Pharmakotherapeutische Akutbehandlung der Depression und Transgenerationale Suizidalität

Die besondere Herausforderung der medizinischen Wissenschaft besteht heutzutage darin, die zunehmend unüberschaubare Fülle weltweiter Forschungsergebnisse in für die Therapie verwertbare Botschaften umzumünzen. Diese Überlegung bildet das Fundament und den Antrieb aller in dieser Habilitationsschrift vorgelegten Arbeiten. Inhaltlich befassen sich die Arbeiten mit der Pharmakotherapie der akuten Depression und der Transgenerationalität des Suizidrisikos. Die Fragen nach der relativen Wirksamkeit von Antidepressiva gegenüber Placebo und nach dem optimalen Behandlungsvorgehen bei unzureichendem Ansprechen auf eine erste Therapie mit Antidepressiva zählen zu den klinisch wohl drängendsten Fragen in der Akutbehandlung der Depression. Vor diesem Hintergrund behandelt der Hauptteil der in der vorliegenden Arbeit präsentierten Studien pharmakotherapeutische Aspekte der Akutbehandlung affektiver Störungen. Im Zentrum der wissenschaftlichen Forschungen steht dabei die Behandlung der unipolaren Depression mit Antidepressiva in der Akutphase der Erkrankung. Gemeinsames Ziel der entsprechenden in der Habilitationsschrift zusammengefassten Studien ist es u.a. der Praxis wissenschaftlich abgesicherte Informationen über den optimalen Einsatz von Antidepressiva zur Verfügung zu stellen. Geforscht wurde u. a. nach statistisch belastbaren Anhaltspunkten, ob eine langfristige antidepressive Wirkung nicht allein auf den natürlichen Verlauf der Erkrankung, sondern auch auf eine pharmakologische Wirkung zurückzuführen ist. Weitere Forschungen behandeln die Fragen nach dem Verlauf des Ansprechens auf eine Pharmakotherapie, dem optimalen Zeitpunkt eines Therapiewechsels bei unzureichendem Ansprechen, sowie die Frage nach Wirksamkeit und Verträglichkeit der antidepressiven Kombinationstherapie. Als eigenständiger weiterer Forschungsschwerpunkt wird die Transgenerationalität affektiver Störungen am Beispiel der Suizidalität betrachtet. Hier ging es dem Verfasser und den weiteren Mitgliedern des Forschungsteams darum, das transgenerationale Suizidrisiko zu quantifizieren, sowie auf Basis der wissenschaftlichen Erkenntnisse zu Transmissionswegen und Einflussfaktoren ein Modell der familiären Weitergabe von Suizidalität zu entwerfen, anhand dessen Strategien zur Suizidprävention für die Praxis entwickelt werden können. Eine verbindende Klammer zwischen allen vorgestellten Studien ist die gewählte Forschungsmethode. So beruhen sämtliche in dieser Arbeit vorgestellten Ergebnisse auf der Methodik der Meta-Analyse. In diese spezifische Methode wird daher in einem einleitenden Kapitel gesondert eingeführt

Antipsychotic Withdrawal Symptoms: A Systematic Review and Meta-Analysis

Objective Avoiding withdrawal symptoms following antipsychotic discontinuation is an important factor when planning a safe therapy. We performed a systematic review and meta-analysis concerning occurrence of withdrawal symptoms after discontinuation of antipsychotics. Data Sources We searched the databases CENTRAL, Pubmed, and EMBASE with no restriction to the beginning of the searched time period and until October 1, 2019 (PROSPERO registration no. CRD42019119148). Study Selection Of the 18,043 screened studies, controlled and cohort trials that assessed withdrawal symptoms after discontinuation of oral antipsychotics were included in the random-effects model. Studies that did not implement placebo substitution were excluded from analyses. The primary outcome was the proportion of individuals with withdrawal symptoms after antipsychotic discontinuation. We compared a control group with continued antipsychotic treatment in the assessment of odds ratio and number needed to harm (NNH). Data Extraction We followed guidelines by the Cochrane Collaboration, PRISMA, and MOOSE. Results Five studies with a total of 261 individuals were included. The primary outcome, proportion of individuals with withdrawal symptoms after antipsychotic discontinuation, was 0.53 (95% CI, 0.37–0.70; I2 = 82.98%, P < 0.01). An odds ratio of 7.97 (95% CI, 2.39–26.58; I2 = 82.7%, P = 0.003) and NNH of 3 was calculated for the occurrence of withdrawal symptoms after antipsychotic discontinuation. Conclusion Withdrawal symptoms appear to occur frequently after abrupt discontinuation of an oral antipsychotic. The lack of randomized controlled trials with low risk of bias on antipsychotic withdrawal symptoms highlights the need for further research

Presentations to the Emergency Department for Problems Related to Mental Health: Sex Differences in Adolescents.

