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Schizophrenia & Psychoses A Clinical Introduction

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


3 Schizophrenia - Outline
1. Phenomenology 2. Epidemiology 3. Etiology ‑ neurodevelopmental & genetic factors 4. Spectrum disorders, biomarkers, Treatments Psychotic mood disorders

4 Core Concepts- 1 Affective Disorder: disturbance of mood
Delirium: disturbance of consciousness Dementia: disturbance of (a prior level of) cognition Schizophrenia: ?????????????????????? No obvious pathognomonic symptoms or core“theme”.

5 Core Concepts II 1. Because it has no pathognomonic symptoms, schizophrenia is a diagnosis of exclusion. 2. Widespread agreement that schizophrenia is a heterogeneous disorder; but no agreement on sub-typing. 3. Traditional subtypes (e.g. hebephrenic, paranoid) mutate over time.


Frank S. 31 y.o. single WM Upper middle class family, no FH of mental illness Mother’s pregnancy – ‘flu’ at 15 weeks, forceps delivery, Apgar in normal range Shy, slightly withdrawn child – ‘grew out of it’ by age 14. IQ = 128 FS. College – electrical engineering major. All ‘A’ grades in freshman year. Sophomore year – age 20, increasingly withdrawn, preoccupied, ‘distant’, odd philosophical worries x 6 months.

Became convinced messages on TV about him, “aliens reading my mind.” “White House controlling my body.” Auditory hallucinations of “robot voices” saying good and bad things about him, arguing. Showed up at police HQ to warn of “plots”, taken to ER for evaluation Alert, O x 3. Not elated or depressed. MMS – 30/30. Urine Toxicology screen negative. Physical exam and labs all WNL. Brain MRI WNL.

Hospitalized three weeks Partial response to Haloperidol Family “lost his spark”……but not due to medications Unable to complete college Halfway house – small apartment Volunteer for state agency 3 subsequent hospitalizations in 10 years Seclusive, poor self-care Some improvement on olanzapine – initial gain Now on ziprasodone – variable compliance

10 Positive and Negative Symptoms
Positive Negative/Deficit Delusions Poverty of speech Hallucinations Flat affect Incoherence Social Withdrawal Bizarre behavior Apathy (Remember-no pathognomonic symptoms.) Source: DSM-IV Draft Criteria, 1993

11 Cognitive Deficits An essential part of the syndrome. Working Memory
Set Shifting Verbal Memory Attention / Continuous Performance

12 Epidemiology of Schizophrenia
About 1% prevalence in the population Occurs in all cultures, all socioeconomic groups Peak onset in men, ages 15 to 25 Peak onset in women, ages 22 to 30 Prevalence ultimately equal in men and women 50% of patients attempt suicide, 10% succeed Most expensive of all mental disorders: Chronic but non-fatal, many incarcerated, homeless Direct costs = 0.4% of the GNP Indirect costs = 1.6% of the GNP

13 20-year Follow-up of Patients with SZ (Iceland)
All first-episode SZ diagnosed in 1966 to 1967 22% mortality and 9% suicide 60% never married; of the rest, most divorced 71% had persistent symptoms despite neuroleptic treatment 95% had impaired social relationships 65% worked fewer than 5 months per year 29% had “an acceptable level of health”

14 Medical Illnesses in Psychosis

15 Proposed Etiology Genetic predisposition / vulnerability
Brain mal-development in utero (genetic, toxic, infective) Pregnancy & birth complications Early psychosocial experience Source: Mednick et al., 1991



18 Brain Structure Electro Physiology Sensory motor Integration Function Clinical Symptoms Cognition

19 Subtle metabolic abnormalities Molecular bottlenecks?
Gene Cell System Behavior Multiple susceptibility alleles, each of small effect, low penetrance, that act in concert Subtle metabolic abnormalities Molecular bottlenecks? Abnormal information processing Cognitive inefficiency – memory and control processes, Biomarkers Not ≡ illness, e.g. as found in unaffected siblings Complex functional interactions Emergent phenomena (After Weinberger, 2003)

Functioning PREMORBID PRODROME ACTIVE Course of Illness

21 Environmental Stress Biological Factors Drug Use
Disease Genes Viral Infection Environmental Toxins Peri-natal/Birth Complications TRIGGERS: Environmental Stress Biological Factors Drug Use SZ B i o l o g i c a l V u l n e r a b i l i t y Structure Biochem Function Neurol + Cognitive Deficits Early Negative Sx Weak Positive Sx Emerging Psychotic Sx Age 5 12 15 18 21 Early Prodrome Late Prodrome Premorbid

22 Diagnostic Criteria for Schizophrenia
DSM-IV -Based on phenomenology Highly reliable, but of dubious validity Could have been written 100 years ago (in fact they were, essentially) No laboratory test, even to confirm diagnosis, let alone a diagnostic test related to pathophysiology

Etiology  • Pathology  • Biologic  • Definition/Test Genes  (partial) • (partial) Biomarkers   (partial)

24 Clues from Type-2 Diabetes “Spectrum Cases”
Impaired GTT + impaired fasting glucose ~ 40% of obese adults Gestational DM (~ 10% of pregnant women) Steroid-induced DM (~ 30% on hi-dose systemic steroids) All of the above are substantially increased in first-degree relatives of Type-2 diabetics (about 50% have insulin resistance), 15% diabetes, 25% abnormal GTT.

