The impact of treatment resistance on outcome and course of electroconvulsive therapy in major depressive disorder.

INTRODUCTION: Major depressive disorder (MDD) is a common psychiatric disorder. Despite several treatment options, a subgroup of patients will not respond to the commonly used antidepressant treatments and thus express treatment resistance (TRD). TRD can be quantified with the Dutch Measure for Treatment Resistance in Depression (DM-TRD). Electroconvulsive therapy (ECT) is an effective treatment for MDD, also in TRD. Yet, the position of ECT as "treatment-of-last-resort" may decrease the likelihood of beneficial outcome. Our aim was to investigate the association between treatment resistance and outcome and course of ECT. METHODS: We performed a retrospective, multicenter cohort study with 440 patients of which data was retrieved from patient records as collected in the Dutch ECT Cohort database. Linear and logistic regression models were used to explore the association between level of treatment resistance and outcome of ECT. Median split was used to explore the differences between high and low level of TRD and course of treatment. RESULTS: A higher DM-TRD score was associated with significantly smaller reduction of depression symptoms (R2 = 0.160; ß = -2.968; p < 0.001) and lower chance of response (OR = 0.821 [95 CI: 0.760-0.888]; ß = -0.197; p < 0.001). Low level TRD patients underwent fewer ECT sessions (mean 13 ± 6 SD vs. 16 ± 7 SD; p < 0.001) and fewer switches from right unilateral tot bifrontotemporal electrode placement (29% vs. 40%; p = 0.032). CONCLUSION: Reserving ECT as "treatment-of-last-resort" in the treatment algorithm for MDD seems questionable, because in our study lower level of treatment resistance predicted more beneficial ECT-outcome. Moreover, providing ECT in less treatment resistant patients showed fewer needed ECT-sessions and less switches to BL electrode placement, which may decrease the risk for cognitive side-effects.

Transdiagnostic psychiatry: Symptom profiles and their direct and indirect relationship with well-being.

BACKGROUND: Heterogeneity and comorbidity in psychiatric disorders are common, however, little is known about the impact on well-being and the role of functional limitations. We aimed to identify transdiagnostic psychiatric symptom profiles and to study their association with well-being and the mediating role of functional limitations in a naturalistic psychiatric patient group. METHODS: We used four disorder-specific questionnaires to assess symptom severity within a sample of 448 psychiatric patients with stress-related and/or neurodevelopmental disorders and 101 healthy controls. Using both exploratory and confirmatory factor analyses we identified transdiagnostic symptom profiles, which we entered into a linear regression analysis to assess their association with well-being and the mediating role of functional limitations in this association. RESULTS: We identified eight transdiagnostic symptom profiles, covering mood, self-image, anxiety, agitation, empathy, non-social interest, hyperactivity and cognitive focus. Mood and self-image showed the strongest association with well-being in both patients and controls, while self-image also showed the highest transdiagnostic value. Functional limitations were significantly associated with well-being and fully mediated the relationship between cognitive focus and well-being. LIMITATIONS: The participant sample consisted of a naturalistic group of out-patients. While this strengthens the ecological validity and transdiagnostic perspective of this study, the patients with a single neurodevelopmental disorder were underrepresented. CONCLUSION: Transdiagnostic symptom profiles are valuable in understanding what reduces well-being in psychiatric populations, thereby opening new avenues for functionally meaningful interventions.

Anhedonia as a transdiagnostic symptom across psychological disorders: a network approach.

BACKGROUND: Anhedonia is apparent in different mental disorders and is suggested to be related to dysfunctions in the reward system and/or affect regulation. It may hence be a common underlying feature associated with symptom severity of mental disorders. METHODS: We constructed a cross-sectional graphical Least Absolute Shrinkage and Selection Operator (LASSO) network and a relative importance network to estimate the relationships between anhedonia severity and the severity of symptom clusters of major depressive disorder (MDD), anxiety sensitivity (AS), attention-deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) in a sample of Dutch adult psychiatric patients (N = 557). RESULTS: Both these networks revealed anhedonia severity and depression symptom severity as central to the network. Results suggest that anhedonia severity may be predictive of the severity of symptom clusters of MDD, AS, ADHD, and ASD. MDD symptom severity may be predictive of AS and ADHD symptom severity. CONCLUSIONS: The results suggest that anhedonia may serve as a common underlying transdiagnostic psychopathology feature, predictive of the severity of symptom clusters of depression, AS, ADHD, and ASD. Thus, anhedonia may be associated with the high comorbidity between these symptom clusters and disorders. If our results will be replicated in future studies, it is recommended for clinicians to be more vigilant about screening for anhedonia and/or depression severity in individuals diagnosed with an anxiety disorder, ADHD and/or ASD.

