Dynamic insulin-stimulated mTOR/GSK3 signaling in peripheral immune cells: Preliminary evidence for an association with lithium response in bipolar disorder.

INTRODUCTION: A key mechanism of lithium is the inhibition of glycogen synthase kinase-3ß (GSK3ß) and activation of mammalian target of rapamycin (mTOR), two contributors to insulin signaling. We explored the relationship between these markers and clinical response to lithium in bipolar disorder (BD). METHODS: Thirty-four subjects with BD who had been taking lithium for ≥2 years and had a maintenance lithium Alda score defined as either high (≥7; n = 20) or low (≤2; n = 14) were included in the study. Baseline protein expression of GSK3ß and mTOR (total and phosphorylated (p)) was obtained from a buffy coat. Peripheral blood mononuclear cells (PBMCs) from a subset of each group (n = 11) were stimulated with insulin (10 µg) and change in protein expression was determined using Western blot. RESULTS: In buffy coat samples, significantly higher levels of pmTOR were present in subjects with an Alda score ≤2 (lithium non-responsive), relative to those with scores ≥7 (lithium-responsive). No differences were observed for pGSK3ß. In contrast, functional PBMC responses to 5 min of insulin stimulation demonstrated robust increases in pGSK3ß (87.05 ± 43.41%) and pmTOR (105.7 ± 66.48%) in the lithium responsive group only. This contrasted observed decreases in pGSK3ß (34.08 ± 16.12%) and pmTOR (37.84 ± 14.39%) 5 mins post-insulin in non-responders. CONCLUSIONS: Dynamic increases in pmTOR and pGSK3ß post-insulin stimulation may reflect an immunometabolic state that facilitates lithium response. Further prospective analyses are needed to replicate and extend these preliminary findings and further investigate the role of insulin signaling in lithium response in BD.

Insulin-stimulated mTOR activation in peripheral blood mononuclear cells associated with early treatment response to lithium augmentation in rodent model of antidepressant-resistance.

Lithium has been shown to have some therapeutic efficacy as an adjunctive treatment for intractable forms of major depression. Activation of mammalian target of rapamycin (mTOR) and inhibition of glycogen synthase kinase-3ß (GSK3ß) have been implicated in its putative mechanisms of action. These proteins are integral components of the insulin signaling pathway, which may serve as a critical co-regulator of drug action. Utilizing an animal model of tricyclic antidepressant resistance, we investigated the relationship between insulin signaling and antidepressant response to lithium augmentation. Pre-treatment with adrenocorticotropic hormone (ACTH 100 µg/day i.p.) for 14 days effectively blocked the immobility-reducing effects of an acute dose of imipramine (10 mg/kg i.p.) in the forced swim test (FST). Lithium augmentation (100 mg/kg i.p.) rescued the antidepressant-like effects of imipramine in this model. Total and phosphorylated (p) levels of protein kinase B (Akt), mTOR, and GSK3ß protein were quantified in the infralimbic cortex (ILPFC) following FST stress via Western blot. Levels of mTOR and pmTOR were further quantified in isolated peripheral blood mononuclear cells (PBMCs) following insulin stimulation (10 mg/mL for 5 min) via ELISA. Elevated levels of phosphorylated insulin signaling proteins were present in the ILPFC of ACTH-pretreated animals that received both imipramine and lithium, together with a concurrent increase in mTOR activation in PBMCs. Large correlations were observed between immobility time and insulin-stimulated mTOR levels in PBMCs. We propose that PBMC insulin challenge may be a useful probe for predicting antidepressant response to lithium administration, and potentially other therapies acting via similar mechanisms of action.

Cytochrome P450 2C19 Poor Metabolizer Phenotype in Treatment Resistant Depression: Treatment and Diagnostic Implications.

