Features of dissociation differentially predict antidepressant response to ketamine in treatment-resistant depression.

BACKGROUND: Ketamine induces rapid and robust antidepressant effects, and many patients also describe dissociation, which is associated with antidepressant response. This follow-up study investigated whether antidepressant efficacy is uniquely related to dissociative symptom clusters. METHODS: Treatment-resistant patients with major depressive disorder (MDD) or bipolar disorder (BD) (n = 126) drawn from three studies received a single subanesthetic (0.5 mg/kg) ketamine infusion. Dissociative effects were measured using the Clinician-Administered Dissociative States Scale (CADSS). Antidepressant response was measured using the 17-item Hamilton Depression Rating Scale (HAM-D). A confirmatory factor analysis established the validity of CADSS subscales (derealization, depersonalization, amnesia), and a general linear model with repeated measures was fitted to test whether subscale scores were associated with antidepressant response. RESULTS: Factor validity was supported, with a root mean square error of approximation of .06, a comparative fit index of .97, and a Tucker-Lewis index of .96. Across all studies and timepoints, the depersonalization subscale was positively related to HAM-D percent change. A significant effect of derealization on HAM-D percent change was observed at one timepoint (Day 7) in one study. The amnesia subscale was unrelated to HAM-D percent change. LIMITATIONS: Possible inadequate blinding; combined MDD/BD datasets might have underrepresented ketamine's antidepressant efficacy; the possibility of Type I errors in secondary analyses. CONCLUSIONS: From a psychometric perspective, researchers may elect to administer only the CADSS depersonalization subscale, given that it was most closely related to antidepressant response. From a neurobiological perspective, mechanistic similarities may exist between ketamine-induced depersonalization and antidepressant response, although off-target effects cannot be excluded.

The antidepressant efficacy of subanesthetic-dose ketamine does not correlate with baseline subcortical volumes in a replication sample with major depressive disorder.

BACKGROUND: This study sought to reproduce, in a larger sample, previous findings of a correlation between smaller raw 3-Tesla (3T) hippocampal volumes and improved antidepressant efficacy of ketamine in individuals with major depressive disorder (MDD). A secondary analysis stratified subjects according to functional BDNF rs6265 (val66met) genotype. METHODS: Unmedicated subjects with treatment-resistant MDD ( n=55) underwent baseline structural 3T MRI. Data processing was conducted with FSL/FIRST and Freesurfer software. The amygdala, hippocampus, and thalamus were selected a priori for analysis. All subjects received a single 0.5mg/kg × 40-minute ketamine infusion. Pearson correlations were performed with subcortical volumes and percent change in MADRS score (from baseline to 230 minutes, 1 day, and 1 week post-infusion). RESULTS: Raw and corrected subcortical volumes did not correlate with antidepressant response at any timepoint. In val/val subjects ( n=23), corrected left and right thalamic volume positively correlated with antidepressant response to ketamine at 230 minutes post-infusion but did not reach statistical significance. In met carriers ( n=14), corrected left and right thalamic volume negatively correlated with antidepressant response to ketamine. CONCLUSION: Baseline subcortical volumes implicated in MDD did not correlate with ketamine's antidepressant efficacy. Baseline thalamic volume and BDNF genotype may be a combinatorial rapid antidepressant response biomarker.

Active suicidal ideation during clinical antidepressant trials.

Suicidal patients are often excluded from clinical trials of psychiatric medications and from investigations using neurobiological techniques. To evaluate the presence, impact, and stability of active suicidal ideation (SI) across a range of antidepressant trials, we reviewed 14 clinical trials conducted in patients with either major depressive disorder (MDD) or bipolar disorder (BD) (N = 269). Active SI at any time point in the clinical trial was identified and linked to participation in other research procedures. Stability of active SI across subsequent days was evaluated using intraclass correlation coefficients (ICCs) and compared to other depressive symptoms. Across 14 clinical trials, 63 participants (23%) reported active SI at some point during study participation. Of these participants, 33 completed a neuroimaging procedure and 16 completed polysomnography within a week of active SI. When active SI was subsequently assessed, only 39% of patients continued to report active SI after three days of assessment, despite receiving no additional treatment. ICCs were not significant for either SI or pessimism; other depressive symptoms showed stability over time. The results suggest that research can be conducted in depressed patients with active SI if such research coincides with careful observation. Active SI and pessimism may be particularly vulnerable to fluctuation.

