The combination of oxytocin and mindfulness-based group therapy for empathy and negative symptoms in schizophrenia spectrum disorders - A double-blinded, randomized, placebo-controlled pilot study.

Treatment options for social cognition and negative symptoms in schizophrenia spectrum disorders (SSD) remain limited. Oxytocin could be a promising augmentation approach, but the social context influences the effect in humans. This pilot study hypothesized that oxytocin in a positive social setting through mindfulness-based group therapy (MBGT) would positively affect empathy and negative symptoms as well as affect and stress in an exploratory approach in SSD. An experimental, randomized, double-blinded (participants, psychotherapists), placebo-controlled pilot study with 41 individuals with SSD was conducted at the Charité - Universitätsmedizin Berlin. Oxytocin or placebo (24 I.U.) was administered intranasally 45 min before two sessions of MBGT each. A 2 × 2 mixed model ANCOVA design was calculated to assess empathy by the Interpersonal Reactivity Index and the Multifaceted Empathy Test and negative symptoms by the Self-Evaluation of Negative Symptoms. No benefit of oxytocin compared to placebo on empathy was observed, but significant between-group differences favoring oxytocin were found regarding the negative symptoms Diminished emotional range and Avolition. Negative affect and stress were significantly reduced compared to baseline. Mindfulness increased in both groups. Results indicated protocol adherence and retention rate of 91.1%, a drop-out rate of 8.9 % and a completion of 96 % of all sessions by the participants. No severe adverse events or side effects were reported. Our findings indicate proof-of-concept and suggest a potential role of oxytocin on negative symptoms and related variables in SSD in combination with MBGT. Future research should examine the stability of these effects with larger sample sizes.

The Relationship Between Mindfulness, Depression, Anxiety, and Quality of Life in Individuals With Schizophrenia Spectrum Disorders.

Background: Schizophrenia spectrum disorders (SSD) are frequently accompanied by comorbid depressive and anxiety symptoms, as well as impaired quality of life (QoL). A growing body of evidence has demonstrated the relevance of mindfulness for SSD in recent years. The study examined the association between mindfulness, depression, anxiety, and QoL. Materials and Methods: A total of 83 participants with SSD were recruited at the in- and outpatient psychiatric hospital care. Participants completed the Southampton Mindfulness Questionnaire, Comprehensive Inventory for Mindful Experiences, and Freiburger Mindfulness Inventory, the Depression, Anxiety, Stress Scale to assess depression and anxiety, and the WHO-QoL Questionnaire. Multiple regression analyses examined the relationship between mindfulness and QoL and the mediating role of depression and anxiety. Results: Mindfulness had a significant statistical positive effect on QoL domains physical health, psychological, and environmental QoL in patients with SSD. Depression was identified as a significant mediator of this relationship. Conclusion: This study provides novel insight into mindfulness' mechanisms and paves the way for a process-oriented approach to treat SSD. The results provide first evidence for the process-based value of mindfulness for SSD; future studies can focus on the role of mindfulness for central therapeutic processes of change by employing longitudinal designs.

Effects of Mindfulness Training on Emotion Regulation in Patients With Depression: Reduced Dorsolateral Prefrontal Cortex Activation Indexes Early Beneficial Changes.

OBJECTIVE: Mindfulness-based interventions (MBIs) have been found to be a promising approach for the treatment of recurrent courses of depression. However, little is known about their neural mechanisms. This functional magnetic resonance imaging study set out to investigate activation changes in corticolimbic regions during implicit emotion regulation. METHODS: Depressed patients with a recurrent lifetime history were randomized to receive a 2-week MBI (n = 16 completers) or psychoeducation and resting (PER; n = 22 completers). Before and after, patients underwent functional magnetic resonance imaging while labeling the affect of angry, happy, and neutral facial expressions and completed questionnaires assessing ruminative brooding, the ability to decenter from such thinking, and depressive symptoms. RESULTS: Activation decreased in the right dorsolateral prefrontal cortex (dlPFC) in response to angry faces after MBI (p < .01, voxel-wise family-wise error rate correction, T > 3.282; 56 mm3; Montreal Neurological Institute peak coordinate: 32, 24, 40), but not after PER. This change was highly correlated with increased decentring (r = -0.52, p = .033), decreased brooding (r = 0.60, p = .010), and decreased symptoms (r = 0.82, p = .005). Amygdala activation in response to happy faces decreased after PER (p < .01, family-wise error rate corrected; 392 mm3; Montreal Neurological Institute peak coordinate: 28, -4, -16), whereas the MBI group showed no significant change. CONCLUSIONS: The dlPFC is involved in emotion regulation, namely, reappraisal or suppression of negative emotions. Decreased right dlPFC activation might indicate that, after the MBI, patients abstained from engaging in elaboration or suppression of negative affective stimuli; a putatively important mechanism for preventing the escalation of negative mood.Trial Registration: The study is registered at ClinicalTrials.gov (NCT02801513; 16/06/2016).

