Rumination in patients with major depressive disorder before and after antidepressant treatment.

BACKGROUND: Rumination is a maladaptive response to distress characteristic of Major Depressive Disorder (MDD). It is unclear to what degree rumination is associated with depression severity prior to treatment and how it responds to antidepressant treatment. Therefore, we evaluated the association between rumination and depression severity in 92 untreated patients with MDD and explored the changes in rumination after initiation of antidepressant medication. METHOD: We measured rumination using the Rumination Response Scale (RRS) and depression severity with the Hamilton Depression Rating Scale (HDRS17 or HDRS6) before and after initiation of 12 weeks of antidepressant treatment. The association between RRS and pre-treatment HDRS17 was evaluated using a linear regression model. RRS at week 4, 8, and 12 across treatment response categories (remission vs. non-response) were evaluated using a mixed effect model. RESULTS: RRS was positively associated with depression severity prior to treatment at a trend level (p = 0.06). After initiation of treatment RRS decreased significantly (p < 0.0001) and remitters exhibited lower rumination compared to non-responders at week 4 (p = 0.03), 8 (p = 0.01), and 12 (p = 0.007). LIMITATIONS: The study had no placebo group. CONCLUSIONS: Although pre-treatment rumination did not significantly associate with depressive symptoms, rumination was closely connected to change in depressive symptoms. Tormented patients could be reassured that rumination symptoms may be alleviated over the course of antidepressant treatment.

Effect of erythropoietin on cognitive side-effects of electroconvulsive therapy in depression: A randomized, double-blind, placebo-controlled trial.

Electroconvulsive therapy (ECT) is one of the most effective and rapid-acting treatment for severe depression but is associated with cognitive side-effects. Identification of add-on treatments that counteract these side-effects would be very helpful. This randomized, double-blinded, placebo-controlled, parallel-group study investigated the effects of four add-on erythropoietin (EPO; 40,000 IU/ml) or saline (placebo) infusions over 2.5 weeks of ECT (eight ECT sessions) in severely depressed patients with unipolar or bipolar depression. Neuropsychological assessments were conducted pre-ECT, three days after the eighth ECT (week 4), and at a 3-month follow-up. Further, functional magnetic resonance imaging (fMRI) was conducted after the eighth ECT. The primary outcome was change from pre- to post-ECT in a 'speed of complex cognitive processing' composite. Secondary outcomes were verbal and autobiographical memory. Of sixty randomized patients, one dropped out before baseline. Data were thus analysed for 59 patients (EPO, n = 33; saline, n = 26), of whom 28 had fMRI data. No ECT-related decline occurred in the primary global cognition measure (ps≥0.1), and no effect of EPO versus saline was observed on this outcome (ps≥0.3). However post-ECT, EPO-treated patients exhibited faster autobiographical memory recall than saline-treated patients (p = 0.02), which was accompanied by lower memory-related parietal cortex activity. The absence of global cognition changes with ECT and EPO, coupled with the specific impact of EPO on autobiographical memory recall speed and memory-related parietal cortex activity, suggests that assessing autobiographical memory may provide increased sensitivity in evaluating and potentially preventing cognitive side-effects of ECT. TRIAL REGISTRATIONS: ClinicalTrials.gov: NCT03339596, EudraCT no.: 2016-002326-36.

EEG abnormalities are not associated with poor antidepressant treatment outcome - A NeuroPharm study.

EEG brain abnormalities, such as slowing and isolated epileptiform discharges (IEDs), has previously been associated with non-response to antidepressant treatment with escitalopram and venlafaxine, suggesting a potential need for treatment with anticonvulsant property in some patients. The current study aims to replicate the reported association of EEG abnormality and treatment outcomes in an open-label trial of escitalopram for major depressive disorder (MDD) and explore its relationship to mood and cognition. Pretreatment, 6 min eyes-closed resting-state 256-channel EEG was recorded in 91 patients with MDD (age 18-57) who were treated with 10-20 mg escitalopram for 12 weeks; patients could switch to duloxetine after four weeks. A certified clinical neurophysiologist rated the EEGs. IED and EEG slowing was seen in 13.2%, and in 6.6% there were findings with unclear significance (i.e., Wicket spikes and theta activity). We saw no group-difference in remission or response rates after 8 and 12 weeks of treatment or switching to duloxetine. Patients with EEG abnormalities had higher pretreatment mood disturbances driven by greater anger (p=.039) and poorer verbal memory (p=.012). However, EEG abnormality was not associated with improved mood or verbal memory after treatment. Our findings should be interpreted in light of the rarity of EEG abnormalities and the sample size. While we cannot confirm that EEG abnormalities are associated with non-response to treatment, including escitalopram, abnormal EEG activity is associated with poor mood and verbal memory. The clinical utility of EEG abnormality in antidepressant treatment selection needs careful evaluation before deciding if useful for clinical implementation.