Anhedonia as a clinical correlate of suicidal thoughts in clinical ketamine trials.

BACKGROUND: Identifying clinical correlates associated with reduced suicidal ideation may highlight new avenues for the treatment of suicidal thoughts. Anhedonia occurs across psychiatric diagnoses and has been associated with specific neural circuits in response to rapid-acting treatments, such as ketamine. This analysis sought to evaluate whether reductions in suicidal ideation after ketamine administration were related to reduced levels of anhedonia, independent of depressive symptoms. METHODS: This post-hoc analysis included treatment-resistant patients with either major depressive disorder (MDD) or bipolar disorder (BD) from several clinical trials of ketamine. Anhedonia was assessed using a subscale of the Beck Depression Inventory (BDI) and the Snaith-Hamilton Pleasure Scale (SHAPS). The outcome of interest was suicidal ideation, as measured by a subscale of the Scale for Suicide Ideation (SSI5), one day post-ketamine administration. RESULTS: Anhedonia, as measured by the SHAPS, was associated with suicidal thoughts independent of depressive symptoms both before and after ketamine administration. One day post-ketamine administration, improvements on the SHAPS accounted for an additional 13% of the variance in suicidal thought reduction, beyond the influence of depressive symptoms. The BDI anhedonia subscale was not significantly associated with suicidal thoughts after adjusting for depressive symptoms. LIMITATIONS: Data were limited to patients experiencing a major depressive episode and may not be generalizable to patients experiencing an active suicidal crisis. CONCLUSIONS: Suicidal thoughts may be related to symptoms of anhedonia independent of other depressive symptoms. These results have implications for the potential mechanisms of action of ketamine on suicidal thoughts.

Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression.

Several pro-inflammatory cytokines have been implicated in depression and in antidepressant response. This exploratory analysis assessed: 1) the extent to which baseline cytokine levels predicted positive antidepressant response to ketamine; 2) whether ketamine responders experienced acute changes in cytokine levels not observed in non-responders; and 3) whether ketamine lowered levels of pro-inflammatory cytokines, analogous to the impact of other antidepressants. Data from double-blind, placebo-controlled studies of patients with major depressive disorder (MDD) or bipolar disorder (BD) who received a single infusion of sub-anesthetic dose ketamine were used (N = 80). Plasma levels of the eight cytokines were measured at baseline and at 230 min, 1 day, and 3 days post-ketamine. A significant positive correlation was observed between sTNFR1 and severity of depression at baseline. Cytokine changes did not correlate with changes in mood nor predict mood changes associated with ketamine administration. Ketamine significantly increased IL-6 levels and significantly decreased sTNFR1 levels. IL-6 and TNF-α levels were also significantly higher-and sTNFR1 levels were significantly lower-in BD compared to MDD subjects. The functional significance of this difference is unknown. Changes in cytokine levels post-ketamine were not related to antidepressant response, suggesting they are not a primary mechanism involved in ketamine's acute antidepressant effects. Taken together, the results suggest that further study of cytokine levels is warranted to assess their potential role as a surrogate outcome in the rapid antidepressant response paradigm.

Sleep architecture parameters as a putative biomarker of suicidal ideation in treatment-resistant depression.

BACKGROUND: Disturbed sleep may confer risk for suicidal behaviors. Polysomnographic (PSG) sleep parameters have not been systematically evaluated in association with suicidal ideation (SI) among individuals with treatment-resistant depression (TRD). METHODS: This secondary data analysis included 54 TRD individuals (N=30 with major depressive disorder (MDD) and N=24 with bipolar depression (BD)). PSG sleep parameters included Sleep Efficiency (SE), Total Sleep Time (TST), Wakefulness After Sleep Onset (WASO), REM percent/latency, and non-REM (NREM) Sleep Stages 1-4. The Hamilton Depression Rating Scale (HAM-D) was used to group participants according to presence or absence of SI. Sleep abnormalities were hypothesized among those with current SI. ANOVA analyses were conducted before (Model 1) and after adjusting for depression (Model 2) and diagnostic variables (Model 3). RESULTS: Significant differences in PSG parameters were observed in Model 1; those with SI had less NREM Stage 4 sleep (p<.05). After adjusting for central covariates, Models 2 and 3 revealed significantly less NREM Stage 4 sleep, lower SE (P<.05), and higher WASO (P<.05) among those with SI. BD participants with SI also had less NREM Stage 4 and more NREM Stage 1 sleep. LIMITATIONS: 1) a predominantly white sample; 2) exclusion of imminent suicide risk; 3) concomitant mood stabilizer use among BD patients; and 4) single-item SI assessment. CONCLUSIONS: Independent of depression severity, SI was associated with less NREM Stage 4 sleep, and higher nocturnal wakefulness across diagnostic groups. Sleep may warrant further investigation in the pathogenesis of suicide risk, particularly in TRD, where risk may be heightened.

