less sedation Cause less sedation Fewer anticholergenic side effectsFewer anticholergenic side effects Less postural hypertensionLess postural hypertension More extrapyrimydal side effectsMore extrapyrimydal side effects

Low Potency PhenothiasapinesLow Potency Phenothiasapines Chlorpromazine, ThioridazineChlorpromazine, Thioridazine Used when sedation is desirableUsed when sedation is desirable Also when Anticholinergic side effects limit complianceAlso when Anticholinergic side effects limit compliance Often combined with benzodiazapinesOften combined with benzodiazapines

Tolerance and DependenceTolerance and Dependence

Rarely abusedRarely abused No toleranceNo tolerance No physical or psychological No physical or psychological

dependencedependence Stopping treatment can either result in Stopping treatment can either result in

relapse or withdrawalrelapse or withdrawal

HaloperidolHaloperidol

First therapeutic alternative to First therapeutic alternative to PhenothiasazinesPhenothiasazines

Similar effects of phenothiasazinesSimilar effects of phenothiasazines Produces sedationProduces sedation Reduces initiative, anxiety and activityReduces initiative, anxiety and activity Well absorbed orallyWell absorbed orally Slow rate of metabolism and excretionSlow rate of metabolism and excretion Acts on D2 receptorsActs on D2 receptors Few side effectsFew side effects Does produce Parkinson like effectsDoes produce Parkinson like effects

Atypical AntipsychoticsAtypical Antipsychotics

MolindoneMolindone Resembles 5HTResembles 5HT

Relation to 5HT therapeutic effect is unknownRelation to 5HT therapeutic effect is unknown Resembles traditional antipsychotics Resembles traditional antipsychotics

Mechanism of action, efficacy, side effects Mechanism of action, efficacy, side effects Moderate sedationModerate sedation Increased motor activityIncreased motor activity Possibly euphoriaPossibly euphoria

LoxapineLoxapine

Similar in structure to atypicalsSimilar in structure to atypicals Actions differ little from traditional Actions differ little from traditional

effectseffects Antipsychotic, antiametic and sedative Antipsychotic, antiametic and sedative

propertiesproperties Causes abnormal motor movementsCauses abnormal motor movements Good absorption, metabolism and Good absorption, metabolism and

excretionexcretion

ClozapineClozapine

Used to treat treatment resistant Used to treat treatment resistant schizophrenicsschizophrenics

Clinically superior to traditional drugsClinically superior to traditional drugs Relieves much of the negative symptomsRelieves much of the negative symptoms Lacks many extrapyramidal effectsLacks many extrapyramidal effects Less of a cognitive inhibitorLess of a cognitive inhibitor Clozapine may cause a loss of white Clozapine may cause a loss of white

blood cells but it reduces suicide ratesblood cells but it reduces suicide rates

PharmacokineticsPharmacokinetics

Varied absorption rates among patientsVaried absorption rates among patients Well absorbed orallyWell absorbed orally Metabolitic half life 9-30hrsMetabolitic half life 9-30hrs Peak plasma levels 1-4hrsPeak plasma levels 1-4hrs Metabolized by the liver into 2 active Metabolized by the liver into 2 active

metabolitesmetabolites Blood levels must be monitored to Blood levels must be monitored to

ensure proper dosingensure proper dosing

PharmacodynamicsPharmacodynamics

High binding affinity for DA, High binding affinity for DA, Seretonin1c, seretonin2, alpha1, Seretonin1c, seretonin2, alpha1, muscaranic and histaminemuscaranic and histamine

Low rate of binding to D2 receptorsLow rate of binding to D2 receptors Blocks 5HT2 at higher levelsBlocks 5HT2 at higher levels

Side Effects and ToxicitySide Effects and Toxicity

SedationSedation 40% of patients 40% of patients Can affect complianceCan affect compliance Bed time dosing may help complianceBed time dosing may help compliance

Weight gainWeight gain 80% of patients80% of patients PersistantPersistant Reason not knownReason not known

WithdrawalWithdrawal Delusions, hallucinations, hostility, paranoid reaction, Delusions, hallucinations, hostility, paranoid reaction,

nausea, vomit, diarraheachachacha, headache, nausea, vomit, diarraheachachacha, headache, restlessness, agitation, confusion, sweating restlessness, agitation, confusion, sweating

