Treatment of Pediatric Obsessive-Compulsive Disorder: A Review

Introduction

O bsessive-compulsive disorder (OCD) is now recognized as a relatively common disorder affecting children and adolescents and is expected to be among the ten leading causes of global disability by the World Health Organization (WHO) (World Health Organization 2005). In the last decade, our knowledge of pediatric OCD has increased with large family genetic studies, elaboration of phenotypic dimensions, description of co-morbid disorders and their moderating effects on treatment response and outcome, research on immune-based neuropsychiatric causes (pediatric neuropsychiatric disorders associated with Streptococcus [PANDAS]), publication of randomized controlled trials of selective serotonin reuptake inhibitors (SSRIs), as well as concern and scrutiny regarding safety of these SSRIs in children, the first large-scale randomized controlled trials of cognitive behavioral therapy (CBT) as single and multimodal treatment, new approaches in behavior therapy, and increased awareness of novel approaches to pharmacotherapy. This review of current treatment strategies aims to incorporate these new developments.

Epidemiology

The high prevalence of OCD in children was not generally recognized until the first epidemiological study just over 20 years ago (Flament et al. 1988). Epidemiological studies in the United States and elsewhere report prevalence rates of around 1–2% in the pediatric population. In an early epidemiological study (Flament et al. 1988), most adolescents identified with OCD had been neither diagnosed nor treated, suggesting that the disorder was under recognized and under treated, leading to the notion of pediatric OCD as a “hidden epidemic.” The more recent British Nationwide Survey of Child Mental Health (Heyman et al. 2003) reported similar findings. There appear to be two peaks of incidence for OCD across the life span, one occurring in preadolescent children (Geller et al. 1998b) and a later peak in early adult life (mean age 21 years) (Geller et al. 1998a).

Pathophysiology, Neurobiology, and Genetics

Several frontal cortico-striatal-thalamic circuits have been implicated in the pathophysiology of OCD, and several neurotransmitter systems modulate this feedback loop, including the excitatory amine glutamate as well as dopamine and serotonin-containing neurons (Rosenberg and Keshavan 1998). Pediatric imaging studies appear similar to those in adults, detecting structural abnormalities in the cingulate cortex, basal ganglia, and thalami of pediatric OCD patients (Rosenberg and Keshavan 1998; Gilbert et al. 2000). A handful of functional imaging studies conducted with children at rest and following treatment have yielded results compatible with those in adults. In a single-photon emission computerized tomography (SPECT) study of 13 adults with early-onset (<10 years) versus later-onset OCD and 22 healthy controls, early-onset cases showed decreased cerebral blood flow in the right thalamus, left anterior cingulate cortex, and bilateral inferior prefrontal cortex relative to late-onset subjects. In early-onset subjects only, severity of obsessive-compulsive (OC) symptoms correlated positively with left orbitofrontal regional cerebral blood flow (rCBF), suggesting that brain mechanisms in OCD may differ depending on the age at which symptoms are first expressed (Busatto et al. 2001).

The contribution of genetic factors to the development of OCD has been explored in twin, family genetic, and segregation analyses studies (Pauls et al. 1995; Nestadt et al. 2000; Grados et al. 2001; Reddy et al. 2001; Pato et al. 2002; Hanna et al. 2005). The concordance rates for monozygotic twins are significantly higher than for dizygotic twins (van Grootheest et al. 2005). While family studies consistently demonstrate that OCD is familial (Pato et al. 2002; Lenane et al. 1990; Leonard et al. 1992; Bellodi et al. 1992; Black et al. 1992; Pauls et al. 1995), the risk of OCD in first-degree relatives appears to be greater for index cases with a childhood onset. For example, in their multisite family study of OCD, Nestadt et al (2000) found a risk for OCD of around 12% in first-degree relatives, whereas relatives of pediatric OCD probands have shown age-corrected morbid risks from 24% to 26% in more recent studies (Hanna et al. 2005; Do Rosario-Campos et al. 2005). These findings suggest a greater genetic loading in pediatric onset OCD. A further substantial proportion of relatives (5–15%) are affected with subthreshold OC symptoms that may be genetic (Nestadt et al. 2000) but may also be relevant to family functioning. A genome-wide linkage scan for OCD showed evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q (Shugart et al. 2006). There is increasing evidence that glutamate receptor/modulating genes may be associated with OCD (Hanna et al. 2007).

