Rebecca B. Price

Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression.

BACKGROUND Intravenous ketamine has shown rapid antidepressant effects in early trials, making it a potentially attractive candidate for depressed patients at imminent risk of suicide. The Implicit Association Test (IAT), a performance-based measure of association between concepts, may have utility in suicide assessment. METHODS Twenty-six patients with treatment-resistant depression were assessed using the suicidality item of the Montgomery-Asberg Depression Rating Scale (MADRS-SI) 2 hours before and 24 hours following a single subanesthetic dose of intravenous ketamine. Ten patients also completed IATs assessing implicit suicidal associations at comparable time points. In a second study, nine patients received thrice-weekly ketamine infusions over a 12-day period. RESULTS Twenty-four hours after a single infusion, MADRS-SI scores were reduced on average by 2.08 points on a 0 to 6 scale (p < .001; d = 1.37), and 81% of patients received a rating of 0 or 1 postinfusion. Implicit suicidal associations were also reduced following ketamine (p = .003; d = 1.36), with reductions correlated across implicit and explicit measures. MADRS-SI reductions were sustained for 12 days by repeated-dose ketamine (p < .001; d = 2.42). CONCLUSIONS These preliminary findings support the premise that ketamine has rapid beneficial effects on suicidal cognition and warrants further study.

Amino Acid Neurotransmitters Assessed by Proton Magnetic Resonance Spectroscopy: Relationship to Treatment Resistance in Major Depressive Disorder

BACKGROUND Significant alterations in gamma-aminobutyric acid (GABA) and glutamate levels have been previously reported in major depressive disorder (MDD); however, no studies to date have investigated associations between these amino acid neurotransmitters and treatment resistance. METHODS The objective of this study was to compare occipital cortex (OCC) and anterior cingulate cortex (ACC) GABA and glutamate+glutamine (Glx) levels measured by proton magnetic resonance spectroscopy ((1)H MRS) in 15 medication-free treatment-resistant depression (TRD) patients with those in 18 nontreatment-resistant MDD (nTRD) patients and 24 healthy volunteers (HVs). RESULTS Levels of OCC GABA relative to voxel tissue water (W) were decreased in TRD patients compared with both HV (20.2% mean reduction; p = .001; Cohens d = 1.3) and nTRD subjects (16.4% mean reduction; p = .007; Cohens d = 1.4). There was a similar main effect of diagnosis for ACC GABA/W levels (p = .047; Cohens d = .76) with TRD patients exhibiting reduced GABA in comparison with the other two groups (22.4% to 24.5% mean reductions). Group differences in Glx/W were not significant in either brain region. Only GABA results in OCC survived correction for multiple comparisons. CONCLUSIONS Our findings corroborate previous reports of decreased GABA in MDD and provide initial evidence for a distinct neuronal amino acid profile in patients who have failed to respond to several standard antidepressants, possibly indicative of abnormal glutamate/glutamine/GABA cycling. Given interest in novel antidepressant mechanisms in TRD that selectively target amino acid neurotransmitter function, the translational relevance of these findings awaits further study.

Recent advances in the neurobiology of anxiety disorders: implications for novel therapeutics.

Anxiety disorders are a highly prevalent and disabling class of psychiatric disorders. This review focuses on new directions in neurobiological research and implications for the development of novel psychopharmacological treatments. Neuroanatomical and neuroimaging research in anxiety disorders has centered on the role of the amygdala, reciprocal connections between the amygdala and the prefrontal cortex, and, most recently, alterations in interoceptive processing by the anterior insula. Anxiety disorders are characterized by alterations in a diverse range of neurochemical systems, suggesting ample novel targets for drug therapies. Corticotropin‐releasing factor (CRF) concentrations are elevated in a subset of anxiety disorders, which suggests the potential utility of CRF receptor antagonists. Pharmacological blockade of the memory‐enhancing effects of stress hormones such as glucocorticoids and noradrenaline holds promise as a preventative approach for trauma‐related anxiety. The glutamatergic system has been largely overlooked as a potential pharmacological target, although convergent preclinical, neuroimaging, and early clinical findings suggest that glutamate receptor antagonists may have potent anxiolytic effects. Glutamatergic receptor agonists (e.g., D‐cycloserine) also have an emerging role in the treatment of anxiety as facilitators of fear extinction during concurrent behavioral interventions. The neuropeptides substance P, neuropeptide Y, oxytocin, orexin, and galanin are each implicated in anxiety pathways, and neuropeptide analogs or antagonists show early promise as anxiolytics in preclinical and/or clinical research. Each of these active areas of research holds promise for expanding and improving evidence‐based treatment options for individuals suffering with clinical anxiety.

