Child & Adolescent Psychopharmacology News Volume 21

Number 1, 2016

Adelaide S. Robb, M.D., EDITOR

ContentS 1

Pediatric ObsessiveCompulsive Disorder: A Psychopharmacology Update

6

New Research • Tics Moderate Sertraline, but Not Cognitive-Behavior Therapy Response in Pediatric ObsessiveCompulsive Disorder Patients Who Do Not Respond to CognitiveBehavior Therapy

9

CME Post-Test

IMPORTANT NOTICE: This publication is intended to provide accurate and authoritative information regarding the subject matter covered. It is sold with the understanding that the publisher is not engaged in rendering medical, psychological, financial, legal, or other professional services.

cme Pediatric ObsessiveCompulsive Disorder: A Psychopharmacology Update

TEST ARTICLE

Marco A. Grados, M.D., M.P.H., Heirangi Torrico, Jennifer Frederick, and Thomas Riley Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by obsessions (recurrent and persistent thoughts, intrusive ideas, urges, or images) and/or compulsions (repetitive behaviors intended to reduce distress). Obsessions are thematically related to contamination, aggressive, religious, or sexual content, as well as reflect a need for symmetry or exactness. Compulsions include washing, checking, counting, repeating, ordering, and/or hoarding repetitively (American Psychiatric Association, 2014). A common characteristic is the inability to disengage behaviors from intrusive thoughts, thus interfering with the ability to control the behaviors with ensuing distress (Goodman, Grice, Lapidus & Coffey, 2014). Similar to other neuropsychiatric conditions, OCD arises during childhood and adolescence in the majority of instances, with prodromal early changes identified as “enhanced feelings of responsibility” and “being eager for order and cleanness,” among others (Juckel, Siebers, Kienast, & Mavrogiorgou, 2014).

The recommended doses of medications cited in this newsletter are not meant to serve as a guide for prescribing of medications. Physicians, please check the manufacturer’s product information sheet or the PHYSICIAN’S DESK REFERENCE for further information and contraindications.

Educational Objectives Upon completion of this activity, participants should be able to: • Evaluate treatment approaches to pediatric OCD. • Review traditional medications useful in treating pediatric OCD with comorbidity and for specific subtypes, such as tic-related OCD. Target Audience This CME activity is intended for child and adult psychiatrists, pediatricians and other healthcare professionals with an interest in the psychopharmacology and treatment practices for child and adolescent psychiatric disorders. Physician Accreditation This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint providership of Medical Education Resources and Guilford Publications. Medical Education Resources is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Medical Education Resources designates this enduring material for a maximum of 1 AMA PRA Category 1 creditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Release Date: 5/16 Expiration Date: 5/17 Estimated time to complete this activity: 1 hour Disclaimer The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Medical Education Resources or Guilford Publications. The authors have disclosed if any discussion of published and/or investigational uses of agents that are not indicated by the FDA in their presentations. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of MER or Guilford Publications. Before prescribing any medicine, primary references and full prescribing information should be consulted.

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Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management. Disclosure of Conflicts of Interest Medical Education Resources (MER) ensures balance, independence, objectivity and scientific rigor in all our educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, planners, managers and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure that all scientific research referred to, reported or used in a CME activity conforms to the generally accepted standards of experimental design, data collection and analysis. MER is committed to providing its learners with high quality CME activities that promote improvements or quality in healthcare and not the business interest of a commercial interest. The faculty reported the following financial relationships with commercial interests: Name of Faculty: Marco A. Grados, M.D., M.P.H., Heirangi Torrico, Jennifer Frederick, and Thomas Riley Reported Financial Relationship: Marco A. Grados, M.D., M.P.H., Heirangi Torrico, Jennifer Frederick, and Thomas Riley have no financial relationships to disclose. Name of Planner or Manager: Julie Johnson, PharmD. Reported Financial Relationship: No financial relationships to disclose. Name of Educational Partner Manager: Adelaide S. Robb, M.D. (Guilford) Reported Financial Relationship: Dr. Robb has disclosed that her research has been supported in part by the pharmaceutical industry. See page 2 for more information. Media Type: Newsletter This activity is jointly provided by Medical Education Resources and Guilford Publications.

