mTORC1 inhibitor effects on rapid ketamine-induced reductions in suicidal ideation in patients with treatment-resistant depression.

Suicide is a public health crisis with limited treatment options. Ketamine has demonstrated rapid and robust improvements in suicidal ideation (SI). The parent study for the secondary pilot analyses presented here was a double-blind, cross-over trial that found pretreatment with the mechanistic target of rapamycin complex 1 (mTORC1) prolonged the antidepressant effects of ketamine. Here we examined the effect of mTORC1 inhibition on ketamine's antisuicidal effects. Twenty patients in a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo prior to IV ketamine (0.5 mg/kg). We found ketamine administration resulted in significant improvements across all measures with the largest effect at 24 h with only the Beck Scale for Suicide remaining significant at the two-week follow-up. There were no significant main effects of pretreatment. While these analyses are pilot in nature and overall severity of SI was relatively low, the antisuicidal findings (no effect of rapamycin) being in contrast to the antidepressant effects (prolonged effect with rapamycin), suggest the rapid-acting antisuicidal and antidepressant effects of ketamine may be mechanistically distinct and the trajectories of response, recovery, and relapse may be independent. These findings provide additional evidence of ketamine's antisuicidal effects and highlight the importance of future studies that continue to examine potential differences in mechanisms and trajectory of outcomes.

Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial.

This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or standard dose (0.5 mg/kg; n = 51) ketamine. Participants were assessed at baseline, during treatment, and for 4 weeks after their last infusion. Primary analyses used mixed effects models. The primary outcome measure was the self-report PTSD Checklist for DSM-5 (PCL-5), and secondary outcome measures were the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Montgomery Åsberg Depression Rating Scale (MADRS). There were no significant group-by-time interactions for PTSD symptoms measured by the PCL-5 or CAPS-5. The standard ketamine dose ameliorated depression measured by the MADRS significantly more than placebo. Ketamine produced dose-related dissociative and psychotomimetic effects, which returned to baseline within 2 h and were less pronounced with repeated administration. There was no evidence of differential treatment discontinuation by ketamine dose, consistent with good tolerability. This clinical trial failed to find a significant dose-related effect of ketamine on PTSD symptoms. Secondary analyses suggested that the standard dose exerted rapid antidepressant effects. Further studies are needed to determine the role of ketamine in PTSD treatment. ClinicalTrials.gov identifier: NCT02655692.

A robust and reproducible connectome fingerprint of ketamine is highly associated with the connectomic signature of antidepressants.

Over the past decade, various N-methyl-D-aspartate modulators have failed in clinical trials, underscoring the challenges of developing novel rapid-acting antidepressants based solely on the receptor or regional targets of ketamine. Thus, identifying the effect of ketamine on the brain circuitry and networks is becoming increasingly critical. In this longitudinal functional magnetic resonance imaging study of data from 265 participants, we used a validated predictive model approach that allows the full assessment of brain functional connectivity, without the need for seed selection or connectivity summaries. First, we identified a connectome fingerprint (CFP) in healthy participants (Cohort A, n = 25) during intravenous infusion of a subanesthetic dose of ketamine, compared to normal saline. We then demonstrated the robustness and reproducibility of the discovered ketamine CFP in two separate healthy samples (Cohort B, n = 22; Cohort C, n = 18). Finally, we investigated the ketamine CFP connectivity at 1-week post treatment in major depressive disorder patients randomized to 8 weeks of sertraline or placebo (Cohort D, n = 200). We found a significant, robust, and reproducible ketamine CFP, consistent with reduced connectivity within the primary cortices and within the executive network, but increased connectivity between the executive network and the rest of the brain. Compared to placebo, the ketamine CFP connectivity changes at 1 week predicted response to sertraline at 8 weeks. In each of Cohorts A-C, ketamine significantly increased connectivity in a previously identified antidepressant CFP. Investigating the brain connectivity networks, we successfully identified a robust and reproducible ketamine biomarker that is related to the mechanisms of antidepressants.

Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin.

Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients suffering a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo 2 h prior to the intravenous administration of ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery-Åsberg Depression Rating Scale (MADRS). Rapamycin pretreatment did not alter the antidepressant effects of ketamine at the 24-h timepoint. Over the subsequent 2-weeks, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), suggesting a prolongation of the antidepressant effects of ketamine by rapamycin. Two weeks following ketamine administration, we found higher response (41%) and remission rates (29%) following rapamycin + ketamine compared to placebo + ketamine (13%, p = 0.04, and 7%, p = 0.003, respectively). In summary, single dose rapamycin pretreatment failed to block the antidepressant effects of ketamine, but it prolonged ketamine's antidepressant effects. This observation raises questions about the role of systemic vs. local blockade of mTORC1 in the antidepressant effects of ketamine, provides preliminary evidence that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that contribute to depression relapse after ketamine administration.

