2Schizophrenia - symptoms Positive SymptomsHallucinationsDelusions (bizarre, persecutory)Disorganized ThoughtPerception disturbancesInappropriate emotionsNegative SymptomsBlunted emotionsAnhedoniaLack of feelingFUNCTIONMood SymptomsLoss of motivationSocial withdrawalInsightDemoralizationSuicideCognitionNew LearningMemory
3Positive/active symptoms include thought disturbances, delusions, hallucinations Negative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech. impaired personal hygiene
5Prevalence of Schizophrenia 1-2% of U.S. population2 million diagnosed in U.S.Median age at diagnosis = mid-20’sMen = Women prevalenceMen earlier diagnosisWorse premorbid historyWorse prognosis
6Prognosis of Schizophrenia 10% continuous hospitalization< 30% recovery = symptom-free for 5 years60% continued problems in living/episodic periods
7EtiologyHereditary Influences may account for 10% of schizophrenia casesPrenatal Biological Trauma 5-10% cases of schizophreniaPerinatal biological traumaDiathesis - Stress Model
8Biological TreatmentInsulin coma therapy, Prefrontal lobotomy, Electroconvulsive therapyDr. Egas Moniz –Developed prefrontal lobotomy technique1935 – heard about work on a chimp “Becky” – Performed surgery on many patientsthey were just calmer, but also more sluggish and apatheticAwarded the Nobel Prize in Physiology and MedicineNext 15 years - 50,000 lobotomies
10Schizophrenia Pathophysiology Schizophrenia Pharmacologic Pathophysiology Profile of APDsPast Excess dopaminergic Dopamine D2-receptor activity antagonistsPresentRenewed interest in the Combined 5-HT2/D2 role of serotonin (5-HT) antagonistsFutureImbalance in cortical More selective antagonists communication and Mixed agonist/antagonists cortical-midbrain Neuropeptide analogs integration, involving multiple neurotransmitters
12Schizophrenia - Dopamine Hypothesis Repeated administration of stimulants like amphetamines and cocaine, which enhance central dopaminergic neurotransmission, can cause a psychosis that resembles the positive symptoms of schizophreniaLow doses of amphetamine can induce a psychotic reaction in schizophrenics in remissionStress, a major predisposing factor in schizophrenia, can produce a psychotic state in recovered amphetamine addicts.Carlsson and Lindqvist (1963) first proposed that drugs such as chlorpromazine and haloperidol alleviate schizophrenic symptoms by blocking DA receptors and thereby reduce DA function.Thess antipsychotic medications, which have been the main stay for treatment for nearly 50 years, have in common their ability to block dopamine D2 receptors
13Schizophrenia - Dopamine Hypothesis A strong correlation between the affinity of antipsychotic drugs for DA receptors and their clinical potencyBut no clear and consistent abnormality in DA function has been detected in schizophrenic patients.Some early studies with postmortem tissue revealed increased numbers of DA receptors (in particular D2-like) in schizophrenic patients, but there are serious problems with these findings. But long-term administration of antipsychotics produces increases in D2 receptors in animals.The reduction in cortical dopamine transmission (both at the pre- and postsynaptic level) in the chronic PCP model seems to be consistent with some findings in schizophrenic patientsReduced cortical dopamine transmission induced by long-term PCP exposure may be associated with a hyperactivity of subcortical dopamine systems
14Other transmitter systems involved.. Glutamatergic system dysfunctione.g. effect of phencyclidine – blocker of NMDA type of glutamate receptorsG-protein signaling abnormalitiesSerotoninergic system abnormalitiesmost antipsychotics also affect serotonin receptors Dopamine and serotonin theory of schizophrenia