You Gotta Work at It: Pupillary Indices of Task Focus Are Prognostic for Response to a Neurocognitive Intervention for Rumination in Depression

Treatments for severe depression have moderate success rates, often take many weeks to yield responses, and are often followed by relapse or recurrence. Neurobehavioral interventions address these limitations by targeting mechanisms of cognitive and emotional dysregulation directly. This study extends data and observations from a pilot study examining effects of 2 weeks (6 sessions) of adjunctive cognitive control training exercises added to medication and psychotherapy in severely depressed patients. We examined acute effects and predictors of change in rumination, and long-term effects on service utilization. Compared with treatment as usual, exercises were associated with decreases in rumination and decreased use of intensive outpatient services in the following year. Responses were strongest among patients who displayed physiological indicators (pupillary oscillations at the task frequency) of task engagement before the intervention. These indices changed following intervention, suggesting that the intervention required capitalization on relevant attentional mechanisms and addressed fundamental emotional processes through their cognitive substrates.

Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial

BACKGROUND Suicide is a devastating public health problem and very few biological treatments have been found to be effective for quickly reducing the intensity of suicidal ideation (SI). We have previously shown that a single dose of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with a rapid reduction in depressive symptom severity and SI in patients with treatment-resistant depression. METHOD We conducted a randomized, controlled trial of ketamine in patients with mood and anxiety spectrum disorders who presented with clinically significant SI (n = 24). Patients received a single infusion of ketamine or midazolam (as an active placebo) in addition to standard of care. SI measured using the Beck Scale for Suicidal Ideation (BSI) 24 h post-treatment represented the primary outcome. Secondary outcomes included the Montgomery-Asberg Depression Rating Scale--Suicidal Ideation (MADRS-SI) score at 24 h and additional measures beyond the 24-h time-point. RESULTS The intervention was well tolerated and no dropouts occurred during the primary 7-day assessment period. BSI score was not different between the treatment groups at 24 h (p = 0.32); however, a significant difference emerged at 48 h (p = 0.047). MADRS-SI score was lower in the ketamine group compared to midazolam group at 24 h (p = 0.05). The treatment effect was no longer significant at the end of the 7-day assessment period. CONCLUSIONS The current findings provide initial support for the safety and tolerability of ketamine as an intervention for SI in patients who are at elevated risk for suicidal behavior. Larger, well-powered studies are warranted.

The relation of worry to prefrontal cortex volume in older adults with and without generalized anxiety disorder.

Despite the widespread prevalence of generalized anxiety disorder (GAD) in later life, almost nothing is known about the neural aspects of worry in adults over the age of 60. Given the ongoing rapid increase in the older adult population, the relatively poor response rates to current interventions for late life GAD, and the effects of age-related changes to the brain, additional research on worry neurobiology is needed. The study group comprised 15 older GAD patients and 15 matched controls who were compared on clinical measures and brain volumes. It was expected that prefrontal cortex (PFC) volumes [medial orbital cortex (mOFC), dorsolateral cortex (DLPFC)] would show positive relations to worry scores, and weaker relations to more general measures of anxiety and depression. Negative relations were expected between amygdala volumes and worry scores. As expected, mOFC volumes were positively related to worry scores; however, DLPFC and amygdala volumes were not. The mOFC is involved in emotional decision-making under uncertain conditions and has the ability to suppress the amygdala, both of which are hypothesized functions of worry. Results are partly consistent with GAD theory and suggest that worry may involve neural areas that are also involved in the successful control of anxiety.

Pooled patient-level meta-analysis of children and adults completing a computer-based anxiety intervention targeting attentional bias

Computer-based approaches, such as Attention Bias Modification (ABM), could help improve access to care for anxiety. Study-level meta-analyses of ABM have produced conflicting findings and leave critical questions unresolved regarding ABMs mechanisms of action and clinical potential. We pooled patient-level datasets from randomized controlled trials of children and adults with high-anxiety. Attentional bias (AB) towards threat, the target mechanism of ABM, was tested as an outcome and a mechanistic mediator and moderator of anxiety reduction. Diagnostic remission and Liebowitz Social Anxiety Scale (LSAS) were clinical outcomes available in enough studies to enable pooling. Per-patient data were obtained on at least one outcome from 13/16 eligible studies [86% of eligible participants; n=778]. Significant main effects of ABM on diagnostic remission (ABM-22.6%, control-10.8%; OR=2.57; p=0.006) and AB (β* (95%CI)=-0.63 (-0.83, -0.42); p<0.00005) were observed. There was no main effect of ABM on LSAS. However, moderator analyses suggested ABM was effective for patients who were younger (≤37y), trained in the lab, and/or assessed by clinicians. Under the same conditions where ABM was effective, mechanistic links between AB and anxiety reduction were supported. Under these specific circumstances, ABM reduces anxiety and acts through its target mechanism, supporting ABMs theoretical basis while simultaneously suggesting clinical indications and refinements to improve its currently limited clinical potential.

