Pharmacological treatment of obsessive-compulsive disorder in children and adolescents: An overview

Abstract

Pediatric obsessive-compulsive disorder (OCD) affects 1%-3% of children and adolescents. It is characterized by obsessions, and compulsions and is associated with significant distress and interference with functioning. The first line treatment for pediatric OCD is cognitive-behavioral therapy, specifically exposure response prevention. In situations where there are challenges to meaningful engagement in therapy, accessing therapy or when the illness is severe, pharmacological interventions can be a useful adjunct to treatment. Selective serotonin reuptake inhibitors are established as the initial pharmacological approach. Clomipramine is also an effective medication option, but its use is limited by tolerability concerns. However, a subset of patients does not respond to these first-line interventions of cognitive-behavioral therapy and serotoninergic medication. In these treatment-resistant patients, antipsychotic augmentation can be helpful as the next pharmacological option but should be used cautiously due to potential for side effects. Glutamate modulating agents are an emerging medication class as augmenting options. Newer treatments for pediatric OCD that are effective, safe, and well-tolerated are needed. This comprehensive review outlines the approach to pharmacological treatment of pediatric OCD and the evidence supporting their use.

Key Words: Obsessive-compulsive disorder; Psychopharmacology; Selective serotonin reuptake inhibitors; Antipsychotics; Glutamate modulators; Pediatric

Core Tip: Pediatric obsessive-compulsive disorder is a common and impairing condition associated with significant distress. First-line treatment is cognitive-behavioral therapy with exposure/response prevention. For moderate-to-severe cases or when therapy is inaccessible, pharmacotherapy is used adjunctively. Selective serotonin reuptake inhibitors are the initial drugs of choice, with clomipramine as an effective but less tolerated alternative. For treatment-resistant cases, antipsychotic augmentation is a next-step option, though used cautiously due to side effects. Glutamate modulators represent an emerging augmenting strategy. This review outlines the current pharmacological approach, highlighting the ongoing need for newer, effective, and well-tolerated treatments.

INTRODUCTION

Pediatric obsessive-compulsive disorder (OCD) is a common mental health condition that affects approximately 1%-3% of children and adolescents worldwide[1-3]. It is characterized by the presence of obsessions, compulsions or both. Obsessions are described as recurrent, intrusive, unwanted thoughts, urges or images that are usually associated with marked anxiety. Compulsions are repetitive behaviors or mental acts that an individual feels driven to perform in response to obsessions or in keeping with rules that must be applied rigidly with the goal of reducing anxious distress[4]. OCD is associated with marked personal distress and typically interferes with functioning across one or more domains. Pediatric OCD is viewed as the developmental subtype of OCD and is associated with the concern of interrupting the normal developmental trajectory[5]. Cognitive-behavioral therapy (CBT) has been seen to be consistently effective in the treatment of pediatric OCD[6,7]. Medication is a valuable adjunctive treatment option for OCD in children and adolescents for severe cases or for those who have a partial response with CBT. This minireview provides an evidence-based overview of the current state of psychopharmacology for pediatric OCD.

TREATMENT APPROACHES FOR PEDIATRIC OCD

Standard treatment for OCD in children and adolescents starts with CBT and may include the use of serotonergic medication, where indicated. CBT is the first-line treatment for OCD in children and adolescents[8]. The specific form of CBT indicated for OCD is termed exposure and response prevention (ERP), which involves systematic exposure to anxiety-provoking stimuli and the prevention of compulsive responses. The goal is a gradual attenuation of the anxiety response over repeated exposures. CBT can be delivered in individual or group formats. Family involvement is integral to the conduct of ERP in pediatric OCD. CBT for OCD in children and adolescents has demonstrated robust efficacy, with remission rates consistently exceeding those of placebo. These rates are comparable to or even superior to treatment with Selective serotonin reuptake inhibitors (SSRIs)[6,7].