Interactive effects of an N-methyl-d-aspartate receptor antagonist and a nicotinic acetylcholine receptor agonist on mismatch negativity: Implications for schizophrenia.

N-methyl-d-aspartate glutamate receptor (NMDAR) hypofunction has been implicated in the pathophysiology of schizophrenia, including auditory processing abnormalities reflected by the mismatch negativity (MMN) event-related potential component. Evidence suggesting cognitive benefits from nicotine administration, together with the high rate of cigarette use in patients with schizophrenia, has stimulated interest in whether nicotine modulates NMDAR hypofunction. We examined the interactive effects of ketamine, an NMDAR antagonist that produces transient schizophrenia-like neurophysiological effects, and nicotine, a nicotinic acetylcholine receptor (nAChR) agonist, in 30 healthy volunteers to determine whether nicotine prevents or attenuates MMN abnormalities. Secondary analyses compared the profile of ketamine and schizophrenia effects on MMN using previously reported data from 24 schizophrenia patients (Hay et al. 2015). Healthy volunteers completed four test days, during which they received ketamine/placebo and nicotine/placebo in a double-blind, counterbalanced design. MMN to intensity, frequency, duration, and frequency+duration double deviant sounds was assessed each day. Ketamine decreased intensity, frequency, and double deviant MMN amplitudes, whereas nicotine increased intensity and double deviant MMN amplitudes. A ketamine×nicotine interaction indicated, however, that nicotine failed to attenuate the decrease in MMN associated with ketamine. Although the present dose of ketamine produced smaller decrements in MMN than those associated with schizophrenia, the profile of effects across deviant types did not differ between ketamine and schizophrenia. Results suggest that while ketamine and schizophrenia produce similar profiles of MMN effects across deviant types, nicotinic agonists may have limited potential to improve these putative NMDAR hypofunction-mediated impairments in schizophrenia.

Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine.

Some schizophrenia patients are more sensitive to amphetamine (AMPH)-induced exacerbations in psychosis-an effect that correlates with higher striatal dopamine release. This enhanced vulnerability may be related to gamma-aminobutyric acid (GABA) deficits observed in schizophrenia. We hypothesized that a pharmacologically induced GABA deficit would create vulnerability to the psychotomimetic effects to the 'subthreshold' dose of AMPH in healthy subjects, which by itself would not induce clinically significant increase in positive symptoms. To test this hypothesis, a GABA deficit was induced by intravenous infusion of iomazenil (IOM; 3.7 µg/kg), an antagonist and partial inverse agonist of benzodiazepine receptor. A subthreshold dose of AMPH (0.1 mg/kg) was administered by intravenous infusion. Healthy subjects received placebo IOM followed by placebo AMPH, active IOM followed by placebo AMPH, placebo IOM followed by active AMPH, and active IOM followed by active AMPH in a randomized, double-blind crossover design over 4 test days. Twelve healthy subjects who had a subclinical response to active AMPH alone were included in the analysis. Psychotomimetic effects (Positive and Negative Syndrome Scale (PANSS)), perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)), and subjective effects (visual analog scale) were captured before and after the administration of drugs. IOM significantly augmented AMPH-induced peak changes in PANSS positive symptom subscale and both subjective and objective CADSS scores. There were no pharmacokinetic interactions. In conclusion, GABA deficits increased vulnerability to amphetamine-induced psychosis-relevant effects in healthy subjects, suggesting that pre-existing GABA deficits may explain why a subgroup of schizophrenia patients are vulnerable to AMPH.

Effects of nicotine on the neurophysiological and behavioral effects of ketamine in humans.

