Accelerated aging in serious mental disorders.

PURPOSE OF REVIEW: Clinical, epidemiological, and biological evidence raises the possibility that serious mental disorders (SMDs) are associated with accelerated biological aging. To the extent this is true; SMDs should not simply be considered in terms of mental illness or brain dysfunction, but also as 'whole body' and multisystem illnesses, or else as conditions with significant somatic concomitants. RECENT FINDINGS: The concept of accelerated biological aging in SMDs is supported by reports of accelerated changes in certain biomarkers normally associated with the aging process. SUMMARY: We define and discuss several proposed biological aging markers that have been examined in SMDs, we review the most recent findings, and we conclude with opinions regarding the merits and meanings of these markers, their usefulness in understanding and treating SMDs, and remaining questions and future directions in this area of research.

Epigenetic Age in Male Combat-Exposed War Veterans: Associations with Posttraumatic Stress Disorder Status.

DNA methylation patterns change with age and can be used to derive an estimate of "epigenetic age," an indicator of biological age. Several studies have shown associations of posttraumatic stress disorder (PTSD) with worse somatic health and early mortality, raising the possibility of accelerated biological aging. This study examined associations between estimated epigenetic age and various variables in 160 male combat-exposed war veterans with (n = 79) and without PTSD (n = 81). DNA methylation was assessed in leukocyte genomic DNA using the Illumina 450K DNA methylation arrays. Epigenetic age was estimated using Horvath's epigenetic clock algorithm and Δage (epigenetic age-chronological age) was calculated. In veterans with PTSD (Δage = 3.2), Δage was on average lower compared to those without PTSD (Δage = 5.0; p = 0.02; Cohen's d = 0.42). This between-group difference was not explained by race/ethnicity, lifestyle factors or childhood trauma. Antidepressant use, however, explained part of the association. In the PTSD positive group, telomerase activity was negatively related to Δage (ß = -0.35; p = 0.007). In conclusion, veterans with PTSD had significantly lower epigenetic age profiles than those without PTSD. Further, current antidepressant use and higher telomerase activity were related to relatively less epigenetic aging in veterans with PTSD, speculative of a mechanistic pathway that might attenuate biological aging-related processes in the context of PTSD.

Circulating cell-free mitochondrial DNA, but not leukocyte mitochondrial DNA copy number, is elevated in major depressive disorder.

Major depressive disorder (MDD) has been linked to mitochondrial defects, which could manifest in mitochondrial DNA (mtDNA) polymorphisms or mutations. Additionally, copy number of mtDNA (mtDNA-cn) can be quantified in peripheral blood mononuclear cells (PBMC)s, indirectly reflecting cellular energetics, or in the circulating cell-free mtDNA (ccf-mtDNA) levels, which may reflect a fraction of the mitochondrial genome released during cellular stress. Few studies have examined ccf-mtDNA in MDD, and no studies have tested its relationship with intracellular mtDNA-cn or with antidepressant treatment response. Here, mtDNA levels were quantified in parallel from: (i) PBMCs and (ii) cell-free plasma of 50 unmedicated MDD subjects and 55 controls, in parallel with PBMC telomere length (TL) and antioxidant enzyme glutathione peroxidase (GpX) activity. MtDNA measures were repeated in 19 MDD subjects after 8 weeks of open-label SSRI treatment. In analyses adjusted for age, sex, BMI, and smoking, MDD subjects had significantly elevated levels of ccf-mtDNA (F = 20.6, p = 0.00002). PBMC mtDNA-cn did not differ between groups (p > 0.4). In preliminary analyses, we found that changes in ccf-mtDNA with SSRI treatment differed between SSRI responders and non-responders (F = 6.47, p = 0.02), with the non-responders showing an increase in ccf-mtDNA and responders not changing. Baseline ccf-mtDNA was positively correlated with GpX (r = 0.32, p = 0.001), and PBMC mtDNA correlated positively with PBMC TL (r = 0.38, p = 0.0001). These data suggest that plasma ccf-mtDNA and PBMC mtDNA-cn reflect different cellular processes and that the former may be more reflective of certain aspects of MDD pathophysiology and of the response to SSRI antidepressants.

Can mobile phone technology support a rapid sharing of information on novel psychoactive substances among health and other professionals internationally?

