Abstract
To The Editor:
O
Selective serotonin reuptake inhibitors (SSRIs) are the first-line medications for OCD in children, adolescents, and adults, either alone or in combination with cognitive behavioral therapy (CBT) (Stein et al. 2012). Albeit their proven effectiveness, both these options often have inadequate results, with almost half of the patients not responding or having residual symptoms (Catapano et al. 2006; Abramowitz et al. 2009). In these cases, clinicians can chose either to switch to an alternative SSRI, bearing in mind that the possibility of response is less likely than expected in naïve patients (Ackerman et al. 1998), or follow an augmentation strategy by adding another agent (National Institute for Health and Clinical Excellence 2005; Stein et al. 2012). Agents that are commonly employed are clomipramine (CMI) (Stein et al. 2012) and the atypical antipsychotics (Bloch et al. 2006; Stein et al. 2012), but a multitude of other drugs have also been tried, such as stimulants, gabapentin, sumatriptan, pindolol, inositol, opiates, St. John's wort, N-acetyl cysteine, memantine, and riluzole, without conclusive evidence (Pittenger 2011, 2012).
Albeit the predominant role of the monoaminergic systems (mainly that of serotonin and, to a lesser extent, dopamine) in neurobiology, and hence in the treatment of OCD, preclinical and clinical data do implicate other neurotransmitters also. Recent evidence suggests that the excitatory neurotransmitter glutamate is dysregulated in OCD, and that this dysregulation may contribute to the pathophysiology of the disorder (Ting and Feng 2008; Pittenger et al. 2011; Wu et al. 2012). Lamotrigine is an antiepileptic drug and mood stabilizer that was proven to reduce excessive glutamate release (Burstein 1995; Reid et al. 2013). Therefore, it is a good candidate agent for augmentation in refractory cases of OCD. Apart from an initial negative case series study (Kumar and Khanna 2000), research data are quite encouraging for its use, with two positive case reports (Uzun 2010; Arrojo-Romero et al. 2013) of successful use in special populations (Bisol and Lara 2009; Poyurovsky et al. 2010), and one recent double-blind, randomized, placebo-controlled trial, also with positive results (Bruno et al. 2012).
Here, we report a case of pediatric OCD who showed a marked response to lamotrigine augmentation. The patient was treatment resistant and received multiple psychotropic trials over a course of >2 years, militating against the possibility of placebo response.
Case Report
History
A Kuwaiti male adolescent was referred to the outpatient clinic of the Child and Adolescent Psychiatric Department (Almanara Unit) of our hospital (Kuwait Center for Mental Health [KCMH]) in December 2012, at the age of 14, presenting with obsessive compulsive (OC) symptoms. He had had an uneventful perinatal history, and normal developmental trajectories, apart from a “ slow-to-warm up” temperament, as described by his parents. Until recently, he had been doing well at school. Medical history and physical examination were unremarkable, with no tics or illicit drug use, and his electroencephalogram (EEG) and MRI had no pathological findings. No neuropsychiatric disorders were reported in the family history.
His symptoms had started 1 year earlier, when he started to have ideas about cleanliness, compelling him to spend hours washing repeatedly. A couple of months later, he began to repeat his prayers because of uncertainty about proper ablution. He started being late to school on most days because he felt obliged to go through a certain lengthy regime of washing. Over the next few months, he was noticed to be too much preoccupied with his uncertainty about cleanliness, with mounting anxiety. He looked distressed most of the time, gave up most of the heretofore pleasurable hobbies that he used to pursue, lost much weight, had fragmented sleep, and felt totally drained and withdrawn.
Management
A few months after symptom onset, his parents sought psychiatric advice at an independent provider in the community (Fig. 1). Baseline laboratory investigations including thyroid function tests were within the normal range. A diagnosis of OCD with secondary depression was set. Fluoxetine 20 mg/day and clonazepam 1 mg/day were prescribed. Over 1 month, fluoxetine was escalated to 40 mg/day, with almost no response, as self-reported by the patient. His parents became concerned, as their son experienced bouts of agitation over these medications, “being not himself” as they described. The treating psychiatrist shifted him to fluvoxamine, rapidly titrated to 300 mg/day over another month, while clonazepam was increased to 2 mg/day. CBT was introduced, but the patient attended only four sessions, finding it ineffective. After 3 months, and because of inadequate response both subjectively and objectively, the treating clinician decided to augment treatment with 1 mg/day of risperidone. After 6 weeks, the combination chosen resulted in demoralizing the patient, who now started harboring passive death wishes, and he was referred to our outpatient clinic.
Case management and relevant responses.
At the initial evaluation in our hospital, the diagnosis of OCD with secondary depressive mood was endorsed, according to Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria (American Psychiatric Association 1994). In an attempt to quantify symptoms, the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) was administered, where the patient scored 28 over 40; that is, in the severe range. CMI was added to his previous regimen, titrated up to 100 mg over 1 month. The patient looked less distressed and had better sleep quality, although his ideas were still of incapacitating severity, and he complained of the sedative side effects of this combination, as well as of poor academic and social functioning. It was not clear if this was the result of a slight improvement, possible oversedation, or an affective block accompanied by losing insight into his ideas (Apter et al. 1996). Therefore, CMI and fluvoxamine were discontinued and the patient was shifted to sertraline 50 mg/day, titrated up to 200 mg/day over another month, with clonazepam and risperidone kept at previous dosing. Psychotherapy incorporating CBT techniques was reinstituted at KCMH, Almanara on a weekly basis. After 2 months, a minimal improvement was objectively reported by the parents, in terms of less time spent by the patient in the bathroom in comparison with previous months. Nevertheless, the readministration of CY-BOCS yielded yet again a severe score of 27, while the patient had a significant weight gain, and a threefold increase in serum prolactin level. Risperidone was discontinued and sertraline was increased up to 250 mg/day. Because of the prolonged unresolved symptoms, after 1 month and for the following 5 months, the parents sought psychiatric help at a hospital abroad. During the patient's hospitalization, and according to the parents and some truncated reports from the hospital, our regimen was kept, but combined in a sequential way with i.v. CMI, lithium up to 600 mg/day (with serum level of 0.6 mmol/L), and buspirone 45 mg/day with minimal results.
