Obsessive-compulsive disorder (OCD) is a complex neuropsychiatric illness impacting approximately 2% of the global population.
The disorder is characterized by intrusive, irrational thoughts (obsessions) and repetitive behaviors (compulsions) that patients feel driven to perform.
OCD typically follows a chronic course and is associated with significant impairment and reduced quality of life.
While effective therapies like cognitive behavioral therapy (CBT) and medications exist, high rates of treatment resistance highlight the need for further research into OCD’s underlying biology to develop more targeted treatments.
Emerging evidence suggests immune system dysfunction, particularly autoantibodies, may play a role in a subset of OCD cases.
Autoantibodies are antibodies directed against the body’s own proteins and cells.
The following key facts highlight the potential link between autoantibodies and OCD:
- Case reports describe patients with OCD and detected autoantibodies who improved with immunotherapy.
- A systematic review identified 9 case reports of autoantibody-associated OCD, and 67% of patients benefited from immunotherapy.
- Six out of eleven cross-sectional studies provided evidence for an association between autoantibodies and OCD.
- Autoantibodies described in OCD target diverse CNS proteins and cells, including NMDA receptors, dopamine receptors, and basal ganglia.
- Some OCD patients have autoantibodies related to systemic autoimmune disorders like lupus and Sjögren’s syndrome.
Source: Transl Psychiatry 2023
The data suggest autoantibodies may represent biological markers and play a causal role in a subset of OCD cases.
More research is needed, but these findings open potential new treatment options like immunotherapy for autoantibody-associated OCD.
Case Reports of Autoantibody-Associated OCD
Case reports offer intriguing preliminary evidence that autoantibodies may directly contribute to OCD symptoms in some patients.
For example, a 2019 case described an 8-year old girl with OCD-like checking behaviors and autoantibodies against NMDA glutamate receptors in her spinal fluid.
After receiving immunotherapy, her symptoms and autoantibody levels improved.
Several other cases have reported OCD patients with neural autoantibodies who also benefited from immunotherapy.
In a systematic review published in 2021, researchers identified 9 total case reports of autoantibody-associated OCD.
Three patients had paraneoplastic disorders with well-characterized anti-neuronal autoantibodies (NMDA receptors, CV2, Ma2).
Two more had neural autoantibodies of unknown significance (voltage-gated potassium channels, “anti-brain”).
The other four cases involved systemic autoimmune disorders like Sjögren’s syndrome and lupus with identified autoantibodies.
Notably, 6 of the 9 patients (67%) experienced OCD symptom improvement after receiving some form of immunotherapy.
While case reports do not prove causation, they provide intriguing clues about autoantibody-mediated OCD subgroups that warrant further research.
The symptom improvements after immunotherapy in many cases also raise the prospect of new OCD treatment options targeting overactive immune functioning.
Cross-Sectional Study Findings: OCD & autoantibodies
In addition to case reports, a growing number of cross-sectional studies have analyzed autoantibody prevalence in OCD patients compared to controls.
The results have been mixed, but several studies suggest meaningful associations.
A 2021 systematic review identified 11 relevant cross-sectional studies on autoantibodies in OCD.
Six studies included healthy control groups, three compared OCD patients to other neurologic or psychiatric groups, and two lacked control groups.
Of these, 6 studies showed evidence for increased autoantibody prevalence in OCD subgroups, including:
- Elevated antinuclear antibodies in 7 OCD patients compared to 52 healthy controls.
- Increased anti-dopamine D1 receptor antibodies in 25 OCD patients versus 28 controls.
- Higher anti-somatostatin and anti-dynorphin autoantibodies in 10 OCD patients relative to 25 healthy and disease controls.
- Significantly more anti-basal ganglia antibodies in 96 OCD patients compared to 50 patients with depression or schizophrenia.
However, other studies in the review found no significant autoantibody differences between OCD and control groups.
The review authors conclude that autoantibodies may represent biological markers in a subset of OCD cases, but more research is needed.
Notable Autoantibody Targets in OCD
While research remains limited, several autoantibodies have emerged as potential players in OCD pathology:
Anti-basal ganglia antibodies (ABGA) are among the most studied autoantibodies in OCD.
The basal ganglia are involved in habit formation and implicating in OCD neurobiology.
