PTSD psychotherapy improves blood pressure but leaves HPA axis feedback sensitivity stable and unaffected: First evidence from a pre-post treatment study.

Although key to development of tailored drugs for augmentation treatment of psychotherapy for posttraumatic stress disorder (PTSD), the biological correlates of PTSD remission are still unknown, probably because pre-post treatment studies searching for them are rare. Not even the feedback sensitivity of the otherwise well-studied hypothalamic-pituitary-adrenal (HPA) axis nor arterial blood pressure (BP), which was previously reported to be elevated in PTSD patients, have so far been analyzed during PTSD treatment. To narrow this knowledge gap, we first performed an overnight dexamethasone suppression test (DST) in a mixed-sex cohort of 25 patients with severe PTSD vs. 20 non-traumatized healthy controls (nt-HC). In addition to hormones, BP and heart rate (HR) were measured at each of the four assessment points (APs). Second, the same parameters were assessed again in 16 of these patients after 12 sessions of integrative trauma-focused cognitive behavioral therapy (iTF-CBT). In relation to nt-HC, PTSD patients showed a significant elevation in HR and diastolic BP while their systolic BP, DST outcomes and basal serum cortisol levels (BSCL) were not significantly altered. In response to iTF-CBT, PTSD symptoms and dysfunctional stress coping strategies improved significantly in PTSD patients. Most important, also their systolic and diastolic BP levels ameliorated at distinct APs while their DST outcomes and BSCL remained unchanged. To our knowledge, this is the first pre-post treatment study assessing the stability of the DST outcome and BP levels during PTSD treatment. Our results provide first evidence for a non-involvement of HPA axis feedback sensitivity in PTSD symptom improvement and, furthermore, suggest a possible role for BP-regulating pathways such as the sympathetic nervous system in PTSD remission. Limitations arise from the small sample size, the lack of an untreated patient group and drug treatment of patients.

Heart rate variability and cordance in rapid eye movement sleep as biomarkers of depression and treatment response.

OBJECTIVES: The relevance of rapid eye movement (REM) sleep in affective disorders originates from its well-known abnormalities in depressed patients, who display disinhibition of REM sleep reflected by increased frequency of rapid eye movements (REM density). In this study we examined whether heart rate variability (HRV) and prefrontal theta cordance, both derived from REM sleep, could represent biomarkers of antidepressant treatment response. METHODS: In an open-label, case-control design, thirty-three in-patients (21 females) with a depressive episode were treated with various antidepressants for four weeks. Response to treatment was defined as a ≥50% reduction of HAM-D score at the end of the fourth week. Sleep EEG was recorded after the first and the fourth week of medication. HRV was derived from 3-min artifact-free electrocardiogram segments during REM sleep. Cordance was computed for prefrontal EEG channels in the theta frequency band during tonic REM sleep. RESULTS: HRV during REM sleep was decreased in depressed patients at week four as compared to controls (high effect size; Cohen's d > 1), and showed a negative correlation with REM density in both, healthy subjects and patients at week four. Further, the fourteen responders had significantly higher prefrontal theta cordance as compared to the nineteen non-responders after the first week of antidepressant medication; in contrast, HRV at week one did not discriminate between responders and non-responders. CONCLUSIONS: Our data suggest that HRV in REM sleep categorizes healthy subjects and depressed patients, whereas REM sleep-derived prefrontal cordance may predict the response to antidepressant treatment in depressed patients.

Improvement of nonsuicidal self-injury following treatment with antipsychotics possessing strong D1 antagonistic activity: evidence from a report of three cases.

INTRODUCTION: There is no drug treatment for nonsuicidal self-injury (NSSI), a highly prevalent and burdensome symptom of several psychiatric diseases like posttraumatic stress disorder (PTSD), personality disorders, and major depression (MD). METHODS: Here, we present a retrospective series of three patients demonstrating a persistent remission in MD-associated NSSI in response to treatment with antipsychotics possessing marked D1 receptor antagonistic activity. RESULTS: To the best of the authors' knowledge, the case series presented is only the second clinical paper suggesting a role for D1 antagonists in NSSI drug therapy. CONCLUSIONS: Together with previously published data from rodent models, the findings suggest a role for D1 antagonists in NSSI drug therapy and hence for the D1 receptor in NSSI pathogenesis. This conclusion is limited by the facts that the patients presented here received polypharmacy and that the D1 receptor antagonistic antipsychotics suggested here as effective 'anti-auto-aggressants' do not address D1 receptors only but multiple neurotransmitter receptors/systems.

Cordance derived from REM sleep EEG as a biomarker for treatment response in depression--a naturalistic study after antidepressant medication.