Multimodal multi-center analysis of electroconvulsive therapy effects in depression: Brainwide gray matter increase without functional changes.

BACKGROUND: Electroconvulsive therapy (ECT) is an effective treatment for severe depression and induces gray matter (GM) increases in the brain. Small-scale studies suggest that ECT also leads to changes in brain functioning, but findings are inconsistent. In this study, we investigated the influence of ECT on changes in both brain structure and function and their relation to clinical improvement using multicenter neuroimaging data from the Global ECT-MRI Research Collaboration (GEMRIC). METHODS: We analyzed T1-weighted structural magnetic resonance imaging (MRI) and functional resting-state MRI data of 88 individuals (49 male) with depressive episodes before and within one week after ECT. We performed voxel-based morphometry on the structural data and calculated fractional amplitudes of low-frequency fluctuations, regional homogeneity, degree centrality, functional connectomics, and hippocampus connectivity for the functional data in both unimodal and multimodal analyses. Longitudinal effects in the ECT group were compared to repeated measures of healthy controls (n = 27). RESULTS: Wide-spread increases in GM volume were found in patients following ECT. In contrast, no changes in any of the functional measures were observed, and there were no significant differences in structural or functional changes between ECT responders and non-responders. Multimodal analysis revealed that volume increases in the striatum, supplementary motor area and fusiform gyrus were associated with local changes in brain function. CONCLUSION: These results confirm wide-spread increases in GM volume, but suggest that this is not accompanied by functional changes or associated with clinical response. Instead, focal changes in brain function appear related to individual differences in brain volume increases.

[Non-invasive brain stimulation for the treatment of depression]. / Niet-invasieve hersenstimulatie als behandeling voor depressie.

Depression is one of the most common psychiatric disorders and is a heavy burden, not only for the patient and his or her environment but also in economic and social terms. 35% of depressed patients do not recover after standard treatment with medication or psychotherapy. There is a need for more effective treatment options for depression. In recent decades, new forms of brain stimulation have been developed for the treatment of depression, the most important of which is transcranial magnetic stimulation (TMS). TMS uses magnetic pulses to influence brain activity. Meta-analyses show approximately 30-40% of patients respond to treatment with repetitive TMS. The depression goes into remission in about 20-30% of cases. Research has led to new treatment protocols and variations on the conventional TMS method. More research into the effectiveness of these developments is needed. We recommend using TMS as an add-on treatment more often when the patient has completed two steps of the treatment guideline.

Negative memory bias as a transdiagnostic cognitive marker for depression symptom severity.

BACKGROUND: Negative memory bias is a strong risk factor for the development and maintenance of depression. Recent evidence also found negative memory bias in other mental disorders. Here, we aim to: 1) assess the presence and strength of negative memory bias in a range of (comorbid) mental disorders, 2) investigate which disorder-specific symptoms are associated with negative memory bias, and 3) test whether negative memory bias might be a transdiagnostic mechanism. METHODS: Negative memory bias was measured in patients with at least one diagnosis of a stress-related disorder (n = 86), a neurodevelopmental disorder (n = 53), or both (n = 68), and 51 controls. Depression, anxiety, attention-deficit/hyperactivity disorder, and autism spectrum disorder symptom severity was assessed using questionnaires. Groups were compared on negative memory bias and the associations between negative memory bias and symptom severity were made using linear regression models. RESULTS: All patient groups showed stronger negative memory bias than the controls. Negative memory bias was individually associated with all symptom severity indices, but when added into a single model, only the association with depressive symptom severity remained. This persisted after controlling for diagnostic group. LIMITATIONS: Due to the cross-sectional sectional study design, we could only look at the associations between negative memory bias and disorder-specific symptoms and not at the direction of the effects. CONCLUSIONS: Negative memory bias is characteristic of a depressotypic processing style and present in different mental disorders. It might play a mechanistic role in the development of (subclinical) co-occurrence between mental disorders.

A randomized controlled trial of a standard 4-week protocol of repetitive transcranial magnetic stimulation in severe treatment resistant depression.

