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Schizophrenia:Diagnosis, Treatment

Options and OutcomesElizabeth Montagnese, M.D.

Adult, Child and Adolescent Psychiatrist, Medical Director of Family and Children Services of Central

PennsylvaniaPrivate Practitioner

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What is schizophrenia?

Theresa- 32 year old woman hospitalized at a State Mental Institution in PANumerous acute hospitalizations in 2 previous years Her psychotic presentation

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Historical Perspectives

Emil Kraeplin- German psychiatrist in late 1800’sCategorized “dementia praecox” as a disease stateAlso described manic depressionFirst descriptive classification system in psychiatry

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Emil Kraeplin (contd.)

Viewed mental illness as brain dysfunctionFocused on commonality of symptoms from patient to patientDisturbance of attention, comprehensionHallucinationsDisturbances in flow of thought

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Eugen Bleuler

Swiss psychiatristElaborated on idea of somatic causeBleuler’s 4A’s: affect, ambivalence, autism, association (loosening of)Proposed specific criteria to diagnosePrimary and secondary symptoms

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Kurt Schneider

Maximize diagnostic specificityFirst rank symptoms: audible thoughts, voices arguing or commenting, influenced thoughts, delusional perceptionsSecond rank symptoms: perplexity, depression, euphoria, emotional impoverishment

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Development of DSM

1st DSM- 1952,clinical consensus, universality of diagnostic criteriaDSM II- 1968DSM III- 1972DSM IIIR- 1987, not just clinical consensus but scientific evidenceDSM IV- 1994DSM IVTR- 2000

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What is psychosis?

What is real vs. fantasyThink of “A Beautiful Mind”

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Hallucinations

Think of 5 senses: visual, auditory, olfactory, gustatory, tactileUsually frightening, morbid, macabreCan be friendly, company

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Delusions

A fixed false beliefBizarre-illogicalNonbizarre- can really occur

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What are the psychotic disorders?

Schizophrenia- 5 typesSchizoaffective DisorderDelusional DisorderBrief Psychotic DisorderShared Psychotic DisorderPsychotic Disorder due to Medical Cond.Substance-induced psychotic disorderPsychotic Disorder NOS (common in kids)

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DSM Criteria for Schizophrenia

Two or more of following for 1 month: (A Criterion)DelusionsHallucinationsDisorganized speechDisorganized behaviorNegative symptoms: flat affect, avolition, alogiaOnly 1 if delusions bizarre or voice keeping commentary or 2 voices conversing

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DSM Criteria for Schizophrenia

Social/occupational dysfunctionDisturbance for at least 6 months with at least 1 month with criterion ANot due to substance, medical condition, mood disorder or PDD

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Schizophrenia Subtypes

CatatonicParanoidDisorganizedUndifferentiatedResidual

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Positive Symptoms

Symptoms associated withdistorted realityDelusionsHallucinations

Things present in those with schizophrenia as compared to those without.

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Negative Symptoms

Affective bluntingPoverty of speechThought blockingPoor grooming Lack of motivation-apathyAnhedoniaSocial withdrawal

Things absent from those with schizophrenia as compared to those without.

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Epidemiology

How common? 1% of world’s populationAcross cultures, racesM:F, 1:1Age of onset is earlier in menM: onset late teens, early 20’sW: onset mid to late 20’sStudies show overdiagnosis in African Americans, not higher incidence

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Course of Disease

Chronic illnessNo cureVery treatableWithout treatment-downhill course

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Course of Disease

Impacts morbidity and mortalityCan be “lethal”50% attempt suicide at least 1x10-15% die in 20 yr f/u after diagnosis75% smoke cigarettes30-50% abuse alcohol1/3-2/3 of homeless have schizophrenia

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Cost of Schizophrenia

1990-accounted for 2.5% of health care expenditures+ nondirect costs($45 billion) 2002- $62.7 billion for direct and nondirect costsUnemployment rate is 70-80%10% of those permanently disabled

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Treatment prior to antipsychotics

Talk therapyECTInsulin induced seizuresFrontal lobotomiesStraight jacketsWet sheet wraps

