Schizophrenia

Schizophrenia

اسلاید 1: SchizophreniaPaul M. MoranMaverick MillerLeslie RadkaJennifer SchmidMichael BallCheryl Rosario

اسلاید 2: Background1% Prevalence10-15% take their own livesWithin first 10yrs of diagnosisOnsetLate teens to early 20’sEarly treatments relied on AntipsychoticsThere were however many adverse effectsEarly 1990’s pharmacological breakthroughs allowed for a more functioning lifestyle in society

اسلاید 3: BackgroundIt is believed that Schizophrenia must be treated in a multifaceted treatmentWhile medication is the first line treatment counseling, social and family services should be provided for proper treatment of patientsFurther developments in pharmacological treatments should increase functioning of patients in society by reducing side effects with more selective drugs

اسلاید 4: EtiologySchizophrenia is a misregulation of information in the brainMany different NT pathways are hypothesized to be involved in the biological basis of the disorderGenetics may be an important roleThe environment may trigger a possible genetic predisposition

اسلاید 5: EtiologyDespite years of research there is no consensus on a single etiology for this disorder

اسلاید 6: SymptomsSchizophrenia has been broken down into two sets of symptomsPositive and NegativePositive SymptomsHallucinationsDelusionsDisorganized Speech, Behavior and MovementsIncrease in goal directed activityIllogical thoughts

اسلاید 7: Negative SymptomsBlunted AffectImpaired emotional responsivenessApathyLoss of motivation and interestSocial withdrawal

اسلاید 8: Atypical vs TraditionalTraditional Antipsychotics only alleviate the positive symptomsAtypical drugs however treat both the positive and negative symptomsLower extrapyrimidal effects Act on 5HT2 as well as D2More expensive

اسلاید 9: Role of DopamineOriginal theory proposed that an over activation of DA led to schizophrenic symptomsMore recently it has been hypothesized that Positive symptoms are caused by an over activation of specific DA pathwaysNegative symptoms arise from and under activation of different DA pathways

اسلاید 10: Role of Dopamine DA subtypesDA1 receptorsDA1, D1BDA2 receptorsD2, D3 and D4DA1 and DA2 exert opposite actions on intracellular mechanismsTraditional view of antipsychotics were that they antagonize D2 and D4 receptorsThe problem with these drugs were that they caused Parkinson like symptoms, tardive dyskinesias and may worsen negative symptoms

اسلاید 11: Atypical AntipsychoticsThere is no agreement on what biological actions define atypical antipsychoticsThese drugs are thought to block D2 receptors Have a possible effect on D1, 5HT2 or adrenergic receptor blockadeSome are thought to effect D3 and D4Problem with atypicals is that their action on D2 receptors also may cause side effects involving movement disorders

اسلاید 12: Serotonin InvolvementObservations of psychedelic drugs psilocybin and LSD Cause a state similar to schizophreniaThese drugs are 5-HT agonist5-HT antagonism may have therapeutic efficacy

اسلاید 13: Serotonin Involvement Serotonin’s exact mechanisms of action are unclearAutopsy results show reduced 5HT2 receptors in the prefrontal cortexPET studies of living schizophrenics have not confirmed these findingsStudies show a possibility of serotonin-glutamate interactionDrug-induced serotonin blocking limits glutamate release

اسلاید 14: Glutamate HypothesisNMDA over activity leads to an excessive excitatory neurotransmission in the fontal cortexThis damages cortical neurons which causes degeneration

اسلاید 15: Summary of TheoriesOverall DA is considered to be involved with the positive symptoms Glutamate is considered to be involved with the negative symptoms

اسلاید 16: Drug ClassificationsStandard, classical, traditionalPhenothiazines are the prototypical agentsNew generation or atypical Clozapine, risperidone, olanzapine, sertindole, quetiapine and ziprazadoneAdvantagesTheputically effective without causing neuroplectic syndromeHelp relive negative symptoms and cognitive dysfunctions

اسلاید 17: PhenothiazinesWidely usedLeast expensive

اسلاید 18: PharmacokineticsAbsorbed unpredictably and erratically through the GI tractDose decisions commonly made by trial and errorOral is still most common Rapid distributed once in bloodstream24-48hr half lifeSlowly metabolized in liverBind extensively to tissueCausing slow eliminationMay be responsible for slow rate of reoccurrence of psychotic episodes

اسلاید 19: Pharmacological EffectsBlocks D2 receptorsAch, 5HT, Histamine and NE receptorsLimbic system Brain StemBasal GangliaHypothalamus-Pituitary

