[Changes in the perception of benefits and risks of antidepressive pharmacotherapy]. / Wandel von Nutzen und Risiko antidepressiver Pharmakotherapie.

Antidepressive pharmacotherapy has undergone various phases in its history. The euphoria of the early years on the relief of depressive symptoms was followed by a long period of clinical experience and intensive scientific work resulting in a more balanced perspective. Current debates circle around the actual effectiveness, especially with respect to long-term treatment, the prevention of suicide and the sequelae of discontinuation of an antidepressant. The evaluation of antidepressants as a group and often also the risk-benefit ratio of an individual treatment change over time. Antidepressants are typical for many forms of psychiatric treatment which, in a term from Hanfried Helmchen, are just as Janus-faced as psychiatry in a general sense is as a science and as a clinical discipline.

Antidepressants and Social Functioning in Patients with Major Depressive Disorder: Systematic Review and Meta-Analysis of Double-Blind, Placebo-Controlled RCTs.

INTRODUCTION: Social functioning (SF) is the ability to fulfil one's social obligations and a key outcome in treatment. OBJECTIVE: The aim of the study was to estimate the effects of antidepressants on SF in patients with major depressive disorder (MDD). METHODS: This meta-analysis and its reporting are based on Cochrane Collaboration's Handbook of Systematic Reviews and Meta-Analyses and PRISMA guidelines (protocol registration at OSF). We systematically searched CENTRAL, Medline, PubMed Central, and PsycINFO for double-blind RCTs comparing antidepressants with placebo and reporting on SF. We computed standardized mean differences (SMDs) with 95% CIs and prediction intervals. RESULTS: We selected 40 RCTs out of 1,188 records screened, including 16,586 patients (mean age 46.8 years, 64.2% women). In 27 studies investigating patients with MDD (primary depression), antidepressants resulted in a SMD of 0.25 compared to placebo ([95% CI: 0.21; 0.30] I2: 39%). In 13 trials with patients suffering from MDD comorbid with physical conditions or disorders, the summary estimate was 0.24 ([0.10; 0.37] I2: 75%). In comorbid depression, studies with high/uncertain risk of bias had higher SMDs than low-risk studies: 0.29 [0.13; 0.44] versus 0.04 [-0.16; 0.24]; no such effect was evident in primary depression. There was no indication of sizeable reporting bias. SF efficacy correlated with efficacy on depression scores, Spearman's rho 0.67 (p < 0.001), and QoL, 0.63 (p < 0.001). CONCLUSIONS: The effect of antidepressants on SF is small, similar to its effect on depressive symptoms in primary MDD, and doubtful in comorbid depression. Strong correlations with both antidepressive and QoL effects suggest overlap among domains.

Antidepressants and quality of life in patients with major depressive disorder - Systematic review and meta-analysis of double-blind, placebo-controlled RCTs.

BACKGROUND: Quality of Life (QoL) is an important outcome in mental disorders. We investigated whether antidepressant pharmacotherapy improved QoL vs. placebo among patients with MDD. METHODS: Systematic literature search in CENTRAL, Medline, PubMed Central, and PsycINFO of double-blind, placebo-controlled RCTs. Screening, inclusion, extraction, and risk of bias assessment were conducted independently by two reviewers. We calculated summary standardized mean differences (SMD) with 95%-CIs. We followed Cochrane Collaboration's Handbook of Systematic Reviews and Meta-Analyses and PRISMA guidelines (protocol registration at OSF). RESULTS: We selected 46 RCTs out of 1807 titles and abstracts screened, including 16.171 patients, 9131 on antidepressants and 7040 on placebo, a mean age of 50.9 years, with 64.8% women. Antidepressant drug treatment resulted in a SMD in QoL of 0.22 ([95%-CI: 0.18; 0.26] I2 39%) vs. placebo. SMDs differed by indication: 0.38 ([0.29; 0.46] I2 0%) in maintenance studies, 0.21 ([0.17; 0.25] I2 11%) in acute treatment studies, and 0.11 ([-0.05; 0.26], I2 51%) in studies focussing on patients with a physical condition and major depression. There was no indication of subtstantial small study effects, but 36 RCTs had a high or uncertain risk of bias, particularly maintenance trials. QoL and antidepressive effect sizes were associated (Spearman's rho 0.73, p < 0.001). CONCLUSIONS: Antidepressants' effects on QoL are small in primary MDD, and doubtful in secondary major depression and maintenance trials. The strong correlation of QoL and antidepressive effects indicates that the current practice of measuring QoL may not provide sufficient additional insights into the well-being of patients.

