Heart Rate Variability Features as Predictors of Intermittent Theta-Burst Stimulation Response in Posttraumatic Stress Disorder

BackgroundPosttraumatic stress disorder (PTSD) is associated with autonomic dysfunction as indicated by deficits in the sympathetic and parasympathetic nervous systems. These abnormalities are expressed as elevated heart rate and reduced heart rate variability (HRV), respectively. Intermittent theta-burst stimulation (iTBS), a form of transcranial magnetic stimulation, has demonstrated effectiveness in PTSD. Nevertheless, it remains unclear whether HRV may be an iTBS biomarker for PTSD and whether iTBS impacts autonomic activity.Materials and MethodsFifty veterans with PTSD participated in a randomized controlled trial, receiving ten daily sessions of sham-controlled iTBS (right dorsolateral prefrontal cortex, 1800 pulses/day, 80% active motor threshold, 9.5 min). With a usable dataset (N = 47), HRV parameters were assessed as predictors of clinical response immediately after stimulation. iTBS effects on autonomic response (mean RR interval, root mean square of successive differences [RMSSD], total power [TP], and low-frequency/high-frequency [LF/HF] ratio) were evaluated using an ultra-short approach.ResultsTP and RMSSD were significant predictors of acute clinical response to iTBS. Individuals with higher TP had better response to iTBS with improved symptoms on the Clinician-Administered PTSD Scale (r_s = ?0.58, p = 0.004), and higher functionality on the Social and Occupational Function Scale (r_s = 0.43, p = 0.04). Similarly, higher RMSSD was associated with superior outcomes (r_s = ?0.44, p = 0.04). No other significant changes in HRV metrics were observed (p ≥ 0.05).ConclusionsOur findings indicate that autonomic activity is a potential low-cost and technically simple predictive biomarker of iTBS response in PTSD. Less autonomic dysfunction was associated with superior clinical improvements with iTBS. Future studies might consider HRV acquisition during iTBS, as well as prospective testing of these findings in patients with elevated hyperarousal.     

Heart rate variability during motor and cognitive tasks in females with major depressive disorder

Research indicates that major depressive disorder (MDD) is associated with alterations in autonomic control, particularly cardiac control as measured by heart rate variability (HRV). In this preliminary study, we investigated the neural correlates of autonomic control by measuring both HRV and associated brain activity during the performance of mildly stressful tasks. Medically healthy female subjects with MDD (N = 10) and healthy controls (N = 7) underwent H₂¹⁵O-positron emission tomography (PET) and electrocardiographic ECG recording while performing a handgrip motor task and an n-back task. Indices of HRV were calculated and correlated with regional cerebral blood flow (rCBF). Differences in the rCBF and HRV correlations between depressed and healthy subjects were evident in both the medial and lateral orbital cortices. In addition, these areas appeared to be involved in different facets of autonomic control with regard to sympathetic or parasympathetic dominance of cardiac control. These results are consistent with the known roles of networks within the orbital cortex in both autonomic control and the pathophysiology of MDD.     

Natural Course of Adolescent Major Depressive Disorder: I. Continuity Into Young Adulthood

ObjectiveTo examine the course of adolescent major depressive disorder (MDD) by comparing rates of mood and non-mood disorders between age 19 and 24 years in participants with a history of adolescent MDD versus participants with adolescent adjustment disorder with depressed mood, nonaffective disorder, and no disorder.MethodParticipants from a large community sample who had been interviewed twice during adolescence completed a third interview assessing Axis I psychopathology and antisocial and borderline personality disorders after their 24th birthday: 261 participants with MDD, 73 with adjustment disorder, 133 with nonaffective disorder, and 272 with no disorder through age 18.ResultsMDD in young adulthood was significantly more common in the adolescent MDD group than the nonaffective and no disorder groups (average annual rate of MDD = 9.0%, 5.6%, and 3.7%, respectively). Adolescents with MDD also had a high rate of nonaffective disorders in young adulthood (annual nonaffective disorder rate = 6.6%) but did not differ from adolescents with nonaffective disorder (7.2%). Prevalence rates of dysthymia and bipolar disorder were low (1%). Adolescents with adjustment disorder exhibited similar rates of MDD and nonaffective disorders in young adulthood as adolescents with MDD.ConclusionsThis study documents the significant continuity of MDD from adolescence to young adulthood. Public health implications of the findings are discussed. J. Am. Acad. Child Adolesc. Psychiatry, 1999, 38(1):56–63.     

