Stress-related gene regulation: Do isolated and connected individuals differ?

BACKGROUND: Social isolation and loneliness (known as social disconnection, collectively) lead to serious downstream health effects, including shortening of lifespan and higher risk for cardiac disease. We must better understand how isolation and loneliness lead to these negative health outcomes. Previous literature has demonstrated that social motivation and social ability are contributors to the likelihood of social isolation and loneliness. We examined the effect of the above social factors on immune gene expression in socially-connected and -isolated individuals. METHODS: Recruitment occurred via two online advertisements, one for socially isolated individuals and another for general research participants. Participants (n = 102) were separated into groups (isolated versus connected) based on which ad they responded to, and provided data on isolation, loneliness, social motivation, and social ability. The Conserved Transcriptional Response to Adversity (CTRA) stress gene regulation program was assessed with genome-wide transcriptional profiling. RESULTS: CTRA gene expression patterns were reversed between connected and isolated groups across several variables. Social isolation was associated with higher CTRA levels in the connected group, but lower levels in the isolated group. Social approach was associated with lower CTRA levels in the connected group, but higher in the isolated group, and the converse was true for social avoidance. CTRA levels were minimally affected by social ability measures. CONCLUSION: Prior work on social isolation and loneliness has focused on loneliness and has identified many negative downstream health effects. In this study we demonstrate that objective social isolation may not be associated with the same negative downstream health effects, and in fact, social interaction may be more stressful than social isolation for some socially-isolated individuals.

Long-Acting Injectable Therapy for People with HIV: Looking Ahead with Lessons from Psychiatry and Addiction Medicine.

Long-acting injectable antiretroviral medications are new to HIV treatment. People with HIV may benefit from a treatment option that better aligns with their preferences, but could also face new challenges and barriers. Authors from the fields of HIV, substance use treatment, and mental health collaborated on this commentary on the issues surrounding equitable implementation and uptake of LAI ART by drawing lessons from all three fields. We employ a socio-ecological framework beginning at the policy level and moving through the community, organizational, interpersonal, and patient levels. We look at extant literature on the topic as well as draw from the direct experience of our clinician-authors.

Brain glutathione levels and age at onset of illness in chronic schizophrenia.

OBJECTIVE: Oxidative stress is implicated in the aetiology of schizophrenia, and the antioxidant defence system (AODS) may be protective in this illness. We examined the major antioxidant glutathione (GSH) in prefrontal brain and its correlates with clinical and demographic variables in schizophrenia. METHODS: GSH levels were measured in the dorsolateral prefrontal region of 28 patients with chronic schizophrenia using a magnetic resonance spectroscopy sequence specifically adapted for GSH. We examined correlations of GSH levels with age, age at onset of illness, duration of illness, and clinical symptoms. RESULTS: We found a negative correlation between GSH levels and age at onset (r = -0.46, p = 0.015), and a trend-level positive relationship between GSH and duration of illness (r = 0.34, p = 0.076). CONCLUSION: Our findings are consistent with a possible compensatory upregulation of the AODS with longer duration of illness and suggest that the AODS may play a role in schizophrenia.

Meta-analytic evidence of elevated choline, reduced N-acetylaspartate, and normal creatine in schizophrenia and their moderation by measurement quality, echo time, and medication status.

BACKGROUND: Brain metabolite abnormalities measured with magnetic resonance spectroscopy (MRS) provide insight into pathological processes in schizophrenia. Prior meta-analyses have not yet answered important questions about the influence of clinical and technical factors on neurometabolite abnormalities and brain region differences. To address these gaps, we performed an updated meta-analysis of N-acetylaspartate (NAA), choline, and creatine levels in patients with schizophrenia and assessed the moderating effects of medication status, echo time, measurement quality, and other factors. METHODS: We searched citations from three earlier meta-analyses and the PubMed database after the most recent meta-analysis to identify studies for screening. In total, 113 publications reporting 366 regional metabolite datasets met our inclusion criteria and reported findings in medial prefrontal cortex (MPFC), dorsolateral prefrontal cortex, frontal white matter, hippocampus, thalamus, and basal ganglia from a total of 4445 patient and 3944 control observations. RESULTS: Patients with schizophrenia had reduced NAA in five of the six brain regions, with a statistically significant sparing of the basal ganglia. Patients had elevated choline in the basal ganglia and both prefrontal cortical regions. Patient creatine levels were normal in all six regions. In some regions, the NAA and choline differences were greater in studies enrolling predominantly medicated patients compared to studies enrolling predominantly unmedicated patients. Patient NAA levels were more reduced in hippocampus and frontal white matter in studies using longer echo times than those using shorter echo times. MPFC choline and NAA abnormalities were greater in studies reporting better metabolite measurement quality. CONCLUSIONS: Choline is elevated in the basal ganglia and prefrontal cortical regions, suggesting regionally increased membrane turnover or glial activation in schizophrenia. The basal ganglia are significantly spared from the well-established widespread reduction of NAA in schizophrenia suggesting a regional difference in disease-associated factors affecting NAA. The echo time findings agree with prior reports and suggest microstructural changes cause faster NAA T2 relaxation in hippocampus and frontal white matter in schizophrenia. Separating the effects of medication status and illness chronicity on NAA and choline abnormalities will require further patient-level studies. Metabolite measurement quality was shown to be a critical factor in MRS studies of schizophrenia.

