Angela Merkl

Two-year outcome of vagus nerve stimulation in treatment-resistant depression.

One of the major goals of antidepressant treatment is a sustained response and remission of depressive symptoms. Some of the previous studies of vagus nerve stimulation (VNS) have suggested antidepressant effects. Our naturalistic study assessed the efficacy and the safety of VNS in 74 European patients with therapy-resistant major depressive disorder. Psychometric measures were obtained after 3, 12, and 24 months of VNS. Mixed-model repeated-measures analysis of variance revealed a significant reduction (P ≤ 0.05) at all the 3 time points in the 28-item Hamilton Rating Scale for Depression (HRSD28) score, the primary outcome measure. After 2 years, 53.1% (26/49) of the patients fulfilled the response criteria (≥50% reduction in the HRSD28 scores from baseline) and 38.9% (19/49) fulfilled the remission criteria (HRSD28 scores ≤ 10). The proportion of patients who fulfilled the remission criteria remained constant as the duration of VNS treatment increased. Voice alteration, cough, and pain were the most frequently reported adverse effects. Two patients committed suicide during the study; no other deaths were reported. No statistically significant differences were seen in the number of concomitant antidepressant medications. The results of this 2-year open-label trial suggest a clinical response and a comparatively benign adverse effect profile among patients with treatment-resistant depression.

Antidepressant electroconvulsive therapy: Mechanism of action, recent advances and limitations

A considerable number of depressive patients do not respond to or remit during pharmacotherapeutical or psychotherapeutical interventions resulting in an increasing interest in non-pharmacological strategies to treat affective disorders. Electroconvulsive therapy (ECT) dates back to the beginning of modern biologic psychiatry and ongoing research has successfully improved efficacy in addition to safety while reducing side effects. Double-blind, randomized, controlled trials have shown powerful interactions between electrode placement (right unilateral, bifrontal, bitemporal) and dosage (relative to seizure threshold) in the efficacy and side effects of ECT. This review aims to summarize current research data on the mechanism of action, efficacy, and recent advances in ECT technique.

Abnormal Cingulate and Prefrontal Cortical Neurochemistry in Major Depression After Electroconvulsive Therapy

BACKGROUND Metabolic changes after electroconvulsive therapy (ECT) have been described in depressed patients, but results are heterogeneous. To determine the concentrations of N-acetyl-aspartate (NAA), choline-containing compounds, creatine + phosphocreatine (tCr), and glutamate in the left dorsolateral prefrontal cortex (DLPFC) and left anterior cingulum of depressed patients before and after ECT, we used proton magnetic resonance spectroscopy. METHODS Metabolite concentrations in the DLPFC and anterior cingulum were determined in 25 patients with major depressive disorder (MDD) and 27 healthy control subjects using the point resolved spectroscopy sequence. Neuropsychological and clinical parameters were determined before and after nine sessions of right unilateral ultrabrief pulse ECT. RESULTS In the cingulum, baseline glutamate and NAA levels were decreased in depressed patients. High glutamate at baseline predicted a greater treatment response. After ECT, increased NAA levels were observed in responders to treatment and tCr levels were significantly decreased across all depressive patients. In the left DLPFC, NAA levels were significantly decreased in responders to ECT compared with nonresponders. Autobiographic memory was deteriorated in all patients after ECT. CONCLUSIONS Low glutamatergic state in depressive patients emphasizes the role of dysfunctional glutamatergic neurotransmission in the pathophysiology of MDD. The low NAA level at baseline in the patients supports neurodegenerative changes in MDD. N-acetyl-aspartate levels might serve as early surrogate marker for dynamic metabolic changes due to ECT, reflecting both neuroprotection and lowered neuronal viability. The tCr decrease in the cingulum suggests altered mitochondrial energy metabolism.

Antidepressant effects after short-term and chronic stimulation of the subgenual cingulate gyrus in treatment-resistant depression.

BACKGROUND Deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) is an experimental approach in treatment-resistant depression (TRD). Apart from its potential long-term antidepressant effects acute stimulation effects have been described. We investigated putative neuroanatomical clusters in which such acute effects accumulate and followed patients over the long-term. METHODS We assessed safety and efficacy of DBS in six patients with TRD receiving bilateral DBS with electrodes implanted in the SCG. First, high intensity 130 Hz stimulation was applied on five consecutive days after surgery for 24 h comprising a sham condition in a double-blind, randomized design. Acute stimulation was conducted at all four homologous electrode contacts on both sides. Afterwards, chronic stimulation was initiated and the clinical effect was evaluated at 24-36 weeks compared to baseline (50% reduction in HAMD scores). The primary outcome criterion was depression severity as assessed with the Hamilton Depression Rating Scale (HAMD-24); secondary outcome parameters were the Montgomery-Åsberg Rating-Scale and Beck Depression Inventory following DBS. The clinical effect over the three scores was compared to sham stimulation and was correlated to the anatomical localization of active contacts by stereotactically delimiting the cluster of most effective contacts in responding patients. RESULTS Acute 24 h of stimulation showed only moderate reductions in mean HAMD-24, MADRS and BDI scores. At the last observation (24-36 weeks), two patients were remitters (HAMD-24 < 10) and the four other patients were non-responders. CONCLUSIONS Our results confirm that stimulation of the SCG is capable of exerting moderate acute and chronic antidepressant effects. The predictive value of these findings needs to be addressed in future studies.