Clinical features of the patients with major depressive disorder co-occurring insomnia and hypersomnia symptoms: a report of NSSD study

BackgroundThe co-occurrence of insomnia and hypersomnia symptoms in patients with major depressive disorder (MDD) is associated with suicidal ideation and functional impairment. The relationship between sleep disturbances and clinical features and outcomes may not be adequately studied. In this study, we measured the functional impairments and clinical features of co-occurring insomnia and hypersomnia symptoms in Chinese patients with MDD.MethodsA post-hoc analysis was performed on data from the National Survey on Symptomatology of Depression (NSSD), which assessed the MDD patients in 32 hospitals by a clinician-rating questionnaire. The clinical features and outcomes were compared among the following four groups: insomnia symptom only, hypersomnia symptom only, both insomnia and hypersomnia symptoms, no sleep disturbance, respectively.ResultsTotally, 234 (7.15%) of 3275 participants with MDD co-occurred insomnia and hypersomnia symptoms. They had more depressive symptoms (27.41 ± 9.123), higher rate of suicide ideation (39.7%), more severe impairment in physical (58.1%), economic (32.9%), work (55.1%), and relationship with families (29.5%). Patients with both sleep disturbances were more likely to excessive worry about sleep, have suicidal ideation, the distress of social disharmony, more somatic symptoms, lack of energy, hyperphagia, loss of mood reactivity, and diurnal change, whereas less likely to have anxious mood.LimitationsSleep disorders were not diagnosed by current standard diagnostic criteria.ConclusionsPatients co-occurring with both sleep disturbances are associated with a higher rate of suicide risk and poorer social function. Our study could provide implications for suicidal risk evaluation and the development of therapeutic strategies for depression.     

Hypoesthesia in generalised anxiety disorder and major depression disorder

Abstract

Objective: The determination of soft signs can be a conducive practice to understand the differential etiology between depression and anxiety. This study aims at examining malleolar hypoesthesia role in distinguishing between patients with generalised anxiety disorder (GAD) and major depression disorder (MDD).

Methods: This study examines the presence of malleolar hypoesthesia in patients with GAD (n?=?47) compared to patients with MDD (n?=?48) and healthy individuals (controls; n?=?99). The Wartenberg wheel, a medical device for neurological use, was employed to determine the presence of hypoesthesia on both sides of the ankles.

Results: The data revealed: i) MDD patients showed higher hypoesthesia than GAD patients (p?=?.008), ii) participants with hypoesthesia had higher anxiety and depression scores than participants without hypoesthesia (all p?<?.001) and iii) logistic regression model indicated that hypoesthesia can be a predictor of MDD relative to GAD diagnosis (Odds Ratio: 17.43 (1.40–217.09; p?=?.026)).

Conclusions: Malleolar hypoesthesia was higher in MDD than GAD. The detection of hypoesthesia may help to investigate the differential etiology between MDD and GAD diagnosis.     

Effects of depression and melatonergic antidepressant treatment alone and in combination with sedative–hypnotics on heart rate variability: Implications for cardiovascular risk

Objectives: To examine heart rate variability (HRV) in unmedicated patients with major depressive disorder (MDD) and its changes after treatment with agomelatine alone and in combination with sedative–hypnotics.

Methods: We recruited 152 physically healthy, unmedicated patients with MDD and 472 age- and sex-matched healthy volunteers. Frequency-domain measures of HRV were obtained during enrolment for all participants and again for MDD patients after 6 weeks of treatment with agomelatine alone and combining sedative–hypnotics.

