The clinical perspective on late-onset depression in European real-world treatment settings.

The clinical phenotype of the so-called late-onset depression (LOD) affecting up to 30% of older adults and yielding heterogeneous manifestations concerning symptoms, severity and course has not been fully elucidated yet. This European, cross-sectional, non-interventional, naturalistic multicenter study systematically investigated socio-demographic and clinical correlates of early-onset depression (EOD) and LOD (age of onset ≥ 50 years) in 1410 adult in- and outpatients of both sexes receiving adequate psychopharmacotherapy. In a total of 1329 patients (94.3%) with known age of disease onset, LOD was identified in 23.2% and was associated with unemployment, an ongoing relationship, single major depressive episodes, lower current suicidal risk and higher occurrence of comorbid hypertension. In contrast, EOD was related to higher rates of comorbid migraine and additional psychotherapy. Although the applied study design does not allow to draw any causal conclusions, the present results reflect broad clinical settings and emphasize easily obtainable features which might be characteristic for EOD and LOD. A thoughtful consideration of age of onset might, hence, contribute to optimized diagnostic and therapeutic processes in terms of the globally intended precision medicine, ideally enabling early and adequate treatment allocations and implementation of respective prevention programs.

Baseline symptom severity and efficacy of Silexan in patients with anxiety disorders: A symptom-based, patient-level analysis of randomized, placebo-controlled trials.

The influence of baseline severity on the efficacy of Silexan, a proprietary essential oil from Lavandula angustifolia, in anxiety disorders has not been investigated in a pooled dataset. We report on an individual patient data analysis of all five double-blind, randomized, placebo-controlled trials with Silexan in anxiety disorders. Eligible participants received Silexan 80 mg/d or placebo for 10 weeks. Analyses were based on the Hamilton Anxiety Rating Scale (HAMA), its psychic and somatic anxiety subscores, and the Clinical Global Impressions (CGI) scale. To correlate baseline severity with outcome, patients were segregated into mild, moderate, and severe cases. Altogether 1,172 patients (Silexan, n = 587; placebo, n = 585) were analyzed. For the HAMA total score, we found a significant association between the score at baseline and the treatment effect of Silexan versus placebo at week 10 (p < 0.001). HAMA items from the somatic domain scored lower at baseline and showed less improvement than items from the psychic domain, particularly in patients with mild or moderate baseline symptoms. For CGI item 2 (global improvement), significant efficacy favoring Silexan were observed in mild, moderate, and severe baseline symptom severity. Although significant improvements were found for all subsets, the more severe the initial symptoms, the greater the treatment effects documented by the HAMA. Overall this analysis confirms that Silexan is an effective treatment option in early or mild stages of anxiety disorder. Given its favorable safety profile, Silexan can thus fill a therapeutic gap in the treatment of (subsyndromal) anxiety disorders.

Age as a moderating factor of treatment resistance in depression.

BACKGROUND: Treatment-resistant depression (TRD) is an important clinical challenge and may present differently between age groups. METHODS: A total of 893 depressed patients recruited within the framework of the European research consortium "Group for the Studies of Resistant Depression" were assessed by generalized linear models regarding age effects (both as numerical and factorial predictors) on treatment outcome, number of lifetime depressive episodes, hospitalization time, and duration of the current episode. Effects of age as numerical predictor on the severity of common depressive symptoms, measured with Montgomery-Åsberg Depression Rating Scale (MADRS) for two-time points, were assessed by linear mixed models, respectively, for patients showing TRD and treatment response. A corrected p threshold of 0.001 was applied. RESULTS: Overall symptom load reflected by MADRS (p < 0.0001) and lifetime hospitalization time (p < 0.0001) increased with age in TRD patients but not treatment responders. In TRD, higher age was predicting symptom severity of inner tension, reduced appetite, concentrations difficulties, and lassitude (all p ≤ 0.001). Regarding clinical significance, older TRD patients were more likely to report severe symptoms (item score > 4) for these items both before and after treatment (all p ≤ 0.001). CONCLUSIONS: In this naturalistic sample of severely ill depressed patients, antidepressant treatment protocols were equally effective in addressing TRD in old age. However, specific symptoms such as sadness, appetite, and concentration showed an age-dependent presentation, impacting residual symptoms in severely affected TRD patients and calling for a precision approach by a better integration of age profiles in treatment recommendations.

