Amanda Levinson

Randomized Controlled Crossover Trial of Ketamine in Obsessive-Compulsive Disorder: Proof-of-Concept

Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two limitations: incomplete symptom relief and 2–3 months lag time before clinically meaningful improvement. New medications with faster onset are needed. As converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, we tested whether a single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid anti-obsessional effects. In a randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n=15) with near-constant obsessions received two 40-min intravenous infusions, one of saline and one of ketamine (0.5 mg/kg), spaced at least 1-week apart. The OCD visual analog scale (OCD-VAS) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) were used to assess OCD symptoms. Unexpectedly, ketamine’s effects within the crossover design showed significant (p<0.005) carryover effects (ie, lasting longer than 1 week). As a result, only the first-phase data were used in additional analyses. Specifically, those receiving ketamine (n=8) reported significant improvement in obsessions (measured by OCD-VAS) during the infusion compared with subjects receiving placebo (n=7). One-week post-infusion, 50% of those receiving ketamine (n=8) met criteria for treatment response (⩾35% Y-BOCS reduction) vs 0% of those receiving placebo (n=7). Rapid anti-OCD effects from a single intravenous dose of ketamine can persist for at least 1 week in some OCD patients with constant intrusive thoughts. This is the first randomized, controlled trial to demonstrate that a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an SRI and is consistent with a glutamatergic hypothesis of OCD.

Reliability of the electrocortical response to gains and losses in the doors task.

The ability to differentiate between rewards and losses is critical for motivated action, and aberrant reward and loss processing has been associated with psychopathology. The reward positivity (RewP) and feedback negativity (FN) are ERPs elicited by monetary gains and losses, respectively, and are promising individual difference measures. However, few studies have reported on the psychometric properties of the RewP and FN-crucial characteristics necessary for valid individual difference measures. The current study examined the internal consistency and 1-week test-retest reliability of the RewP and FN as elicited by the doors task among 59 young adults. The RewP, FN, and their difference score (ΔRewP) all showed significant correlations between Time 1 and Time 2. The RewP and FN also achieved acceptable internal consistency at both time points within 20 trials using both Cronbachs α and a generalizability theory-derived dependability measure. Internal consistency for ΔRewP was notably weaker at both time points, which is expected from two highly intercorrelated constituent scores. In conclusion, the RewP and FN have strong psychometric properties in a healthy adult sample. Future research is needed to assess the psychometric properties of these ERPs in different age cohorts and in clinical populations.

In vivo effects of ketamine on glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder: Proof of concept

We previously reported the rapid and robust clinical effects of ketamine versus saline infusions in a proof-of-concept crossover trial in unmedicated adults with obsessive-compulsive disorder (OCD). This study examined the concurrent neurochemical effects of ketamine versus saline infusions using proton magnetic resonance spectroscopy ((1)H MRS) during the clinical proof-of-concept crossover trial. Levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the excitatory neurochemicals glutamate+glutamine (Glx) were acquired in the medial prefrontal cortex (MPFC), a region implicated in OCD pathology. Seventeen unmedicated OCD adults received two intravenous infusions at least 1 week apart, one of saline and one of ketamine, while lying supine in a 3.0 T GE MR scanner. The order of each infusion pair was randomized. Levels of GABA and Glx were measured in the MPFC before, during, and after each infusion and normalized to water (W). A mixed effects model found that MPFC GABA/W significantly increased over time in the ketamine compared with the saline infusion. In contrast, there were no significant differences in Glx/W between the ketamine and saline infusions. Together with earlier evidence of low cortical GABA in OCD, our findings suggest that models of OCD pathology should consider the role of GABAergic abnormalities in OCD symptomatology.

Prevalence and correlates of difficulty discarding: results from a national sample of the US population.

Abstract This study presents nationally representative data on the prevalence and the correlates of difficulty discarding, a behavior described in many psychiatric disorders, including a new diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, called hoarding disorder. Data were derived from the National Epidemiologic Survey on Alcohol and Related Conditions, a national sample of the US population (N=43,093). Difficulty discarding worn-out/worthless items (assessed by a single item) and diagnoses of psychiatric disorders were based on the Alcohol Use Disorder and Associated Disabilities Interview Schedule. The prevalence of difficulty discarding worn-out/worthless items in the general population was 20.6%. Difficulty discarding strongly correlated with axis I and axis II disorders, level of impairment, and use of mental health services. Difficulty discarding worn-out/worthless items is a common behavior that can be associated with various forms of psychopathology. When reported in a clinical setting, it may signal that careful assessment is needed to clarify diagnosis and inform treatment strategies.