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS)

No issue in OCD remains as controversial as the debate around PANDAS. Infection with group A β-hemolytic streptococcus (GABHS) has been regarded as a potential precipitant for sudden onset or exacerbation of OCD (Swedo et al. 1998). GABHS is potentially indicated in acute and dramatic onsets or exacerbations in preadolescent patients or when a child in remission suddenly relapses. While anti-streptococcal antibodies such as anti-streptolysin O (ASO) and anti-DNase B are present in most children by early adolescence, a 0.2 log rise in titers is considered evidence of a recent infection. Antibiotic treatment should be initiated if signs and symptoms of pharyngitis and a positive GABHS culture are present. Antibiotic prophylaxis, intravenous immune globulin (IVIG), and plasma exchange are novel and experimental treatments for putative PANDAS cases of OCD. Diagnostic criteria laid out by Swedo et al. (1997) have been used in a variety of studies of antibiotic prophylaxis (Garvey et al. 1999; Snider et al. 2005) and immune-modulating therapies, but detractors argue that GABHS is but one of many nonspecific physiological stressors that can trigger an increase in tics or OCD (Kurlan and Kaplan 2004). Even when PANDAS is suspected as an etiology, data are insufficient to meet minimal standards to recommend routine antibiotic prophylaxis for children with OCD. Instead, standard treatments for both OCD and streptococcal infections are recommended.

Clinical Presentation

Despite overall similarities, there may be some differences in the phenotypic expression of OCD across the life cycle. In an examination of this subject (Geller et al. 2001a), several differences between children, adolescents, and adults were noted in the frequency of particular obsessions and compulsions. Children with OCD may display compulsions without well-defined obsessions, and rituals other than typical washing or checking (e.g., blinking and breathing rituals) (Rettew et al. 1992). Contamination, sexual, somatic obsessions and excessive scruples/guilt are the most commonly reported obsessions and washing, repeating, checking, and ordering are the most commonly reported compulsions (Geller et al. 2001a). Children and adolescents had high rates of aggressive/harm obsessions (including fears of catastrophic events, such as death or illness in self or loved ones). OCD symptoms tend to wax and wane and are persistent in the majority of patients, changing over time so that the presenting symptom constellation is not maintained (Rettew et al. 1992).

In a review of 11 reported clinical series comprising 419 juvenile OCD patients, age at onset ranged from 7.5 to 12.5 years (mean 10.3 years) while mean age at assessment was 13 years, indicating a delay of several years between onset and ascertainment. By contrast, the mean age at OCD onset in adult studies was 21 years, suggesting a bimodal distribution of incidence for this disorder. Most pediatric studies show a male predominance with a 3:2 male:female ratio. In contrast, there is a slight female preponderance in adult OCD subjects (Karno et al. 1988; Black 1974).

Assessment

OCD is characterized by the presence of either obsessions (“worries”) or compulsions (“rituals”). Although OCD is categorized among the anxiety disorders in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) (American Psychiatric Association 2000), especially in younger children, a variety of hidden or poorly articulated affects may drive the symptoms. The simplest probes derive from the DSM-IV diagnostic criteria of the American Psychiatric Association (American Psychiatric Association 2000).