BACKGROUND Adolescents aged sixteen to eighteen years are mostly treated in adult emergency departments. In a study at our tertiary adult emergency department (ED) at the University Hospital in Bern (Inselspital), Switzerland, we found that adolescents significantly more often present with psychiatric problems than adults. The study at hand aimed to characterise those adolescents presenting to the ED triaged with a chief complaint regarding mental health. Furthermore, the goal was to assess sex differences in terms of diagnosis, suicidal ideation, substance use, as well as social impact. METHODS We conducted a single-centre, retrospective review of presentations to our adult ED related to the mental health of adolescents aged 16 to 18 years, covering the period from January 2013 to July 2017. Anonymised data were extracted from medical reports referring to the ED visits that were triaged as mental-health-related, and we assessed these for diagnosis, acute and previous suicidal ideation, history of self-harm, external aggression, substance use and social problems. We focused on patient characterisation and defining sex differences. RESULTS Data were analysed for a total of 612 consultations by adolescents who presented to our ED with problems related to mental health. Women accounted for 61.1% of cases. The most frequent diagnoses were reactions to severe stress and adjustment disorders (19.1%), followed by alcohol use disorders (17.6%), intentional self-harm (17.3%), and affective disorders (13.7%). Males had lower odds for intentional self-harm (OR 0.10, 95% 0.05-0.21, p &lt; 0.001) as well as disorders of personality and behaviour (OR 0.09, 95% 0.21-0.37, p &lt; 0.001), whereas they had higher odds of being admitted due to use of alcohol (OR 2.51, 95% 1.65-3.83, p &lt; 0.001). Of all cases, 31.7% reported acute suicidal ideation, with a significantly lower odds ratio in males (OR 0.58, 95% 0.41-0.84, p = 0.004). The most common source for referral to the ED was family members (25.2%). Males had twice the odds of reporting alcohol consumption as well as use of cannabis (in both cases p &lt; 0.001). In 27.9% of all cases, familial problems were reported, with males having significantly lower odds of being exposed to these (OR 0.64, 95% 0.44-0.94, p = 0.021), whereas they had higher odds of reporting educational problems (OR 1.68, 95% 1.04-2.72, p = 0.035). CONCLUSIONS Adolescents aged sixteen to eighteen years presenting to the ED with problems related to mental health are an important subgroup of ED presentations and should be thoroughly assessed for suicidal ideation, substance use, as well as familial and educational problems. Assessment and establishment of post-ED care are of particular importance in this vulnerable patient group

Controlled drinking-non-abstinent versus abstinent treatment goals in alcohol use disorder: a systematic review, meta-analysis and meta-regression.

BACKGROUND AND AIMS: The proportion of untreated patients with alcohol use disorder (AUD) exceeds that of any other mental health disorder, and treatment alternatives are needed. A widely discussed strategy is to depart from the abstinence paradigm as part of controlled drinking approaches. This first systematic review with meta-analysis aims to assess the efficacy of non-abstinent treatment strategies compared with abstinence-based strategies. METHODS: CENTRAL, PubMed, PsycINFO and Embase databases were searched until February 2019 for controlled (randomized and non-randomized) clinical trials (RCTs and non-RCTs) among adult AUD populations, including an intervention group aiming at controlled drinking and a control group aiming for abstinence. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane Collaboration guidelines, literature search, data collection and risk of bias assessment were carried out independently by two reviewers [International Prospective Register of Systematic Reviews (PROSPERO), registration no. CRD42019128716]. The primary outcome was the proportion of participants consuming alcohol at or below the recommended threshold. Secondary outcomes were social functioning, drinking reductions, abstinence rates and dropouts. Using random-effects models, RCTs and non-RCTs were analyzed separately. Sensitivity and subgroup analyses accounted for methodological rigor, inclusion of goal-specific treatment, length of follow-up and AUD severity. RESULTS: Twenty-two studies (including five RCTs) with 4204 patients were selected. There was no statistically significant difference between both treatment paradigms in RCTs [odds ratio (OR) = 1.32, 95% confidence interval (CI) = 0.51-3.39]. Non-randomized studies of free goal choice favored abstinence-orientation (OR = 0.60, 95% CI = 0.40-0.90), unless goal-specific treatment was provided (OR = 0.79, 95% CI = 0.40-1.56), or in studies of low risk of bias (OR = 0.73, 95% CI = 0.49-1.09) or with long follow-up (OR = 1.49, 95% CI = 0.78-2.85). Effect sizes were not clearly dependent upon AUD severity. Abstinence- and controlled drinking interventions did not clearly differ in their effect on social functioning and drinking reductions. CONCLUSIONS: Available evidence does not support abstinence as the only approach in the treatment of alcohol use disorder. Controlled drinking, particularly if supported by specific psychotherapy, appears to be a viable option where an abstinence-oriented approach is not applicable