BACKGROUND: The diffusion of novel psychoactive substances (NPSs), combined with the ability of the Internet to act as an online marketplace, has led to unprecedented challenges for governments, health agencies, and substance misuse services. Despite increasing research, there is a paucity of reliable information available to professionals working in the field. The paper will present the pilot results of the first mobile application (SMAIL) for rapid information sharing on NPSs among health professionals. METHODS: The development of SMAIL was divided into 2 parts: (a) the creation of the application for registered users, enabling them to send an SMS or email with the name or "street name" of an NPS and receive within seconds emails or SMS with the information, when available and (b) the development of a database to support the incoming requests. RESULTS: One hundred twenty-two professionals based in 22 countries used the service over the pilot period of 16 months (from May 2012 to September 2013). Five hundred fifty-seven enquires were made. Users received rapid information on NPSs, and 61% of them rated the service as excellent. CONCLUSIONS: This is the right time to use mobile phone technologies for rapid information sharing and prevention activities on NPSs.

A population of atypical CD56(-)CD16(+) natural killer cells is expanded in PTSD and is associated with symptom severity.

INTRODUCTION: Post-traumatic stress disorder (PTSD) has been associated with immune disturbances, including a higher incidence of infections and autoimmune diseases as well as a net pro-inflammatory state. Natural killer (NK) cells, a key component of the innate immune system, have been less well-studied in PTSD despite their importance in immunity. METHODS: We studied two independent samples of combat-exposed male war veterans with or without PTSD, the first ("Discovery Sample") to generate hypotheses, and the second ("Validation Sample") to replicate the findings. The Discovery Sample was comprised of 42 PTSD subjects and 42 controls. The Validation Sample was comprised of 25 PTSD subjects and 30 controls. Participants had fasting, morning blood samples collected for examination of the frequency of NK cell subsets, determined by flow cytometry. The current and lifetime Clinician Administered PTSD Scale (CAPS) was used to assess symptom severity. Statistical analyses were adjusted for age and BMI. RESULTS: PTSD subjects compared to controls had (i) a significantly higher relative frequency of atypical CD56(-)CD16(+) NK cells in the Discovery Sample (p=0.027), which was replicated in the Validation Sample (p=0.004) and the combined sample (p<0.001), and (ii) a non-significantly lower relative frequency of CD56(bright)CD16(-) NK cells in the two samples (p=0.082; p=0.118), which became statistically significant in the combined sample (p=0.020). Further, within subjects with PTSD of both samples, the relative frequency of atypical CD56(-)CD16(+) NK cells was near significantly positively correlated with lifetime PTSD severity (p=0.074). DISCUSSION: This study is the first to characterize NK cell subsets in individuals with PTSD. The results suggest that combat-exposed men with PTSD exhibit an aberrant profile of NK cells with significantly higher frequencies of an atypical population of CD56(-)CD16(+) cells and possibly lower frequencies of the functional CD56(bright)CD16(-) NK cell subsets. Higher proportions of dysfunctional CD56(-)CD16(+) cells have been reported in certain chronic viral infections and in senescent individuals. It is possible that this could contribute to immune dysfunctions and prematurely senescent phenotypes seen in PTSD.

Association of dimensional psychological health measures with telomere length in male war veterans.

BACKGROUND: Several psychiatric disorders may be characterized by peripheral telomere shortening. However, it is unclear whether telomere shortening is associated with these psychiatric disorders per se or, rather, with underlying dimensional parameters that are often, but not necessarily, associated with them. We explored the association between dimensional psychopathological measures and telomere length (TL) in granulocytes among veterans independent of psychiatric diagnosis. METHODS: Seventy-six combat-exposed male veterans (41 psychiatrically healthy, 18 with Posttraumatic Stress Disorder [PTSD] and 17 with concomitant PTSD and Major Depressive Disorder [MDD]) had TL assayed. Assessments included Clinician-Administered PTSD Scale (CAPS), Beck Depression Inventory-II (BDI-II), Early Trauma Inventory (ETI), Symptom Checklist-90-R Global Severity Index (SCL-90-GSI), Perceived Stress Scale (PSS) and Positive and Negative Affect Schedule (PANAS). Correlations were corrected for age, BMI, antidepressants and ethnicity. RESULTS: Across subjects, TL was negatively correlated with early trauma (p<0.001), global psychopathological severity (p=0.044) and perceived stress (p=0.019), positively correlated with positive affect (p=0.026), not significantly correlated with symptom severity of PTSD, depression or negative affect. Across these dimensions, early trauma and positive affect were associated with TL after excluding subjects with somatic illnesses. LIMITATIONS: The study was cross-sectional with a moderate sample size and only male combat-exposed subjects. CONCLUSIONS: These preliminary findings suggest that early trauma, severity of perceived stress and general psychopathological symptoms are more closely associated with shorter TL than is the severity of core diagnostic symptoms of PTSD or MDD, whereas positive affect is associated with longer TL. Larger-scale studies should assess TL associated with specific psychiatric dimensions, apart from only categorical psychiatric diagnoses, to develop more specific biologically-relevant endophenotypes.