Results: Compared to the controls, unmedicated patients exhibited significantly lower mean R-R intervals, low-frequency (LF) HRV, and high-frequency (HF) HRV, but higher LF/HF ratios. Fifty-six and 49 patients successfully completed agomelatine monotherapy and the combination therapy of agomelatine and sedative–hypnotics, respectively. Between-group analyses showed significant treatment-by-group interactions for LF-HRV, HF-HRV and LF/HF ratio. The results showed a significant increase in HF-HRV after agomelatine monotherapy, a significant decrease in LF-HRV and HF-HRV, and a increase in the LF/HF ratio after combination therapy.

Conclusions: MDD patients had reduced HRV, and the patterns of HRV changes differed between patients treated with agomelatine alone and in combination with sedative–hypnotics. Clinicians should consider HRV effects when adding sedative–hypnotics to agomelatine, which is important for depressed patients who already have decreased cardiac vagal tone.     

Heart rate variability predicts therapy outcome in pain-predominant multisomatoform disorder

BackgroundAutonomic imbalance establishes an important model to understand organically unexplained physical complaints. Our study aimed to investigate whether the functioning of the autonomous nervous system corresponds with somatoform symptoms and predicts the outcome of brief psychotherapy in these patients.MethodAs a part of multicenter study assessing effects of brief psychodynamic interpersonal therapy on multisomatoform disorder (PISO-study), 106 patients participated in a stress experiment investigating autonomic reactivity during application of the Stroop-test. Patients were randomized receiving either enhanced medical care (EMC, N = 49) or psychotherapy (N = 57). Autonomic baseline functioning as well as stress reactivity of heart rate (HR) and heart rate variability (HRV) were analyzed in their relation to symptom measures and as potential predictors of the primary outcome (Physical Component Score of the SF-36) during 9-month follow-up.ResultsAfter therapy patients markedly and sustainably improved in physical quality of life, and this long-term improvement was predicted by baseline HR and HRV. HRV also predicted change in pain symptoms following psychotherapy. A responder analysis revealed a significant better treatment outcome in patients with high pre-treatment HRV (OR 3.4, CI: 1.2–9.9, p = .0035). No significant associations between HR or HRV and outcome measures were found in the EMC group.ConclusionIn our study, the adaptability of the autonomous nervous system as indicated by low pretreatment HR and high HRV was associated with a more pronounced benefit from psychotherapy. This finding can be explained by a possible association between autonomic self-regulation and emotional learning capacities.     

Cardiac autonomic tone,plasma BDNF levels and paroxetine response in newly diagnosed patients of generalised anxiety disorder

Abstract

Objective: The study examined the effect on cardiac autonomic tone via heart rate variability (HRV), brain derived neurotrophic factor (BDNF) in newly diagnosed generalised anxiety disorder (GAD) cases with paroxetine-controlled release (PX) CR intervention.

Methods: Fifty GAD cases using DSM-5 criteria, matched with healthy controls (HC) were assessed with clinical measures (Hamilton Anxiety Scale (HAM-A), Clinical Global Impression- Severity Scale (CGI-Severity), General Health Questionnaire -12 (GHQ-12), HRV, plasma BDNF levels initially and 6?weeks postintervention with paroxetine CR.

Results: HRV parameters were significantly lower in GAD vs HC at baseline for standard deviation of normal to normal intervals (SDNN) and proportion of differences in consecutive NN intervals that are longer than 50?ms (pNN50). Significantly higher plasma BDNF levels were noted between HC versus GAD at baseline. Postintervention HAM-A, CGI scores, GHQ-12 item scores showed significant reduction. Significant differences also noted in square root of mean squared difference of successive NN intervals (RMSSD), (SDNN), pNN50 and in plasma BDNF levels after intervention within GAD group. Significant negative correlation observed between HAM-A scores and SDNN parameter after taking PX CR in GAD.

