Cardiovascular Effects of Combining Subcutaneous or Intravenous Esketamine and the MAO Inhibitor Tranylcypromine for the Treatment of Depression: A Retrospective Cohort Study.

BACKGROUND: (Es)ketamine and monoamine oxidase inhibitors (MAOIs), e.g., tranylcypromine, are therapeutic options for treatment-resistant major depression. Simultaneous administration is currently not recommended because of concern about hypertensive crises. OBJECTIVE: Our objective was to evaluate whether changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) during esketamine administration differed between patients who concomitantly received tranylcypromine and those who did not. METHODS: This was a retrospective cohort study utilizing cardiovascular monitoring data from inpatients treated for severe depression in unipolar, bipolar, and schizoaffective disorder. Primary outcomes were change in mean BP and HR during the first hour after intravenous or subcutaneous esketamine administration compared with baseline, controlled for confounders. Secondary analyses quantify differences in absolute BP during esketamine treatment and comparisons of BP peaks, temporal effects, and intraindividual comparisons before and after tranylcypromine initiation. RESULTS: Our analysis included 509 esketamine administrations in 43 patients, 14 of whom concomitantly received tranylcypromine. Controlling for creatinine and age, mean ± standard deviation (SD) BP changes were significantly increased by concomitant tranylcypromine treatment (ΔSBP: F[1,503] = 86.73, p < 0.001; ΔDBP: F[1,503] = 55.71, p < 0.001), but HR remained unaffected. Mean SBP change during esketamine administration was 2.96 ± 18.11 mmHg in patients receiving tranylcypromine (TCP+) and -8.84 ± 11.31 mmHg in those who did not (TCP-). Changes in DBP were -2.81 ± 11.20 mmHg for TCP+ and -10.77 ± 9.13 mmHg for TCP-. Moreover, we found a significant dose-response relationship between tranylcypromine dose and BP (SBP: B = 0.35, standard error [SE] = 0.12, 95% confidence interval [CI] 0.12-0.60, p = 0.004; adjusted R2 = 0.11, p = 0.008; DBP: B = 0.21, SE = 0.08, 95% CI 0.06-0.36, p = 0.007; adjusted R2 = 0.08; p = 0.023). CONCLUSIONS: Although statistically significant changes in BP were identified in patients receiving tranylcypromine and esketamine, these changes were clinically insignificant. Thus, combining esketamine and this MAOI appears to be safe at standard doses. The dose-response relationship calls for caution with higher doses of tranylcypromine.

Association between depressive symptoms and objectively measured daily step count in individuals at high risk of cardiovascular disease in South London, UK: a cross-sectional study.

OBJECTIVES: Depressive symptoms are common but rarely considered a risk factor for unhealthy lifestyles associated with cardiovascular disease (CVD). This study investigates whether depressive symptoms are associated with reduced physical activity (PA) in individuals at high risk of developing CVD. DESIGN: Secondary analysis of the cross-sectional baseline data from a randomised controlled trial of an intensive lifestyle intervention. SETTING: 135 primary care practices in South London, UK. PARTICIPANTS: 1742 adults, 49-74 years, 86% male at high (≥20%) risk of developing CVD in the next 10 years as defined via QRISK2 score. OUTCOME MEASURES: The main explanatory variable was depressive symptoms measured via the Patient Health Questionnaire-9 (PHQ-9). The main outcome was daily step count measured with an accelerometer (ActiGraph GT3X) stratified by weekdays and weekend days. RESULTS: The median daily step count of the total sample was 6151 (IQR 3510) with significant differences (P<0.001) in mean daily step count between participants with low (PHQ-9 score: 0-4), mild (PHQ-9 score: 5-9) and moderate to severe depressive symptoms (PHQ-9 score: ≥10). Controlling for age, gender, ethnicity, education level, body mass index (BMI), smoking, consumption of alcohol, day of the week and season, individuals with mild depressive symptoms and those with moderate to severe depressive symptoms walked 13.3% (95% CI 18.8% to 7.9%) and 15.6% (95% CI 23.7% to 6.5%) less than non-depressed individuals, respectively. Furthermore, male gender, white ethnicity, higher education level, lower BMI, non-smoking, moderate alcohol intake, weekdays and summer season were independently associated with higher step count. CONCLUSIONS: People at high risk of CVD with depressive symptoms have lower levels of PA. TRIAL REGISTRATION: ISRCTN84864870; Pre-results.