Editorial Board Editor: Adelaide S. Robb, M.D. Children’s National Health System; George Washington University A ssociate Editor: Molly K. McVoy, M.D. Case Western Reserve University Cleveland, OH Research Editor: Jess Levy, M.D. University Hospitals, Case Medical Center Cleveland, OH Gabrielle Carlson, M.D. Stony Brook University School of Medicine Stony Brook, NY Normand Carrey, M.D. IWK Health Centre, Halifax, NS Laurence Greenhill, M.D. NYS Psychiatric Institute, New York, NY Sarah B. Johnson, M.D., MSc University of Louisville Bruce Meltzer, M.D. UMass Memorial Medical Center Westborough, MA Lukas Propper, M.D. IWK Health Centre, Halifax, NS Dara J. Sakolsky, M.D., Ph.D. University of Pittsburgh Medical Center Pittsburgh, PA Robert Stansbrey, M.D. University Hospitals of Cleveland Cleveland, OH Adelaide S. Robb, M.D., is on the Advisory Board or Speaker’s Bureau, has received Research Support from and/or is a shareholder with the following: Actavis/Allergan, Eli Lilly and Company, Forest Laboratories, Inc., GlaxoSmithKline, Janssen Pharmaceuticals, Inc., Lundbeck, Ironshore, Neuronetics, Pfizer Inc., Rhodes Pharmaceutical, Sunovion, SyneuRx, and Takeda. Child & Adolescent Psychopharmacology News (ISSN 10850295) is published six times per year (Feb [1], Apr [2], June [3], Aug [4], Oct [5], Dec [6]) by Guilford Publications, 370 Seventh Avenue, Suite 1200, New York, NY 10001-1020. SUBSCRIPTION PRICE: Volume 21, 2016 (six issues) Individuals $150.00 ($160.00, Canada and foreign) and Institutions, $417.00 ($432.00, Canada and foreign). Orders by MasterCard, VISA, or American Express can be placed by Phone at 800-3657006, Fax 212-966-6708, or E-mail [email protected]; in New York, 212-431-9800. Payment must be made in U.S. dollars through a U.S. bank. All prices quoted in U.S. dollars. Pro forma invoices issued upon request. Visit our website at www.guilford.com. Guilford’s GST registration number: 137401014. CHANGE OF ADDRESS: Please inform publisher at least six weeks prior to move. Enclose mailing label with change of address. Claims for lost issues cannot be honored four months after mailing date. Duplicate copies cannot be sent to replace issues not delivered because of failure to notify publisher of change of address. Postmaster: Send address changes to Child & Adolescent Psychopharmacology News, Guilford Press, 370 Seventh Avenue, Suite 1200, New York, NY 10001-1020. Photocopying of this newsletter is not permitted. Inquire for bulk rates. Printed in the United States of America. Copyright © 2016 Guilford Publications, Inc.