If screening questions suggest that OC symptoms are present, clinicians should follow with more in depth assessment using the DSM IV-TR criteria of: (1) Time occupied by OC symptoms, (2) level of subjective distress, and (3) functional impairment, as well as a standardized inventory of symptoms and scalar assessment of severity, subjective distress, impairment, resistance, control, and insight, such as the Children's Yale–Brown Obsessive-Compulsive Scale (CY-BOCS) (Scahill et al. 1997). The CY-BOCS remains the gold standard for both baseline assessment and for monitoring effects of treatment. Other validated OCD scales with acceptable psychometric properties include the children's Florida Obsessive-Compulsive Inventory (FOCI) (Storch et al. 2007a), the children's Obsessive-Compulsive Inventory (CHOCI) (Shafran et al. 2003), and the Obsessive-Compulsive Inventory–Child Version (OCI-CV) (Foa et al. 2010) and interviews that assess more broadly for internalizing symptoms (Ten Year Review of Rating Scales II: Scales for Internalizing Disorders) (Myers and Winters 2002) and anxiety, such as the Anxiety Disorders Interview Schedule for DSM-IV: Child version (ADIS-C) (Silverman and Albano 1996), Pediatric Anxiety Rating Scale (PARS) (The Research Units on Pediatric Psychopharmacology Anxiety Study Group 2002), Self-Report for Childhood Anxiety Related Disorders (SCARED) (Birmaher et al. 1997), and Multidimensional Anxiety Scale for Children (MASC) (March et al. 1997b), may also be helpful.

Outcome

The long-term prognosis for pediatric OCD is better than originally conceived. Many children will remit entirely or become clinically subthreshold over time (Stewart et al. 2004). Earlier age of OCD onset, increased duration of OCD, inpatient treatment, and, perhaps, specific symptom subtypes such as sexual, religious, or hoarding obsessions predict greater persistence. Co-morbid psychiatric illness and poor initial treatment response are adverse prognostic factors. In contrast, gender, age at assessment, and length of follow up are not reported as predictors of remission or persistence. Psychosocial function is frequently compromised. Studies report high levels of social/peer problems (55–100%), isolation, unemployment (45%), and difficulties sustaining a job (20%). However, at follow up, pediatric OCD subjects showed no difference from controls in educational achievement, with 30–70% having attended college (Stewart et al. 2004).

Treatment

Augmentation Strategies

Impediments to SSRI medication response include presence of co-morbid disorders, especially tic and disruptive behavior disorders (Geller et al. 2003a; Storch et al. 2008). Similar findings were reported for CBT response from a post hoc analysis of the POTS trial data (March et al. 2007). Medication augmentation strategies are reserved only for treatment-resistant cases. By expert consensus, the term “treatment resistant” applied to children with OCD indicates a child who has persistent and substantial OCD symptomatology in the face of adequate treatment known to be effective in childhood OCD. Persistent symptoms of at least moderate severity (e.g., CY-BOCS ≥16 or CGI-S of marked or severe impairment) are useful guidelines. At least two serotonin reuptake inhibitor (SRI) trials are necessary to declare adequate medication therapy. Therefore, failure of adequate trials of at least two SSRIs or one SSRI and a clomipramine trial as well as a failure of adequately delivered CBT would constitute treatment resistance. Children should have a minimum of 10 weeks of each SSRI or clomipramine at maximum recommended (or tolerated) doses, with no change in dose for the preceding 3 weeks. In terms of adequate CBT dose, if a child has not shown any improvement after eight to ten total sessions (or five to six sessions of exposure), or has substantial residual OC psychopathology after completing standard CBT treatment, he may be considered a CBT nonresponder. To summarize, failure of at least two monotherapies as well as combined treatment is required prior to labeling someone as treatment resistant.

