Adjunctive Topiramate for Treatment-Resistant OCD

David L. Ginsberg, MD

Director of Outpatient Services, Tisch Hospital’s Department of Psychiatry, New York University Medical Center

While currently available treatments such as serotonin reuptake inhibitors (SRIs), augmentation with dopamine antagonists, and cognitive-behavioral therapy (CBT) are efficacious in obsessive-compulsive disorder (OCD), only about 40–60% of patients experience significant reduction of symptoms, with many others demonstrating either partial or no response. Little practical advice is available to clinicians on next-step treatment strategies for patients who have not responded to 2 or more trials of SRIs. In severe, resistant cases, neurosurgery may even be recommended. Now comes a small, open-label study on the use of adjunctive (to SRIs) topiramate for treatment-resistant OCD (Rubio et al. 2006).

Participants included 12 consecutive patients (7 men, 5 women, mean age 46.6 years) with OCD of at least 3 years in duration that had not responded to two or more adequate serotonin reuptake inhibitor (SRI) courses of at least 14 weeks. Before beginning the 16 weeks of open-label topiramate, patients had to have been on a stable and adequate antidepressant dose (fluoxetine 80 mg/d, paroxetine 60 mg/d, fluvoxamine 300 mg/d, clomipramine 250 mg/d, sertraline 200 mg/d, citalopram 60 mg/d, or venlafaxine 300 mg/d) for at least 8 weeks. Two patients were also taking benzodiazepines. Exclusion criteria included any of the following: another primary Axis I psychiatric diagnosis; current eating disorder, body dysmorphic disorder, alcohol or substance abuse disorder, borderline or antisocial personality disorders, history of bipolar disorder, schizophrenia, delirium, dementia or other cognitive disorders, initiation of psychotherapy within 4 months, seizure disorders, history of kidney stones, and Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) baseline score of 16 or lower.

Topiramate was initially started at 25 mg/day, then increased by 25 mg the first week, then by 50 mg increments the following week, up to 100 mg/day at the end of week 3. The dose was titrated upward until a clinical response was achieved. At the end of week 5, the topiramate dose could be further increased by 50 mg/day each week up to a maximum dose of 400 mg/day at week 9. If intolerance occurred the dose was adjusted accordingly. Subjects were permitted to continue taking concurrent benzodiazepines (n=2) or antidepressant medications, provided that they had been on a stable dose of these medications for at least 8 weeks before entering the study and agreed not to change the dose of the concurrent medication over the course of the study. Patients were evaluated every 2 weeks with response defined as a greater than or equal to 30% decline in the Y-BOCS score. Social function was assessed with the Global Assessment of Functioning (GAF) Scale. The primary efficacy measurement was the number of responders with a Y-BOCS less than 30% of the Y-BOCS-baseline score.

All 12 patients completed treatment, with 10 patients (83%) meeting response criteria. Among responders, Y-BOCS scores decreased from a baseline mean of 28 to 16 (P=0.002). Scores also declined in non-responders. The average time to response was 9.5 weeks. Compulsions improved first, followed by obsessions. By the second month of therapy, patients reported improved social functioning. Final topiramate dosages ranged from 200 to 300 mg/day (mean dose=237.5 mg/day) with no dose-response relationship was evident. Significant improvement of 35% (P=0.002) in mean Global Assessment of Function scores also occurred. The most common side effects were weight loss in 3 patients and in 2 patients, sedation, memory/word-finding difficulties, and paresthesia.

This is the first study in which topiramate has been used in the treatment of OCD. The results presented suggest that adjunctive topiramate may be an effective strategy to treat patients with OCD resistant to SRI antidepressant therapy. Other anticonvulsants, valproate and carbamazepine, have also been used in the treatment of OCD associated to other psychiatric conditions (Freeman et al. 2002). Topiramate possesses several mechanisms of action: enhances the activity of gamma-aminobutyric acid (GABA) at nonbenzodiazepine sites, blocks voltage-gated sodium channels, weakly inhibits carbonic anhydrase (CA) isoenzymes CAII and CAIV, and inhibits glutamate via alpha adenosine monophosphate/kainite (White et al. 2000; Gibbs et al. 2002). While the precise neurochemical mechanism by which topiramate improves the efficacy of antidepressant treatment in resistant OCD patients remains to be elucidated, it is possible that modifications in glutamatergic function may be responsible, at least in part, as proton magnetic resonance spectroscopy has demonstrated abnormally high glutamatergic concentrations in the caudate nuclei of children with OCD (Rosenberg et al. 2000). Furthermore, after SSRI treatment, a decrease in OCD symptoms severity has been associated with a reduction in caudate glutamatergic concentrations. Additional studies, but with a greater number of subjects and in a randomized, double-blind, placebo-control design, are indicated to confirm these preliminary findings.

References

Rubio G, Jimenez-Arriero MA, Martinez-Gras I, et al. The effects of topiramate adjunctive treatment added to antidepressants in patients with resistant obsessive-compulsive disorder (letter). J Clin Psychopharmacol 2006; 26:341-343.

Freeman MP, Freeman SA, McElroy SL. The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology and treatment issues. J Affect Disord 2002; 68:1-23.

White HS, Brown SD, Woodhead JH, et al. Topimate modulates GABA-evoked currents in murine cortical neurons by non-benzodiazepine mechanism. Epilepsia 2000; 41:S17-S20.

Gibbs JW, Sombati S, DeLorenzo RJ, et al. Cellular actions of topiramate: blockade of kainate-evoked inward currents in cultured hippocampal neurons. Epilepsia 2002;41:S10-S16.

Rosenberg DR, MacMaster FP, Keshavan MS, et al. Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine. J Am Acad Child Adolesc Psychiatry 2000; 39:1096-1103.