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 2-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 2-autoreceptors seems to be significantly more effective than other combinations. Overall, our search revealed a dearth of well-designed studies. Objectif: Combiner les antidepresseurs pour traiter la depression aigue est une methode frequemment utilisee, mais les etudes randomisees ont offert des resultats conflictuels. Nous avons mene une revue systematique et une meta-analyse visant a determiner l'efficacite et la tolerabilite du traitement combine ou polytherapie. Methodes: Une recherche des bases de donnees MEDLINE, Embase, PsycINFO, et CENTRAL a ete systematiquement menee jusqu'en mars 2014 pour reperer les etudes controlees comparant les polytherapies d'antidepresseurs avec la monotherapie d'antidepresseur chez des patients adultes souffrant de depression aigue. Le resultat principal predetermine etait la difference des moyennes standardisees (DMS), et les resultats secondaires etaient la reponse, la remission, et les abandons. Resultats: Sur 8688 articles examines, 38 etudes etaient admissibles, portant sur 4511 patients. La polytherapie etait statistiquement significativement superieure a la monotherapie (DMS 0,29; IC a 95% 0,16 a 0,42). Durant la monotherapie, un nombre legerement moindre de patients ont abandonne en raison d'effets indesirables (RC 0,90; 0,53 a 1,53). Les etudes etaient heterogenes (I-2 = 63%), et il y avait une indication d'un biais de publication modere (N a securite integree pour un effet de 0,1: 44), mais les resultats demeuraient solides dans les resultats secondaires predetermines et les sous-groupes, y compris les analyses restreintes aux essais randomises et aux etudes a faible risque de biais. La meta-regression a revele une association de la DMS avec une difference d'imipramine pour une dose equivalente. Combiner un inhibiteur du recaptage avec un antagoniste des autorecepteurs 2 presynaptiques etait superieur aux autres combinaisons. Conclusion: Combiner des antidepresseurs semble etre superieur a la monotherapie, et un nombre legerement plus eleve de patients seulement abandonnent le traitement. Combiner un inhibiteur du recaptage avec un antagoniste des autorecepteurs 2 presynaptiques semble etre significativement plus efficace que les autres combinaisons. En general, notre recherche a revele une penurie d'etudes bien concues

Mental health effects of infection containment strategies: quarantine and isolation—a systematic review and meta-analysis

Due to the ongoing COVID-19 pandemic, an unprecedented number of people worldwide is currently affected by quarantine or isolation. These measures have been suggested to negatively impact on mental health. We conducted the first systematic literature review and meta-analysis assessing the psychological effects in both quarantined and isolated persons compared to non-quarantined and non-isolated persons. PubMed, PsycINFO, and Embase databases were searched for studies until April 22, 2020 (Prospero Registration-No.: CRD42020180043). We followed PRISMA and MOOSE guidelines for data extraction and synthesis and the Newcastle-Ottawa Scale for assessing risk of bias of included studies. A random-effects model was implemented to pool effect sizes of included studies. The primary outcomes were depression, anxiety, and stress-related disorders. All other psychological parameters, such as anger, were reported as secondary outcomes. Out of 6807 screened articles, 25 studies were included in our analyses. Compared to controls, individuals experiencing isolation or quarantine were at increased risk for adverse mental health outcomes, particularly after containment duration of 1 week or longer. Effect sizes were summarized for depressive disorders (odds ratio 2.795; 95% CI 1.467-5.324), anxiety disorders (odds ratio 2.0; 95% CI 0.883-4.527), and stress-related disorders (odds ratio 2.742; 95% CI 1.496-5.027). Among secondary outcomes, elevated levels of anger were reported most consistently. There is compelling evidence for adverse mental health effects of isolation and quarantine, in particular depression, anxiety, stress-related disorders, and anger. Reported determinants can help identify populations at risk and our findings may serve as an evidence-base for prevention and management strategies

Switching the Antidepressant After Nonresponse in Adults With Major Depression: A Systematic Literature Search and Meta-Analysis

