Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors' previous proof-of-concept randomized controlled ...trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD.
Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures.
The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events.
This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine's full potential as a treatment for chronic PTSD.
•The aggregated effect size of early adversity on CRP is very small, z = .07.•The aggregated effect size of early adversity on IL-6 is very small, z = .17.•More studies looking at TNF-α are ...needed.•More studies using in vitro assays of immune cells are needed.
This study provides a comprehensive review of the published research on the association between early life adversity and markers of inflammation in children and adolescents. We conducted a systematic review of the published literature on the association between early life adversity and markers of inflammation in pediatric populations. To date, 27 studies have been published in this area representing a wide range of global populations and diverse methods of which nearly half were prospective, longitudinal studies. Of these 27, only 12 studies shared an inflammatory outcome with 4 or more other studies; 9 for CRP, and 6 for IL-6. The association between early life adversity and both CRP, z = .07 .04, .10, and IL-6, z = .17 −.07, .42, were small and only significant for CRP although comparable in magnitude to the effects observed in adult samples. Descriptively, the association between early life adversity and CRP appeared to be stronger in studies conducted in infants and adolescents compared with middle childhood. There was minimal evidence of publication bias for studies measuring CRP, but evidence of publication bias for studies using IL-6. Eight studies have looked at the association between early life adversity and stimulated inflammatory cytokines in vitro, and both the methods and results of these studies were mixed; the majority observed exaggerated production of inflammatory cytokines despite mixed methodological approaches that make comparisons across studies difficult. In summary, the evidence supporting an association between early life adversity and inflammation in pediatric samples is limited so far by the number of studies and their heterogeneous methodological approaches. More research that is grounded in a developmental framework and informed by the complexity of the innate immune system is needed in this area.
Resilience is defined as the dynamic ability to adapt successfully in the face of adversity, trauma, or significant threat. Some of the key early studies of resilience were observational studies in ...children. They were followed by research in adults, studies testing interventions to promote resilience in different populations, and a recent upsurge of studies on the underlying genomic and neurobiological mechanisms. Neural and molecular studies in preclinical models of resilience are also increasingly identifying active stress adaptations in resilient animals. Knowledge gained from animal and human studies of resilience can be harnessed to develop new preventive interventions to enhance resilience in at-risk populations. Further, treatment interventions focused on enhancing potentially modifiable protective factors that are consistently linked to psychological resilience can enrich currently available treatment interventions for individuals with posttraumatic stress disorder (PTSD). Translating our expanding knowledge of the neurobiology of resilience additionally promises to yield novel therapeutic strategies for treating this disabling condition. This review summarizes the vast field of resilience research spanning genomic, psychosocial, and neurobiological levels, and discusses how findings have led and can lead to new preventive and treatment interventions for PTSD.
All individuals experience stressful life events, and up to 84% of the general population will experience at least one potentially traumatic event. In some cases, acute or chronic stressors lead to ...the development of posttraumatic stress disorder (PTSD) or other psychopathology; however, the majority of people are resilient to such effects. Resilience is the ability to adapt successfully in the face of stress and adversity. A wealth of research has begun to identify the genetic, epigenetic, neural, and environmental underpinnings of resilience, and has indicated that resilience is mediated by adaptive changes encompassing several environmental factors, neural circuits, numerous neurotransmitters, and molecular pathways. The first part of this review focuses on recent findings regarding the genetic, epigenetic, developmental, psychosocial, and neurochemical factors as well as neural circuits and molecular pathways that underlie the development of resilience. Emerging and exciting areas of research and novel methodological approaches, including genome-wide gene expression studies, immune, endocannabinoid, oxytocin, and glutamatergic systems, are explored to help delineate innovative mechanisms that may contribute to resilience. The second part reviews several interventions and preventative approaches designed to enhance resilience in both developmental and adult populations. Specifically, the review will delineate approaches aimed to bolster resilience in individuals with PTSD. Furthermore, we discuss novel pharmacologic approaches, including the N-methyl-d-aspartate (NMDA) receptor ketamine and neuropeptide Y (NPY), as exciting new prospects for not only the treatment of PTSD but as new targets to enhance resilience. Our growing understanding of resilience and interventions will hopefully lead to the development of new strategies for not just treating PTSD but also screening and early identification of at-risk youth and adults. Taken together, efforts aimed at dissemination and implementation of novel interventions to enhance resilience will have to keep pace with the growth of new preventive and treatment strategies.