INDICATIONS FOR THE USE OF PHARMACOLOGICAL INTERVENTIONS FOR OCD IN CHILDREN AND ADOLESCENTS

CBT is favored as the initial treatment modality in the pediatric population, especially when presenting with a mild or moderate illness severity. However it may be justified to consider initiation of medication in combination with or preceding therapy in the following circumstances[8]: (1) Moderate to severe presentations that often significantly impede functioning or is a source of significant personal distress or poor insight into the clinical severity or the need for treatment; (2) Comorbid psychiatric conditions like severe mood or anxiety disorders, or disruptive behavior disorders such as attention deficit hyperactivity disorder, can hinder engagement in ERP by affecting motivation and focus; (3) An unwillingness to participate in CBT regardless of whether this stems from a concomitant mental disorder; and (4) Limited access to therapists or long waits to establish care with qualified therapists.

One or more of these factors are commonly observed in real-world contexts and may justify early pharmacological intervention to facilitate more effective engagement in CBT.

PHARMACOLOGICAL INTERVENTIONS FOR PEDIATRIC OCD

Medications approved by the United States Food and Drug Administration (FDA) for treating pediatric OCD include serotonin uptake inhibitors such as clomipramine and SSRIs.

Clomipramine

Clomipramine is classified as a tricyclic antidepressant and was the first medication approved by the FDA for treating pediatric OCD in individuals aged ten years and older. Although it is part of the tricyclic antidepressant class, its therapeutic efficacy in OCD is primarily attributed to its inhibition of serotonin reuptake, which also underpins its association with other serotonin reuptake inhibitors. The recommended dosage range for children and adolescents is 25-150 mg[8].

Although clomipramine has demonstrated efficacy as a treatment option for OCD, its use, especially in young people, is limited by tolerability concerns and the requirement for regular laboratory monitoring. Similar to other tricyclic antidepressants, clomipramine has numerous receptor actions, including the adrenergic, histaminergic and cholinergic systems. These actions increase the risk of various adverse effects such as sedation, dizziness, postural hypotension, increased appetite, dry mouth, blurred vision, and weight gain. More severe adverse effects can include prolonged corrected QT interval, which raises the risk of arrhythmias, a lowered seizure threshold, and an increased risk of overdose, potentially resulting in fatality. These potential side effects require close monitoring, including electrocardiogram and plasma drug levels, particularly at higher doses, contributing to decreased usage, especially among pediatric patients[9,10].

SSRIs

SSRIs are regarded as the first line pharmacological option for OCD, especially in pediatric patients, due to their strong safety and tolerability profiles. The United States FDA has approved sertraline, fluoxetine, and fluvoxamine for treating pediatric OCD in children aged six, seven, and eight years or older, respectively; their effectiveness is supported by randomized controlled trials[11-13]. Currently, there is no definitive evidence that one SSRI outperforms another, so choices should be guided by factors like a patient’s prior response, family treatment history, drug half-life, and parental input[14,15].

For pediatric OCD, the recommended FDA dosing ranges are: Fluoxetine: 20-60 mg; fluvoxamine: 100-300 mg; sertraline: 100-200 mg. Though adult research suggests that higher dosages might offer added benefits, similar studies are absent for younger populations. There is also limited support for using higher SSRI doses in children and adolescents. Concerns about negative side effects, including behavioral activation, mania, and suicidal thoughts highlight the importance of starting at the lowest effective dose and gradually increasing it every two to three weeks until reaching the maximum tolerated dose[8].

When initiating medication therapy, it is important to discuss safety and tolerability with families. Information should be provided regarding potential SSRI side effects, such as gastrointestinal symptoms (including nausea, abdominal pain, and diarrhea), sleep disturbances, headache, weight changes, and sexual side effects[16,17]. Additionally, discussions should address adverse effects that may be particularly relevant for children and adolescents: (1) Behavioral activation: Restlessness and disinhibition have been reported in 10%-50% of pediatric patients and may result in discontinuation of treatment[18]. Younger children and rapid dose increases are associated with greater risk. Management typically involves reducing the dose[19,20]; (2) FDA black box warning for suicidality: The United States FDA has issued a black box warning indicating an increased risk of suicidal thoughts when SSRIs are used in young people. While this may be a concern for parents, clinical trials in pediatric OCD have reported no suicides, and available data do not demonstrate a clear increase in risk of suicidal thinking from SSRIs in OCD[16,21]. The estimated benefit of treatment (number needed to treat = 6) is substantially higher than the estimated risk (number needed to harm = 200)[21]; and (3) Risk of manic switch: The risk of conversion to mania is higher in children aged 10-14 years, with rates up to 10%[22], and a family history of bipolar disorder further increases this risk.

