Reporting Psychiatric Disease Characteristics in Post-Mortem- and Biological Research.

Inflammation is a prominent hypothesis in the neurobiology of depression. In our transcriptomic profiling study of microglia in chronic major depressive disorder (MDD), we revealed a distinct disease-associated microglia (DAM) transcriptomic profile exclusively found in cortical gray matter, that we have designated DepDAM. These DepDAM revealed an immune-suppressed state, with a possible upstream mechanism for microglial suppression, by upregulation of CD200 and CD47 ("don't eat me signals") located on synapses. We extensively report on disease characteristics, such as cause of death, reason for euthanasia, and psychiatric state when deceased. When excluding MDD donors in a euthymic state, the trend of lower CD45 membrane expression on white matter microglia became significant, and the difference in gray matter microglia became larger. For Western blot analysis of CD47 and CD200, both means of the definitely depressed donor groups (MDD-D) increased. This underscores the utmost importance of reporting on patient and episode characteristics, such as severity, episode traits, (type of) suicidality, mode of decease, and state of illness at death in post-mortem- and biological psychiatric research. For psychiatric post-mortem research, we suggest using well-characterized donors (eg, after "psychological autopsy") selected by an experienced clinician.

A Multicenter Retrospective Chart Review on the Effectiveness and Tolerability of Electroconvulsive Therapy in Adolescents and Young Adults With Major Depressive Disorder or Bipolar Depression.

BACKGROUND: Major depressive disorder and bipolar depression in adolescents and young adults are prevalent and major contributors to the global burden of disease, whereas effective interventions are limited. Available evidence is insufficient to assess effectiveness and tolerability of electroconvulsive therapy in depressed adolescents and young adults. METHODS: A retrospective chart review was conducted in patients with major depressive disorder or bipolar depression who underwent electroconvulsive therapy from 2001 to 2021 in 12 centers in the Netherlands. Patients were classified as young (15-25 years) and older adults (26-80 years). Primary outcome was effectiveness, expressed as response (≥50% reduction in rating scale score compared with baseline) and remission. Rating scale scores were cross-sectionally assessed at baseline and at the end of the index course. Outcomes of remitters were included in responders. Secondary outcome was occurrence of subjective cognitive impairment and adverse events. Long-term outcomes were not available. RESULTS: In the young (n = 57) and older adult (n = 41) group, 40.4% and 56.1% (P = 0.153) of patients achieved response and 28.1% and 39.0% (P = 0.281) remission, respectively. Subjective cognitive impairment (80.5% vs 56.3%; P = 0.001) and transient cardiac arrhythmia (14.6% vs 2.8%; P = 0.020) were reported significantly more frequently in the older adult group. CONCLUSIONS: Despite significantly more comorbidity of personality disorders, autism spectrum disorders, and anxiety disorders, effectiveness in the young was similar to the older adults. Tolerability was even superior in the young, despite significantly more bilateral treatment. Electroconvulsive therapy could be considered a viable treatment option in depressed adolescents and young adults.

Accelerated intermittent theta burst stimulation in major depressive disorder: A systematic review.

BACKGROUND: Major depressive disorder [MDD] is expected to be the leading cause of overall global burden of disease by the year 2030 [WHO]. Non-response to first line pharmacological and psychotherapeutic antidepressive treatments is substantial, with treatment-resistant depression [TRD] affecting approximately one third of depressed patients. There is an urgent need for rapid acting and effective treatments in this population. Repetitive Transcranial Magnetic Stimulation [rTMS] is an non-invasive treatment option for patients with MDD or TRD. Recent studies have proposed new paradigms of TMS, one paradigm is accelerated intermittent Theta Burst Stimulation [aiTBS]. OBJECTIVE: This systematic review assesses the efficacy, safety and tolerability of aiTBS in patients with MDD. METHODS: This review was registered with PROSPERO [ID number: 366556]. A systematic literature review was performed using Pubmed, Web of Science and PsycINFO. Case reports/series, open-label and randomized controlled trials [RCTs] were eligible for inclusion if they met the following criteria; full text publication available in English describing a form of aiTBS for MDD or TRD. aiTBS was defined as at least three iTBS treatments sessions per day, during at least four days for one week. RESULTS: 32 studies were identified describing aiTBS in MDD, 13 studies described overlapping samples. Six articles from five unique studies met eligibility criteria; two open-label studies and three RCTs [two double blind and one quadruple blind]. Response rates directly after treatment ranged from 20.0% to 86.4% and remission rates ranged from 10.0 to 86.4%. Four weeks after treatment response rates ranged from 0.0% to 66.7% and remission rates ranged from 0.0% to 57.1%. Three articles described a significant reduction in suicidality scores. aiTBS was well tolerated and safe, with no serious adverse events reported. CONCLUSIONS: aiTBS is a promising form of non-invasive brain stimulation [NIBS] with rapid antidepressant and antisuicidal effects in MDD. Additionally, aiTBS was well tolerated and safe. However, the included studies had small samples sizes and differed in frequency, intersession interval, neuro localization and stimulation intensity. Replication studies and larger RCTs are warranted to establish efficacy, safety and long term effects.

