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Neurobiology and Natural History of Schizophrenia:
Jeffrey Lieberman, MD
Department of Psychiatry and New York State Psychiatric Institute
Columbia University College of Physicians and Surgeons
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E. Kraepelin 1919
Dementia Praecox
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Cell
Development :
Multiple subtle
abnormalities in
induction,
patterning,
synaptogenesis
Neural
Systems:
Abnormal
connectivity in
local and
macrocircuits
Mental-
Behavioral
Functions:
Disturbances
in perception,
cognition,
mood
regulation.
Genes
Polygenic
susceptibility
alleles and
mutations
Cellular
Programming
Gene and
Protein
Expression Adapted from Manji and Weinberger, 2002, Freedman 2003
Pathogenesis of Schizophrenia and Related
Psychotic Disorders “Triggers” Maturational
Environmental “Environmental Insults” (e.g. trauma, toxins)
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Natural History of Schizophrenia
Stages of Illness
Healthy
Worsening Severity of Signs and Symptoms
Gestation/Birth 10 20 30 40 50
Years
Premorbid Prodromal Onset/Progression
Chronic/Residual
Deterioration
Puberty
First Break
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Gray matter thickness changes in schizophrenia
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Neurodevelopmental Versus
Neurodegenerative
Can we change the course or prevent the illness?
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Natural History of Schizophrenia Opportunities for Disease Modification
Stages of Illness
Healthy
Worsening Severity of Signs and Symptoms
Gestation/Birth 10 20 30 40 50
Years
Premorbid Prodromal Onset/Progression
Chronic/Residual
Deterioration Puberty Negative Symptoms
Cognitive Deficits
Functional Impairment
PREEMPTIVE PREVENTIVE
REGENERATIVE
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Regenerative Drugs that Restore and Enhance Neural Connectivity
BDNF, ERKs, Bcl-2
Downregulation
PKC isozymes
Adapted from H. Manji
7 7
7 17
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Utility of a Biomarker to Diagnose Disease
Diagnosis =
Negative Diagnosis = Positive
Test Result =
Positive False Positive True Positive
Positive
Predictive
Value:
TP/(TP+FP)
Test Result =
Negative True Negative False Negative
Negative
Predictive
Value:
TN/(TN+FN)
Specificity:
TN/(TN + FP)
Sensitivity:
TP/(TP + FN)
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Genetic Variation
Mismatch
Repetition or
Duplication
Deletion
Deletion
Copy Number Variant (CNV)
Single Nucleotide (ATCG) Polymorphism (SNP)
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Understanding Genetic Predisposition Genes affect synaptic physiology
Disease
Phenotype
Disease
Mutation
Molecule Cell Circuit System Sxs&Behavior
?
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Glutamate Hypothesis of Schizophrenia Pathogenesis
(a) Inhibitory neurons monitor levels of excitatory activity via NMDA receptor (NMDAR) signaling. Normally, the inhibitory neuron maintains sufficient GABA
release to balance inhibition with excitation. (b) In the cortex of individuals with schizophrenia, decreased NMDA receptor signaling disrupts this monitoring
function, fooling inhibitory neurons into acting as if there is insufficient excitatory activity. The inhibitory neurons downregulate their output, disinhibiting
the excitatory neurons. Gordon JA, Nature Neuroscience, 2010; 13(1):2-4
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Ferrarelli F, et al. Am J Psychiatry 2008; 165:996-1005
TMS-evoked
Gamma Band
activity in
Schizophrenia
and
HealthyControl
subjects
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Natural History of Schizophrenia Stages of Illness
Healthy Worsening Severity of Signs and Symptoms
Gestation/Birth 10 20 30 40
Deterioration Margin of Prevention
Deterioration
50
Years
Puberty
Premorbid Chronic/Residual Prodromal/Onset/Deterioration
Lieberman JA, et al. Biol Psychiatry. 2001;50(11):884-897.
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Healthy Person Person with Schizophrenia
Dr. Martha Shenton, Psychiatry Neuroimaging Laboratory, Brigham & Women’s Hospital, Harvard Medical School; N Engl J Med 1992 327(9):604-12. Copyright Massachusetts Medical Society.
Enlarged Lateral Ventricles
Temporal Cortex Atrophy
Hippocampus Atrophy
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Diagnosing Disease
Adapated from S. Small
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Diagnosing Psychosis
Postsynaptic Neuron
Presynaptic
Neuron [18F]f-DOPA:
synthesis and
presynaptic
storage (activity
of AADC)
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F-dopa in Prodromal Subjects
Howes et al , 2011Am J Psychiatry
No transition to psychosis (N=15) Transition to psychosis (N=9)
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Gray matter thickness changes in schizophrenia
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Whole Brain Gray Matter Volumes Over 52 Wks on MRI
Lieberman JA, et al. 2005.
580
600
620
640
660
680
700
720
740
760
780 Healthy volunteers (n=58)
Patients (n=75)
0 12 52 Relative Week of Therapy
Vo
lum
e (c
c)
Haloperidol Olanzapine
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Whole Brain Gray Matter Volumes Over 52 Wks on MRI
Lieberman JA, et al. 2005.
580
600
620
640
660
680
700
720
740
760
780 Healthy volunteers (n=58)
Patients (n=75)
0 12 52 Relative Week of Therapy
Vo
lum
e (c
c)
Haloperidol Olanzapine
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Diagnosing Psychosis in the Hippocampus
Adapated from Schobel, Small et al
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Diagnosing Psychosis in the Hippocampus
Adapated from Schobel, Small et al
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Progression in Hippocampal Volume vs.
CBV
- Schobel et al., Neuron 78:81-93, 2013
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Columbia Psychiatry
Therapeutic modulation of NMDA antagonist
induced glutamate increases in CA1
6
9
12
15
18
0 21
Sco
re
Day of Study
Gabapentin vs. placebo SOPS negative (n=24)
GABA (p=0.14) Placebo
Gabapentin (3600 mg/d) -presynaptic release modulator
CA1 Glutamate Change Ketamine challenge 30mg/kg
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Phenocopies and Genocopies
Congenital brain anomalies; e.g. congenital hydrocephalus
Velocardiofacial (DiGeorge) Syndrome; 22q11 microdeletion
Spongiform encephalopathies
Chronic substance use; e.g. methamphetamine, PCP
Neuronal autoimmune syndromes; e.g.limbic encephalitis
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Neuronal Autoimmune Syndromes
The concept that neurons can be the target of an autoimmune attack is
not widely known in medical community
A large number of patients with neuronal antibodies against extracellular
antigens have been described
Proposed classification by:
- Location of the antigen: intracellular vs extracellular (within
the cell membrane)
- Whether associated with cancer: paraneoplastic vs non-
paraneoplastic
Limbic Encephalitis (LE) – antibodies against limbic structures,
present with memory/attention deficits, seizures, psychosis,
delirium & autonomic instability
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Brain on Fire: My Month of Madness by Susannah Cahalan
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Treatment of Limbic Encephalitis
Any combination of:
Intravenous IgG – 400ug/kg x 5 days
Corticosteroids (prednisone)
Plasma exchange
Rituximab (‘resetting B-cell memory’)
Cyclophosphamide
Surgical removal of tumor
Repeated courses of treatment are sometimes necessary
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Take Home Points
Disease modification for SCZ is possible
Therapeutic strategy must be stage specific • Premorbid
• Progressive
• Chronic Residual
Most realistic goal is the progressive phase
Identify geno and phenocopies
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That’s all folks !
Have a good day and good luck !