Real-world characteristics of European patients receiving SNRIs as first-line treatment for major depressive disorder.

BACKGROUND: Serotonin-norepinephrine reuptake inhibitors (SNRIs) are among the most frequently prescribed antidepressants (ADs) for major depressive disorder (MDD), with an increasing trend in the last decade. Given the relative dearth of information regarding rationales for their preferred use as first-line ADs in the broad clinical routine, the present study systematically investigated real-world characteristics of MDD patients prescribed either SNRIs or other AD substances across different countries and treatment settings. METHODS: In the present secondary analyses based on a large European, multi-site, naturalistic and cross-sectional investigation with a retrospective assessment of treatment outcome, we firstly defined the proportion of MDD patients receiving SNRIs as first-line AD psychopharmacotherapy and secondly compared their sociodemographic and clinical characteristics to those patients prescribed alternative first-line ADs during their current major depressive episode (MDE). RESULTS: Within the total sample of 1410 MDD patients, 336 (23.8 %) received first-line SNRIs. Compared to other ADs, SNRIs were significantly associated with inpatient care, suicidality and treatment resistance during the current MDE, and a longer lifetime duration of psychiatric hospitalizations. Moreover, greater severity of depressive symptoms at study entry, higher daily doses of the administered ADs, as well as more frequent prescriptions of psychopharmacotherapeutic add-on strategies in general and antipsychotic augmentation in particular, were significantly related to first-line SNRIs. CONCLUSIONS: Considering the limitations of a cross-sectional and retrospective study design, our data point towards a preferred use of first-line SNRIs in a generally more severely ill MDD patients, although they did not lead to superior treatment outcomes compared to alternative ADs.

Efficacy of Silexan in patients with anxiety disorders: a meta-analysis of randomized, placebo-controlled trials.

INTRODUCTION: We report on a meta-analysis of Silexan, a proprietary active substance produced from Lavandula angustifolia, in subthreshold anxiety, mixed anxiety and depressive disorder (MADD), and generalized anxiety disorder (GAD). METHODS: The present analyses are based on all currently completed 5 double-blind, randomized, placebo-controlled trials investigating Silexan in adult out-patients who received Silexan 1 × 80 mg/day or placebo for ten weeks according to random assignment (n = 1213). Efficacy was assessed based on the Hamilton Anxiety Rating Scale (HAMA), several anxiety self-rating scales, the Clinical Global Impression (CGI) scale, and the Short Form-36 (SF-36) health status questionnaire. RESULTS: After ten weeks' treatment, Silexan was significantly superior to placebo in reducing the HAMA total score (including the psychic and somatic anxiety sub-scores) and self-rated anxiety. Based on a ≥ 50% HAMA total score reduction, the responder rate ratio was 1.34 favoring Silexan, and the rate ratio of subjects much or very much improved according to the CGI was 1.51. Silexan was also significantly superior in improving the physical and mental health summary scores of the SF-36. There were no significant between-group differences concerning the occurrence of adverse events (AEs), serious AEs, and premature withdrawal due to AEs. CONCLUSIONS: This meta-analysis demonstrates that Silexan exerts significant anxiolytic effects in subthreshold anxiety, GAD and MADD that were consistently reflected in investigator ratings and patient-reported outcomes, including improvement of health-related life-quality, while showing favorable tolerability and safety.

Beneficial effects of Silexan on co-occurring depressive symptoms in patients with subthreshold anxiety and anxiety disorders: randomized, placebo-controlled trials revisited.