Multiple studies have detected elevated ABGA levels in OCD patients, suggesting they may disrupt basal ganglia circuits and contribute to obsessive-compulsive symptoms.
Autoantibodies against neuronal cell surface receptors may also elicit direct effects on brain function in OCD.
For instance, NMDA glutamate receptors and dopamine receptors help modulate cortico-striato-thalamo-cortical pathway signaling integral to OCD.
Autoantibodies targeting these receptors could interfere with their roles in OCD-relevant brain circuits.
Autoantibodies related to systemic autoimmune disorders like Sjögren’s syndrome, lupus, and antiphospholipid syndrome have additionally been reported in OCD cases.
These conditions frequently have neuropsychiatric manifestations, and their autoantibodies may potentially access the brain and drive neurological symptoms.
While many autoantibody targets have been proposed in OCD, replication is needed to determine which hold up as reliable disease biomarkers or contributors to pathology.
Studying autoantibody signatures and roles across OCD subtypes may help refine our understanding of how the immune system interacts with OCD’s heterogeneous biology.
Mechanisms of Autoantibody-Mediated Effects on OCD
If autoantibodies do contribute to OCD in some patients, how might they exert brain effects that could lead to obsessive-compulsive symptoms?
A few possible mechanisms have been proposed based on autoantibody actions in other neurological disorders:
- Direct effects on neurotransmitter receptors: Autoantibodies may bind to glutamate, dopamine or serotonin receptors and interfere with neurotransmission.
- Basal ganglia inflammation: Pro-inflammatory autoantibodies targeting basal ganglia cells could set off localized brain inflammation affecting basal ganglia circuits.
- Blood-brain barrier (BBB) damage: Certain autoantibodies might weaken the BBB, enabling additional autoantibodies and pro-inflammatory molecules to enter the brain from the bloodstream.
- Intrathecal antibody production: B cells within the central nervous system could produce neurotoxic autoantibodies that directly damage brain tissue.
- Molecular mimicry: Viral or bacterial infections may induce autoantibodies that cross-react with similar host antigens in the brain.
While speculative, these potential mechanisms illustrate pathways by which brain-reactive autoantibodies could theoretically contribute to OCD pathogenesis.
Relevance for OCD Subtypes and Treatment Resistance
Notably, autoantibodies associated with OCD generally appear to occur in a small subset of cases rather than all patients.
Autoantibody-mediated immune pathology could help account for some of the observed heterogeneity in OCD clinical presentation and biology.
Certain clinical features like acute onset or neurological comorbidities may be more common in autoantibody OCD subgroups.
Autoantibody presence may also contribute to poor treatment response in some OCD patients by perpetuating ongoing neuroinflammation and neurocircuit dysfunction.
Case reports of OCD patients with autoantibodies responding to immunotherapies support this idea.
Identifying predictive autoantibody biomarkers could allow more personalized application of anti-inflammatory therapies in OCD.
Future Research Directions: OCD & Antibodies
The prospect of immune dysfunction and autoantibodies representing treatable contributors to OCD is exciting.
But considerably more research is still needed to clarify if and how autoantibodies participate in OCD subgroups.
Key future research directions include:
- Large OCD cohort studies with multimodal autoantibody testing to identify consistent biomarkers
- Longitudinal studies tracking autoantibody levels over the OCD disease course
- Comparisons of autoantibody profiles across clinical OCD subtypes
- Studies examining autoantibody associations with OCD onset triggers like infection
- Trials assessing immunotherapy efficacy in autoantibody-positive OCD
- Animal models exploring causal roles for autoantibodies in OCD-like behavior
- Identifying specific neuronal targets and mechanisms of OCD-linked autoantibodies
Auto-Antibodies as OCD Biomarkers?
In summary, a growing body of preliminary evidence suggests autoantibodies may serve as biological markers and, in some cases, play a pathogenic role in OCD.
While larger studies are needed, these findings open the door for exciting new research into autoimmune contributions to OCD biology as well as more targeted immunomodulatory treatment opportunities tailored to autoantibody-mediated disease subtypes.
A greater understanding of the immune system’s interaction with the dysfunctional brain circuits underlying obsessive-compulsive symptoms could transform our approach to managing this challenging neuropsychiatric illness.
References
- Study: Autoantibodies in patients with obsessive-compulsive disorder: a systematic review
- Authors: Dominik Denzel et al. (2023)
