Adverse Effects Reduce Drug Efficacy in OCD

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Activating adverse effects of an SSRI were found to interfere with multimodal treatment of OCD in a new study of treatment tolerance and therapeutic response in children and adolescents.¹ Higher levels of irritability, akathisia, or disinhibition, but not mania or self-injury of the 5 measured domains of “activation syndrome” (AS), predicted less response than a combination of psychopharmacologic and psychotherapeutic treatment over the 17 weeks of the study. Irritability in particular appeared to interfere with treatment outcome: session-to-session OCD symptom severity increased after the onset of irritability.

“According to our findings, irritability does immediately slow treatment outcome,” lead author Adam Reid told Psychiatric Times. “Irritability can be very difficult for therapists and patients to handle during psychological treatment for OCD,” he explained. “The treatment involves encouraging the youth to conduct anxiety-provoking exposures that are emotionally taxing. . . . While higher levels of mania and suicidality (components of the AS self-injury domain) were not significantly associated with worse outcome, these side effects are more rare and thus a larger sample may be needed to more appropriately study them.”

Validated assessment of activation syndrome

[[{"type":"media","view_mode":"media_crop","fid":"44003","attributes":{"alt":"OCD","class":"media-image media-image-right","id":"media_crop_5717428775798","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4895","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"width: 159px; height: 165px; float: right;","title":" ©logolord/Shutterstock.com","typeof":"foaf:Image"}}]]This examination of the dynamics between pharmacotherapy and psychotherapy for OCD was undertaken with the recent availability of the validated, comprehensive assessment measure of AS. The Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP), published in 2013, measures 5 clusters of potential adverse effects: irritability, akathisia, disinhibition, mania, and self-harm.² With the new measure, the study authors suggest that “clinicians are now better positioned to track AS during SSRI administration and may be more effective at modulating dosage if AS emerges.”

The study population was chosen both for the potential to benefit from multimodal treatment and for being at risk for adverse drug effects. “Due to its frequency of use and the high doses of SSRIs required to treat pediatric OCD, pediatric OCD would be a logical population to investigate how AS may impact multimodal treatment outcome,” Reid and colleagues noted.

Their provision of cognitive-behavioral therapy with exposure and response prevention (CBT-ERP) along with an SSRI antidepressant follows the treatment recommendations of several organizations, including the Academy of Child and Adolescent Psychiatry.

Evaluating adverse effects and efficacy

The double-blind, randomized, controlled trial at 2 OCD specialty clinics assessed 56 children and adolescents who received 17 weeks of CBT-ERP and either placebo or sertraline. CBT-ERP was started at week 4; and medication was initiated in the first week, with dosage increased in either a slow or regular titration from 25 mg daily to 200 mg over 9 weeks. A therapeutic dose, defined as a balance of efficacy and tolerability at up to 150 mg daily, was attained by week 4 with regular titration and by 8 weeks with slow titration. Dosing in both medication arms was adjusted for poor tolerability by delaying titration or by reducing dose.

The TEASAP, a parent-report measure of 38 items scored on a 4-point Likert scale, was completed by a parent at every weekly visit throughout the 17 weeks. The researchers point out that analysis of these weekly measures was baseline- centered; it captured treatment-emergent effects and excluded baseline comorbid symptoms.

To describe therapeutic outcome in relation to AS, the levels of AS were categorized as low, average, or high. In the low AS group, 58% received placebo, 25% had slow titration of the SSRI, and 17% had regular titration. Of those in the average AS group, 28% received placebo, 41% had slow titration, and 31% had regular titration. In the high AS group, 8% received placebo, 46% were on slow titration, and another 46% were on regular titration.

While 40% of the study population had at least a 50% reduction in OCD symptoms during treatment, 74% of those with the lowest levels of AS achieved at least that reduction in symptoms-as did 37% of those with average AS levels. Only 5% of the participants with high levels of AS attained a 50% reduction of symptoms during treatment.

When final SSRI dosage was analyzed against symptom reduction outcome, the higher average doses significantly predicted lower average obsessive-compulsive severity. The higher, most therapeutic dosages for OCD were not associated with the highest AS levels, nor did they alter the association of irritability, akathisia, and disinhibition as moderators of treatment outcome or of the session-to-session impact of irritability. The highest AS levels occurred at the transition from 0 mg to 25 mg daily and from 50 mg to 75 mg daily.

Preventing adverse effects from disrupting drug treatment

Although several mechanisms for the negative effect of AS on treatment outcome have been discussed in the literature, including interference with the therapeutic alliance or the capacity of patients to engage in exposures, these study results also suggest that the emergence of AS prevented optimal pharmacologic treatment. “Yet another possibility is that AS does not interfere with the effectiveness of behavioral treatment but instead disrupts pharmacological treatment,” noted Reid. He reflected that the data may suggest “that the more activated youth in our study were never able to reach the higher dose levels.”

The finding of the highest AS levels in the transition between 0 and 25 mg and between 50 and 75 mg, rather than at the higher, therapeutic dosage for OCD, supports the need to be particularly vigilant when initiating and increasing SSRI dosage. “I think the results of this study underscore the importance of monitoring how patients tolerate the medications they are prescribed,” Reid said.

This article was originally posted 12/8/2015 and has since been updated.

References:

1. Reid AM, McNamara JPH, Murphy TK, et al. Side-effects of SSRIs disrupt multimodal treatment for pediatric OCD in a randomized-controlled trial. J Psychiatr Res. 2015;71:140-147.

2. Bussing R, Murphy TK, Storch EA, et al. Psychometric properties of the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP) in youth with OCD. Psychiatry Res. 2013;763:1078-1086.