Supplementary Material for: Fifty Years of Lithium in OCD and Related Disorders: A Systematic Review of Clinical Evidence Challenging a Theoretical Assumption

Introduction: Obsessive-compulsive disorder (OCD) and related disorders (OCRDs) represent a group of conditions in which lack of response to first-line treatments, such as serotonin reuptake inhibitors (SRIs) is common. Therefore, exploring alternative strategies is necessary. We conducted a systematic review of the use of lithium in OCRDs. Methods: This systematic review was conducted in accordance with PRISMA guidelines. We included studies evaluating the use of lithium for OCRDs in adults. Eligible designs included case reports, case series, observational studies, and clinical trials. Four databases (PubMed, PsycInfo, Web of Science, and ClinicalTrials.gov) were searched on January 21, 2025. Response to lithium was defined by improvement on validated scales or, when unavailable, based on clinical descriptions. Results: Twenty-nine studies met inclusion criteria, including 25 case reports or case series and four clinical trials. Most studies focused on obsessive-compulsive disorder (OCD; n = 20), followed by trichotillomania (TTM; n = 5), tic disorders (n = 3), and body dysmorphic disorder (BDD; n = 1). Across the full sample (n = 97), 38.1% of the subjects showed “clinical improvement”, although only 54.6% were assessed using validated instruments. Among case reports and case series (n = 37), 89.2% reported “improvement”. However, three crossover RCTs found no consistent benefit of lithium, and the only placebo-controlled trial did not detect significant differences between groups in the final pooled analysis. Analysis of individual data showed response to lithium to be more common among younger individuals (p = 0.02), those with comorbid bipolar disorder (p = 0.005), individuals receiving lithium as monotherapy (p < 0.018), and those without prior exposure to SRIs (p < 0.001). Additionally, responders were less likely to have been assessed using standardized instruments (p < 0.001). Conclusion: This is the first systematic review to evaluate lithium as a treatment strategy for OCRDs. While some reports suggest potential benefits, current evidence—largely based on low-quality studies without standardized assessments—does not support its use. Findings from randomized trials remain inconclusive, and further high-quality research is needed.