Schizophrenia & Psychoses A Clinical Introduction Godfrey D. Pearlson, M.D. Neuropsychiatry Research Center Institute of Living Yale University School.

Schizophrenia & PsychosesSchizophrenia & Psychoses AA Clinical Introduction Clinical Introduction

Godfrey D. Pearlson, M.D.Godfrey D. Pearlson, M.D.

Neuropsychiatry Research CenterNeuropsychiatry Research Center

Institute of LivingInstitute of Living

Yale University School of MedicineYale University School of Medicine

Schizophrenia - OutlineSchizophrenia - Outline

1. Phenomenology1. Phenomenology

2. Epidemiology2. Epidemiology

3. Etiology ‑ neurodevelopmental & 3. Etiology ‑ neurodevelopmental & genetic factorsgenetic factors

4. Spectrum disorders, biomarkers, 4. Spectrum disorders, biomarkers,

5.5. TreatmentsTreatments

6.6. Psychotic mood disordersPsychotic mood disorders

Core Concepts- 1Core Concepts- 1

Affective Disorder:Affective Disorder: disturbance of mooddisturbance of mood

Delirium:Delirium: disturbance ofdisturbance of consciousnessconsciousness

Dementia:Dementia: disturbance of (a prior level disturbance of (a prior level of) of) cognitioncognition

Schizophrenia: ??????????????????????Schizophrenia: ??????????????????????

No obvious pathognomonic symptoms or No obvious pathognomonic symptoms or core“theme”. core“theme”.

Core Concepts IICore Concepts II

1. Because it has no pathognomonic symptoms, 1. Because it has no pathognomonic symptoms, schizophrenia is a diagnosis of exclusion.schizophrenia is a diagnosis of exclusion.

2. Widespread agreement that schizophrenia is 2. Widespread agreement that schizophrenia is a heterogeneous disorder; but no agreement a heterogeneous disorder; but no agreement on sub-typing.on sub-typing.

3. Traditional subtypes (e.g. hebephrenic, 3. Traditional subtypes (e.g. hebephrenic, paranoid) mutate over time.paranoid) mutate over time.

DELIRIUMDELIRIUM PLUSPLUS DISTURBED DISTURBED

CONSCIOUSNESSCONSCIOUSNESS

DEMENTIADEMENTIA PLUSPLUS COGNITIVECOGNITIVE

DECLINEDECLINE

AFFECTIVEAFFECTIVE PLUSPLUS CHANGE IN CHANGE IN

DISORDERDISORDER MOOD, SELF-ATTITUDEMOOD, SELF-ATTITUDE

AND VITAL SENSEAND VITAL SENSE

SCHIZOPHRENIASCHIZOPHRENIA HALLUCINATIONS,HALLUCINATIONS,

DELUSIONS,DELUSIONS,

FORMAL THOUGHT DISORDERFORMAL THOUGHT DISORDER

Frank S.Frank S. 31 y.o. single WM 31 y.o. single WM

Upper middle class family, no FH of mental illnessUpper middle class family, no FH of mental illness

Mother’s pregnancy – ‘flu’ at 15 weeks, forceps Mother’s pregnancy – ‘flu’ at 15 weeks, forceps delivery, Apgar in normal rangedelivery, Apgar in normal range

Shy, slightly withdrawn child – ‘grew out of it’ by age Shy, slightly withdrawn child – ‘grew out of it’ by age 14. IQ = 128 FS.14. IQ = 128 FS.

College – electrical engineering major. All ‘A’ grades in College – electrical engineering major. All ‘A’ grades in freshman year.freshman year.

Sophomore year – age 20, increasingly withdrawn, Sophomore year – age 20, increasingly withdrawn, preoccupied, ‘distant’, odd philosophical worries x 6 preoccupied, ‘distant’, odd philosophical worries x 6 months.months.

SCHIZOPHRENIA– CASE STUDY 1

Became convinced messages on TV about him, Became convinced messages on TV about him, “aliens reading my mind.” “White House controlling my “aliens reading my mind.” “White House controlling my body.”body.”