Viral epitranscriptomics is a newly emerging field that has identified unique roles for RNA modifications in modulating life cycles of RNA viruses. Despite the observation of a handful of modified ...viral RNAs five decades ago, very little was known about how these modifications regulate viral life cycles, until recently. Here we review the pro- and anti-viral effects of methyl-6-adenosine in distinct viral life cycles, the role of 2′ O-methyl modifications in RNA stability and innate immune sensing, and functions of adenosine to inosine modifications in retroviral life cycles. With roles for over 100 modifications in RNA still unknown, this is a rapidly emerging field that is destined to suggest novel antiviral therapies.
Viral epitranscriptomics has identified unique roles for RNA modifications. Gonzales-van Horn and Sarnow review how adenosine modifications play a role in the life cycle of certain RNA viruses. The host machineries that modulate these modifications may offer putative targets for antiviral interventions.
•Inflammation has been identified as a biological process relevant in depression.•C-reactive protein is a biomarker of inflammation.•Methodological inconsistences are widespread in the ...field.•Methodological inconsistences in the literature hinder reproducibility.•Methodologically rigorous studies are needed to drive progress in the field.
One of the most common inflammatory markers examined in depression is C-reactive protein (CRP). However, the magnitude of the association between CRP and depression when controlling for potentially confounding factors such as age, sex, socio-economic status, body mass index, medication and other substance use, and medical illness, is unclear. Inconsistencies in other methodological practices, such as sample collection, assaying, and data cleaning and transformation, may contribute to variations in results. We aggregate studies that examined the association between CRP and depression in two ways. First, a systematic review summarizes how studies of CRP and depression have reported on methodological issues. Second, a tiered meta-analysis aggregates studies that have adhered to various levels of methodological rigor. Findings from the systematic review indicate a lack of protocol detail provided. The effect between depression and CRP was small, but highly significant across all stages of the meta-analysis (p < 0.01). The effect size in the most methodologically rigorous stage of the meta-analysis, which included studies controlling for age, sex, obesity, medical conditions and substance, medication, or psychosocial factors, was small (r = 0.05). There were also only 26 articles in this stage (13% of studies from the systematic review), suggesting that more studies that consistently account for these confounding factors are needed. Additionally, an a priori quality score of methodological rigor was a significant moderator in this stage of the meta-analysis. The effect size was strikingly attenuated (r = 0.005) and non-significant in studies with higher quality scores. We describe a set of recommended guidelines for future research to consider, including sample collection and assaying procedures, data cleaning and statistical methods, and control variables to assess.
Childhood adversity is a potent risk factor for mental health conditions via disruptions to stress response systems. Dysregulations in oxidative stress systems have been associated with both ...childhood adversity and several psychological disorders (e.g., major depressive disorder) in adult populations. However, few studies have examined associations between childhood adversity, oxidative stress, and mental health in pediatric populations. Childhood adversity (Adverse Childhood Events ACE), oxidative stress F2t-isoprostanes (IsoPs), and mental health pathology were assessed in 50 adolescent females recruited primarily through the Department of Youth Services. Standard ordinary least squares regression models were run co-varying for age, race/ethnicity, adolescent nicotine use, study condition, and parent history of ACEs. Adolescents who reported experiencing four or more ACEs had significantly elevated IsoP levels. Further, internalizing symptom scores across diagnoses were significantly associated with elevated IsoPs, whereas no externalizing symptoms scores, except Attention Deficit Hyperactivity Disorder, were related to altered oxidative stress. Results indicate that IsoPs may be a global marker of childhood adversity and mental health symptomatology, particularly within internalizing symptom domains. A limitation is that body mass index was not collected for this sample. Future studies are needed to replicate and extend these findings in larger, more diverse samples.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Review of the immune response to allergens and viral infections and how their distinct pathways regulate each other in the atopic host.
