Glutamic Acid Decarboxylase (GAD) Autoantibody Positivity in Schizophrenia




Kemether*, William Byne, James Schmeidler, Liesl Jones, Robert

McEvoy, and Kenneth Davis. Mount Sinai School of Medicine, New

York, NY

Various etiopathogenic mechanisms

for schizophrenia have been proposed, including autoimmune

dysregulation. Accounts of non-specific autoantibody responses, T

cells and interleukin disorders, and intrathecal production of

immunoglobulins have been reported. Glutamic acid decarboxylase

(GAD) catalyzes the decarboxylation of glutamate to form the

inhibitory neurotransmitter gamma-aminobutyric acid (GABA).

Antibodies targeting GAD have been implicated in Stiff-Man

Syndrome (SMS) and Insulin-Dependent Diabetes Mellitus (IDDM).

Both disorders are thought to result from autoimmune destruction

of GAD-containing cells. In SMS, the targeted cells are GABAergic


Abnormalities of the GABAergic

system have been described in schizophrenia including the loss of

small interneurons believed to be GABAergic in layer II of the

prefrontal and cingulate cortices and decreased GAD activity in

the frontal cortex. While a loss of GABA neurons could be

accounted for by a variety of mechanisms, the possibility of GAD

autoantigenicity has not been investigated. Because GABAergic

neuronal loss and dysregulation have been implicated in

schizophrenia by empirical evidence as well as theory, and

because GAD autoantigenicity may disrupt GABAergic neurons in

SMS, we conducted the present study to examine the prevalence of

GAD autoantibodies in schizophrenia.

Sera were collected from 186

patients at Mount Sinai Medical Center meeting DSM-IV criteria

for schizophrenia or schizoaffective disorder and from 220

healthy adult controls. Antibodies to recombinant human GAD65

were measured by a commercial immunoprecipitation assay (Kronus).

The proportion of schizophrenics

(5.4%) who tested positive for the antibody did not differ

significantly from controls (3.2%). These data do not support a

role for GAD autoantigenicity in the pathogenesis of

schizophrenia. However, it remains possible that GAD

autoantigenicity plays a role early in the pathogenesis of at

least some cases of schizophrenia and that the prevalence of the

antibody decreases with time after the initial insult. If so, an

increase in the prevalence of GAD autoantibodies might only be

detected shortly after the onset of the illness.