Hair cortisol as a biological marker for burnout symptomatology.

Burnout is a syndrome with negative impact on cognitive performance and mood as a consequence of long-term stress at work. It is further associated with increased risk for mental and physical diseases. One potential pathway to mediate chronic work-stress and adverse health conditions in burnout is through alterations in long-term glucocorticoid secretion. Here, we present cross-sectional data on hair cortisol/cortisone (hairF/hairE) concentrations and burnout from a population-based sample of the Dresden Burnout Study (DBS; N=314 hair samples). Burnout symptoms (emotional exhaustion, cynical attitudes toward work, and reduced efficacy) were assessed with the Maslach Burnout Inventory-General Survey (MBI-GS). To control for potential confounds, depressivity was as well assessed using the Patient Health Questionnaire (PHQ-9) screening instrument for major depression. The present findings indicate specific hypercortisolism in participants who suffer from burnout. No significant associations were found between depressivity and hairF/hairE.

Distinct Contributions of Dorsal and Ventral Streams to Imitation of Tool-Use and Communicative Gestures.

Imitation of tool-use gestures (transitive; e.g., hammering) and communicative emblems (intransitive; e.g., waving goodbye) is frequently impaired after left-hemispheric lesions. We aimed 1) to identify lesions related to deficient transitive or intransitive gestures, 2) to delineate regions associated with distinct error types (e.g., hand configuration, kinematics), and 3) to compare imitation to previous data on pantomimed and actual tool use. Of note, 156 patients (64.3 ± 14.6 years; 56 female) with first-ever left-hemispheric ischemic stroke were prospectively examined 4.8 ± 2.0 days after symptom onset. Lesions were delineated on magnetic resonance imaging scans for voxel-based lesion-symptom mapping. First, while inferior-parietal lesions affected both gesture types, specific associations emerged between intransitive gesture deficits and anterior temporal damage and between transitive gesture deficits and premotor and occipito-parietal lesions. Second, impaired hand configurations were related to anterior intraparietal damage, hand/wrist-orientation errors to premotor lesions, and kinematic errors to inferior-parietal/occipito-temporal lesions. Third, premotor lesions impacted more on transitive imitation compared with actual tool use, pantomimed and actual tool use were more susceptible to lesioned insular cortex and subjacent white matter. In summary, transitive and intransitive gestures differentially rely on ventro-dorsal and ventral streams due to higher demands on temporo-spatial processing (transitive) or stronger reliance on semantic information (intransitive), respectively.

Brain activity underlying tool-related and imitative skills after major left hemisphere stroke.

Apraxia is a debilitating cognitive motor disorder that frequently occurs after left hemisphere stroke and affects tool-associated and imitative skills. However, the severity of the apraxic deficits varies even across patients with similar lesions. This variability raises the question whether regions outside the left hemisphere network typically associated with cognitive motor tasks in healthy subjects are of additional functional relevance. To investigate this hypothesis, we explored regions where functional magnetic resonance imaging activity is associated with better cognitive motor performance in patients with left hemisphere ischaemic stroke. Thirty-six patients with chronic (>6 months) large left hemisphere infarcts (age ± standard deviation, 60 ± 12 years, 29 male) and 29 control subjects (age ± standard deviation, 72 ± 7, 15 male) were first assessed behaviourally outside the scanner with tests for actual tool use, pantomime and imitation of tool-use gestures, as well as for meaningless gesture imitation. Second, functional magnetic resonance imaging activity was registered during the passive observation of videos showing tool-associated actions. Voxel-wise linear regression analyses were used to identify areas where behavioural performance was correlated with functional magnetic resonance imaging activity. Furthermore, lesions were delineated on the magnetic resonance imaging scans for voxel-based lesion-symptom mapping. The analyses revealed two sets of regions where functional magnetic resonance imaging activity was associated with better performance in the clinical tasks. First, activity in left hemisphere areas thought to mediate cognitive motor functions in healthy individuals (i.e. activity within the putative 'healthy' network) was correlated with better scores. Within this network, tool-associated tasks were mainly related to activity in supramarginal gyrus and ventral premotor cortex, while meaningless gesture imitation depended more on the anterior intraparietal sulcus and superior parietal lobule. Second, repeating the regression analyses with total left hemisphere lesion volume as additional covariate demonstrated that tool-related skills were further supported by right premotor, right inferior frontal and left anterior temporal areas, while meaningless gesture imitation was also driven by the left dorso-lateral prefrontal cortex. In summary, tool-related and imitative skills in left hemisphere stroke patients depend on the activation of spared left hemisphere regions that support these abilities in healthy individuals. In addition, cognitive motor functions rely on the activation of ipsi- and contralesional areas that are situated outside this 'healthy' network. This activity may explain why some patients perform surprisingly well despite large left brain lesions, while others are severely impaired.