Electroconvulsive therapy-induced volumetric brain changes converge on a common causal circuit in depression.

Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this causal depression network (CDN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis Principal Component Analysis (PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CDN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CDN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes (t = -2.35, p = 0.019). This evidence further supports that treatment interventions converge on a CDN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.

Stress Hormone Dynamics Are Coupled to Brain Serotonin 4 Receptor Availability in Unmedicated Patients With Major Depressive Disorder: A NeuroPharm Study.

BACKGROUND: A prominent finding in major depressive disorder (MDD) is distorted stress hormone dynamics, which is regulated by serotonergic brain signaling. An interesting feature of the cerebral serotonin system is the serotonin 4 receptor (5-HT4R), which is lower in depressed relative to healthy individuals and also has been highlighted as a promising novel antidepressant target. Here, we test the novel hypothesis that brain 5-HT4R availability in untreated patients with MDD is correlated with cortisol dynamics, indexed by the cortisol awakening response (CAR). Further, we evaluate if CAR changes with antidepressant treatment, including a selective serotonin reuptake inhibitor, and if pretreatment CAR can predict treatment outcome. METHODS: Sixty-six patients (76% women) with a moderate to severe depressive episode underwent positron emission tomography imaging with [11C]SB207145 for quantification of brain 5-HT4R binding using BPND as outcome. Serial home sampling of saliva in the first hour from awakening was performed to assess CAR before and after 8 weeks of antidepressant treatment. Treatment outcome was measured by change in Hamilton Depression Rating Scale 6 items. RESULTS: In the unmedicated depressed state, prefrontal and anterior cingulate cortices 5-HT4R binding was positively associated with CAR. CAR remained unaltered after 8 weeks of antidepressant treatment, and pretreatment CAR did not significantly predict treatment outcome. CONCLUSIONS: Our findings highlight a link between serotonergic disturbances in MDD and cortisol dynamics, which likely is involved in disease and treatment mechanisms. Further, our data support 5-HT4R agonism as a promising precision target in patients with MDD and disturbed stress hormone dynamics.

Association between brain serotonin 4 receptor binding and reactivity to emotional faces in depressed and healthy individuals.

Brain serotonergic (5-HT) signaling is posited to modulate neural responses to emotional stimuli. Dysfunction in 5-HT signaling is implicated in major depressive disorder (MDD), a disorder associated with significant disturbances in emotion processing. In MDD, recent evidence points to altered 5-HT4 receptor (5-HT4R) levels, a promising target for antidepressant treatment. However, how these alterations influence neural processing of emotions in MDD remains poorly understood. This is the first study to examine the association between 5-HT4R binding and neural responses to emotions in patients with MDD and healthy controls. The study included one hundred and thirty-eight participants, comprising 88 outpatients with MDD from the NeuroPharm clinical trial (ClinicalTrials.gov identifier: NCT02869035) and 50 healthy controls. Participants underwent an [11C]SB207145 positron emission tomography (PET) scan to quantify 5-HT4R binding (BPND) and a functional magnetic resonance imaging (fMRI) scan during which they performed an emotional face matching task. We examined the association between regional 5-HT4R binding and corticolimbic responses to emotional faces using a linear latent variable model, including whether this association was moderated by depression status. We observed a positive correlation between 5-HT4R BPND and the corticolimbic response to emotional faces across participants (r = 0.20, p = 0.03). This association did not differ between groups (parameter estimate difference = 0.002, 95% CI = -0.008: 0.013, p = 0.72). Thus, in the largest PET/fMRI study of associations between serotonergic signaling and brain function, we found a positive association between 5-HT4R binding and neural responses to emotions that appear unaltered in MDD. Future clinical trials with novel pharmacological agents targeting 5-HT4R are needed to confirm whether they ameliorate emotion processing biases in MDD.

