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Background Therapeutic sleep deprivation (SD) presents a unique paradigm to study the neurobiology of major depressive disorder (MDD). However, the rapid antidepressant mechanism, which differs from today's slow first-line treatments, is not sufficiently understood. We recently integrated two prominent hypotheses of MDD and sleep, the synaptic plasticity hypothesis of MDD and the synaptic homeostasis hypothesis of sleep-wake regulation, into a synaptic plasticity model of therapeutic SD in MDD. Here, we further tested this model positing that homeostatically elevating net synaptic strength through therapeutic SD shifts the initially deficient inducibility of associative synaptic long-term potentiation (LTP)-like plasticity in patients with MDD into a more favorable window of associative plasticity. Methods We used paired associative stimulation (PAS), a transcranial magnetic stimulation protocol (TMS), to quantify cortical LTP-like plasticity after one night of therapeutic sleep deprivation in 28 patients with MDD. Results We demonstrate a significantly different inducibility of associative plasticity in clinical responders to therapeutic SD (> 50% improvement on the 6-item Hamilton-Rating-Scale for Depression, n=13) compared to non-responders (n=15), which was driven by a long-term depression (LTD)-like response in SD-non-responders. Indices of global net synaptic strength (wake EEG theta activity, intracortical inhibition and BDNF serum levels) were increased after SD in both groups, with responders showing a generally lower intracortical inhibition than non-responders. Limitations Repetitive assessments prior to and after treatment would be needed to further determine potential mechanisms. Conclusion After a night of therapeutic SD, clinical responders show a significantly higher inducibility of associative LTP-like plasticity than non-responders.

ObjectivesThe aim was to use routine data available at a patient’s admission to the hospital to predict polypharmacy and drug–drug interactions (DDI) and to evaluate the prediction performance with regard to its usefulness to support the efficient management of benefits and risks of drug prescriptions.DesignRetrospective, longitudinal study.SettingWe used data from a large multicentred pharmacovigilance project carried out in eight psychiatric hospitals in Hesse, Germany.ParticipantsInpatient episodes consecutively discharged between 1 October 2017 and 30 September 2018 (year 1) or 1 January 2019 and 31 December 2019 (year 2).Outcome measuresThe proportion of rightly classified hospital episodes.MethodsWe used gradient boosting to predict respective outcomes. We tested the performance of our final models in unseen patients from another calendar year and separated the study sites used for training from the study sites used for performance testing.ResultsA total of 53 909 episodes were included in the study. The models’ performance, as measured by the area under the receiver operating characteristic, was ‘excellent’ (0.83) and ‘acceptable’ (0.72) compared with common benchmarks for the prediction of polypharmacy and DDI, respectively. Both models were substantially better than a naive prediction based solely on basic diagnostic grouping.ConclusionThis study has shown that polypharmacy and DDI can be predicted from routine data at patient admission. These predictions could support an efficient management of benefits and risks of hospital prescriptions, for instance by including pharmaceutical supervision early after admission for patients at risk before pharmacological treatment is established.

Single-pulse and repetitive transcranial magnetic stimulation (rTMS) are used in clinical practice for diagnostic and therapeutic purposes. However, rTMS-based therapies that lead to a significant and sustained reduction in neuropsychiatric symptoms remain scarce. While it is generally accepted that the stimulation frequency plays a crucial role in producing the therapeutic effects of rTMS, less attention has been dedicated to determining the role of the electric field strength. Conventional threshold-based intensity selection approaches, such as the resting motor threshold, produce variable stimulation intensities and electric fields across participants and cortical regions. Insufficient standardization of electric field strength may contribute to the variability of rTMS effects and thus therapeutic success. Computational approaches that can prospectively optimize the electric field and standardize it across patients and cortical targets may overcome some of these limitations. Here, we discuss these approaches and propose that electric field standardization will be instrumental for translational science frameworks (e.g., multiscale modeling and basic science approaches) aimed at deciphering the subcellular, cellular, and network mechanisms of rTMS. Advances in understanding these mechanisms will be important for optimizing rTMS-based therapies in psychiatry.