N-Acetylcysteine effects on glutathione and glutamate in schizophrenia: A preliminary MRS study.

N-acetylcysteine (NAC) is a commonly used antioxidant that may have beneficial effects for schizophrenia. In this double-blind, randomized, placebo-controlled preliminary study, 40 patients with schizophrenia or schizoaffective disorder were randomized to receive 2400 mg NAC daily or placebo over eight weeks to examine the effects of NAC on prefrontal magnetic resonance spectroscopy levels of glutathione and glutamate. Secondary outcomes included negative symptoms, cognition, and plasma glutathione levels. We found that NAC treatment was associated with increased glutathione (statistically significant) and decreased glutamate (trend-level) compared with placebo in medial prefrontal cortex but not dorsolateral prefrontal cortex. We also observed a baseline association between medial prefrontal cortex levels of glutathione and plasma reduced / oxidized glutathione ratios. No treatment effects on symptoms or cognition were observed. Taken together, these findings indicate that treatment with N-acetylcysteine may increase medial prefrontal cortical levels of glutathione after eight weeks of treatment. These changes in cortical levels of glutathione may serve as an early biomarker of later clinical change and may underlie the cognitive and symptomatic improvements reported in longer-term treatment studies.

Reticulon-4A (Nogo-A) redistributes protein disulfide isomerase to protect mice from SOD1-dependent amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease inherited in a small subset of patients. The SOD1(G93A) transgenic mouse models this subset of patients, and studies of this strain have suggested that endoplasmic reticulum (ER) stress and deficits in ER chaperone function are contributors to ALS pathophysiology. Here, we demonstrate that the reticulon family of proteins is a novel regulator of the ER chaperone protein disulfide isomerase (PDI), and that through PDI, reticulon-4A (Nogo-A) can protect mice against the neurodegeneration that characterizes ALS. We show that overexpressing reticulon protein induces a punctate redistribution of PDI intracellularly, both in vitro and in vivo. Conversely, reduction of endogenous NogoA expression causes a more homogeneous expression pattern in vivo. These effects occur without induction of the unfolded protein response. To examine the effect of PDI redistribution on ALS disease progression, we conducted survival and behavior studies of SOD1(G93A) mice. Deletion of a single copy of the NogoA,B gene accelerates disease onset and progression, while deletion of both copies further worsens disease. We conclude that NogoA contributes to the proper function of the ER resident chaperone PDI, and is protective against ALS-like neurodegeneration. Our results provide a novel intracellular role for reticulon proteins and support the hypothesis that modulation of PDI function is a potential therapeutic approach to ALS.

Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers.

Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = -0.41; p = 0.04, d = -0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = -0.36; p = 0.008, d = -0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = -0.56; p = 0.079, d = -0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.

The reticulons: a family of proteins with diverse functions.

The reticulon family is a large and diverse group of membrane-associated proteins found throughout the eukaryotic kingdom. All of its members contain a carboxy-terminal reticulon homology domain that consists of two hydrophobic regions flanking a hydrophilic loop of 60-70 amino acids, but reticulon amino-terminal domains display little or no similarity to each other. Reticulons principally localize to the endoplasmic reticulum, and there is evidence that they influence endoplasmic reticulum-Golgi trafficking, vesicle formation and membrane morphogenesis. However, mammalian reticulons have also been found on the cell surface and mammalian reticulon 4 expressed on the surface of oligodendrocytes is an inhibitor of axon growth both in culture and in vivo. There is also growing evidence that reticulons may be important in neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. The diversity of structure, topology, localization and expression patterns of reticulons is reflected in their multiple, diverse functions in the cell.