Auditory hallucinations of “robot voices” saying good Auditory hallucinations of “robot voices” saying good and bad things about him, arguing.and bad things about him, arguing.

Showed up at police HQ to warn of “plots”, taken to Showed up at police HQ to warn of “plots”, taken to ER for evaluationER for evaluation

Alert, O x 3. Not elated or depressed. MMS – 30/30. Alert, O x 3. Not elated or depressed. MMS – 30/30. Urine Toxicology screen negative. Physical exam and Urine Toxicology screen negative. Physical exam and labs all WNL. Brain MRI WNL.labs all WNL. Brain MRI WNL.

SCHIZOPHRENIA– CASE STUDY 2SCHIZOPHRENIA– CASE STUDY 2

SCHIZOPHRENIA– CASE STUDY 3SCHIZOPHRENIA– CASE STUDY 3

Hospitalized three weeksHospitalized three weeks

Partial response to HaloperidolPartial response to Haloperidol

Family “lost his spark”……but not due to medicationsFamily “lost his spark”……but not due to medications

Unable to complete collegeUnable to complete college

Halfway house – small apartmentHalfway house – small apartment

Volunteer for state agencyVolunteer for state agency

3 subsequent hospitalizations in 10 years3 subsequent hospitalizations in 10 years

Seclusive, poor self-careSeclusive, poor self-care

Some improvement on olanzapine – initial gainSome improvement on olanzapine – initial gain

Now on ziprasodone – variable complianceNow on ziprasodone – variable compliance

Positive and Negative SymptomsPositive and Negative Symptoms

PositivePositive Negative/DeficitNegative/Deficit

DelusionsDelusions Poverty of speechPoverty of speech

HallucinationsHallucinations Flat affectFlat affect

IncoherenceIncoherence Social WithdrawalSocial Withdrawal

Bizarre behaviorBizarre behavior ApathyApathy

((Remember-no pathognomonic symptoms.) Remember-no pathognomonic symptoms.) Source: DSM-IV Draft Criteria, 1993Source: DSM-IV Draft Criteria, 1993

Cognitive DeficitsCognitive Deficits

An essential part of the syndrome.An essential part of the syndrome.

Working MemoryWorking Memory

Set ShiftingSet Shifting

Verbal MemoryVerbal Memory

Attention / Continuous PerformanceAttention / Continuous Performance

Epidemiology of SchizophreniaEpidemiology of Schizophrenia

About 1% prevalence in the populationAbout 1% prevalence in the population

Occurs in all cultures, all socioeconomic groupsOccurs in all cultures, all socioeconomic groups

Peak onset in men, ages 15 to 25Peak onset in men, ages 15 to 25

Peak onset in women, ages 22 to 30Peak onset in women, ages 22 to 30

Prevalence ultimately equal in men and womenPrevalence ultimately equal in men and women

50% of patients attempt suicide, 10% succeed50% of patients attempt suicide, 10% succeed

Most expensive of all mental disorders:Most expensive of all mental disorders:

Chronic but non-fatal, many incarcerated, homelessChronic but non-fatal, many incarcerated, homeless

– Direct costs = 0.4% of the GNPDirect costs = 0.4% of the GNP

– Indirect costs = 1.6% of the GNPIndirect costs = 1.6% of the GNP

20-year Follow-up of Patients with 20-year Follow-up of Patients with SZ (Iceland)SZ (Iceland)

All first-episode SZ diagnosed in 1966 to 1967All first-episode SZ diagnosed in 1966 to 1967

22% mortality and 9% suicide22% mortality and 9% suicide

60% never married; of the rest, most divorced60% never married; of the rest, most divorced

71% had persistent symptoms despite 71% had persistent symptoms despite neuroleptic treatmentneuroleptic treatment

95% had impaired social relationships95% had impaired social relationships

65% worked fewer than 5 months per year65% worked fewer than 5 months per year

29% had “an acceptable level of health”29% had “an acceptable level of health”