Zusammenfassung Einleitung Stationäre Psychotherapien können u. a. aufgrund der kurzen, aber intensiven Behandlung Nebenwirkungen auslösen. In der vorliegenden Pilotstudie wurden daher bestimmte Nebenwirkungen eines multidisziplinären, stationären CBASP-Programms (Cognitive Behavioral Analysis System of Psychotherapy) für Patienten mit therapieresistenter chronischer Depression sowie deren Zusammenhang mit dem Therapieerfolg (Response-, Remissions- und Rückfallraten) untersucht. Material & Methoden 50 Patienten mit therapieresistenter chronischer Depression nahmen an einem strukturierten 12-wöchigen, stationären CBASP-Programm teil. Nebenwirkungen wurden erfasst durch 1) eine Verschlechterung der depressiven Symptomatik im Fremdbericht bei Entlassung (Wert auf der Hamilton Depression Rating Scale, HDRS24) und 2) einem Selbstbeurteilungsfragebogen zur Erfassung von Nebenwirkungen in der stationären Psychotherapie (NESTAP), welcher von Patienten 6–12 Monate nach Entlassung ausgefüllt wurde. Ergebnisse Nach der 12-wöchigen Behandlung konnten 84% der Patienten als Responder klassifiziert werden, von denen 44% das Remissionskriterium erfüllten. 16% waren Non-Responder, wobei kein Patient gemäß HDRS eine fremdbeurteilte Verschlechterung der depressiven Symptomatik zeigte. Sechs Monate nach Entlassung erlitten 40% der Responder einen Rückfall. Im NESTAP gaben 66% der Patienten an, dass sich während der Behandlung ihre Symptomatik vorübergehend verschlechtert habe. Bei diesen Patienten zeigte sich eine geringere Remissionsrate. Über 50% berichteten von interpersonellen Konflikten mit Teammitgliedern oder anderen Patienten, wobei kein Zusammenhang mit dem Therapieerfolg nachweisbar war. Schließlich berichteten über 50% der Patienten, nach Entlassung Veränderungen in sozialen Beziehungen erlebt zu haben. Diese Patienten hatten seltener einen Rückfall. Insgesamt gaben 94% aller Patienten an, mindestens eine der in dieser Studie erhobenen Nebenwirkungen erlebt zu haben. Schlussfolgerung Diese Pilotstudie gibt trotz einiger Limitationen erste Hinweise, dass das stationäre CBASP-Programm Nebenwirkungen verursacht, wobei nur eine subjektiv wahrgenommene vorübergehende Verschlechterung den individuellen Therapieerfolg kurzfristig negativ zu beeinflussen scheint. Die Ergebnisse sprechen dafür, Nebenwirkungen im Kontext des kurz- und langfristigen Therapieerfolges zu untersuchen, um herauszufinden, wie relevant Nebenwirkungen sind.

We investigated if sleep deprivation (SD) and electroconvulsive therapy (ECT) affect striatal dopamine transporter (DAT) availability assessed by single-photon emission computed tomography (SPECT) and 123I-FP-CIT, if dopamine transporter gene (SLC6A3; DAT) variation modifies aforementioned parameters, and if SD response or SD-induced DAT changes correlate with ECT response. Sixteen patients with major depression (MDD) referred for ECT and 12 matched controls were prospectively recruited for imaging and SLC6A3 VNTR genotyping. After withdrawal from any psychiatric medication, 123I-FP-CIT-SPECT was acquired at baseline, after SD and after ECT series. Striatal DAT availability was assessed by volume-of-interest analysis of SPECT data. Eleven patients underwent combined treatment with SD and ECT (five ECT responders and six non-responders). Per-protocol analyses yielded no significant effect of SD or ECT on striatal DAT availability using repeated-measures ANOVA. However, intention-to-treat analysis indicated a significant decrease of striatal DAT availability due to SD (paired t test, p