A cautious dosing approach (“start low, go slow”) is recommended to maximize tolerability and minimize adverse effects. The recommendation is to continue pharmacological treatment for OCD for a minimum duration of ten to twelve weeks at either the maximal tolerated or recommended dose to determine effectiveness. Medication for OCD should be continued for at least ten to twelve weeks at the maximum recommended or tolerated dose to determine effectiveness. A minimum duration of six months, preferably extending to twelve months following symptom remission, is recommended. After this period, it is advisable to reassess risks and benefits before discontinuing treatment, engaging in detailed discussions with the child and their parents or guardians.

Table 1 provides a summary of studies, including meta-analyses[6,7,15,23-28], comparing first line treatments such as SSRIs, clomipramine, and combination therapy involving CBT and SSRIs.

Table 1 Evidence on effectiveness of first line treatment in pediatric obsessive-compulsive disorder.

Year	Ref./meta-analysis	Treatment(s) examined	Sample size	Key findings
2004	Pediatric OCD Treatment Study (POTS) Team[6]	CBT, sertraline, or both combined	112	Remission rates were highest for combination therapy (53.6%), followed by CBT (39.3%), sertraline (21.4%), and placebo (3.6%). Both combination and CBT outperformed sertraline and placebo
2015	McGuire et al[23]	CBT, SSRI	CBT: 507, SSRI: 789	CBT demonstrates a large effect size with a remission rate of 53%, while SSRIs show a moderate effect and a 24% remission rate. The NNT is 3 for CBT and 5 for SSRIs
2015	Ivarsson et al[24]	CBT, sertraline, or both combined	14 RCTs	SSRIs outperform placebo; CBT outperforms SSRIs; combining both adds little to CBT; adding CBT to SSRIs benefits non-responders
2016	Öst et al[25]	CBT, sertraline, or both combined	34 RCTs	CBT led to 53% remission, combination therapy 49%, SSRI 24%, and placebo 15%. Combining treatments was no more effective than CBT alone
2016	Varigonda et al[15]	SSRIs, clomipramine	801	The most significant effect is observed early in treatment; clomipramine is more effective than SSRIs
2020	Uhre et al[7]	CBT vs no intervention, CBT vs SSRIs	645 (CBT vs no intervention), 146 (CBT vs SSRIs)	CBT is more effective than no treatment and similar in efficacy to SSRIs
2023	Mendez et al[26]	CBT, SSRI, or both combined	1146	Both SSRI and SSRI + CBT outperform placebo; the combination shows higher scores than SSRI alone, but the difference is not statistically significant. Improvement depends on sample characteristics
2024	Steele et al[27]	ERP, SSRIs, clomipramine, or combining SSRI/clomipramine with ERP	71 RCTs	ERP demonstrates greater efficacy than SSRIs when used alone; combining ERP with SSRIs also produces better outcomes compared to SSRIs alone. Both SSRIs and clomipramine show effectiveness
2025	Cohen et al[28]	SSRIs vs placebo	614	SSRIs result in a modest CY-BOCS decrease (average 3 points) with a small effect size; higher initial severity reduces response

OCD: Obsessive compulsive disorder; CBT: Cognitive behavioral therapy; SSRI: Selective serotonin reuptake inhibitors; ERP: Exposure and response prevention; RCT: Randomized controlled trial; NNT: Number needed to treat; CY-BOCS: Children’s Yale-Brown Obsessive Compulsive Scale.

TREATMENT RESISTANCE IN OCD

Treatment resistant OCD is understood to reflect inadequate clinical improvement after at least eight to ten sessions of ERP and treatment with at least two serotonin reuptake inhibitors (SSRIs or clomipramine) at maximum recommended or maximum tolerated doses for a length of ten to twelve weeks at the minimum[8]. Assessment of treatment response is facilitated by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) and its updated version, the CY-BOCS-II. These instruments are widely recognized as standard clinician-administered measures for evaluating baseline OCD severity and monitoring changes during the course of treatment[29,30]. Per expert consensus, “response” is categorized as a ≥ 35% decrease in CY-BOCS severity scores and a Clinical Global Impression - Improvement score of one or two (much or very much improved) for at least one week. Remission is when OCD diagnostic criteria are no longer met or when a CY-BOCS score of ≤ 12 and a Clinical Global Impression - Improvement score of one or two for a minimum length of a week is noted[31].

