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Background: Sex-related effects on the evolution and phenotype of major depressive disorder (MDD) were reported previously. Methods: This European multicenter cross-sectional study compared sociodemographic, clinical, and treatment patterns between males and females in a real-world sample of 1410 in- and outpatients with current MDD. Results: Male MDD patients (33.1%) were rather inpatients, suffered from moderate to high suicidality levels, received noradrenergicand specific serotonergic antidepressants (ADs) as first-line AD treatment, generally higher mean AD daily doses, and showed a trend towards a more frequent administration of add-on treatments. Female MDD patients (66.9%) were rather outpatients, experienced lower suicidality levels, comorbid thyroid dysfunction, migraine, asthma, and a trend towards earlier disease onset. Conclusions: The identified divergencies may contribute to the concept of maleand female depressive syndromes and serve as predictors of disease severity and course, as they reflect phenomena that were repeatedly related to treatment-resistant depression (TRD). Especially the greater necessity of inpatient treatment and more complex psychopharmacotherapy in men may reflect increased therapeutic efforts undertaken to treat suicidality and to avoid TRD. Hence, considering sex may guide the diagnostic and treatment processes towards targeting challenging clinical manifestations including comorbidities and suicidality, and prevention of TRD and chronicity.

Background Augmentation with second-generation antipsychotics (SGAs) represents an evidence-based psychopharmacotherapeutic strategy recommended in case of insufficient response to the first-line antidepressant (AD) treatment in major depressive disorder (MDD). Comparative evidence regarding efficacy and prescription preferences of the individual SGAs is scarce. Methods In the scope of this European, multi-site, naturalistic cross-sectional investigation with retrospective assessment of treatment outcome, we compared sociodemographic and clinical characteristics of 187 MDD patients receiving either quetiapine (n = 150) or aripiprazole (n = 37) as augmentation of their first-line AD psychopharmacotherapy. Results Comorbid posttraumatic stress disorder and diabetes were significantly associated with aripiprazole augmentation in our primary and post-hoc binary logistic regression analyses. Furthermore, we identified an association between aripiprazole co-administration and the presence of additional psychotic features, higher rates of AD combination treatment, and a longer duration of psychiatric hospitalizations during the lifetime, which, however, lost significance after correcting for multiple comparisons. Regarding treatment outcome, we found a trend of higher response rates and greater reductions in severity of depressive symptoms in MDD patients dispensed quetiapine. Conclusions Factors associated with a more chronic and severe profile of MDD seem to encourage clinicians to choose aripiprazole over quetiapine, that was, however, administered in the majority of our MDD patients, which might reflect the current approval situation allowing to prescribe exclusively quetiapine as on-label augmentation in MDD in Europe. Given the retrospective assessment of treatment response, the markedly smaller proportion of patients receiving aripiprazole augmentation generally showing an unfavorable disease profile, and the partially heterogeneous statistical robustness of our findings, further studies are required to elaborate on our observation and to generate unambiguous recommendations regarding the choice of first-line SGA augmentation in MDD.

About two thirds of the patients with major depressive disorder (MDD) do not sufficiently respond to monotherapy with antidepressants (ADs) which makes them reliant on further treatment approaches. Hereby, combination of different ADs and augmentation with second-generation antipsychotics (SGAs) are widely used and recommended psychopharmacotherapeutic strategies. The present secondary analyses are based on an international, naturalistic, cross-sectional multicenter study conducted by the European Group for the Study of Resistant Depression. Comparing socio-demographic and clinical characteristics of 436 adult MDD patients receiving either SGAs (N = 191, 43.8%) or ADs (N = 245, 56.2%), that were additionally administered to their first-line AD psychopharmacotherapy, we aimed to identify possible trajectories of decision-making for clinicians regarding which treatment option to prefer in individual patients. Our most robust findings represent an association of SGA augmentation with the presence of psychotic symptoms, longer mean duration of lifetime psychiatric hospitalizations, employment of further augmentation strategies with mood-stabilizers and benzodiazepines, and a trend towards higher mean daily dosages of their first-line ADs and current suicidal risk. Treatment outcome was not significantly different between patients receiving either SGA augmentation or AD combination. Being aware of limitations inherent to the cross-sectional study design and the lack of randomization, more severe and rather chronic conditions in MDD seemed to encourage clinicians to choose SGA augmentation over AD combination. The fact that mood-stabilizers and/or benzodiazepines were more frequently co-administered with SGAs may represent a requirement of an overall refined psychopharmacotherapy including additional fast-acting agents with potent AD, tranquilizing and anti-suicidal effects in MDD patients experiencing challenging clinical manifestations. New glutamatergic substances seem to be promising in this regard.