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Treatment

Not just meds but definitely medsPsychosocial and cognitive rehabClubhouse model-deinstitutionalizationSupportive psychotherapyFamily therapy

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Now, let’s get to the meds

Antipsychotics revolutionized treatmentChlorpromazine (Thorazine) – 19521st of the “Typical” antipsychoticsFirst used as an anesthestic

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Conventional Antipsychotics

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Generic Name

Brand Name Dose Equiv.(mg)

Common Dose Range

Relative Potency

EPS

Chlorproma-zine

Thorazine 100 200-900 Low Low

Mesorida-zine

Serentil 50 100-400 Low Low

Thiorida-zine

Mellaril 100 200-800 Low Low

Perphena-zine

Trilafon 8 16-64 Intermediate Intermediate

Trifluopera-zine

Stelazine 5 5-40 High High

Fluphena-zine

Prolixin 2 5-20 High High

Haloperidol Haldol 2 5-20 High HighChlorprothi-

xeneTaractan 75 100-600 Low Low

Thiothixene Navane 5 5-60 High LowLoxapine Loxitane 15 25-250 Intermediate Intermediate

Molindone Moban 10 50-225 Intermediate Intermediate

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Neuroanatomy 101

Neuron- brain cells, 100 trillion cellsWe lose them as we ageCommunicate with each other via chemical called neurotransmittersPsychotropic medications affect these neurotransmitters

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How do these meds work?

Target dopamanergic neuronsIncrease dopamine=psychosisDopamine blockersTypical agents affect nigrostriatal tract andmesolimbic tractNigrostriatal area also affects involuntary movementsReason for EPS

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Extra Pyramidal Symptoms

Akathesia-uncontrolled restlessnessDystonic reactions- muscle spasms, usually eyes, neck, back and tongueParkinsonism- shuffling gait, stiffness, tremor, masked facesCan be intolerable, very frighteningCommon reason for medication noncompliance

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Acetylcholine-Dopamine Balance

DA

ACHDA

ACH

Excess ACH- high EPS, decreased psychosis

Excess DA-psychosis

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EPS (Contd.)

Higher incidence with higher potencyHigher incidence at start of txRisk factors for EPS: young age, male, IM administrationTreat with anticholinergic or antihistaminergicPrevent with anticholinergic or antiparkinsoniandrugs

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Treating EPS

Generic Name Trade Name Dose (mg/day) Duration of Action (hrs)

Benztropine mesylate

Cogentin 0.5-6mg 24

Trihexyphenidyl hydrochloride

Artane 1-15 6-12

Amantadine Symmetrel 100-300 12

Diphenhydramine Benadryl 25-150 8

Propranolol Inderal 20-120 8

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Tardive Dyskinesia

Tardive dyskinesiaAbnormal involuntary movementsDyskineticChoreoathetoidUsually face, tongue, mouthCan involve trunk, armsCan occur after brief exposureStop meds, lower doseCan be permanentMust get informed consent

Risk increases with longer use (4%/yr tx)Risk increases with age, female gender, affective disorder, GMC, high dosesCan be disfiguringClozapine may helpVit E, lithium, amantadine

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Atypical Agents

NewerAffect D2 and 5HT(2A) receptorsReason for increased efficacyAffects positive (D2) and negative (5HT) symptomsDon’t effect nigrostriatal tract as much-less EPSAffect mesolimbic and mesocortical tracts

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Atypical Agents

Generic Name Trade Name Daily Dosage(mg)

Forms available

Aripiprazole Abilify 10-30 INJ, soln, tabs-D

Clozapine Clozaril 25-900 tabs-D

Olanzapine Zyprexa 5-20 INJ, tabs-D

Palipaeridone Invega 6-12 tabs

Quetiapine Seroquel 300-800 tabs

Risperidone Risperdal 1-12 tabs-D, soln, INJ

Ziprasidone Geodon 40-160 tabs

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How do we choose an atypical?