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Epidemiology OCD affects approximately 1% to 3% of the world population (Angst et al., 2004), with bimodal distribution peaks occurring during preadolescence and emerging adulthood (Geller et al., 1998). The prevalence rates among child and adolescent populations range from 0.5% to 2%; according to the British Child Mental Health Survey of over 10,000 5- to 15-year-old children and adolescents, pediatric OCD is often underdiagnosed (Heyman et al., 2003). Pathophysiology Convergent pathophysiological evidence in OCD implicates overactivity in the information-processing networks that connect prefrontal cortex to the basal ganglia, the cortico-subcortical-thalamo-cortical (CSTC) loops (Aouizerate et al., 2004). More specifically, orbitofrontal cortex overactivity is observed in neuroimaging studies of OCD (Kwon et al., 2003). Other key brain regions in OCD pathophysiology include the anterior cingulate cortex (ACC) (Diwadkar et al., 2015) and possibly the corpus callosum (Rosso et al., 2014). Animal models reinforce the notion that synaptic abnormalities due to genetic differences in individuals with OCD also play a key role (Monteiro & Feng, 2016). The general impact on brain function of the etiologic agents additionally predisposes subgroups of patients with OCD to deficits in executive functioning, visual memory, and shifting difficulties (Abramovitch, Mittelman, Tankersley, Abramowitz, & Schweiger, 2015). Clinical Presentation and Subtypes Pediatric OCD has a male-to-female ratio of 3:2, with a higher number of boys than girls at younger ages. Comorbidities occur commonly, with attention-deficit hyperactivity disorder (ADHD) and tic disorders being the most common, along with depressive episodes and anxiety disorders. Children with at least one comorbid diagnosis have lower treatment response and remission rates with cognitive behavior therapy (CBT) compared to children without a comorbid diagnosis (Storch et al., 2008). A developmental discontinuity exists between pediatric and adult OCD. Children may exhibit compulsions while lacking defined obsessions (Geller et al., 2001); in addition, over time the presenting symptom constellation may vary (Rettew, Swedo, Leonard, Lenane, & Rapoport, 1992). Subtypes of pediatric OCD include tic-related and early onset groups; however, treatment implications are still under investigation. An autoimmune subtype has been postulated, with evidence accumulating slowly for a more defined understanding of this putative group of children with OCD (Singer et al., 2015). Treatment Approaches Monitoring of Treatment Response The Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) is the instrument of choice to assess the severity of OCD and follow treatment response. The CY-BOCS is modeled after the adult Y-BOCS and classifies OCD symptoms in obsessional and compulsive categories (Scahill et al., 1997). The key symptoms are then assessed in toto for severity using five rubrics: time spent, distress caused, interference in daily activity, resistance to the symptom, and control over the symptom. These five categories are scored from 0–4 for obsessions and compulsions separately, yielding a total score maximum of 40 points. The threshold for clinical severity is set at 16 or over, with a 25%–35% change in CY-BOCS denoting response in many clinical trials.

Table 1. Selective Serotonin Reuptake-Inhibitors and Neuroleptics for Pediatric Obsessive-Compulsive Disorder: Dosing and Side Effects Medication

Dosage

Side Effects

Sertraline (Zoloft)

100–200 mg

Nausea, appetite loss, diarrhea, GI discomfort, insomnia

Fluoxetine (Prozac)

20–60 mg

Insomnia, diarrhea, dizziness, behavioral activation

Fluvoxamine (Luvox)

150–300 mg

Nausea, somnolence, feeling tired, indigestion, sweating

Citalopram (Celexa)

20–40 mg

Nausea, somnolence, weakness, dizziness, anxiety

Escitalopram (Lexapro)

20–40 mg

Nausea, somnolence, weakness, dizziness, anxiety

Clomipramine (Anafranil)

1–3 mg/kg

Drowsiness, dry mouth, GI discomfort, constipation, urinary retention

Haloperidol

0.5–2 mg

Drowsiness, dry mouth, sialorrhea, blurry vision, dystonia

Risperidone

0.5–2 mg

Drowsiness, dizziness, nausea, tachycardia, sialorrhea

Aripripazole

2.5–7.5 mg

Nausea, drowsiness, GI discomfort, headache, dizziness

Neuroleptics

Cognitive Behavior Therapy Cognitive behavior therapy (CBT) uses cognitive and behavioral interventions, designed to change mental frameworks that predispose to mental illness, and engages the patient in behavior strategies that are counter to the illness. Exposure response prevention (ERP) is a form of CBT, which uses exposure of the patient to a hierarchy of feared stimuli with the aim of desensitizing the patient to items that are OCD behavioral triggers. Seeking to tolerate the feared items, in CBT-ERP the patient is asked to refrain from responding compulsively to the stimuli (McKay et al., 2015). CBT-ERP is thus an empirically supported treatment for children and adolescents with OCD (Freeman et al., 2012; Torp et al., 2015). Moderators associated with higher CBT effects are concomitant anxiety disorders, more therapeutic contact, and lower treatment attrition (McGuire et al., 2015). In conclusion, CBT-ERP, alongside the use of medication (reviewed below), poses the most effective approach for the treatment of pediatric OCD (Franklin et al., 2015). Psychopharmacology SSRIs Selective serotonin reuptake-inhibitors (SS-

