Handout for Biology of Mental Disorders (BCS 246)

Session 19 (11/19)

Today's Handout: Trimble C.8 (Schizophrenia pp. 183-225) with emphasis on DSM IV and Mesulam integration (can we make sense of this syndrome in terms of our previous knowledge?)

Introduction

Not a disease but a collection of signs and symptoms, which may have diverse pathology Like Parkinson's, dementia, or epilepsy; clinical entities that may have similar underlying "functional" change explaining symptom pattern, but with several pathological antecedents DSM IV criteria Characteristic symptoms: Two or more of following, each present for sig. portion of time during a 1-month period (or less if successfully treated)
Delusions
Hallucinations
Disorganized speech (e.g. frequent derailment or incoherence)
Grossly disorganized or catatonic behavior
Negative symptoms (i.e. affective flattening, alogia, or avolition) * Only one Criterion A symptom necessary if delusions are bizarre or hallucinations consist of a voice keeping us a running commentary on the person's behavior or thoughts, or two or more voices conversing with each other Social/occupational dysfunction: Work, interpersonal, self care belowlevel previously
Duration: Continuous signs for at least 6 months
Schizoaffective and mood disorder exclusion !!!
Substance/general medical condition exclusion
Relationship to pervasive developmental disorder Types: Paranoid, Disorganized, Catatonic, Undifferentiated, Residual

Subclassification by Liddle et al. 1992

Factor analysis of symptomatology of patients revealed generally 3 "clusters" of symptoms: Psychomotor poverty (poverty of movement, speech, and affect)
Reality distortion (hallucinations and delusions)
Disorganization (inappropriate affect, thought disorder [derailment, tangentiality, illogicality]) Hypothesized that these sxs could occur in same patient but they related to different (independent)
functional systems of the brain, corresponding to limbic and subcortical distributed brain systems Related these clusters to PET findings (15O2 regional uptake) Psychomotor poverty related to Decreased prefrontal and left parietal uptake
Increased caudate (basal ganglia) uptake Reality distortion related to : Increased parahippocampal and ventral striatal (nucleus accumbens) uptake
Decreased posterior cingulate and posterior temporal uptake Disorganization related to: Increased anterior cingulate and mediodorsal nucleus of thalamus uptake
Decreased R fronto-temporal, Broca's (motor speech area), and R&L angular gyrus uptake

Put in terms of "state" functions and regions of particular focus (Mesulam) and make some predictions: 

Arousal                 (cholinergic, dopaminergic, noradrenergic etc.)
Attention               (cholinergic, dopaminergic, noradrenergic, R parietal area esp?)
Vigilance               (as with attention, pos. more dopaminergic, noradrenergic etc.)
Mood                    (serotonergic, noradrenergic, hypothalamic cholinergic etc.)
Motor changes           (dopaminergic "tone" of striatum, also overall
arousal)
Diurnal rhythms         (cholinergic, serotonergic, thalamic/hypothalamic centers)
"Logical flow of
  cognition/ motor act  (striatal function: serotonin, dopamine, cholinergic)
Bizarreness             (?lack of integration of external/internal realities, pos. predominance
                         of internal state at cost of relevance to external demands)
Genetics Major findings so far are the familial pattern, including MZ/DZ twin studies
Strong evidence of genetic factor, strong evidence for other factors in addition
Note: Study showing offspring of "unaffected" MZ twin have just as high a risk as offspring of the affected twin ("carrier" of risk genes or presence of epistasis?) Limited evidence of syndromal heritability (i.e. paranoid vs. non-paranoid sub-type), actually better evidence for paranoia vs. schizophrenia in this regard (now called delusional disorder) "Schizophrenia spectrum" big these days: paranoid personality disorder, schizotypal, schizoid Caution: "positive" schizotypy does not seem specific to schizophrenia (also increased in families of bipolar patients), whereas "negative" schizotypy may be more specific Gottesman at recent meeting indicates that there are now over six replications of strong linkage of several genetic markers in MULTIPLE FAMILIES!!! This has to date never been shown and would be most exciting. This data is in abstract form only and will be published soon. Bad news is that none of the markers make a lot of sense in terms of current theories (linked to dopamine or serotonin receptors, enzymes for catechol metabolism (tyrosine hydroxylase [TH], monoamine oxidase [MAO], etc.) HLA A9 higher in paranoid schizophrenia, the pseudoautosomal area has not shown promise (Crow's theory) Peripheral metabolic and biochemical findings and dopamine (DA) hypothesis Transmethylation theory (methionine loading causes increased psychosis in some patients), unclear whether methionine is causing increase in abnormal substance or interfering with tryptophan uptake (acting as serotonin depleter) MAO tends to be decreased in paranoid patients and those with a family history of psychosis
Dopamine (DA) hypothesis (supported entirely by indirect evidence), more appropriately the dopamine theory of antipsychotic efficacy
Many DA agonists cause psychosis (but this is usually after prolonged use)
Amphetamine can cause increase in psychotic symptoms in schizophrenic patients
Antipsychotics share ability to block DA receptors
Clinical potency of antipsychotics highly correlated with D2 DA receptor affinity (not D1 DA receptors, noradrenergic, serotonergic, or histamine receptors Note: the time course problem has been somewhat solved by Grace et al., who showed depolarization block of DA cells occurring 3 weeks after initiation of antipsychotic meds Limited evidence of DA metabolite abnormalities (HVA excess), this found mostly in positive symptom patients and those with pos. family history Plasma HVA positively associated with positive schizotypal sxs, and negatively with negative schizotypy
Fairly well replicated finding of increase in plasma HVA after initiation of antipsychotic, with gradual decline over 2-3 weeks Problems with hypothesis include: Not all patients get worse with amphetamine (some improve!!)
No direct evidence of a dopamine excess, and some evidence of decreased DA in a subgroup
Excess receptors, increased sensitivity actually more consistent with DA reductions! Brain tissue and CSF findings
Neurochemistry High HVA in family history positive patients
Generally, no change in overall group means compared to controls, but relationships between HVA and symptoms (low HVA -> greater DA sensitivity and increased "first rank
symptoms" and thought disorder; low HVA linked to poorer prognosis) Increased NE metabolite MHPG in paranoid patients
Most post-mortem studies show normal levels as group, but some found increased DA in basal ganglia regions and septum (and relation to paranoid sub-group) Increased DA in left amygdala found in two studies
Increased D2 binding, complicated by previous drug treatment, with some studies examining non-medicated patients, including a study showing increased D4 receptor density Peptide levels in brain regions seem to be altered but unclear how medication affects this, CCK most promising lead at this time (decreased in hippocampus, amygdala of negative sx patients) Excitatory amino acid and GABA assays show evidence for decreased cortical excitatory transmission in some areas of limbic cortex