Microglia Transcriptional Profiling in Major Depressive Disorder Shows Inhibition of Cortical Gray Matter Microglia.

BACKGROUND: Microglia have been implicated in the pathophysiology of major depressive disorder (MDD), but information on biological mechanisms is limited. Therefore, we investigated the gene expression profile of microglial cells in relation to neuronal regulators of microglia activity in well-characterized MDD and control autopsy brains. METHODS: Pure, intact microglia were isolated at brain autopsy from occipital cortex gray matter (GM) and corpus callosum white matter of 13 donors with MDD and 10 age-matched control donors for RNA sequencing. Top differentially expressed genes were validated using immunohistochemistry staining. Because gene expression changes were only detected in GM microglia, neuronal regulators of microglia were investigated in cortical tissue and synaptosomes from the cortex by reverse transcriptase-quantitative polymerase chain reaction and Western blot. RESULTS: Transcriptome analysis revealed 92 genes differentially expressed in microglia isolated from GM, but none in microglia from white matter in donors with MDD, compared with control donors. Of these, 81 genes were less abundantly expressed in GM in MDD, including CD163, MKI67, SPP1, CD14, FCGR1A/C, and C1QA/B/C. Accordingly, pathways related to effector mechanisms, such as the complement system and phagocytosis, were differentially regulated in GM microglia in MDD. Immunohistochemistry staining revealed significantly lower expression of CD163 protein in MDD. Whole tissue analysis showed an increase in CD200 (p = .0009) and CD47 (p = .068) messenger RNA, and CD47 protein was significantly elevated (p = .0396) in synaptic fractions of MDD cases. CONCLUSIONS: Transcriptional profiling indicates an immune-suppressed microglial phenotype in MDD that is possibly caused by neuronal regulation.

Sleep predicts the response to rTMS and CBT in patients with OCD: an open label effectiveness study.

Background: Although many OCD patients benefit from repetitive transcranial magnetic stimulation (rTMS) as treatment, there is still a large group failing to achieve satisfactory response. Sleep problems have been considered transdiagnostic risk factors for psychiatric disorders, and prior work has shown comorbid sleep problems in OCD to be associated with non-response to rTMS in OCD. We therefore set out to investigate the utility of sleep problems in predicting response to rTMS in treatment resistant OCD. Method: A sample of 61 patients (treated with 1-Hz SMA or sequential 1-Hz SMA+DLPFC rTMS, combined with cognitive behavioral therapy) were included. Sleep disturbances were measured using the PSQI, HSDQ and actigraphy. Treatment response was defined as a decrease of at least 35% in symptom severity as measured with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Results: 32 of 61 patients (52.5%) responded to rTMS, and trajectories of response were similar for both rTMS protocols. Three PSQI items (Subjective Sleep Quality; Sleep Latency and Daytime Dysfunction) and the HSDQ-insomnia scale were found to predict TMS response. A discriminant model yielded a significant model, with an area under the curve of 0.813. Conclusion: Future replication of these predictors could aid in a more personalized treatment for OCD.

Severe postpartum hemorrhage increases risk of posttraumatic stress disorder: a prospective cohort study.