Most children are not nonresponders, but rather, are partial responders. To meet the definition of partial response, children must have (1) had at least 3 weeks of stable and persistent moderate (or worse) OCD symptoms at an SSRI dose equal to the maximal dose or (2) shown a flat dose–response curve for one dose increment above the minimum expected starting dose, or (3) experienced adverse effects as a result of dosage increase. For patients with partial or no therapeutic response after several successive SSRI trials, augmentation strategies may be useful. A common approach in difficult-to-treat cases would be the combination of clomipramine (CMI) with a SSRI; several reports lend support to this practice (Simeon and Thatte 1990; Figueroa et al. 1998). The rationale is to combine serotonergic effects of each while minimizing adverse events across differing drug classes. Fluvoxamine is the SSRI with the most synergistic effect when added to clomipramine, given its ability to inhibit the conversion of clomipramine to desmethyl-clomipramine and increase the ratio in favor of the serotonergic parent compound. Even low-dose augmentation (25–75 mg/day) may be useful, but care must be taken when combining clomipramine with fluvoxamine (a CYP450 3A4 inhibitor) and with CYP450 2D6 inhibitors such as fluoxetine or paroxetine due to potentially toxic increases in serum CMI levels, which must be monitored along with electrocardiogram (EKG) indices.

Clonazepam was also shown to be helpful in adults (Hewlett 1993) and children (Leonard et al. 1994) with OCD, but sedation, as well as behavioral disinhibition in children in particular, may limit the use of clonazepam and lorazepam, which should be used with caution. By far, the commonest drug augmentation strategies have employed (atypical) neuroleptics. High-quality RCTs using atypicals have been done in adults with OCD and are summarized in a comprehensive meta-analysis by Bloch et al. (2006), who found a NNT of 4.5, with risperidone and haloperidol showing significant advantage over placebo and even better response for those with co-morbid tic disorder (NNT 2.3). Adverse events reported included sedation; NNH was 1.5–3) and weight gain (NNH not computed). This meta-analysis also suggested that at least 12 weeks of SSRI treatment was required before atypical augmentation was effective. Other authors have found less evidence for use of atypical antipsychotics in severe and treatment-resistant cases (Matsunaga et al. 2009; Kordon et al. 2008). Unfortunately no controlled data exist in children and only case reports and open trials are reported. However, expert consensus suggests that some children with treatment-resistant OCD may benefit from judicious neuroleptic augmentation, particularly children with tic disorders (McDougle et al. 2000), poor insight, pervasive developmental disorder symptoms, and mood instability. In adults, a personal or family history of chronic tic disorder was associated with a positive response to haloperidol augmentation to fluvoxamine (McDougle et al. 1994). Case reports also support this approach in children (Hawkridge et al. 1996).

Novel Treatments

Novel augmentation trials are also reported for stimulants, gabapentin, sumatriptan, pindolol, inositol, opiates, St. John's wort, and more recently, N-acetyl cysteine, and the glutamate antagonists memantine and riluzole, but none of these meet minimal evidence-based standards that permit recommendation for their routine use. Other approaches for treatment resistance in pediatric OCD that are not supported by randomized controlled evidence but derive from expert opinion include use of venlafaxine or duloxetine, which possess similar combined monoamine uptake inhibition properties to clomipramine but with less potential cardiovascular adverse effects.

Novel therapeutic approaches are derived from clinical, translational, and basic research. For example, approaches manipulating glutamatergic, γ-amino butyric acid (GABA)-ergic and peptide neurotransmitter pathways are underway and will likely be informed by genome-wide association studies. Real challenges remain in identifying environmental triggers (such as intrauterine, birth and postnatal experiences, and immune-mediated pathophysiology) in genetically susceptible individuals, as only prospective “at-risk” longer-term studies can hope to understand the complex gene–environment interactions that underlie most cases of OCD.