Since selective serotonin reuptake inhibitors, that are recommended as first-line antidepressant psychopharmacotherapy for major depressive disorder (MDD), may not be the optimal choice for every patient, antidepressants with different modes of action exerting a distinct set of expectant effects, represent a valuable alternative. Despite the previously observed increased prescription rates of noradrenergic and specific serotonergic antidepressants (NaSSAs) particularly mirtazapine in Europe, the individual profiles of patients primarily prescribed NaSSAs in real-world settings have not been systematically investigated yet. In this secondary analysis based on a European, cross-sectional, naturalistic, multicenter study involving 1410 adult males and females with primary MDD, sociodemographic and clinical variables were compared between patients dispensed NaSSAs and those with alternative first-line antidepressants. Hereby, NaSSAs were administered in 8.6 % of the sample (mirtazapine: n = 114, mianserin: n = 7). We detected associations with older mean age, male sex, unemployment, as well as additional melancholic and catatonic features, inpatient treatment, lower mean daily dosages of the administered antidepressants but higher rates of augmentation with low-potency antipsychotics, and greater mean reductions of depressive symptoms during their current major depressive episodes. Although the study design is unsuitable to draw any causal conclusions, our findings provide a realistic picture of patients eligible for first-line antidepressant treatment with NaSSAs, especially mirtazapine, and underscore the role of this AD substance class in severe MDD. Further, they may represent a promising basis for future systematic research focusing on precision diagnostics and treatment in MDD, that would ideally result in faster responses and better outcomes, especially in the so-called difficult-to-treat conditions including treatment resistant depression.

Seasonal fluctuations in mood, drive, energy, sleeping- and eating behavior, weight, as well as further important mental and physical functions, and the utilization of light as an effective treatment option were already described by Hippocrates of Kos and Araeteus, the Cappadocian. The concept of the so-called seasonal affective disorder (SAD) as a disruption of the circadian rhythm precipitated by a deficiency of environmental light during darker seasons was first described in the 1980s. Furthermore, chronobiological and hormonal dysregulation in SAD patients was repeatedly shown to be accompanied by alterations on a neuroreceptor and neurotransmitter level and to normalize after remission. Hence, SAD represents one of the most important models of a chronobiological disorder with over 1000 international publications on its aetiology and treatment options, whereby their underpinnings could be elucidated on a clinical as well as molecular level. The present article summarizes the current understanding of etiological mechanisms of SAD and provides an overview of diagnostic and therapeutic strategies, which are based on available international evidence including clinical trials, systematic reviews, and meta-analyses. According to current recommendations of international guidelines, promising treatment options as bright light therapy, psychopharmacotherapy, therapeutic sleep deprivation, and their underlying mechanisms of action are presented.