Medical Illnesses in PsychosisMedical Illnesses in Psychosis

Genetic predisposition / vulnerabilityGenetic predisposition / vulnerability

Brain mal-development in uteroBrain mal-development in utero

(genetic, toxic, infective)(genetic, toxic, infective)

Pregnancy & birth complicationsPregnancy & birth complications

Early psychosocial experienceEarly psychosocial experience

Source: Mednick et al., 1991Source: Mednick et al., 1991

Proposed Etiology

GENE GENE CELL CELL SYSTEM SYSTEM BEHAVIOR BEHAVIOR

Brain

Struct

ureElectro

Physiology

Senso

ry m

oto

rIn

tegra

tion

BrainFunction

Clinical

Symptom

s

Cog

nit

ion

Multiple susceptibility alleles, each of small Multiple susceptibility alleles, each of small effect, low penetrance, that act in concerteffect, low penetrance, that act in concert

Subtle metabolic abnormalitiesSubtle metabolic abnormalitiesMolecular bottlenecks?Molecular bottlenecks?

Abnormal information processingAbnormal information processingCognitive inefficiency – memory and control Cognitive inefficiency – memory and control processes, Biomarkersprocesses, BiomarkersNot Not ≡ illness, e.g. as found in unaffected siblings≡ illness, e.g. as found in unaffected siblings

Complex functional interactionsComplex functional interactionsEmergent phenomenaEmergent phenomena

Gene

Cell

System

Behavior

(After Weinberger, 2003)

PHASES OF SCHIZOPHRENIAPHASES OF SCHIZOPHRENIA

PREMORBID PRODROME ACTIVE

Fu

nct

ion

ing

Course of Illness

Environmental StressEnvironmental StressBiological FactorsBiological FactorsDrug UseDrug Use

StructureBiochemFunction

Neurol +CognitiveDeficits

EarlyNegativeSx

WeakPositiveSx

EmergingPsychoticSx

B i o l o g i c a l V u l n e r a b i l i t y

Age5 12 15 180 21

Premorbid EarlyProdrome

LateProdrome

Disease GenesViral InfectionEnvironmental Toxins

Peri-natal/BirthComplications

TRIGGERS:

• DSM-IV -Based on phenomenologyDSM-IV -Based on phenomenology

• Highly reliable, but of dubious validityHighly reliable, but of dubious validity

• Could have been written 100 years agoCould have been written 100 years ago

(in fact they were, essentially)(in fact they were, essentially)

• No laboratory test, even to confirm No laboratory test, even to confirm diagnosis, let alone a diagnostic test diagnosis, let alone a diagnostic test related to pathophysiologyrelated to pathophysiology

Diagnostic Criteria for SchizophreniaDiagnostic Criteria for Schizophrenia

EtiologyEtiology ••

PathologyPathology ••

Biologic Biologic • • Definition/TestDefinition/Test

GenesGenes (partial) (partial) • (partial)• (partial)

BiomarkersBiomarkers (partial) (partial)

DIABETESDIABETES SCHIZOPHRENIASCHIZOPHRENIA

• Impaired GTT Impaired GTT ++ impaired fasting glucose impaired fasting glucose ~~ 40% of obese adults40% of obese adults

• Gestational DM (Gestational DM (~~ 10% of pregnant women) 10% of pregnant women)

• Steroid-induced DM (Steroid-induced DM (~~ 30% on hi-dose 30% on hi-dose systemic steroids)systemic steroids)

All of the above are substantially increased in All of the above are substantially increased in first-degree relatives of Type-2 diabetics first-degree relatives of Type-2 diabetics (about 50% have insulin resistance), 15% (about 50% have insulin resistance), 15% diabetes, 25% abnormal GTT.diabetes, 25% abnormal GTT.

Clues from Type-2 Diabetes “Spectrum Cases”Clues from Type-2 Diabetes “Spectrum Cases”

Early researchers into schizophrenia noticed Early researchers into schizophrenia noticed that unaffected family members exhibited that unaffected family members exhibited oddities and eccentricities.oddities and eccentricities.