Mindfulness-based group therapy for in-patients with schizophrenia spectrum disorders - Feasibility, acceptability, and preliminary outcomes of a rater-blinded randomized controlled trial.

BACKGROUND: A Growing body of literature indicates therapeutic effectiveness of mindfulness for mental disorders. Only few trials have been conducted with schizophrenia spectrum disorders (SSD), mostly in outpatient settings. Primary objective was to assess feasibility, acceptability, and preliminary outcomes of mindfulness-based group therapy (MBGT) for in-patients with SSD. METHODS: A pre-registered randomized controlled trial was conducted to assess feasibility and acceptability of the MBGT. The primary outcome was mindfulness measured with the Southampton Mindfulness Questionnaire (SMQ). Secondary outcomes were rater-blinded positive- and negative symptoms, depression, social functioning, and self-reported mindfulness, depression, anxiety, psychological flexibility, quality of life, and medication regime at baseline, post-intervention, and follow-up (Clinical Trails NCT03671005). RESULTS: 40 participants received either treatment-as-usual (TAU; n=19) or (MBGT+TAU; n = 21) for four weeks. At post-intervention, protocol adherence was 95.2%, and retention rate was 95%. ANCOVA revealed significant improvements in the MBGT+TAU for the primary outcome SMQ as well as negative symptoms at post-intervention between groups. In exploratory analyses, secondary outcomes showed medium-to-large pre-to-post-intervention effects on mindfulness, positive-, negative-, and depressive symptoms, psychological flexibility, quality of life, and social functioning for MBGT+TAU and small-to-moderate changes on positive symptoms and social functioning for TAU. No serious adverse effects were reported. CONCLUSIONS: MBGT appears feasible and acceptable for in-patient settings, with high protocol adherence and retention rates. Preliminary findings highlight a proof of concept of MBGT and various improvements in clinical- and process dimensions. A fully powered trial is warranted to determine efficacy, cost-efficiency, and longitudinal changes based on these promising outcomes.

Mindfulness-Based Interventions for In-Patients With Schizophrenia Spectrum Disorders-A Qualitative Approach.

In recent years, mindfulness-based interventions (MBI) have gained clinical relevance in the treatment of patients with schizophrenia spectrum disorders (SSDs). High symptom burden, long durations of hospitalization and high rehospitalization rates demonstrate the severity and cost-intensity of these disorders. MBIs have shown promising treatment outcomes in a small number of trials, primarily taking place in English-speaking countries. The current study aims to explore mechanisms and processes as well as adverse effects of MBIs on in-patients with SSDs in a German university hospital setting. A qualitative design based on inductive thematic analysis accompanied by quantitative assessments was chosen. A semi-structured interview guide was developed by psychiatrists and psychologists to assess patient experiences, perceptions, thoughts, and feelings during and after taking part in a MBI. Twenty-seven interviews were conducted between September 2017 and October 2018 with in-patients who are diagnosed with schizophrenia or schizoaffective disorder. Rater-based questionnaires, such as the Positive and Negative Syndrome Scale (PANSS), Montgomery Asberg Depression Rating Scale (MADRS), and Psychotic Symptom Rating Scales-Auditory Hallucination (PSYRATS-AH) were administered at baseline to collect clinical outcomes. Qualitative analysis revealed two domains: content and function. In the first domain related to content with the core elements "detachment and rumination", "presence and getting lost", "non-judgment and judgment", and effects with "emotions", "cognition", and "symptom changes". A second domain related to function was extracted, including the relevance of perception of context and transfer to everyday life. Overall, improvements concerning cognition, distress, and psychopathology were detected, while no adverse effects, such as increased psychotic symptoms, were revealed. As the first study of its kind, mechanisms, processes, and the safety of MBIs were explored and confirmed in a sample of German in-patients with SSDs. The results of this qualitative study are in line with recent findings on MBIs amongst patients with psychotic disorders from other countries. Results lay the ground for future research to focus on the systematic study of MBIs in large samples, its treatment processes, outcomes, and effectiveness for in-patients with SSDs.

