Questions of how altered functioning of the hypothalamic pituitary adrenal (HPA) axis contribute to the development and maintenance of posttraumatic stress disorder (PTSD) have been the focus of ...extensive animal and human research. As a rule, results have been inconsistent across studies, likely due to a variety of confounding variables that have received inadequate attention. Important confounding factors include the effects of early life stress, biological sex, and the glucocorticoid used for interventions. In this manuscript we review: 1) the literature on identified abnormalities of HPA axis function in PTSD, both in terms of basal functioning and as part of challenge paradigms; 2) the role of HPA axis function pre- and immediately post-trauma as a risk factor for PTSD development; 3) the impact of HPA axis genes' allelic variants and epigenetic modifications on PTSD risk; 4) the contributions of HPA axis components to fear learning and extinction; and 5) therapeutic manipulations of the HPA axis to both prevent and treat PTSD, including the role of glucocorticoids as part of medication enhanced psychotherapy.
•The inconsistencies in HPA axis associations with PTSD likely derive from methodological differences.•Effects of the HPA axis alteration may differ across the symptom clusters of PTSD.•Dexamethasone and hydrocortisone should not be considered equivalent glucocorticoids in PTSD research.•Hydrocortisone given to prevent PTSD following a trauma is the best supported HPA axis intervention for PTSD.•Future studies of the HPA axis in PTSD must control for early life stress and biological sex.
The link between dysregulated serotonergic activity and depression and anxiety disorders is well established, yet the molecular mechanisms underlying these psychopathologies are not fully understood. ...Here, we explore the role of microRNAs in regulating serotonergic (5HT) neuron activity. To this end, we determined the specific microRNA “fingerprint” of 5HT neurons and identified a strong microRNA-target interaction between microRNA 135 (miR135), and both serotonin transporter and serotonin receptor-1a transcripts. Intriguingly, miR135a levels were upregulated after administration of antidepressants. Genetically modified mouse models, expressing higher or lower levels of miR135, demonstrated major alterations in anxiety- and depression-like behaviors, 5HT levels, and behavioral response to antidepressant treatment. Finally, miR135a levels in blood and brain of depressed human patients were significantly lower. The current results suggest a potential role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into the onset, susceptibility, and heterogeneity of stress-related psychopathologies.
•miRs “fingerprint” of 5HT neurons position miR135 as potent regulator of 5HT system•miR135a levels are upregulated following 5HT-linked antidepressants treatment•miR135 levels in vivo influence behavior, 5HT levels, and antidepressant treatment•Lower levels of miR135a in blood and brain of depressed human patients
Issler et al. identify microRNA135 as potent regulator of serotonergic activity known to be associated with depression and anxiety disorders and suggest a role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into stress-related psychopathologies.
The degree of agreement between four commercial pharmacogenetic-based decision support tools (DSTs) was examined in five outpatients with major depressive disorder and at least two previous ...antidepressant failures. Comparisons were made across seven pharmacokinetic (CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, and UGT2B15) and seven pharmacodynamic (BDNF, COMT, HLA-A, HTR2A, HTR2C, OPRM1, and SLC6A4) genes that were included on ≥2 of the four DST testing panels. Among these overlapping genes, genotype (33-100%) and predicted phenotype (20-100%) agreement varied substantially. Medication recommendation agreement was the greatest for mood stabilizers (84%), followed by antidepressants (56%), anxiolytics/hypnotics (56%), and antipsychotics (55%). Approximately one-quarter (26%) of all medication recommendations were jointly flagged by two or more DSTs as "actionable" but 19% of these recommendations provided conflicting advice (e.g., dosing) for the same medication.The level of disagreement in medication recommendations across the pharmacogenetic DSTs indicates that these tests cannot be assumed to be equivalent or interchangeable. Additional efforts to standardize genetic-based phenotyping and to develop medication guidelines are warranted.
Current prescribing practices for major depressive disorder (MDD) produce limited treatment success. Although pharmacogenomics may improve outcomes by identifying genetically inappropriate ...medications, studies to date were limited in scope. Outpatients (N = 1167) diagnosed with MDD and with a patient- or clinician-reported inadequate response to at least one antidepressant were enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial – a rater- and patient-blind randomized controlled trial. Patients were randomized to treatment as usual (TAU) or a pharmacogenomics-guided intervention arm in which clinicians had access to a pharmacogenomic test report to inform medication selections (guided-care). Medications were considered congruent (‘use as directed’ or ‘use with caution’ test categories) or incongruent (‘use with increased caution and with more frequent monitoring’ test category) with test results. Unblinding occurred after week 8. Primary outcome was symptom improvement change in 17-item Hamilton Depression Rating Scale (HAM-D17) at week 8; secondary outcomes were response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. At week 8, symptom improvement for guided-care was not significantly different than TAU (27.2% versus 24.4%, p = 0.107); however, improvements in response (26.0% versus 19.9%, p = 0.013) and remission (15.3% versus 10.1%, p = 0.007) were statistically significant. Patients taking incongruent medications prior to baseline who switched to congruent medications by week 8 experienced greater symptom improvement (33.5% versus 21.1%, p = 0.002), response (28.5% versus 16.7%, p = 0.036), and remission (21.5% versus 8.5%, p = 0.007) compared to those remaining incongruent. Pharmacogenomic testing did not significantly improve mean symptoms but did significantly improve response and remission rates for difficult-to-treat depression patients over standard of care (ClinicalTrials.gov NCT02109939).