Antisuicidal Response Following Ketamine Infusion Is Associated With Decreased Nighttime Wakefulness in Major Depressive Disorder and Bipolar Disorder.

OBJECTIVE: Insomnia and disrupted sleep are associated with increased risk of suicide. The N-methyl-d-aspartate antagonist ketamine has been associated with reduced suicidal thoughts, but the mechanism of action is unknown. This study sought to evaluate differences in nocturnal wakefulness in depressed individuals who did and did not have an antisuicidal response to ketamine. METHODS: Thirty-four participants with baseline suicidal ideation diagnosed with either DSM-IV major depressive disorder (n = 23) or bipolar depression (n = 11) between 2006 and 2013 completed nighttime electroencephalography (EEG) the night before and the night after a single ketamine infusion (0.5 mg/kg over 40 minutes). Suicidal ideation was assessed at baseline and the morning after ketamine infusion via several measures, including the Hamilton Depression Rating Scale suicide item, the suicide item of the Montgomery-Asberg Depression Rating Scale, and the first 5 items of the Scale for Suicide Ideation. A generalized linear mixed model evaluated differences in nocturnal wakefulness, as verified by EEG, between those who had an antisuicidal response to ketamine and those who did not, controlling for baseline nocturnal wakefulness. Results were also compared to the sleep of healthy controls (n = 22). RESULTS: After analyses adjusted for baseline sleep, participants with an antisuicidal response to ketamine showed significantly reduced nocturnal wakefulness the night after ketamine infusion compared to those without an antisuicidal response (F1,22 = 5.04, P = .04). Level of nocturnal wakefulness after antisuicidal response to ketamine did not differ significantly from nocturnal wakefulness in the control sample but did differ at a trend level (F1,40 = 3.15, P = .08). CONCLUSIONS: Reductions in wakefulness following ketamine may point to a biological mechanism underlying the effect of ketamine on suicidal ideation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00088699.

Symptomatology and predictors of antidepressant efficacy in extended responders to a single ketamine infusion.

BACKGROUND: Antidepressant response to a single subanesthetic dose infusion of the glutamatergic modulator ketamine is transient in most depressed patients; however, a minority continue to experience an extended response. This study examined depressive symptoms and potential clinical predictors of extended response to ketamine in subjects with mood disorders. METHODS: Subjects were diagnosed with either major depressive disorder (MDD) or bipolar depression. All subjects were treatment-resistant and experiencing a major depressive episode of at least moderate severity. MDD subjects were unmedicated and those with bipolar depression were receiving therapeutic-dose lithium or valproate. All subjects received a single 0.5mg/kg ketamine infusion. Data were collected pre-infusion (baseline) and at days one, 14, and 28 post-infusion. RESULTS: Twelve of 93 (12.9%) participants continued to meet response criteria (50% reduction in Montgomery-Asberg Depression Rating Scale (MADRS) score) at two weeks. All depressive symptoms assessed by the MADRS were improved at two weeks in ketamine responders except for sleep duration/depth. A positive family history of alcohol use disorder in a first-degree relative (FHP) and greater dissociation during the infusion were associated with better antidepressant response at two weeks. Improved measures of apparent sadness, reported sadness, inability to feel, and difficulty concentrating at day 1 correlated most strongly with antidepressant effects at two weeks. LIMITATIONS: Post-hoc design, small sample size, diagnostic heterogeneity. CONCLUSIONS: Static (FHP) and dynamic (improved depressive symptoms) factors may be clinically useful in predicting whether a patient will have an extended response to ketamine.