Highlights • Disturbed glycemic control is an intrinsic feature of schizophrenia. • The neurotransmitter dopamine has a key role in regulating glucose homeostasis. • We studied brain dopamine and blood glucose levels in first episode psychosis. • The relationship between glucose and brain dopamine is altered in schizophrenia., An elemental function of brain dopamine is to coordinate cognitive and motor resources for successful exploitation of environmental energy sources. Dopamine transmission, goal-directed behavior, and glucose homeostasis are altered in schizophrenia patients prior to and after initiation of pharmacological treatment. Thus, we investigated the relationship between blood glucose levels and brain dopamine signaling in drug-naïve patients with first-episode psychosis. We quantified blood glucose levels and binding of the dopamine D2/3 receptor agonist radioligand (+)-[11C]-PHNO in 15 medication-naïve patients and 27 healthy volunteers employing positron emission tomography. Whole-brain voxel-wise linear model analysis identified two clusters of significant interaction between blood glucose levels and diagnosis on (+)-[11C]-PHNO binding-potential values. We observed positive relationships between blood glucose levels and binding-potential values in healthy volunteers but negative ones in patients with first episode psychosis in a cluster surviving rigorous multiple testing correction located in the in the right ventral tegmental area. Another cluster of homologous behavior, however at a lower level of statistical significance, comprised the ventral striatum and pallidum. Extracellular dopamine levels are a major determinant of (+)-[11C]-PHNO binding in the brain. In line with the concept that increased dopamine signaling occurs when goal-directed behavior is needed for restoring energy supply, our data indicate that in healthy volunteers, extracellular dopamine levels are high when blood glucose levels are low and vice-versa. This relationship is reversed in patients with first-episode psychosis, possibly reflecting an underlying pathogenic alteration that links two seemingly unrelated aspects of the illness: altered dopamine signaling and dysfunctional glucose homeostasis.

Since many patients with major depressive disorder (MDD) do not satisfactorily respond to initial antidepressant monotherapy, add-on treatment strategies with other psychiatric compounds are often established. The present European multicenter cross-sectional study comprising 1410 MDD in- and outpatients investigated the prescription pattern of benzodiazepines as add-on treatment in the psychopharmacotherapy of MDD. Analyses of variance, chi-squared tests, and logistic regression analyses were conducted to examine differences in socio-demographic, clinical, and treatment characteristics between benzodiazepine users and non-users. The prescription rate for adjunctive benzodiazepine treatment amounted to 31.35%. The most often administered benzodiazepines were lorazepam (11.13%), clonazepam (6.74%), and alprazolam (6.60%). Benzodiazepine users exhibited more severe depressive symptoms expressed by a higher mean Montgomery and Åsberg Depression Rating Scale total score at study entry (26.92 ± 11.07 vs 23.55 ± 11.23, p

Objectives: Clinical variables were investigated in the ‘treatment resistant depression (TRD)- III’ sample to replicate earlier findings by the European research consortium ‘Group for the Study of Resistant Depression’ (GSRD) and enable cross-sample prediction of treatment outcome in TRD. Experimental procedures: TRD was defined by a Montgomery and Åsberg Depression Rating Scale (MADRS) score ≥22 after at least two antidepressive trials. Response was defined by a decline in MADRS score by ≥50% and below a threshold of 22. Logistic regression was applied to replicate predictors for TRD among 16 clinical variables in 916 patients. Elastic net regression was applied for prediction of treatment outcome. Results: Symptom severity (odds ratio (OR) = 3.31), psychotic symptoms (OR = 2.52), suicidal risk (OR = 1.74), generalized anxiety disorder (OR = 1.68), inpatient status (OR = 1.65), higher number of antidepressants administered previously (OR = 1.23), and lifetime depressive episodes (OR = 1.15) as well as longer duration of the current episode (OR = 1.022) increased the risk of TRD. Prediction of TRD reached an accuracy of 0.86 in the independent validation set, TRD-I. Conclusion: Symptom severity, suicidal risk, higher number of lifetime depressive episodes, and comorbid anxiety disorder were replicated as the most prominent risk factors for TRD. Significant predictors in TRD-III enabled robust prediction of treatment outcome in TRD-I., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: This European multicenter study aimed to elucidate suicidality in major depressive disorder. Previous surveys suggest a prevalence of suicidality in major depressive disorder of ≥50%, but little is known about the association of different degrees of suicidality with socio-demographic, psychosocial, and clinical characteristics. Methods: We stratified 1410 major depressive disorder patients into 3 categories of suicidality based on the Hamilton Rating Scale for Depression item 3 (suicidality) ratings (0 = no suicidality; 1–2 = mild/moderate suicidality; 3–4 = severe suicidality). Chi-squared tests, analyses of covariance, and Spearman correlation analyses were applied for the data analyses. Results: The prevalence rate of suicidality in major depressive disorder amounted to 46.67% (Hamilton Rating Scale for Depression item 3 score ≥1). 53.33% were allocated into the no, 38.44% into the mild/moderate, and 8.23% into the severe suicidality patient group. Due to the stratification of our major depressive disorder patient sample according to different levels of suicidality, we identified some socio-demographic, psychosocial, and clinical variables differentiating from the patient group without suicidality already in presence of mild/moderate suicidality (depressive symptom severity, treatment resistance, psychotic features, add-on medications in general), whereas others separated only when severe suicidality was manifest (inpatient treatment, augmentation with antipsychotics and benzodiazepines, melancholic features, somatic comorbidities). Conclusions: As even mild/moderate suicidality is associated with a failure of achieving treatment response, adequate recognition of this condition should be ensured in the clinical practice., SCOPUS: ar.j, info:eu-repo/semantics/published