Interpretation:Interpretation:

1.1. Consequence of close association with Consequence of close association with someone whose behavior was disturbed or someone whose behavior was disturbed or disturbingdisturbing

2.2. Lesser, “dilute” form of the disorderLesser, “dilute” form of the disorder

Schizotypy and Spectrum Conditions 1Schizotypy and Spectrum Conditions 1

Kety’s genetic studies with the Danish twin and Kety’s genetic studies with the Danish twin and disease registries, & Kendler’s Irish disease registries, & Kendler’s Irish kindreds confirm these ideas.kindreds confirm these ideas.

Mild or dilute forms of schizophrenia, or oddities Mild or dilute forms of schizophrenia, or oddities of thought and behavior occur more of thought and behavior occur more commonly among close relatives of patients commonly among close relatives of patients with schizophrenia than in the population at with schizophrenia than in the population at large. Genetic explanations best fit the large. Genetic explanations best fit the facts. These individuals have vulnerability facts. These individuals have vulnerability genes, insufficient for full-fledged genes, insufficient for full-fledged schizophrenia.schizophrenia.

< Introduces concept of biomarkers >< Introduces concept of biomarkers >

Schizotypy and Spectrum Conditions 2Schizotypy and Spectrum Conditions 2

SCHIZOPHRENIA VULNERABILITY SCHIZOPHRENIA VULNERABILITY MARKERS “Biomarkers”MARKERS “Biomarkers”

Definition:Definition:

Physiological and clinical phenomena found Physiological and clinical phenomena found in association with a disorder, which are in association with a disorder, which are quantifiable, and presumed to be more quantifiable, and presumed to be more closely connected to the vulnerability closely connected to the vulnerability

gene than the illness diagnosis.gene than the illness diagnosis.

BIOMARKERSBIOMARKERS

• Gene markers – a few in last 3 yrs.Gene markers – a few in last 3 yrs.• Electrophysiology – P-300, N-400, P450Electrophysiology – P-300, N-400, P450• Psychophysiology – oculomotor, PPIPsychophysiology – oculomotor, PPI• Brain structure – Volumes of LV, STG, HippoBrain structure – Volumes of LV, STG, Hippo• Brain Function – PET, fMRI with WCST, WMBrain Function – PET, fMRI with WCST, WM• Brain Chemistry – DA receptors, releaseBrain Chemistry – DA receptors, release• Development – neurologic, cognitive, socialDevelopment – neurologic, cognitive, social• Clinical exam – MPA’s, ‘soft’ neurologic signsClinical exam – MPA’s, ‘soft’ neurologic signs• Cognition – WM, attentionCognition – WM, attention• Niacin flush, fingerprintsNiacin flush, fingerprints

Schizophrenia BiomarkersSchizophrenia Biomarkers

Summary:

• Promising avenue of research.

• Approach very useful in diabetes, hypertension- may work for schizophrenia.

Biomarkers and Schizophrenia

Major defects in:Major defects in:• Working memoryWorking memory• Executive functioning (Executive functioning (abstraction, problem solving, abstraction, problem solving,

conceptualization, sequencing, inhibition, planning)conceptualization, sequencing, inhibition, planning)

• AttentionAttention• Verbal memoryVerbal memory• Semantic tasksSemantic tasks

Symptoms suggest frontal lobe dysfunctionSymptoms suggest frontal lobe dysfunction

Schizophrenia and CognitionSchizophrenia and Cognition

Magnitude of Cognitive Deficits in SchizophreniaMagnitude of Cognitive Deficits in Schizophrenia

TestTest DomainDomain Md (mean effect Md (mean effect size difference)size difference)