15Serotonergic Pathways and Innervation Hypo = hypothalamus SN = substantia nigra Thal = thalamus
16Schizophrenia - Serotonin Hypothesis correlation between DA affinity and antipsychotic efficacy has become weaker as a result of recently developed atypical antipsychotic medications that also show substantial affinity for 5HT2 receptorsAlteration of 5-HT transmission in the brains of schizophrenics patients have been reported in post-mortem studies and serotonin-agonists challenge studiesThere are widespread and complex changes in the 5-HT system in schizophrenics patientsThese changes suggest that 5-HT dysfunction is involved in the pathophysiology of the disease
17Serotonin-Dopamine Interactions Ventral Tegmental Area (A10) Prefrontal CortexDopamine (DA)Serotonin (5-HT)GABA GlutamateStriatumGABA/AChMotor OutputsLimbic SystemBlockade of D2 receptors by conventional APDs causes EPSVentral Tegmental Area (A10)Substantia Nigra (A9)5-HT2A antagonists release dopamine from inhibition and decrease EPSMedian RapheDorsal Raphe
18Serotonin-Dopamine Interactions: Behavioral Studies Amphetamine-Induced and Spontaneous Locomotor ActivitySerotonin depletion (tryptophan-free diet, lesions by 5,6-dihydroxytryptamine) enhances amphetamine-induced hyperlocomotionSerotonin depletion or lesions of midbrain raphe increase spontaneous locomotor activityCatalepsyInhibition of serotonin induced by electrolytic lesions of the raphe, administration of 5-HT antagonists decreases neuroleptic-induced catalepsySerotonergic enhancement via the addition of 5-HT agonists, precursors, and uptake inhibitors increases neuroleptic-induced catalepsy
19Schizophrenia - Glutamate Hypothesis Preclinical as well as clinical studies provide evidence of hypofunction of NMDA receptors as a primary, or at least, a contributory process in the pathophysiology of schizophreniaSeveral clinical trials with agents that act at the glycine modulatory site on the NMDA receptor have revealed consistent reductions in negative symptoms and variable effects of cognitive and positive symptomsThese studies also provide evidence that suggests the effects of clozapine on negative symptoms and cognition may be through activation of the glycine modulatory site on the NMDA receptor.
20Serotonin-Glutamate-Dopamine Interactions Ventral Tegmental Area (A10) 5-HT2A antagonists restore dopaminergic function in the prefrontal cortexNMDA antagonists elevate extracellular brain levels of 5-HT in the prefrontal cortexPrefrontal CortexDopamine (DA)GlutamateSerotonin (5-HT)GABANMDA antagonists increase the firing of DA in limbic areasStriatumLimbic SystemVentral Tegmental Area (A10)Substantia Nigra (A9)NMDA antagonists reduce burst firing of VTA DA neuronsMedian RapheDorsal Raphe5-HT2 antagonists block the effects of NMDA antagonists
21ANIMAL MODEL OF SCHIZOPHRENIA High doses of amphetamine produce a syndrome of repetitive behaviours (sniffing, head movements, gnawing and licking) known as stereotypy or stereotyped behaviour.Because stereotyped behaviour also occurs in humans after higher doses of amphetamine and is similar to the repetitions of meaningless behaviour seen in schizophrenia, the amphetamine-induced stereotypy has been used as an animal model of schizophrenia.DA receptor antagonists block amphetamine stereotypy and there is a strong correlation between their potency in this model and in ameliorating schizophrenic symptoms.Other more complicated models are based on attentional and cognitive abnormalities observed in schizophrenia.
