MMPI-2-RF validity scales add utility for predicting treatment engagement during partial psychiatric hospitalizations.

Partial psychiatric hospitalizations are resource-intensive clinical services designed to stabilize patients in the short term, prevent inpatient hospitalizations, and encourage long-term recovery. Typically, providers base their referral decisions on categorical diagnoses and subjective impressions of patient distress without closely considering the evidence for reporting biases. The present study followed veterans (n = 430) participating in partial psychiatric hospitalization services. We evaluated the extent to which clinical diagnoses at intake predicted treatment variables and changes in later mental health care utilization. Using hierarchical linear regressions with bootstrap confidence intervals, Minnesota Multiphasic Personality Inventory-2-Restructured Form content-based validity scales demonstrated incremental utility for predicting patient outcomes beyond intake diagnoses. Elevated Fp-r ("Infrequent Psychopathology Responses") scores independently predicted an increased number of times arriving late for partial hospitalization programming, self-report of worse current functioning at intake, and a relative increase in mental health care encounters in the 12 months following discharge. Low K-r ("Adjustment Validity") scores independently predicted self-report of worse current functioning at both intake and later discharge from partial hospitalization. Thus, indicators of severe psychopathology overreporting as well as the unlikely disavowal of emotional adjustment (i.e., high Fp-r, low K-r) predicted engagement with health care services and self-presentations of symptoms over and above the diagnostic impressions from referring providers. We discuss how indicators of content-based invalid responding on the Minnesota Multiphasic Personality Inventory-2-Restructured Form have real-world value for understanding patient behavior and shaping clinical interventions among vulnerable populations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Adaptation in Young Military Recruits: Protocol for the Advancing Research on Mechanisms of Resilience (ARMOR) Prospective Longitudinal Study.

BACKGROUND: Military services provide a unique opportunity for studying resilience, a dynamic process of successful adaptation (ie, doing well in terms of functioning and symptoms) in response to significant adversity. Despite the tremendous interest in positive adaptation among military service members, little is known about the processes underlying their resilience. Understanding the neurobiological, cognitive, and social mechanisms underlying adaptive functioning following military stressor exposure is essential for enhancing the resilience of military service members. OBJECTIVE: The primary objective of the Advancing Research on Mechanisms of Resilience (ARMOR) longitudinal study is to characterize the trajectories of positive adaptation among young military recruits in response to basic combat training (BCT), a well-defined, uniform, and 10-week period of intense stress (aim 1), and identify promotive and protective processes contributing to individual variations in resilience (aim 2). The secondary objective is to investigate the pathways by which neurobehavioral markers of self-regulation assessed using electroencephalography and magnetic resonance imaging contribute to adaptive trajectories (aim 3). METHODS: ARMOR is an ongoing, prospective longitudinal cohort study of young military recruits who recently joined the National Guard but have not yet shipped out for BCT. Participants (N=1201) are assessed at 5 time points over the initial >2 years of military service beginning before BCT (baseline) and followed up at 2 weeks and 6, 12, and 18 months after BCT. Participants complete web-based questionnaires assessing vulnerability and protective factors, mental health, and socioemotional functioning at each time point and a battery of neurocognitive tests at time 0. A subset of participants also complete structured diagnostic interviews and additional self-report measures and perform neurobehavioral tasks before and after BCT during electroencephalography sessions and before BCT only during magnetic resonance imaging sessions. RESULTS: This UG3/UH3 project was initially funded in August 2017, with the UG3 pilot work completed at the end of 2018. The UH3 phase of the project was funded in March 2019. Study enrollment for the UH3 phase began on April 14, 2019, and ended on October 16, 2021. A total of 1201 participants are enrolled in the study. Follow-up data collection for the UH3 phase is ongoing and projected to continue through February 2024. We will disseminate the findings through conferences, webinars, open access publications, and communications with participants and stakeholders. CONCLUSIONS: The ARMOR study provides a rich data set to identify the predictors and mechanisms of resilient and nonresilient outcomes in the context of military stressors, which are intended to empirically inform the development of prevention and intervention strategies to enhance the resilience of military trainees and potentially other young people facing significant life challenges. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51235.

