mTORC1 activation in presumed classical monocytes: observed correlation with human size variation and neuropsychiatric disease.

BACKGROUND: Gain of function disturbances in nutrient sensing are likely the largest component in human age-related disease. Mammalian target of rapamycin complex 1 (mTORC1) activity affects health span and longevity. The drugs ketamine and rapamycin are effective against chronic pain and depression, and both affect mTORC1 activity. Our objective was to measure phosphorylated p70S6K, a marker for mTORC1 activity, in individuals with psychiatric disease to determine whether phosphorylated p70S6K could predict medication response. METHODS: Twenty-seven females provided blood samples in which p70S6K and phosphorylated p70S6K were analyzed. Chart review gathered biometric measurements, clinical phenotypes, and medication response. Questionnaires assessed anxiety, depression, autism traits, and mitochondrial dysfunction, to determine neuropsychiatric disease profiles. Univariate and multivariate statistical analyses were used to identify predictors of medication response. RESULTS: mTORC1 activity correlated highly with both classical biometrics (height, macrocephaly, pupil distance) and specific neuropsychiatric disease profiles (anxiety and autism). Across all cases, phosphorylated p70S6K was the best predictor for ketamine response, and also the best predictor for rapamycin response in a single instance. CONCLUSIONS: The data illustrate the importance of mTORC1 activity in both observable body structure and medication response. This report suggests that a simple assay may allow cost-effective prediction of medication response.

Cerebrospinal fluid metabolomes of treatment-resistant depression subtypes and ketamine response: a pilot study.

Depression is a disorder with variable presentation. Selecting treatments and dose-finding is, therefore, challenging and time-consuming. In addition, novel antidepressants such as ketamine have sparse optimization evidence. Insights obtained from metabolomics may improve the management of patients. The objective of this study was to determine whether compounds in the cerebrospinal fluid (CSF) metabolome correlate with scores on questionnaires and response to medication. We performed a retrospective pilot study to evaluate phenotypic and metabolomic variability in patients with treatment-resistant depression using multivariate data compression algorithms. Twenty-nine patients with treatment-resistant depression provided fasting CSF samples. Over 300 metabolites were analyzed in these samples with liquid chromatography-mass spectrometry. Chart review provided basic demographic information, clinical status with self-reported questionnaires, and response to medication. Of the 300 metabolites analyzed, 151 were present in all CSF samples and used in the analyses. Hypothesis-free multivariate analysis compressed the resultant data set into two dimensions using Principal Component (PC) analysis, accounting for ~ 32% of the variance. PC1 accounted for 16.9% of the variance and strongly correlated with age in one direction and 5-methyltetrahydrofolate, homocarnosine, and depression and anxiety scores in the opposite direction. PC2 accounted for 15.4% of the variance, with one end strongly correlated with autism scores, male gender, and cognitive fatigue scores, and the other end with bipolar diagnosis, lithium use, and ethylmalonate disturbance. This small pilot study suggests that complex treatment-resistant depression can be mapped onto a 2-dimensional pathophysiological domain. The results may have implications for treatment selection for depression subtypes.

Rapamycin Augmentation of Chronic Ketamine as a Novel Treatment for Complex Regional Pain Syndrome.

This case report describes the dramatic clinical response of refractory chronic complex regional pain syndrome to combined immunomodulatory treatment. Ketamine and rapamycin markedly minimized pain historically associated with suicidal behavior, increased baseline activity, and allowed for a reduction in palliative polypharmacy. The piecewise mechanism of action is unclear given multiple postulated targets, such as microglia, astroglia, T-regulatory cells, B-regulatory cells, or neurons. Relevant laboratory and genetic information may allow the application of this treatment to other affected individuals.

An Online Survey of Patients' Experiences Since the Rescheduling of Hydrocodone: The First 100 Days.

OBJECTIVE: To conduct an Internet patient survey through the National Fibromyalgia & Chronic Pain Association on reactions to the first 100 days following the rescheduling of hydrocodone. METHODS: Face-valid survey questions were created with expert consensus along with repurposed questions used on previous NFMCPA surveys covering domains such as demographics and symptoms. The questionnaire was designed to be administered over the Internet. RESULTS: 6,420 responders met screening criteria and completed the survey. Most (5,181, or 82.5%) had been prescribed hydrocodone for more than 1 year. 2,296, (39.0%) reported no changes in access to hydrocodone, while the majority experienced some barriers. Of those who could no longer get hydrocodone, 1,067 (18.1%) borrowed pain medications, 1,007 (17.1%) turned to marijuana, 773 (13.1%) used alcohol, and 135 (2.3%) used illicit drugs. Most respondents had to visit their healthcare providers more often (N = 3,699, 64.2%) and 1,735 (30.3%) reported some type of issue interacting with their pharmacy. Most felt that the rescheduling was neither a fair nor appropriate solution to the abuse of hydrocodone (N = 4,938, 88.3%). For those still working, 801 (46.2%) reported that they had missed work because of the stricter regulations. 1,462 (27.2%) reported having thoughts of suicide since the rescheduling. SIGNIFICANCE: The unintended consequences for people with chronic pain that have been caused by the rescheduling effort to impede hydrocodone abuse are negatively impacting thousands. These consequences include suffering from being placed on less effective drugs, increased cost, inconvenience, and negative influence on physician-patient and pharmacist-patient relationships.

Sodium oxybate intolerance associated with familial serum acylcarnitine elevation.

Our case describes clinical features of two families defined by joint phenotypes: sodium oxybate intolerance and elevated serum acylcarnitines. Oxybate intolerance variably presents as either cervical dystonia or sleep-related eating disorder. Our objective is to identify biological markers which predict a poor response to sodium oxybate as a treatment for disturbed sleep. Familial inheritance pattern, genotype analysis, multiorgan system involvement, and response to treatment suggest the presence of a secondary cause of fatty oxidation defect, i.e., mitochondrial disorder. Our case report supports the possible conclusion that variance in human mitochondrial metabolism may affect sodium oxybate tolerability.

Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification.

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41% of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.