Focuses on association at common polymorphisms in several serotonin transmitter system genes have shifted to include interest in glutamatergic mechanisms and the glutamate transporter gene SLC1A1 (Arnold et al. 2006). Consistent with the hypothesis of glutamatergic dysregulation's role in the pathophysiology of OCD, N-acetyl cysteine (NAC) augmentation of SRI treatment resulted in decreased symptoms in a single OCD case (Lafleur et al. 2006). In addition, an open-label augmentation trial of riluzole, an antiglutamatergic agent, was effective and well tolerated in a small sample of children with residual OCD symptoms following standard SSRI treatment (Grant et al. 2007). Such findings require replication before they can be generalized and a double-blind, placebo-controlled study is currently underway at the National Institute of Mental Health (NIMH). In a single-blinded case–control study augmenting intensive residential treatment with memantine, also a glutamate receptor antagonist, responders showed clinically significant improvement. However, only 36% of case patients were found to be responders (Stewart et al. 2010), raising the possibility of a subtype of OCD for which this approach is beneficial. Further research is warranted to investigate the use of NAC and other glutamate-modulating agents. d-Cycloserine (DCS), a partial agonist of N-methyl-d-aspartic acid (NMDA), has been found to enhance extinction effects in combination with exposure-based behavior therapy (Wilhelm et al. 2008). A meta-analysis of DCS augmentation of CBT in adults suggests efficacy (Norberg et al. 2008). A pilot randomized controlled trial in children also showed promising results (Storch et al. 2010).

Information regarding augmentation of SRIs with stimulants is limited and has provided mixed results. While some suggest dextroamphetamine may be effective in reducing symptoms, case studies point to stimulant treatment leading to worsening of symptoms. A review of four cases showed Adderall^® as an effective augmentation to SRI treatment, but this finding may be confounded by co-morbid ADHD in three of the four patients (Owley et al. 2002). In a controlled trial of d-amphetamine augmentation treatment in adult patients with treatment resistant OCD, half of the patients assigned to d-amphetamine showed immediate reduction in symptom severity, while just over half of those assigned to caffeine responded. This finding of equivalent efficacy of caffeine and d-amphetamine could suggest that neither produced an effective pharmacological effect because a placebo effect could not be ruled out as the cause of improvement (Koran et al. 2009).

Opiate drugs for treatment-refractory OCD have recently been explored. One study found evidence to support the convergent effects of the 5-hydroxytryptamine (5-HT) and opiate systems in brain areas (Rojas-Corrales et al. 2007). Opiates reduced both 5-HTP and 2,5-dimethoxy-4-iodophenyl-induced head twitches and showed no sedative effects at the doses used. In adults, morphine was shown to be effective and well tolerated in a treatment-refractory OCD population, but given abuse potential, such approaches are unlikely to be useful in children (Koran et al. 2005). Overall atypical opiates may offer the potential for therapeutic advances in stereotypies and compulsive symptoms (Rojas-Corrales et al. 2007).

Based on findings of the role of orbitofrontal cortex in OCD from functional imaging studies, repetitive transcranial magnetic stimulation (rTMS) is currently being explored as a noninvasive and safe treatment approach. Although TMS treatment of OCD has not been studied extensively, or focused on a specific brain region, one study found that magnetic stimulation of the left oribtofrontal cortex showed short-term improvement of OC symptoms in adults, with symptom reduction lasting up to 10 weeks (Ruffini et al. 2009). Early augmentation trials show some promise but further controlled studies will be needed to determine efficacy of these treatments.

Conclusions

Effective treatments for pediatric OCD are well documented but frequently provide less than complete remission. Standard approaches call for CBT as initial treatment for mild-to-moderate cases and combined medication plus CBT for severe cases as the default treatment option. Novel approaches for implementation of CBT that take into account the child's family and social context are increasingly applied and successful. Augmentation strategies are less well documented in pediatric OCD cases than in adults and are fraught with more risk. Systematic research is needed to establish their role despite suggestions of positive effects from adult studies. Attention to novel approaches derived in part from translational research such as glutamate neurotransmission modulators, for example, use of d-cycloserine to enhance CBT effect and efficiency, are being investigated. As clinical and translational research intersect, new therapeutic approaches and strategies will be incorporated into treatment.