Due to lacking predictors of depression recovery, successful treatment of major depressive disorder (MDD) is frequently only achieved after therapeutic optimization leading to a prolonged suffering of patients. This study aimed to determine neural prognostic predictors identifying non-remitters prior or early after treatment initiation. Moreover, it intended to detect time-sensitive neural mediators indicating depression recovery. This longitudinal, interventional, single-arm, open-label, phase IV, pharmacological functional magnetic resonance imaging (fMRI) study comprised four scans at important stages prior (day 0) and after escitalopram treatment initiation (day 1, 28, and 56). Totally, 22 treatment-free MDD patients (age mean ± SD: 31.5 ± 7.7; females: 50%) suffering from a concurrent major depressive episode without any comorbid DSM-IV axis I diagnosis completed the study protocol. Primary outcome were neural prognostic predictors of depression recovery. Enhanced de-activation of anterior medial prefrontal cortex (amPFC, single neural mediator) indicated depression recovery correlating with MADRS score and working memory improvements. Strong dorsolateral PFC (dlPFC) activation and weak dlPFC-amPFC, dlPFC-posterior cingulate cortex (PCC), dlPFC-parietal lobe (PL) coupling (three prognostic predictors) hinted at depression recovery at day 0 and 1. Preresponse prediction of continuous (dlPFC-PL: R2day1 = 55.9%, 95% CI: 22.6–79%, P day1 = 0.91/0.82) recovery definitions remained significant after leave-one-out cross-validation. Identified prefrontal neural predictors might propel the future development of fMRI markers for clinical decision making, which could lead to increased response rates and adherence during acute phase treatment periods. Moreover, this study underscores the importance of the amPFC in depression recovery.

Objective: This multicenter, multinational, cross-sectional study aimed to investigate clinical characteristics and treatment outcomes associated with augmentation/combination treatment strategies in major depressive disorder (MDD). Method: Sociodemographic, clinical, and treatment features of 1410 adult MDD patients were compared between MDD patients treated with monotherapy and augmentation/combination medication using descriptive statistics, analyses of covariance (ancova), and Spearman's correlation analyses. Results: 60.64% of all participants received augmentation and/or combination strategies with a mean number of 2.18 ± 1.22 simultaneously prescribed psychiatric drugs. We found male gender, older age, Caucasian descent, higher weight, low educational status, absence of occupation, psychotic symptoms, melancholic and atypical features, suicide risk, in-patient treatment, longer duration of hospitalization, some psychiatric comorbidities (panic disorder, agoraphobia, obsessive-compulsive disorder, and bulimia nervosa), comorbid somatic comorbidity in general and concurrent hypertension, thyroid dysfunction, diabetes, and heart disease in particular, higher current and retrospective Montgomery and Åsberg Depression Rating Scale total scores, treatment resistance, and higher antidepressant dosing to be significantly associated with augmentation/combination treatment. These findings were corroborated when examining the number of concurrently administered psychiatric drugs in the statistical analyses. Conclusion: Our findings suggest a clear association between augmentation/combination strategies and treatment-resistant/difficult-to-treat MDD conditions characterized by severe symptomatology and high amount of psychiatric and somatic comorbidities., SCOPUS: ar.j, info:eu-repo/semantics/published