Objective: Nonresponders to antidepressant monotherapy during acute treatment of major depression are often switched to a new antidepressant. The objective of this meta-analysis was to compare the efficacy of switching to a new antidepressant with continuation of the first antidepressant. Data Sources: PubMed, Embase, PsycINFO, and Cochrane Central Register of Controlled Trials (CENTRAL) databases and additional sources were systematically searched independently by 2 authors up to March 2015 without language limitations. With employment of a sensitivity-enhancing search strategy, generic terms for major depression, switching, and randomized trials were combined. Study Selection: Articles (3,234) were screened for trials of patients with major depression who had not responded to antidepressant monotherapy who were then randomized either to a new antidepressant or to continuation of the first antidepressant. Studies were subdivided into those not allowing for dose escalation in the continuation arm (strict analysis) and those allowing for dose escalation (broad analysis). Data Extraction: Data were extracted and risk of bias was assessed independently by 2 authors, and data were pooled using random effects models. Results: Four randomized controlled trials were included in the strict analysis and 8 in the broad analysis. In both analyses, switching was not superior to continuation: the standardized mean difference in the strict analysis was -0.17 (95% CI, -0.59 to 0.26; P =.45; I-2 = 77.8%) and in the broad analysis was 0.031 (95% CI, -0.26 to 0.32; P =.836; I-2 = 85.3%). All secondary outcome analyses (response and remission rates, low risk of bias studies only, leave-one-out analysis, dropouts) supported the results. There was no indication of publication bias. Conclusions: There is a dearth of randomized controlled trials investigating switching. There is no high-level evidence that switching the antidepressant is effective when compared to simply continuing the initial antidepressant. Since there are better treatment options than switching, physicians should be cautious to switch antidepressants

Long-Term Acute-Phase Treatment With Antidepressants, 8 Weeks and Beyond: A Systematic Review and Meta-Analysis of Randomized, Placebo-Controlled Trials

Objective: In clinical practice, acute antidepressant treatment is often applied for several months until remission is achieved. However, data on treatment outcomes beyond 8 weeks are sparse and no systematic review exists to date. This study aims at assessing efficacy and tolerability of antidepressants compared to placebo in acute treatment at and beyond 8 weeks. Data Sources: MEDLINE, Embase, PsycINFO, and CENTRAL databases were systematically searched through March 2014 using generic terms for depressive and affective disorders combined with generic terms for individual drugs and placebo. Study Selection: Double- blind, randomized, placebo- controlled studies of 8 weeks or more comparing antidepressant monotherapy to placebo in adult patients with acute depressive disorder. Data Extraction: Data extraction and synthesis followed guidelines of the Cochrane Collaboration. All data were extracted independently by 2 reviewers. Primary outcome was standardized mean difference (SMD) between antidepressant and placebo; secondary outcomes were response, remission, and dropouts. Results: Of 6,043 articles screened, we selected 104 studies that met criteria and included 35,052 patients. Active treatment was statistically significantly superior to placebo, with consistent effect sizes (SMD [95% CL]) after 8, 12, 16, 20, and 24 weeks: 0.27 (0.24, 0.30), 0.34 (0.25, 0.43), 0.24 (0.09, 0.40), 0.31 (0.12, 0.51), and 0.34 (0.18, 0.50), respectively. Results remained stable across secondary outcomes and subgroup and sensitivity analyses. Conclusions: Effect sizes of antidepressant monotherapy compared to placebo seem to be stable over 6 months. These results challenge the assumption that long- term antidepressant effects are due to the natural course of the disorder rather than to a pharmacologic effect

Trajectories of Acute Antidepressant Efficacy: How Long to Wait for Response? A Systematic Review and Meta-Analysis of Long-Term, Placebo-Controlled Acute Treatment Trials

Background: In patients who are not responding to antidepressant pharmacotherapy, information regarding the future probability of response with the same treatment is scarce. Specifically, it is unclear at what point in time the probability to respond or remit ceases to increase, because few studies report data on response or remission at repeated time points beyond 4 or 8 weeks of treatment. Consequently, treatment recommendations in clinical practice guidelines differ widely. Data Sources: We systematically searched MEDLINE, Embase, PsycINFO, and CENTRAL databases through March 2014 using generic terms for depressive or affective disorders, individual drug names, and placebo (Prospero Registration: CRD42014010105). Study Selection:We identified double-blind, randomized studies with continuous outcome reporting from 4 weeks up to at least 12 weeks that compared antidepressant monotherapy to placebo in adult patients suffering from acute depressive disorder. Data Extraction: Data extraction and synthesis followed Cochrane Collaboration guidelines. Primary outcome was response; secondary outcomes were remission and changes in rating scale scores in previously unresponsive patients, respectively. Results: Of 6,043 articles screened, we selected 9 studies including 3,466 patients. Altogether, 21.6% (18.6%, 24.9%) of previously nonresponsive patients achieved response with ongoing antidepressant treatment between weeks 5 and 8, and 9.9% (7.5%, 12.7%), between weeks 9 and 12. Probability of response when taking placebo was 13.0% (9.9%, 16.5%) between weeks 5 and 8 and 2.4% (1.2%, 4.6%) between weeks 9 and 12. Differences in the probability of response between antidepressant and placebo translated into a number needed to treat of 11 after 4 weeks and 17 after 8 weeks. Heterogeneity was low to moderate, and results remained stable across subgroup and sensitivity analyses. Conclusions: In patients unresponsive to antidepressant pharmacotherapy, improvements in psychopathology can be expected with ongoing antidepressant treatment for up to 3 months. After 8 weeks of treatment, improvement with ongoing monotherapy is relatively small