Among multiple etiological factors of depressive disorders, childhood maltreatment (CM) gains increasing attention as it confers susceptibility for depression and predisposes to chronicity. CM assumedly inhibits social-cognitive development, entailing interactional problems as observed in chronic depression (CD), especially in affective theory of mind (ToM). However, the extent of CM among CD patients varies notably as does the severity of depressive symptoms. We tested whether the extent of CM or depressive symptoms correlates with affective ToM functions in CD patients. Regional brain activation measured by functional magnetic resonance imaging during an affective ToM task was tested for correlation with CM, assessed by the Childhood Trauma Questionnaire (CTQ), and symptom severity, assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS), in 25 unmedicated CD patients (mean age 41.52, SD 11.13). Amygdala activation during affective ToM correlated positively with CTQ total scores, while (para)hippocampal response correlated negatively with MADRS scores. Our findings suggest that differential amygdala activation in affective ToM in CD is substantially modulated by previous CM and not by the pathophysiological equivalents of current depressive symptoms. This illustrates the amygdala's role in the mediation of CM effects. The negative correlation of differential (para)hippocampal activation and depressive symptom severity indicates reduced integration of interactional experiences during depressive states.

Die chronische Depression ist eine haufige und subjektiv wie gesamtwirtschaftlich sehr belastende psychische Erkrankung. Die effektive storungsspezifische Therapie dieser Storung setzt eine entsprechende Finanzierung des Ressourcenaufwandes voraus. Ermittlung einer normativen Bedarfsdefinition der Behandlungsdauer und -intensitat fur eine leitliniengerechte und empirisch nachweisbar wirksame stationare Behandlung der chronischen Depression und des daraus abgeleiteten Personalbedarfs im Vergleich mit den aktuell im Rahmen der Psychiatrie-Personalverordnung (Psych-PV) verfugbaren Ressourcen. Der entsprechend der nationalen Versorgungsgleitlinie und empirischer Befunde ableitbare Ressourcenbedarf wurde mit der Personalbemessung nach Psych-PV verglichen. Es zeigt sich fur ein normativ festgelegtes Behandlungsprogramm, selbst bei Anwendung eines 100%igen Psych-PV-Satzes, eine deutliche Unterdeckung der Finanzierung des ermittelten Ressourcenbedarfs. Die Ergebnisse zeigen deutlich, dass selbst bei Annahme einer vollstandigen Umsetzung der Psych-PV eine spezifische und wirksame stationare Therapie der chronischen Depression deutlich unterfinanziert ist. Zusatzlich besteht die Schwierigkeit der fehlenden Abbildung der chronischen Depression in der ICD-10, die eine zukunftige Differenzierung des Ressourcenbedarfs im Rahmen des PEPP-Systems verhindert.

BACKGROUND Chronic depression poses a particular challenge for the psychiatric and psychotherapeutic care system. Owing to high rates of psychiatric comorbidities and multiple pharmacological and psychotherapeutic treatment resistance, novel treatment strategies are urgently required. AIM In this article, we describe the clinical characteristics of chronic and treatment-resistant depression and review the pharmacological and psychotherapeutic treatment options currently available. We focus on the Cognitive Behavioral Analysis System of Psychotherapy (CBASP), the first specific psychotherapy approach to chronic depression. Finally, we discuss the role of psychotherapeutic inpatient programs and stepped care concepts in chronic and treatment-resistant depression.