Cognitive-Behavioral Therapy as Continuation Treatment to Sustain Response After Electroconvulsive Therapy in Depression: A Randomized Controlled Trial

BACKGROUND Although electroconvulsive therapy (ECT) is the most effective acute antidepressant intervention, sustained response rates are low. It has never been systematically assessed whether psychotherapy, continuation ECT, or antidepressant medication is the most efficacious intervention to maintain initial treatment response. METHODS In a prospective, randomized clinical trial, 90 inpatients with major depressive disorder (MDD) were treated with right unilateral ultra-brief acute ECT. Electroconvulsive therapy responders received 6 months guideline-based antidepressant medication (MED) and were randomly assigned to add-on therapy with cognitive-behavioral group therapy (CBT-arm), add-on therapy with ultra-brief pulse continuation electroconvulsive therapy (ECT-arm), or no add-on therapy (MED-arm). After the 6 months of continuation treatment, patients were followed-up for another 6 months. The primary outcome parameter was the proportion of patients who remained well after 12 months. RESULTS Of 90 MDD patients starting the acute phase, 70% responded and 47% remitted to acute ECT. After 6 months of continuation treatment, significant differences were observed in the three treatment arms with sustained response rates of 77% in the CBT-arm, 40% in the ECT-arm, and 44% in the MED-arm. After 12 months, these differences remained stable with sustained response rates of 65% in the CBT-arm, 28% in the ECT-arm, and 33% in the MED-arm. CONCLUSIONS These results suggest that ultra-brief pulse ECT as a continuation treatment correlates with low sustained response rates. However, the main finding implicates cognitive-behavioral group therapy in combination with antidepressants might be an effective continuation treatment to sustain response after successful ECT in MDD patients.

Different patterns of local field potentials from limbic DBS targets in patients with major depressive and obsessive compulsive disorder

The role of distinct limbic areas in emotion regulation has been largely inferred from neuroimaging studies. Recently, the opportunity for intracranial recordings from limbic areas has arisen in patients undergoing deep brain stimulation (DBS) for neuropsychiatric disorders including major depressive disorder (MDD) and obsessive compulsive disorder (OCD). Here we test the hypothesis that distinct temporal patterns of local field potential (LFP) activity in the human limbic system reflect disease state and symptom severity in MDD and OCD patients. To this end, we recorded LFPs via implanted DBS electrodes from the bed nucleus of stria terminalis (BNST area) in 12 patients (5 OCD, 7 MDD) and from the subgenual cingulate cortex in 7 MDD patients (CG25 area). We found a distinct pattern of oscillatory activity with significantly higher α-power in MDD compared with OCD in the BNST area (broad α-band 8–14 Hz; P<0.01) and a similar level of α-activity in the CG25 area as in the BNST area in MDD patients. The mean α-power correlated with severity of depressive symptoms as assessed by the Beck depression inventory in MDD (n=14, r=0.55, P=0.042) but not with severity of obsessive compulsive symptoms in OCD. Here we show larger α-band activity in MDD patients compared with OCD recorded from intracranial DBS targets. Our results suggest that α-activity in the limbic system may be a signature of symptom severity in MDD and may serve as a potential state biomarker for closed loop DBS in MDD.

Clonidine Improves Hyperarousal in Borderline Personality Disorder With or Without Comorbid Posttraumatic Stress Disorder : A Randomized, Double-Blind, Placebo-Controlled Trial

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition borderline personality disorder (BPD) seems to constitute a very heterogeneous category. Therefore, pharmacological therapy is symptom-oriented or targets comorbid conditions. A high comorbidity exists between BPD and posttraumatic stress disorder (PTSD). In a double-blind, randomized, placebo-controlled crossover study, we sought to determine whether the antinoradrenergic agent clonidine was effective in reducing hyperarousal and measures of BPD-specific and general psychopathology in a sample of 18 patients with BPD, with or without comorbid PTSD, and with a prominent hyperarousal syndrome. Hyperarousal as measured by the Clinician Administered PTSD scale improved significantly compared with placebo (P = 0.003) irrespective of PTSD comorbidity. Improvements in general and BPD-typical psychopathology were mainly seen in the PTSD-positive subgroup, whereas the subjective sleep latency (P = 0.005) and the restorative qualities of the sleep (P = 0.014) improved in the whole sample. Improvements, despite the small sample size of this pilot study, lead us to conclude that clonidine might be a useful adjunct to pharmacotherapy in patients with BPD who have marked hyperarousal and/or sleep problems and, in particular, in patients with BPD who have a PTSD comorbidity.

