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GADA IN MDs an increased prevalence of autoimmune disease
and/or autoantibodies in patients with BD, including
As we have previously described, MDs may be associated autoimmune thyroiditis and autoimmune atrophic
with low levels of GABA following a decreased activity gastritis. More specifically, Padmos et al. [67] studied
of GAD. It would, therefore, be reasonable to assume 239 patients with DSM‑IV BD, 74 patients with DSM‑IV
that its antibody, GADA, can somehow be involved in schizophrenia, and 220 healthy control subjects
the pathogenesis of MD inhibiting GABAergic function. for detection of GAD , GAD , and thyroperoxidase
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Support to this hypothesis came from research on the antibodies (TPOA), formerly reported to have an
Stiff Person syndrome (SPS). In 1956, Moersh and increased prevalence in patients with BD. The presence
Woltman [60] observed this syndrome in 14 patients over of GAD (and not that of TPOA and H /K adenosine
+
+
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the age of 35 years, characterized by fluctuating rigidity triphosphatase antibody) tended to be associated with
and spasms without pyramidal tract dysfunction, BD. [67] Psychiatric symptoms, such as depression and
or any other known neurologic disorders that could anxiety, may be prominent, resulting in an incorrect
explain the stiffness. Moreover, Levy et al. [61] observed diagnosis. Culav‑Sumic et al. [68] described a case
muscular rigidity and episodic spasms superimposed of a woman who initially presented with anxious
on the rigidity in 20 consecutive patients. They reported depression and remained resistant to treatment with
as the hallmark sign the continuous contraction of the different classes of antidepressants and additional
agonist and antagonist muscles in the trunk that caused therapy with lithium and atypical antipsychotics until
hyperlordosis and respiratory problems. Interestingly, the detection of GADA supported the diagnosis of SPS.
several patients initially received a tentative diagnosed Even the benefit obtained with immunosuppressive
of the psychogenic process because their presentation treatment with methylprednisolone might support the
was dominated by task‑specific phobias and their findings of anxious and depressive symptoms in SPS
stiffness was precipitated by unexpected noises following the abnormal GABAergic neurotransmission.
or mental anticipation. In addition, seizures were Finally, Yarlagadda et al. [69] found elevated, but not
observed in 10% of cases. Anxious and depressive statistically significant, levels of GADA in 12 patients
symptoms in SPS can be explained by alterations in with chronic psychotic disorders (schizophrenia and
GABAergic neurotransmission. It was demonstrated schizoaffective disorder) compared to healthy controls
that stiffness was caused by a reduction of GABA or suggesting a link between antibodies to GAD and
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glycine, the two main inhibitory neurotransmitters chronic psychotic disorders as well as an autoimmune
and was improved by drugs increasing brain levels mechanism in the pathogenesis of these disorders.
of GABA, such as diazepam or VPA. [62] It was found
later that up to 65% of patients may have antibodies FUTURE DIRECTIONS
GADA against both GAD and GAD :GAD and
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GAD . [62,63] In contrast, patients with type‑1 diabetes Existing evidence supports the role of GADA in the
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had anti‑GAD antibody titers 50 times lower than those pathophysiology of a set of heterogeneous disorders
of patients with SPS. The epitope of the GAD antigen that share clinical manifestations of severe motor,
may also differ between patients with type‑1 diabetes behavioral and mood symptoms. It is of interest that
and those with the SPS. [64] These autoantibodies cause BD patients might present increasing titers of GADA
a functional impairment in the synthesis of GABA compared to healthy controls. It is conceivable (and
in persons with SPS; therefore, GADA should be remains to be tested) that GADA levels might be
considered to play a pathogenic role in this disease. one of the causative phenotypic manifestations of
In this context, it is noteworthy that patients with BD. Indeed, findings of a decreased GABAergic tone
type‑1 diabetes mellitus, particularly those with poor during mania might be explained by the diminished
glycemic control, often undergo CNS related changes synthesis of this inhibitory neurotransmitter due to the
with low cognitive performance and depression. action of GADA. Carefully designed studies targeting
Short‑term treatment of depression in patients with subsets of BD patients could clarify this hypothesis.
diabetes improves their dysphoria and other signs and The implications for diagnosis and treatment are
symptoms of depression. [65] In Batten disease, a rare significant. Detecting GADA in peripheral tissues is
genetic neurodegenerative disorder characterized by a feasible procedure that may assist the diagnostic
severe mental impairment, Chattopadhyay et al. [66] assessment and depending on the specificity and
studied a mouse model reporting the presence of an sensitivity, could be considered a screening test
autoantibody to GAD . These authors hypothesized for BD patients. Moreover, GADA could be tested
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that an autoimmune response to GAD may contribute as a marker of response to treatment, particularly
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to a preferential loss of GABAergic neurons associated to GABAergic agents, such as VPA. Further works
with Batten disease. [66] Several groups observed are needed to identify the exact pathophysiological

240 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 241