Posttraumatic reexperiencing and alcohol use: mediofrontal theta as a neural mechanism for negative reinforcement.

Objective: Over half of US military veterans with posttraumatic stress disorder (PTSD) use alcohol heavily, potentially to cope with their symptoms. This study investigated the neural underpinnings of PTSD symptoms and heavy drinking in veterans. We focused on brain responses to salient outcomes within predictive coding theory. This framework suggests the brain generates prediction errors (PEs) when outcomes deviate from expectations. Alcohol use might provide negative reinforcement by reducing the salience of negatively-valenced PEs and dampening experiences like loss. Methods: We analyzed electroencephalography (EEG) responses to unpredictable gain/loss feedback in veterans of Operations Enduring and Iraqi Freedom. We used time-frequency principal components analysis of event-related potentials to isolate neural responses indicative of PEs, identifying mediofrontal theta linked to losses (feedback-related negativity, FRN) and central delta associated with gains (reward positivity, RewP). Results: Intrusive reexperiencing symptoms of PTSD were associated with intensified mediofrontal theta signaling during losses, suggesting heightened negative PE sensitivity. Conversely, increased hazardous alcohol use was associated with reduced theta responses, implying a dampening of these negative PEs. The separate delta-RewP component showed associations with alcohol use but not PTSD symptoms. Conclusions: Findings suggest a common neural component of PTSD and hazardous alcohol use involving altered PE processing. We suggest that reexperiencing enhances the intensity of salient negative PEs, while chronic alcohol use may reduce their intensity, thereby providing negative reinforcement by muting emotional disruption from reexperienced trauma. Modifying the mediofrontal theta response could address the intertwined nature of PTSD symptoms and alcohol use, providing new avenues for treatment.

Advancing Research on Mechanisms of Resilience (ARMOR) Prospective Longitudinal Study of Adaptation in Young Military Recruits: Protocol and rationale for methods and measures.

Background: Military service provides a unique opportunity for studying resilience, a dynamic process of successful adaptation (i.e., doing well in terms of functioning and symptoms) in response to significant adversity. Despite tremendous interest in positive adaptation among military service members, little is known about the processes underlying their resilience. Understanding neurobiological, cognitive, and social mechanisms underlying adaptive functioning following military stressor exposure is essential to enhance the resilience of military service members. Objectives: The primary objective of the Advancing Research on Mechanisms of Resilience (ARMOR) longitudinal study is to characterize trajectories of positive adaptation among young military recruits in response to Basic Combat Training (BCT), a well-defined, uniform, 10-week period of intense stress (Aim 1) and identify promotive and protective processes contributing to individual variations in resilience (Aim 2). The secondary objective is to investigate pathways by which neurobehavioral markers of self-regulation assessed by electroencephalography (EEG) and magnetic resonance imaging (MRI) contribute to adaptive trajectories (Aim 3). Methods: ARMOR is an ongoing, prospective longitudinal cohort study of young military recruits who recently joined the National Guard but have not yet shipped for BCT. Participants (N=1,201) are assessed at five timepoints over the initial 2+ years of military service beginning before BCT (baseline) and followed up at 2 weeks, 6, 12, and 18 months post-BCT. At each time point, participants complete online questionnaires assessing vulnerability and protective factors, mental health and social-emotional functioning, and, at Time 0 only, a battery of neurocognitive tests. A subset of participants also complete structured diagnostic interviews, additional self-report measures, and perform neurobehavioral tasks before and after BCT during EEG sessions, and, at pre-BCT only, during MRI sessions. Results: Study enrollment began April 14, 2019 and ended in October 16, 2021. A total of 1,201 participants are enrolled in the study (68.9% male; mean age = 18.9, SD = 3.0). Follow-up data-collection is ongoing and projected to continue through March 2024. We will disseminate findings through conferences, webinars, open access publications, and communications with participants and stakeholders. Conclusions: Results are expected to elucidate how young military recruits adapt to military stressors during the initial years of military service. Understanding positive adaptation of military recruits in the face of BCT has implications for developing prevention and intervention strategies to enhance resilience of military trainees and potentially other young people facing significant life challenges.

