A rapid clinical response to etifoxine in treatment-resistant obsessive-compulsive disorder: a case report of a patient with comorbid bipolar disorder

Abstract

This case report describes the rapid clinical response to etifoxine, an oral translocator protein 18 kDa (TSPO) ligand, in a patient with severe, treatment-resistant obsessive-compulsive disorder (OCD) with comorbid bipolar I disorder. Despite extensive prior pharmacological treatments and neurosurgical interventions, the patient experienced significant symptom amelioration within days of etifoxine initiation (the Yale-Brown Obsessive-Compulsive Scale (YBOCS) score decreased from 50 to 29). We discussed the potential mechanisms underlying this rapid response, including direct γ-aminobutyric acid (GABA) receptor modulation, increased endogenous neurosteroidogenesis, reduced neuroinflammation, and modulation of the gut-brain axis. This case highlights etifoxine as a novel therapeutic option for treatment-resistant OCD and underscores the need for further research into TSPO ligands in this context.

Plain language summary

A dramatic improvement in obsessive thoughts after taking a medicine usually used for anxiety

This case report tells the story of a man with long-standing obsessive-compulsive disorder (OCD) who had not improved despite trying many medications and even undergoing brain surgery. He was given a medicine called etifoxine, which is usually used to treat anxiety. Surprisingly, within just two days, he experienced a major improvement in his obsessive thoughts and suicidal feelings. However, he developed a mild allergic skin reaction and swelling in his legs, so the medicine was stopped. After the side effects went away, his doctor slowly reintroduced etifoxine at a lower dose. His symptoms improved again, but not as dramatically as the first time. This is the first report of etifoxine being used for OCD. Researchers believe it might work by helping the brain make calming chemicals, reducing inflammation, and possibly affecting the gut-brain connection. This case gives hope that etifoxine could become a new treatment option for people whose OCD doesn’t respond to usual therapies. More research is needed to understand how it works and how to use it safely.

Introduction

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric condition often associated with significant functional impairment and reduced quality of life. Despite available treatments, a substantial number of patients experience treatment resistance. Neurosteroidogenesis, mediated by the translocator protein 18-kDa (TSPO), a transmembrane protein primarily located in mitochondria (formerly known as the peripheral benzodiazepine receptor), is increasingly recognized for its influence on OCD pathology. ¹ TSPO ligands have been explored in mood, anxiety, and stress-related disorders,^2,3 but their role in OCD treatment remains largely unelucidated.

Etifoxine is a unique oral TSPO ligand that not only binds directly to the GABA (γ-aminobutyric acid) type A (GABAA) receptor but also enhances neurosteroid synthesis through its affinity for TSPO. ⁴ This dual mechanism of action suggests a broad therapeutic potential. Etifoxine is approved, in some countries and regions, for “adjustment disorder with anxiety” and “psychosomatic manifestation of anxiety.”^2,3 The starting dose is 150 mg/day, and the therapeutic range is 150–200 mg/day in divided doses of 50–100 mg two to three times per day. However, etifoxine is not approved in the United States and the United Kingdom.

This report aims to describe the short-term use of etifoxine in a bipolar disorder patient with treatment-resistant OCD who experienced a dramatic and rapid clinical response and to discuss the possible underlying mechanisms. It was prepared and written following the guidance provided by the CARE guidelines ⁵ to ensure accuracy and completeness in reporting (Supplemental File 1: CARE Checklist).

Case presentation

A 36-year-old man presented with a long-standing history of OCD, diagnosed at age 14. His OCD symptoms were severe and significantly impacted his daily life. He also developed bipolar I disorder at age 28. There was no family history of psychiatric disorders. After consulting three psychiatrists, he later decided to undergo psychiatric treatment at our university hospital at age 29. He had previously undergone extensive pharmacological treatments with adequate dose and duration, including multiple selective serotonin reuptake inhibitors such as escitalopram (20 mg/day) and sertraline (100–200 mg/day), serotonin-norepinephrine reuptake inhibitors like venlafaxine (150–375 mg/day), and tricyclic antidepressants including clomipramine (100–150 mg/day) and imipramine (200 mg/day). Nonetheless, titration of high-dose psychotropic medications with antidepressant effects had been challenging, since it often precipitated manic symptoms, such as irritability and verbal aggression, which in turn exacerbate OCD symptoms, causing a vicious cycle. Augmentation strategies with lithium (300–900 mg/day), risperidone (2–8 mg/day), aripiprazole (15–30 mg/day), brexpiprazole (2–4 mg/day), and quetiapine (300–800 mg/day) had also been attempted without sustained success. The patient did not respond to risperidone and brexpiprazole. He had a partial response to lithium and quetiapine in terms of bipolar depression and anxiety symptoms, but they were discontinued due to metabolic side effects and the inadequate ability to control mania in this patient. The optimal antipsychotic for this patient was aripiprazole, which contributed to the management of manic episodes and served as an adjunctive therapy for OCD. The combination of venlafaxine 375 mg/day and clomipramine 150 mg/day, at their maximum approved dosing in OCD, demonstrated acceptable effectiveness for OCD in this patient, yet did not achieve remission. However, higher doses were not tried because the patient’s contamination fear prevented him from taking an electrocardiogram (EKG) for cardiac safety monitoring, which was necessary, particularly when off-label higher dosing was warranted. Clonazepam was prescribed to relieve his anxiety and insomnia.