Side effect profile- make them work for patientAny absolute contraindications or medical risksOther meds: drug-drug interactionsCost!!!!InsurancePatient/family perceptionsDoctor’s own perceptions about meds

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General Side Effects of Atypicals

Less likely to cause EPS or TDProlactin elevation-galactorhea, gynecomastiaSedationAnticholinergicWeight gainAlso seen with typicals

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Risperidone (Risperdal)

1993Only depot form of atypicalDepot form q 2 weeksWeight gain, sedation and high prolactin most commonAbove 6 mg daily- EPS

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Olanzipine (Zyprexa)

Very sedatingExcessive weight gainMetabolic syndrome

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Quetiapine (Seroquel)

Moderate for weight gainSlit lamp eye exam recommended-cataracts, not often doneVery sedatingUsed in low doses for sleep-off label

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Ziprasidone (Geodon)

2001Short acting injectable availableCan be used for acute agitationMore weight neutral than other atypicalsLower incidence of metabolic syndrome

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Aripiprazole (Abilify)

Not a full DA agonist“Dopamine stabilizer”Agonist in areas of low activityMore weight neutralLow incidence of metabolic syndrome

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Clozapine (Clozaril)

1989Weight gainAgranulocytosis- serious, fatal Weekly WBC countSpecific protocol-complex to manageUsed in refractory casesSeizuresExcessive salivation

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Palipaeridone (Invega)

2007Active metabolite of risperidoneSlow release over 24 hours

Comparison of Atypicals

Typicals Cloz Arip Olanz Risp Que Zip

Prolactin Elev

+ to ++ 0 0 to + + ++ + +

Weight Gain

++ +++ 0 to+ +++ ++ to +++

++ 0 to +

Anticholinergic

+ to +++

+++ +/- +/- + +/- +/-

Sedation + to ++ +++ 0 to +/- +++ ++ +++ 0 to +/-

Cloz=clozapine, Arip=aripiprazole, Olanz=olanzapine, Risp=risperidone, Que=quetiapine, Zip=ziprasidone

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Are Atypicals Worth It?

CATIE-Sept 2005NIMH study in NEJMGround breakingOutcome stated typicals=atypicals in efficacyCost of atypicals may not always be justifiedPatients stopped both meds at a high rate

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Cost of Meds

Medication Typical monthly cost

Aripiprazole(Abilify) $500

Paliperidone(Invega) $400

Ziprasidone(Geodon) $400

Risperidone(Risperdal) $200

Clozapine(Clozaril) $300

Quetiapine(Seroquel) $400

Olanzapine(Zyprexa) $350

Haloperidol(Haldol) $45

Perphenazine(Trilafon) $25

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Use of Atypicals in Children

ControversialMostly off label useAutism spectrum disordersSevere behavioral problemsHugh increase in RXs written for kids in last 5 years.

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Atypicals-other uses

Bipolar disorder- FDA approvalOCD-severe, refractoryDementia- in past, black box warning

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Treatment- 3 phases

Phase I- acute phasePrevent harmControl disturbed behaviorReduce psychosisReturn to best level of functioningPatient/family allianceFormulate short and long term treatment palnsConnect with community aftercare

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Phase II- Stabilization

Minimize risk of relapseMaximize adaptation to return to communityContinue symptom reductionConsolidate recoveryPromote recovery

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Phase III- Stable Phase

Sustain remissionMaintain or improve functioning and quality of lifePromptly treat symptom exacerbation/relapseMonitor for side effects

Case Study

References

Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Text Revision, American Psychiatric Association, 2000Physicians Desk Reference, 2008Schizophrenia, A Clinician’s Guide, 1995, American Psychiatric PressLieberman JA, Stroup TS, McEvoy JP, et al, “Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia”, N Engl J Med, 2005;353: 1209-1223NIMH, Questions and Answers about the NIMH Clinical Antipsychotic Trials of Intervention Effectiveness Study (CATIE), http://www.nimh.gov/healthinformation.catieqa.cfmWu EQ, Birnbaum HG, et al,“The Economic Burden of Schizophrenia in the United States in 2002”, JClinPsych, 2005 Sept;66(9):1122-1129 Practice Guidelines for the Treatment of Patients with Schizophrenia, Second Edition, 2002, American Psychiatric Association