Aberrant Long-Range Temporal Correlations in Depression Are Attenuated after Psychological Treatment.

The spontaneous oscillatory activity in the human brain shows long-range temporal correlations (LRTC) that extend over time scales of seconds to minutes. Previous research has demonstrated aberrant LRTC in depressed patients; however, it is unknown whether the neuronal dynamics normalize after psychological treatment. In this study, we recorded EEG during eyes-closed rest in depressed patients (N = 71) and healthy controls (N = 25), and investigated the temporal dynamics in depressed patients at baseline, and after attending either a brief mindfulness training or a stress reduction training. Compared to the healthy controls, depressed patients showed stronger LRTC in theta oscillations (4-7 Hz) at baseline. Following the psychological interventions both groups of patients demonstrated reduced LRTC in the theta band. The reduction of theta LRTC differed marginally between the groups, and explorative analyses of separate groups revealed noteworthy topographic differences. A positive relationship between the changes in LRTC, and changes in depressive symptoms was observed in the mindfulness group. In summary, our data show that aberrant temporal dynamics of ongoing oscillations in depressive patients are attenuated after treatment, and thus may help uncover the mechanisms with which psychotherapeutic interventions affect the brain.

How emotional abilities modulate the influence of early life stress on hippocampal functioning.

Early life stress (ELS) is known to have considerable influence on brain development, mental health and affective functioning. Previous investigations have shown that alexithymia, a prevalent personality trait associated with difficulties experiencing and verbalizing emotions, is particularly related to ELS. The aim of the present study was to investigate how neural correlates of emotional experiences in alexithymia are altered in the presence and absence of ELS. Therefore, 50 healthy individuals with different levels of alexithymia were matched regarding ELS and investigated with respect to neural correlates of audio-visually induced emotional experiences via functional magnetic resonance imaging. The main finding was that ELS modulated hippocampal responses to pleasant (>neutral) stimuli in high-alexithymic individuals, whereas there was no such modulation in low-alexithymic individuals matched for ELS. Behavioral and psychophysiological results followed a similar pattern. When considered independent of ELS, alexithymia was associated with decreased responses in insula (pleasant > neutral) and temporal pole (unpleasant > neutral). Our results show that the influence of ELS on emotional brain responses seems to be modulated by an individual's degree of alexithymia. Potentially, protective and adverse effects of emotional abilities on brain responses to emotional experiences are discussed.

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 < or = 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 (> or =50% reduction in the HRSD28 scores from baseline) and 38.9% (19/49) fulfilled the remission criteria (HRSD28 scores < or = 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.

Motor cortex excitability after vagus nerve stimulation in major depression.

Recent data suggest that inhibitory pathways may be involved in the pathophysiology of depression and in the mode of action of some antidepressant interventions. The aim of the present study was to test whether vagus nerve stimulation (VNS) can affect motor cortex excitability. Measures of motor cortical excitability were probed by using single-pulse and paired-pulse transcranial magnetic stimulation at baseline, after 10 weeks of left VNS, and additionally, in an on-off paradigm in 10 patients with treatment-resistant unipolar depression. Ten weeks of VNS was associated with a selective and pronounced increase in intracortical inhibition, whereas no changes occurred in the on-off paradigm. These results suggest that VNS is capable of changing motor cortical excitability in patients with depression.