Because of contamination fear, he preferred telemedicine to on-site sessions and consistently refused to receive any intervention requiring frequent hospital visits, including psychotherapy, electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and intravenous ketamine infusion. He also declined hospitalization in any shared unit where he would be required to interact with other patients. Our psychiatric inpatient unit lacked any suitable single-occupancy rooms for him. Consequently, inpatient psychiatric care was not selected, and his condition was neither severe nor sufficiently risky to warrant involuntary hospitalization.

Given his treatment resistance, he decided to undergo neurosurgical interventions for OCD. At the time of the decision, his mental capacity was intact. His family, including his parents and sibling, who was a medical doctor, also participated in the counseling session by the neurosurgeon and agreed with the patient’s decision. He preferred neurosurgical intervention to neuromodulation (e.g., ECT and rTMS) because, in his perspective, frequent on-site hospital visits or several weeks of admission to a cluster ward were more distressing than being hospitalized in a single-occupancy neurosurgery unit and brain surgery. At age 30, he received a bilateral anterior cingulotomy, which resulted in a significant improvement in his OCD symptoms, with a 90% reduction in the Yale-Brown Obsessive-Compulsive Scale (YBOCS) score that was sustained for 1.5 years. At age 32, he underwent bilateral subcaudate tractotomy, which the neurosurgeon intentionally combined with the previous anterior cingulotomy, resulting in bilateral limbic leukotomy and full remission of his bipolar disorder symptoms. However, his OCD symptoms improved by only 36% (YBOCS score reduction) for approximately 6 months, after which they relapsed to a milder degree. Overall, his quality of life improved significantly, and no manic episodes appeared again in the next 5 years (up to the time of this case report submission). He could enter into a long-term romantic relationship and take care of himself. However, the OCD symptoms never remit.

At age 36, without any significant external stressor, his OCD symptoms became more distressing (YBOCs score = 50), particularly contamination fears, leading to a gradual development of sleep disturbance and suicidal ideation within a month. He refused hospitalization due to his severe contamination fear.

In Thailand, etifoxine is approved for psychosomatic manifestations of anxiety. Its mechanisms are unique, and it is the only available medication in Thailand that has effects on neurosteroidogenesis, which may be involved in the pathophysiology of OCD.¹ The treating psychiatrist explained this to the patient. After extensive discussion, he agreed to try etifoxine 150 mg/day, in addition to his ongoing medication regimen, and scheduled a follow-up in 1 week. His current medication regimen at the time of etifoxine initiation included venlafaxine 375 mg/day, clomipramine 150 mg/day, aripiprazole 15 mg/day, and clonazepam 4 mg/day.

Timeline of etifoxine treatment

• Day 1 of Etifoxine use: Etifoxine 50 mg was administered thrice daily (total 150 mg/day).

• Day 2: The patient and his sibling reported a dramatic reduction in his obsessive-compulsive (OC) symptoms. His suicidal ideation disappeared, and he experienced better sleep and increased engagement in family activities.

• Day 3: He developed a generalized itchy maculopapular rash and pitting edema in both legs. He was seen by a board-certified doctor specialized in internal medicine and nephrology, and blood tests for complete blood count, renal function(blood urea nitrogen [BUN] 20 mg/dL, creatinine [Cr] 0.72 mg/dL), liver function tests (aspartate aminotransferase [AST] 22 U/L, alanine aminotransferase [ALT] 38 U/L, alkaline phosphatase [ALP] 88 U/L, albumin 4.7 g/dL, globulin 2.8 g/dL), and other physical examinations were unremarkable. The internist liaised with the treating psychiatrist about the patient’s psychiatric conditions by telemedicine. After discussion with the internist and psychiatrist about the risk and benefit of taking etifoxine, he continued etifoxine, as it dramatically helped ameliorate his OC symptoms. Supportive treatment with hydroxyzine 30 mg/day was initiated.