Evaluating resilience in response to COVID-19 pandemic stressors among veteran mental health outpatients.

There is a public health need to understand mental health vulnerabilities to COVID-19 pandemic-related stressors and promote resilience among high-risk populations with preexisting psychiatric conditions. Recent cross-sectional studies suggest increases in mental health distress (e.g., depression and anxiety) during the pandemic. The present study expands upon these emerging findings using longitudinal latent modeling and hierarchical linear regressions. Consistent with the developmental psychopathology literature on resilience, we distinguished between promotive or risk (i.e., main effect), and protective or vulnerability (i.e., moderation) effects on mental health during the pandemic. At a large medical center, 398 veterans receiving outpatient mental health care provided prepandemic (Time 1) and during pandemic (Time 2) assessments of mental and physical health-related distress. Additional Time 2 questionnaires assessed pandemic-related stressors and positive behavioral adaptations in the summer of 2020. As expected, total stressor scores predicted longitudinal worsening of self-reported mental (ß = -.205) and physical health (ß = -.217). Positive behavioral adaptations enacted during the pandemic moderated and protected against stressor effects on mental health (ß = .160). In addition, the presence of substance use disorders moderated and conferred vulnerability to stressor effects on physical health (ß = -.158). Thus, higher COVID-19 pandemic stressor exposure may have exacerbated mental and physical health distress among veterans with common forms of psychopathology. Nevertheless, behavioral activation, purposeful maintenance of social connections, and focused treatment for substance misuse may be important intervention targets for reducing the longitudinal impact of pandemic stressors and enhancing resilience among people with mental illness. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Inconsistent Reporting of Adverse Life Events Is Predicted by Current Internalizing Distress Among Military Service Members.

INTRODUCTION: Accurate measurement of adverse life events is critical for understanding the effects of stressors on health outcomes. However, much of this research uses cross-sectional designs and self-report years after the events take place. The reliability of this retrospective reporting and the individual difference factors associated with inconsistent recall over time are not frequently addressed, especially among military service members. MATERIALS AND METHODS: A longitudinal cohort of National Guard service members (n = 801) completed the Deployment Risk and Resilience Inventory-2 Prior Stressors scale and several measures of general well-being, including anxious depressive symptomatology, personal functioning, perceived social support, and overall health at two time points (before and after completion of basic combat training; median 11-month interval). RESULTS: Consistency in reporting the life event items ranged from 69.5% to 99.7%, with an overall Cohen's kappa coefficient of 0.215 for the scale, indicating minimal agreement. Lower well-being scores at Time 1 independently predicted yes-to-no changes in responding, whereas lower well-being scores at Time 2 independently predicted no-to-yes changes in responding. Follow-up mediations were conducted using study measures available only at Time 2. For all study measures, Time 2 well-being independently predicted changes from no-to-yes responding by way of indirect effects through self-reported non-specific internalizing distress and arousal. CONCLUSIONS: These findings highlight the confounding effects of fluctuations in current emotional distress on past stressor recall. There is a need for additional caution regarding the use of retrospective self-report of adverse life events in research and clinical practice and greater consideration of current psychological distress at the time of measurement completion.

Inefficient Attentional Control Explains Verbal-Memory Deficits Among Military Veterans With Posttraumatic Reexperiencing Symptoms.

Among individuals with posttraumatic stress disorder (PTSD), verbal learning and memory are areas of weakness compared with other cognitive domains (e.g., visuospatial memory). In this study, previously deployed military veterans completed clinical assessments of word memory and vocabulary (n = 243) and a laboratory task measuring encoding, free recall, repetition priming, and recognition of words (n = 147). Impaired verbal memory was selectively related to reexperiencing symptoms of PTSD but was not associated with other symptom groupings or blast-induced traumatic brain injury. Implicit priming of response times following word repetition was also unrelated to clinical symptoms. Instead, slowed response times during encoding explained associations between reexperiencing and memory performance. These findings are consistent with alterations in attentional control explaining PTSD-related verbal-memory deficits. Such findings have implications for understanding trauma-focused psychotherapy and recovery, which may depend on efficient attentional processing of words to alter posttraumatic reexperiencing symptoms.