Offspring's risk for suicidal behaviour in relation to parental death by suicide: systematic review and meta-analysis and a model for familial transmission of suicide.

BACKGROUND: Exposure to parental suicide has been associated with increased risk for suicide and suicide attempts, although the strength of this association is unclear as evidence remains inconsistent. AIMS: To quantify this risk using meta-analysis and identify potential effect modifiers. METHOD: A systematic search in PubMed, PsycInfo and Embase databases to 2020 netted 3614 articles. Inclusion criteria were: observation of history of parental death by suicide, comparison with non-exposed populations and definition of suicide and suicide attempt according to standardised criteria. We focused on population-based studies. The primary outcome was the pooled relative risk (RR) for incidence of suicide attempt and suicide in offspring of a parent who died by suicide compared with offspring of two living parents. Additionally, we compared the RR for attempted and completed suicide after parental suicide with the RR for attempted and completed suicide after parental death by other causes. RESULTS: Twenty studies met our inclusion criteria. Offspring exposed to parental suicide were more likely to die by suicide (RR = 2.97, 95% CI 2.50-3.53) and attempt suicide (RR = 1.76, 95% CI 1.58-1.96) than offspring of two living parents. Furthermore, their risk of dying by or attempting suicide was significantly higher compared with offspring bereaved by other causes of death. CONCLUSIONS: The experience of losing a parent to suicide is a strong and independent risk factor for suicidal behaviour in offspring. Our findings highlight the need for prevention strategies, outreach programmes and support interventions that target suicide-related outcomes in the exposed population.

Dose-Response Relationship in Selective Serotonin and Norepinephrine Reuptake Inhibitors in the Treatment of Major Depressive Disorder: A Meta-Analysis and Network Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Selective serotonin and norepinephrine reuptake inhibitors (SNRI) are among the most prescribed antidepressants, and dose escalation is a frequently applied strategy after non-response to an initially prescribed dose. OBJECTIVE: This meta-analysis aimed to find evidence of a dose-response relationship or to the contrary in direct comparisons of different SNRI doses in patients with major depressive disorder. METHODS: A systematic literature search for RCTs comparing at least two doses of SNRIs was carried out in CENTRAL, PubMed, PsycINFO, and EMBASE. Doses were classified as high, medium, and low according to manufacturers' product monographs and analyses at the level of SNRIs as a group and for single substances, accompanied by sensitivity network meta-analyses (Prospero CRD42018081031). RESULTS: From 2,070 studies screened, we included 26 studies with a total of 10,242 patients. Comparisons of medium versus low and high versus medium doses resulted in clinically and statistically non-significant standardized mean differences of -0.06 (-0.16 to 0.04) and -0.06 (-0.16 to 0.03) in favor of higher doses. In the analyses of single substances, no statistically significant results emerged, and many contrasts yielded very small effect sizes. Dropouts due to side effects tended to be more frequent with higher doses. Heterogeneity was low. Network meta-analyses of direct comparisons supported the findings, as did a risk of bias analysis. CONCLUSION: Based on the lack of positive evidence for a dose-response relationship in SNRIs as a group and in single SNRIs, we recommend prescribing medium doses. In case of insufficient response, we do not recommend increasing the dose of SNRIs.

Importance, Errors, and Patterns of Quotations to Psychiatric Original Articles.

INTRODUCTION: A substantial rate of quotation errors has been reported in medical journal publications: about 25% of all quotations are wrong. It is, however, entirely unclear how important quotation errors are for the message of quoting articles. METHODS: This is a case study in form of a retrospective quotation analysis of a cohort of 72 psychiatric original articles (index articles) from 5 German-language general psychiatric journals. Main outcomes were importance and accuracy of quotations from the 2 calendar years following the publication of index articles. RESULTS: Fifty-one index articles were quoted 235 times in 109 quoting articles. Almost all quotations were of medium (76% [95% CI: 70%; 81%]) or high (20% [15%, 25%]) importance for the message of the quoting paper. Regarding quotation accuracy, 44 quotations (19% [14%; 24%]) were rated as minor, and 51 (22% [17%; 27%]) as major errors. In multivariable analyses, no statistically significant and practically relevant factors associated with quotation inaccuracy emerged, such as self-quotation, impact factor of the quoting journal, or importance. Among quoting articles, 7 (6% [3%; 13%]) showed a pattern of predominantly quoting index articles from the time span relevant to the calculation of the impact factor. DISCUSSION: Quotations are important for the message of the quoting paper. Therefore, quotation errors may be detrimental to scientific reasoning and may undermine public trust in medical science. The present investigation is a case study, and its results are exploratory. While it is plausible that the findings translate into other environments, independent replication is needed.