Acceptability of treatments and services for individuals with hoarding behaviors

OBJECTIVE To explore the acceptability of currently available treatments and services for individuals who self-report hoarding behaviors. METHOD Between 10/2013 and 8/2014, participants were invited to complete an online survey that provided them descriptions of eleven treatments and services for hoarding behaviors and asked them to evaluate their acceptability using quantitative (0 [not at all acceptable] -10 [completely acceptable]) Likert scale ratings. The a priori definition of acceptability for a given resource was an average Likert scale score of six or greater. Two well-validated self-report measures assessed hoarding symptom severity: the Saving Inventory-Revised and the Clutter Image Rating Scale. RESULTS Two hundred and seventy two participants who self-reported having hoarding behaviors completed the questionnaire. Analyses focused on the 73% of responders (n=203) who reported clinically significant hoarding behaviors (i.e., Saving Inventory-Revised scores of ≥40). The three most acceptable treatments were individual cognitive behavioral therapy (6.2 ±3.1 on the Likert scale), professional organizing service (6.1 ±3.2), and use of a self-help book (6.0 ±3.0). CONCLUSION In this sample of individuals with self-reported clinically significant hoarding behaviors (n=203), only 3 out of 11 treatments and services for hoarding were deemed acceptable using an a priori score. While needing replication, these findings indicate the need to design more acceptable treatments and services to engage clients and maximize treatment outcomes for hoarding disorder.

Emotion regulation to idiographic stimuli: Testing the Autobiographical Emotion Regulation Task

Mounting evidence suggests that the ability to regulate emotion is crucial for psychological well-being. However, one important limitation of prior emotion regulation studies is that they rely on standardized stimuli low in personal relevance. To address this limitation, the current study employed a novel event-related potential (ERP) paradigm designed to investigate the late positive potential (LPP) as a measure of emotional reactivity and regulation to idiographic stimuli in 49 young adults. The Autobiographical Emotion Regulation Task (AERT) is a word-viewing task in which participants identify neutral and emotionally-charged autobiographical memories and generate keywords unique to each memory. First, participants are instructed to simply view the keywords. Then, participants are presented with keywords from negative memories and are either instructed to react normally (react condition), or to use cognitive reappraisal to decrease negative emotion (reappraise condition). Results indicate that the LPP was potentiated when initially viewing keywords for negative compared to neutral memories. Furthermore, the LPP was reduced during reappraise compared to react trials, demonstrating successful down-regulation of neural activity to negative idiographic stimuli. These findings suggest that the AERT is a feasible and effective probe of emotion regulation to idiographic stimuli.

Open-Label trial on the effects of memantine in adults with obsessive-compulsive disorder after a single ketamine infusion.

History of Ketamine Response by Patient Age/Sex/ Ethnicity Duration of Illness (y) No. of Prior SRI Trials Prior EX/RP Trials KETAMINE Memantine Start ↓ MEMANTINE PreBaseline Y-BOCS Post– 1-Week Y-BOCS Days Post-Ketamine Infusion PreBaseline Y-BOCS Y-BOCS at Dropb Post– 6-Week Y-BOCS Memantine Continuation 12-Weekc Y-BOCS Ketamine responders 1 47/M/AA 19 3 Yes 26 14 84 25 14 22 2 53/M/W 15 1 No 29 12 28 11 12 ...d 3 32/M/H 25 3 Yes 29 17 21 21 19 25 4 24/F/AA 12 0 Yes 25 7 14 0 0 ... ... Ketamine nonresponders 5 24/M/H 5 0 No 24 27 73 27 23 ... 6 32/M/W 11 3 Yes 23 19 62 18 23 ... ... 7 38/F/A 22 2 No 36 31 25 31 28 ... 8 29/F/AA 14 4 No 29 30 14 31 23 ... 9 33/M/W 30 5 No 24 26 14 26 21 ... 10 22/F/AA 10 0 No 25 24 7 24 24 ... ... 11 33/M/AA 21 0 No 20 23 7 23 26 ... 12 36/M/W 20 1 Yes 23 20 7 20 23 ... ... aHistory of ketamine response in a prior study (see Koran et al1) was defined as a ≥ 35% Y-BOCS reduction 1 week after intravenous ketamine. bY-BOCS score at drop visit. Participant 4 dropped at week 4 due to no longer having OCD symptoms. Participants 6, 10, and 12, dropped at week 2 due to increased anxiety. cMemantine was continued to 12 weeks in those with treatment response (see Goodman et al12) either to ketamine (≥ 35% Y-BOCS reduction 1 week after intravenous ketamine) or to memantine (≥ 35% Y-BOCS reduction from pre– to post–6 weeks of memantine). dParticipant 2 reported continued low OCD symptoms while on his medication, but was unable to have week 12 independent evaluation until 2 weeks after his medications ran out. His Y-BOCS score at week 14 independent evaluation was 26. Abbreviations: A = Asian, AA = African American; EX/RP = Cognitive Behavioral Therapy with Exposure and Response Prevention; F = female; H = Hispanic, M = male; OCD = obsessive-compulsive disorder, SRI = serotonin reuptake inhibitor; W = white; Y-BOCS = Yale-Brown Obsessive Compulsive Scale. Symbol: ... = not applicable. Open-Label Trial on the Effects of Memantine in Adults With Obsessive-Compulsive Disorder After a Single Ketamine Infusion