IFN‐α/β was first described as a potent inhibitor of viral ...replication, but it is now appreciated that IFN signaling plays a pleiotropic role in regulating peripheral T cell functions. Recently, IFN‐α/β was shown to block human Th2 development by suppressing the transcription factor GATA3. This effect is consistent with the role for IFN‐α/β in suppressing allergic inflammatory processes by blocking granulocyte activation and IL‐4‐mediated B cell isotype switching to IgE. With the consideration of recent studies demonstrating a defect in IFN‐α/β secretion in DCs and epithelial cells from individuals with severe atopic diseases, there is an apparent reciprocal negative regulatory loop in atopic individuals, whereby the lack of IFN‐α/β secretion by innate cells contributes to the development of allergic Th2 cells. Is it possible to overcome these events by treating with IFN‐α/β or by inducing its secretion in vivo? In support of this approach, case studies have documented the therapeutic potential of IFN‐α/β in treating steroid‐resistant allergic asthma and other atopic diseases. Additionally, individuals with asthma who are infected with HCV and respond to IFN therapy showed a reduction in symptoms and severity of asthma attacks. These findings support a model, whereby allergic and antiviral responses are able to cross‐regulate each other, as IgER cross‐linking of pDCs prevents IFN‐α/β production in response to viral infection. The clinical importance of upper‐respiratory viruses in the context of allergic asthma supports the need to understand how these pathways intersect and to identify potential therapeutic targets.
Cell surface localization of the Glut (glucose transporter), Glut1, is a cytokine-controlled process essential to support the metabolism and survival of haemopoietic cells. Molecular mechanisms that ...regulate Glut1 trafficking, however, are not certain. In the present study, we show that a C-terminal PDZ-binding motif in Glut1 is critical to promote maximal cytokine-stimulated Glut1 cell surface localization and prevent Glut1 lysosomal degradation in the absence of growth factor. Disruption of this PDZ-binding sequence through deletion or point mutation sharply decreased surface Glut1 levels and led to rapid targeting of internalized Glut1 to lysosomes for proteolysis, particularly in growth factor-deprived cells. The PDZ-domain protein, GIPC (G(alpha)-interacting protein-interacting protein, C-terminus), bound to Glut1 in part via the Glut1 C-terminal PDZ-binding motif, and we found that GIPC deficiency decreased Glut1 surface levels and glucose uptake. Unlike the Glut1 degradation observed on mutation of the Glut1 PDZ-binding domain, however, GIPC deficiency resulted in accumulation of intracellular Glut1 in a pool distinct from the recycling pathway of the TfR (transferrin receptor). Blockade of Glut1 lysosomal targeting after growth factor withdrawal also led to intracellular accumulation of Glut1, a portion of which could be rapidly restored to the cell surface after growth factor stimulation. These results indicate that the C-terminal PDZ-binding motif of Glut1 plays a key role in growth factor regulation of glucose uptake by both allowing GIPC to promote Glut1 trafficking to the cell surface and protecting intracellular Glut1 from lysosomal degradation after growth factor withdrawal, thus allowing the potential for a rapid return of intracellular Glut1 to the cell surface on restimulation.
•CRP is consistently associated with fatigue and changes in appetite.•CRP might be associated with anhedonia and difficulty concentrating.•Exclusion of CRP >10 mg/L attenuates CRP—symptom ...associations.•Nonregularized networks should be considered in immunopsychiatry.
Increasingly, it has been recognized that analysis at the symptom, rather than diagnostic, level will drive progress in the field of immunopsychiatry. Network analysis offers a useful tool in this pursuit with the ability to identify associations between immune markers and individual symptoms, independent of all other variables modeled. However, investigation into how methodological decisions (i.e., including vs. excluding participants with C-reactive protein (CRP) >10 mg/L, regularized vs. nonregularized networks) influence results is necessary to establish best practices for the use of network analysis in immunopsychiatry. In a sample of 3,464 adult participants from the 2015–2016 National Health and Nutrition Examination Survey dataset, this study found consistent support for associations between CRP and fatigue and changes in appetite and some support for additional CRP—criterion associations. Methodologically, results consistently demonstrated that including individuals with CRP >10 mg/L and estimating nonregularized networks provided better estimates of these associations. Thus, we recommend considering the use of nonregularized networks in immunopsychiatry and inclusion of cases with CRP values >10 mg/L when testing the association between CRP and depression criteria, unless contraindicated by the research question being tested. Additionally, results most consistently suggest that CRP is uniquely related to fatigue and changes in appetite, supporting their inclusion in an immunometabolic phenotype of depression. Finally, these associations suggest that fatigue and changes in appetite might be particularly receptive to anti-inflammatory treatments. However, future research with more nuanced measures is necessary to parse out whether appetite increases or decreases drive this association. Further, longitudinal research is an important next step to test how these relationships manifest over time.
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