Advancing Research on Mechanisms of Resilience (ARMOR) Longitudinal Cohort Study of New Military Recruits: Results from a Feasibility Pilot Study.

Psychological resilience as a longitudinal process is highly relevant for understanding the functioning outcomes of military populations. Here, we review the extant literature on resilience among military service members, focusing on National Guard Soldiers. Our specific project (Advancing Research on Mechanisms of Resilience, "ARMOR") aims to develop a comprehensive model of resilience using a multilevel perspective. We report results from our prospective pilot study (n = 103) conducted in preparation for our large-scale longitudinal cohort study of Basic Combat Training (BCT) and its impact on military recruits' wellbeing. Results support feasibility of the larger study, evidence for a new measure of BCT stressor exposure, and demonstrate preliminary associations with BCT-related stressors and longitudinal changes in adaptive functioning. Future directions for our larger study will utilize data from survey responses, structured clinical interviews, neurobehavioral tasks, and neurobiological measures (functional and structural MRI and electroencephalography [EEG]) to examine individual differences in self-regulation as a predictor of resilience-related processes. ARMOR is well positioned to elucidate mechanisms that could be targeted for promoting wellbeing, preventing psychopathology, and facilitating long-term recovery.

Auditory evoked brain potentials as markers of chronic effects of mild traumatic brain injury in mid-life.

OBJECTIVE: Auditory event-related potential (ERP) correlates of pre-dementia in late-life may also be sensitive to chronic effects of mild traumatic brain injury (mTBI) in mid-life. In addition to mTBI history, other clinical factors may also influence ERP measures of brain function. This study's objective was to evaluate the relationship between mTBI history, auditory ERP metrics, and common comorbidities. METHODS: ERPs elicited during an auditory target detection task, psychological symptoms, and hearing sensitivity were collected in 152 combat-exposed veterans and service members, as part of a prospective observational cohort study. Participants, with an average age of 43.6 years, were grouped according to positive (n = 110) or negative (n = 42) mTBI history. Positive histories were subcategorized into repetitive mTBI (3 + ) (n = 40) or non-repetitive (1-2) (n = 70). RESULTS: Positive history of mTBI was associated with reduced N200 amplitude to targets and novel distractors. In participants with repetitive mTBI compared to non-repetitive and no mTBI, P50 was larger in response to nontargets and N100 was smaller in response to nontargets and targets. Changes in N200 were mediated by depression and anxiety symptoms and hearing loss, with no evidence of a supplementary direct mTBI pathway. CONCLUSIONS: Auditory brain function differed between the positive and negative mTBI groups, especially for repetitive injury, which implicated more basic, early auditory processing than did any mTBI exposure. Symptoms of internalizing psychopathology (depression and anxiety) and hearing loss are implicated in mTBI's diminished brain responses to behaviorally relevant and novel stimuli. SIGNIFICANCE: A mid-life neurologic vulnerability conferred by mTBI, particularly repetitive mTBI, may be detectable using auditory brain potentials, and so auditory ERPs are a target for study of dementia risk in this population.

Posttraumatic stress symptom dimensions and brain responses to startling auditory stimuli in combat veterans.