BACKGROUND: N-methyl-d-aspartate (NMDA) receptor hypofunction has been implicated in the pathophysiology of schizophrenia and its associated neurocognitive impairments. The high rate of cigarette smoking in schizophrenia raises questions about how nicotine modulates putative NMDA receptor hypofunction in the illness. Accordingly, we examined the modulatory effects of brain nicotinic acetylcholine receptor (nAChR) stimulation on NMDA receptor hypofunction by examining the interactive effects of nicotine, a nAChR agonist, and ketamine, a non-competitive NMDA receptor antagonist, on behavioral and neurophysiological measures in healthy human volunteers. METHODS: From an initial sample of 17 subjects (age range 18-55 years), 8 subjects successfully completed 4 test sessions, each separated by at least 3 days, during which they received ketamine or placebo and two injections of nicotine or placebo in a double-blind, counterbalanced manner. Schizophrenia-like effects Positive and Negative Syndrome Scale, perceptual alterations Clinician Administered Dissociative Symptoms Scale, subjective effects Visual Analog Scale and auditory event-related brain potentials (mismatch negativity, MMN; P300) were assessed during each test session. RESULTS: Consistent with existing studies, ketamine induced transient schizophrenia-like behavioral effects. P300 was reduced and delayed by ketamine regardless of whether it was elicited by a target (P3b) or novel (P3a) stimulus, while nicotine only reduced the amplitude of P3a. Nicotine did not rescue P300 from the effects of ketamine; the interactions of ketamine and nicotine were not significant. While nicotine significantly reduced MMN amplitude, ketamine did not. CONCLUSION: Nicotine failed to modulate ketamine-induced neurophysiological and behavioral effects in this preliminary study. Interestingly, ketamine reduced P3b amplitude and nicotine reduced P3a amplitude, suggesting independent roles of NMDA receptor and nAChR in the generation of P3b and P3a, respectively.

Prefrontal and temporal gray matter density decreases in opiate dependence.

RATIONALE: There have been only a few structural brain-imaging studies, with varied findings, of opiate-dependent subjects. Voxel-based morphometry (VBM) is suitable for studying whole brain-wise structural brain changes in opiate-dependent subjects. OBJECTIVES: The objective of the current study is to explore gray matter density in opiate-dependent subjects. METHODS: Gray matter density in 63 opiate-dependent subjects and 46 age- and sex-matched healthy comparison subjects was compared using VBM. RESULTS: Relative to healthy comparison subjects, opiate-dependent subjects exhibited decreased gray matter density in bilateral prefrontal cortex [Brodmann areas (BA) 8, 9, 10, 11, and 47], bilateral insula (BA 13), bilateral superior temporal cortex (BA 21 and 38), left fusiform cortex (BA 37), and right uncus (BA 28). CONCLUSIONS: This study reports that opiate-dependent subjects have gray matter density decreases in prefrontal and temporal cortex, which may be associated with behavioral and neuropsychological dysfunction in opiate-dependent subjects.

In vivo proton magnetic resonance spectroscopy of the temporal lobe in Alzheimer's disease.

PURPOSE: Prior proton magnetic resonance spectroscopy (MRS) studies have consistently reported decreased brain n-acetyl aspartate (NAA) levels and increased myo-inositol (mI) levels in subjects with Alzheimer's disease (AD) relative to healthy comparison subjects. These studies have usually been conducted in small and homogeneous populations of patients with established Alzheimer's disease. Few studies have tested the usefulness of this finding in a general population seeking evaluation for memory loss and other cognitive declines. We designed a study to evaluate the significance of single-voxel proton MRS findings in these patients with memory loss and other cognitive declines. GENERAL METHOD: Thirty-five subjects with a primary complaint of memory loss and other cognitive declines were consecutively referred over a period of 13 months to a specialty clinic. Patients with a diagnosis of mild to moderate probable Alzheimer's disease (N = 22), non-Alzheimer's dementia (depression, multiinfarct dementia, Parkinson's Disease, Korsakoff's Psychosis, and bipolar disorder; N = 13), and healthy comparison subjects (N = 18) were examined with respect to possible differences in metabolites using proton MRS in a 3.4-ml anterior temporal lobe voxel. FINDINGS: The Alzheimer's disease group had 10.7% lower NAA/creatine (Cr) ratios relative to the healthy comparison group and 9.4% lower NAA/creatine relative to the non-Alzheimer's dementia group (15.0% lower NAA/creatine relative to the depression subgroup of the non-Alzheimer's dementia group). There were no significant differences in choline (Cho) or myo-inositol ratios among the groups. There were significant correlations between NAA/creatine ratios and mini-mental status exam (MMSE) scores in subjects with Alzheimer's disease (t = 2.41, p = 0.032) but not in subjects with non-Alzheimer's dementia or in its depression subgroup. CONCLUSIONS: This study found a reduction in the neuronal marker NAA in the anterior temporal lobe of patients diagnosed with probable Alzheimer's disease, using a short add-on proton MRS exam. This change was not observed in patients whose memory loss and other cognitive declines were not attributed to Alzheimer's disease, suggesting that it may aid in the diagnosis or detection of Alzheimer's disease.

