Caloric Restriction Enhances Fear Extinction Learning in Mice

IMPORTANCE Cognitive behavior therapy (CBT) among youth with obsessive-compulsive disorder (OCD) is effective, but many patients remain symptomatic after intervention. D-cycloserine, a partial agonist at the N-methyl-D-aspartate receptor in the amygdala, has been associated with enhanced CBT outcome for OCD among adults but requires evaluation among youth. OBJECTIVES To examine the relative efficacy of weight-adjusted D-cycloserine (25 or 50 mg) vs placebo augmentation of CBT for youth with OCD and to assess if concomitant antidepressant medication moderated effects. DESIGN, SETTING, AND PARTICIPANTS In a placebo-controlled randomized clinical trial, 142 youths (age range, 7-17 years) enrolled between June 1, 2011, and January 30, 2015, at 2 academic health science centers (University of South Florida and Massachusetts General Hospital) with a primary diagnosis of OCD were randomized in a double-blind fashion to D-cycloserine plus CBT or placebo plus CBT. Intent-to-treat analysis was performed. INTERVENTIONS Patients were randomly assigned in a 1:1 ratio to either 10 sessions of D-cycloserine plus CBT or placebo plus CBT. D-cycloserine (25 or 50 mg) or placebo was taken 1 hour before sessions 4 through 10. MAIN OUTCOMES AND MEASURES Children’s Yale-Brown Obsessive Compulsive Scale at randomization, biweekly, midtreatment, and posttreatment. Secondary outcomes included the Clinical Global Impressions–Severity or Clinical Global Impressions–Improvement, remission status, Children’s Depression Rating Scale, Multidimensional Anxiety Scale for Children, and Children’s Obsessive-Compulsive Impact Scale–Parent Version. RESULTS The study cohort comprised 142 participants. Their mean (SD) age was 12.7 (2.9) years, and 53.5% (76 of 142) were female. A mixed-effects model using all available data indicated significant declines in the Children’s Yale-Brown Obsessive Compulsive Scale total score and Clinical Global Impressions–Severity. No significant interaction between treatment group and changes in the Children’s Yale-Brown Obsessive Compulsive Scale and Clinical Global Impressions–Severity indicated that the D-cycloserine plus CBT group and the placebo plus CBT group declined at similar rates per assessment point on the Children’s Yale-Brown Obsessive Compulsive Scale total score (estimate, −2.31, 95% CI, −2.79 to −1.83 and estimate, −2.03, 95% CI, −2.47 to −1.58, respectively) and Clinical Global Impressions–Severity (estimate, −0.29, 95% CI, −0.35 to −0.22 and estimate, −0.23, 95% CI, −0.29 to −0.17, respectively). No group differences in secondary outcomes were present. Antidepressant medication use at baseline did not moderate changes for either group. CONCLUSIONS AND RELEVANCE D-cycloserine augmentation of CBT did not confer additional benefit relative to placebo among youth with OCD. Other augmentation approaches should be examined to enhance outcome. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00864123

show abstract

“…Conversely, other animal research suggests that SSRIs and other behaviors can enhance fear extinction. 45,46 …”

Section: Discussionmentioning

confidence: 99%

Efficacy of Augmentation of Cognitive Behavior Therapy With Weight-Adjustedd-Cycloserine vs Placebo in Pediatric Obsessive-Compulsive Disorder

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Interesting findings in rodents were recently presented by Riddle et al [58]. In their study, female adolescent mice and adults of both sexes that underwent 60% CR for only 7 days exhibited enhanced fear extinction learning and retention, a process normally impaired in patients with anxiety disorders [59] and which requires active neural plasticity [60].…”

Section: Calorie Restriction: Effects Of Reducing What You Eatmentioning

confidence: 99%

Effects of Diet on Brain Plasticity in Animal and Human Studies: Mind the Gap

2014

View full text Add to dashboard Cite

Dietary interventions have emerged as effective environmental inducers of brain plasticity. Among these dietary interventions, we here highlight the impact of caloric restriction (CR: a consistent reduction of total daily food intake), intermittent fasting (IF, every-other-day feeding), and diet supplementation with polyphenols and polyunsaturated fatty acids (PUFAs) on markers of brain plasticity in animal studies. Moreover, we also discuss epidemiological and intervention studies reporting the effects of CR, IF and dietary polyphenols and PUFAs on learning, memory, and mood. In particular, we evaluate the gap in mechanistic understanding between recent findings from animal studies and those human studies reporting that these dietary factors can benefit cognition, mood, and anxiety, aging, and Alzheimer's disease—with focus on the enhancement of structural and functional plasticity markers in the hippocampus, such as increased expression of neurotrophic factors, synaptic function and adult neurogenesis. Lastly, we discuss some of the obstacles to harnessing the promising effects of diet on brain plasticity in animal studies into effective recommendations and interventions to promote healthy brain function in humans. Together, these data reinforce the important translational concept that diet, a modifiable lifestyle factor, holds the ability to modulate brain health and function.

show abstract

“…In contrast, fear extinction is the process of learning that a CS is now safe, by repeatedly presenting it without the US until the conditioned fear response is extinguished. Fear conditioning and fear extinction are believed to be distinct active learning processes affected by different genetic and pharmacological factors influencing neural plasticity [58,59]. Fear extinction has been described as easy to learn but difficult to remember, as extinguished fears are easily reactivated and can return with a change of environment, context, or internal state [60].…”

Section: Learning Habit Formation Stress and Fear Conditioning: Relmentioning

confidence: 99%

Anorexia nervosa as a motivated behavior: Relevance of anxiety, stress, fear and learning

Guarda¹,

Schreyer²,

Boersma³

et al. 2015

Physiology & Behavior

View full text Add to dashboard Cite

Caloric Restriction Enhances Fear Extinction Learning in Mice

Cited by 41 publications

References 47 publications

Efficacy of Augmentation of Cognitive Behavior Therapy With Weight-Adjustedd-Cycloserine vs Placebo in Pediatric Obsessive-Compulsive Disorder

Efficacy of Augmentation of Cognitive Behavior Therapy With Weight-Adjustedd-Cycloserine vs Placebo in Pediatric Obsessive-Compulsive Disorder

Effects of Diet on Brain Plasticity in Animal and Human Studies: Mind the Gap

Anorexia nervosa as a motivated behavior: Relevance of anxiety, stress, fear and learning

Contact Info

Product

Resources

About