Up to one-third of pediatric patients with OCD may demonstrate a pattern of treatment resistance[6]. Prior to considering the introduction of additional medication, it is imperative to evaluate the following pertinent aspects: (1) Dosage adequacy: It is essential to administer treatment at the highest tolerated dose to optimize therapeutic outcomes; (2) Adequate length of treatment: Ensuring that medication is continued for at least ten to twelve weeks and CBT for at least eight to ten weekly sessions is important; (3) Accuracy of the OCD diagnosis: Conditions such as tics, ruminations related to major depression, generalized anxiety disorder, early symptoms of psychosis, repetitive behaviors observed in autism spectrum disorder, and perfectionistic traits can resemble OCD in children and may not respond to typical OCD interventions. In such cases, treatment approaches should be selected based on the specific condition presenting with OCD-like symptoms[32]; (4) Comorbidity can influence treatment outcomes: In pediatric OCD, comorbid disorders commonly occur and require appropriate management to achieve effective symptom relief and functional improvement. Tic disorders are a recognized comorbidity, and research suggests there may be reduced effectiveness of SSRIs in treating OCD when tics are also present[33,34]. Approaches that specifically address tics, such as comprehensive behavioral intervention for tics, the use of alpha agonists (e.g., clonidine or guanfacine), or consideration of low-dose antipsychotic medication (e.g., aripiprazole or risperidone) may be relevant; (5) Insight and need for treatment: Limited insight can impede motivation to engage in treatment and predict poorer response to treatment[35,36]; (6) Presence of symptoms of hoarding: These symptoms have been linked to lower response rates to SSRI treatment in young people[37], indicating a need for targeted cognitive behavioral therapy strategies[38]; and (7) Family accommodations: Family accommodations frequently occur within families of children diagnosed with OCD, encompassing behaviors such as tolerating or facilitating the child’s rituals, providing reassurance, completing tasks for the child, or other actions aimed at alleviating distress. Although these responses are well-intentioned, they may unintentionally reinforce OCD symptoms and hinder normative patterns of coping and adaptation. Therefore, addressing family participation in treatment is an essential consideration[38,39].

AUGMENTATION STRATEGIES IN PEDIATRIC OCD

It is advisable to consider the addition of augmentation agents only after potential factors hindering treatment response have been thoroughly evaluated and optimally managed. The following pharmacological options are commonly utilized for augmentation.

Clomipramine

As previously mentioned, clomipramine was the initial medication approved for treating pediatric OCD, and existing evidence indicates that it may be more effective than SSRIs. Potential for side effects and the need for careful lab monitoring have remained the primary factors that have limited the use of clomipramine in children and adolescents. However, if treatment with up to two SSRIs proves insufficiently effective, it may be appropriate to consider the use of clomipramine. When combining with SSRIs, a specific advantage has been noted by using clomipramine together with fluvoxamine. Fluvoxamine inhibits cytochrome P450 (CYP) 2C19, CYP1A2 and CYP2D6. As a result, it blocks the enzymatic conversion of clomipramine to desmethylclomipramine, which is associated with greater adrenergic receptor action. By favoring clomipramine over desmethylclomipramine, it facilitates the therapeutic serotonergic effects while limiting the risk of arrhythmogenic activity from adrenergic receptor action. There is data that supports the tolerability advantage of this combination although these studies do not comment on effectiveness[40,41]. Concerns arise when fluoxetine or sertraline are combined with clomipramine because these drugs inhibit CYP2D6. This inhibition can reduce the breakdown of desmethylclomipramine, leading to higher blood levels and an increased risk of cardiac rhythm disturbances.

Antipsychotics

Antipsychotics have been seen to be effective options for augmenting SSRI responses in OCD. They also aid the treatment of comorbid disorders, including tic disorders, mood disorders and disruptive behavior disorders. Their use continues to be off-label for pediatric OCD. Haloperidol, Aripiprazole and Risperidone have been seen to be beneficial in adults with OCD. However, olanzapine, quetiapine and paliperidone did not outperform placebo[42]. Such controlled data is lacking in the pediatric population. Available pediatric data from naturalistic studies examines the use of aripiprazole and risperidone and is given in Table 2[43-45]. Despite effectiveness, concerns related to metabolic side effects, weight gain and potential for movement disorders call for judicious use of these medications, especially in youth.