To conducted a systematic review and meta-analysis of prospective, randomized controlled trials (RCTs) that examined pharmacogenetic-guided decision support tools (DSTs) relevant to depressive ...symptom remission in major depressive disorder (MDD).
Random-effects meta-analysis was performed on RCTs that examined the effect of DSTs on remission rates in MDD. RCT quality was assessed using the Cochrane Collaboration Criteria.
A total of 1737 eligible subjects from five RCTs were examined. Individuals receiving pharmacogenetic-guided DST therapy (n = 887) were 1.71 (95% CI: 1.17-2.48; p = 0.005) times more likely to achieve symptom remission relative to individuals who received treatment as usual (n = 850). Pharmacogenetic-guided DSTs might improve symptom remission among those with MDD.
Objective:The purpose of this article was to inform the first-line treatment choice between cognitive-behavioral therapy (CBT) or an antidepressant medication for treatment-naive adults with major ...depressive disorder by defining a neuroimaging biomarker that differentially identifies the outcomes of remission and treatment failure to these interventions.Method:Functional MRI resting-state functional connectivity analyses using a bilateral subcallosal cingulate cortex (SCC) seed was applied to 122 patients from the Prediction of Remission to Individual and Combined Treatments (PReDICT) study who completed 12 weeks of randomized treatment with CBT or antidepressant medication. Of the 122 participants, 58 achieved remission (Hamilton Depression Rating Scale HAM-D score ≤7 at weeks 10 and 12), and 24 had treatment failure (<30% decrease from baseline in HAM-D score). A 2×2 analysis of variance using voxel-wise subsampling permutation tests compared the interaction of treatment and outcome. Receiver operating characteristic curves constructed using brain connectivity measures were used to determine possible classification rates for differential treatment outcomes.Results:The resting-state functional connectivity of the following three regions with the SCC was differentially associated with outcomes of remission and treatment failure to CBT and antidepressant medication and survived application of the subsample permutation tests: the left anterior ventrolateral prefrontal cortex/insula, the dorsal midbrain, and the left ventromedial prefrontal cortex. Using the summed SCC functional connectivity scores for these three regions, overall classification rates of 72%−78% for remission and 75%−89% for treatment failure was demonstrated. Positive summed functional connectivity was associated with remission with CBT and treatment failure with medication, whereas negative summed functional connectivity scores were associated with remission to medication and treatment failure with CBT.Conclusions:Imaging-based depression subtypes defined using resting-state functional connectivity differentially identified an individual’s probability of remission or treatment failure with first-line treatment options for major depression. This biomarker should be explored in future research through prospective testing and as a component of multivariate treatment prediction models.
Posttraumatic stress disorder (PTSD) is a common condition for which existing treatments are ineffective for many patients. Recent discoveries in the neurobiology of learning and memory, along with ...expanding knowledge of how those systems are impacted by the biology of the stress response, have opened new arenas for potential medication treatments for PTSD. We conducted a review of registered clinical trials investigating the efficacy of new agents for PTSD. The glucocoritcoid and adrenergic signaling systems are the most frequent targets of these investigational approaches to the prevention and treatment of PTSD. Additional trials are evaluating modulation of other CNS targets, including neurosteroids, glutamate, gamma-amino butyric acid, endocannabinoids, oxytocin, neurokinin/Substance P, and dopamine. A particularly exciting area of research is studies examining Medication-Enhanced Psychotherapy (MEP). Medications provided before or after exposure therapy for PTSD can enhance outcomes by: 1) strengthening learning and memory of fear extinction; 2) disrupting reconsolidation, thereby weakening fear memories; or 3) facilitating engagement in psychotherapy by reducing fear and enhancing openness to experience. The next few years promise to produce insight into the neurobiology and clinical efficacy of several novel approaches in the pharmacologic treatment and prevention of PTSD.
To evaluate lithium in the treatment of acute bipolar depression.
We conducted a systematic literature review for: 1) cross-over or parallel-group design studies comparing lithium response in bipolar ...versus unipolar depressed patients, and 2) parallel group studies of bipolar depressed patients comparing lithium versus placebo or other psychotropics. Meta-analyses using response rate as the primary outcome were conducted to evaluate lithium's efficacy.
The literature search yielded 947 records. Ultimately, 17 studies were included, totaling 1545 patients, including 676 who received lithium. The overall summary effects reveal that there were no statistically significant differences between lithium versus antidepressants or placebo, however, lithium performed numerically worse than antidepressants (RR = 0.61; 95%CI, 0.37–1.02; p = 0.06) but better than placebo (RR = 1.18; 95%CI, 0.99–1.41; p = 0.07). The specificity of lithium for bipolar versus unipolar depression was not supported in the primary analysis of all trials, though an analysis limited to double-blinded, monotherapy, cross-over studies revealed a statistically significant result supporting lithium's efficacy for those with bipolar depression.
Limitations include study selection rules, the use of response rates rather than remission rates or continuous score outcomes, and the small number of studies included in each meta-analysis.
These meta-analyses do not support lithium as a first-line treatment for acute bipolar depression. However, the bipolar vs. unipolar sensitivity analysis and the modest, though non-significant advantage over placebo suggest lithium may still be a viable treatment option. Larger and more rigorously-designed studies are needed to determine lithium's full range of efficacy relative to placebo and other psychotropics.
•Lithium was not statistically significantly different than placebo or antidepressants in the treatment of bipolar depression.•Lithium was superior for bipolar versus unipolar depression based on an analysis limited to double-blinded, monotherapy, cross-over studies.•These meta-analyses do not support lithium as a first-line treatment for acute bipolar but it may still be a viable option.
PDF
