4Core Concepts- 1 Affective Disorder: disturbance of mood Delirium: disturbance of consciousnessDementia: disturbance of (a prior level of) cognitionSchizophrenia: ??????????????????????No obvious pathognomonic symptoms or core“theme”.
5Core Concepts II1. 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.
6DELIRIUM PLUS DISTURBED CONSCIOUSNESSDEMENTIA PLUS COGNITIVEDECLINEAFFECTIVE PLUS CHANGE INDISORDER MOOD, SELF-ATTITUDEAND VITAL SENSESCHIZOPHRENIA HALLUCINATIONS,DELUSIONS,FORMAL THOUGHT DISORDER
7SCHIZOPHRENIA– CASE STUDY 1 Frank S. 31 y.o. single WMUpper middle class family, no FH of mental illnessMother’s pregnancy – ‘flu’ at 15 weeks, forceps delivery, Apgar in normal rangeShy, slightly withdrawn child – ‘grew out of it’ by age 14.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 All ‘A’ grades in freshman year.Sophomore year – age 20, increasingly withdrawn, preoccupied, ‘distant’, odd philosophical worries x 6 months.
8SCHIZOPHRENIA– CASE STUDY 2 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 evaluationAlert, O x 3. Not elated or depressed. MMS – 30/30. Urine Toxicology screen negative. Physical exam and labs all WNL. Brain MRI WNL.
9SCHIZOPHRENIA– CASE STUDY 3 Hospitalized three weeksPartial response to HaloperidolFamily “lost his spark”……but not due to medicationsUnable to complete collegeHalfway house – small apartmentVolunteer for state agency3 subsequent hospitalizations in 10 yearsSeclusive, poor self-careSome improvement on olanzapine – initial gainNow on ziprasodone – variable compliance
10Positive and Negative Symptoms Positive Negative/DeficitDelusions Poverty of speechHallucinations Flat affectIncoherence Social WithdrawalBizarre behavior Apathy(Remember-no pathognomonic symptoms.)Source: DSM-IV Draft Criteria, 1993
11Cognitive Deficits An essential part of the syndrome. Working Memory Set ShiftingVerbal MemoryAttention / Continuous Performance
12Epidemiology of Schizophrenia About 1% prevalence in the populationOccurs in all cultures, all socioeconomic groupsPeak onset in men, ages 15 to 25Peak onset in women, ages 22 to 30Prevalence ultimately equal in men and women50% of patients attempt suicide, 10% succeedMost expensive of all mental disorders:Chronic but non-fatal, many incarcerated, homelessDirect costs = 0.4% of the GNPIndirect costs = 1.6% of the GNP
1320-year Follow-up of Patients with SZ (Iceland) All first-episode SZ diagnosed in 1966 to 196722% mortality and 9% suicide60% never married; of the rest, most divorced71% had persistent symptoms despite neuroleptic treatment95% had impaired social relationships65% worked fewer than 5 months per year29% had “an acceptable level of health”
19Subtle metabolic abnormalities Molecular bottlenecks? GeneCellSystemBehaviorMultiple susceptibility alleles, each of small effect, low penetrance, that act in concertSubtle metabolic abnormalitiesMolecular bottlenecks?Abnormal information processingCognitive inefficiency – memory and control processes, BiomarkersNot ≡ illness, e.g. as found in unaffected siblingsComplex functional interactionsEmergent phenomena(After Weinberger, 2003)
20PHASES OF SCHIZOPHRENIA FunctioningPREMORBIDPRODROMEACTIVECourse of Illness
21Environmental Stress Biological Factors Drug Use Disease GenesViral InfectionEnvironmental ToxinsPeri-natal/BirthComplicationsTRIGGERS:Environmental Stress Biological Factors Drug UseSZB i o l o g i c a l V u l n e r a b i l i t yStructureBiochemFunctionNeurol +CognitiveDeficitsEarlyNegativeSxWeakPositiveSxEmergingPsychoticSxAge512151821EarlyProdromeLateProdromePremorbid
22Diagnostic Criteria for Schizophrenia DSM-IV -Based on phenomenologyHighly reliable, but of dubious validityCould 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
24Clues from Type-2 Diabetes “Spectrum Cases” Impaired GTT + impaired fasting glucose ~ 40% of obese adultsGestational 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.
25Schizotypy 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 disturbingLesser, “dilute” form of the disorder
26Schizotypy 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 >
28BIOMARKERS 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.
29Schizophrenia Biomarkers Gene markers – a few in last 3 yrs.Electrophysiology – P-300, N-400, P450Psychophysiology – oculomotor, PPIBrain structure – Volumes of LV, STG, HippoBrain Function – PET, fMRI with WCST, WMBrain Chemistry – DA receptors, releaseDevelopment – neurologic, cognitive, socialClinical exam – MPA’s, ‘soft’ neurologic signsCognition – WM, attentionNiacin flush, fingerprints
30Biomarkers and Schizophrenia Summary:Promising avenue of research.Approach very useful in diabetes, hypertension- may work for schizophrenia.
31Schizophrenia and Cognition Major defects in:Working memoryExecutive functioning (abstraction, problem solving, conceptualization, sequencing, inhibition, planning)AttentionVerbal memorySemantic tasksSymptoms suggest frontal lobe dysfunction
32Magnitude of Cognitive Deficits in Schizophrenia TestDomainMd (mean effect size difference)# of studies% Patients Below MedianVerbal MemoryMemory1.413178Wisconsin Card SortExecutive Function0.884369Verbal Fluency1.152975Continuous PerformanceSustained Attention1.1614Bilateral Motor SkillMotor1.3577Heinrichs RW, Zakanis KK, Neuropsychology 2:
33Cognitive Deficits in Schizophrenia Core Features of IllnessPrecede Onset of Illness½ SD lower IQReading difficulties in grade through high schoolDelayed onset of hand dominancePresent at Disease OnsetContinued…Sources: Green 1996; Heinrichs and Zakzanis 1998; Saykin 1991, 1994
34Cognitive Deficits in Schizophrenia Resist Medication EffectsPersist into SenescenceMay Predict Psychosocial Function Better Than Positive or Negative Symptoms
36Symptoms suggestive of frontal lobe dysfunction Emotional dullnessImpaired judgmentPoor initiative, motivation, driveLack of insightDifficulty in planningImpaired problem-solving/abstract reasoningDecreased concern for personal hygieneSocial withdrawal
47Phenomenology 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.”
48Why we Downgraded FRSThree 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.
49Carlson 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.”
50Example 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.
55Summary: Levels of identification of diseases 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