1. What drugs can mimic schizophrenia?
a. Amphetamine-induced pyschosis (positive symptoms)
b. Ketamine (NMDA antagonist) elicits both negative and
NMDA antagonists are SUFFICIENT
Evidence that NMDA-mediated transmission is
compromised in Schizophrenia
1. NAAG elevation in some patients
2. Elevation of kynurenic acid
3. Genes associated with schizophrenia
4. Mismatch negativity is an NMDA-dependent evoked
potential recorded from the scalp. This is reduced in
amplitude in schizophrenia.
5. Agents that enhance NMDA receptors (glycine site)
appear to be therapeutic
1: Arch Gen Psychiatry. 2005 May;62(5):495-504.Related Articles, Links
Early-stage visual processing and cortical amplification deficits in schizophrenia.
Butler PD, Zemon V, Schechter I, Saperstein AM, Hoptman MJ, Lim KO, Revheim N, Silipo G, Javitt
Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA. email@example.com
BACKGROUND: Patients with schizophrenia show deficits in early-stage visual processing, potentially
reflecting dysfunction of the magnocellular visual pathway. The magnocellular system operates normally in
a nonlinear amplification mode mediated by glutamatergic (N-methyl-D-aspartate) receptors. Investigating
magnocellular dysfunction in schizophrenia therefore permits evaluation of underlying etiologic
hypotheses. OBJECTIVES: To evaluate magnocellular dysfunction in schizophrenia, relative to known
neurochemical and neuroanatomical substrates, and to examine relationships between
electrophysiological and behavioral measures of visual pathway dysfunction and relationships with higher
cognitive deficits. DESIGN, SETTING, AND PARTICIPANTS: Between-group study at an inpatient state
psychiatric hospital and outpatient county psychiatric facilities. Thirty-three patients met DSM-IV criteria for
schizophrenia or schizoaffective disorder, and 21 nonpsychiatric volunteers of similar ages composed the
control group. MAIN OUTCOME MEASURES: (1) Magnocellular and parvocellular evoked potentials,
analyzed using nonlinear (Michaelis-Menten) and linear contrast gain approaches; (2) behavioral contrast
sensitivity measures; (3) white matter integrity; (4) visual and nonvisual neuropsychological measures, and
(5) clinical symptom and community functioning measures. RESULTS: Patients generated evoked
potentials that were significantly reduced in response to magnocellular-biased, but not
parvocellular-biased, stimuli (P = .001). Michaelis-Menten analyses demonstrated reduced contrast gain
of the magnocellular system (P = .001). Patients showed decreased contrast sensitivity to magnocellular-
biased stimuli (P<.001). Evoked potential deficits were significantly related to decreased white matter
integrity in the optic radiations (P<.03). Evoked potential deficits predicted impaired contrast sensitivity (P
= .002), which was in turn related to deficits in complex visual processing (P< or =.04). Both evoked
potential (P< or =.04) and contrast sensitivity (P = .01) measures significantly predicted community
functioning. CONCLUSIONS: These findings confirm the existence of early-stage visual processing
dysfunction in schizophrenia and provide the first evidence that such deficits are due to decreased
nonlinear signal amplification, consistent with glutamatergic theories. Neuroimaging studies support the
hypothesis of dysfunction within low-level visual pathways involving thalamocortical radiations. Deficits in
early-stage visual processing significantly predict higher cognitive deficits.
Electroencephalogr Clin Neurophysiol. 1998 Mar;108(2):143-53.Related Articles, Links
Impaired mismatch negativity (MMN) generation in schizophrenia as a function of
stimulus deviance, probability, and interstimulus/interdeviant interval.
Javitt DC, Grochowski S, Shelley AM, Ritter W.
Nathan Kline Institute for Psychiatric Research/New York University School of Medicine,
Orangeburg 10962, USA. firstname.lastname@example.org
Schizophrenia is a severe mental disorder associated with disturbances in perception and
cognition. Event-related potentials (ERP) provide a mechanism for evaluating potential
mechanisms underlying neurophysiological dysfunction in schizophrenia. Mismatch
negativity (MMN) is a short-duration auditory cognitive ERP component that indexes
operation of the auditory sensory ('echoic') memory system. Prior studies have
demonstrated impaired MMN generation in schizophrenia along with deficits in auditory
sensory memory performance. MMN is elicited in an auditory oddball paradigm in which a
sequence of repetitive standard tones is interrupted infrequently by a physically deviant
('oddball') stimulus. The present study evaluates MMN generation as a function of deviant
stimulus probability, interstimulus interval, interdeviant interval and the degree of pitch
separation between the standard and deviant stimuli. The major findings of the present
study are first, that MMN amplitude is decreased in schizophrenia across a broad
range of stimulus conditions, and second, that the degree of deficit in schizophrenia is
largest under conditions when MMN is normally largest. The pattern of deficit observed in
schizophrenia differs from the pattern observed in other conditions associated with MMN
dysfunction, including Alzheimer's disease, stroke, and alcohol intoxication.
Javitt DC, Steinschneider M, Schroeder CE, Arezzo JC.
If NMDA hypofunction is everywhere, are there special
functions and brain regions where the
consequences of NMDA hypofunction are
1. Other forms of damage to the hippocampus can
2. Hippocampal pathology (Benes)
3. Volume changes of the hippocampus
4. Hypoactivation of the hippocampus under basal
Comparison of sensory input to
Predicted input occurs in CA1
Potential for positive feedback: mismatch
generates more mismatch: stuck in “write
Large NMDA component in perforant path (PP)
Work of Nonna Otmakhova in Lisman Lab
0 10 20 30 40 50 60
T I M E (min)dopamine
Otmakhova and Lisman
Second action of dopamine: blocking the PP input to CA1
this effect of dopamine is
blocked by clozapine
Positive Feedback hypothesis
Connects dopamine and NMDA theories
Clozapine could break the positive feedback loop and
thereby be therapeutic (supported by fact that clozapine
makes hippocampus less active)
1. Hallucinated voice speaking the patient’s thoughts out loud.
2. Hallucinated voices arguing about the patient.
3. Hallucinated voices describing the patient’s activity as it takes place.
4. The patient believes he is the passive recipient of sensations imposed
from the outside.
5. The patient believes his thoughts/actions are controlled from the
6. The patient believes his thoughts can be withdrawn from his mind.
Schneider’s First Rank Symptoms of Schizophrenia
Correct comparator function allows the conscious brain to determine
whether a percept is generated by “other” or by one’s own unconscious