[Changes in Patient and Disease Characteristics in a Psychiatric Clinic After Adopting the Model of Sectorized Mandatory Care]. / Wie verändert sich die Patienten- und Krankheitsstruktur einer psychiatrischen Krankenhausabteilung durch Übernahme der sektorisierten Pflichtversorgung?

BACKGROUND: Regional mandatory care is a special feature of psychiatric inpatient care in Germany. There is practically no systematic information on the changes in patient and disease characteristics a clinic is confronted with when adopting regional mandatory care. METHOD: Changes in inpatient characteristics were assessed by analyzing the whole set of the basic documentation inpatient data (BADO) of 2 years at Schlosspark-Klinik in Berlin (SPK) which switched to mandatory care in one regional sector in the year between the 2 years. We analyzed 863 vs. 1345 cases for the 2 years (without vs. with mandatory care). RESULTS: On average, patients were younger (M=50 vs. 48 y, p<0.05), fewer patients lived independently (97 vs. 89%, p<0.05), fewer were in partnership (42 vs. 29%, p<0.05), and fewer were employed (34 vs. 28%, p<0.05). The percentage of emergency cases (13 vs. 35%, p<0.001) and compulsory admissions (0.2 vs. 8.5%, p<0.001) was higher after adopting mandatory care. More patients terminated their treatment without their physician's consent (9 vs. 22%, p<0.001). There was a proportional increase of F1x ICD-10 diagnoses (11 vs. 22%) and F2x (14 vs. 20%), while there was a proportional decrease of F3x (38 vs. 30%) and F4x diagnoses (26 vs. 13%). CONCLUSION: After adoption of regional mandatory care, clinical structures need to be adjusted to deal with an increase in emergency cases and a larger number of patients with unfavorable sociodemographic and disease characteristics. To be able to do this, clinics should be equipped with the required organizational and financial means.

Data Sharing Statements for Clinical Trials: A Requirement of the International Committee of Medical Journal Editors.

The International Committee of Medical Journal Editors announces requirements that a data sharing plan be prospectively registered, and a data sharing statement be included in submitted manuscripts, for clinical trials to be published in ICMJE journals.

Psychopathological and demographic characteristics of hallucinating patients with schizophrenia and schizoaffective disorder: an analysis based on AMDP data.

Hallucinations are at the core of the diagnosis of schizophrenia and schizoaffective disorders, and many neuroscience studies focus on hallucinations. However, there is a lack of data on prevalence, subtyping, and clinical correlates of hallucinations as well as on the comparison of hallucinating schizophrenia versus hallucinating schizoaffective patients. Analysis of all psychopathology evaluations is based on the AMDP scale in a German psychiatric university hospital between 2007 and 2013 regarding patients with schizophrenia or schizoaffective disorder (diagnosed according to ICD-10). Hallucinating versus non-hallucinating patients and age- and gender-matched hallucinating schizophrenic versus schizoaffective patients were compared with regard to key psychopathological and demographic characteristics. Relative to patients with schizoaffective disorder, patients with schizophrenia more often hallucinated at admission (36.6 vs. 16.2 %, RR: 2.3, p < 0.001). By subtype, frequency of hallucinations ranked auditory verbal > other auditory > visual > somatic/tactile > olfactory/gustatory. Hallucinating patients of either disorder were more often affected with respect to delusions (83 vs. 62 % and 81 vs. 48 % among patients with schizophrenia and schizoaffective disorder, respectively [both p < 0.0001]) and anxiety. Hallucinating patients with schizoaffective disorder did not differ from hallucinating patients with schizophrenia. This is one of the few studies providing data on hallucinations in a routine clinical care setting. Hallucinations are a sign and likely a cause of greater illness severity. Patients with schizoaffective disorder less often experience hallucinations than patients with schizophrenia, but if they do, they seem to resemble patients with schizophrenia with regard to illness severity.