PURPOSE: To evaluate whether severe postpartum hemorrhage (PPH) is a risk factor for posttraumatic stress disorder (PTSD). Severe PPH can be experienced as a traumatic event. PTSD leads to negative mental health effects. Knowing risk factors for PTSD during childbirth offers opportunities for early interventions, which may prevent the development of PTSD. MATERIALS AND METHODS: In this prospective study, we compared two groups of participants; women with ≥2000 mL of blood loss (severe PPH, patients) and women with ≤500 mL of blood loss (controls). Participants were screened for PTSD using the PCL-5 four to six weeks after delivery. Positive screening was followed by the CAPS-5 to diagnose PTSD. RESULTS: We included 187 PPH patients and 121 controls. Median PCL-5 scores were higher for PPH patients (5.0) than controls (4.0, p = 0.005). Thirteen PPH patients (7.0%) and two controls (1.7%) scored ≥32 on the PCL-5, indicative of probable PTSD (OR 4.45, 95% CI 0.99-20.06, p = 0.035). Significant more PPH patients than controls met criteria for a clinical diagnosis of PTSD on the CAPS-5 (n = 10, 5.6% vs n = 0, 0.0%; p = 0.007). CONCLUSIONS: There is a significant and clinically relevant increased risk for developing PTSD after severe PPH. Gynecologists and midwives are advised to screen for PTSD at postpartum follow-up visits to prevent long-term negative mental health effects. CLINICAL TRIAL REGISTRATION: NL50273.100.14.

Potential traumatic events in the workplace and depression, anxiety and post-traumatic stress: a cross-sectional study among Dutch gynaecologists, paediatricians and orthopaedic surgeons.

OBJECTIVE: To compare the prevalence of work-related potential traumatic events (PTEs), support protocols and mental health symptoms across Dutch gynaecologists, orthopaedic surgeons and paediatricians. DESIGN: Cross-sectional study, supplementary analysis of combined data. SETTING: Nationwide survey between 2014 and 2017. PARTICIPANTS: An online questionnaire was sent to all Dutch gynaecologists, orthopaedic surgeons and paediatricians, including resident physicians (4959 physicians). 1374 questionnaires were eligible for analysis, corresponding with a response rate of 27.7%. OUTCOME MEASURES: Primary outcome measures were the prevalence of work-related PTEs, depression, anxiety, psychological distress and traumatic stress, measured with validated screening instruments (Hospital Anxiety and Depression Scale, Trauma Screening Questionnaire). Secondary outcomes were the association of mental health and defensive practice to traumatic events and support protocols. RESULTS: Of the respondents, 20.8% experienced a work-related PTE at least 4 weeks ago. Prevalence rates indicative of depression, anxiety or post-traumatic stress disorder (PTSD) were 6.4%, 13.6% and 1.5%, respectively. Depression (9.2% vs 5.2%, p=0.019), anxiety (18.2% vs 8.2%, p<0.001) and psychological distress (22.8% vs 12.5%, p<0.001) were significantly more prevalent in female compared with male attendings. The absence of a support protocol was significantly associated with more probable PTSD (p=0.022). Those who witnessed a PTE, reported more defensive work changes (28.0% vs 20.5%, p=0.007) and those with probable PTSD considered to quit medical work more often (60.0% vs 35.8%, p=0.032). CONCLUSION: Physicians are frequently exposed to PTEs with high emotional impact over the course of their career. Lacking a support protocol after adverse events was associated with more post-traumatic stress. Adverse events were associated with considering to quit medical practice and a more defensive practice. More awareness must be created for the mental health of physicians as well as for the implementation of a well-organised support system after PTEs.

Mental-health, coping and support following adverse events on the work-floor : a cross-sectional study among Dutch orthopaedic surgeons.