OBJECTIVE: To evaluate whether prefrontal cordance in theta frequency band derived from REM sleep EEG after the first week of antidepressant medication could characterize the treatment response after 4 weeks of therapy in depressed patients. METHOD: 20 in-patients (15 females, 5 males) with a depressive episode and 20 healthy matched controls were recruited into 4-week, open label, case-control study. Patients were treated with various antidepressants. No significant differences in age (responders (mean ± SD): 45 ± 22) years; non-responders: 49 ± 12 years), medication or Hamilton Depression Rating Scale (HAM-D) score (responders: 23.8 ± 4.5; non-responders 24.5 ± 7.6) at inclusion into the study were found between responders and non-responders. Response to treatment was defined as a ≥50% reduction of HAM-D score at the end of four weeks of active medication. Sleep EEG of patients was recorded after the first and the fourth week of medication. Cordance was computed for prefrontal EEG channels in theta frequency band during tonic REM sleep. RESULTS: The group of 8 responders had significantly higher prefrontal theta cordance in relation to the group of 12 non-responders after the first week of antidepressant medication. This finding was significant also when controlling for age, gender and number of previous depressive episodes (F1,15 = 6.025, P = .027). Furthermore, prefrontal cordance of all patients showed significant positive correlation (r = 0.52; P = .019) with the improvement of HAM-D score between the inclusion week and fourth week of medication. CONCLUSIONS: The results suggest that prefrontal cordance derived from REM sleep EEG could provide a biomarker for the response to antidepressant treatment in depressed patients.

Identification and characterization of HPA-axis reactivity endophenotypes in a cohort of female PTSD patients.

Analysis of the function of the hypothalamic-pituitary-adrenal (HPA)-axis in patients suffering from posttraumatic stress disorder (PTSD) has hitherto produced inconsistent findings, inter alia in the Trier Social Stress Test (TSST). To address these inconsistencies, we compared a sample of 23 female PTSD patients with either early life trauma (ELT) or adult trauma (AT) or combined ELT and AT to 18 age-matched non-traumatized female healthy controls in the TSST which was preceded by intensive baseline assessments. During the TSST, we determined a variety of clinical, psychological, endocrine and cardiovascular parameters as well as expression levels of four HPA-axis related genes. Using a previously reported definition of HPA-axis responsive versus non-responsive phenotypes, we identified for the first time two clinically and biologically distinct HPA-axis reactivity subgroups of PTSD. One subgroup ("non-responders") showed a blunted HPA-axis response and distinct clinical and biological characteristics such as a higher prevalence of trauma-related dissociative symptoms and of combined AT and ELT as well as alterations in the expression kinetics of the genes encoding for the mineralocorticoid receptor (MR) and for FK506 binding protein 51 (FKBP51). Interestingly, this non-responder subgroup largely drove the relatively diminished HPA axis response of the total cohort of PTSD patients. These findings are limited by the facts that the majority of patients was medicated, by the lack of traumatized controls and by the relatively small sample size. The here for the first time identified and characterized HPA-axis reactivity endophenotypes offer an explanation for the inconsistent reports on HPA-axis function in PTSD and, moreover, suggest that most likely other factors than HPA-axis reactivity play a decisive role in determination of PTSD core symptom severity.

Noise-induced precursors of tonic-to-bursting transitions in hypothalamic neurons and in a conductance-based model.

The dynamics of neurons is characterized by a variety of different spiking patterns in response to external stimuli. One of the most important transitions in neuronal response patterns is the transition from tonic firing to burst discharges, i.e., when the neuronal activity changes from single spikes to the grouping of spikes. An increased number of interspike-interval sequences of specific temporal correlations was detected in anticipation of temperature induced tonic-to-bursting transitions in both, experimental impulse recordings from hypothalamic brain slices and numerical simulations of a stochastic model. Analysis of the modelling data elucidates that the appearance of such patterns can be related to particular system dynamics in the vicinity of the period-doubling bifurcation. It leads to a nonlinear response on de- and hyperpolarizing perturbations introduced by noise. This explains why such particular patterns can be found as reliable precursors of the neurons' transition to burst discharges.

Clinical characteristics and treatment outcome in a representative sample of depressed inpatients - findings from the Munich Antidepressant Response Signature (MARS) project.

Depression is a common and often difficult-to-treat clinical condition with a high rate of patients showing insufficient treatment response and persistence of symptoms. We report the characteristics of a representative sample of depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Eight hundred and forty-two inpatients admitted to a psychiatric hospital for treatment of a major depressive episode, recurrent or bipolar depression were thoroughly characterized with respect to demographic factors, clinical history, and the degree of HPA-axis dysregulation evaluated by means of combined dex/CRH tests, and the predictive value of these factors for treatment outcome is investigated. 80.8% of patients responded to treatment (i.e., improvement in symptom severity of at least 50%) and 57.9% reached remission (i.e., near absence of residual depressive symptoms) at discharge after a mean treatment period of 11.8 weeks. Regression analysis identified early partial response (within 2 weeks) as the most important positive predictor for achieving remission. Previous ineffective treatment trials in the current episode and presence of a migration background are potent negative predictors for treatment outcome. In addition, remitters were characterized by a more pronounced normalization of an initially dysregulated HPA-axis. We could show that a large majority of inpatients suffering from depression benefits from antidepressant treatment during hospitalization. However, a considerable number of patients failed to achieve remission. We demonstrated that this subgroup can be characterized by a set of demographic, clinical and neuroendocrine variables allowing to predict unfavorable outcome at an early stage of treatment.