An Analysis of 2.3 Million Participations in the Continuing Medical Education Program of a General Medical Journal: Suitability, User Characteristics, and Evaluation by Readers.

BACKGROUND: Physicians frequently use continuing medical education (CME) in journals. However, little is known of the evaluation of journal CME by readers and also user and participation characteristics. Deutsches Ärzteblatt, the journal of the German Medical Association, is distributed to every physician in Germany and regularly offers its readers CME articles. Therefore, it provides a unique opportunity to analyze a journal CME program directed at an entire population of physicians. OBJECTIVE: The aim is to show key sociodemographic characteristics of participants, frequency and temporal distributions of participations, and to analyze whether the articles are suitable for a general medical audience, how physicians rate the CME articles, how successful they were in answering simple multiple-choice questions, and to detect distinct clusters of participants. METHODS: Using obligatory online evaluation forms and multiple-choice questions, we analyzed all participations of the entire 142 CME articles published between September 2004 and February 2014. We compared demographic characteristics of participants with official figures on those characteristics as provided by the German Medical Association. RESULTS: A total of 128,398 physicians and therapists (male: 54.64%, 70,155/128,393; median age class 40 to 49 years) participated 2,339,802 times (mean 16,478, SD 6436 participations/article). Depending on the year, between 12.33% (44,064/357,252) and 16.15% (50,259/311,230) of all physicians in the country participated at least once. The CME program was disproportionally popular with physicians in private practice, and many participations took place in the early mornings and evenings (4544.53%, 1,041,931/2,339,802) as well as over the weekend (28.70%, 671,563/2,339,802). Participation by specialty (ranked in descending order) was internal medicine (18.25%, 23,434/128,392), general medicine (16.38%, 21,033/128,392), anesthesiology (10.00%, 12,840/128,392), and surgery (7.06%, 9059/128,392). Participants rated the CME articles as intelligible to a wider medical audience and filling clinically relevant knowledge gaps; 78.57% (1,838,358/2,339,781) of the sample gave the CME articles very good or good marks. Cluster analysis revealed three groups, one comprised of only women, with two-thirds working in private practice. CONCLUSIONS: The CME article series of Deutsches Ärzteblatt is used on a regular basis by a considerable proportion of all physicians in Germany; its multidisciplinary articles are suitable to a broad spectrum of medical specialties. The program seems to be particularly attractive for physicians in private practice and those who want to participate from their homes and on weekends. Although many physicians emphasize that the articles address gaps in knowledge, it remains to be investigated how this impacts professional performance and patient outcomes.

Data Sharing Statements for Clinical Trials: A Requirement of the International Committee of Medical Journal Editors.

El Comité Internacional de Editores de Revista Médicas (ICMJE) ha tomado la posición que el compartir los datos generados por los ensayos clínicos es una obligación ética, por cuanto los participantes en esos estudios se colocaron en riesgo al aceptar su inclusión. En esta editorial el ICMJE expresa que requerirá desde Julio 2018 que los manuscritos enviados a sus revistas deben incluir una declaración sobre compartir datos. A su vez, los ensayos clínicos que comiencen a enrolar pacientes a partir de Enero 2019, deben incluir un plan sobre compartir datos en el registro de tales ensayos. Se dan en esta declaración cuatro ejemplos de declaraciones sobre compartir datos, referidos a qué datos se compartirán, cuándo estarán disponibles y qué criterios de acceso se establecerán. El ICMJE visualiza un futuro cercano en el cual el compartir los datos será la norma, con el fin de maximizar el conocimiento ganado por los esfuerzos y sacrificios de los participantes.

Diagnostic shift in patients diagnosed with schizoaffective disorder: a systematic review and meta-analysis of rediagnosis studies.