23ANTIPSYCHOTICS Pre-90’s Post-90’s “Typical”, conventional, traditional neuroleptics, major tranquilizorsModeled on D2 antagonismEPS/TDPost-90’s“Atypical”, novel, 2nd generationModeled on 5-HT2/D2 antagonismLess EPS, prolactin effectsWeight gain, sedation, diabetes
28Adverse Effects Summary Sedation ‑ initially considerable; tolerance usually develops after a few weeks of therapy; dysphoriaPostural hypotension ‑ results primarily from adrenergic blockade; tolerance can developAnticholinergic effects ‑ include blurred vision, dry mouth, constipation, urinary retention; results from muscarinic cholinergic blockadeEndocrine effects ‑ increased prolactin secretion can cause galactorhea; results from antidopamine effectHypersensitivity reactions ‑ jaundice, photosensitivity, rashes, agranulocytosis can occurIdiosyncratic reactions ‑ malignant neuroleptic syndromeWeight gainNeurological side effects - see next
29Neurological Side Effects of antipsychotics REACTIONFEATURESTIME OF MAXIMAL RISKPROPOSED MECHANISMTREATMENTAcute dystoniaSpasm of muscles of tongue, face, neck, back; may mimic seizures; not hysteria1 to 5 daysUnknownAntiparkinsonian agents are diagnostic and curativeAkathisiaMotor restlessness; not anxiety or "agitation"5 to 60 daysReduce dose or change drug: antiparkinsonian agents,b benzodiazepines or propranololc may helpParkinsonismBradykinesia, rigidity, variable tremor, mask facies, shuffling gait5 to 30 daysAntagonism of dopamineAntiparkinsonian agents helpfulNeuroleptic malignant syndromeCatatonia, stupor, fever, unstable blood pressure, myoglobinemia; can be fatalWeeks; can persist for days after stopping neurolepticAntagonism of dopamine may contributeStop neuroleptic immediately: dantrolene or bromocriptined may help: antiparkinsonian agents not effectivePerioral tremor ("rabbit" syndrome)Perioral tremor (may be a late variant of parkinsonism)After months or years of treatmentAntiparkinsonian agents often helpTardive dyskinesiaOral-facial dyskinesia; widespread choreoathetosis or dystoniaAfter months or years of treatment (worse on withdrawal)Excess function of dopamine hypothesizedPrevention crucial; treatment unsatisfactorya. Many drugs have been claimed to be helpful for acute dystonia. Among the most commonly employed treatments are diphenhydramine hydrochloride, 25 or 50 mg intramuscularly, or benztropine mesylate, 1 or 2 mg intramuscularly or slowly intravenously, followed by oral medication with the same agent for a period of days to perhaps several weeks thereafter. b. For details regarding the use of oral antiparkinsonian agents, see the rest of slides c. Propranolol often is effective in relatively low doses (20-80 mg per day). Selective beta1-adrenergic receptor antagonists are less effective. d. Despite the response to dantrolene, there is no evidence of an abnormality of Ca2+ transport in skeletal muscle; with lingering neuroleptic effects, bromocriptine may be tolerated in large doses (10-40 mg per day).
30Adverse Effects - EPS Parkinson-like symptoms Tardive dyskinesia Details on two main extrapyramidal disturbances (EPS):Parkinson-like symptomstremor, rigiditydirect consequence of block of nigrostriatal DA2 Rreversible upon cessation of antipsychoticsTardive dyskinesiainvoluntary movement of face and limbsless likely with atypical antipsychotics (AP)appears months or years after start of AP? result of proliferation of DA R in striatumpresynaptic?treatment is generally unsuccessful
31Phenothiazines - Side effects Weight gain – 40% - weight gain now attributed to ratio of binding to D2 and 5-HT2 receptors; possibly also histamine (for newer antipsychotics anyway)Sexual dysfunctionresult from NE and SE blockadeerectile dysfunction in 23-54% of menretrograde ejaculation inloss of libido and anorgasmia in men and womenSeizures - <1% for generalized grand mal
32M, et al: Weight gain associated with conventional ESTIMATED MEAN WEIGHT GAIN AT 10 WEEKSA comprehensive literature search identified 78 studies that included data on weight change in patients treated with a specific antipsychotic.For each agent a meta-analysis and random effects regression estimated the change in weight at 10 weeks of treatment.543Mean change in body weight (kg)21The new EPS-1PlaceboMolindoneHaloperidolSertindoleClozapineZiprasidoneRisperidoneFluphenazineThioridazineOlanzapineChlorpromazineNon-pharmcontrolAllison DB,MentoreJL,HeoM, et al: Weight gain associated with conventionaland newerantipsychotics: a meta-Analysis. AJP, 1999.