Silexan is a proprietary active substance produced from Lavandula angustifolia, with proven anxiolytic efficacy in subthreshold and generalized anxiety disorder as well as in mixed anxiety and depressive disorder with beneficial impact on anxiety-related sleep disturbances. The pharmacological profile and clinical observations suggest that Silexan may also have an antidepressant effect. To investigate the effect of Silexan on co-occurring depressive symptoms, we present a meta-analysis of the five placebo-controlled clinical trials hitherto performed with Silexan in subthreshold anxiety (n = 3) and anxiety disorders (n = 2). Patients of all trials received Silexan 1 × 80 mg/day or placebo for 10 weeks according to random assignment. Assessment of the antidepressant effect was based on item 'depressed mood' from the Hamilton Anxiety Rating Scale (HAMA) administered in all trials and on the total scores of the Montgomery Åsberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAMD) used in three trials. After 10-week treatment, patients receiving Silexan showed significantly more pronounced score reduction for HAMA item 'depressed mood' than those in the placebo group (p = 0.01). Significant superiority of Silexan over placebo could also be shown for mean MADRS or HAMD total score reduction (three studies; p < 0.01). Silexan-treated patients with more severe depressive symptoms at baseline showed more pronounced improvements than those with milder symptoms. Our meta-analysis clearly shows that Silexan has a beneficial effect on co-occurring depressive symptoms in patients with subthreshold anxiety and anxiety disorders and may, hence, lead to important therapeutic implications for depressive disorders.

The sociodemographic and clinical profile of patients with major depressive disorder receiving SSRIs as first-line antidepressant treatment in European countries.

INTRODUCTION: Due to favorable antidepressant (AD) efficacy and tolerability, selective-serotonin reuptake inhibitors (SSRIs) are consistently recommended as substances of first choice for the treatment of major depressive disorder (MDD) in international guidelines. However, little is known about the real-world clinical correlates of patients primarily prescribed SSRIs in contrast to those receiving alternative first-line ADs. METHODS: These secondary analyses are based on a naturalistic, multinational cross-sectional study conducted by the European Group for the Study of Resistant Depression at ten research sites. We compared the socio-demographic and clinical characteristics of 1410 patients with primary MDD, who were either prescribed SSRIs or alternative substances as first-line AD treatment, using chi-squared tests, analyses of covariance, and logistic regression analyses. RESULTS: SSRIs were prescribed in 52.1% of MDD patients who showed lower odds for unemployment, current severity of depressive symptoms, melancholic features, suicidality, as well as current inpatient treatment compared to patients receiving alternative first-line ADs. Furthermore, patients prescribed SSRIs less likely received add-on therapies including AD combination and augmentation with antipsychotics, and exhibited a trend towards higher response rates. CONCLUSION: A more favorable socio-demographic and clinical profile associated with SSRIs in contrast to alternative first-line ADs may have guided European psychiatrists' treatment choice for SSRIs, rather than any relevant pharmacological differences in mechanisms of action of the investigated ADs. Our results must be cautiously interpreted in light of predictable biases resulting from the open treatment selection, the possible allocation of less severely ill patients to SSRIs as well as the cross-sectional study design that does not allow to ascertain any causal conclusions.

Pregabalin augmentation of antidepressants in major depression - results from a European multicenter study.