Conclusion: GAD showed cardiac autonomic dysfunction, lowered plasma BDNF levels and their improvement with paroxetine CR.

• Key message

• GAD is associated with significantly lower HRV, suggestive of cardiac autonomic dysfunction and lowered plasma BDNF levels, an indicator of stress.

• Therapeutic intervention with Paroxetine in GAD patients showed clinically significant improvement reflecting restoration of the cardiac autonomic tone and BDNF levels, thus implying their role as potential biomarkers.

     

Descriptive Epidemiology of Major Depressive Disorder in Canada in 2012

Objective:

The epidemiology of major depressive disorder (MDD) was first described in the Canadian national population in 2002. Updated information is now available from a 2012 survey: the Canadian Community Health Study—Mental Health (CCHS-MH).

Method:

The CCHS-MH employed an adaptation of the World Health Organization World Mental Health Composite International Diagnostic Interview and had a sample of n = 25 113. Demographic variables, treatment, comorbidities, suicidal ideation, and perceived stigma were assessed. The analysis estimated adjusted and unadjusted frequencies and prevalence ratios. All estimates incorporated analysis methods to account for complex survey design effects.

Results:

The past-year prevalence of MDD was 3.9% (95% CI 3.5% to 4.2%). Prevalence was higher in women and in younger age groups. Among respondents with past-year MDD, 63.1% had sought treatment and 33.1% were taking an antidepressant (AD); 4.8% had past-year alcohol abuse and 4.5% had alcohol dependence. Among respondents with past-year MDD, the prevalence of cannabis abuse was 2.5% and that of dependence was 2.9%. For drugs other than cannabis, the prevalence of abuse was 2.3% and dependence was 2.9%. Generalized anxiety disorder was present in 24.9%. Suicide attempts were reported by 6.6% of respondents with past-year MDD. Among respondents accessing treatment, 37.5% perceived that others held negative opinions about them or treated them unfairly because of their disorder.

Conclusions:

MDD is a common, burdensome, and stigmatized condition in Canada. Seeking help from professionals was reported at a higher frequency than in prior Canadian studies, but there has been no increase in AD use among Canadians with MDD.     

Psychophysiological assessment of stress reactivity and recovery in anxiety disorders

The present study aimed to examine changes in psychophysiological arousal from baseline to a stressor phase (reactivity) and from the stressor phase to a second resting phase (recovery) in patients with anxiety disorders. Fifty adult patients with DSM-5 anxiety disorders (panic disorder, generalized anxiety disorder, or social anxiety disorder) and 28 healthy control (HC) participants underwent psychophysiological monitoring including electrocardiogram, respiration rate, electrodermal activity, gastrocnemius electromyograph, and end-tidal CO₂ for a 3-min resting phase, a 6-min mild stressor phase, and a 3-min recovery phase. Anxious patients then went on to receive naturalistic cognitive-behavioral therapy (CBT) in a specialty outpatient clinic. Results for the reactivity phase indicated that compared to HCs, patients with social anxiety disorder exhibited heightened psychophysiological reactivity while patients with panic disorder and generalized anxiety disorder exhibited attenuated reactivity. Results for physiological recovery (return to baseline after the stressor was withdrawn) were mixed, but provided some support for slower autonomic recovery in patients with generalized anxiety disorder and panic disorder compared to HCs. Participants with all anxiety disorders exhibited diminished change in high frequency heart rate variability compared to HCs. Generally, psychophysiological reactivity and recovery were not associated with CBT outcome, though exploratory analyses indicated that greater respiration rate reactivity and stronger respiration rate recovery were associated with better CBT outcomes in patients with panic disorder.     

Post-Traumatic Stress Disorder, Depression, and Heart-Rate Variability among North Korean Defectors

Objective

This study evaluated the symptoms of post-traumatic stress disorder (PTSD) among North Korean defectors and their level of suicidal ideation and the correlation between these and heart-rate variability (HRV) to explore the possibility of using HRV as an objective neurobiological index of signs of autonomic nervous system disorder.

