Successful Early Lamotrigine and Aripiprazole Augmentation of Clomipramine in Severe Obsessive-compulsive Disorder

Abstract

Lamotrigine and aripiprazole have shown efficacy as augmentation agents of serotonin reuptake inhibitors for treatment-resistant obsessive-compulsive disorder (OCD). To date, the efficacy of lamotrigine/aripiprazole augmentation has not been reported in OCD treatment. Herein, we report the case of a 37-year-old male with severe OCD and comorbid depression whose symptoms markedly improved after low-dose lamotrigine/aripiprazole augmentation to clomipramine. Our report suggests that early glutamatergic/antipsychotic augmentation contributes to rapid remission of OCD symp-toms.

INTRODUCTION

Serotonin reuptake inhibitors (SRIs), including clomipramine, and selective SRIs (SSRIs) used at high-dosages are effective in reducing the symptoms of obsessive-compulsive disorder (OCD) [1]. However, 40−60% of the patients with OCD did not achieve a full response after an adequate SRI monotherapy trial with a sufficient dose and duration [2]. As such, switching to another SRI or SRI augmentation treatment with drugs of different classes was required in these patients. Existing evidence suggests that atypical antipsychotics, particularly aripiprazole and risperidone, could augment the effects of SRIs in the treatment of OCD [3]. More recently, two randomized controlled trials (RCTs) reported that lamotrigine augmentation to SRIs improved significantly the outcome in patients with treatment-resistant OCD [4,5]. To date, the efficacy of lamotrigine/aripiprazole augmentation to SRIs has not been described in SRI resistant or severe OCD. Herein, we report a patient with OCD who benefited from the addition of low-dose lamotrigine/aripiprazole to clomipramine. Written informed consent was obtained from the patient for the publication of this report.

CASE

A 37-year-old married male presented with a depressed mood, diminished interest, decreased appetite, and significant weight loss in late February, 2020. After 3 months, he was diagnosed with major depressive disorder (MDD) and treated with a combination of escitalopram (10 mg/day), alprazolam (0.5 mg/day), tofisopam (100 mg/day), and diazepam (2 mg/day) at a psychiatric clinic. Despite continuous treatment for 16 weeks, his depressive symptoms remained unchanged, and contamination/doubting obsessions and cleaning/checking compulsions occurred abruptly in early October, 2020. Although the dose of escitalopram was raised to 20 mg/day and continued for 8 weeks, neither his MDD nor OCD symptoms were responsive to the medication. He was subsequently referred and admitted to the in-patient psychiatric ward at Chosun University hospital. Upon admission, he was found to have no family or personal history of psychiatric disorders, including alcohol use disorder and medical disorders, before his first depressive episode in 2020. He did not take other medications except psychiatric medi-cations. Laboratory tests and brain magnetic resonance imaging showed no abnormalities. Obsessive-compulsive and depressive symptoms were assessed using the Yale–Brown Obsessive-Compulsive Scale (Y-BOCS) and Beck Depression Inventory II (BDI-II) score. The Y-BOCS and BDI-II scores were 30 and 26, respectively. He was initially treated with clomipramine (25 mg/day titrated up to 150 mg/day) in combination with fluoxetine (20 mg/day titrated up to 60 mg/day) over 2 weeks for treatment of OCD with comorbid MDD. We tried implementing cognitive-behavioral intervention, such as exposure and response prevention, but he refused to partake. From the 7th day, quetiapine (25 mg/day) was added to clomipramine (75 mg/day) with fluoxetine (40 mg/day) to alleviate in-somnia. On the 18th day, his depressive symptoms significantly improved (BDI-II score: 16) though his obsessive-compulsive symptoms persisted without change. Therefore, the dosage of clomipramine was increased to 200 mg/day over 3 days. Twenty-one days after admission, the patient experienced a single generalized tonic-clonic seizure. Physical examination and further investigations, including brain computed tomography and electroencephalography, were all normal. The most likely cause of seizure was thought to be a high plasma clomipramine level resulting from fluoxetine-induced metabolism inhibition. Accordingly, the dosage of clomipramine was lowered to 150 mg/day, and fluoxetine was disconti-nued. Considering the seizure, lamotrigine was started at 12.5 mg/day, titrated up to 25 mg/day over 1 week, and then maintained with clomipramine (150 mg/day) and quetiapine (25 mg/day). After 2 weeks of lamotrigine add- on therapy, his OCD symptoms responded partially. This was supported by a reduction in Y-BOCS from 30 to 22. In addition, his core symptoms related to MDD had improved; however, he still complained of residual symptoms, including fatigue and moderate anxiety. Therefore, aripiprazole (5 mg/day) was added, and 5 days later he was discharged on an increased dose of aripiprazole (7 mg/day) with the triple regimen. Two weeks following discharge, he visited our hospital and reported a dramatic improvement in his OCD symptoms. Moreover, his residual MDD symptoms had also abated. His Y-BOCS score was 12, and a lowered dose of aripiprazole (5 mg/day) with the previous regimen was maintained. The patient continued taking the medication for 2 months without any adverse events and made a full recovery.

DISCUSSION

To the best of our knowledge, this is the first case report of lamotrigine/aripiprazole add-on to clomipramine for severe OCD with MDD treatment. Early low-dose lamotrigine/aripiprazole augmentation showed a remarkable antiobsessive efficacy, as demonstrated by a significant reduction in Y-BOCS scores over time (Table 1).

Table 1.