A comparison of the electrocortical response to monetary and social reward

Abstract Affective science research on reward processing has primarily focused on monetary rewards. There has been a growing interest in evaluating the neural basis of social decision-making and reward processing. The present study employed a within-subject design and compared the reward positivity (RewP), an event-related potential component that is present following favorable feedback and absent or reduced following unfavorable feedback, during monetary and social reward tasks. Specifically, 114 participants (75 females) completed a monetary reward task and a novel social reward task that were matched on trial structure, timing, and feedback stimuli in a counterbalanced order. Results indicated that the monetary and social RewP were of similar magnitude, positively correlated and demonstrated comparable psychometric properties, including reliability and dependability. Across both the monetary and social tasks, women demonstrated a greater RewP compared with men. This study provides a novel methodological approach toward examining the electrocortical response to social reward that is comparable to monetary reward.

Neural Response to Pleasant Pictures Moderates Prospective Relationship Between Stress and Depressive Symptoms in Adolescent Girls

Adolescent girls are at increased risk for depression, which is thought to result from the interaction of biological vulnerabilities and life stressors common to adolescent girls. A blunted late positive potential (LPP) to emotional stimuli (i.e., pleasant and unpleasant) has been associated with depressive symptoms and risk. The current study of adolescent girls examines the moderating effects of the LPP, a candidate biomarker of depression, of the link between life stress and increases in depressive symptoms over 1 year. We measured LPP to pleasant and unpleasant pictures from the International Affective Picture Set among 143 predominantly Caucasian adolescent girls ages 8 to 14, who also reported on the frequency of common life stressors. Self-reported depressive symptoms were assessed both at baseline and 1 year after the initial lab visit. The LPP to pleasant pictures moderated the relationship between baseline life stressors and the change in depressive symptoms. Specifically, life stress was associated with increases in depressive symptoms when the LPP to pleasant pictures was blunted, whereas life stress was associated with decreases in depressive symptoms when the LPP to pleasant pictures was potentiated. These effects showed some specificity to family and school-related stressors and to anhedonic and efficacy-related depressive symptoms. A similar pattern, though not statistically significant, was found for the LPP to unpleasant pictures. Together, these findings suggest that the LPP to pleasant pictures may represent a useful biomarker in identifying individuals at greatest risk of experiencing depressive symptoms following stress.

Extraversion, neuroticism, and the electrocortical response to monetary rewards in adolescent girls

Affective personality traits, such as extraversion and neuroticism, are associated with individual differences in reward system functioning. The reward positivity (ΔRewP) is an event-related potential (ERP) component that indexes sensitivity to reward, and can be elicited by feedback indicating monetary gains relative to losses. In a sample of 508 adolescent girls, the current study examined the relationship between extraversion, neuroticism, and their respective facets and the ΔRewP. Results indicated an Extraversion × Neuroticism interaction, such that greater extraversion was associated with an increased ΔRewP, but only in the context of low neuroticism. This association was primarily due to the extraversion facet positive emotionality-high levels of positive emotionality were associated with an increased ΔRewP, but only in the context of low neuroticism. In addition, increased neuroticism diminished the age-related increase in the ΔRewP. The current study suggests that both extraversion and neuroticism are associated with reward system function in adolescence.