Association between the loudness dependence of auditory evoked potential, serotonergic neurotransmission and treatment outcome in patients with depression.

Previous studies have suggested that the loudness dependence of auditory evoked potential (LDAEP) is associated with the effectiveness of antidepressant treatment in patients with major depressive disorders (MDD). Furthermore, both LDAEP and the cerebral serotonin 4 receptor (5-HT4R) density is inversely related to brain serotonin levels. We included 84 patients with MDD and 22 healthy controls to examined the association between LDAEP and treatment response and its association with cerebral 5-HT4R density. Participants underwent both EEG and 5-HT4R neuroimaging with [11C]SB207145 PET. Thirty-nine patients with MDD were re-examined after 8 weeks of treatment with selective serotonin reuptake inhibitors/serotonin noradrenaline reuptake inhibitor (SSRI/SNRI). We found that the cortical source of LDAEP was higher in untreated patients with MDD compared to healthy controls (p=0.03). Prior to SSRI/SNRI treatment, subsequent treatment responders had a negative association between LDAEP and depressive symptoms and a positive association between scalp LDAEP and symptom improvement at week 8. This was not found in source LDAEP. In healthy controls, we found a positive correlation between both scalp and source LDAEP and cerebral 5-HT4R binding but that was not observed in patients with MDD. We did not see any changes in scalp and source LDAEP in response to SSRI/SNRI treatment. These results support a theoretical framework where both LDAEP and cerebral 5-HT4R are indices of cerebral 5-HT levels in healthy individuals while this association seems to be disrupted in MDD. The combination of the two biomarkers may be useful for stratifying patients with MDD. Clinical Trials Registration:https://clinicaltrials.gov/ct2/show/NCT02869035?draw=1Registration number: NCT0286903.

Serotonin 4 Receptor Brain Binding in Major Depressive Disorder and Association With Memory Dysfunction.

Importance: The cerebral serotonin 4 (5-HT4) receptor is a promising novel target for treatment of major depressive disorder (MDD), and pharmacological stimulation of the 5-HT4 receptor has been associated with improved learning and memory in healthy individuals. Objective: To map the neurobiological signatures of patients with untreated MDD compared with healthy controls and to examine the association between cerebral 5-HT4 receptor binding and cognitive functions in the depressed state. Design, Setting, and Participants: This case-control study used baseline data from the NeuroPharm clinical depression trial in Denmark. Adult participants included antidepressant-free outpatients with a current moderate to severe depressive episode and healthy controls. All participants completed positron emission tomography (PET) scanning with [11C]SB207145 for quantification of brain 5-HT4 receptor binding, but only the patients underwent cognitive testing. Data analyses were performed from January 21, 2020, to April 22, 2022. Main Outcomes and Measures: The main study outcome was the group difference in cerebral 5-HT4 receptor binding between patients with MDD and healthy controls. In addition, the association between 5-HT4 receptor binding and verbal memory performance in the patient group was tested. Other cognitive domains (working memory, reaction time, emotion recognition bias, and negative social emotions) were assessed as secondary outcomes. Results: A total of 90 patients with untreated MDD (mean [SD] age, 27.1 [8.2] years; 64 women [71.1%]) and 91 healthy controls (mean [SD] age, 27.1 [8.0] years; 55 women [60.4%]) were included in the analysis. Patients with current MDD had significantly lower cerebral 5-HT4 receptor binding than healthy controls (-7.0%; 95% CI, -11.2 to -2.7; P = .002). In patients with MDD, there was a correlation between cerebral 5-HT4 receptor binding and verbal memory (r = 0.29; P = .02). Conclusions and Relevance: Results of this study show that cerebral 5-HT4 receptor binding was lower in patients with MDD than in healthy controls and that the memory dysfunction in patients with MDD was associated with lower cerebral 5-HT4 receptor binding. The cerebral 5-HT4 receptor is a promising treatment target for memory dysfunction in patients with MDD.