BACKGROUND: Treatment options for major depressive disorder (MDD) in individuals who are depressed for at least 2 years and failed two or more different types of therapeutic intervention, remain scarce. Being less invasive than electroconvulsive therapy, repetitive transcranial magnetic stimulation (rTMS) might be an alternative treatment option. RESEARCH QUESTION: Does high frequency rTMS applied over the left prefrontal cortex ameliorate depressive symptoms in patients with treatment resistant major depressive disorder and is the efficacy dependent on treatment resistance? METHOD: We performed a randomized controlled trial investigating the effect of twenty sessions of real or sham-rTMS, during 4 consecutive weeks. Efficacy was blindly rated with the Hamilton depression rating scale (HDRS-17) at baseline and 1 week after end of treatment, and the Dutch method for quantification of treatment resistance in Depression (DM-TRD) was assessed at baseline. RESULTS: An interim analysis showed no differences in antidepressant response between real and sham rTMS and we therefore discontinued the RCT after 31 patients. The mean difference of the HDRS score between baseline and post-treatment was 3.7 (± 4.0; change 16%), indicating a small but significant improvement across time (F(1,30)=25.4;p < 0.01). There were no differences however between the treatment arms (F(1.30) = 1.5;p = 0.23). We did find a negative correlation between the change in HDRS score and DM-TRD in the active rTMS group, but this correlation was not significantly different from the sham group. CONCLUSION: "Standard" 4-week rTMS treatment is not effective in chronic, severe treatment-resistant depressed patients. While a replication of our data in this patient group may be ethically difficult, further research with less treatment resistant patients might help in positioning rTMS within the current stepped care approach to depression.

Absence of default mode downregulation in response to a mild psychological stressor marks stress-vulnerability across diverse psychiatric disorders.

Clinically, it is well-established that vulnerability to stress is a common feature across a broad spectrum of psychiatric disorders. However, this link has been mechanistically studied almost exclusively in patients with so-called stress-related disorders such as depression and anxiety. To probe transdiagnostic mechanisms, we set out to study the acute stress response across a broader range of psychiatric disorders taking a large-scale brain network perspective. We investigated the brain's response to a mild, experimentally well-controlled psychological stressor in the form of an aversive movie. We studied 168 patients with stress-related and/or neurodevelopmental disorders (including comorbidity) and 46 control subjects. We focused on three networks that have a central role in the brain's stress response and are affected in a wide range of psychiatric disorders: the salience network (SN), default mode network (DMN) and frontoparietal network (FPN). Our results support an increased vulnerability to stress across all patients, indicated by a higher subjective stress level at baseline and follow-up compared to matched controls. At the brain systems level, the stress response was characterized by a relatively decreased FPN connectivity and an absence of a decrease in the within DMN connectivity across all disorders compared to controls. At the neurocognitive level, these findings may reflect a diminished top-down control and a tendency to more pronounced (negative) self-referential processing. Besides these shared aspects of the maladaptive stress response, we also discuss indications for disorder-specific aspects. Taken together, our results emphasize the importance of investigating the mechanistic underpinnings of psychiatric disorders transdiagnostically as recently done in neurogenetics.

[Consensus statement on the application of rTMS in depression in the Netherlands and Belgium]. / Consensusverklaring voor de toepassing van rTMS bij depressie in Nederland en België.

BACKGROUND: Since 2017, repetitive transcranial magnetic stimulation (rTMS) has become eligible for reimbursement for the treatment of therapy-resistant depression in the Dutch healthcare system.
AIM: To initiate a guideline in the Netherlands and Belgium for the safe and effective application of rTMS for the treatment of depression.
METHOD: Based on literature review, existing guidelines and consensus among Dutch rTMS experts, recommendations were developed regarding the implementation of rTMS as a treatment of depression. All available evidence was weighed and discussed among all co-authors and recommendations were reached by consensus among the group.
RESULTS: rTMS targeting the dorsolateral prefrontal cortex (DLPFC) should be seen as a first choice in the treatment of depression using high-frequency rTMS (left) or, as an alternative, low-frequency rTMS (right). Stimulation protocols should use more than 1000 pulses per session for an average of 20-30 sessions, offered in 2-5 sessions per week. Contraindications for rTMS include epilepsy, intracranial presence of (magnetisable) metals, pacemaker and cochlear implant.
CONCLUSION: rTMS, performed by competent professionals is an effective and safe treatment for depression.

[Minimally invasive brain stimulation for unipolar depression]. / Minimaal invasieve hersenstimulatie bij unipolaire depressie.

BACKGROUND: Unipolar depression is one of the most prevalent psychiatric disorders and has a high impact at individual and societal level. Commonly used treatments such as antidepressants and psychotherapy are often not effective. AIM: To determine the efficacy of repetitive transcranial magnetic stimulation (rTMS) and direct current stimulation (tDCS) as minimally invasive forms of treatment for unipolar depression. METHOD: We searched the literature. RESULTS: rTMS is effective in treating unipolar depression and is comparable to existing forms of medication and behavioural therapy. The effects of tDCS are promising, but more research is needed. CONCLUSION: rTMS is a useful addition to the existing arsenal of treatment for unipolar depression.