Background: Pharmacogenomic testing, specifically for pharmacokinetic (PK) and pharmacodynamic (PD) genetic variation, may contribute to a better understanding of baseline genetic differences in patients seeking treatment for depression, which may further impact clinical antidepressant treatment recommendations. This study evaluated PK and PD genetic variation and the clinical use of such testing in treatment seeking patients with bipolar disorder (BP) and major depressive disorder (MDD) and history of multiple drug failures/treatment resistance. Methods: Consecutive depressed patients evaluated at the Mayo Clinic Depression Center over a 10-year study time frame (2003-2013) were included in this retrospective analysis. Diagnoses of BP or MDD were confirmed using a semi-structured diagnostic interview. Clinical rating scales included the Hamilton Rating Scale for Depression (HRSD24), Generalized Anxiety Disorder 7-item scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Adverse Childhood Experiences (ACE) Questionnaire. Clinically selected patients underwent genotyping of cytochrome P450 CYP2D6/CYP2C19 and the serotonin transporter SLC6A4. PK and PD differences and whether clinicians incorporated test results in providing recommendations were compared between the two patient groups. Results: Of the 1795 patients, 167/523 (31.9%) with BP and 446/1272 (35.1%) with MDD were genotyped. Genotyped patients had significantly higher self-report measures of depression and anxiety compared to non-genotyped patients. There were significantly more CYP2C19 poor metabolizer (PM) phenotypes in BP (9.3%) vs. MDD patients (1.7%, p = 0.003); among participants with an S-allele, the rate of CYP2C19 PM phenotype was even higher in the BP (9.8%) vs. MDD (0.6%, p = 0.003). There was a significant difference in the distribution of SLC6A4 genotypes between BP (l/l = 28.1%, s/l = 59.3%, s/s = 12.6%) and MDD (l/l = 31.4%, s/l = 46.1%, s/s = 22.7%) patients (p < 0.01). Conclusion: There may be underlying pharmacogenomic differences in treatment seeking depressed patients that potentially have impact on serum levels of CYP2C19 metabolized antidepressants (i.e., citalopram / escitalopram) contributing to rates of efficacy vs. side effect burden with additional potential risk of antidepressant response vs. induced mania. The evidence for utilizing pharmacogenomics-guided therapy in MDD and BP is still developing with a much needed focus on drug safety, side effect burden, and treatment adherence.

Use of a Gabapentin Protocol for the Management of Alcohol Withdrawal: A Preliminary Experience Expanding From the Consultation-Liaison Psychiatry Service.

BACKGROUND: Benzodiazepines are the conventional mainstay to manage alcohol withdrawal; however, patients are subsequently at increased risk for poor sleep, cravings, and return to drinking. Research on alternative pharmacologic agents to facilitate safe alcohol withdrawal is scant. Gabapentin is one medication shown in small studies to reduce the need for benzodiazepines in the setting of alcohol withdrawal. The continuation of gabapentin after alcohol withdrawal appears to be safe during early sobriety and may aid in reducing alcohol-related cravings or returning to alcohol consumption. Use of a gabapentin-based, benzodiazepine-sparing protool began in early 2015 by the Mayo Clinic, Rochester, Consultation-Liaison Psychiatry Service. OBJECTIVE: A retrospective chart review was conducted to detect any safety concerns with use of a gabapentin protocol for alcohol withdrawal syndrome. METHODS: Secondary outcomes were derived by comparing a matched cohort of patients who received benzodiazepines for alcohol withdrawal syndrome. RESULTS: Seventy-seven patients had their alcohol withdrawal managed via a gabapentin protocol during the study period. No patients required transfer to a higher level of care or had a documented withdrawal seizure. Length of stay between the gabapentin protocol group and benzodiazepine group were similar. CONCLUSION: This preliminary data has supported the frequent use of this protocol in the general internal medicine practice and formalization of an institutional order set of this protocol for mild to moderate alcohol withdrawal syndrome. Prospective studies are required to validate findings.

Mirtazapine for Symptomatic Relief on a Psychiatric Consultation Service: A Case Series.

BACKGROUND: With a complex pharmacologic profile, mirtazapine may promote sleep, stimulate appetite, improve nausea, and reduce pain. Some practitioners working on the Mayo Clinic inpatient psychiatric consultation/liaison service have recommended mirtazapine in medically ill patients with or without formal psychiatric comorbidity to target these symptoms. OBJECTIVE: To assess the success of this practice, we conducted a retrospective chart review covering a 4.5-year period. METHODS: For patients recommended to start mirtazapine, global improvement in specific symptoms and suspected side effects were recorded. RESULTS: During the study period, 528 medically ill patients started mirtazapine following a recommendation from the psychiatric consultation service. In total, 475 patients were provided mirtazapine to specifically target sleep, nausea, pain, or appetite. There was documented improvement in these symptoms for 37.7%, 37.0%, 36.4%, and 23.5% of the patients, respectively. These rates of improvement are conservative for the 229 patients without documented response, i.e., 48% of the patients who were given the medication for a somatic symptom were counted as having no improvement. Commonly documented adverse effects were daytime sedation (5.3%), worsening mental status (2.3%), and nightmares (1%). CONCLUSIONS: Despite the limitations of this retrospective, qualitative study, these data confirm that mirtazapine is generally well tolerated and can provide at least short-term relief of certain symptoms in medically ill patients. Controlled trials are needed to assess these benefits more systematically, and it is not clear how long mirtazapine should be used for these symptoms.