Neuropathology

Generally positive findings (only 5/60 studies negative) but very inconsistent in their findings
Overall brain volume decreased by approximately 6-8 percent
Regions with specific abnormalities include thalamic (medial dorsal nucleus), hypothalamic, periventricular, periaqueductal and basal forebrain areas Entorhinal cortex and hippocampal cytoarchitectural abnormalities (abnormal cell positions, apparent lack of "normal" migration, reduced cell sizes etc.) Decreased neuronal density of certain layers of frontal, cingulate, and motor cortex, with evidence of excessive association cortex connections Decreased small interneurons (inhibitory) of cingulate cortex

Electrophysiology

Clinical EEG findings (many studies showing abn. particularly in non-familial patients)
Very important, older findings in patients with depth electrodes inserted for epilepsy study: Limbic abnormalities
Spiking in septal region (septum, olfactory tubercle, nucleus accumbens, diagonal band, part of gyrus rectus), an area with extensive frontal/temporal connections Spiking occurred only when patients were actively psychotic
Violence and aggression related to amygdala and hippocampal discharges
Auditory thalamus activated during hallucinations (auditory likely) Increased beta and slow activity with little alpha noted in patients and "high risk" subjects
"Ramp" activity in patients during psychotic behavior (monotonic decrease in power from low frequency to high frequency [no alpha peak]) similar to epilepsy patients at time of subcortical
discharge Some studies, poorly replicated suggest left sided abnormalities related to positive psychotic symptoms
Plug for our findings: late waveforms all reduced with no relation to symptoms, while middle latency waveforms not reduced as group (compared to controls), but highly correlated with symptom subtype (in agreement with DA modulation and excess DA -> reduced amplitude)

Radiological findings

Pneumoencephalography (30 studies, most showed increased ventricular size)
CT data (first study 1976) similar to neuropathologic findings, with almost all positive studies but no "specific" finding
Lateral and 3rd ventricular enlargement, cortical widening (called atrophy by some but very unlikely, most likely neurodevelopmental) A number of studies find greater left than right abnormalities
Another plug for our data: lateral ventricular enlargement not specific, but 3rd ventricular enlargement in over 1/3 of patients and none of controls Low HVA noted in patients with large ventricles in some studies (as well as negative sxs)
Unclear as to whether a subgroup may have progressive changes (as a group, the abnormality seems fairly stable over time) See table 7 page 206 for MRI summary

Functional imaging and PET using receptor ligands

Hypofrontality earliest sign
Findings mixed from one sample to another
Hyperfrontality noted in acute patients, hypofrontality in medicated and chronic Frontal activity decreases with chronicity and medication administration Activated studies (i.e. cognitive task at time of ligand injection) Inability to "light up" or activate frontal regions
One study showed nl pattern with continuous performance test, abn. with Wisconsin Card Sort (seems to control for attention, motivation, but WCST still much harder test!!) Hallucinations related to increased activity in anterior cingulate, striatum, and unimodal auditory cortices
D2 density findings totally controversial, with an initial study showing increased D2 receptors and all subsequent studies failing to show this

Viral hypothesis

Again, controversial. No direct evidence of slow virus or typical viral cause
Pattern of increased winter births in schizophrenia
Viral illness in 2nd trimester of pregnancy may increase risk of schizophrenia

Other neurologic illnesses and psychosis

Temporal lobe epilepsy (TLE), Huntington's, narcolepsy, "midline" cerebral pathology
Motor abnormalities in family members of SZ patients, and in "high risk" children
Smooth pursuit eye movements abn. in most? patients as well as many 1st degree relatives

Neuropsychological abnormalities

Numerous, with paranoid patients having least and disorganized having most
Medication improves impairment generally (decreased distraction by psychosis?)
Liddle again Poverty of movement, speech, affect -> impaired abstract thinking and long term memory
Disorganization syndrome (thought disorder, etc.) -> impaired concentration, new learning
Reality distortion -> only impairment was in figure/ground perception

Notes for me:

- Slides of syndromal pies
- Slides of brain regions: Mesulam, MRI, anatomic cross sections
- Discuss Tony Grace's theory?

December 4, 1996