Schizophrenia Paul M. Moran Maverick Miller Leslie Radka Jennifer Schmid Michael Ball Cheryl...
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Transcript of Schizophrenia Paul M. Moran Maverick Miller Leslie Radka Jennifer Schmid Michael Ball Cheryl...
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