25 Schizotypy and Spectrum Conditions 1
Early researchers into schizophrenia noticed that unaffected family members exhibited oddities and eccentricities. Interpretation: Consequence of close association with someone whose behavior was disturbed or disturbing Lesser, “dilute” form of the disorder

26 Schizotypy and Spectrum Conditions 2
Kety’s genetic studies with the Danish twin and disease registries, & Kendler’s Irish kindreds confirm these ideas. Mild or dilute forms of schizophrenia, or oddities of thought and behavior occur more commonly among close relatives of patients with schizophrenia than in the population at large. Genetic explanations best fit the facts. These individuals have vulnerability genes, insufficient for full-fledged schizophrenia. < Introduces concept of biomarkers >


28 BIOMARKERS Definition:
Physiological and clinical phenomena found in association with a disorder, which are quantifiable, and presumed to be more closely connected to the vulnerability gene than the illness diagnosis.

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

30 Biomarkers and Schizophrenia
Summary: Promising avenue of research. Approach very useful in diabetes, hypertension- may work for schizophrenia.

31 Schizophrenia and Cognition
Major defects in: Working memory Executive functioning (abstraction, problem solving, conceptualization, sequencing, inhibition, planning) Attention Verbal memory Semantic tasks Symptoms suggest frontal lobe dysfunction

32 Magnitude of Cognitive Deficits in Schizophrenia
Test Domain Md (mean effect size difference) # of studies % Patients Below Median Verbal Memory Memory 1.41 31 78 Wisconsin Card Sort Executive Function 0.88 43 69 Verbal Fluency 1.15 29 75 Continuous Performance Sustained Attention 1.16 14 Bilateral Motor Skill Motor 1.3 5 77 Heinrichs RW, Zakanis KK, Neuropsychology 2:

33 Cognitive Deficits in Schizophrenia
Core Features of Illness Precede Onset of Illness ½ SD lower IQ Reading difficulties in grade through high school Delayed onset of hand dominance Present at Disease Onset Continued… Sources: Green 1996; Heinrichs and Zakzanis 1998; Saykin 1991, 1994

34 Cognitive Deficits in Schizophrenia
Resist Medication Effects Persist into Senescence May Predict Psychosocial Function Better Than Positive or Negative Symptoms

35 Core Cognitive Domains Compromised in Schizophrenia
Sustained attention Working memory Set shifting Verbal Memory Problem solving Abstraction These suggest compromised neural circuits

36 Symptoms suggestive of frontal lobe dysfunction
Emotional dullness Impaired judgment Poor initiative, motivation, drive Lack of insight Difficulty in planning Impaired problem-solving/abstract reasoning Decreased concern for personal hygiene Social withdrawal




40 Cognitive Rehabilitation
Remediation- Repeated practice and acquisition of compensatory strategies on cognitive exercises designed to engage under-functioning brain circuits Adaptation

41 History of Antipsychotic Medications

42 Dopamine and other Neurotransmitters

43 Atypical neuroleptics
Off D2 graph Other receptors Antipsychotic with EPS! Effective against negative symptoms (late!) Atypically expensive

44 Annual Cost Estimates of Typical Doses
Clozaril (Sandoz) $3,694 (Not including monitoring , which adds significant extra cost) 5 mg. BID, Haldol $944 (McNeil) Haldol (Generic) $254 3 mg. BID, Risperdal $2,843 (Janssen) 10mg of Zyprexa $1/mg = $3,650 (Pfizer)


46 Psychosis in Mood Disorders

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

48 Why we Downgraded FRS Three sets of observations tend to undermine this distinction. These come from the work of Gabrielle Carlson, Carpenter and Strauss and the St. Louis group. First-rank symptoms occur commonly in cases of mania (up to 40%). Not useful in terms of diagnostic distinction, do not predict outcome of illness or response to treatment.

49 Carlson describes a “third stage" of mania
Manifested by bizarre behavior, mood-incongruent hallucinations & delusions paranoia and extreme dysphoria. “Despite symptoms that might have otherwise prompted the diagnosis of schizophrenia, …. patients appeared clearly manic both earlier in the course and later as the episode was resolving.”

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


52 Chromosomal locations of potential BP/SZ overlap genes
Chromosomal locations of potential BP/SZ overlap genes. Berretini and others

53 Separate Genes May Code for Sub-Syndromes ?
E.G. Psychosis, Mood Instability

54 Assortative Mating Muddies the Waters

55 Summary: Levels of identification of diseases
Etiology: e.g. genes, viral infections Pathophysiology: e.g. developmental or degenerative process Brain structure: e.g. structures, circuits Brain function: e.g. neurotransmitters, rCBF, metabolism Cognitive function: e.g. memory, attention, executive function Epidemiology: e.g. sex ratios, age cohort effects Clinical presentation: e.g. symptoms, age of onset, course Response to treatment



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