Posttraumatic stress disorder (PTSD) is marked by alterations in emotional functioning, physiological reactivity, and attention. Neural reactivity to acoustic startle stimuli can be used to understand brain functions related to these alterations. Investigations of startle reactivity in PTSD have yielded inconsistent findings, which may reflect the heterogeneity of the disorder. Furthermore, little is known of how the common co-occurrence of mild traumatic brain injury (mTBI; i.e., concussion) may influence neural reactivity. We examined the event-related potentials (ERPs) of combat veterans (n = 102) to acoustic startle probes delivered during viewing of pleasant, neutral, unpleasant, and combat-related pictures. Interview-based assessments yielded dimensional characterizations of PTSD and mTBI. The P3 ERP response to startle probes was reduced during all affective relative to neutral pictures but failed to be associated with a PTSD diagnosis. However, two separable domains of PTSD symptomatology were associated with startle ERPs regardless of the picture conditions. Maladaptive avoidance was associated with smaller N1, P2, and P3 amplitudes, while intrusive reexperiencing was associated with larger P2 amplitudes. There were no main effects of mTBI. Findings suggest that level of symptomatology rather than a formal diagnosis of PTSD better explains alterations in neural reactivity after traumatic events, while mild brain injuries have little impact. Avoidance symptoms of PTSD may dampen neural functions that facilitate reorientation to threat while intrusive reexperiencing of traumatic events appears to heighten sensory reactivity. Considering specific aspects of symptomatology provides insight into the neural basis of trauma-related psychopathology and may help guide individualization of clinical interventions. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Development of the Multidimensional Personality Questionnaire-55 abbreviated research scales.

The Multidimensional Personality Questionnaire (MPQ) is a normal range inventory for assessing a variety of empirically derived primary traits. These trait scores can be differentially weighted to estimate higher-order broad dimensions such as Positive Emotionality (PEM), Negative Emotionality (NEM), and Constraint (CON). However, broad trait scores are estimated using proprietary regression equations and necessitate near complete administration of the inventory. We aimed to increase measurement efficiency by creating abbreviated item-based approximations of these weighted scores. To parsimoniously delineate and differentiate the broad traits, classical test theory and item response theory approaches were used to identify five items from each primary trait scale approximating the weighted estimates while also maintaining the breadth of MPQ content coverage. Initial scale development relied on the MPQ-276 (standard form) normative sample (n = 1,237), which was followed by cross-validation using two samples of twins and cotwins from the Minnesota Twin Family Study (n = 1,304, n = 1,305). Additional validation was conducted using a third sample of undergraduate students (n = 201).The resulting item-based scales (PEM-20, NEM-15, CON-15) demonstrated strong convergence with the established proprietary broad trait estimates. Furthermore, these abbreviated scales exhibited similar associations with the external measures of personality and psychopathology. Abbreviated item-based scales may have utility for efficient estimation of the same broadband personality dimensions assessed by longer forms of the MPQ. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Posttraumatic stress symptomatology and abnormal neural responding during emotion regulation under cognitive demands: mediating effects of personality.

Posttraumatic stress disorder (PTSD) is often complicated by the after-effects of mild traumatic brain injury (mTBI). The mixture of brain conditions results in abnormal affective and cognitive functioning, as well as maladaptive behavior. To better understand how brain activity explains cognitive and emotional processes in these conditions, we used an emotional N-back task and functional magnetic resonance imaging (fMRI) to study neural responses in US military veterans after deployments to Iraq and Afghanistan. Additionally, we sought to examine whether hierarchical dimensional models of maladaptive personality could account for the relationship between combat-related brain conditions and fMRI responses under cognitive and affective challenge. FMRI data, measures of PTSD symptomatology (PTSS), blast-induced mTBI (bmTBI) severity, and maladaptive personality (MMPI-2-RF) were gathered from 93 veterans. Brain regions central to emotion regulation were selected for analysis, and consisted of bilateral amygdala, bilateral dorsolateral prefrontal (dlPFC), and ventromedial prefrontal/subgenual anterior cingulate (vmPFC-sgACC). Cognitive load increased activity in dlPFC and reduced activity in emotional responding brain regions. However, individuals with greater PTSS showed blunted deactivations in bilateral amygdala and vmPFC-sgACC, and weaker responses in right dlPFC. Additionally, we found that elevated emotional/internalizing dysfunction (EID), specifically low positive emotionality (RC2), accounted for PTSS-related changes in bilateral amygdala under increased cognitive load. Findings suggest that PTSS might result in amygdala and vmPFC-sgACC activity resistant to moderation by cognitive demands, reflecting emotion dysregulation despite a need to marshal cognitive resources. Anhedonia may be an important target for interventions that improve the affective and cognitive functioning of individuals with PTSD.