33Phenothiazines - Side effects Neuroleptic malignant syndrome (1-2% early in trt)combination of motor rigidity, hyperthermia, and autonomic dysregulation of blood pressure and heart rate (both go up)can be fatal in 5-20% of cases if untreatedtreatment – discontinue meds; give trts for fever and cardiac problems
34Sensitivity to sunsome phenothiazines collect in skin (chlorpromazine)sunlight causes pigmentation changes – grayish-purple splotching (look bruised)can also occur in eye and cause brown in corneathis produces a brownish cloud to vision and possibly permanent impairmentAgranulocytosis - <1%reduced white blood cell countlowered resistance to infectioncan be fatalJaundice – elevated bilirubin in liver - < ½%
35Phenothiazines - Drug Interactions enzyme interactions with barbiturates (phenobarbital); phenytoin (Dilantin); carbamazepine (Tegretol) – reduce phenothiazine levelsco-administration must be carefully monitored to prevent toxicityenzyme competition with SSRIs increases levels and may increase side effects
36Haloperidole entered US market in 1967 more potent than phenothiazines, so doses are loweralso have long half-lifelike phenothiazines, they block dopamine and norepinephrine receptors and show the related side effectsextrapyramidal effects are worse (due to low blockade of ACh and thus worse ratio)but blood pressure effects are lessreduced sedationno blood abnormalities or jaundice
37Limitations Of Conventional Antipsychotics Approximately one-third of patients with schizophrenia fail to respondLimited efficacy againstNegative symptomsAffective symptomsCognitive deficitsHigh proportion of patients relapseSide effects and compliance issuesSome safety issues are prominent
38Antipsychotic Drugs – New Generations „atypical“ About 40-60% do not respond to phenothiazines or cannot handle side effectsQuestions remain about the efficacy of phenothiazines and haloperidole for negative symptomsDrugs needed that are low in extrapyramidal side effects and at least equal in efficacy for positive symptoms, perhaps better for negative
39Antipsychotic Drugs – New Generations „atypical“ clozapinerisperidoneolanzapinesertindolequetiapine etc.
41Clozapine (1989)Selectively blocks dopamine D2 receptors, avoiding nigrostriatal pathwayAlso blocks NEMore strongly blocks 5-HT2 receptors in cortex which then acts to modulate some dopamine activityAmong non-responders to first generation meds or those who cannot tolerate side effects, about 30% do respond to Clozapine
42Clozapine Extrapyramidal side effects are minimal May help treat tarditive dyskinesiaStill shows orthostatic hypotension effects, sedation, weight gain, increased heart rateIncreased risk for seizures (2-3%)Agranulocytosis in 1%Agranulocytosis risks increase when co-administered with carbamazepineInteractions with SSRIs and valproic acid increase Clozapine levels and risks
43Risperidone (Risperdal; 1994) Fewer side effects than ClozapineMarketed as first line approach to treatmentBlocks selective D2, norepinephrine, and 5-HT2Argued as effective for positive and negative symptoms (controversial)Extrapyramidal side effects low (but are shown at high doses) - controversialShares sedation, weight gain, rapid heart beat, orthostatic hypotension, and elevated prolactinNo agranulocytosis risksMay cause anxiety/agitation (possible OCD)
44Risperidone (Risperdal) Research designs clearly stacked in favor of Risperidone re showing better profile for extrapyramidal side effects and for symptom reductionAdvantages unclear other than agranulocytosis issue
45Olanzipine - Zyprexa – 1996Same poorly supported arguments about improved negative symptom reductionArgued to be better than risperidone in extrapyramidal issuesDoes not cause prolactin elevationSame claim to fame reduced agranulocytosis risks
46Sertindole – Serlect – 1995Some poorly supported arguments about improved negative symptom reductionLow risk for extrapyramidal side effects – major advantageNo sedation and very mild prolactin elevation– major advantagesShares orthostatic hypotension, tachycardia, and weight gainCommon side effects are rhinitis and reduced ejaculatory volume (not associated with disturbed function)concern about sudden cardiac death or episodes due to cardiac arrhythmia led to its voluntary removal in 1998
47Quetiapine – Seroquel - 1997 No increased risks for extrapyramidal symptomsShares sedation, orthostatic hypotension, weight gainDoes cause anticholinergic side effects (like older and Clozapine) – dry mouth, constipationDoes not elevate prolactinZiprasidoneSimilar to advantages of others, but argued not to cause weight gain
48StatusLimited evidence to support arguments about improved treatment of negative symptomsVery limited data on effects on cognitive featuresNewest meds clearly do have reduced extrapyramidal side effects, reduced sedation, and do not cause prolactin elevationWeight gain issue – is ziprasidone better?Wetterling Evaluation of published data from varying designs, etc:Clozapine – 1.7 kg/month Risperidone – 1 kg/monthOlanzipine – 2.3 kg/month Ziprasidone – 0.8 kg/monthQuetiapine kg/month