Novel magnetomechanical MR compatible vibrational device for producing kinesthetic illusion during fMRI.

PURPOSE: Functional MRI (fMRI) can provide insights into the functioning of the sensorimotor system, which is of particular interest in studying people with movement disorders or chronic pain conditions. This creates a demand for manipulanda that can fit and operate within the environment of a MRI scanner. Here, the authors present a magnetomechanical device that delivers a vibrotactile sensation to the skin with a force of approximately 9 N. METHODS: MRI compatibility of the device was tested in a 3 T scanner using a phantom to simulate the head. Preliminary investigation into the effectiveness of the device at producing cortical and subcortical activity was also conducted with a group of seven healthy subjects. The vibration was applied to the right extensor carpi ulnaris tendon to induce a kinesthetic illusion of flexion and extension of the wrist. RESULTS: The MRI compatibility tests showed the device did not produce image artifacts and the generated electromagnetic field did not disrupt the static magnetic field of the scanner or its operation. The subject group results showed activity in the contralateral putamen, premotor cortex, and dorsal lateral prefrontal cortex. Ipsilaterally, there was increased activity in the superior and inferior parietal lobules. Areas that activated bilaterally included the thalamus, anterior cingulate, secondary somatosensory areas (S2), temporal lobes, and visual association areas. CONCLUSIONS: This device offers an effective tool with precise control over the vibratory stimulus, delivering higher forces than some other types of devices (e.g., piezoelectric actuators). It can be useful for investigating sensory systems and sensorimotor integration.

Temporal dynamics of the action-sentence compatibility effect.

A number of recent studies have demonstrated variants of the action-sentence compatibility effect (ACE), wherein the execution of a motor response is facilitated by the comprehension of sentences that describe actions taking place in the same direction as the motor response (e.g., a sentence about action towards one's body facilitates the execution of an arm movement towards the body). This paper presents an experiment that explores how the timing of the motor response during the processing of sentences affects the magnitude of the ACE that is observed. The results show that the ACE occurs when the motor response is executed at an early point in the comprehension of the sentence, disappears for a time, and then reappears when the motor response is executed right before the end of the sentence. These data help to refine our understanding of the temporal dynamics involved in the activation and use of motor information during sentence comprehension.

Is long-term structural priming affected by patterns of experience with individual verbs?

Several recent papers have reported long-term structural priming effects in experiments where previous patterns of experience with the double object and prepositional object constructions are shown to affect later patterns of language production for those constructions. The experiments reported in this paper address the extent to which these long-term priming effects are modulated by the participants' patterns of experience with particular verbs within the double object and prepositional object constructions. The results of three experiments show that patterns of experience with particular verbs using the double object or prepositional object constructions do not have much effect on the shape of the longterm structural priming effects reported elsewhere in the literature. These findings lend support to the claim that structural priming is the result of adaptations to the language production system that occur on an abstract, structural level of representation that is separate from representations regarding the behavior of particular lexical items in particular constructions [e.g., Chang, F., Dell, G. S., & Bock, K. (2006). Becoming syntactic. Psychological Review, 113, 234-272]. 2007 Elsevier Inc. All rights reserved.

Recent experience affects the strength of structural priming.

In two experiments, we explore how recent experience with particular syntactic constructions affects the strength of the structural priming observed for those constructions. The results suggest that (1) the strength of structural priming observed for double object and prepositional object constructions is affected by the relative frequency with which each construction was produced earlier in the experiment, and (2) the effects of relative frequency are not modulated by the temporal placement of the tokens of each construction within the experiment.

The Action-Sentence Compatibility Effect: It's All in the Timing.

When participants are asked to make sensibility judgments on sentences that describe action toward the body (i.e., "Mark dealt the cards to you") or away from the body (i.e., "You dealt the cards to Mark"), they are faster to respond when the response requires an arm movement in the same direction as the action described by the sentence. This congruence effect is known as the Action-Sentence Compatibility Effect (ACE). This study reports 4 experiments that extend our understanding of the ACE by exploring how the time at which one prepares the motor response required for the sensibility judgment affects the magnitude of the ACE. Results show that the ACE arises only when participants have the opportunity to plan their motor response while they are processing the sentence.