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.

Sex-specifics of ECT outcome.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most effective treatment for patients with severe major depressive disorder (MDD). Given the known sex differences in MDD, improved knowledge may provide more sex-specific recommendations in clinical guidelines and improve outcome. In the present study we examine sex differences in ECT outcome and its predictors. METHODS: Clinical data from 20 independent sites participating in the Global ECT-MRI Research Collaboration (GEMRIC) were obtained for analysis, totaling 500 patients with MDD (58.6 % women) with a mean age of 54.8 years. Severity of depression before and after ECT was assessed with validated depression scales. Remission was defined as a HAM-D score of 7 points or below after ECT. Variables associated with remission were selected based on literature (i.e. depression severity at baseline, age, duration of index episode, and presence of psychotic symptoms). RESULTS: Remission rates of ECT were independent of sex, 48.0 % in women and 45.7 % in men (X2(1) = 0.2, p = 0.70). In the logistic regression analyses, a shorter index duration was identified as a sex-specific predictor for ECT outcome in women (X2(1) = 7.05, p = 0.01). The corresponding predictive margins did show overlapping confidence intervals for men and women. CONCLUSION: The evidence provided by our study suggests that ECT as a biological treatment for MDD is equally effective in women and men. A shorter duration of index episode was an additional sex- specific predictor for remission in women. Future research should establish whether the confidence intervals for the corresponding predictive margins are overlapping, as we find, or not.

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.

[Electroencephalography and connectivity in delirium]. / Eeg en innovatieve behandeling van verminderde hersenconnectiviteit bij delirium.

BACKGROUND: Delirium is associated with neurophysiological changes that can be identified with quantitative EEG analysis techniques (qEEG). AIM: To provide an overview of studies on neurophysiological changes in delirium using various qEEG analysis techniques. METHOD: Literature review. RESULTS: In delirium, there is an increase in delta and theta activity but a decrease in activity in the alpha frequency band. Additionally, there is a decrease in functional connectivity and efficiency of the brain network in the alpha frequency band. CONCLUSION: Delirium is characterized by diffuse slowing of the EEG, reduced functional connectivity, and decreased efficiency of the brain network. Improved functional connectivity could be a new approach to treat delirium.

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.

[Neuropsychiatric recovery after COVID-19 - an observational cohort-study]. / Neuropsychiatrisch herstel na COVID-19; een observationeel cohortonderzoek.

BACKGROUND: Since the end of 2019, COVID-19 and its consequences are present everywhere. Dutch professionals are concerned about the mental consequences, and in particular that during and after hospitalization little attention is paid to psychological problems. AIM: To monitor the short-term course and severity of (neuro)psychiatric symptoms after hospitalization for COVID-19. To make a recommendation regarding whether or not to follow-up these patients psychiatrically to optimize care. METHOD: In an observational cohort-study screening questions and additional questionnaires were used during two follow-up contacts to monitor cognition (MoCA), affective symptoms (HADS and IES) and overall functioning. RESULTS: More than half of the 29 included patients showed (neuro)psychiatric problems at both follow-up moments. Two weeks after discharge, we mainly saw symptoms related to anxiety and depression. Except for complaints related to the traumatic experience of the COVID-19, these seemed to have a favorable natural course. A negative time effect was seen for complaints consistent with post-traumatic stress disorder. Two months after discharge limitations in cognition and overall functioning appeared to be the main complaints after COVID-19. CONCLUSION: (Neuro)psychiatric symptoms after a COVID-19 are common. The natural course for affective complaints is more favorable than for cognitive functions. Specialist follow-up of patients with post-COVID psychological problems is recommended.

Beloop van covid-19-infecties en impact op mentale gezondheid; opzet van een landelijk casusregister.

Course of covid-19 infections and impact on mental health; setting up a national case register.

[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.

[Education and training in psychiatry in 2019]. / Onderwijs en opleiding in de psychiatrie anno 2019.

.

[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.

Long-term depressive symptoms and anxiety after transient ischaemic attack or ischaemic stroke in young adults.

BACKGROUND AND PURPOSE: Few studies exist on long-term post-stroke depressive symptoms and anxiety in young adults, although these young patients have a particular interest in their long-term prognosis, given their usually long life expectancy and being in the midst of an active social, working and family life. The aims of this study were to investigate the prevalence of depressive symptoms and anxiety and their association with clinical and demographic variables and with functional outcome after stroke in young adults. METHODS AND RESULTS: Long-term prevalence of depressive symptoms and anxiety was calculated in 511 patients with a transient ischaemic attack or ischaemic stroke, aged 18-50 years, using the Hospital Anxiety and Depression scale, compared with 147 controls. Functional outcome was assessed with the modified Rankin Score (mRS) and the Instrumental Activities of Daily Living scale (IADL). 16.8% of patients had depressive symptoms and 23.0% had anxiety, versus 6.1% (P = 0.001) and 12.2% (P < 0.001) in controls. In ischaemic stroke patients, depressive symptoms and anxiety were associated with poor functional outcome (mRS > 2 or IADL < 8). CONCLUSION: Even a decade after stroke at young age, depressive symptoms and anxiety were prevalent and associated with poor functional outcome. Therefore, even in the long term, treating physicians should be aware of the long-term presence of these symptoms as their recognition may be the first step in improving long-term functional independence.

[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.

Chronic depression is associated with a pronounced decrease in serum brain-derived neurotrophic factor over time.

One of the leading neurobiological hypotheses on depression states that decreased expression of brain-derived neurotrophic factor (BDNF) contributes to depression. This is supported by consistent findings of low serum BDNF levels in depressed patients compared with non-depressed controls. Whereas it has been generally assumed that this is a state characteristic of depression, strong inferences about state or trait effects require a longitudinal study design. To investigate the longitudinal association between serum BDNF and depression, we measured serum BDNF, (current and past) depression status, use of antidepressants, and all potential covariates at baseline and after 2 years in 1751 individuals, consisting of patients with an incident (n=153), remitted (n=420) and persistent depression (n=310) and non-depressed controls (n=868). We analyzed change/differences in serum BDNF across these four groups with analyses of covariance adjusted for covariates and baseline BDNF value, together with the effects of starting and stopping antidepressant treatment. Our analyses revealed a significant difference for the depression course groups (P=0.007). Compared with non-depressed controls, persistently depressed and remitted patients had a steeper decrease of BDNF levels over time (-1.33 (P=0.001) and -0.97 ng ml(-1) (P=0.011), respectively), whereas BDNF reductions in patients with incident depression were similar to those in healthy controls. Initiation or discontinuation of antidepressants was not associated with BDNF change (P=0.72). These findings suggest that BDNF not only contributes to depression, but that depression in turn may also contribute to low BDNF.