At his reevaluation at KCMH, Almanara, the patient's CY-BOCS score was still in the severe range. At this point, 25 mg/day of lamotrigine was added to the 250 mg/day of sertraline and the 2 mg/day of clonazepam, and it was escalated to 100 mg/day over 1 month, at the end of which the patient started to feel better for the first time. One month later, his CY-BOCS score decreased from 28 to 11 (mild range) and he was less distressed, more insightful in acknowledging the irrationality of his ideas, less involved in washing compulsions, back to school, and into socializing with his peers. He reported that, on a Likert scale, he rated his improvement as 9 out of 10. At his 6 month follow-up, the patient was still tangibly improved, reporting only some mild OC symptoms with limited impact on his life (CY-BOCS score: 11).
At his last follow up visit before this report, after 12 months, the patient continued to be in remission with a CY-BOCS score of 10, mainly reporting infrequent fleeting contamination obsessions that were brief, fuelled by stressful events, and readily dismissed at will. He exhibited adequate scholastic achievement as well as social capacity and he remained insightful, and made a request to stop medications. Compliance was generally ensured through his father's report, and treatment sheets showing prescriptions refilled on time, as well as by lamotrigine blood levels (4.8 μg/mL); for a brief period during summer holidays sertraline dose was dropped to 150mg/day.
Discussion
Although “resistance” in OCD has no consensus operational definition, our case definitely represents a clear case of resistance in clinical terms. Despite the use of four different SSRIs, two of which were of “adequate” dose and duration (Walsh and McDougle 2004), with augmentation strategies following with clonazepam (Leonard 1997) and risperidone (Bloch et al. 2006), as well as the parallel use of CBT (Simpson et al. 2008), the results were minimal. With the CY-BOCS remaining practically stable (Goodman 1999) and the impact of the disorder in the patient's own context of living still detrimental, the case could readily be categorised as refractory OCD (Pallanti and Quercioli 2006).
In such challenging cases, in which multiple pharmacological agents have failed to produce any positive effect, the off-label use of novel medications that hold promising theoretical potential is an appropriate clinical practice. Converging findings from neuroimaging, animal, and treatment studies, as well as genetics, indicate a glutamate signalling dysfunction in the cortico-striato-pallido-thalamo-cortical neurocircuity in OCD (Pittenger et al. 2011; Wu et al. 2012). A plethora of psychotropic drugs possessing antiglutamate actions have been employed with some tangible success in treatment-refractory OCD, such as riluzole (Coric et al. 2005; Grant et al. 2007), memantine (Haghighi et al. 2013), N-acetylcysteine (Lafleur et al. 2006), topiramate (Mowla et al. 2010), and lamotrigine (Bisol and Lara 2009; Poyurovsky et al. 2010; Uzun 2010; Bruno et al. 2012; Arrojo-Romero et al. 2013). Furthermore, Lamotrigine is also a weak 5-HT3 inhibitor (van der Loos et al. 2011). Because ondansetron, a potent 5HT3 inhibitor, has been successfully used as an augmentation strategy in refractory OCD (Pallanti et al. 2009; Soltani et al. 2010), we could assume that efficacy of lamotrigine in OCD might also be attributed, at least in part, to this contributory serotonergic mechanism (Serata et al. 2015) in addition to its glutamate modulating actions, although this has yet to be elucidated.
In addition to its theoretical potential, lamotrigine was also chosen as the augmentative strategy here for two reasons: 1) Its relative safety and tolerability (Seo et al. 2011) with the incidence of a serious rash diminishing substantially in cases with slow titration (Hurley 2002), as followed in this case; and 2) the lack of cognitive dysfunction associated with its use (Pressler et al. 2006), an important consideration in children and adolescents. Its addition had a quick and substantial positive effect on the illness course: CY-BOCS was reduced by 60% to 11 fulfilling the criteria of remission (Pallanti and Quercioli 2006), there was a significant improvement in patient's quality of life, and the patient himself reported major improvement. Moreover, this positive effect was sustained for >18 months. The few remaining symptoms were to be expected, as full recovery is a rare occurrence in nonepisodic OCD (Pallanti and Quercioli 2006).
Clinical Significance
To our knowledge, this case is the first reporting successful lamotrigine augmentation in refractory juvenile OCD. In line with the relevant adult literature (Uzun 2010; Bruno et al. 2012; Arrojo-Romero et al. 2013), it supports lamotrigine as a potential addition to our drug armamentarium in cases of clinically challenging OCD.
Footnotes
Disclosures
Dr Konstantinos Francis has received an honorarium from Eli-Lilly for delivering a talk, and for travel to a conference. The other authors have nothing to disclose.