This is a randomized, double-blind, placebo-controlled study investigating N-acetylcysteine (NAC) as an augmentation therapy for individuals with treatment-resistant obsessive-compulsive disorder (TR-OCD), studied within a broader cohort of treatment-resistant Obsessive-Compulsive and Related Disorders (OCRDs).

The study's primary aim is to investigate the neurobiological mechanism by which NAC improves inhibitory control deficits in TR-OCD. This is achieved by using Magnetic Resonance Spectroscopy (MRS) to measure changes in thalamic glutamatergic metabolism. A secondary aim is to assess the clinical efficacy of this augmentation strategy on symptom severity. The central hypothesis is that improvements in inhibitory control are mediated by NAC-induced changes in brain glutamate levels.

Please note: This study was initially designed to investigate the effects of N-acetylcysteine (NAC) across the broader spectrum of treatment-resistant Obsessive-Compulsive and Related Disorders (OCRDs), including cohorts such as Excoriation (Skin-Picking) Disorder. The overarching scientific objective was to use NAC to elucidate the neurobiological mechanisms underlying inhibitory control deficits in this difficult-to-treat population, and thereby inform the development of novel therapeutic strategies.

Upon completion of recruitment for the current analysis phase and prior to any unblinking, we finalized our analytical strategy. To ensure the primary analysis was adequately powered to yield a definitive conclusion, it was focused on the treatment-resistant OCD (TR-OCD) cohort, which comprised the substantial majority of the sample accrued to date.

Consequently, the TR-OCD cohort was designated as the primary population for the main efficacy and mechanistic analyses. Other OCRD subgroups enrolled under the same protocol were designated for planned secondary and exploratory analyses, in line with their respective sample sizes. Analyses of these subgroups, including the SPD cohort, will be conducted once sufficient data have been accrued for robust statistical testing.

This registration has been updated to accurately and transparently reflect this final, pre-specified analytical plan, ensuring the public record aligns with the study's primary, hypothesis-driven conclusions.

1.Inclusion Criteria for Patient:

(1) Age between 12 and 55 years. (2) A primary diagnosis of OCD according to DSM-5 criteria. (3) Excoriation (Skin-Picking) Disorder (SPD) according to DSM-5 criteria.

(4) Met criteria for treatment resistance, defined as: (a) A Y-BOCS score ≥ 16. (b) A history of inadequate response (<25% reduction in Y-BOCS score) to at least two different serotonin reuptake inhibitors (SSRIs) at an adequate dose for at least 12 weeks each.

1.2 Inclusion Criteria for Healthy Controls:

(1) Age and sex-matched to the patient group. (2) No personal history of any psychiatric disorder.

1.3 Exclusion Criteria for All Participants: (1) Presence of any contraindications to 3T MRI scanning (e.g., metallic implants, claustrophobia). (2) Current (within the past 6 months) diagnosis of a substance use disorder. (3) Significant or unstable neurological illness (e.g., epilepsy, multiple sclerosis, brain tumor). (4) History of significant head trauma or neurosurgery.

1.4 Additional Exclusion Criteria for Patients with TR-OCD:

(1) Current or lifetime diagnosis of a primary psychotic disorder (e.g., schizophrenia), bipolar I/II disorder, or intellectual disability. (2) Any contraindication to the use of N-acetylcysteine.