The Role of Glutamatergic Dysfunction in Treatment-Resistant Obsessive-Compulsive Disorder: Treatment of an Adolescent Case with N -Acetylcysteine Augmentation

To The Editor:

Obsessive compulsive disorder (OCD) is a common, chronic, and treatment resistant neuropsychiatric disorder that frequently begins during childhood and adolescence (Jenike 2004; Heyman et al. 2006). The recommended treatment strategy for OCD in children and adolescents includes cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs), either individually or combined. However, treatment with SSRIs in addition to clomipramine and typical/atypical antipsychotic agents is recommended for cases that do not respond to normal OCD treatment (American Academy of Child and Adolescent Psychiatry 2012; Arumugham and Reddy 2013). Despite these various treatment approaches, the desired reduction in symptom severity is not always achieved, and, therefore, other treatment options must be considered (Abudy et al. 2011; Arumugham and Reddy 2013).

N-acetylcysteine (NAC) is an antioxidant molecule that modulates glutamate (glu) transmission in the brain (Berk et al. 2013). Recent reports have indicated the importance of glutamatergic dysfunction in OCD pathophysiology and the influence of glutamatergic agents in OCD (Chakrabarty et al. 2005; Pittenger et al. 2011; Kariuki-Nyuthe et al. 2014), which has led to the increased use of NAC for the treatment of OCD (Lafleur et al. 2006; Afshar et al. 2012; Van Ameringen et al. 2013). Herein, we discuss the use of NAC to treat a 15-year-old girl with treatment-resistant OCD.

Case Report

A 15-year-old female patient was brought to our clinic by her mother, who indicated that the girl had the following complaints: Fear of becoming ill, anxiety about becoming infected from touching strangers, frequent hand washing, staying in the bathroom for extended periods, checking and rechecking homework and school bags before going to school, and returning to check the door just after leaving the house. Based on the history reported by her and her mother, the patient's obsessive tendencies began ∼3 years ago, and she was diagnosed with OCD at that time by another child psychiatrist in a different center. First, she underwent CBT for 1 month, but had no reduction in her complaints. Therefore, in addition to the CBT, she was started on sertraline therapy, which was increased until the dose reached 150 mg/day. However, she reported that her obsessive thoughts and behaviors continued without any decrease, and over the next 2 years, she was treated with fluoxetine (40 mg/day), citalopram (60 mg/day), fluvoxamine (200 mg/day), clomipramine (150 mg/day), risperidone (3 mg/day) and aripiprazole (15 mg/day) for at least 16 weeks, either individually or combined. After a period of time, she refused to visit the doctor because she was not benefiting from the medication. She reported a minor reduction in her complaints while using citalopram alone, and, therefore, made her own decision to use only citalopram. However, she decided to seek medical treatment at our clinic as a result of family pressure, additional complaints of moodiness and unhappiness, and continued obsessive thoughts and behaviors, which were still severe. She had been using 60 mg/day of citalopram for ∼ 4 months when she came to our clinic. Her history had no indications of any mental or motor development problems. Her family history revealed that her aunt had received treatment for 10 years for OCD. Our psychological assessment revealed that the patient had contamination and pathological doubt obsessions, and checking/rechecking and frequent hand washing compulsions, but no depressive symptoms. Based on her symptoms, she was diagnosed with OCD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-V) (American Psychiatric Association 2013). The Yale Brown Obsessive Compulsive Scale (YBOCS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Clinical Global Impressions-Severity Scale (CGI-S) and Clinical Global Impressions-Improvement Scale (CGI-I) were used in evaluation and clinical follow-up. As she did not benefit from any of her former medications, NAC 600 mg/day treatment was initiated, and she continued treatment with 60 mg/day citalopram. The NAC dose was increased to 2400 mg/day at the end of 6 weeks, with the dose increasing every 2 weeks. The aforementioned assessments were performed at 4 week intervals during clinical follow-up. After the dose of NAC was increased to 2400 mg/day, there was a significant improvement in the patient's complaints, and the dose was kept at 2400 mg/day. Significant improvements in obsession and compulsion were observed at the end of the 24 week follow-up. The patient's clinical rating scale scores at 4 week intervals are shown in Table 1.