Association of Hormone Therapy With Depression During Menopause in a Cohort of Danish Women.

Importance: During menopause, the levels of estrogen and progesterone decrease and 60% to 70% of women experience menopausal symptoms, including mood disturbances. The latter might be prevented by hormone therapy (HT), yet some studies have suggested that use of HT might be associated with increased risk of depression. Objective: To examine whether use of HT during menopause was associated with a subsequent diagnosis of depression. Design, Setting, and Participants: This nationwide register-based cohort and self-controlled case series study included all women in Denmark aged 45 years between January 1, 1995, through December 31, 2017 (n = 825 238), without prior oophorectomy, breast cancer, or cancer in reproductive organs. Follow-up was completed on December 31, 2018. The statistical analysis was performed from September 1, 2021, through May 31, 2022. Exposures: Redeemed prescriptions of different types of HT identified by the Anatomical Therapeutic Chemical classification system codes (G03C [estrogen] and G03F [estrogen combined with progestin]) in the Danish National Prescription Registry between 1995 and 2017. Type of administration was divided into systemic (oral or transdermal) and local (intravaginal or intrauterine). Main Outcomes and Measures: A hospital diagnosis of depression (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes F32-F33 and International Classification of Diseases, Eighth Revision, codes 296.09, 296.29, 298.0, and 300.49) between 1995 through 2018. Associations were examined in cohort and self-controlled case series analysis using Cox proportional hazards and fixed-effects Poisson regression models. Results: During follow-up from 45 years of age to a mean of 56.0 (range, 45.1-67.7) years, 189 821 women (23.0%) initiated systemically or locally administered HT and 13 069 (1.6%) were diagnosed with depression. Systemically administered HT was mainly initiated before 50 years of age and was associated with a higher risk of a subsequent depression diagnosis (hazard ratio [HR] for 48-50 years of age, 1.50 [95% CI, 1.24-1.81]). The risk was especially elevated the year after initiation of both treatment with estrogen alone (HR, 2.03 [95% CI, 1.21-3.41]) and estrogen combined with progestin (HR, 2.01 [95% CI,1.26-3.21]). Locally administered HT was initiated across all ages and was not associated with depression risk (HR, 1.15 [95% CI, 0.70-1.87]). It was, however, associated with a lower risk of depression when initiated after 54 years of age (HR for 54-60 years of age, 0.80 [95% CI, 0.70-0.91]). In self-controlled analysis, which efficiently accounts for time-invariant confounding, users of systemically administered HT had higher rates of depression in the years after initiation compared with the years before treatment (incidence rate ratio for 0-1 year after initiation, 1.66 [95% CI, 1.30-2.14]). Conclusions and Relevance: These findings suggest that systemically administered HT before and during menopause is associated with higher risk of depression, especially in the years immediately after initiation, whereas locally administered HT is associated with lower risk of depression for women 54 years or older.

The association of anxiety and other clinical features with CACNA1C rs1006737 in patients with depression.

Background: The CACNA1C protein is a L-type calcium channel, which influence affective disorders. Purpose: The purpose of the present study was to examine the possible association between the different genotypes of rs100677 CACNA1C gene and anxiety and other clinical symptoms in patients with unipolar depression. Patients and controls: A total of 754 patients and 708 controls from the Danish Psychiatric Biobank participated. Results: A significant correlation was found between anxiety and the A allele. It was further found that patients with the A allele more often were treated with electroconvulsive therapy and patients with the AA phenotype had the highest age. Limitations: The only information about controls was their sex and that they were recruited from the blood bank. Two types of inclusion criteria were used. The clinical data were not complete for all patients.

Generalizability of treatment outcome prediction in major depressive disorder using structural MRI: A NeuroPharm study.