Physicians are frequently exposed to adverse events on the work-floor, which puts them at risk for depression, anxiety- or posttraumatic stress disorder. This study aims to explore what events orthopaedic surgeons consider to have the highest emotional impact as well as support, coping strategies and mental health. A questionnaire was emailed to all members of the Dutch Society of Orthopaedic Surgeons which included resident, attending, non-practicing and retired orthopaedic surgeons. The questionnaire in- cluded questions about demographics, personal experiences and subsequent support and coping. Also the Hospital Anxiety and Depression Scale and the Trauma Screening Questionnaire were included, which are validated screening instruments for anxiety, depression and posttraumatic stress disorder (PTSD), respectively. A total of 292 questionnaires were eligible for analysis. Most common events considered a high emotional impact stressor were : missing a diagnosis (59.2%), when a patient becomes severely handicapped (36.6%) or doubting whether one is making the right decision (36.6%). The prevalence of depression was higher compared to the general population with a high income in the Netherland (4.8 vs. 3.0 %,) and for anxiety as well (8.3 vs. 6.0%). Fifty-seven (19.5%) participants expe- rienced an adverse event as traumatic. Prevalence of PTSD was 0.3% among the whole sample. Most common coping strategies after adverse events were support from colleagues (80.7%), support from friends and family (59.3%) or doing sports (26.6%). Orthopaedic surgeons are exposed to many adverse events over the course of their career, which may have a high emotional impact. The prevalence rate found for depression and anxiety were both higher compared to the general population, while the rate for PTSD was lower. Still, more awareness must be created for the mental health of physicians as well as the implementation of a well-organized support system.

Posttraumatic stress disorder in partners following severe postpartum haemorrhage: A prospective cohort study.

BACKGROUND: Partners of women are increasingly present during childbirth and may be exposed to a traumatic experience. Since parents' mental health issues (i.e. posttraumatic stress disorder) have been shown to increase the risk of problems in the child's development, it is important to identify these risk factors. Partners often describe severe postpartum haemorrhage as traumatic. AIM: Whether witnessing severe postpartum haemorrhage is a risk factor for developing posttraumatic stress disorder in partners. METHODS: In this prospective cohort study, we compared partners of women with severe postpartum haemorrhage (≥2000 mL) and partners of women with ≤500 mL of blood loss (controls). Four weeks after birth partners were screened for posttraumatic stress disorder symptoms with a self-report questionnaire. Scores ≥11 were followed by a gold standard clinical interview to diagnose posttraumatic stress disorder. FINDINGS: We included 123 severe postpartum haemorrhage partners and 62 control partners. Partners of women with severe postpartum haemorrhage reported higher scores than control partners (median 3.0 (0.0-7.0) vs 2.0 (0.0-4.0), p = 0.04) on symptoms of posttraumatic stress, but no significant difference in probable posttraumatic stress disorder diagnosis according to the self-report questionnaire was found. According to the clinical interview no partners were diagnosed with posttraumatic stress disorder. Severe postpartum haemorrhage was experienced as traumatic by the partners who felt excluded. CONCLUSION: None of the partners developed posttraumatic stress disorder, revealing the resilience of young fathers. Because some partners reported severe postpartum haemorrhage as traumatic, we recommend sufficient information and support is provided during childbirth.

Occupational well-being in pediatricians-a survey about work-related posttraumatic stress, depression, and anxiety.

The objective of this study was to study mental health, coping, and support after work-related adverse events among pediatricians. Physicians are frequently exposed to adverse events. It makes them at risk for posttraumatic stress disorder (PTSD), depression, and anxiety disorders. Besides the personal impact, physicians could pose a threat towards patients, as mental health problems are associated with medical errors. A questionnaire was sent to all members of the Pediatric Association of The Netherlands in October 2016. The questionnaire focused on adverse events, coping, and support. The Hospital Anxiety and Depression Scale and the Trauma Screening Questionnaire were included for evaluation of anxiety, depression, and posttraumatic stress. Four hundred ten questionnaires (18.9%) were eligible for analysis. Seventy-nine % (n = 325) of the respondents experienced adverse events, with "missing a diagnosis" having the most emotional impact and "aggressive behavior" as the most common adverse event. Nine (2.2%) pediatricians scored above the cut-off value on the Trauma Screening Questionnaire, indicative of PTSD. In total, 7.3% (n = 30) and 14.1% (n = 58) scored above the cut-off values in the Hospital Anxiety and Depression Scale, indicative of depression and anxiety. Only 26.3% reported to have a peer support protocol available for emotional support following adverse events.Conclusion: Pediatricians experience a considerable amount of adverse and potentially traumatizing events associated with significantly higher mental health problems compared to the general high-income population. Aggression towards pediatricians seems to be a common problem. Protocolled (peer) support should be implemented. What is known: • Physicians are frequently exposed to adverse events. It makes physicians at risk for depression, anxiety, and posttraumatic stress. • Physicians who are affected by these events pose a threat towards patients, as mental health problems are associated with medical errors. What is new: • Pediatricians experience a considerable amount of adverse and potentially traumatizing events associated with significantly higher mental health problems. • It is advised that (peer) support after adverse events is protocolled and education on coping strategies is implemented, to improve mental well-being of pediatricians.