Methods

A total of 32 North Korean defectors (nine men, 23 women) were selected as subjects, and their HRV was measured after they completed the Minnesota Multiphasic Personality Inventory-PTSD (MMPI-PTSD) scale and the Beck Depression Inventory (BDI).

Results

1) Low-frequency (LF)/high-frequency (HF) ratios in the HRV index and MMPI-PTSD scores were correlated (r=0.419, p<0.05), as were BDI item 9 (suicidal ideation) and MMPI-PTSD scores (r=0.600, p<0.01). 2) A regression analysis of LF/HF ratios and MMPI-PTSD scores revealed an R-value of 13.8% (Adj. R²=0.138, F=4.695, p=0.041), and a regression analysis of BDI item 9 and MMPI-PTSD scores showed an R-value of 32.8% (Adj. R²=0.328, F=11.234, p=0.003). In other words, the LF/HF ratio (β=0.419) and BDI item 9 (β=0.600) appear to be risk factors in predicting MMPI-PTSD scores.

Conclusion

The LF/HF ratio, a standard index of autonomic nervous system activity, can be used as an objective neurobiological index to analyze PTSD among North Korean defectors presenting with various mental and physical symptoms, and the approximate level of suicide -ideation can act as a predicting factor for PTSD.     

Interpreting resting heart rate variability in complex populations: the role of autonomic reflexes and comorbidities

Purpose

Resting heart rate variability (HRV) is an important biomarker linking mental health to cardiovascular outcomes. However, resting HRV is also impaired in autonomic neuropathy, a common and underdiagnosed complication of common medical conditions which is detected by testing autonomic reflexes. We sought to describe the relationship between autonomic reflex abnormalities and resting HRV, taking into consideration medical comorbidities and demographic variables.

Methods

Participants (n = 209) underwent a standardized autonomic reflex screen which was summarized as the Composite Autonomic Severity Score (CASS) and included measures of reflexive HRV, e.g., heart rate with deep breathing (HRDB). Resting HRV measures were: pNN50 (percentage of NN intervals that differ by > 50 ms) and cvRMSSD (adjusted root mean square of successive differences).

Results

In univariate analyses, lower resting HRV was associated with: older age, higher CASS, neuropathy on examination, hypertension, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, and psychiatric disease. Adaptive regression spline analysis revealed that HRDB explained 27% of the variability in resting HRV for participants with values of HRDB in the normal range. Outside this range, there was no linear relationship because: (1) when HRDB was low (indicating autonomic neuropathy), resting HRV was also low with low variance; and (2) when HRDB was high, the variance in resting HRV was high. In multivariate models, only HRDB was significantly independently associated with cvRMSSD and pNN50.

Conclusion

Subclinical autonomic neuropathy, as evidenced by low HRDB and other autonomic reflexes, should be considered as a potential confounder of resting HRV in research involving medically and demographically diverse populations.

     

Autonomic modulation in healthy first-degree relatives of patients with major depressive disorder

Background

Cardiac mortality is known to be increased in patients with major depression. Several studies have reported an imbalance within the autonomic nervous system (ANS) of patients with major depressive disorder (MDD) as one putative cause. Since a heritability of autonomic modulation was demonstrated in healthy subjects, we aimed to investigate autonomic modulation in first-degree relatives of patients with MDD to find potential autonomic imbalances.

Methods

We included 30 patients with MDD, 30 of their first-degree relatives (siblings or offspring) and 30 matched healthy controls in our study. We obtained a high resolution electrocardiogram and beat to beat blood pressure measurements for 30 min at rest. Linear and nonlinear parameters of heart rate variability (HRV) and baroreflex sensitivity (BRS) were calculated.

Results

Parameters of HRV and BRS did not differ significantly between relatives and controls. We found significant differences between patients and controls for some HRV and BRS parameters confirming results of previous studies.