Objective The study objective was to generate a prediction model for treatment-resistant depression (TRD) using machine learning featuring a large set of 47 clinical and sociodemographic predictors of treatment outcome. Method 552 Patients diagnosed with major depressive disorder (MDD) according to DSM-IV criteria were enrolled between 2011 and 2016. TRD was defined as failure to reach response to antidepressant treatment, characterized by a Montgomery-Asberg Depression Rating Scale (MADRS) score below 22 after at least 2 antidepressant trials of adequate length and dosage were administered. RandomForest (RF) was used for predicting treatment outcome phenotypes in a 10-fold cross-validation. Results The full model with 47 predictors yielded an accuracy of 75.0%. When the number of predictors was reduced to 15, accuracies between 67.6% and 71.0% were attained for different test sets. The most informative predictors of treatment outcome were baseline MADRS score for the current episode; impairment of family, social, and work life; the timespan between first and last depressive episode; severity; suicidal risk; age; body mass index; and the number of lifetime depressive episodes as well as lifetime duration of hospitalization. Conclusions With the application of the machine learning algorithm RF, an efficient prediction model with an accuracy of 75.0% for forecasting treatment outcome could be generated, thus surpassing the predictive capabilities of clinical evaluation. We also supply a simplified algorithm of 15 easily collected clinical and sociodemographic predictors that can be obtained within approximately 10 minutes, which reached an accuracy of 70.6%. Thus, we are confident that our model will be validated within other samples to advance an accurate prediction model fit for clinical usage in TRD.

Background This cross-sectional European multicenter study examined the association between major depressive disorder (MDD) and comorbid obsessive-compulsive disorder (OCD). Methods Socio-demographic, clinical, and treatment features of 1346 adult MDD patients were compared between MDD subjects with and without concurrent OCD using descriptive statistics, analyses of covariance (ANCOVA), and binary logistic regression analyses. Results We determined a point prevalence of comorbid OCD in MDD of 1.65%. In comparison to the MDD control group without concurrent OCD, a higher proportion of patients in the MDD + comorbid OCD group displayed concurrent panic disorder (31.81% vs 7.77%, p

Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecular mechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice. New insights into the neurobiology of TRD have shed light on the role of a number of different mechanisms, including the glutamatergic system, immune/inflammatory systems, neurotrophin function, and epigenetics. Advances in drug discovery processes in TRD have also influenced the classification of antidepressant drugs and novel classifications are available, such as the neuroscience-based nomenclature that can incorporate such advances in drug development for TRD. This review aims to provide an up-to-date description of key mechanisms in TRD and describe current therapeutic strategies for TRD before examining novel approaches that may ultimately address important neurobiological mechanisms not targeted by currently available antidepressants. All in all, we suggest that drug targeting different neurobiological systems should be able to restore normal function but must also promote resilience to reduce the long-term vulnerability to recurrent depressive episodes.