Symptoms of Posttraumatic Stress Rather Than Mild Traumatic Brain Injury Best Account for Altered Emotional Responses in Military Veterans.

Emotional dysfunction is evident in posttraumatic stress disorder (PTSD), yet it is unclear what aspects of the disorder most directly relate to aberrant emotional responding. Also, the frequent co-occurrence of blast-related mild traumatic brain injuries (mTBIs) among recently deployed U.S. military personnel complicates efforts to understand the basis for emotional disruption. We studied a cross-sectional sample (enriched for PTSD and mTBI) of 123 U.S. veterans of wars in Iraq and Afghanistan. We measured subjective affective evaluations and peripheral psychophysiological responses to images with pleasant, neutral, unpleasant, and combat-related aversive content. When compared with other postdeployment participants, those who had combat-related PTSD rated pleasant image content as less positive (ηp2 = .04) and less arousing (ηp2 = .06), and exhibited heightened physiological responsivity to combat image content (ηp2 = .07). Symptoms of PTSD were associated with elevated skin conductance responses (ß = .28), reduced heart rate deceleration (ß = .44 to .47), and increased corrugator facial muscle electromyography (ß = .47). No effects for blast-related mTBI were observed across any affective modulation measures. These findings point to a greater impact of PTSD symptomatology than blast-related mTBI on emotional functioning and highlight the utility of dimensional assessments of psychopathology for understanding the effects of combat-stress conditions on adjustment to civilian life.

Spontaneous neural activity differences in posttraumatic stress disorder: A quantitative resting-state meta-analysis and fMRI validation.

Identifying the pathophysiology of posttraumatic stress disorder (PTSD) is a critical step toward reducing its debilitating impact. Spontaneous neural activity, measured at rest using various neuroimaging techniques (e.g., regional homogeneity [ReHo], amplitude of low frequency fluctuations [ALFF]), can provide insight about baseline neurobiological factors influencing sensory, cognitive, or behavioral processes associated with PTSD. The present study used activation likelihood estimation (ALE) to conduct the largest-to-date quantitative meta-analysis of spontaneous neural activity in PTSD, including 457 PTSD cases, 292 trauma-exposed controls (TECs), and 293 non-traumatized controls (NTCs) across 22 published studies. Five regions-of-interest (ROIs) were identified where activity differed between PTSD cases and controls: one when compared to all controls (left globus pallidus), two when compared to TECs (left inferior parietal lobule [IPL] and right lingual gyrus), and two when compared to NTCs (left amygdala and right caudate head). To corroborate these results, a second analysis was conducted using resting-state functional magnetic resonance imaging on an independent sample of 205 previously-deployed US military veterans. In this analysis, converging evidence from ReHo and ALFF showed that spontaneous neural activity in the left IPL alone was positively correlated with PTSD symptom severity. This result is consistent with theoretical accounts that link left IPL activity with PTSD-relevant processes such as processing of emotional stimuli (e.g., fearful faces) and the extent that attention is captured by salient autobiographical memories. By modeling the neurobiological correlates of PTSD, we can increase our understanding of this debilitating disorder and guide the development of future clinical innovations.

Reduced P3b brain response during sustained visual attention is associated with remote blast mTBI and current PTSD in U.S. military veterans.

Approximately 275,000 American service members deployed to Iraq or Afghanistan have sustained a mild traumatic brain injury (mTBI), with 75% of these incidents involving an explosive blast. Combat-related mTBI is frequently associated with comorbid mental health disorders, especially posttraumatic stress disorder (PTSD). Attention problems, including sustained attention, are common cognitive complaints of veterans with TBI and PTSD. The present study sought to examine neural correlates of sustained attention in veterans with blast mTBI and/or current PTSD. In 124 veterans of Operations Enduring and Iraqi Freedom (OEF/OIF), we examined event-related potentials (ERPs) elicited by targets and non-targets during performance of a degraded-stimulus continuous performance task (DS-CPT). Four groups, consisting of veterans with blast-related mTBI only, current PTSD only, both blast mTBI and PTSD, and a control group, were studied. Compared to all other groups, blast mTBI only participants were more likely to respond regardless of stimulus type during the DS-CPT. During target detection, the three mTBI/PTSD groups showed reduced amplitude of the P3b (i.e., P300) ERP at Pz compared to the control group. P3b of the three affected groups did not differ from each other. These results suggest that parietal P3b amplitude reduction during target detection in the DS-CPT task may be an index of brain pathology after combat trauma, yet the diminished brain response fails to differentiate independent effects of blast-related mTBI or severity of PTSD symptomatology.