Increased Activity or Energy as a Primary Criterion for the Diagnosis of Bipolar Mania in DSM-5: Findings From the STEP-BD Study.

OBJECTIVE: DSM-5 describes "a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy" as a primary criterion for mania. Thus, increased energy or activity is now considered a core symptom of manic and hypomanic episodes. Using data from the Systematic Treatment Enhancement Program for Bipolar Disorder study, the authors analyzed point prevalence data obtained at the initial visit to assess the diagnostic validity of this new DSM-5 criterion. The study hypothesis was that the DSM-5 criterion would alter the prevalence of mania and/or hypomania. METHOD: The authors compared prevalence, clinical characteristics, validators, and outcome in patients meeting the DSM-5 criteria (i.e., DSM-IV criteria plus the DSM-5 criterion of increased activity or energy) and those who did not meet the new DSM-5 criterion (i.e., who only met DSM-IV criteria). RESULTS: All 4,360 participants met DSM-IV criteria for bipolar disorder, and 310 met DSM-IV criteria for a manic or hypomanic episode. When the new DSM-5 criterion of increased activity or energy was added as a coprimary symptom, the prevalence of mania and hypomania was reduced. Although minor differences were noted in clinical and concurrent validators, no changes were observed in longitudinal outcomes. CONCLUSIONS: The findings confirm that including increased activity or energy as part of DSM-5 criterion A decreases the prevalence of manic and hypomanic episodes but does not affect longitudinal clinical outcomes.

Recognition of emotional facial expressions in anxious and nonanxious depression.

BACKGROUND: Anxiety and depression have each been independently associated with impairments in emotional face recognition. However, little is known about the nature of these impairments when anxiety and depression co-occur. METHODS: This post-hoc analysis evaluated the relationship between anxiety status and performance on the Emotional Expression Multimorph Task within a clinical sample of individuals with major depressive disorder (MDD). RESULTS: Participants with anxious depression (n=14) and nonanxious depression (n=14) completed the Emotional Expression Multimorph Task. Those with anxious depression required greater intensity of emotion to identify both happy (p=.01) and sad (p=.04) facial expressions than those with nonanxious depression. Severity of anxiety also correlated with greater intensity of emotion required to detect sad faces. Contrary to prediction, hypervigilance to angry and fearful facial expressions was not observed in anxious depression. LIMITATIONS: The present study did not include an anxiety-only group for comparison, and did not assess state anxiety at time of administration. In addition, the extent to which the experimental task correlates with social functioning is not fully understood. CONCLUSIONS: These findings suggest a diminished sensitivity to happy and sad facial expressions specific to anxious depression, but not a hypervigilance toward threatening facial expressions. Further research on the nature of emotion recognition in anxiety and depression may inform improved clinical interventions.

Nocturnal Wakefulness Is Associated With Next-Day Suicidal Ideation in Major Depressive Disorder and Bipolar Disorder.

OBJECTIVE: Self-reported sleep disturbances may confer elevated risk for suicidal ideation, suicide attempts, and death. However, limited research has evaluated polysomnographically determined sleep disturbance as an acute physiologic risk factor for suicidal thoughts. This study sought to investigate the relationship between nocturnal wakefulness in association with next-day suicidal ideation using overnight polysomnography assessment from data collected between 2006 and 2013. METHODS: Sixty-five participants with DSM-IV-diagnosed major depressive disorder or bipolar depression underwent overnight polysomnography monitoring in a sleep laboratory. The Hamilton Depression Rating Scale (HDRS) was administered the morning after polysomnography recording to assess next-day suicidal ideation, severity of depressive symptoms, and subjective sleep disturbances. RESULTS: Using a generalized linear mixed model, a significant time-by-ideation interaction was found indicating greater nocturnal wakefulness at 4:00 am among participants with suicidal ideation (F4,136 = 3.65, P = .007). Increased time awake during the 4:00 am hour (4:00 to 4:59) was significantly associated with elevated suicidal thoughts the next day (standardized ß = 0.31, P = .008). This relationship persisted after controlling for age, gender, diagnosis, and severity of depressive symptoms. CONCLUSIONS: Greater nocturnal wakefulness, particularly in the early morning hours, was significantly associated with next-day suicidal thoughts. Polysomnographically documented sleep disruption at specific times of night may represent an acute risk factor of suicidal ideation that warrants additional research. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00024635.