Discussion

Findings of our study suggest that an imbalance of autonomic function is related to patients with depression and not to first-degree relatives. Thus, a genetic background for autonomic dysfunction is rather unlikely.     

Posttraumatic Stress Disorder Symptomatology and Substance Use in an Outpatient Concurrent Disorders Sample

Objective:Posttraumatic stress disorder (PTSD) and substance use disorders (SUDs) present a complex and often severe clinical presentation within a concurrent disorders context. The objective of this study was to examine associations between PTSD symptoms and SUD outcomes to better understand the clinical phenomenon of comorbid PTSD and SUD. Multivariate statistical methods were used to test the hypothesis that elevated PTSD symptoms, both at the level of global severity and specific PTSD symptom clusters, are associated with greater substance use and related problems.Methods:Data were collected from an intake assessment battery within a specialized concurrent disorders outpatient service in Hamilton, ON. The sample comprised 326 participants (mean age = 37.19, 45.4% female). Structural equation models examined associations between PTSD and alcohol, cannabis, and substance use frequency and problems, controlling for age and sex. Alcohol was ultimately dropped from the model due to non-significant bivariate associations.Results:Higher global PTSD symptomatology was significantly associated with higher cannabis and other substance use frequency and related problems. Analyses using PTSD cluster scores showed higher scores for alterations in arousal were positively associated with cannabis-related problems, drug-related problems, and cannabis and other substance use frequency. Avoidance was significantly associated with cannabis frequency and cannabis-related problems. In general, effect sizes were small in magnitude, accounting for between 9% and 25% of variance.Conclusion:Significant cluster-level associations indicate the importance of specific PTSD symptoms (hyperarousal, avoidance) in relation to substance use when identifying therapeutic targets among individuals presenting with comorbid PTSD-SUD. This multivariate approach provides a higher resolution and potentially more clinically informative representation of the complex clinical presentation of PTSD and SUD in a concurrent disorder population and could guide the development of more effective treatment paths.     

Predictive value of heart rate in treatment of major depression with ketamine in two controlled trials

ObjectiveKetamine has been shown to be effective in treatment of episodes of major depressive disorder (MDD). This controlled study aimed to analyse the predictive and discriminative power of heart rate (HR) and heart rate variability (HRV) for ketamine treatment in MDD.MethodsIn 51 patients, HR and HRV were assessed at baseline before and during ketamine infusion and 24 hours post ketamine infusion. Montgomery–Åsberg Depression Rating Scale (MADRS) was used to assess changes of depressive symptoms. A 30% or 50% reduction of symptoms after 24 hours or within 7 days was defined as response. A linear mixed model was used for analysis.ResultsKetamine infusion increased HR and HRV power during and after infusion. Responders to ketamine showed a higher HR during the whole course of investigation, including at baseline with medium effect sizes (Cohen’s d = 0.47–0.67). Furthermore, HR and HRV power discriminated between responders and non-responders, while normalized low and high frequencies did not.ConclusionThe findings show a predictive value of HR and HRV power for ketamine treatment. This further underlines the importance of the autonomous nervous system (ANS) and its possible malfunctions in MDD.SignificanceThe predictive power of HR and HRV markers should be studied in prospective studies. Neurophysiological markers could improve treatment for MDD via optimizing the choice of treatments.     

Repetitive Transcranial Magnetic Stimulation for Depression and Posttraumatic Stress Disorder in Veterans With Mild Traumatic Brain Injury