OBJECTIVES: The diagnosis of schizoaffective disorder (SAD) is well established in clinical practice but is heavily disputed on theoretical grounds. We analyzed the extent and direction of diagnostic shift in SAD patients. METHODS: We searched Medline, Embase, and PsycINFO systematically for all studies documenting two diagnostic assessments at different points in time (rediagnosis studies) and used meta-analytic methods to quantify diagnostic shift. Multiple prespecified and post-hoc subgroup analyses (e.g., rater blinding) and meta-regressions (e.g., year of publication) were carried out. RESULTS: We included 31 studies out of 4,415 articles screened: 27 studies on the shift from and 23 studies on the shift to SAD (median time span was two years). A total of 36% of patients with a diagnosis of SAD at first assessment switch, many to schizophrenia (19%), 14% to affective disorders, and 6% to other disorders. Among patients diagnosed with SAD at second assessment, 55% had received a different diagnosis at first assessment, a large portion of whom had been initially diagnosed with affective disorder (24%), schizophrenia (18%), and other disorders (12%). CONCLUSIONS: Diagnostic shift in SAD patients is substantial. Psychiatrists need to reassess the diagnosis during the course of the illness and to adjust treatment. Slightly more diagnoses of SAD are changed to schizophrenia than to affective disorders, and among patients rediagnosed with SAD, fewer have been diagnosed with schizophrenia than with affective disorders. Thus, at the diagnostic level, there seems to be a slight trend toward schizophrenia during the course of functional psychoses.

Suicides and Suicide Attempts during Long-Term Treatment with Antidepressants: A Meta-Analysis of 29 Placebo-Controlled Studies Including 6,934 Patients with Major Depressive Disorder.

BACKGROUND: It is unclear whether antidepressants can prevent suicides or suicide attempts, particularly during long-term use. METHODS: We carried out a comprehensive review of long-term studies of antidepressants (relapse prevention). Sources were obtained from 5 review articles and by searches of MEDLINE, PubMed Central and a hand search of bibliographies. We meta-analyzed placebo-controlled antidepressant RCTs of at least 3 months' duration and calculated suicide and suicide attempt incidence rates, incidence rate ratios and Peto odds ratios (ORs). RESULTS: Out of 807 studies screened 29 were included, covering 6,934 patients (5,529 patient-years). In total, 1.45 suicides and 2.76 suicide attempts per 1,000 patient-years were reported. Seven out of 8 suicides and 13 out of 14 suicide attempts occurred in antidepressant arms, resulting in incidence rate ratios of 5.03 (0.78-114.1; p = 0.102) for suicides and of 9.02 (1.58-193.6; p = 0.007) for suicide attempts. Peto ORs were 2.6 (0.6-11.2; nonsignificant) and 3.4 (1.1-11.0; p = 0.04), respectively. Dropouts due to unknown reasons were similar in the antidepressant and placebo arms (9.6 vs. 9.9%). The majority of suicides and suicide attempts originated from 1 study, accounting for a fifth of all patient-years in this meta-analysis. Leaving out this study resulted in a nonsignificant incidence rate ratio for suicide attempts of 3.83 (0.53-91.01). CONCLUSIONS: Therapists should be aware of the lack of proof from RCTs that antidepressants prevent suicides and suicide attempts. We cannot conclude with certainty whether antidepressants increase the risk for suicide or suicide attempts. Researchers must report all suicides and suicide attempts in RCTs.

Combining Antidepressants in Acute Treatment of Depression: A Meta-Analysis of 38 Studies Including 4511 Patients.

OBJECTIVE: Combining antidepressants (ADs) for therapy of acute depression is frequently employed, but randomized studies have yielded conflicting results. We conducted a systematic review and meta-analysis aimed at determining efficacy and tolerability of combination therapy. METHODS: MEDLINE, Embase, PsycINFO, and CENTRAL databases were systematically searched through March 2014 for controlled studies comparing combinations of ADs with AD monotherapy in adult patients suffering from acute depression. The prespecified primary outcome was standardized mean difference (SMD), secondary outcomes were response, remission, and dropouts. RESULTS: Among 8688 articles screened, 38 studies were eligible, including 4511 patients. Combination treatment was statistically, significantly superior to monotherapy (SMD 0.29; 95% CI 0.16 to 0.42). During monotherapy, slightly fewer patients dropped out due to adverse events (OR 0.90; 95% CI 0.53 to 1.53). Studies were heterogeneous (I(2) = 63%), and there was indication of moderate publication bias (fail-safe N for an effect of 0.1:44), but results remained robust across prespecified secondary outcomes and subgroups, including analyses restricted to randomized controlled trials and low risk of bias studies. Meta-regression revealed an association of SMD with difference in imipramine-equivalent dose. Combining a reuptake inhibitor with an antagonist of presynaptic α2-autoreceptors was superior to other combinations. CONCLUSION: Combining ADs seems to be superior to monotherapy with only slightly more patients dropping out. Combining a reuptake inhibitor with an antagonist of presynaptic α2-autoreceptors seems to be significantly more effective than other combinations. Overall, our search revealed a dearth of well-designed studies.