Evolving OCD treatment: breaking the loop – Nature Mental Health

Before modern nosological frameworks emerged, the symptoms associated with OCD were often referred to as ‘scrupulosity’ or ‘melancholy madness.’ German and French psychiatrists in the 19th century attempted to understand obsessions and compulsions as disorders of the will, emotions or intellect. The German term Zwangsvorstellung was translated differently across countries — ‘obsession’ in the UK and ‘compulsion’ in the USA — eventually coalescing into the term ‘obsessive–compulsive disorder.’

Credit: Marina Spence

OCD, as it is now understood, is a spectrum of disorders sharing recurrent and persistent thoughts, urges, sensations or images (obsessions) and repetitive behaviors (compulsions) performed to reduce anxiety. These thoughts and the related actions that the person feels driven to perform to manage fears or to prevent some dreaded situation, cause severe distress and can be time-consuming consequently leading to substantial disruptions in daily life.

Affecting 1–3% of the global population, OCD can present at any age but typically manifests between the ages of 8 and 12, or during the late teenage years and early adulthood. OCD presentations are consistent around the world, with similar prevalence rates across countries. Nonetheless, its expression and experience can be influenced by cultural norms, values and belief systems. For instance, particular triggers for obsessions related to contamination may differ among cultures, with certain objects or practices considered taboo or dangerous.

More recent formulations of OCD have shifted from an emphasis on the relationship with anxiety disorders and instead emphasize transdiagnostic dimensions with disorders defined by obsessions and compulsions, such as hoarding disorder, body dysmorphic disorder, hair pulling (trichotillomania) and skin-picking disorder. In addition to shared phenomenology, age of onset, clinical trajectory and treatment response, these conditions show marked deficits in behavioral inhibition and common pathophysiology.

Structural and functional neuroimaging studies have begun to clarify the neurobiological basis of OCD, focusing on the changes in the cortico–striato–thalamo–cortical circuitry as a core mechanism underlying the obsessive and compulsive symptoms. Together with dysfunctions in the default mode and sensorimotor networks, these impairments can contribute to deficits in response inhibition and cognitive flexibility. Being a multifactorial condition, however, OCD also involves polygenic and environmental risk factors, including perinatal complications, trauma and stress, that could affect neurodevelopment and induce neural changes.

First-line treatments include exposure and response prevention (ERP) therapy and selective serotonin reuptake inhibitors. Treatment resistance is a major clinical issue, affecting up to 60% of patients, and is driven by clinical heterogeneity, symptom severity and duration, and comorbidities with other mental health conditions. For treatment-resistant cases, pharmacological options include clomipramine or augmentation with atypical antipsychotics such as aripiprazole or risperidone. Emerging drug classes under investigation include glutamatergic agents, cannabinoids, opioid-based treatments and psychedelics. Alternative psychotherapy approaches involve mixed-reality ERP, inference-based cognitive behavioral therapy focused on reasoning processes, and internet- or webcam-delivered modalities. Mindfulness-based therapies, which emphasize accepting rather than suppressing intrusive thoughts, may also benefit some individuals.

In recent decades, neuromodulation has emerged as an effective alternative therapeutic approach for individuals affected by treatment-resistant OCD. The modulation of neural activity is achieved non-invasively through repetitive transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) or transcranial alternating current stimulation. Deep TMS received US FDA (Food and Drug Administration) clearance with dorsal medial prefrontal cortex and anterior cingulate cortex as target regions. Still, no consensus on optimal stimulation frequency, target sites and duration has been reached among clinicians. For most severe and chronic cases when all other options have been tried, invasive methods such as deep brain stimulation, neurosurgery via gamma knife or focused ultrasound ablation can be used.

In this issue of Nature Mental Health, we feature three pieces that address different aspects of current OCD treatments, such as neuromodulation and psychedelic drugs.

An Analysis by Gouveia et al. explores the comparative efficacy of neuromodulatory invasive interventions, including deep brain stimulation and lesion-based neurosurgery, and non-invasive methods, such as TMS and tDCS. All four neuromodulation methods were linked to substantial decreases in OCD symptom severity, highlighting the therapeutic promise of neuromodulation treatments for cases that are resistant to standard therapies. Invasive methods exhibited the largest effects, whereas non-invasive approaches provided modest, yet clinically relevant, advantages. The network-based analysis of stimulation targets revealed three principal modules: frontostriatal, limbic and thalamocortical, suggesting that effective neuromodulation may depend on targeting key integrative nodes within these networks. The study also highlights the need for improved methodological rigor, as many trials exhibited high risk of bias (particularly invasive interventions) in randomization and adherence to protocols. While invasive techniques showed greater efficacy and remain the most potent interventions for patients with highly refractory OCD, non-invasive methods remain valuable due to their safety and accessibility.

In another Analysis by Salehinejad and coauthors, the authors evaluated the effectiveness of transcranial electrical stimulation (tES) for treating OCD by using three meta-analytic approaches: classic meta-analysis for identifying effect size, network meta-analysis for comparing efficacy of different interventions, and meta-modeling to explore the correlation between symptom reduction and induced electrical field. The study revealed a moderate therapeutic effect of tES on OCD symptoms with larger effects from twice-daily intervention and particularly when targeting specific brain regions such as the supplementary motor area, the orbitofrontal cortex and the left dorsolateral prefrontal cortex. These findings suggest that tES is a promising alternative to traditional treatments, with potential for home-based applications. Future research should focus on optimizing stimulation parameters, include people with other comorbidities and explore in more detail the long-term safety of tES.

A Review by Ali et al. proposes a mechanistic framework for how classical psychedelics, such as psilocybin and lysergic acid diethylamide, may help treat OCD, offering insight into the potential evolution of treatment paradigms for OCD in the future. The authors integrate receptor-level pharmacology, alterations in large-scale brain networks and neuroplasticity to explain the emergence of a critical therapeutic window for reorganizing maladaptive circuitry. When combined with psychotherapy, this may facilitate the lasting integration of more flexible mindsets and actions.

As these pieces underscore, both neuromodulation and novel classes of drugs such as psychedelics could offer a crucial alternative for people with OCD who do not experience adequate relief from first-line treatments. There remains a great need for personalizing target networks to improve the effectiveness of brain stimulation that, ideally, would be tailored to individual symptoms.

To bridge the gap between research and clinical care in OCD, clinical trials must be implemented in community-based settings to ensure that the findings are applicable beyond academic environments and to make evidence-based treatments more accessible. Embracing the cultural context when making a diagnosis and providing therapy is also essential for offering empathetic and informed treatment that fosters healing for every patient.

Despite being a widely recognized condition, demand for OCD diagnosis and treatment exceeds the availability of specialized practitioners. Delays in diagnosis and care can have life-altering consequences, leading to more severe and protracted cases, treatment resistance and increased distress and suicidality. Expanding the clinical workforce via specialized training as well as enhancing accessibility to treatment via digital tools, remote specialized care and home-based scalable interventions will be essential to begin addressing these challenges.