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Advanced OCD Treatment Strategies & New Drugs Under Investigation (2023)

OCD affects approximately 1-3% of the population and often begins in childhood or adolescence.

While OCD was previously considered untreatable, advances in the past few decades have led to effective evidence-based treatments.

Key Facts:

  • Glutamatergic medications like memantine, ketamine, and N-acetylcysteine have shown preliminary evidence of efficacy in small trials, but larger studies have been inconsistent.
  • Device-based neuromodulation techniques like repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) show moderate effectiveness for OCD in meta-analyses.
  • Innovations in psychotherapy include internet-based CBT, optimizations of exposure therapy based on inhibitory learning, and acceptance-based approaches.
  • Early stage agents like ondansetron, scopolamine, etc. have shown initial promising results but require more research to confirm efficacy and safety.

However, a substantial proportion of patients do not achieve full remission with standard interventions.

This has driven investigation into novel pharmacological agents, device-based neuromodulation, and innovative adaptations of psychotherapy to improve outcomes.

Changing Perceptions of OCD

Throughout history, OCD has been interpreted through various lenses, from religious and guilt-based explanations to psychoanalytic perspectives.

Early interventions were psychodynamically oriented, derived from psychoanalysis.

However, the advent of exposure and response prevention (ERP) in the 1970s demonstrated the potential for behaviorally oriented treatments.

ERP, which involves systematic exposure to obsessions without engaging in compulsions, has become a gold-standard psychotherapeutic intervention for OCD.

Pathophysiology of OCD

Recent advances in neuroimaging have shed light on the neurobiological underpinnings of OCD.

Dysfunctional neurotransmitter systems, particularly serotonin, dopamine, and possibly glutamate, are implicated in OCD’s pathophysiology.

The “cortico-striato-thalamo-cortical” (CSTC) circuits, which include the orbitofrontal cortex, caudate nucleus, and thalamus, are central to OCD’s pathology.

Neuroimaging studies consistently show dysregulation in these circuits, which can be modulated with successful treatment.

Additionally, alterations in the immune system have been observed in OCD patients.

Advances in Treatment for OCD in Adults (2023)

OCD is most commonly treated with a combination of pharmacotherapy (medications) and psychotherapy (e.g. CBT).

In refractory cases that are unresponsive to conventional pharmacotherapy and/or psychotherapy – neurostimulation technology and/or neurosurgery may prove therapeutic.

Additionally, there are various drugs under investigation as monotherapy or adjunct therapy for the treatment of OCD.

Pharmacotherapy (Medication Strategies)

  • Selective Serotonin Reuptake Inhibitors (SSRIs): SSRIs, including fluoxetine, sertraline, and paroxetine, are first-line pharmacological treatments for OCD. They have demonstrated efficacy, tolerability, and safety, making them preferred choices. Maximum tolerable doses are often recommended.
  • Clomipramine: Clomipramine, a tricyclic antidepressant with serotonin-selective properties, is another effective option. However, its side-effect profile is less favorable than SSRIs, making it a second-line choice.
  • Augmentation Strategies: Approximately 40-60% of patients do not achieve a satisfactory response with SSRIs alone. Augmentation with antipsychotic medications like aripiprazole and risperidone has shown promise, particularly in SSRI-resistant cases. Other agents under investigation for augmentation include memantine, ketamine, troriluzole, ondansetron, and tolcapone.
  • Switching to Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Switching to SNRIs like venlafaxine may be considered if SSRI treatment is ineffective.

Psychotherapy (CBT, ACT, ILT)

  • Cognitive Behavioral Therapy (CBT) and Exposure and Response Prevention (ERP): CBT/ERP is the gold standard psychotherapeutic approach for OCD. It involves cognitive reappraisal, restructuring, and ERP, which systematically exposes patients to their obsessions without allowing compulsive behaviors.
  • Internet-Based Cognitive Behavioral Therapy (iCBT): iCBT has emerged as a convenient and effective alternative, especially when traditional face-to-face therapy is inaccessible.
  • Acceptance and Commitment Therapy (ACT): ACT focuses on fostering psychological flexibility through acceptance, mindfulness, and values-based commitment.
  • Inhibitory Learning Theory (ILT)-Based Approaches: ILT-based ERP aims to maximize treatment effectiveness by facilitating the development of new safety-based learning to inhibit old fear-based learning.
  • Inference-Based Therapy (IBT): IBT targets obsessive beliefs and assumptions, directly addressing their content through imaginative interventions.