Other ConcernsOther Concerns

ExpensiveExpensive Due to blood monitoringDue to blood monitoring

RisperidoneRisperidone

Potent inhibitor of D2 and 5HT2Potent inhibitor of D2 and 5HT2 PharmacokineticsPharmacokinetics

Orally administeredOrally administered Rate of metabolism variesRate of metabolism varies 3hr half life3hr half life Active metabolite 9-hydroxy-risperidoneActive metabolite 9-hydroxy-risperidone

Half life 22hrsHalf life 22hrs Considered a first-line treatment for schizophreniaConsidered a first-line treatment for schizophrenia

High efficancy High efficancy SafeSafe Few detrimental effects on memoryFew detrimental effects on memory Minimal extrapyramidal side effectsMinimal extrapyramidal side effects

Other side effectsOther side effects Agitation, anxiety, insomnia, headache, nausea, extrpyramidal side Agitation, anxiety, insomnia, headache, nausea, extrpyramidal side

effects (only at high doses)effects (only at high doses)

OlanzapineOlanzapine

Structurally related to clozapine Structurally related to clozapine Blocks many receptors, but dopamine and serotonin Blocks many receptors, but dopamine and serotonin

interaction are thought to be responsible for therapeutic interaction are thought to be responsible for therapeutic effecteffect

PharmacokineticsPharmacokinetics Well absorbed orallyWell absorbed orally Peak plasma levels at 5 to 8 hoursPeak plasma levels at 5 to 8 hours Elimination half-life 27-38 hoursElimination half-life 27-38 hours

Overall effectivenessOverall effectiveness improvements in both positive and negative symptoms improvements in both positive and negative symptoms Studies seem to show better results with less severely Studies seem to show better results with less severely

impaired patientsimpaired patients Also used in bipolarAlso used in bipolar

SertindoleSertindole

5-HT2, D2, and alpha1-adrenoreceptors 5-HT2, D2, and alpha1-adrenoreceptors antagonistantagonist

Treats both positive and negative Treats both positive and negative symptomssymptoms

Minimal extrapyramidal side effectsMinimal extrapyramidal side effects Reduced sedative effects due to no affinity Reduced sedative effects due to no affinity

for histamine receptorsfor histamine receptors Half-life 60 hours to 95 hoursHalf-life 60 hours to 95 hours Can lead to severe cardiac arrythmiasCan lead to severe cardiac arrythmias

Quetiapine (Seroquel)Quetiapine (Seroquel)

5-HT2/D2 receptor antagonst5-HT2/D2 receptor antagonst Half life 7hrsHalf life 7hrs

Two or more daily doses neededTwo or more daily doses needed Greater affinity for 5HT2 than D2Greater affinity for 5HT2 than D2

Separates the antipsychotic action from Separates the antipsychotic action from the extrapyramidal side effectsthe extrapyramidal side effects

Reduces expression of glutamate Reduces expression of glutamate receptor mRNAreceptor mRNA

ZiprasidoneZiprasidone

Similar in effect to HaloperidalSimilar in effect to Haloperidal Weight gain is negliableWeight gain is negliable Inactive byproductsInactive byproducts Poorly absorbed orallyPoorly absorbed orally Unique actions on receptorsUnique actions on receptors

Blocks 5HT2 and D2Blocks 5HT2 and D2 Agonist at 5HT1aAgonist at 5HT1a

May cause an antidepresant functionMay cause an antidepresant function

AmisulprideAmisulpride

Yet to be releasedYet to be released D2 and D3 subtypes blocked in limbic system D2 and D3 subtypes blocked in limbic system

but not in Basal Gangliabut not in Basal Ganglia Twice as selective for D3 than D2Twice as selective for D3 than D2 Low doses blocks presynaptic receptors Low doses blocks presynaptic receptors

increasing DAincreasing DA Higher doses it antagonizes DA Higher doses it antagonizes DA

At these doses it has efficacy for negative At these doses it has efficacy for negative symptomssymptoms

Low incidence of extrapyramidal side effectsLow incidence of extrapyramidal side effects No affinity for 5HT which is unusual for AtypicalNo affinity for 5HT which is unusual for Atypical