White matter hyperintensities in subjects with bipolar disorder.

There have been divergent reports on the prevalence and severity of white matter hyperintensities (WMH) on brain magnetic resonance (MR) images in subjects with bipolar disorder. In the present study, evaluations were made on the prevalence and severity of WMH in subjects with bipolar disorder using contiguous 3-mm thick MR slices as well as fluid attenuated inversion recovery (FLAIR) images. A detailed WMH rating system was employed to assess these WMH. A total of 43 bipolar patients, as diagnosed by the Structured Clinical Interview from the Diagnostic and Statistical Manual-IV (SCID-IV), and 39 healthy comparison subjects were scanned using a 1.5-T whole body GE magnetic resonance scanner. WMH were assessed with a modified composite version of the Fazekas' and Coffey's rating scales to detect less severe WMH. Periventricular and subcortical WMH were coded separately. Subjects with bipolar disorder had greater prevalence of WMH abnormalities than comparison subjects (Bipolar, grade 1 = 11.6%, grade 2 = 9.3%, grade 3 = 7.0%; Comparison, grade 1 = 5.1%, grade 2 = 2.6%, grade 3 = 0%). This difference is mainly due to the differences in deep WMH (Bipolar, grade 1 = 14.0%, grade 2 = 14.0%; Comparison, grade 1 = 7.7%, grade 2 = 0%). The current study confirms the higher prevalence of WMH in subjects with bipolar disorder. Differences of small-sized WMH abnormalities between groups were successfully detected using a large number of bipolar subjects and thinner sliced MR images with FLAIR.

White matter hyperintensities in subjects with cocaine and opiate dependence and healthy comparison subjects.

The prevalence, severity, and location of white matter signal hyperintensities (WMH) on brain magnetic resonance images were compared in patients with cocaine or opiate dependence and healthy subjects. Patients with cocaine (n=32) and opiate dependence (n=32), whose diagnoses were confirmed with the Structured Clinical Interview for DSM-IV, and age- and sex-matched healthy subjects (n=32) were scanned using a 1.5 T whole body GE magnetic resonance scanner. Axial proton-density and T2-weighted images were obtained as well as fluid-attenuated inversion recovery axial images. The severity of WMH was assessed separately for deep (and insular) and periventricular WMH, using a modified composite version of the rating scales of Fazekas and Coffey. The cocaine-dependent group had greater severity of WMH than the opiate-dependent group, which in turn had greater severity of WMH than the healthy comparison group (odds ratios=2.54 and 2.90, respectively). The cocaine-dependent group had greater lesion severity of deep and insular WMH than the opiate-dependent group and the healthy comparison group (odds ratio>3.25 for deep WMH; odds ratio>4.38 for insular WMH). For periventricular WMH, there were no significant differences between the three groups. The frontal lobes were the predominant locations of WMH in both substance-dependent groups. The greater prevalence and severity of WMH in cocaine-dependent subjects than in opiate-dependent subjects may reflect the fact that cocaine induces more ischemia via vasoconstriction than opiates. Also, there was a trend for lower WMH severity in substance-dependent women relative to the healthy comparison group, possibly due to estrogen's protective effect against cerebrovascular accidents.

Reduced cortical gray matter density in human MDMA (Ecstasy) users: a voxel-based morphometry study.

The popular recreational drug, 3,4-methylenedioxymethamphetamine (MDMA) exerts its actions in part via blockade of serotonin and dopamine reuptake. Many animal and human studies have demonstrated long-lasting reductions in measures of central nervous system (CNS) serotonin function following MDMA administration. One emerging role of serotonin function in the CNS is a positive trophic effect via stimulation of intracellular signaling pathways and trophic factors. We hypothesized that human MDMA users might display neocortical gray matter reductions due to loss of serotonergically mediated trophic effects on cortical cells. However, unlike animal models, most human MDMA users worldwide are polydrug users, thereby complicating the assessment of MDMA toxicity in this group. Structural magnetic resonance imaging (MRI) scans of 31 MDMA polydrug users versus 29 non-MDMA users were compared using voxel-based morphometry (VBM) to assess regional brain gray and white matter concentration. VBM employs gray/white matter segmentation and statistical parametric mapping (SPM) analysis to calculate a voxel-wise comparison of regional gray or white matter concentration. Using this method, we consistently found several brain regions having decreased gray matter concentration in MDMA polydrug users. These regions were localized to neocortex in bilateral Brodmann area (BA) 18, left BA 21, and left BA 45, as well as bilateral cerebellum, and midline brainstem. Overall, these preliminary findings suggest that MDMA polydrug users have multiple regions of gray matter reduction, potentially accounting for previously reported neuropsychiatric impairments in MDMA users. Additional animal model and human studies of the CNS effects of MDMA and combined MDMA-polydrug toxicity are needed to further explain these findings. Potential explanations for our results including pre-existing brain differences predisposing to MDMA polydrug use, direct MDMA and polydrug toxicity, indirect changes due to MDMA and polydrug toxicity, or combinations of all these factors.