Brain morphology has been suggested to be predictive of drug treatment outcome in major depressive disorders (MDD). The current study aims at evaluating the performance of pretreatment structural brain magnetic resonance imaging (MRI) measures in predicting the outcome of a drug treatment of MDD in a large single-site cohort, and, importantly, to assess the generalizability of these findings in an independent cohort. The random forest, boosted trees, support vector machines and elastic net classifiers were evaluated in predicting treatment response and remission following an eight week drug treatment of MDD using structural brain measures derived with FastSurfer (FreeSurfer). Models were trained and tested within a nested cross-validation framework using the NeuroPharm dataset (n = 79, treatment: escitalopram); their generalizability was assessed using an independent clinical dataset, EMBARC (n = 64, treatment: sertraline). Prediction of antidepressant treatment response in the Neuropharm cohort was statistically significant for the random forest (p = 0.048), whereas none of the models could significantly predict remission. Furthermore, none of the models trained using the entire NeuroPharm dataset could significantly predict treatment outcome in the EMBARC dataset. Although our primary findings in the NeuroPharm cohort support some, but limited value in using pretreatment structural brain MRI to predict drug treatment outcome in MDD, the models did not generalize to an independent cohort suggesting limited clinical applicability. This study emphasizes the importance of assessing model generalizability for establishing clinical utility.

Concurrent anxiety in patients with major depression and cerebral serotonin 4 receptor binding. A NeuroPharm-1 study.

Concurrent anxiety is frequent in major depressive disorder and a shared pathophysiological mechanism between anxiety and other depressive symptoms is plausible. The serotonin 4 receptor (5-HT4R) has been implicated in both depression and anxiety. This is the first study to investigate the association between the cerebral 5-HT4R binding and anxiety in patients with depression before and after antidepressant treatment and the association to treatment response. Ninety-one drug-free patients with depression were positron emission tomography scanned with the 5-HT4R ligand [11C]-SB207145. Depression severity and concurrent anxiety was measured at baseline and throughout 8 weeks of antidepressant treatment. Anxiety measures included four domains: anxiety/somatization factor score; Generalized Anxiety Disorder 10-items (GAD-10) score; anxiety/somatization factor score ≥7 (anxious depression) and syndromal anxious depression. Forty patients were rescanned at week 8. At baseline, we found a negative association between global 5-HT4R binding and both GAD-10 score (p < 0.01) and anxiety/somatization factor score (p = 0.06). Further, remitters had a higher baseline anxiety/somatization factor score compared with non-responders (p = 0.04). At rescan, patients with syndromal anxious depression had a greater change in binding relative to patients with non-syndromal depression (p = 0.04). Concurrent anxiety in patients with depression measured by GAD-10 score and anxiety/somatization factor score is negatively associated with cerebral 5-HT4R binding. A lower binding may represent a subtype with reduced natural resilience against anxiety in a depressed state, and concurrent anxiety may influence the effect on the 5-HT4R from serotonergic antidepressants. The 5-HT4R is a promising neuroreceptor for further understanding the underpinnings of concurrent anxiety in patients with depression.

Systemic DNA and RNA damage from oxidation after serotonergic treatment of unipolar depression.

Previous studies have indicated that antidepressants that inhibit the serotonin transporter reduces oxidative stress. DNA and RNA damage from oxidation is involved in aging and a range of age-related pathophysiological processes. Here, we studied the urinary excretion of markers of DNA and RNA damage from oxidation, 8-oxodG and 8-oxoGuo, respectively, in the NeuroPharm cohort of 100 drug-free patients with unipolar depression and in 856 non-psychiatric community controls. Patients were subsequently treated for 8 weeks with escitalopram in flexible doses of 5-20 mg; seven of these switched to duloxetine by week 4, as allowed by the protocol. At week 8, 82 patients were followed up clinically and with measurements of 8-oxodG/8-oxoGuo. Contextual data were collected in patients, including markers of cortisol excretion and low-grade inflammation. The intervention was associated with a substantial reduction in both 8-oxodG/8-oxoGuo excretion (25% and 10%, respectively). The change was not significantly correlated to measures of clinical improvement. Both markers were strongly and negatively correlated to cortisol, as measured by the area under the curve for the full-day salivary cortisol excretion. Surprisingly, patients had similar levels of 8-oxodG excretion and lower levels of 8-oxoGuo excretion at baseline compared to the controls. We conclude that intervention with serotonin reuptake inhibitors in unipolar depression is associated with a reduction in systemic DNA and RNA damage from oxidation. To our knowledge, this to date the largest intervention study to characterize this phenomenon, and the first to include a marker of RNA oxidation.