Change in scores of psychiatric symptom rating scales after admission

Symptoms	Admission	18th day	35th day (2 weeks after augmentation)	14th day after discharge
Y-BOCS	30	30	22	12
BDI-II	26	16	12	5

Y-BOCS, Yale-Brown Obsessive-Compulsive Scale; BDI-II, Beck Depression Inventory II.

Although hypotheses regarding the underlying pathophysiology of OCD are mainly based on the serotonergic system [6], about half of the patients with OCD do not respond to SRI monotherapy. Beyond the serotonergic hypothesis, glutamatergic and dopaminergic hypotheses have been proposed as underlying mechanisms of OCD [7,8]. Lamotrigine blocks voltage-dependent sodium channels and decreases synaptic glutamate and aspartate release [9]; thus, it has been considered as an augmenting agent in SRI refractory OCD, with growing evidence suggesting glutamatergic neurotransmission is dysregulated in OCD [8]. Unlike other atypical antipsychotics with dopamine D₂ receptor antagonism, aripiprazole acts as a partial agonist at D₂ and 5-HT_1A receptors and an antagonist at 5- HT_2A receptors [10]. This unique dopamine-serotonin system stabilizer action could account for the antiobsessional mechanism of aripiprazole, as complex interplay between dopaminergic and serotonergic systems appears import-ant in the pathophysiology and treatment of OCD [11]. In a recent network meta-analysis of augmenting agents to SRIs for treatment-resistant OCD, glutamatergic agents and atypical antipsychotic drugs were significantly superior to placebos, though there was no evidence suggesting significant differences between these agents [12]. These results support the idea that glutamatergic and dopami-nergic systems, as well as the serotonergic system, may play an important role in OCD treatment. Figure 1 shows the updated algorithm for pharmacotherapy of treatment- resistant OCD [3,13].

Fig. 1.

Algorithm for pharmacotherapy of OCD patients resistant to treatment with an SSRI.

In previous augmentation studies using lamotrigine or aripiprazole in treatment-resistant OCD, the target dosage of lamotrigine was 100 mg/day, and aripiprazole was titrated up to 10 or 15 mg/day [12]. Interestingly, in the present case, severe obsessive-compulsive symptoms improved dramatically following augmentation treatment with low-dose lamotrigine and subsequently aripiprazole. Although it is difficult to classify the patient as having treatment-resistant OCD, this case suggests that adding low-dose lamotrigine/aripiprazole to SRIs may have the desired synergistic antiobsessive effect in patients who are nonresponders to SRIs monotherapy. Evidence-based algorithms for OCD recommend that the highest-dose trial using SSRIs should be undertaken for at least 6 to 12 weeks before considering switching or augmentation [3]. Moreover, early augmentation or combination strategies may be required in clinical practice, particularly in severe cases. Our case suggests that early trial of glutamatergic/ antipsychotic augmentation to SRIs may be safe and contribute to rapid remission of severe OCD.

Clomipramine has been the most effective monotherapy for OCD in the past. The discovery that clomipramine was especially effective for patients with OCD was important in the development of the serotonergic hypothesis of OCD [14]. However, clomipramine is associated with anticholinergic and other serious adverse events, such as seizures. Hence, SSRIs are now chosen as first-line agents for OCD. Unfortunately, a substantial portion of patients with OCD do not show a response to initial SSRI treatment. Browne et al. [15] reported the successful combination of clomipramine-fluoxetine in four patients with severe OCD. Moreover, in a 12-week RCT [16], combination of clomipramine-fluoxetine was safe and effective for fluoxetine nonresponders. However, despite clinical benefits, clomipramine-fluoxetine may trigger adverse events through pharmacokinetic mechanisms [17]. Clomipramine is metabolized by cytochrome P450 (CYP) 3A4, CYP 2C19, and CYP 2D6 enzymes, which are inhibited by fluoxetine. Thus, the risk of adverse effects increases with increasing doses. Besides seizure [18], as in our case, the clomipramine-SSRI combination may cause QTc prolongation and myoclonic jerk [19,20]. Therefore, both drugs need to be prescribed in the lowest effective doses possible, and potential adverse events should be carefully moni-tored.

This report had several limitations. Firstly, it could not be ruled out that the observed antiobsessive effect may have been fully due to clomipramine, not the low-dose lamotrigine/aripiprazole add-on. This is due to the onset of the therapeutic effects of clomipramine being delayed in OCD. Secondly, although quetiapine was coadministered at a low-dose of 25 mg/day for the alleviation of insomnia, quetiapine may partly influence the antiobsessive efficacy. In a previous study, the efficacy of quetiapine as an augmentation agent in OCD was significantly superior to the placebo after baseline severity adjustment [12]. Thirdly, there is a possibility that augmentation treatment with lamotrigine without aripiprazole could show sufficient antiobsessional efficacy. In our case, low-dose aripiprazole was added to the prior regimen for treatment of residual MDD symptoms [21,22]. Fourthly, it cannot be ruled out that OCD symptoms may have improved after a seizure. Finally, we did not check the serum levels of clomipramine immediately following the patient’s seizure.

In conclusion, early low-dose lamotrigine/aripiprazole augmentation to clomipramine showed excellent therapeutic efficacy in the treatment of severe OCD, implying a synergistic effect that was safe, with no adverse events. However, further studies using a large sample are needed to confirm this synergistic effect. Moreover, the clomipramine-SSRI combination strategy should be cautiously implemented using lower doses and close monitoring for potential serious adverse events.

Funding Statement

Funding None.