This multicenter study of the European Group for the Study of Resistant Depression (GSRD) aimed to explore the association between major depressive disorder (MDD) and comorbid thyroid disease. A total number of 1410 patients` characteristics in terms of demographic and clinical information were compared between MDD subjects with and without concurrent thyroid disease using descriptive statistics, analyses of covariance (ANCOVA) and binary logistic regression analyses. We determined a point prevalence rate for comorbid hypothyroidism of 13.2% and 1.6% for comorbid hyperthyroidism respectively. Patients with MDD+comorbid hypothyroidism were significantly older, more likely to be female, inpatient and suffering from other comorbid chronic somatic conditions. Furthermore, MADRS score at onset of the current depressive episode was significantly higher, psychotic features of depression were more likely pronounced. Overall, patients in the MDD+comorbid hypothyroidism group were rather treated with a combination of drugs, for example, pregabalin, antipsychotic drugs and mood stabilizers. In the MDD+comorbid hyperthyroidism group patients were significantly older, of Caucasian origin and diagnosed with other somatic comorbidities. In conclusion, our analyses suggest that abnormal thyroid function, especially hypothyroidism, is linked to depression severity and associated with distinct psychopathologic features of depression. However, comorbid thyroid disease has no influence on treatment response. A combination or augmentation of psychopharmacological drugs, especially with antipsychotics, mood stabilizers and pregabalin is more likely in patients with hypothyroid conditions. Thyroid disorder is frequently found in combination with other chronic somatic diseases including hypertension and heart disease.

Objectives There is evidence for a bipolar diathesis in postpartum depression (PPD) and women presenting with a first PPD frequently receive a diagnosis of bipolar type II disorder (BD-II). However formal evidence for an association between BD-II and PPD has not yet been reported. In the present study we tested a potential association between BD-II and PPD. Methods Parous women with a diagnosis of bipolar type I disorder (BD-I) (n=93), BD-II (n=36) or major depressive disorder (MDD) (n=444) were considered in the present study. All women were retrospectively evaluated for history of PPD (DSM-IV criteria) and other clinical and socio-demographic features. Results Women with a history of PDD (n=139, 24%) were younger, younger at illness onset and had more family history for BD compared to women without history of PPD (n=436, 75.9%). Half of BD-II women reported PPD (50%), compared to less than one-third of BD-I and MDD women (respectively 27.5% and 21.6%) (p=0.004). Limitations Limitations include the retrospective assessment of PPD and no available data about the timing of postpartum episodes, illness onset or psychiatric care before or after childbirth, and the number of postpartum episodes. Conclusions BD-II may confer a remarkable risk for PPD, which may be even higher than that of women affected by BD-I disorder. Careful monitoring of BD-II women during the pregnancy and postpartum period, as well as assessment of bipolar features in women with a PPD without a current diagnosis of BD are recommended.

This multicenter, cross-sectional study with retrospective assessment of treatment response evaluated the current prescription trends and pharmacological treatment strategies applied in European university/academic psychiatric centers in unipolar depression. Altogether, 1181 adult in- and outpatients with major depressive disorder (MDD) were enrolled in 9 academic sites in 8 European countries. Socio-demographic, clinical, and medication information were retrieved and the present symptom severity was assessed by the Montgomery and Asberg Depression Rating Scale (MADRS). The symptom improvement during the current MDD episode was covered by retrospective MADRS measurements. Beyond descriptive statistics, analyses of variance (ANOVA) and Spearman correlation analyses were accomplished to determine the influence of symptom severity and treatment response on the prescription patterns. 53.4% of all MDD patients received a selective serotonin reuptake inhibitor (SSRI) and 23.6% a serotonin–norepinephrine reuptake inhibitor (SNRI) as first-line treatment. The majority of participants (59.4%) were treated with polypharmaceutical strategies (median: 2 psychiatric compounds per patient) and for the number of individual drugs we found a significant correlation with the current MADRS total score and the MADRS total score change during the present depressive episode. Benzodiazepines (33.2% of patients), antidepressants (29.0%), antipsychotics (24.2%), and mood stabilizers (10.1%) were the most frequently prescribed adjunctive agents. There were no significant differences between the different psychopharmacological classes used as augmentors in terms of symptom severity and treatment response. In summary, this international cross-sectional study revealed the widespread use of polypharmaceutical treatment strategies in European tertiary psychiatric treatment centers for the management of MDD.