From anxious youth to depressed adolescents: prospective prediction of 2-year depression symptoms via attentional bias measures

Anxious youth are at heightened risk for subsequent development of depression; however, little is known regarding which anxious youth are at the highest prospective risk. Biased attentional patterns (e.g., vigilance and avoidance of negative cues) are implicated as key mechanisms in both anxiety and depression. Aberrant attentional patterns may disrupt opportunities to effectively engage with, and learn from, threatening aspects of the environment during development and/or treatment, compounding risk over time. Sixty-seven anxious youth (ages 9-14; 36 female) completed a dot-probe task to assess baseline attentional patterns provoked by fearful-neutral face pairs. The time course of attentional patterns both during and after threat was assessed via eye-tracking and pupilometry. Self-reported depressive and anxiety symptoms were assessed 2 years after the conclusion of a larger psychotherapy treatment trial. Eye-tracking patterns indicating threat avoidance predicted greater 2-year depression scores, over and above baseline and posttreatment symptoms. Sustained, postthreat pupillary avoidance (reflecting preferential neural engagement with the neutral relative to the previously threatening location) predicted additional variance in depression scores, suggesting sustained avoidance in the wake of threat further exacerbated risk. Identical eye-tracking and pupil indices were not predictive of anxiety at 2 years. These biobehavioral markers imply that avoidant attentional processing in the context of anxiety may be a gateway to depression across a key maturational window. Excessive avoidance of threat could interfere with acquisition of adaptive emotion regulation skills during development, culminating in the broad behavioral deactivation that typifies depression. Prevention efforts explicitly targeting avoidant attentional patterns may be warranted.

Emotional Stroop Performance in Older Adults: Effects of Habitual Worry

OBJECTIVE In clinically anxious individuals, selective attention to negative cues in the environment may perpetuate a vicious cycle of emotional dysfunction. However, very little is known regarding the role of negative attentional bias in anxious older adults. There is evidence that in older adults without clinical anxiety, the opposite bias (toward positive, and away from negative, emotional material) is present. We explored how these age-related changes in emotional processing interact with anxiety. METHOD Sixty older adults (age 60+) completed the emotional Stroop (eStroop) task, a widely used measure of attentional bias, which requires rapid identification of the color in which neutral and emotional words are printed. Participants were stratified into high-, mid-, and low-worry groups on the basis of a self-report measure, the Penn State Worry Questionnaire. RESULTS The high-worry group exhibited a bias toward threat-related words whereas the low- and mid-worry groups showed a bias away from threat-related words. By contrast, the low- and mid-worry groups showed a bias toward positive words, potentially consistent with an established positivity effect in older adults whereas the high-worry group showed a bias away from positive items. CONCLUSION Older adults who worry frequently exhibit a pattern of eStroop performance that is broadly consistent with the younger adult literature, suggesting that selective attention toward threat-related information may be seen as a relevant factor in older, as in younger, anxiety.

Neural Correlates of Three Neurocognitive Intervention Strategies: A Preliminary Step Towards Personalized Treatment for Psychological Disorders

Brain-based behavioral interventions targeting specific neurocognitive mechanisms show initial promise in the treatment of emotional disorders, but personalization of such approaches will be facilitated if brain targets are empirically established. As a preliminary step, we conducted a proof-of-concept study to test whether particular emotion regulatory neural circuitry can be differentially targeted by specific neurocognitive tasks, and whether these tasks effectively inhibit amygdala activity. Eleven healthy individuals underwent an idiographic sadness and guilt induction. Brain response was measured via fMRI during 4 subsequent emotion regulation conditions: fixation, cognitive reappraisal (selected to target the ventrolateral prefrontal cortex), working memory practice (selected to target the dorsolateral prefrontal cortex), and visual distraction (Tetris; selected to target occipital cortex). In whole-brain comparisons to fixation, hypotheses were upheld. Reappraisal uniquely activated left venrolateral prefrontal cortex, working memory practice uniquely activated left dorsolateral prefrontal cortex, and Tetris uniquely activated bilateral occipitoparietal cortex, activations that were largely robust at the single-subject level. All tasks inhibited amygdala activity relative to fixation. Data support examining whether repeated exposure to these tasks in psychiatric patients affects neural abnormalities implicated in emotional disorders. Ideally, psychiatric treatment will be accelerated by matching specific treatments to patients with specific neural profiles.