RIs) are the mainstay of the pharmacologic treatment of pediatric OCD due to their efficacy and low side effect profile. Multiple SSRIs have been used in pediatric populations for the treatment of OCD, including sertraline (Zoloft), fluoxetine (Prozac), fluvoxamine (Luvox), citalopram (Celexa), and escitalopram (Lexapro). There is no evidence base for the use of paroxetine (Paxil) in pediatric OCD. Sertraline was used in the Pediatric Obsessive-Compulsive Treatment Study (POTS), with good efficacy at earlier time intervals than previously noted with other SSRIs (POTS Team, 2004). Fluoxetine also benefits from positive results in a randomized clinical trial experience (Riddle et al., 1992), while fluvoxamine was equally efficacious in a randomized clinical

trial in children with OCD (Riddle et al., 2001). Less controlled data are available for citalopram (Celexa) and escitalopram (Lexapro) (Zohar, 2008), but they are, in practice, generally efficacious for pediatric OCD. As with adults, the dosage scheme for SSRIs in pediatric OCD calls for higher dosing and longer time response intervals. Sertraline, fluoxetine, and fluvoxamine are FDA– approved for use in pediatric OCD based on clinical trial data. The titration to maximum dosages includes up to 200 mg for sertraline, 60 mg for fluoxetine, and 300 mg for fluvoxamine. The time interval for efficacy determination, as in adults, is up to 4–6 weeks for a given drug and dosage. Individual titration, especially in adolescents or rapid-metabolizers, may occasionally require higher doses than those outlined above, with additional careful monitoring. The more common side effects of SSRIs are overall benign, including headaches and GI discomfort (Table 1). Less common, except in the context of rapid upward titration in susceptible individuals, is “behavioral activation” manifesting as restlessness, insomnia, and irritability. More concerning is the occurrence of a “manic switch,” which is fortunately uncommon in children with pediatric OCD, and can occur after several weeks of SSRI treatment. Finally, serotonin syndrome or serotonin toxicity, caused by a surge of serotonin due to SSRI overdosage or drug interactions, is characterized initially by tachycardia, sweating, pupillary dilation, myoclonus, and hyperreflexia. When severe, serotonin toxicity can result in seizures, hypertension, rhabdomyolysis, and shock. When SSRIs are not indicated or ineffective, the agent of choice is clomipramine (Anafranil), a tricyclic chlorinated analogue of imipramine. Clomipramine has strong serotonergic properties that were shown to be amply effective in adults (DeVeaugh-Geiss, Katz, Landau, Goodman, & Rasmussen, 1990) and in children (Gentile, 2011) with OCD. When used in children, dosing of clomipramine is guided by weight, with an optimal range of 3 mg/kg per day in single or divided doses. EKG baseline and periodic monitorCAPN 21(1) • 3

ing are also indicated for potential QTc changes. Clomipramine, the active compound, is metabolized to a partially active compound, desmethyl-clomipramine by cytrochrome p450 enzymes CYP3A4, CYP2C19, and CYP1A2 (BalantGorgia, Gex-Fabry, & Balant, 1991). Clomipramine blood levels are not predictive of response, but toxicity can be monitored, as well as the ratio of desmethyl-clomipramine to clomipramine. It should be noted that effective slowing down of the metabolism by competitive antagonism with low-dose fluvoxamine (25–50 mg) can increase the potency of clomipramine by increasing the active component of clomipramine, but careful monitoring is indicated with this approach (Andrade, 2013). Neuroleptics Neuroleptics can be used when single