Processing of visual stimuli in borderline personality disorder: A combined behavioural and magnetoencephalographic study

BACKGROUND Behavioral studies on facial emotion recognition yielded heterogeneous results in patients with Borderline Personality Disorder (BPD). Extrastriate cortex hyperactivation has been demonstrated in imaging studies in patients with BPD during face recognition, but electrophysiological studies are lacking. The aim was to investigate temporal processes following face perception in patients with BPD. METHODS Magnetoencephalography (MEG) was used in eleven non-medicated patients with BPD and nine age-matched healthy subjects. Behavioral responses to visual stimuli and an emotion discrimination task were evaluated. First, participants had to silently watch faces, houses and animals. Emotional expressive faces then had to be judged from two basic emotions in a two-alternative forced choice task. Regional field power (RFP) of MEG signals was obtained from two regions of interest: Temporal and occipital areas. Psychometric assessment was performed. RESULTS Patients with BPD had significantly reduced RFP amplitudes in the right posterior occipital region of interest, for the time window between 150 and 160 ms, irrespective of the type of visual stimulus or the emotional face category. Patients with BPD had significantly higher error rates for recognition of emotional expressive faces compared to healthy controls though they showed a higher accuracy in detecting fearful faces. Controls improved during face recognition, whereas patients showed no learning effect. CONCLUSION This MEG study provides evidence for disturbances in cortical visual perception in BPD patients regardless of emotional salience of the stimulus. In line with previous studies subtle deficits in visual perception might be related to impairment in interpersonal communication in BPD.

Dialectic behavioural therapy has an impact on self-concept clarity and facets of self-esteem in women with borderline personality disorder

Identity disturbance and an unstable sense of self are core criteria of borderline personality disorder (BPD) and significantly contribute to the suffering of the patient. These impairments are hypothesized to be reflected in low self-esteem and low self-concept clarity. The objective of this study was to evaluate the impact of an inpatient dialectic behavioral therapy (DBT) programme on self-esteem and self-concept clarity. Forty women with BPD were included in the study. Twenty patients were treated with DBT for 12 weeks in an inpatient setting and 20 patients from the waiting list served as controls. Psychometric scales were used to measure different aspects of self-esteem, self-concept clarity and general psychopathology. Patients in the treatment group showed significant enhancement in self-concept clarity compared with those on the waiting list. Further, the scales of global self-esteem and, more specifically, the facets of self-esteem self-regard, social skills and social confidence were enhanced significantly in the intervention group. Additionally, the treatment had a significant impact on basic self-esteem in this group. On the other hand, the scale of earning self-esteem was not significantly abased in patients with BPD and did not show significant changes in the intervention group. Our data provide preliminary evidence that DBT has an impact on several facets of self-esteem and self-concept clarity, and thus on identity disturbance, in women with BPD.

Gender differences in a clinical sample of patients with borderline personality disorder.

The aim of the study was to investigate gender differences and similarities in patients with borderline personality disorder (BPD) with respect to Axis I comorbidity, Axis II comorbidity, general psychopathology (Symptom Checklist 90-Revised), and dimensional personality traits (NEO-Personality-Inventory Revised [NEO-PI-R] and the Dimensional Assessment of Personality Profile Basic questionnaire [DAPP-BQ]). Fifty-seven men and 114 women with BPD were included in the study. Regarding Axis I and II disorders in an exploratory analysis, men with BPD more often fulfilled the diagnostic criteria for binge eating disorder, antisocial personality disorder, narcissistic personality disorder, and conduct disorder in childhood, whereas women had higher frequencies of bulimia nervosa, posttraumatic stress disorder, and panic disorder with agoraphobia. After correcting for multiple tests, only the gender differences in narcissistic and antisocial personality disorder remained significant. In the SCL-90-R profile, no significant gender differences could be identified. In the exploratory analysis of the dimensional personality traits, women showed higher rates on the NEO-PI-R main factors (Neuroticism and Agreeableness) compared to men. In the DAPP-BQ profile, men reached higher sores on the main factor, Dissocial Behavior. When correcting for multiple tests, gender differences still existed for Neuroticism and Dissocial Behavior. Our results argue for gender differences in Axis I and II comorbidity and dimensional personality traits in BPD. However, in general, more similarities than differences were shown in this study.