ObjectivesMild traumatic brain injury (mTBI) is a signature injury of military conflicts and is prevalent in veterans with major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Although therapeutic transcranial magnetic stimulation (TMS) can reduce symptoms of depression and PTSD, whether traumatic brain injury (TBI) affects TMS responsiveness is not yet known. We hypothesized mTBI would be associated with higher pretreatment symptom burden and poorer TMS response.Materials and MethodsWe investigated a registry of veterans (N = 770) who received TMS for depression across the US Veterans Affairs system. Of these, 665 (86.4%) had data on TBI and lifetime number of head injuries while 658 had complete data related to depression outcomes. Depression symptoms were assessed using the nine-item Patient Health Questionnaire and PTSD symptoms using the PTSD Checklist for DSM-5. Linear mixed effects models and t-tests evaluated whether head injuries predicted symptom severity before treatment, and how TBI status affected clinical TMS outcomes.ResultsOf the 658 veterans included, 337 (50.7%) reported previous mTBI, with a mean of three head injuries (range 1–20). TBI status did not predict depressive symptom severity or TMS-associated changes in depression (all p’s > 0.1). TBI status was associated with a modest attenuation of TMS-associated improvement in PTSD (in patients with PTSD Checklist for DSM-5 scores > 33). There was no correlation between the number of head injuries and TMS response (p > 0.1).ConclusionsContrary to our hypothesis, presence of mTBI did not meaningfully change TMS outcomes. Veterans with mTBI had greater PTSD symptoms, yet neither TBI status nor cumulative head injuries reduced TMS effectiveness. Limitations include those inherent to retrospective registry studies and self-reporting. Although these findings are contrary to our hypotheses, they support the safety and effectiveness of TMS for MDD and PTSD in patients who have comorbid mTBI.     

Salivary alpha-amylase response following repeated psychosocial stress in patients with panic disorder

BackgroundThis study examined autonomic responses (salivary alpha-amylase, sAA; heart rate, HR) to repeated psychosocial stress as a candidate mechanism linking autonomic hyper-arousal and sensitization to the occurrence of panic disorder (PD).MethodsThirty-three patients with PD and 34 healthy controls were exposed to the Trier Social Stress Test (TSST) twice on consecutive days.ResultssAA changes were comparable between PD and controls on both testing days with overall decreasing sAA responses (delta) on day two. In contrast, HR delta increased on day two in both groups. This sensitization was driven by female controls while male PD showed most pronounced HR changes to the first TSST.ConclusionsOverall, a general autonomic hyper-arousal in PD could not be confirmed. In contrast, sAA responses slightly habituated to repeated stress. Whether sAA findings mirror assumed habituation effects of repeated stress exposure on normalizing autonomic reactivity remains to be investigated in longitudinal studies.     

Pre-treatment peripheral biomarkers associated with treatment response in panic symptoms in patients with major depressive disorder and panic disorder: A 12-week follow-up study

ObjectivePeripheral biomarkers have been studied to predict treatment response of panic symptoms. We hypothesized that depressive disorder (MDD) vs. panic disorder (PD) would exhibit different peripheral biomarkers, and their correlation with severity of panic attacks (PA) would also differ.MethodsForty-one MDD patients, 52 PD patients, and 59 healthy controls were followed for 12 weeks. We measured peripheral biomarkers along with the Panic Disorder Severity Scale (PDSS) at each visit—pre-treatment, 2, 4, 8, and 12 weeks on a regular schedule. Peripheral biomarkers including serum cytokines, plasma and serum brain-derived neurotrophic factor (BDNF), leptin, adiponectin, and C-reactive protein (CRP) were quantified using enzyme-linked immunosorbent assay (ELISA).ResultsPatients with MDD and PD demonstrated significantly higher levels of pre-treatment IL-6 compared to controls, but no differences were seen in plasma and serum BDNF, leptin, adiponectin, and CRP. Pre-treatment leptin showed a significant clinical correlation with reduction of panic symptoms in MDD patients at visit 5 (p = 0.011), whereas pre-treatment IL-6 showed a negative correlation with panic symptom reduction in PD patients (p = 0.022). An improvement in three panic-related items was observed to be positively correlated with pre-treatment leptin in MDD patients: distress during PA, anticipatory anxiety, and occupational interference.ConclusionHigher pre-treatment leptin was associated with better response to treatment regarding panic symptoms in patients with MDD, while higher IL-6 was associated with worse response regarding panic symptoms in PD patients. Different predictive peripheral biomarkers observed in MDD and PD suggest the need for establishing individualized predictive biomarkers, even in cases of similar symptoms observed in different disorders.     