# of studies# of studies % Patients % Patients Below MedianBelow Median

Verbal Verbal MemoryMemory

MemoryMemory 1.411.41 3131 7878

Wisconsin Wisconsin Card SortCard Sort

Executive Executive FunctionFunction

0.880.88 4343 6969

Verbal Verbal FluencyFluency

1.151.15 2929 7575

Continuous Continuous PerformancePerformance

Sustained Sustained AttentionAttention

1.161.16 1414 7575

Bilateral Bilateral Motor SkillMotor Skill

MotorMotor 1.31.3 55 7777

Heinrichs RW, Zakanis KK, Heinrichs RW, Zakanis KK, NeuropsychologyNeuropsychology 2: 426-445 2: 426-445

Cognitive Deficits in Schizophrenia Cognitive Deficits in Schizophrenia

Core Features of IllnessCore Features of Illness

Precede Onset of IllnessPrecede Onset of Illness– ½ SD lower IQ½ SD lower IQ– Reading difficulties in grade through high schoolReading difficulties in grade through high school– Delayed onset of hand dominanceDelayed onset of hand dominance

Present at Disease OnsetPresent at Disease Onset

Continued…Continued…

Sources: Green 1996; Heinrichs and Zakzanis 1998; Saykin 1991, 1994

Cognitive Deficits in Schizophrenia Cognitive Deficits in Schizophrenia

Resist Medication EffectsResist Medication Effects

Persist into SenescencePersist into Senescence

May Predict Psychosocial Function May Predict Psychosocial Function Better Than Positive or Negative Better Than Positive or Negative SymptomsSymptoms

Core Cognitive Domains Core Cognitive Domains Compromised in SchizophreniaCompromised in Schizophrenia

Sustained attentionSustained attentionWorking memoryWorking memorySet shiftingSet shiftingVerbal MemoryVerbal MemoryProblem solvingProblem solvingAbstractionAbstraction

These suggest compromised neural circuitsThese suggest compromised neural circuits

Symptoms suggestive of frontal Symptoms suggestive of frontal lobe dysfunctionlobe dysfunction

Emotional dullnessEmotional dullness

Impaired judgmentImpaired judgment

Poor initiative, motivation, drivePoor initiative, motivation, drive

Lack of insightLack of insight

Difficulty in planningDifficulty in planning

Impaired problem-solving/abstract Impaired problem-solving/abstract reasoningreasoning

Decreased concern for personal hygieneDecreased concern for personal hygiene

Social withdrawalSocial withdrawal

Cognitive RehabilitationCognitive Rehabilitation

RemediationRemediation--

Repeated practice and acquisition of Repeated practice and acquisition of compensatory strategies on cognitive exercises compensatory strategies on cognitive exercises designed to engage under-functioning brain designed to engage under-functioning brain circuitscircuits

AdaptationAdaptation

History of Antipsychotic Medications

Dopamine and other Neurotransmitters

• Off D2 graphOff D2 graph

• Other receptorsOther receptors

• Antipsychotic with EPS!Antipsychotic with EPS!

• Effective against negative symptoms Effective against negative symptoms (late!)(late!)

• Atypically expensiveAtypically expensive

Atypical neurolepticsAtypical neuroleptics

Clozaril (Sandoz)Clozaril (Sandoz) $3,694 $3,694 (Not including (Not including monitoring , monitoring , which which adds significant adds significant extra cost)extra cost)

5 mg. BID, Haldol5 mg. BID, Haldol $944$944(McNeil)(McNeil)

Haldol (Generic)Haldol (Generic) $254$254

3 mg. BID, Risperdal 3 mg. BID, Risperdal $2,843$2,843(Janssen)(Janssen)

10mg of Zyprexa $1/mg = $3,65010mg of Zyprexa $1/mg = $3,650(Pfizer) (Pfizer)

Annual Cost Estimates of Typical DosesAnnual Cost Estimates of Typical Doses

Psychosis in Mood DisordersPsychosis in Mood Disorders

Phenomenology and Schneider’s Phenomenology and Schneider’s First-Rank SymptomsFirst-Rank Symptoms