Telomerase activation as a possible mechanism of action for psychopharmacological interventions.

Originally studied in relation to aging and cancer research, telomerase is now also investigated in relation to psychiatric disorders and treatments. Based on emerging clinical and preclinical data, we hypothesise that telomerase activation could represent a novel element mediating the mechanism of action of certain psychopharmacological interventions (e.g. antidepressants, lithium and antipsychotics). The modulation of intracellular Wnt/ß-catenin or PI3K/Akt signalling pathways, the interaction with BDNF and 5-HT, and the antioxidant properties could represent possible mechanisms by which the different types of psychiatric medications could modulate telomerase activity. The potential of telomerase in promoting cellular survival and/or function in the brain and in the periphery could, in turn, represent a neurobiological substrate through which the enzyme can mediate the therapeutic effect of such interventions.

P300 component in euthymic patients with bipolar disorder type I, bipolar disorder type II and healthy controls: a preliminary event-related potential study.

The aim of the present study was to investigate P300 event-related potential components in euthymic bipolar disorder type I (BDI) and bipolar disorder type II (BDII) patients and matched controls. A total of 10 BDI patients, 10 BDII patients and 10 healthy individuals were enrolled in the study. Event-related potential data were collected according to a standard auditory 'oddball' paradigm. A significant groups effect in both the peak amplitude (P<0.001) and the mean amplitude (P<0.001) was observed; post-hoc comparisons showed that the peak and mean amplitudes of BDI and BDII patients were significantly lower than the peak and mean amplitudes of the healthy controls. The neurophysiological patterns found in the present study might at least partially reflect the presence of a mild selective cognitive impairment in euthymic BDI and BDII patients. From a clinical point of view, these evidences support the potential role of cognitive interventions in the treatment of BD.

Efficacy of add-on deep transcranial magnetic stimulation in comorbid alcohol dependence and dysthymic disorder: three case reports.

BACKGROUND: Craving for alcohol is associated with abnormal activation in the dorsolateral prefrontal cortex. Deep transcranial magnetic stimulation (dTMS) has shown promise in the treatment of depression. There are few treatment options for treatment-resistant dysthymic disorder comorbid with alcohol use disorder. OBJECTIVE: To investigate the possible anticraving efficacy of bilateral dorsolateral prefrontal cortex high-frequency dTMS in 3 patients with comorbid long-term DSM-IV-TR dysthymic disorder and alcohol use disorder. METHOD: Three patients with alcohol use disorder with dysthymic disorder in their detoxification phase (abstaining for > 1 month) underwent twenty 20-minute sessions of 20 Hz dTMS over the dorsolateral prefrontal cortex over 28 days between 2011 and 2012. Alcohol craving was rated with the Obsessive Compulsive Drinking Scale and depressive symptoms with the Hamilton Depression Rating Scale. RESULTS: All 3 patients responded unsatisfactorily to initial intravenous antidepressant and antianxiety combinations but responded after 10 dTMS sessions, improving on both anxiety-depressive symptoms and craving. This improvement enabled us to reduce antidepressant dosages after dTMS cycle completion. DISCUSSION: High-frequency bilateral dorsolateral prefrontal cortex dTMS with left prevalence was found to produce significant anticraving effects in alcohol use disorder comorbid with dysthymic disorder. The potential of dTMS for reducing craving in patients with substance use disorder deserves to be further investigated.