medications (SSRIs) in the treatment of pediatric OCD result in a partial response. For example, even though the decrease in CY-BOCS scores can be substantial (25–35% or more), at times this reduction in symptom severity does not result in a fully functional state, with OCD continuing to be impairing (CY-BOCS scores above 15). In these cases, neuroleptic augmentation may be indicated. Earlier studies suggested that neuroleptic augmentation in OCD using haloperidol might mostly benefit patients with comorbid tic disorders (tic-related OCD) (McDougle, Goodman, & Price, 1994). Later data suggest that neuroleptics, such as risperidone, can be of benefit even in non-tic-related OCD (McDougle, Epperson, Pelton, Wasylink, & Price, 2000). Only lesser doses are needed to augment the anti-OCD effect of SSRIs, such 0.5–1.0 mg of risperidone or similar doses of haloperidol. More recently, aripripazole (Abilify) has been tried as an augmenting agent in OCD, with isolated case reports suggesting some efficacy (Delle Chiaie, Scarciglia, Pasquini, Caredda, & Biondi, 2011; Gentile, 2011). In a metaanalysis with adults with OCD, neither olanzapine (Zyprexa) nor quetiapine (Seroquel) showed efficacy, while risperidone was of benefit for refractory patients (Dold, Aigner, Lanzenberger, & Kasper, 2013). Glutamate Modulators Glutamate modulators are

emerging as an alternative to standard treatments for pediatric OCD, although efficacy data is still nascent. Among the glutamate-modulator candidate agents are riluzole (Rilutek), memantine (Namenda), ketamine (Ketalar), and d-cycloserine (DCS). The overarching effect of glutamate modulators is neuroprotection through glutamate-stabilizing mechanisms, decreasing the neurotoxic effect of excess glutamate. Riluzole inhibits the release of glutamate at the presynaptic nerve cell terminus, which likely occurs by blockade of voltage-gated sodium channels (Wang, Wang & Wang, 2004). Additional mechanisms may include increasing glial glutamate reuptake and facilitating clearance from presynaptic terminals. In an open-label study of 13 treatmentresistant adult OCD patients, 50 mg of riluzole reduced Y4 • CAPN 21(1)

BOCS score by 35% in over half the sample. Additionally, anxiety and depression symptoms decreased without side effects (Coric et al., 2005). A 12-week open-label study in 6 children and adolescents with OCD showed benefit for 4 of 6 subjects (Grant, Lougee, Hirschtritt, & Swedo, 2007). However, in a larger sample of children and adolescents, a subsequent double-blind placebo-controlled trial using 100 mg of riluzole showed no significant improvement of OCD symptoms (Grant et al., 2014). Ketamine (Ketalar), a voltage-dependent, non-competitive and non-selective N-methyl-D-aspartate (NMDA) receptor antagonist, acts by inhibiting the fluidity of calcium and sodium cations in the presence of glutamate and glycine (Niciu, Henter, Luckenbaugh, Zarate, Jr., & Charney, 2014). In adults with OCD, ketamine infusions appear to normalize low GABA levels in medial prefrontal cortex (Rodriguez et al., 2015). While ketamine has shown utility in the treatment of refractory depression (Iadarola et al., 2015), only case reports are available for the use of ketamine in OCD. In one report, a 24-year-old female with OCD experienced no improvement in OCD symptoms after placebo infusion, but two weekly ketamine infusions (0.5 mg/kg) decreased OCD symptoms through 7 days post-administration (Feusner, Kerwin, Saxena, & Bystritsky, 2009). In a randomized, double-blind, placebo-controlled, crossover design, ten patients with refractory obsessional OCD received sham infusion or ketamine infusion (0.5 mg/kg) one week apart. There was carryover effect for a positive effect of ketamine, with over a week of reduced symptoms. After one week, 50% of subjects receiving ketamine (n = 8) met criteria for treatment response compared to 0% of those receiving placebo (Rodriguez et al., 2013). Seven trials using ketamine for OCD are now listed in www.clinicaltrials.gov with four of them actively recruiting, including the use of an intranasal form, although none are in children. Memantine (Namenda) is a non-competitive NMDA receptor antagonist with neuroprotective properties. Open-label trials in adults with OCD (Aboujaoude, Barry, & Gamel, 2009; Feusner et al., 2009) showed significant promise for memantine. An 8-week double-blind placebo-controlled study (n = 42) in adults with moderate-severe OCD resulted in 89% of patients reporting a positive response, while others had a partial response, compared to 32% of placebo with positive response (p < 0.001) (Ghaleiha et al., 2013). One case of a 15-year-old female with severe OCD reported a response to 5 mg bid of memantine without side effects, an effect that was sustained at 9-month follow-up (Hezel, Beattie, & Stewart, 2009). There are four completed or closed clinical trials listing memantine for OCD in www.clinicaltrials.gov but none in children. D-cycloserine (DCS) is a selective partial NMDA receptor agonist that increases excitatory NMDA neurotransmission by binding to glycine-binding sites, resulting in the opening of the NMDA channel. The effect of DCS in the basolateral amygdala appears to facilitate extinction learning and can be used to accelerate the response to CBT-ERP (Ren et al., 2013). In a double-blind placebo study in adults with OCD, a dosage of 125 mg DCS 2 hours before exposure