• Day 6: OCD symptoms improved (Day 2–Day 6: YBOCS score = 29, obsession score = 14, compulsion score = 15), and the patient had no suicidal ideation. He could sleep well, and his mood was euthymic. Considering the better overall psychiatric symptoms, etifoxine was discontinued by the psychiatrist, as the risks of rash and edema were considered to outweigh the suicidal risk.

• Within 2 weeks of discontinuation: The rash, limb edema, and all drug-related adverse reactions completely resolved, and the patient stopped taking hydroxyzine. The inflammatory marker, erythrocyte sedimentation rate, was normal (2 mm/h). The renal (BUN 17 mg/dL, Cr 0.76 mg/dL) and LFT (AST 23 U/L, ALT 41, ALP 87 U/L, total bilirubin 0.36 mg/dL, direct bilirubin 0.34 mg/dL, albumin 4.8 g/dL, globulin 2.5 g/dL) remained unremarkable. The patient was clinically stable and continued to be followed up in the outpatient setting.

• One month after etifoxine discontinuation, his self-reported OCD symptoms became slightly worse (both the obsession and compulsion), and the patient and family requested the opportunity to resume using etifoxine. Following informative counseling with the patient and family regarding the risks and benefits of each treatment option, he chose to receive etifoxine again.

• Etifoxine rechallenge with a slow titration over 6 weeks: Etifoxine was gradually rechallenged with a slow titration, starting at 50 mg/day and increasing by 50 mg every 2 weeks, up to a dose range of 50–200 mg/day. During this slow titration, his OC symptoms improved to the same level of previous etifoxine use (YBOCs score = 29) without any recurrence of rash or edema, but the response was not as rapid or dramatic as observed with the initial loading regimen.

Long-term follow-up

Since etifoxine initiation, the patient had been regularly followed up for 1 year (up to the time of this case report submission). After receiving the twice-daily etifoxine at 200 mg/day (maximum therapeutic dose), he had been at a lower anxiety level and had less severe contamination fear. This had a major impact on his ability to engage in subsequent treatment. After 2 months of taking 200 mg of daily etifoxine, he could tolerate the EKG procedure for drug safety monitoring, particularly the QT prolongation risk of many antidepressants. Clomipramine was increased from 150 to 175 mg/day. After 3 months, he could also undergo rTMS with OCD protocol to the left dorsolateral prefrontal cortex. After 4–5 months, marriage anxiety triggered his obsession and insomnia. Therefore, venlafaxine was increased from 375 to 450 mg/day, and trazodone (50–100 mg/day) was later initiated. His blood pressure was normal, and there was no sign of serotonin syndrome. Not only was the marriage anxiety better, but also the OCD symptoms. He noticed that, although all the OCD symptoms persisted, they were less impactful. After 6 months, he could get married to his wife as planned. His most recent medications were venlafaxine 450 mg/day, clomipramine 175 mg/day, aripiprazole 15 mg/day, clonazepam 4 mg/day, and etifoxine 200 mg/day.

Discussion

This case represents the first reported use of a TSPO ligand in the treatment of OCD and illustrates the potential therapeutic utility of etifoxine for treatment-resistant forms of the disorder. The rapid and dramatic response observed in this patient, particularly the rapid reduction in suicidal ideation and OCD symptoms, is noteworthy given his extensive history of treatment resistance and neurosurgical interventions.

Four possible mechanisms could account for the rapid response to etifoxine (Figure 1).

1. Direct GABAergic modulation: OCD pathophysiology is linked to dysregulation of the GABAergic system, with studies reporting lowered concentrations of GABA in the orbitofrontal cortex and anterior cingulate cortex of unmedicated OCD patients. ⁶ Etifoxine is a direct positive allosteric modulator of GABAA receptors. Enhancing GABAergic signaling immediately can address these neurochemical imbalances.