Table 2 Studies examining the use of antipsychotics in resistant obsessive-compulsive disorder.

Ref.	Study design	Sample size	Population	Medication (dose)	Response	Side effects
Masi et al[43]	Open label	39	Adolescents with SSRI-resistant OCD	Aripiprazole (12.2 ± 3.4 mg)	59.5% responded	Mild agitation and sleep disturbances (approximately of 10% of cohort)
Masi et al[44]	Open label	69	Children with tic-related OCD	Risperidone (1.7 ± 0.8 mg) or aripiprazole (8.9 ± 3.1 mg)	56.5% responded	Risperidone: Weight gain, sedation. Aripiprazole: Mild to moderate agitation
Akyol Ardic et al[45]	Retrospective chart review	48	Children and adolescents with treatment resistant OCD	Aripiprazole (3.4 ± 2.2 mg)	Significant improvement in YBOCS/CGI scores	Statistically significant weight gain

SSRI: Selective serotonin reuptake inhibitors; OCD: Obsessive compulsive disorder; YBOCS: Yale-Brown Obsessive Compulsive Scale; CGI: Clinical Global Impression.

Glutamate modulators

Neuroimaging and genetic studies have implicated the involvement of the glutamate system in addition to the serotoninergic and dopaminergic pathways in OCD[46]. The glutamate modulating medication listed below have been evaluated for their role in pediatric OCD.

Memantine: A small randomized controlled trial examined memantine and placebo in 7 children with autism spectrum disorder and/or OCD and reported a promising decrease in the Clinical Global Impression score and Yale-Brown Obsessive Compulsive Scale score in the memantine group[47]. Case reports have described benefits from memantine in the treatment of pediatric OCD[48,49].

Riluzole: A randomized placebo-controlled trial that recruited 60 children with OCD did not differentiate adjunctive riluzole from placebo. There was no statistically significant difference in the rate of side effects between groups. However, five patients discontinued riluzole treatment due to asymptomatic elevation in hepatic transaminase levels, and one patient developed pancreatitis while also receiving multiple medications[46].

D-cycloserine: D-cycloserine (DCS) is a partial agonist at the N-methyl-d-aspartate receptor. Augmenting CBT with DCS is believed to support the extinction of learned fear. Even though a small randomized controlled trial favored DCS augmentation, a larger randomized controlled trial conducted subsequently involving 142 youth did not establish superiority of CBT augmented with DCS over CBT alone[50,51]. Variability has been observed with other trials that have evaluated DCS augmentation of CBT[52,53]. Current evidence does not support DCS augmentation of CBT.

N-acetyl cysteine: N-acetyl Cysteine (NAC) is proposed to reduce oxidative stress through modulation of glutamate[54]. A smaller, underpowered randomized controlled trial that included 11 children and adolescents revealed superiority of NAC (up to doses of 2700 mg/day) over placebo[55]. This was similarly established in another larger trial that included 34 children, adolescents and young adults wherein NAC was used at doses between 1200 mg/day to 2400 mg/day[56]. The most frequently observed side effects of NAC were tremors, dizziness, insomnia, fatigue, and blurred vision. The incidence of these side effects in the NAC group was comparable to that seen in the placebo group.

Other medication

Lamotrigine[57], vortioxetine[58], sumatriptan[59], stimulants[60,61] and benzodiazepines[62,63] are other medications whose utility as augmenting agents in pediatric OCD has been suggested by case studies. However, in the absence of controlled trials, their effectiveness and safety cannot be supported for pediatric OCD treatment.

CONCLUSION

For pediatric OCD, CBT is generally considered the initial treatment approach, while psychopharmacology may be utilized if therapy alone does not sufficiently reduce symptoms or when severe impairment is present. SSRIs are commonly prescribed due to established efficacy and tolerability profiles. In cases where response is partial or absent, Clomipramine or antipsychotic medications may be added for augmentation. Research is ongoing regarding potential treatments involving glutaminergic agents and neuromodulators.