resulted in lower levels of obsession-related distress after the 4-hour exposure-therapy sessions (Kushner et al., 2007). DCS was used in 30 youth with OCD in a double-blind placebo-controlled study which compared CBT + DCS vs. CBT + placebo. DCS (0.7 mg/kg) was administered 60 minutes before each session. There was no significant difference in the treatment arms, with 57% symptom reduction for the CBT + DCS group and 41% symptom reduction in the CBT + placebo group, with no adverse effects recorded (Storch et al., 2010). However, a later study showed a greater effect for a CBT + DCS group compared to CBT + placebo at one-month follow-up in 17 children with OCD (Farrell et al., 2013).

Conclusions The pharmacologic treatment of pediatric OCD is now well established, with efficacy for uncomplicated patients up to 70%. However, further research is required for comorbid cases, those who are initially non-responders and for spe-

cific subtypes, such as tic-related OCD (March et al., 2007). While serotonin-augmenting agents with neuroleptic augmentation is a proven strategy for symptom amelioration, glutamate-modulating agents are increasingly being tested in OCD and OCD-related disorders. In the future, new pharmacologic agents and augmented CBT strategies will provide novel treatment strategies to address the difficultto-treat clinical presentations in pediatric OCD. Marco A. Grados, M.D., M.P.H., and Jennifer Frederick are affiliated with Johns Hopkins University in Baltimore, Maryland. Heirangi Torrico is with the University of Maryland in College Park. Thomas Riley is with Elon University, North Carolina. Address correspondence to Marco A. Grados, M.D., M.P.H., Associate Professor, Clinical Director, Division of Child and Adolescent Psychiatry, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Charlotte R. Bloomberg Children’s Center, Baltimore, MD 21287. E-mail: [email protected]

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Pediatric Obsessive-Compulsive Disorder: A Psychopharmacology Update (continued from page 5)

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Hezel, D. M., Beattie, K., & Stewart, S. E. (2009). Memantine as an augmenting agent for severe pediatric OCD. American Journal of Psychiatry, 166, 237.

Niciu, M. J., Henter, I. D., Luckenbaugh, D. A., Zarate, C. A., Jr., & Charney, D. S. (2014). Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: Ketamine and other compounds. Annual Review of Pharmacology and Toxicology, 54, 119-139.

Iadarola, N. D., Niciu, M. J., Richards, E. M., Vande Voort, J. L., Ballard, E. D., Lundin, N. B., et al. (2015). Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: A perspective review. Therapeutic Advances in Chronic Disease, 6, 97-114.

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