2. Increased endogenous neurosteroidogenesis: A TSPO-PET study in OCD patients has demonstrated increased TSPO expression in the dorsal caudate, orbitofrontal cortex, thalamus, ventral striatum, and dorsal putamen, suggesting a link between neurosteroids and OCD pathology. ⁴ Exposure of frog hypothalamic explants to an etifoxine solution demonstrated an increase in the concentration of neurosteroids after 2 h. ⁷ This could lead to a synergistic anxiolytic effect and contribute to symptom improvement. Neurosteroids target both synaptic and extrasynaptic GABAA receptors, potentially offering a more favorable side-effect profile and a distinct clinical efficacy compared with benzodiazepines, which act only on synaptic receptors.^2,3 Moreover, neurosteroids have shown a rapid-acting effect on psychiatric symptoms. A randomized placebo-controlled trial demonstrated that brexanolone, an intravenous form of the neurosteroid allopregnanolone, provided a rapid alleviation of anxiety and depressive symptoms by day 3 (within 60 h) of postpartum depression. ³

3. Reduced neuroinflammation: Emerging evidence suggests a role for neuroinflammation in the pathophysiology of OCD.¹ Etifoxine has been shown to possess anti-inflammatory properties by modulating microglial function, ⁸ which could contribute to its therapeutic effects by modulating neuroinflammatory pathways.

4. Gut-brain axis modulation: Microbiome dysbiosis has been linked with OCD pathology. ⁹ A 5-day etifoxine treatment study in healthy humans demonstrated reductions in specific bacterial species, ¹⁰ suggesting that etifoxine may directly influence gut microbiome composition. This modulation could be a bidirectional communication between this peripheral mechanism and both etifoxine’s central actions, which may contribute to a longer-term mechanism leading to a clinical response. ¹¹

The transient adverse effects (rash and edema) observed with the etifoxine initiation at the target dose highlight the importance of careful titration and monitoring. ¹² The successful rechallenge with a slower titration suggests that the adverse effects may be dose- or rate-dependent (Figures 2 and 3).

Figure 1.

Case summary.

Figure 2.

Timeline of etifoxine treatment.

Figure 3.

Possible mechanisms for the rapid response to etifoxine in obsessive-compulsive disorder.

Regarding the limited treatment options for refractory OCD, many drugs with different mechanisms of action from the approved medications are used off-label. ¹³ A 5-HT3 serotonin receptor antagonist, ondansetron, and glutamate modulating drugs, for example, N-acetylcysteine, ketamine, and troriluzole, have shown some evidence in OCD, but larger randomized controlled trials are needed. ¹⁴ To our knowledge, this is the first case report regarding the potential benefit of TSPO ligands in OCD. Our case also supports the role of neurosteroids in the pathophysiology of OCD and further investigation of etifoxine in OCD.

Limitations

This case report has several limitations. First, it describes a single patient, which limits the generalizability of the findings. Second, the patient was on multiple concurrent psychotropic medications, which makes it difficult to isolate the therapeutic effects of etifoxine alone. Third, standard measurements like YBOCS were rated only during admission or outpatient follow-up, whereas most symptoms and the clinical responses occurred when the patient was not at the hospital. In that case, symptom severity was assessed through subjective self-report of symptoms and the patient’s recall of symptoms at each timepoint to rate YBOCS. Lastly, while the patient experienced a rapid and significant improvement in symptoms, the presence of comorbid bipolar disorder may complicate the interpretation of treatment effects and clinical trajectory.

Conclusion

This case report suggests that etifoxine may represent a promising therapeutic option for treatment-resistant OCD comorbid with bipolar disorder, particularly in cases where conventional interventions have failed. The rapid clinical response observed in this patient, potentially mediated by mechanisms such as neurosteroidogenesis, anti-inflammatory effects, and modulation of the gut-brain axis, highlights the therapeutic potential of TSPO ligands for treatment-resistant psychiatric conditions. However, the limitations emphasize the need for controlled trials to further assess the efficacy and safety of etifoxine in treatment-resistant OCD, to clarify the underlying mechanisms, and to establish safe and effective dosing strategies.

Supplemental Material

sj-pdf-1-tpp-10.1177_20451253261429968 – Supplemental material for A rapid clinical response to etifoxine in treatment-resistant obsessive-compulsive disorder: a case report of a patient with comorbid bipolar disorder

Supplemental material, sj-pdf-1-tpp-10.1177_20451253261429968 for A rapid clinical response to etifoxine in treatment-resistant obsessive-compulsive disorder: a case report of a patient with comorbid bipolar disorder by Pornjira Pariwatcharakul and Punyisa Prachgosin in Therapeutic Advances in Psychopharmacology