Differential Roles of Ventral and Dorsal Streams for Conceptual and Production-Related Components of Tool Use in Acute Stroke Patients.

Impaired tool use despite preserved basic motor functions occurs after stroke in the context of apraxia, a cognitive motor disorder. To elucidate the neuroanatomical underpinnings of different tool use deficits, prospective behavioral assessments of 136 acute left-hemisphere stroke patients were combined with lesion delineation on magnetic resonance imaging (MRI) images for voxel-based lesion-symptom mapping. Deficits affecting both the selection of the appropriate recipient for a given tool (ToolSelect, e.g., choosing the nail for the hammer), and the performance of the typical tool-associated action (ToolUse, e.g., hammering in the nail) were associated with ventro-dorsal stream lesions, particularly within inferior parietal lobule. However, ToolSelect compared with ToolUse deficits were specifically related to damage within ventral stream regions including anterior temporal lobe. Additional retrospective error dichotomization based on the videotaped performances of ToolUse revealed that spatio-temporal errors (movement errors) were mainly caused by inferior parietal damage adjacent to the intraparietal sulcus while content errors, that is, perplexity, unrecognizable, or semantically incorrect movements, resulted from lesions within supramarginal gyrus and superior temporal lobe. In summary, our results suggest that in the use of tools, conceptual and production-related aspects can be differentiated and are implemented in anatomically distinct streams.

Neural bases of imitation and pantomime in acute stroke patients: distinct streams for praxis.

Apraxia is a cognitive disorder of skilled movements that characteristically affects the ability to imitate meaningless gestures, or to pantomime the use of tools. Despite substantial research, the neural underpinnings of imitation and pantomime have remained debated. An influential model states that higher motor functions are supported by different processing streams. A dorso-dorsal stream may mediate movements based on physical object properties, like reaching or grasping, whereas skilled tool use or pantomime rely on action representations stored within a ventro-dorsal stream. However, given variable results of past studies, the role of the two streams for imitation of meaningless gestures has remained uncertain, and the importance of the ventro-dorsal stream for pantomime of tool use has been questioned. To clarify the involvement of ventral and dorsal streams in imitation and pantomime, we performed voxel-based lesion-symptom mapping in a sample of 96 consecutive left-hemisphere stroke patients (mean age ± SD, 63.4 ± 14.8 years, 56 male). Patients were examined in the acute phase after ischaemic stroke (after a mean of 5.3, maximum 10 days) to avoid interference of brain reorganization with a reliable lesion-symptom mapping as best as possible. Patients were asked to imitate 20 meaningless hand and finger postures, and to pantomime the use of 14 common tools depicted as line drawings. Following the distinction between movement engrams and action semantics, pantomime errors were characterized as either movement or content errors, respectively. Whereas movement errors referred to incorrect spatio-temporal features of overall recognizable movements, content errors reflected an inability to associate tools with their prototypical actions. Both imitation and pantomime deficits were associated with lesions within the lateral occipitotemporal cortex, posterior inferior parietal lobule, posterior intraparietal sulcus and superior parietal lobule. However, the areas specifically related to the dorso-dorsal stream, i.e. posterior intraparietal sulcus and superior parietal lobule, were more strongly associated with imitation. Conversely, in contrast to imitation, pantomime deficits were associated with ventro-dorsal regions such as the supramarginal gyrus, as well as brain structures counted to the ventral stream, such as the extreme capsule. Ventral stream involvement was especially clear for content errors which were related to anterior temporal damage. However, movement errors were not consistently associated with a specific lesion location. In summary, our results indicate that imitation mainly relies on the dorso-dorsal stream for visuo-motor conversion and on-line movement control. Conversely, pantomime additionally requires ventro-dorsal and ventral streams for access to stored action engrams and retrieval of tool-action relationships.