Acute risk factors for suicide attempts and death: prospective findings from the STEP-BD study.

OBJECTIVES: Suicide is unfortunately common in psychiatric practice, but difficult to predict. The present study sought to assess which clinical symptoms increase in the months before suicidal behavior in a sample of psychiatric outpatients with bipolar disorder. METHODS: Data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial were used. A total of 103 participants who attempted suicide or died by suicide during the trial were included; a 15% random sample of the remaining participants (n = 427) was used as a comparison sample. Linear mixed models in the six months before suicidal behavior were conducted for each of five proposed acute risk factors for suicidal behavior. Participants were assessed using the Clinical Monitoring Form (CMF) at each visit for the following potential acute risk factors for suicidal behavior: suicidal ideation, loss of interest, anxiety, psychomotor agitation, and high-risk behavior. RESULTS: Each of the five symptoms was elevated overall in individuals who engaged in suicidal behavior (p < 0.05). The severity of both suicidal ideation and loss of interest significantly increased in the months before suicidal behavior (p < 0.001). Anxiety demonstrated comparable effect sizes across multiple models. Psychomotor agitation and high-risk behavior were not significantly elevated before suicidal behavior. CONCLUSIONS: Suicidal ideation, loss of interest and, to a lesser extent, anxiety may represent acute suicide risk factors up to four months before suicidal behavior in outpatients with bipolar disorder. Further investigation of these potential acute risk factors in prospective analyses is warranted.

Safety of research into severe and treatment-resistant mood disorders: analysis of outcome data from 12 years of clinical trials at the US National Institute of Mental Health.

BACKGROUND: Placebo-controlled trials in drug-free patients have long been considered a key research component in the study of mood disorders and relevant treatment mechanisms. However, concerns have been raised about the ethics of such research, leading to an ongoing debate as to whether placebo controls are ethically acceptable. We aimed to assess the cumulative effects of research in individuals with mood disorders and to provide data to address ethical concerns regarding research in this population. METHODS: We obtained empirical data for patients screened between between Dec 13, 2001, and Jan 31, 2014, with either major depressive disorder or bipolar disorder who were enrolled in one or more of 18 clinical trials at a US National Institute of Mental Health (NIMH) inpatient or outpatient behavioural health research clinic. We assessed the cumulative effects of research in our patient population, including the effects of drug taper, drug washout, and placebo administration on mood state. Two subgroups were examined: patients enrolled in trials explicitly requiring treatment resistance and patients with a current or past history of suicidal ideation or behaviour. We used the percentage change from screening as the primary outcome measure for statistical analysis of change in mood over study periods. This study is registered with ClinicalTrials.gov, number NCT00024635. FINDINGS: We obtained data for 540 patients; 360 (71%) patients were enrolled in trials requiring treatment resistance, 58 (12%) of 465 patients had suicidal ideation at screening, and 191 (60%) of 321 patients had a history of suicidal ideation. Mean mood severity at screening was in the moderate to severe range. Full participation in research, including drug tapers, drug-free periods, and placebo-controlled trials, had a low risk of symptom exacerbation. Patients undergoing drug taper had a mean increase in symptom severity of 4·2% (SD 19·56, tdegrees of freedom 96=1·85; p=0·036). We recorded modest increases in the subgroup who tapered to no medications (mean percentage change 5·1% [SD 18·10], t56=2·12; p=0·039), but increases were not significant in participants enrolled in trials requiring treatment resistance (4·3% [18·60], t72=1·96; p=0·054) and those with a current or past history of suicidal ideation or behaviour (1·8% [18·78], t51=0·68; p=0·50). Six serious adverse events were reported, including one suicide attempt that occurred during the standard treatment phase and not during the clinical trial. INTERPRETATION: In general, research participation at the NIMH was not detrimental to health and safety, and conferred benefit in many cases. This finding was true not only in our entire research population, but also in treatment-resistant subgroups and subgroups with a history of suicidality. Our study provides evidence to guide ethical analysis of issues in psychiatric research, and to support continued scientific investigation. FUNDING: Intramural Research Program, NIMH, National Institutes of Health.

