The LIPS assay format was used to screen a cohort of mood disorder patients and controls for autoantibodies to several targets including TPO, Ro52 and GAD65. For each antigen tested, we used a cutoff based on the average plus five standard deviations of the healthy controls. None of the psychiatric patients showed autoantibody titers to TPO, a known thyroid autoantigen, above the established cutoff (data not shown). One MDD patient and one control were seropositive for ATP4B (data not shown). One control and three MDD patients had significant autoantibody titers to Ro52 (). The highest anti-Ro52 autoantibody titer was MDD patient 225 (). Testing for anti-GAD65 autoantibodies revealed two MDD patients with markedly elevated anti-GAD65 antibody titers (). Interestingly, it was also patient 225 who showed the highest anti-GAD65 autoantibodies, which were 200 standard deviations higher than the control mean. The anti-GAD65 autoantibody titer in patient 225 was comparable to the highest 10% of titers seen in type I diabetes patients and similar to patients with SPS (Burbelo et al., 2008a
; Burbelo et al., 2008b
). Based on these observations, patient 225 was studied in detail to understand the pathophysiological significance of these high autoantibody titers.
Identification of a patient with significant autoantibody titers to both Ro52 and GAD65
Patient 225, an African-American woman with MDD (whose family history included a first-degree relative with bipolar disorder), initially presented (March 2004) at age 24 with depressed mood of 12 months duration, anhedonia, guilt, self-depreciation, diminished libido, weight gain and initial insomnia. Particularly striking were her clinical manifestations of psychomotor disturbance, including restricted facial mobility and markedly reduced psychomotor activity; rating 6 on the retardation subscale of the CORE melancholia scale (Hadzi-Pavlovic et al., 1993
; Parker and Hadzi-Pavlovic, 1996
). There was no evidence of other autoimmune disease or diabetes, as additional testing for type I diabetes-associated autoantibodies (IA2 and Zinc Transporter-8) was negative.
Anti-GAD65 autoantibodies are associated with neurological disease, including SPS in which patients present with motor impairment including rigidity of axial and/or appendicular muscles and altered startle response in addition to showing high levels of anti-GAD65 autoantibodies in serum and cerebral spinal fluid (CSF) (Levy et al., 1999
; Solimena et al., 1990
). Thus, we next tested for autoantibodies in the CSF of patient 225 along with CSF from four random controls and one other MDD patient with available CSF. Only patient 225 showed titers of anti-GAD65 and anti-Ro52 autoantibodies in CSF that were above the normal range. These results establish that patient 225 displays high levels of anti-GAD65 and anti-Ro52 autoantibodies in serum and CSF and suggest that her psychomotor disturbance may be related to CNS autoimmunity.
Due to these molecular and clinical findings, patient 225 was reevaluated in August, 2009 at which time her depressive symptoms had been in remission for over a year. However, her symptoms of psychomotor retardation had become more pronounced, and she now showed restricted range of facial expression, reduced gesticulation and fixed posture at the torso while seated (rating 8 on the CORE-retardation subscale). Reevaluation of serum autoantibodies revealed that anti-GAD65 autoantibody titers had increased four-fold, and her anti-Ro52 autoantibody titer doubled (). Testing also showed that her anti-IA2 antibody status, previously negative, was now positive. At this time, she displayed mild hyperglycemia and elevated C peptide. She showed evidence of hyperthyroidism (increased T4, reduced TSH, tachycardia, weight loss).
Autoantibody titers in patient 225 increase over time