Emotional faces processing in major depressive disorder and prediction of antidepressant treatment response: A NeuroPharm study.

BACKGROUND: Major depressive disorder (MDD) is a prevalent neuropsychiatric illness for which it is important to resolve underlying brain mechanisms. Current treatments are often unsuccessful, precipitating a need to identify predictive markers. AIM: We evaluated (1) alterations in brain responses to an emotional faces functional magnetic resonance imaging (fMRI) paradigm in individuals with MDD, compared to controls, (2) whether pretreatment brain responses predicted antidepressant treatment response, and (3) pre-post change in brain responses following treatment. METHODS: Eighty-nine medication-free, depressed individuals and 115 healthy controls completed the fMRI paradigm. Depressed individuals completed a nonrandomized, open-label, 8-week treatment with escitalopram, including the option to switch to duloxetine after 4 weeks. We examined patient-control group differences in regional fMRI responses at baseline, whether baseline fMRI responses predicted treatment response at 8 weeks, including early life stress moderating effects, and change in fMRI responses in 36 depressed individuals rescanned following 8 weeks of treatment. RESULTS: Task reaction time was 5% slower in patients. Multiple brain regions showed significant task-related responses, but we observed no statistically significant patient-control group differences (Cohen's d < 0.35). Patient pretreatment brain responses did not predict antidepressant treatment response (area under the curve of the receiver operator characteristic (AUC-ROC) < 0.6) and brain responses were not statistically significantly changed after treatment (Cohen's d < 0.33). CONCLUSION: This represents the largest prediction study to date examining emotional faces fMRI features as predictors of antidepressant treatment response. Brain response to this fMRI emotional faces paradigm did not distinguish depressed individuals from healthy controls, nor was it predictive of antidepressant treatment response.Clinical Trial Registration: Site: https://clinicaltrials.gov, Trial Number: NCT02869035, Trial Title: Treatment Outcome in Major Depressive Disorder.

Association of benzodiazepines, Z-drugs, pregabalin, and melatonin with traffic accidents: A nationwide cohort and case-crossover study in Danish adults.

BACKGROUND: Benzodiazepines, Z-drugs, pregabalin, and melatonin (BZPMs) have been associated with a higher risk of traffic accidents, but the evidence is inconsistent, and lacking for newer drugs. AIM: To examine the association of BZPMs with risk of traffic accidents. METHODS: All Danish adults (n = 3,823,588) were followed for redeemed prescriptions of BZPM and for incident traffic accidents registered in Danish registers from 2002 through 2018. Associations were examined in cohort and case-crossover designs using Cox proportional hazard and conditional logistic regression with adjustment for co-variables. RESULTS: A total of 19.3% (n = 738,019) of all participants initiated treatment with BZPMs. During the mean follow-up of 10.3 years, 595,173(15.5%) of participants were involved in a traffic accident. In the cohort analysis, all BZPMs besides pregabalin were associated with a higher risk of traffic accidents in adults below 70 years, with chlordiazepoxide showing the strongest association (hazard ratio (HR)age 18-49 = 1.76, 95% confidence interval (CI): 1.67-1.86 and HRage 50-69 = 1.84, 95% CI: 1.70-2.00). In the older age groups, the specific BZPM medications were associated with lower or no risk of traffic accidents. However, in case-time-crossover analysis with inherited control for confounders, no BZPM medication was positively associated with traffic accidents, except for chlordiazepoxide, which had a higher odds ratio in middle-aged group (1.62, 95% CI: 1.15-2.29). CONCLUSIONS: This study does not fully support that BZPM use is a risk factor for traffic accidents. However, a positive association was found for chlordiazepoxide, which is approved for treatment of acute alcohol withdrawal.

Mortality and acute somatic events following electroconvulsive therapy in patients with pre-existing somatic comorbidity - A register-based nationwide Danish cohort study.

