Historical figures in schizophrenia research Emil Kraepelin 1883: “Dementia Praecox” separated schizophrenia from bipolar disorder (manic-depressive psychosis) based on the clinical course of the syndromes Eugene Bleuler 1911: “Schizophrenia” – 1909: Genetic splitting of the mind  between thought and emotion Associations Affect Ambivalence Autism

Epidemiology Prevalence ~1%; male = female Right now over 2 million adult Americans have schizophrenia Seen in all cultures at similar frequency Onset usually late adolescence to young adulthood, earlier in males than females (reactive: leaving home, loss of parent, 1st sex experience) Increased chance of being born in the winter or early spring

Prevalence of Selected DSM-IV Axis I Disorders M F Total Major Depression 12.7 21.3 17.1 Panic Disorder 2.0 5.0 3.5 Social Phobia 11.1 15.5 13.3 Schizophrenia 1.3 0.7 1.0

Prevalence relative to medical disorders

Schizophrenics have: Increased mortality rate from accidents and natural causes: life span is shortened by about a decade some under-diagnosis of medical illness is present ~10-15% suicide; ~50% attempt early in illness and young age high premorbid function depression the latter two often contributing to demoralization Illness seems concentrated in urban settings, i.e., it is somewhat correlated with population density in larger cities Illness seems concentrated in lower socioeconomic classes (1/3 of homeless)

Diagnosis of Schizophrenia A. Characteristic symptoms: > 2 of 5 (active phase symptoms – Criterion A) delusions hallucinations disorganized speech (incoherence-”word salad”) grossly disorganized or catatonic behavior negative symptoms, i.e., affective flattening, alogia, or avolition * bizarre delusions or running commentary voices or voices conversing with each other

Diagnosis of Schizophrenia B. Social/occupational dysfunction (50% unemployed) Duration: at least 6 mo. (include at least 1 month of symptoms from Criterion A) D&E. Mood Disorder, Substance/general medical condition exclusion F. No Pervasive Developmental Disorder: (ex:Autism) (only if prominent delusions or hallucinations are also present for at least a month)

Subtypes Catatonic Disorganized (hebephrenic) Paranoid Catatonic behavior dominates (catalepsy-muscle rigidity/agitation) Less common nowadays Disorganized (hebephrenic) Disorganized speech, behavior, and affect (flat or inappropriate) Paranoid Delusions and/or auditory hallucinations Not limited to persecutory themes Tends to have a later onset and better course

Etiology of Schizophrenia Genetic Influences

Adoption Studies Implies genetic factors not environmental

Genetics and Family Studies

Etiology of Schizophrenia Brain Abnormalities

Hippocampus

Due to virus (Flu) 2nd trimester: adhesion molecules causing pathological migration

Frontal Lobe Issues Functional brain imaging (PET, rCBF) Failure to increase blood flow to the dorsolateral prefrontal cortex while performing the activation task of the Wisconsin Card Sorting Test Reduced blood flow to the left globus pallidus (an even earlier finding in the course of illness) suggests a problem in the system connecting the basal ganglia to the frontal lobes Correlation with severity of disease present

Wisconsin Card Sorting Task Subjects are asked to sort each upcoming card on to one of the four piles (they are not directed but may use shape, color or number). They are told correct/incorrect. Whichever category they choose is correct for a given number of categories then is met with an “incorrect” response. Subjects must “switch sets” to get a correct response. Failure to switch sets is termed “perseveration”. Schizophrenic subjects perseverate relative to normal controls, Green et al, 1992

Frontal Lobe Abnormalities - PET image of twins during WCST

Ventricles Enlarged

MRI – Discordant

(bigger differences in males- ventricle size

Post-Mortem Neuroanatomy Disturbed connection between thalamus and PFC Schematic diagram summarizing disturbances in the connectivity between the mediodorsal (MD) thalamic nucleus and the dorsal prefrontal cortex (PFC) in schizophrenia. Postmortem studies have reported that subjects with schizophrenia have 1) decreased number of neurons in the mediodorsal thalamic nucleus; 2) diminished density of parvalbumin-positive varicosities, a putative marker of thalamic axon terminals, selectively in deep layers 3-4, the termination zone of MD projections to the PFC; 3) preferential reduction in spine density on the basilar dendrites of deep layer 3 pyramidal neurons, a principal synaptic target of the excitatory projections from the MD; 4) reduced expression of the mRNA for glutamic acid decarboxylase (GAD67), the synthesizing enzyme for GABA, in a subset of PFC GABA neurons; 5) decreased density of GABA transporter (GAT-1)-immunoreactive axon cartridges, the distinctive, vertically-arrayed axon terminals of GABAergic chandelier neurons, which synapse exclusively on the axon initial segment of pyramidal neurons; 6) decreased dopamine innervation of layer 6, the principal location of pyramidal neurons that provide corticothalamic feedback projections (From Lewis & Lieberman, Neuron 28:325-334, 2000.).

Serendipity Strikes Again!!!!

1960 – discovery that striatums (caudate putamens) depleted of Dopamine

Dopamine Hypotheses of Schizophrenia Schizophrenia due to over activity

Dopamine of Antagonist

Clorpromazine (Carlsson, 1963) - expected DA levels to decrease Metabolite increased D2 receptor blockers work not because to much dopamine but Because to many receptors or too Sensitive…

Dopamine Hypotheses of Schizophrenia (revised) Positive symptoms of schizophrenia attributed to hyperdopaminergic function (more receptors or increased sensitivity, etc, D2)

Evidence in Support

Dopamine hypothesis - weaknesses: Some atypical antipsychotics such as clozapine are not as well correlated with respect to D2 dopamine receptor binding and clinical potency Does not account for negative symptoms of schizophrenia

Evidence against DA hypothesis of Schizophrenia – Glutamate??? Disorganized thought symptoms of schizophrenia attributed to hypofunctional glutamate system Glutamate antagonists such as PCP and ketamine mimic disorganized thought, may also cause psychosis and negative symptoms?