Autoantibodies against voltage‐gated potassium channel and glutamic acid decarboxylase in psychosis: A systematic review, meta‐analysis, and case series

Abstract

Antibodies to the voltage-gated potassium channel (VGKC) complex and glutamic acid decarboxylase (GAD) have been reported in some cases of psychosis. We conducted the first systematic review and meta-analysis to investigate their prevalence in people with psychosis and report a case series of VGKC-complex antibodies in refractory psychosis. Only five studies presenting prevalence rates of VGKC seropositivity in psychosis were identified, in addition to our case series, with an overall prevalence of 1.5% (25/1720) compared to 0.7% in healthy controls (12/1753). Meta-analysis established that the pooled prevalence of GAD65 autoantibodies was 5.8% (95% confidence interval [CI]: 2.0-15.6%; I = 91%; nine studies) in psychotic disorders, with a prevalence of 4.6% (95%CI: 1.2-15.9%; nine studies; I = 89%) and 6.2% (95%CI: 1.2-27.0%; two studies; I = 69%) in schizophrenia and bipolar disorder, respectively. People with psychosis were more likely to have GAD65 antibodies than controls (odds ratio [OR], 2.24; 95%CI: 1.28-3.92%; P = 0.005; eight studies; I = 0%). Among 21 participants with treatment-resistant psychosis, none had VGKC antibodies. The prevalence of VGKC antibodies is low in psychosis. Our preliminary meta-analysis suggests that GAD autoantibodies are more common in people with psychosis than in controls, although few studies accounted for the possibility of co-existing type 1 diabetes mellitus and the clinical significance of reported GAD titers remains unclear. The paucity of studies reporting thresholds for defining GAD abnormality and rates of comorbid type 1 diabetes mellitus precludes interpretations regarding the influence of GAD antibodies on the development of psychotic disorders and may have led to an overestimate of the prevalence of GAD. Our case series fails to support the hypothesis that VGKC antibodies are linked to treatment resistance in psychosis, but the literature to date is remarkably sparse.

Anti-GAD antibodies in a cohort of neuropsychiatric patients

“…Lately, there has been interest in patients with psychosis who may have serum antibodies to neuronal antigens [12][13][14]. Furthermore, a recent meta-analysis suggests that anti-GAD antibodies are more common in patients with psychosis than in controls [15]. Interestingly, our study showed the contrary: we found a lower prevalence of psychiatric symptoms in anti-GAD positive patients compared with anti-GAD negative patients.…”

Autoantibody-associated psychiatric symptoms and syndromes in adults: A narrative review and proposed diagnostic approach

“…In presumed psychosis and schizophrenia spectrum disorders associated with psychotic symptoms, various antibodies in serum have been reported: α7nAChR (alpha 7 subunit nicotinergic acethylcholine receptor), CV2/CRMP5-, CRHM1 (cholinergic receptor, muscarinergic 1), DPPX, GABAAR, HuD, LGI1, NMDAR, Recoverin, Synapsin and VGKC ( Chandley et al., 2009 ; Dahm et al., 2014 ; Endres et al., 2015 ; Grain et al., 2017 ; Lennox et al., 2017 ; Mantere et al., 2018 ; Oviedo-Salcedo et al., 2018 ; Sæther et al., 2017 , 2019 ; Shiwaku et al., 2020 , Steiner et al., 2013 ; Tanaka et al., 2003 ; Tong et al., 2019 ; Yarlagadda, 2008 ; Zandi et al., 2011 ; Zandian et al., 2017 ) ( Table 1 ). A much smaller group of CSF antibodies (CV2/CRMP5, DPPX, Hu, NMDAR, VGKC and Yo-antibodies, Table 1 ) is known to be associated with psychotic disorders ( Endres et al., 2015 ) suggesting a high probability of this disorder’s CNS autoimmune origin ( Table 1 , Table 2 ).…”

Diagnosing Organic Causes of Schizophrenia Spectrum Disorders: Findings from a One-Year Cohort of the Freiburg Diagnostic Protocol in Psychosis (FDPP)

“…Low levels of positive anti-GAD56 antibodies are found in diabetes mellitus, however, in our cohort, one patient had increased concentrations of anti-GAD65 antibodies in RIA without diabetes mellitus. Increased levels of anti-GAD65 antibodies are found more frequently in patients with psychosis than in control groups [31] and can be associated with limbic encephalitis in a subgroup of the patients with high titers; however, their pathophysiological role is not yet clear [32]. The rheumatic screening showed CRP increases in 17% of the patients.…”