Brain-derived neurotrophic factor serum concentrations in depressive patients during vagus nerve stimulation and repetitive transcranial magnetic stimulation.

BACKGROUND: Vagus nerve stimulation (VNS) and repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex are brain stimulation techniques used as therapeutic interventions in major depression. METHODS: In this study, we report the impact of these stimulation techniques on serum concentrations of brain-derived neurotrophic factor (BDNF) in treatment-resistant patients with a diagnosis of major depression. RESULTS: We found no changes of BDNF serum concentrations and no association of neurotrophin concentrations in serum with clinical parameters in our sample. CONCLUSION: Our preliminary results suggest that brain stimulation techniques-in contrast to several antidepressant medications-do not change BDNF serum concentrations.

Evidence for impaired cortical inhibition in patients with unipolar major depression.

BACKGROUND: Several lines of evidence suggest that central cortical inhibitory mechanisms, especially associated with gamma-aminobutyric acid (GABA) neurotransmission, may play a role in the pathophysiology of major depression. Transcranial magnetic stimulation is a useful tool for investigating central cortical inhibitory mechanisms associated with GABAergic neurotransmission in psychiatric and neurological disorders. METHODS: By means of transcranial magnetic stimulation, different parameters of cortical excitability, including motor threshold, the cortical silent period, and intracortical inhibition/facilitation, were investigated in 20 medication-free depressed patients and 20 age- and gender-matched healthy volunteers. RESULTS: Silent period and intracortical inhibition were reduced in depressed patients, consistent with a reduced GABAergic tone. Moreover, patients showed a significant hemispheric asymmetry in motor threshold. CONCLUSIONS: This study provides evidence of reduced GABAergic tone and motor threshold asymmetry in patients with major depression.

Cerebral blood flow during vagus nerve stimulation--a transcranial Doppler study.

BACKGROUND AND OBJECTIVES: Vagus nerve stimulation (VNS) is an approved treatment of partial onset seizures and has recently shown antidepressant effects in patients with treatment-resistant depression. This study was conducted to investigate whether acute VNS has an influence on cerebral blood flow (CBF) in humans. METHODS: This investigation was designed as an add-on study. In 10 patients with an implanted stimulator who participated in a multicenter clinical trial to evaluate the efficacy of VNS in depression, CBF was investigated by functional transcranial Doppler at baseline (before the stimulator was turned on for the first time) and during stimulation with three different stimulation intensities in a randomized order. RESULTS: Immediately after every increase of the current, CBF velocity showed a nonsignificant increase. Otherwise, no change of CBF above standard deviation could be registered. CONCLUSION: Acute VNS does not have an influence on CBF velocity in depressive patients.

Frontal and temporal dysfunction of auditory stimulus processing in schizophrenia.

Attention deficits have been consistently described in schizophrenia. Functional neuroimaging and electrophysiological studies have focused on anterior cingulate cortex (ACC) dysfunction as a possible mediator. However, recent basic research has suggested that the effect of attention is also observed as a relative amplification of activity in modality-associated cortical areas. In the present study, the question was addressed whether an amplification deficit is seen in the auditory cortex of schizophrenic patients during an attention-requiring choice reaction task. Twenty-one drug-free schizophrenic patients and 21 age- and sex-matched healthy controls were studied (32-channel EEG). The underlying generators of the event-related N1 component were separated in neuroanatomic space using a minimum-norm (LORETA) and a multiple dipole (BESA) approach. Both methods revealed activation in the primary auditory cortex (peak latency approximately 100 ms) and in the area of the ACC (peak latency approximately 130 ms). In addition, the adapted multiple dipole model also showed a temporal-radial source activation in nonprimary auditory areas (peak latency approximately 140 ms). In schizophrenic patients, significant activation deficits were found in the ACC as well as in the left nonprimary auditory areas that differentially correlated with negative and positive symptoms. The results suggest that (1) the source in the nonprimary auditory cortex is detected only with a multiple dipole approach and (2) that the N1 generators in the ACC and in the nonprimary auditory cortex are dysfunctional in schizophrenia. This would be in line with the notion that attention deficits in schizophrenia involve an extended cortical network.