Factors causing a relapse of major depressive disorders following successful electroconvulsive therapy: A retrospective cohort study

BACKGROUNDElectroconvulsive therapy (ECT) is used to treat major depressive disorder (MDD). Relapse is often observed even after successful ECT, followed by adequate pharmaceutical treatment for MDD. AIMTo investigate the diagnostic factors and treatment strategies associated with depression relapse.METHODSWe analyzed the relationships between relapse, the diagnostic change from MDD to bipolar disorder (BP), and treatment after the initial ECT. We performed a 3-year retrospective study of the prognoses of 85 patients of the Shiga University of Medical Science Hospital. The relative risk of relapse of depressive symptoms was calculated based on the diagnostic change from MDD to BP. A receiver operating characteristic (ROC) curve was generated to evaluate the predictive accuracy of diagnostic changes from MDD to BP based on the duration between the first course of ECT and the relapse of depressive symptoms.RESULTSEighty-five patients initially diagnosed with MDD and successfully treated with ECT were enrolled in the study. Compared with the MDD participants, more BP patients experienced relapses and required continuation and/or maintenance ECT to maintain remission (65.6% vs 15.1%, P < 0.001; relative risk = 4.35, 95%CI: 2.19-8.63, P < 0.001). Twenty-nine patients experienced relapses during the three-year follow-up. In 21 (72.4%, 21/29) patients with relapse, the diagnosis was changed from MDD to BP. The duration from the first course of ECT to relapse was shorter for the BP patients than for the MDD patients (9.63 ± 10.4 mo vs 3.38 ± 3.77 mo, P = 0.022); for most patients, the interval was less than one month. The relative risk of depressive symptoms based on diagnostic changes was 4.35 (95% confidence interval: 2.19–8.63, P < 0.001), and the area under the ROC curve for detecting diagnostic changes based on relapse duration was 0.756 (95%CI: 0.562-0.895, P = 0.007).CONCLUSIONIt may be beneficial to suspect BP and change the treatment strategy from MDD to BP for patients experiencing an early relapse.     

The 5-HTTLPR genotype modulates heart rate variability and its adjustment by pharmacological panic challenge in healthy men

Abnormal serotonin transporter (5-HTT) function and autonomic nervous system (ANS) dysregulation has been proposed in panic disorder. However, in contrast to hypothalamo-pituitary-adrenocortical (HPA) functioning, ANS reactivity during panic response has yet not been investigated in humans with respect to the 5-HTT genotype. The present study assessed the influence of challenging by cholecystokinin tetrapeptide (CCK-4) on heart rate variability (HRV) measures, to monitor autonomic reactivity and its relationship to 5-HTT-linked polymorphic region (5-HTTLPR) genotypes. We hypothesized substantial effects of the 5-HTTLPR genotype on autonomic reactivity. We studied 30 healthy young men, 15 of each with the long/long (l/l) or short/short (s/s) genotype for the 5-HTTLPR. All participants received an intravenous application of 50 μg CCK-4. HRV measures were assessed in both groups at baseline and immediately after CCK-4 application. Our results indicated lower parasympathetic activity in s/s carriers during baseline, time and frequency domain measures. CCK-4 application significantly enhanced the sympathetic tone in both groups, leading to diminished group differences. A significant treatment by genotype effect indicated reduced autonomic reactivity to CCK-4 challenge in the s/s compared to l/l carriers. Our findings show enhanced sympathetic and/or diminished cardiac vagal activity under basal conditions and blunted autonomic reactivity in s/s vs. l/l carriers. Our study provides novel data supporting claims that the s/s genotype represents a genetic vulnerability factor associated with inadequate hyporeactivity to stress and extends current knowledge on the impact of the central serotonergic activity on the sympathoadrenal pathway.