اسلاید 20: Side Effects and ToxicityHigh Potency PhenothiazapinesFluphenazine, Trifluphenazine, PerphenazineCause less sedation Fewer anticholergenic side effectsLess postural hypertensionMore extrapyrimydal side effectsLow Potency PhenothiasapinesChlorpromazine, ThioridazineUsed when sedation is desirableAlso when Anticholinergic side effects limit complianceOften combined with benzodiazapines

اسلاید 21: Tolerance and DependenceRarely abusedNo toleranceNo physical or psychological dependenceStopping treatment can either result in relapse or withdrawal

اسلاید 22: HaloperidolFirst therapeutic alternative to PhenothiasazinesSimilar effects of phenothiasazinesProduces sedationReduces initiative, anxiety and activityWell absorbed orallySlow rate of metabolism and excretionActs on D2 receptorsFew side effectsDoes produce Parkinson like effects

اسلاید 23: Atypical AntipsychoticsMolindoneResembles 5HTRelation to 5HT therapeutic effect is unknownResembles traditional antipsychotics Mechanism of action, efficacy, side effects Moderate sedationIncreased motor activityPossibly euphoria

اسلاید 24: LoxapineSimilar in structure to atypicalsActions differ little from traditional effectsAntipsychotic, antiametic and sedative propertiesCauses abnormal motor movementsGood absorption, metabolism and excretion

اسلاید 25: ClozapineUsed to treat treatment resistant schizophrenicsClinically superior to traditional drugsRelieves much of the negative symptomsLacks many extrapyramidal effectsLess of a cognitive inhibitorClozapine may cause a loss of white blood cells but it reduces suicide rates

اسلاید 26: PharmacokineticsVaried absorption rates among patientsWell absorbed orallyMetabolitic half life 9-30hrsPeak plasma levels 1-4hrsMetabolized by the liver into 2 active metabolitesBlood levels must be monitored to ensure proper dosing

اسلاید 27: PharmacodynamicsHigh binding affinity for DA, Seretonin1c, seretonin2, alpha1, muscaranic and histamineLow rate of binding to D2 receptorsBlocks 5HT2 at higher levels

اسلاید 28: Side Effects and ToxicitySedation40% of patients Can affect complianceBed time dosing may help complianceWeight gain80% of patientsPersistantReason not knownWithdrawalDelusions, hallucinations, hostility, paranoid reaction, nausea, vomit, diarraheachachacha, headache, restlessness, agitation, confusion, sweating

اسلاید 29: Other ConcernsExpensiveDue to blood monitoring

اسلاید 30: RisperidonePotent inhibitor of D2 and 5HT2PharmacokineticsOrally administeredRate of metabolism varies3hr half lifeActive metabolite 9-hydroxy-risperidoneHalf life 22hrsConsidered a first-line treatment for schizophreniaHigh efficancy SafeFew detrimental effects on memoryMinimal extrapyramidal side effectsOther side effectsAgitation, anxiety, insomnia, headache, nausea, extrpyramidal side effects (only at high doses)

اسلاید 31: OlanzapineStructurally related to clozapine Blocks many receptors, but dopamine and serotonin interaction are thought to be responsible for therapeutic effectPharmacokineticsWell absorbed orallyPeak plasma levels at 5 to 8 hoursElimination half-life 27-38 hoursOverall effectivenessimprovements in both positive and negative symptoms Studies seem to show better results with less severely impaired patientsAlso used in bipolar

اسلاید 32: Sertindole5-HT2, D2, and alpha1-adrenoreceptors antagonistTreats both positive and negative symptomsMinimal extrapyramidal side effectsReduced sedative effects due to no affinity for histamine receptorsHalf-life 60 hours to 95 hoursCan lead to severe cardiac arrythmias

اسلاید 33: Quetiapine (Seroquel)5-HT2/D2 receptor antagonstHalf life 7hrsTwo or more daily doses neededGreater affinity for 5HT2 than D2Separates the antipsychotic action from the extrapyramidal side effectsReduces expression of glutamate receptor mRNA

اسلاید 34: ZiprasidoneSimilar in effect to HaloperidalWeight gain is negliableInactive byproductsPoorly absorbed orallyUnique actions on receptorsBlocks 5HT2 and D2Agonist at 5HT1aMay cause an antidepresant function

اسلاید 35: AmisulprideYet to be releasedD2 and D3 subtypes blocked in limbic system but not in Basal GangliaTwice as selective for D3 than D2Low doses blocks presynaptic receptors increasing DAHigher doses it antagonizes DA At these doses it has efficacy for negative symptomsLow incidence of extrapyramidal side effectsNo affinity for 5HT which is unusual for Atypical