N-methyl-D-aspartate receptor in working memory impairments in schizophrenia: event-related potential study of late stage of working memory process.

Working memory (WM) deficit in schizophrenic patients has been well established. Still, underlying biological substrate of the impairment is not clear. Among neurotransmitter hypotheses of schizophrenia, N-methyl-D-aspartate (NMDA) receptor model is mostly supported, considering that NMDA receptor antagonist can elicit both psychosis and cognitive impairment observed in schizophrenic patients. In current study, to test the neuropsychological and the electrophysiological effects of NMDA receptor in WM, event-related potentials (ERPs) of Sternberg's short-term memory scanning task (SMST) were analyzed in 10 healthy subjects under intravenous administration of a subanesthetic dose of ketamine (0.65 mg/kg/h) or placebo (normal saline). Late positive component (LPC) of ERP was hypothesized to reflect later stage of WM. Brief Psychiatric Rating Scale score was significantly increased (t=-5.75, df=9, P<.001) and correct response rate was significantly decreased (t=2.21, df=9, P=.054) after ketamine administration. Neither reaction time nor LPC latency, which reflect memory scanning time, was changed. Amplitude of LPC was significantly reduced after ketamine administration (z=-2.31, number of observations=120, P=.021). In conclusion, NMDA receptor antagonist administration elicited WM deficit both in behavioral and electrophysiological level. Electrophysiological component reflecting later stage of WM was impaired by NMDA antagonist.

Oral choline decreases brain purine levels in lithium-treated subjects with rapid-cycling bipolar disorder: a double-blind trial using proton and lithium magnetic resonance spectroscopy.

OBJECTIVES: Oral choline administration has been reported to increase brain phosphatidylcholine levels. As phospholipid synthesis for maintaining membrane integrity in mammalian brain cells consumes approximately 10-15% of the total adenosine triphosphate (ATP) pool, an increased availability of brain choline may lead to an increase in ATP consumption. Given reports of genetic studies, which suggest mitochondrial dysfunction, and phosphorus (31P) magnetic resonance spectroscopy (MRS) studies, which report dysfunction in high-energy phosphate metabolism in patients with bipolar disorder, the current study is designed to evaluate the role of oral choline supplementation in modifying high-energy phosphate metabolism in subjects with bipolar disorder. METHODS: Eight lithium-treated patients with DSM-IV bipolar disorder, rapid cycling type were randomly assigned to 50 mg/kg/day of choline bitartrate or placebo for 12 weeks. Brain purine, choline and lithium levels were assessed using 1H- and 7Li-MRS. Patients received four to six MRS scans, at baseline and weeks 2, 3, 5, 8, 10 and 12 of treatment (n = 40 scans). Patients were assessed using the Clinical Global Impression Scale (CGIS), the Young Mania Rating Scale (YRMS) and the Hamilton Depression Rating Scale (HDRS) at each MRS scan. RESULTS: There were no significant differences in change-from-baseline measures of CGIS, YMRS, and HDRS, brain choline/creatine ratios, and brain lithium levels over a 12-week assessment period between the choline and placebo groups or within each group. However, the choline treatment group showed a significant decrease in purine metabolite ratios from baseline (purine/n-acetyl aspartate: coef = -0.08, z = -2.17, df = 22, p = 0.030; purine/choline: coef = -0.12, z = -1.97, df = 22, p = 0.049) compared to the placebo group, controlling for brain lithium level changes. Brain lithium level change was not a significant predictor of purine ratios. CONCLUSIONS: The current study reports that oral choline supplementation resulted in a significant decrease in brain purine levels over a 12-week treatment period in lithium-treated patients with DSM-IV bipolar disorder, rapid-cycling type, which may be related to the anti-manic effects of adjuvant choline. This result is consistent with mitochondrial dysfunction in bipolar disorder inadequately meeting the demand for increased ATP production as exogenous oral choline administration increases membrane phospholipid synthesis.