Family history of alcohol dependence and antidepressant response to an N-methyl-D-aspartate antagonist in bipolar depression.

OBJECTIVES: Both ketamine and ethanol are N-methyl-d-aspartate (NMDA) receptor antagonists. Ketamine has rapid antidepressant properties in major depressive disorder (MDD) as well as bipolar depression. In individuals with MDD, a positive family history of alcohol dependence (FHP) was associated with greater improvement in depressive symptoms after ketamine administration compared to individuals whose family history of alcohol dependence was negative (FHN). This study investigated whether FHP influences ketamine's antidepressant and perceptual effects in individuals with bipolar depression. METHODS: A post hoc analysis was conducted on 33 subjects with DSM-IV bipolar disorder (BD) type I or II depression pooled from two previously published studies. All subjects had undergone a double-blind, randomized, crossover trial of a single intravenous infusion of ketamine (0.5 mg/kg) combined with lithium or valproate therapy. Subjects were rated at baseline; at 40, 80, 120, and 230 min; and at days 1, 2, 3, 7, 10, and 14 post-infusion. The primary outcome measure was Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Patients were categorized as FHP when they reported at least one first-degree relative with alcohol dependence. Measures of psychosis, dissociation, and dysphoria were also collected. RESULTS: After ketamine infusion, subjects with FHP showed significantly greater improvement on MADRS scores than FHN subjects. In addition, patients with FHP had attenuated psychotomimetic and dissociative scores compared to FHN patients. CONCLUSIONS: FHP appears to predict a more sustained antidepressant response to ketamine in individuals with BD. Family history of alcoholism may be an important consideration in the development of glutamatergic-based therapies for depression.

Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depression.

BACKGROUND: Clinical evidence that ketamine, a nonselective N-methyl-D-aspartate receptor (NMDAR) antagonist, has therapeutic effects within hours in people suffering from depression suggests that modulating glutamatergic neurotransmission is a fundamental step in alleviating the debilitating symptoms of mood disorders. Acutely, ketamine increases extracellular glutamate levels, neuronal excitability, and spontaneous γ oscillations, but it is unknown whether these effects are key to the mechanism of antidepressant action of ketamine. METHODS: Twenty drug-free major depressive disorder patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made approximately 3 days before and approximately 6.5 hours after the infusion, whereas patients passively received tactile stimulation to the right and left index fingers and also while they rested (eyes-closed). Antidepressant response was assessed by percentage change in Montgomery-Åsberg Depression Rating Scale scores. RESULTS: Patients with robust improvements in depressive symptoms 230 min after infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical responses increase after infusion, relative to pretreatment responses in responders but not in treatment nonresponders. Spontaneous somatosensory cortical γ-band activity during rest did not change within the same timeframe after ketamine in either responders or nonresponders. CONCLUSIONS: These findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later and thus might not be sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depressive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic potentiation is central to the antidepressant effect of ketamine.

Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial.

BACKGROUND: Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N-methyl-D-aspartate antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample. METHODS: In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days 2 weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline; at 40, 80, 110, and 230 minutes postinfusion; and on days 1, 2, 3, 7, 10, and 14 postinfusion. RESULTS: Within 40 minutes, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine compared with placebo (d = .89, 95% confidence interval = .61-1.16, and .98, 95% confidence interval = .64-1.33, respectively); this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time point. CONCLUSIONS: This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients.