Electroconvulsive therapy and adiposity-related parameters in treatment-resistant depressed patients.

Obesity is often accompanied by major depressive disorder (MDD), and vice versa. Latest research findings suggest the body mass index (BMI) to play a role in antidepressant treatment response in general. Our study aims to examine whether adiposity-related parameters such as BMI, glucose homeostasis, or serum lipids are associated with remission to electroconvulsive therapy (ECT). A pilot study (PS, n = 9) and a glucose study (GS, n = 29) were conducted. Blood was withdrawn directly before and 15 min (GS) as well as 1 h (PS) after the first ECT and directly before the last one (usually an ECT series comprised up to twelve sessions). BMI was associated with remission in the PS (remitters: M = 28, SD = 2.5; non-remitters: M = 22, SD = 2.08; t(7) = 3.325, p < 0.001, d = 0.24) but not in the GS or when pooled together. Glucose and insulin levels increased significantly after a single ECT session (GS: glucose: F (2,25.66) = 39.04, p < 0.001; insulin: PS: F (2,83) = 25.8, p < 0.001; GS: F (2,25.87) = 3.97, p < 0.05) but no chronic effect was detectable. Serum lipids were neither significantly altered after a single ECT session nor during a whole course of ECT. There was no difference between remitters and non-remitters in insulin, glucose, or serum lipid levels. Our study is lacking the differentiation between abdominal and peripheral fat distribution, and the sample size is small. Unexpectedly, BMI, glucose homeostasis, and lipid serum levels did not differ in patients remitting during ECT. In contrast to recently published studies, we cannot confirm the hypothesis that BMI may have an impact on ECT response.

S100B, Homocysteine, Vitamin B12, Folic Acid, and Procalcitonin Serum Levels in Remitters to Electroconvulsive Therapy: A Pilot Study.

BACKGROUND: Electroconvulsive therapy (ECT) is one of the most effective treatment options for refractory depressed patients. To date, there are only a few predictors of response. AIM: The aim was to identify predictive biomarkers of remission to ECT on a molecular level. METHODS: 11 patients suffering from a major depressive episode-according to the Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-underwent 10 ECT sessions. Blood samples were taken, and the depression severity was assessed before, one hour and 24 hours after sessions 1, 4, 7, and 10 using the Montgomery Asberg Depression Rating Scale (MADRS). A MADRS total score < 12 was interpreted as remission. RESULTS: Patients remitting under ECT had significantly higher homocysteine (p < 0.001), S100B (p < 0.001), and procalcitonin (PCT) (p = 0.027) serum levels. On the contrary, serum levels of vitamin B12 (p < 0.001) and folic acid (p = 0.007) were significantly lower in remitters compared to those in nonremitters. Levels remained unchanged throughout the whole ECT course. CONCLUSIONS: Our findings indicate that lower levels of vitamin B12 and folic acid associated with higher levels of homocysteine, S100B, and PCT point to a subgroup of depressed patients sensitive to ECT. Due to the limited sample size, further studies are required to replicate our findings.

P11 promoter methylation predicts the antidepressant effect of electroconvulsive therapy.

Although electroconvulsive therapy (ECT) is among the most effective treatment options for pharmacoresistant major depressive disorder (MDD), some patients still remain refractory to standard ECT practise. Thus, there is a need for markers reliably predicting ECT non/response. In our study, we have taken a novel translational approach for discovering potential biomarkers for the prediction of ECT response. Our hypothesis was that the promoter methylation of p11, a multifunctional protein involved in both depressive-like states and antidepressant treatment responses, is differently regulated in ECT responders vs. nonresponders and thus be a putative biomarker of ECT response. The chronic mild stress model of MDD was adapted with the aim to obtain rats that are resistant to conventional antidepressant drugs (citalopram). Subsequently, electroconvulsive stimulation (ECS) was used to select responders and nonresponders, and compare p11 expression and promoter methylation. In the rat experiments we found that the gene promoter methylation and expression of p11 significantly correlate with the antidepressant effect of ECS. Next, we investigated the predictive properties of p11 promoter methylation in two clinical cohorts of patients with pharmacoresistant MDD. In a proof-of-concept clinical trial in 11 patients with refractory MDD, higher p11 promoter methylation was found in responders to ECT. This finding was replicated in an independent sample of 65 patients with pharmacoresistant MDD. This translational study successfully validated the first biomarker reliably predicting the responsiveness to ECT. Prescreening of this biomarker could help to identify patients eligible for first-line ECT treatment and also help to develop novel antidepressant treatment procedures for depressed patients resistant to all currently approved antidepressant treatments.

Intravenous theophylline is the most effective intervention to prolong EEG seizure duration in patients undergoing electroconvulsive therapy.

BACKGROUND: Seizure duration in electroconvulsive therapy (ECT) is positively related with patients' outcome. This study sought to investigate the impact of anesthetic management on seizure duration, and the impact of selected drugs (theophylline, remifentanil, S-ketamine) on seizure duration. METHODS: Retrospective analysis of all patients undergoing ECT at our institution from January 2011 to April 2012 was performed based on electronic medical chart and review of existing quality improvement data. Patient data (N = 78), including gender, age, height, weight, and administered drugs, energy levels, and electroencephalic seizure duration were analyzed. Statistical analysis was performed using a generalized linear model. RESULTS: A total of 78 patients (male = 39, female = 39, age 51 ± 12 years) were included. Average number of session was 10 ± 6 (1-30). In our patient population, theophylline administration was the only parameter, which significantly prolonged seizure duration, whereas S-ketamine, remifentanil, thiopental, age, sex, session or energy level had no significant effect. CONCLUSION: Theophylline can be a useful adjunct for patients with inadequate seizure duration. If there is a concomitant beneficial effect on patients' outcome needs to be investigated in further studies.

Efficacy and long-term tuning parameters of vagus nerve stimulation in long-term treated depressive patients.

Vagus nerve stimulation (VNS) is a promising neurostimulation tool for the treatment of treatment-resistant depression. Here, we report the effects of positive remission rates and tuning parameters in a group of 18 (6 female, 12 male, mean age 54) long-term treated patients. Treatment varied between 3 and 200months (mean 104.9months). Mean stimulation intensity was 1.46mA, ranging from 0.5 to 2.0mA and high-frequency stimulation of 20-25Hz (mean 23.61Hz). The remission rates in our study population clearly indicate ongoing positive effects of VNS and highlight stimulation tunings between 0.5 and 2.0mA and 20-25Hz as best dosage for achieving remittance in long-term treatment of VNS.

Differences in Intrusive Memory Experiences in Post-traumatic Stress Disorder after Single, Re- and Prolonged Traumatization.

Intrusive memory experiences (IMEs) are a common symptom of post-traumatic stress disorder (PTSD). Sensory perceptions of IMEs in the PTSD context vary substantially. The present research examined 20 patients with a single trauma, 20 re-traumatized patients and 80 Holocaust-traumatized patients who suffered from PTSD. Our results revealed significant differences in IME frequency based on the types of trauma experience. The findings suggest that patients with prolonged (Holocaust) traumata suffered from visual (65%) and combined visual/acoustic intrusive memories (29%), whereas visual memory experiences were most frequent (90%) among single-trauma patients. The trauma experience and the intrusive memory trigger stimulus were interdependent. The type of trauma critically affects the traumatic experience. Future studies should focus on these findings to improve PTSD therapeutic options.

The Role of Prefrontal Inhibition in Regulating Facial Expressions of Pain: A Repetitive Transcranial Magnetic Stimulation Study.

UNLABELLED: Although research on facial expressions of pain has a long history, little is known about the cerebral mechanisms regulating these expressions. It has been suggested that the medial prefrontal cortex (mPFC) might be involved in regulating/inhibiting the degree to which pain is facially displayed. To test whether such a prefrontal regulation does indeed take place, we reduced medial prefrontal excitability via repetitive transcranial magnetic stimulation (rTMS) and assessed its effect on facial expressions. In a within-subject design, facial and subjective responses to experimental pain as well as "situational" pain catastrophizing were assessed in 35 healthy participants; once after receiving low-frequency rTMS over the mPFC (1 Hz) and once after sham stimulation. Compared with sham stimulation, rTMS over the mPFC resulted in enhanced facial expressions of pain, whereas self-report and pain catastrophizing did not change. The current data show that reducing medial prefrontal excitability (via low-frequency rTMS) makes individuals facially more expressive to pain. This finding indicates that the mPFC is crucially involved in the inhibition of facial expressions of pain. Because this effect was independent of changes in self-report and pain catastrophizing suggests that this inhibitory mechanism is mainly governing the facial expression and not the underlying experience of pain. PERSPECTIVE: Using rTMS, it was shown that the mPFC is causally involved in the downregulation or silencing of one's facial expression of pain. This might explain why individuals with low mPFC functioning (eg, patients with dementia) are facially more expressive in response to pain.

The behavioral profile of spice and synthetic cannabinoids in humans.

The use of synthetic cannabinoids (spice) is increasing. The number of descriptions of (new) clinical side effects is also increasing. We screened relevant publications for articles about spice with a focus on the clinical manifestations of the use of this drug. Spice creates diffuse psychiatric and somatic effects that are only partially similar to those of natural cannabinoids. Most of the observed effects are related to sympathomimetic-cardiac effects and neuropsychiatric manifestations. Clinical treatment is primarily based on intensive apparative and laboratory monitoring and supportive therapy. Because the exact active ingredients of spice are often difficult to determine with standard specific toxicology testing, the assessment and analysis of consumed substances by specialized laboratories is recommended.

Prognostic influence of witness/victim experiences and PTSD-specific symptoms on working and educational capacity: a comparison between two groups of individuals post-trauma.

BACKGROUND: Trauma exposure depends of the type of trauma and can result in the development of posttraumatic stress disorder (PTSD). The type of traumatization (such as Holocaust experiences and other sources of trauma) and specific symptoms of PTSD have influences on the outcome, and specific symptoms of PTSD influence personal and professional outcomes. Another factor is the role of the victim in their traumatization. Some patients are actively traumatized through being victims of torture, while others are passively traumatized by witnessing the traumatization of others. METHODS: We compared two groups of victim/witness trauma sufferers (PTSD vs. Holocaust-experience PTSD (HE-PTSD)) with regard to PTSD symptoms, educational and working capacity, and functional outcome parameters. RESULTS: HE-PTSD survivors with victim/witness trauma experience showed substantially more specific PTSD symptoms and higher symptom-specific intensities but had high social function and education levels. The intensity and type of intrusive memories and sociodemographic factors do not seem to have a prognostic influence on working or educational outcomes. CONCLUSIONS: Identifying the combined victim/witness experience seems to play an important prognostic role in the assessment of PTSD victims. Further studies should consider these findings within other specific traumatization groups.

BDNF serum levels and promoter methylation of BDNF exon I, IV and VI in depressed patients receiving electroconvulsive therapy.

We examined potential changes in brain-derived neurotrophic factor (BDNF) serum levels and promoter methylation of the BDNF gene in 11 patients with treatment-resistant major depressive disorder during a series of electroconvulsive therapy (ECT). Blood samples were taken before, 1 and 24 h after ECT treatment sessions 1, 4, 7 and 10. Patients remitting under ECT had significantly lower mean promoter methylation rates, especially concerning the exon I promoter, compared to non-remitters (both p < 0.002). These findings may point to a depression subtype in which ECT is particularly beneficial.

Physical activity and energy expenditure during depressive episodes of major depression.

BACKGROUND: Recent data suggest a substantial association between physical activity and depressive symptoms, but there is a lack of research evaluating the physical activity levels in patients suffering from unipolar depression across different stages of disease in an objective way. The aim of the present pilot study was to objectively examine physical activity levels of this patient group compared to healthy controls. METHODS: Physical activity performance of 19 patients with major depressive episode and 19 healthy controls was assessed at three different time points using a multisensory armband device (SenseWear® Pro3 Armband) and was reported as total energy expenditure (TEE), active energy expenditure (EE), metabolic equivalents (METs), physical activity (PA) and time of lying down (LD), in each case over 24h. RESULTS: Over all measurements, depressive patients presented a significantly lower mean TEE and EE over 24h. Moreover, the patient group showed significantly shorter duration of PA and lower average MET over 24h. When depressive symptoms abated, physical activity parameters significantly increased in the patient group. Correlation analyses demonstrated a significant relation between depressive status/anhedonia and parameters of physical activity, especially in healthy subjects. LIMITATIONS: Results represented valid data for inpatients only. CONCLUSION: Acute unipolar depression was associated with a significantly lower level of physical activity and showed a significant increase in parallel to clinical improvement. Electronic monitoring of physical activity may be an additional tool for evaluating and controlling therapeutic effects.

Serial repetitive transcranial magnetic stimulation (rTMS) decreases BDNF serum levels in healthy male volunteers.

Although repetitive transcranial magnetic stimulation (rTMS) is established in the treatment of depression, there is little knowledge about the underlying molecular mechanisms. In the last decade, the neurotrophic hypothesis of depression entailed a plethora of studies on the role of neurogenesis-associated factors in affective disorders and rTMS treatment. In the present study, we hypothesised a sham-controlled increase of peripheral brain-derived neurotrophic factor (BDNF) levels following serial rTMS stimulations in healthy individuals. We investigated the influence of a cycle of nine daily high-frequency (HF)-rTMS (25 Hz) stimulations over the left dorsolateral prefrontal cortex (DLPFC) on serum levels of BDNF in 44 young healthy male volunteers. BDNF serum concentrations were measured at baseline, on day 5 and on day 10. Overall, the statistical analyses showed that the active and sham group differed significantly regarding their responses of BDNF serum levels. Contrary to our expectations, there was a significant decrease of BDNF only during active treatment. Following the treatment period, significantly lower BDNF serum levels were quantified in the active group on day 10, when compared to the sham group. The participants' smoking status affected this effect. Our results suggest that serial HF-rTMS stimulations over the left DLPFC decrease serum BDNF levels in healthy male volunteers. This provides further evidence for an involvement of BDNF in clinical rTMS effects.

The effects of stimulation parameters on clinical outcomes in patients with vagus nerve stimulation implants with major depression.

Stimulation techniques, such as vagus nerve stimulation, are a promising new approach for treatment-resistant depression. Most international studies have used fixed stimulation parameters or have varied the stimulation frequencies. Our retrospective examination of 2 parallel groups of 10 patients each compared low-strength/high-frequency vagus nerve stimulation parameters (≤1.5 mA, 20 Hz) with high-strength/low-frequency ( >1.5 mA, 15 Hz) parameters. We found a significant decrease in the Hamilton Rating Scale for Depression scores in patients who were treated using the low-strength/high-frequency stimulation parameters. In contrast, the scores of the patients treated with high-strength/low-frequency stimulation did not change.

Facilitative effects of VNS on the motor threshold: implications for its antidepressive mode of action?

In the present study, the effects of vagus nerve stimulation (VNS) on the resting motor threshold (rMT) of patients treated with repetitive transcranial magnetic stimulation were evaluated. Patients showed a significant decrease in the rMT during VNS-on stimulation. VNS was the only significant factor affecting rMT changes and did not appear to be a static variable. Further studies should focus on the effect of VNS on neural neurogenesis in depressive disorders, and the effects of other treatment options for major depressive disorder on the rMT should also be determined.

iPad-assisted measurements of duration estimation in psychiatric patients and healthy control subjects.

Handheld devices with touchscreen controls have become widespread in the general population. In this study, we examined the duration estimates (explicit timing) made by patients in a major general hospital and healthy control subjects using a custom iPad application. We methodically assessed duration estimates using this novel device. We found that both psychiatric and non-psychiatric patients significantly overestimated time periods compared with healthy control subjects, who estimated elapsed time very precisely. The use of touchscreen-based methodologies can provide valuable information about patients.

Changes of cytokine profiles during electroconvulsive therapy in patients with major depression.

OBJECTIVES: Electroconvulsive therapy (ECT) is an effective treatment of depression, but its mechanism of action still remains unknown. Some studies emphasize that epileptic seizures result in cerebral production of cytokines, including the cytokine network in association with the pathophysiology of depression. We hypothesized that depressed patients would show a dysregulated profile of peripheral cytokines before and after ECT treatment. METHODS: Fifteen hospitalized subjects with major depressive disorder were recruited. Human cytokine array IV was used to determine the profile of cytokines in the serum during the course of ECT. Positive results of the cytokine assay were verified by reverse transcriptase-polymerase chain reaction. Depressive symptoms were evaluated before and after ECT series. RESULTS: The signal intensity of eotaxin-3 and interleukin (IL)-5 changed statistically significantly between the first ECT and 24 hours after the last ECT. Furthermore, there were significant correlations between the signal intensities of eotaxin-3, bone morphogenetic protein 6, IL-5, and transforming growth factor-ß and the severity of depression. The results of Cytoray assays were confirmed partly by reverse transcriptase-polymerase chain reaction. The changes of tumor necrosis factor ß in pre-post comparison of ECT and the correlation of the Montgomery-Asberg Depression Scale score with tumor necrosis factor ß, IL-5, and bone morphogenetic protein 6 expression could be verified. Only the relative signal intensity of IL-16 correlated significantly with the clinically as well as electroencephalographically measurable seizure duration. CONCLUSION: Electroconvulsive therapy treatment seems to change the expression of various cytokines in relation to changes of affective states such as mood. Therefore, cytokines might play a specific role within the treatment and pathogenesis of affective disorders.

No evidence for effects of a high-frequency repetitive transcranial magnetic stimulation series on verbal and figural fluency and TAP task performance in healthy male volunteers.

BACKGROUND: Study results on cognitive effects of repetitive transcranial magnetic stimulation (rTMS) in healthy people are inconsistent. Moreover, former trials performed exclusively single-session stimulations. This sham-controlled study analyzed the influence of 9 serial high-frequency rTMS on cognition. METHODS: 44 young healthy male volunteers received active or sham rTMS. We evaluated verbal fluency tasks, the Ruff Figural Fluency Test and different Test for Attentional Performance tasks (alertness, go/no-go, divided attention, working memory, flexibility) prior to the first stimulation, immediately (within 5-30 min) after stimulation on day 5 and on day 10 (1 day after the last stimulation). RESULTS: Overall, our statistical analyses revealed no significant cognitive effects of serial rTMS. CONCLUSION: In this sham-controlled study design, 9 serial rTMS over the left dorsolateral prefrontal cortex (targeted by the 5-cm rule) did neither enhance nor impair the assessed cognitive functions in healthy male volunteers.