The aetiology of suicidal behaviour is complex, and knowledge about its neurobiological mechanisms is limited. Neuroimaging methods provide a noninvasive approach to explore the neural correlates of suicide vulnerability in vivo. The ENIGMA-MDD Working Group is an international collaboration evaluating neuroimaging and clinical data from thousands of individuals collected by research groups from around the world. Here we present analyses in a subset sample (n = 3097) for whom suicidality data were available. Prevalence of suicidal symptoms among major depressive disorder (MDD) cases ranged between 29 and 69% across cohorts. We compared mean subcortical grey matter volumes, lateral ventricle volumes and total intracranial volume (ICV) in MDD patients with suicidal symptoms (N = 451) vs healthy controls (N = 1996) or MDD patients with no suicidal symptoms (N = 650). MDD patients reporting suicidal plans or attempts showed a smaller ICV (P = 4.12 × 10 - 3) or a 2.87% smaller volume compared with controls (Cohen's d = - 0.284). In addition, we observed a nonsignificant trend in which MDD cases with suicidal symptoms had smaller subcortical volumes and larger ventricular volumes compared with controls. Finally, no significant differences (P = 0.28-0.97) were found between MDD patients with and those without suicidal symptoms for any of the brain volume measures. This is by far the largest neuroimaging meta-analysis of suicidal behaviour in MDD to date. Our results did not replicate previous reports of association between subcortical brain structure and suicidality and highlight the need for collecting better-powered imaging samples and using improved suicidality assessment instruments.

Major Depressive Disorder (MDD) is one of the most prevalent psychiatric disorders worldwide. About 20-30% of patients do not respond to the standard psychopharmacological and/or psychotherapeutic interventions. Mounting evidence from neuroimaging studies in MDD patients reveal altered activation patterns in lateral prefrontal brain areas. Successful cognitive behavioral therapy (CBT) is associated with a recovery of these neural alterations. Moreover, it has been demonstrated that transcranial direct current stimulation (tDCS) is capable of influencing prefrontal cortex activity and cognitive functions such as working memory and emotion regulation. Thus, a clinical trial investigating the effects of an antidepressant intervention combining CBT with tDCS seems promising. The present study investigates the antidepressant efficacy of a combined CBT-tDCS intervention as compared to CBT with sham-tDCS or CBT alone. A total of 192 patients (age range 20-65 years) with MDD (Hamilton Depression Rating Scale Score ≥ 15, 21-item version) will be recruited at four study sites across Germany (Berlin, Munich, Tuebingen, and Freiburg) and randomly assigned to one of the following three treatment arms: (1) CBT + active tDCS; (2) CBT + sham-tDCS; and (3) CBT alone. All participants will attend a 6-week psychotherapeutic intervention comprising 12 sessions of CBT each lasting 100 min in a closed group setting. tDCS will be applied simultaneously with CBT. Active tDCS includes stimulation with an intensity of 2 mA for 30 min with the anode placed over F3 and the cathode over F4 according to the EEG 10-20 system, if assigned. The primary outcome measure is the change in Montgomery-Asberg Depression Rating Scale scores from baseline to 6, 18, and 30 weeks after the first session. Participants also undergo pre- and post-treatment neuropsychological testing and functional magnetic resonance imaging (fMRI) to assess changes in prefrontal functioning and connectivity. The study investigates whether CBT can be augmented by non-invasive brain stimulation techniques such as tDCS in the treatment of MDD. It is designed as a proof-of-principle trial for the combined tDCS-CBT treatment, but also allows the investigation of the neurobiological underpinnings of the interaction between both interventions in MDD. Trial registration ClinicalTrials.gov Identifier NCT02633449.