Neuromodulation & Neurosurgery for OCD

Approximately 20-25% of OCD patients are resistant to standard treatments. Neuromodulation and neurosurgical approaches target the CSTC circuits involved in OCD.

Neuromodulation (TMS & TDCS)

  • Repetitive Transcranial Magnetic Stimulation (rTMS): rTMS, particularly low-frequency stimulation of cortical regions like the supplementary motor area and orbitofrontal cortex, has shown promise in reducing OCD symptoms.
  • Transcranial Direct Current Stimulation (tDCS): tDCS, a non-invasive technique, involves applying a weak electrical current to the scalp, modulating cortical activity. It holds potential but requires further research.

Neurosurgery (DBS & Ablation)

  • Deep Brain Stimulation (DBS): DBS involves implanting electrodes to stimulate specific subcortical regions, like the nucleus accumbens or thalamus, with promising results in treatment-resistant OCD.
  • Traditional Neurosurgery: Irreversible focal tissue ablation procedures are considered in severe, chronic, treatment-refractory cases.

New Drugs for OCD (2023): Investigational Agents

There are a variety of drugs under investigation for the treatment of OCD – either as a standalone (monotherapy) or adjunct (combined with other interventions).

Most of these drugs are not “new” compounds, however, they are new in the sense that they are newly under investigation specifically for OCD management.


Emerging evidence suggests that glutamate signaling dysfunction may play a crucial role in the pathogenesis of OCD.

As such, researchers are investigating agents that modulate the glutamatergic system.

One such candidate is Memantine, originally approved for Alzheimer’s disease.

Memantine targets the N-methyl-D-aspartate (NMDA) receptor and may have potential in treating OCD.

Some preliminary studies and open-label trials have shown promise, but larger, controlled trials are needed to confirm its efficacy.


Another glutamatergic modulator under investigation for OCD treatment is Lamotrigine.

This drug has shown some evidence of safety and efficacy in small randomized controlled trials (RCTs) and open-label studies.

Researchers are exploring its potential as a treatment option for OCD.

However, further research is required to establish its role definitively in the management of OCD symptoms.

N-Acetylcysteine (NAC)

N-Acetylcysteine (NAC) modulates glutamatergic transmission in subcortical brain regions via the cystine-glutamate antiporter.

While it has shown promise in reducing symptoms in disorders like trichotillomania and excoriation disorder, its effectiveness in OCD remains inconsistent.

Recent trials have yielded mixed results, emphasizing the need for more rigorous investigations.


Ketamine, known for its rapid-acting antidepressant effects, has garnered attention for its potential in treating OCD.

Some open-label trials and a randomized crossover study have reported anti-obsessional effects of intravenous ketamine infusion.

However, further controlled trials with larger samples are necessary to establish its efficacy and safety in OCD treatment.


Troriluzole is a new drug that functions as a glutamate modulating agent.

While it is currently undergoing phase 2-3 controlled trials for OCD, meaningful results have not yet been reported.

Troriluzole’s potential as an OCD treatment awaits further investigation.


Ondansetron, a 5-HT3 serotonin receptor antagonist, has shown promise as an augmentation strategy in the treatment of refractory OCD.

Several RCTs have indicated its efficacy when added to SSRIs.

However, long-term safety and efficacy data are still needed to establish its role definitively.

Benzodiazepines (BDZs)

Although not recommended as a primary treatment option for OCD in recent guidelines due to limited efficacy data, a small study found that clonazepam was significantly effective in a subset of patients who did not respond to clomipramine.

Further research is necessary to determine the specific patient population that may benefit from BDZs.


Tolcapone, a catechol-O-methyl-transferase (COMT) enzyme inhibitor, enhances dopamine signaling in the cortex.

It demonstrated efficacy in a randomized, placebo-controlled crossover trial.

However, further evaluation is necessary to determine its role as a candidate medication for OCD.

Takeaways: New OCD Treatments

In summary, ongoing research has identified various emerging pharmacological, device-based, and psychotherapeutic approaches that show preliminary promise for improving OCD treatment outcomes.

However, the majority require larger, high-quality controlled trials to firmly establish their safety, efficacy, and optimal applications.

Continuing research in coming years will clarify which of these novel approaches translate into validated clinical treatments for OCD patients.


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