Kurt Schneider, 1939, places high value on certain Kurt Schneider, 1939, places high value on certain symptoms in the diagnosis of schizophrenia, naming them symptoms in the diagnosis of schizophrenia, naming them “ first rank symptoms”. “ first rank symptoms”. These include: audible thoughts, voices heard arguing, These include: audible thoughts, voices heard arguing, voices heard commenting on one's actions, somatic voices heard commenting on one's actions, somatic passivity experiences, thought withdrawal & diffusion, passivity experiences, thought withdrawal & diffusion, delusional perception, and “made” impulses, drives and delusional perception, and “made” impulses, drives and volitional acts experienced by the patient as the work or volitional acts experienced by the patient as the work or influence of others. influence of others. ““When any of these modes of experience is undeniably When any of these modes of experience is undeniably present and no basis of somatic illness can be found, we present and no basis of somatic illness can be found, we may make the decisive clinical diagnosis of schizophrenia.”may make the decisive clinical diagnosis of schizophrenia.”

Why we Downgraded FRSWhy we Downgraded FRS

Three sets of observations tend to undermine Three sets of observations tend to undermine this distinction. These come from the work of this distinction. These come from the work of Gabrielle Carlson, Carpenter and Strauss and Gabrielle Carlson, Carpenter and Strauss and the St. Louis group. the St. Louis group.

First-rank symptoms occur commonly in cases First-rank symptoms occur commonly in cases of mania (up to 40%). of mania (up to 40%).

Not useful in terms of diagnostic distinction, do Not useful in terms of diagnostic distinction, do not predict outcome of illness or response to not predict outcome of illness or response to treatment.treatment.

Carlson describes a “third Carlson describes a “third stage" of maniastage" of mania

Manifested by bizarre behavior, mood-Manifested by bizarre behavior, mood-incongruent hallucinations & delusions incongruent hallucinations & delusions paranoia and extreme dysphoria. paranoia and extreme dysphoria.

““Despite symptoms that might have Despite symptoms that might have otherwise prompted the diagnosis of otherwise prompted the diagnosis of schizophrenia, …. patients appeared schizophrenia, …. patients appeared clearly manic both earlier in the course clearly manic both earlier in the course and later as the episode was resolving.”and later as the episode was resolving.”

Example from Carlson:Example from Carlson:Patient frightened, talking and crying Patient frightened, talking and crying constantly, pacing. “I will never get out”. “I constantly, pacing. “I will never get out”. “I have cats eyes”. “He crawls around inside have cats eyes”. “He crawls around inside me, and he cannot stand the light.” Profane, me, and he cannot stand the light.” Profane, hypersexual, uncooperative. “Oh please let me hypersexual, uncooperative. “Oh please let me die, I can’t take it anymore”. “National die, I can’t take it anymore”. “National Institute of Hell.”Institute of Hell.”Following treatment, patient reverted to a Following treatment, patient reverted to a typical manic state: hypersexual, bizarre attire typical manic state: hypersexual, bizarre attire (wearing three dresses at a time), grandiose, (wearing three dresses at a time), grandiose, incessant talking.incessant talking.

Chromosomal locations of potential Chromosomal locations of potential BP/SZ overlap genes.BP/SZ overlap genes.

Berretini and othersBerretini and others

Separate Genes May Code for Separate Genes May Code for Sub-Syndromes ?Sub-Syndromes ?

E.G. Psychosis, Mood Instability

Assortative Mating Muddies the Assortative Mating Muddies the WatersWaters

?

Etiology: e.g. genes, viral infectionsPathophysiology: e.g. developmental or degenerative

processBrain structure: e.g. structures, circuitsBrain function: e.g. neurotransmitters, rCBF,

metabolismCognitive function: e.g. memory, attention, executive

functionEpidemiology: e.g. sex ratios, age cohort effectsClinical presentation: e.g. symptoms, age of onset,

courseResponse to treatment

Summary: Levels of identification of diseases

GENE GENE CELL CELL SYSTEM SYSTEM BEHAVIOR BEHAVIOR

THANK YOU!THANK YOU!