A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression.

RATIONALE: Patients with anxious major depressive disorder (AMDD) have more severe symptoms and poorer treatment response than patients with non-AMDD. Increasing evidence implicates the endogenous opioid system in the pathophysiology of depression. AZD2327 is a selective delta opioid receptor (DOR) agonist with anxiolytic and antidepressant activity in animal models. OBJECTIVE: This double-blind, parallel group design, placebo-controlled pilot study evaluated the safety and efficacy of AZD2327 in a preclinical model and in patients with AMDD. METHODS: We initially tested the effects of AZD2327 in an animal model of AMDD. Subsequently, 22 subjects with AMDD were randomized to receive AZD2327 (3 mg BID) or placebo for 4 weeks. Primary outcome measures included the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A). We also evaluated neurobiological markers implicated in mood and anxiety disorders, including vascular endothelial growth factor (VEGF) and electroencephalogram (EEG). RESULTS: Seven (54 %) patients responded to active drug and three (33 %) responded to placebo. No significant main drug effect was found on either the HAM-D (p = 0.39) or the HAM-A (p = 0.15), but the HAM-A had a larger effect size. Levels of AZ12311418, a major metabolite of AZD2327, were higher in patients with an anti-anxiety response to treatment compared to nonresponders (p = 0.03). AZD2327 treatment decreased VEGF levels (p = 0.02). There was a trend (p < 0.06) for those with an anti-anxiety response to have higher EEG gamma power than nonresponders. CONCLUSION: These results suggest that AZD2327 has larger potential anxiolytic than antidepressant efficacy. Additional research with DOR agonists should be considered.

An assessment of the anti-fatigue effects of ketamine from a double-blind, placebo-controlled, crossover study in bipolar disorder.

BACKGROUND: Fatigue is a multidimensional condition that is difficult to treat with standard monoaminergic antidepressants. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist produces rapid and robust improvements in depressive symptoms in treatment-resistant depression. However, there is a dearth of literature examining the anti-fatigue effects of ketamine. We hypothesize that ketamine will rapidly improve fatigue symptoms in treatment-resistant depressed patients. METHODS: This is an exploratory analysis of data obtained from two double-blind, randomized, placebo-controlled, crossover trials. A total of 36 participants with treatment-resistant bipolar I or II disorder in a depressive episode (maintained on therapeutic levels of lithium or valproate) received a single infusion of ketamine hydrochloride intravenously (0.5 mg/kg over 40 min) or placebo. A post-hoc analysis compared fatigue scores on ketamine vs. placebo at 10 time points from baseline through 14 days post-treatment using the National Institute of Health-Brief Fatigue Inventory. RESULTS: A linear mixed model showed that ketamine significantly lowered fatigue scores compared to placebo from 40 min post-treatment to Day 14 with the exception of Day 7. The largest difference in anti-fatigue effects between placebo and ketamine was at day 2 (d=0.58, p<0.05). The effect remained significant after controlling for changes in non-fatigue depressive symptoms. LIMITATION: The retrospective nature and a small sample size are study limitations. CONCLUSIONS: Ketamine rapidly improved fatigue relative to placebo in a group of individuals with treatment-resistant bipolar depression. NMDAR is a glutamate receptor; hence, glutamate may represent a valuable target to study the clinical efficacy of new anti-fatigue approaches in multiple disorders.

Reliability of 7T (1) H-MRS measured human prefrontal cortex glutamate, glutamine, and glutathione signals using an adapted echo time optimized PRESS sequence: A between- and within-sessions investigation.