Discussion

In DSM-V, OCD is classified in the group of “Obsessive Compulsive and Related Disorders,” which also includes trichotillomania, skin picking disorder, body dysmorphic disorder, and hoarding disorder. The standard neurobiological model of OCD is especially focused on the cortico-striato-thalamic-cortical pathway, and most of the OCD-related research has been related to the serotonergic and dopaminergic systems (Maia et al. 2008; Kariuki-Nyuthe et al. 2014). However, evidence-based pharmacological studies have indicated that serotonergic and dopaminergic agents are not always efficacious in OCD (Pittenger et al. 2011; Kariuki-Nyuthe et al. 2014). Between 40% and 60% of OCD patients do not respond to SSRI treatment (Pallanti et al. 2002), and, therefore, they often undergo augmentation treatment with clomipramine and/or typical/atypical antipsychotic agents (American Academy of Child and Adolescent Psychiatry 2012; Arumugham and Reddy 2013). In recent years, glutamatergic agents have been increasingly used in the treatment of OCD and disorders within the OCD spectrum (Lafleur et al. 2006; Grant et al. 2007; Odlaug and Grant 2007; Hezel et al. 2009; Abudy et al. 2011; Arumugham and Reddy 2013). NAC is an antioxidant molecule that modulates glu transmission in the brain. It is particularly effective in the nucleus accumbens. NAC acts as a substrate of the glu/cystine antiporter, which is located on glial cells. This antiporter works bidirectionally with the effects of NAC, and plays a role in the regulation of glu levels. When NAC is ingested, cysteine oxidizes into cystine. When cystine enters glial cells, glu exits the cells via the glu/cystine antiporter, causing the glu concentration to increase in the extracellular space. This stimulates the metabotropic glutamate receptors (mGluR2/3) located in the presynaptic neuron plasma membrane. mGluR2/3 receptors are autoreceptors. When they are stimulated, the glu concentration in the synaptic space is reduced. The glu modulation in the nucleus accumbens caused by NAC is reported to be effective for reward-seeking repetitive behaviors (Xi et al. 2002; Odlaug and Grant 2007; Berk et al. 2013). Preclinical studies also have shown that the regulation of the extracellular glu concentration in the nucleus accumbens prevents craving and compulsive behaviors (Baker et al. 2003).

In the literature, there are one double-blind randomized placebo-controlled trial (RCT) and two case reports regarding the use of NAC in the treatment of OCD. These studies were conducted with adult patients, and we could not find any reports discussing this issue in children and adolescents. The YBOCS scores of the patients who underwent NAC augmentation were significantly improved in the above-referenced RCT, in which 48 adult patients with OCD who did not respond to SSGI treatment were given NAC augmentation over 12 weeks (Afshar et al. 2012). In addition, one case report indicated that NAC treatment in combination with fluvoxamine was effective a patient with OCD (Lafleur et al. 2006). On the other hand, a recent case series indicated that NAC augmentation in resistant OCD patients did not have any significant effects. In this study, six resistant OCD patients were given NAC augmentation for 6–12 weeks. Although one patient improved at the end of the study, further aggravation of symptoms was observed in two patients (Van Ameringen et al. 2013).

The patient in this case report was diagnosed with treatment-resistant OCD. When she applied to our clinic, she was using citalopram (60 mg/day). In addition to her existing treatment, we initiated NAC treatment (600–2400 mg). Pallanti and Quercioli defined seven stages in the response to treatment in OCD. According to this often-used scale, a decrease>35% in the YBOCS scores and a score of 1 or 2 in the CGI-S is considered a “full response” (Pallanti and Quercioli 2006). Based on the YBOCS scores of our patient, there was a partial response in the 8th week and a full response in the 12th week of NAC augmentation (Table 1). During the 24 week clinical follow-up process, the patient's YBOCS scores improved, relapses were not observed, and there were no side effects related to NAC. It is remarkable that there are a limited number of studies regarding NAC augmentation in treatment-resistant OCD. The existing studies include only adult patients, and their results are conflicting. Our findings are consistent with the studies reporting that NAC augmentation in resistant OCD improves patient symptoms (Lafleur et al. 2006; Afshar et al. 2012). To our knowledge, ours is the first case report in the literature reporting a significant clinical response to NAC augmentation in treatment-resistant OCD in children and adolescents. In addition, childhood-onset OCD is associated with more severe symptoms and worse prognosis (Taylor 2011). The results of this case report indicate that there should be further randomized, controlled studies with larger sample sizes on the treatment of early-onset OCD patients.