Work-related adverse events leaving their mark: a cross-sectional study among Dutch gynecologists.

BACKGROUND: Health care professionals who are frequently coping with traumatic events have an increased risk of developing a posttraumatic stress disorder. Research among physicians is scarce, and obstetrician-gynecologists may have a higher risk. Work-related traumatic events and posttraumatic stress disorder among obstetricians-gynecologists and the (desired) type of support were studied. METHODS: A questionnaire was emailed to all members of the Dutch Society of Obstetrics and Gynaecology, which included residents, attending, retired and non-practicing obstetricians-gynecologists. The questionnaire included questions about personal experiences and opinions concerning support after work-related events, and a validated questionnaire for posttraumatic stress disorder. RESULTS: The response rate was 42.8% with 683 questionnaires eligible for analysis. 12.6% of the respondents have experienced a work-related traumatic event, of which 11.8% met the criteria for current posttraumatic stress disorder. This revealed an estimated prevalence of 1.5% obstetricians-gynecologists with current posttraumatic stress disorder. 12% reported to have a support protocol or strategy in their hospital after adverse events. The most common strategies to cope with emotional events were: to seek support from colleagues, to seek support from family or friends, to discuss the case in a complication meeting or audit and to find distraction. 82% would prefer peer-support with direct colleagues after an adverse event. CONCLUSIONS: This survey implies that work-related events can be traumatic and subsequently can lead to posttraumatic stress disorder. There is a high prevalence rate of current posttraumatic stress disorder among obstetricians-gynecologists. Often there is no standardized support after adverse events. Most obstetrician-gynecologists prefer peer-support with direct colleagues after an adverse event. More awareness must be created during medical training and organized support must be implemented.

Possible effects of EXT2 on mesenchymal differentiation--lessons from the zebrafish.

BACKGROUND: Mutations in the EXT genes disrupt polymerisation of heparan sulphates (HS) and lead to the development of osteochondroma, an isolated/sporadic- or a multifocal/hereditary cartilaginous bone tumour. Zebrafish (Danio rerio) is a very powerful animal model which has shown to present the same cartilage phenotype that is commonly seen in mice model and patients with the rare hereditary syndrome, Multiple Osteochondroma (MO). METHODS: Zebrafish dackel (dak) mutant that carries a nonsense mutation in the ext2 gene was used in this study. A panel of molecular, morphological and biochemical analyses was used to assess at what step bone formation is affected and what mechanisms underlie changes in the bone formation in the ext2 mutant. RESULTS: During bone development in the ext2-/- zebrafish, chondrocytes fail to undergo terminal differentiation; and pre-osteoblasts do not differentiate toward osteoblasts. This inadequate osteogenesis coincides with increased deposition of lipids/fats along/in the vessels and premature adipocyte differentiation as shown by biochemical and molecular markers. Also, the ext2-null fish have a muscle phenotype, i.e. muscles are shorter and thicker. These changes coexist with misshapen bones. Normal expression of runx2 together with impaired expression of osterix and its master regulator--xbp1 suggest that unfolded protein responses might play a role in MO pathogenesis. CONCLUSIONS: Heparan sulphates are required for terminal differentiation of the cartilaginous template and consecutive formation of a scaffold that is needed for further bone development. HS are also needed for mesenchymal cell differentiation. At least one copy of ext2 is needed to maintain the balance between bone and fat lineages, but homozygous loss of the ext2 function leads to an imbalance between cartilage, bone and fat lineages. Normal expression of runx2 and impaired expression of osterix in the ext2-/- fish indicate that HS are required by osteoblast precursors for their further differentiation towards osteoblastic lineage. Lower expression of xbp1, a master regulator of osterix, suggests that HS affect the 'unfolded protein response', a pathway that is known to control bone formation and lipid metabolism. Our observations in the ext2-null fish might explain the musculoskeletal defects that are often observed in MO patients.