PURPOSE: To ascertain the mechanisms of neuropsychiatric illnesses and their treatment, accurate and reliable imaging techniques are required; proton magnetic resonance spectroscopy ((1) H-MRS) can noninvasively measure glutamatergic function. Evidence suggests that aberrant glutamatergic signaling plays a role in numerous psychopathologies. Until recently, overlapping glutamatergic signals (glutamate, glutamine, and glutathione) could not easily be separated. However, the advent of novel pulse sequences and higher field magnetic resonance imaging (MRI) allows more precise resolution of overlapping glutamatergic signals, although the question of signal reliability remains undetermined. MATERIALS AND METHODS: At 7T MR, we acquired (1) H-MRS data from the medial pregenual anterior cingulate cortex of healthy volunteers (n = 26) twice on two separate days. An adapted echo time optimized point-resolved spectroscopy sequence, modified with the addition of a J-suppression pulse to attenuate N-acetyl-aspartate multiplet signals at 2.49 ppm, was used to excite and acquire the spectra. In-house software was used to model glutamate, glutamine, and glutathione, among other metabolites, referenced to creatine. Intraclass correlation coefficients (ICCs) were computed for within- and between-session measurements. RESULTS: Within-session measurements of glutamate, glutamine, and glutathione were on average reliable (ICCs ≥0.7). As anticipated, ICCs for between-session values of glutamate, glutamine, and glutathione were slightly lower but nevertheless reliable (ICC >0.62). A negative correlation was observed between glutathione concentration and age (r(24) = -0.37; P < 0.05), and a gender effect was noted on glutamine and glutathione. CONCLUSION: The adapted sequence provides good reliability to measure glutamate, glutamine, and glutathione signals.

Assessing measures of suicidal ideation in clinical trials with a rapid-acting antidepressant.

Rapid reduction of suicidal thoughts is critical for treating suicidal patients. Clinical trials evaluating these treatments require appropriate measurement. Key methodological issues include: 1) the use of single or multi-item assessments, and 2) evaluating whether suicidal ideation measures can track rapid change over time. The current study presents data from two randomized, placebo-controlled, crossover clinical trials evaluating ketamine in individuals with treatment-resistant depression (n = 60). Participants were assessed for suicidal thoughts using the Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), and Scale for Suicidal Ideation (SSI) at eight time points over three days. Assessments were compared using correlational analyses and effect sizes at 230 min and three days after ketamine infusion. Linear mixed models evaluated change in ideation across all time points. The HAM-D and MADRS suicide items demonstrated correlations of r > .80 with the first five items of the SSI (SSI5). On linear mixed models, an effect for ketamine was found for the HAM-D, MADRS, BDI items, and SSI5 (p < .001), but not for the full SSI (p = .88), which suggests a limited ability to assess change over time in patients with low levels of suicidal thoughts. Taken together, the results suggest that repeated suicidal assessments over minutes to days appear to detect improvement in suicidal thoughts after ketamine infusion compared to placebo. The MADRS suicide item, BDI suicide item, and SSI5 may be particularly sensitive to rapid changes in suicidal thoughts.

Development of a clinician-administered National Institutes of Health-Brief Fatigue Inventory: A measure of fatigue in the context of depressive disorders.

OBJECTIVE: Fatigue is a complex, multidimensional condition. Although it is often associated with depression, it is not known whether it has a distinct network from depression or whether it can be clinically evaluated, separately. This study describes preliminary findings in the development of a brief, clinician-administered instrument to measure fatigue in the context of depressive disorders using items from existing clinician-administered depression and mania scales. METHODS: Based on items from prior fatigue measurements, items were selected from the Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale, and Structured Interview Guide for HDRS with Atypical Depression. The final items composed the NIH-Brief Fatigue Inventory (NIH-BFI). Responses from 89 depressed adults collected pre- and post-antidepressant therapy (ADT) determined the reliability and consistency of the NIH-BFI using Cronbach's alpha and principal components analysis (PCA). Correlations of the NIH-BFI and fatigue items from other scales before and after ADT explored validity. RESULTS: The 7-item NIH-BFI had Cronbach alphas ranging from 0.81 to 0.88 and PCA indicating a single dimension. The NIH-BFI score was strongly correlated (r = 0.73, p < 0.001) with fatigue items from Beck Depression Index, with MADRS without fatigue items (r = 0.77, p < 0.001), and HDRS without fatigue items (pre: r = 0.69, p < 0.001). CONCLUSIONS: Preliminary findings show support for internal consistency reliability and validity of the NIH-BFI, a clinician-administered measure of fatigue. Further testing in other clinical populations is recommended to obtain additional information on reliability and validity. The NIH-BFI provides a method for clinician-rated fatigue that may be a separate from depression.