The Cognitive Behavioral Analysis System of Psychotherapy (CBASP) is a relatively new approach in the treatment of chronic depression (CD). Adapted as group psychotherapy for inpatients, CBASP is attracting increasing attention. In this naturalistic multicenter trial, we investigated its feasibility after 10 sessions of CBASP group therapy over a treatment time of at least 5 to a maximum of 10 weeks. Treatment outcome was additionally assessed. Across four centers, 116 inpatients with CD (DSM-IV-TR) attended CBASP group psychotherapy. Feasibility was focused on acceptance, and evaluated for patients and therapists after five (t1) and ten sessions (t2) of group psychotherapy. Observer- and self-rating scales (Hamilton Depression Rating Scale—24 items, HDRS24; Beck Depression Inventory-II, BDI-II; World Health Organization Quality of Life assessment, WHOQOL-BREF) were applied before group psychotherapy (t0) and at t2. Dropouts were low (10.3%). Patients’ evaluation improved significantly from t1 to t2 with a medium effect size (d = 0.60). Most of the patients stated that the group had enriched their treatment (75.3%), that the size (74.3%) and duration (72.5%) were ‘optimal’ and 37.3% wished for a higher frequency. Patients gave CBASP group psychotherapy an overall grade of 2 (‘good’). Therapists’ evaluation was positive throughout, except for size of the group. Outcome scores of HDRS24, BDI-II, and WHOQOL-BREF were significantly reduced from t0 to t2 with medium to large effect sizes (d = 1.48; d = 1.11; d = 0.67). In this naturalistic open-label trial, CBASP, when applied as inpatient group psychotherapy, was well accepted by patients and therapists. The results point towards a clinically meaningful effect of inpatient treatment with CBASP group psychotherapy on depression and quality of life. Other potential factors that could have promoted symptom change were discussed. A future controlled study could investigate the safety and efficacy of CBASP group psychotherapy for inpatients.

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Childhood maltreatment (CM) has been indicated as a predictor of a differential response to antidepressant treatment with psychotherapy compared to medication. In this secondary analysis, we investigated whether the presence of CM results in a differential indication for the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) or escitalopram plus clinical management (ESC). Sixty patients with chronic depression were randomized to either 22 sessions of CBASP or ESC over the course of 8 weeks of acute and 20 weeks of extended treatment at 2 German treatment sites. CM was assessed using the Childhood Trauma Questionnaire and the clinician rated Early Trauma Inventory. Intention-to-treat analyses were used to examine the impact of CM on depression, global functioning, and quality of life. The presence of CM did not result in significant differences in treatment response to CBASP or ESC on any outcome measure after 28 weeks of treatment independent of the type of CM assessment. After 8 weeks, a significant CM × treatment interaction was found for scores on the Montgomery-Asberg Depression Rating Scale. Patients with a history of CM receiving CBASP had a significantly lower response rate compared to patients without CM and to those receiving ESC after 8 weeks. Conclusively, CBASP and ESC are equally effective treatment options for the difficult to treat subgroup of patients with chronic depression and a history of CM. CM may be a predictor of a longer latency of treatment response in the case of psychotherapy. Key Practitioner Message CBASP and escitalopram are equally effective treatment options for chronic depression. Both treatments are also equally effective for the difficult to treat subgroup of patients with chronic depression and a history of childhood maltreatment. Childhood maltreatment may result in a longer latency of treatment response in the case of psychotherapy.

Objectives Difficulties in social interaction are characteristic for depressive disorders and one of the cardinal symptoms of Autism Spectrum Disorders (ASD). It has been proposed that chronically depressed persons have profoundly impaired empathic abilities in comparison to episodically depressed persons, and that specifically they exhibit a deficit in cognitive empathy, but not in affective empathy, a pattern also reported in ASD. This study aimed to explore autistic traits and empathy deficits in chronic depression, and identify specific differences to episodic depression. Method Autistic traits and multimodal empathy were assessed in chronically depressed patients (n=59), episodically depressed patients (n=40), and a healthy control group (n=55) using standardized questionnaires. Results Regardless of the disorder's chronicity, depressed patients exhibited higher levels of autistic traits and lower levels of perspective-taking than healthy controls. Chronically depressed patients reported significantly higher impairment in social skills and higher levels of personal distress in social interactions than episodic patients. Discussion Our results suggest that patients with chronic depression share two distinct characteristics, namely lower levels of social skills and higher levels of distress in tense social situations than patients with episodic depression. Future studies will need to determine whether the elevated autistic traits in chronic depression are specific to chronic depression, or represent the general tendency to withdraw from social situations. We conclude that chronically depressed patients are not specifically impaired in understanding another person's state of mind, but are unable to deal with another person's suffering or negative affective state.