[Usefulness of repetitive transcranial magnetic stimulation (rTMS) in the treatment of bipolar depression]. / Repetitieve transcraniële magnetische stimulatie (rTMS) als behandeling van bipolaire depressie.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been found to be an effective technique in the treatment of unipolar depression. However, it is not yet clear whether rTMS is also useful in the treatment of bipolar depression. AIM: To evaluate the available evidence that rTMS is effective in the treatment of bipolar depression. METHOD: Review of available literature (RCTs and open-label studies). RESULTS: We looked closely at four RCTs and four open-label studies. In three of the four RCTs the results for patients who had received rTMS were no better than those for patients who had received a placebo. Patients in all four open-label studies showed significant improvement. One individual developed hypomanic symptoms. The studies used many different parameters; some studies included diagnoses, some referred to the type of medication used. CONCLUSION: So far, there is a lack of high quality studies on which we can base our conclusions about the effectiveness of rTMS for the treatment of bipolar depression. The use of rTMS to treat patients with bipolar depression does not seem to increase the risk that a patient will develop (hypo)mania.

How the brain connects in response to acute stress: A review at the human brain systems level.

The brain's response to stress is a matter of extensive neurocognitive research in an attempt to unravel the mechanistic underpinnings of neural adaptation. In line with the broadly defined concept of acute stress, a wide variety of induction procedures are used to mimic stress experimentally. We set out to review commonalities and diversities of the stress-related functional activity and connectivity changes of functional brain networks in healthy adults across procedures. The acute stress response is consistently associated with both increased activity and connectivity in the salience network (SN) and surprisingly also with increased activity in the default mode network (DMN), while most studies show no changes in the central executive network. These results confirm earlier findings of an essential, coordinating role of the SN in the acute stress response and indicate a dynamic role of the DMN whose function is less clear. Moreover, paradigm specific brain responses have to be taken into account when investigating the role and the within and between network connectivity of these three networks.

Bilateral ECT induces bilateral increases in regional cortical thickness.

Electroconvulsive therapy (ECT) is the most effective treatment for patients suffering from severe or treatment-resistant major depressive disorder (MDD). Unfortunately its underlying neurobiological mechanisms are still unclear. One line of evidence indicates that the seizures produced by ECT induce or stimulate neuroplasticity effects. Although these seizures also affect the cortex, the effect of ECT on cortical thickness is not investigated until now. We acquired structural magnetic resonance imaging data in 19 treatment-resistant MDD patients before and after a bilateral ECT course, and 16 healthy controls at 2 time points, and compared changes in cortical thickness between the groups. Our results reveal that ECT induces significant, bilateral increases in cortical thickness, including the temporal pole, inferior and middle temporal cortex and the insula. The pattern of increased cortical thickness was predominant in regions that are associated with seizure onset in ECT. Post hoc analyses showed that the increase in thickness of the insular cortex was larger in responders than in non-responders, which may point to a specific relationship of this region with treatment effects of ECT.

[Anxiety disorders during pregnancy and the post-partum period]. / Angststoornissen tijdens de zwangerschap en post-partumperiode.

BACKGROUND: Although anxiety disorders are more prevalent during the perinatal period, little attention has been given so far to the influence that pregnancy and the post-partum period can have on anxiety disorders. AIM: To review the literature concerning the prevalence, presentation and treatment of anxiety disorders during pregnancy and the post-partum period and to identify the risk factors involved. METHOD: We reviewed the literature in order to find articles concerning the influence of the post-partum period on various types of anxiety disorders. RESULTS: Having selected the most relevant articles, we discuss the findings in relation to specific types of anxiety disorder. CONCLUSION: Women are more vulnerable to anxiety disorders during the perinatal period. Because anxiety disorders can have a significant impact on the mother and her foetus/infant it is important that anxiety disorders are identified and treated at the earliest opportunity.

Neural basis of emotion recognition deficits in first-episode major depression.

BACKGROUND: Depressed individuals demonstrate a poorer ability to recognize the emotions of others, which could contribute to difficulties in interpersonal behaviour. This emotion recognition deficit appears related to the depressive state and is particularly pronounced when emotions are labelled semantically. Here, we investigated its neural basis by comparing emotion recognition processing between depressed, recovered and healthy individuals. METHOD: Medication-naive patients with a first major depressive episode, medication-free patients who had recovered from a first episode, and a group of matched healthy individuals participated. They were requested to identify the emotion of angry and fearful face stimuli, either by matching them to other emotional faces on a perceptual basis or by matching them to a semantic label, while their brain activity was measured with functional magnetic resonance imaging. RESULTS: The depressed individuals performed worse than recovered and healthy individuals on the emotion-labelling but not the emotion-matching task. The labelling deficit was related to increased recruitment of the right amygdala, left inferior frontal gyrus and anterior cingulate cortex. CONCLUSIONS: Deficits in semantic labelling of negative emotions are related to increased activation in specific brain regions and these abnormalities are mood state-dependent. These results indicate that accessing semantic knowledge about negative information triggers increased amygdala and left inferior frontal gyrus processing, which subsequently impairs task-relevant behaviour. We propose that this may reflect the activation of negative schemas.