OBJECTIVE: To examine whether electroconvulsive therapy (ECT) is associated with risk of mortality and acute somatic events in patients with or without somatic comorbidity. METHODS: A total of 174,495 patients with an affective disorder, of whom 41% had somatic comorbidity, were followed from 2005 through 2018 for ECT, mortality, and acute somatic outcomes using Danish registers. The association of ECT with outcomes was estimated using Cox proportional hazard regression. RESULTS: Patients, of whom 6943 (4.0%) had ECT, were followed for a median of 6.7 years. Compared to non-ECT treated patients, ECT was associated with a lower risk of death from natural causes, which was independent of somatic comorbidity. ECT was not associated with the risk of acute somatic events neither in patients with somatic comorbidity nor in patients without somatic comorbidity, except for cardiac events within 0-30 days of follow-up after the first ECT, for which there was a 3.7-fold higher risk in patients with no somatic comorbidity. This analysis, however, was based on few events. CONCLUSION: In modern clinical practice, in patients with affective disorders and somatic comorbidity, ECT is not associated with a higher risk of death from natural causes or acute somatic events.

Cognitive Adverse Effects of Electroconvulsive Therapy: A Discrepancy Between Subjective and Objective Measures?

OBJECTIVES: The character and duration of cognitive adverse effects of electroconvulsive therapy (ECT) are unclear. This study investigated (1) the sensitivity of a short cognitive test battery to cognitive adverse effects of ECT, (2) the relation between subjective and objective cognitive adverse effects, and (3) patient characteristics associated with more subjective than objective adverse effects. METHODS: Forty-one patients with unipolar or bipolar depression referred to ECT underwent assessments at baseline, 5 to 7 days post-ECT, and 3 months post-ECT. Patients rated their fear of various aspects of ECT on a visual analog scale. At each assessment, patients were evaluated for depressive symptoms, completed the Screen for Cognitive Impairment in Psychiatry (SCIP) and Trail Making Test-Part B (TMT-B), and rated their cognitive difficulties. RESULTS: Patients feared cognitive adverse effects and lack of treatment efficacy more than other aspects of ECT. The SCIP and TMT-B revealed transient decline in objective cognition after ECT, which was reversed after 3 months. Patients presented with more subjective than objective cognitive difficulties at baseline and more subjective than objective cognitive adverse effects of ECT. This discrepancy was significantly reduced at follow-up. Younger age and poorer objective cognition pretreatment were associated with more subjective than objective cognitive adverse effects 5 to 7 days after ECT. CONCLUSIONS: The SCIP and TMT-B are sensitive to cognitive adverse effects of ECT. Patients show more subjective than objective cognitive adverse effects of ECT. These insights can be used clinically to inform patients of treatment choice and expected cognitive consequences.

Elevated body weight modulates subcortical volume change and associated clinical response following electroconvulsive therapy.

Background: Obesity is a frequent somatic comorbidity of major depression, and it has been associated with worse clinical outcomes and brain structural abnormalities. Converging evidence suggests that electroconvulsive therapy (ECT) induces both clinical improvements and increased subcortical grey matter volume in patients with depression. However, it remains unknown whether increased body weight modulates the clinical response and structural neuroplasticity that occur with ECT. Methods: To address this question, we conducted a longitudinal investigation of structural MRI data from the Global ECT-MRI Research Collaboration (GEMRIC) in 223 patients who were experiencing a major depressive episode (10 scanning sites). Structural MRI data were acquired before and after ECT, and we assessed change in subcortical grey matter volume using FreeSurfer and Quarc. Results: Higher body mass index (BMI) was associated with a significantly lower increase in subcortical grey matter volume following ECT. We observed significant negative associations between BMI and change in subcortical grey matter volume, with pronounced effects in the thalamus and putamen, where obese participants showed increases in grey matter volume that were 43.3% and 49.6%, respectively, of the increases found in participants with normal weight. As well, BMI significantly moderated the association between subcortical grey matter volume change and clinical response to ECT. We observed no significant association between BMI and clinical response to ECT. Limitations: Because only baseline BMI values were available, we were unable to study BMI changes during ECT and their potential association with clinical and grey matter volume change. Conclusion: Future studies should take into account the relevance of body weight as a modulator of structural neuroplasticity during ECT treatment and aim to further explore the functional relevance of this novel finding.