The synaptic plasticity hypothesis of major depressive disorder (MDD) posits that alterations in synaptic plasticity represent a final common pathway underlying the clinical symptoms of the disorder. This study tested the hypotheses that patients with MDD show an attenuation of cortical synaptic long-term potentiation (LTP)-like plasticity in comparison with healthy controls, and that this attenuation recovers after remission. Cortical synaptic LTP-like plasticity was measured using a transcranial magnetic stimulation protocol, ie, paired associative stimulation (PAS), in 27 in-patients with MDD according to ICD-10 criteria and 27 sex- and age-matched healthy controls. The amplitude of motor-evoked potentials was measured before and after PAS. Patients were assessed during the acute episode and at follow-up to determine the state- or trait-character of LTP-like changes. LTP-like plasticity, the PAS-induced increase in motor-evoked potential amplitudes, was significantly attenuated in patients with an acute episode of MDD compared with healthy controls. Patients with remission showed a restoration of synaptic plasticity, whereas the deficits persisted in patients without remission, indicative for a state-character of impaired LTP-like plasticity. The results provide first evidence for a state-dependent partial occlusion of cortical LTP-like plasticity in MDD. This further identifies impaired LTP-like plasticity as a potential pathomechanism and treatment target of the disorder.

ObjectivesTo meta-analytically summarize lamotrigine’s effectiveness and safety in unipolar and bipolar depression.MethodsWe conducted systematic PubMed and SCOPUS reviews (last search =10/01/2015) of randomized controlled trials comparing lamotrigine to placebo or other agents with antidepressant activity in unipolar or bipolar depression. We performed a random-effects meta-analysis of depression ratings, response, remission, and adverse effects calculating standardized mean difference (SMD) and risk ratio (RR) ±95% confidence intervals (CIs).ResultsEighteen studies (n=2152, duration=9.83 weeks) in patients with unipolar depression (studies=4, n=187; monotherapy vs lithium=1, augmentation of antidepressants vs placebo=3) or bipolar depression (studies=14, n=1965; monotherapy vs placebo=5, monotherapy vs lithium or olanzapine+fluoxetine=2, augmentation of antidepressants vs placebo=1, augmentation of mood stabilizers vs placebo=3, augmentation of mood stabilizers vs trancylpromine, citalopram, or inositol=3) were meta-analyzed. Lamotrigine’s efficacy for depressive symptoms did not differ significantly in monotherapy vs augmentation studies (vs. placebo: p=0.98, I2=0%; vs active agents: p=0.48, I2=0%) or in unipolar vs bipolar patients (vs placebo: p=0.60, I2=0%), allowing pooling of each placebo-controlled and active-controlled trials. Lamotrigine outperformed placebo regarding depressive symptoms (studies=11, n=713 vs n=696; SMD=–0.15, 95% CI=–0.27, –0.02, p=0.02, heterogeneity: p=0.24) and response (after removing one extreme outlier; RR=1.42, 95% CI=1.13–1.78; p=0.003, heterogeneity: p=0.08). Conversely, lamotrigine did not differ regarding efficacy on depressive symptoms, response, or remission from lithium, olanzapine+fluoxetine, citalopram, or inositol (studies=6, n=306 vs n=318, p-values=0.85–0.92). Adverse effects and all-cause/specific-cause discontinuation were similar across all comparisons.ConclusionsLamotrigine was superior to placebo in improving unipolar and bipolar depressive symptoms, without causing more frequent adverse effects/discontinuations. Lamotrigine did not differ from lithium, olanzapine+fluoxetine, citalopram, or inositol.