BACKGROUND: We aimed to investigate the prescription pattern of pregabalin augmentation of antidepressants in major depressive disorder (MDD) and to explore variables associated with add-on pregabalin treatment. METHODS: 1410 MDD patients participated in this naturalistic European multicenter study with retrospective assessment of treatment response. Analyses of covariance, chi-squared tests, and binary logistic regressions were accomplished to determine differences in socio-demographic and clinical characteristics between MDD patients with and without pregabalin augmentation. RESULTS: Add-on pregabalin was established in 102 (7.23%) MDD patients. Compared to those without receiving pregabalin, pregabalin-treated patients were characterized by a significantly higher likelihood for older age (mean: 54.74 ± 13.08 vs 49.93 ± 14.13 years), unemployment (78.43% vs 51.23%), melancholic features (83.33% vs 58.94%), inpatient treatment (72.55% vs 31.65%), previous psychiatric hospitalizations (13.52 ± 24.82 vs 4.96 ± 19.93 weeks), any somatic comorbidity (68.63% vs 44.57%), comorbid hypertension (37.25% vs 17.51%), more severe depressive symptom severity at the onset of the current episode (mean MADRS: 37.55 ± 9.00 vs 33.79 ± 7.52), receiving augmentation/combination treatment strategies in general (mean number of psychotropic drugs: 3.64 ± 0.92 vs 2.07 ± 1.17), and with antidepressants (50.00% vs 27.91%) and antipsychotics (46.08% vs 24.08%) in particular. LIMITATIONS: Due to its observational cross-sectional study design, our patient sample might not be fully representative for MDD patients in primary care settings. CONCLUSIONS: Our findings suggest that add-on pregabalin is particularly administered in more severe/difficult-to-treat MDD conditions, whereas no association between the prescription of adjunctive pregabalin and comorbid anxiety symptoms could be determined.

The Choice of Either Quetiapine or Aripiprazole as Augmentation Treatment in a European Naturalistic Sample of Patients With Major Depressive Disorder.

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.

Evidence on sociodemographic and clinical correlates of antidepressant combination or augmentation with second-generation antipsychotics in major depressive disorder.

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.

Combining psychopharmacotherapy and psychotherapy is not associated with better treatment outcome in major depressive disorder - evidence from the European Group for the Study of Resistant Depression.

Despite plenty of effective antidepressant (AD) treatments, the outcome of major depressive disorder (MDD) is often unsatisfactory, probably due to improvable exploitation of available therapies. This European, cross-sectional, naturalistic multicenter study investigated the frequency of additional psychotherapy in terms of a manual-driven psychotherapy (MDP) in 1410 adult in- and outpatients with MDD, who were primarily treated with AD psychopharmacotherapy. Socio-demographic and clinical patterns were compared between patients receiving both treatments and those lacking concomitant MDP. In a total of 1279 MDD patients (90.7%) with known status of additional MDP, those undergoing a psychopharmacotherapy-MDP combination (31.2%) were younger, higher educated, more often employed and less severely ill with lower odds for suicidality as compared to patients receiving exclusively psychopharmacotherapy (68.8%). They experienced an earlier mean age of MDD onset, melancholic features, comorbid asthma and migraine and received lower daily doses of their first-line ADs. While agomelatine was more often established in these patients, MDD patients without MDP received selective serotonin reuptake inhibitors more frequently. These two patient groups did not differ in terms of response, non-response and treatment resistant depression (TRD). Accordingly, the employment of additional MDP could not be related to better treatment outcomes in MDD. The fact that MDP was applied in a minority of patients with rather beneficial socio-demographic and clinical characteristics might reflect inferior accessibility of these psychotherapeutic techniques for socially and economically disadvantaged populations.

Sex-related effects in major depressive disorder: Results of the European Group for the Study of Resistant Depression.

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 noradrenergic and 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 male and 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.

The Role of Relationship Status in Major Depressive Disorder - Results of the European Group for the Study of Resistant Depression.

BACKGROUND: While the association between relationship status and the development of depressive symptoms in the general population were reported previously, its relation to the severity and the course of major depressive disorder (MDD) as well as the treatment patterns and response rates needs to be elucidated. METHODS: The present international multicenter cross-sectional study performed by the European Group for the Study of Resistant Depression (GSRD) investigated socio-demographic and clinical patterns of relationship status in a real-world sample of 1410 adult in- and outpatients with MDD as primary diagnosis. RESULTS: While 49.9% of all MDD patients were partnered, 25.4% were separated, and 24.8% were single. Single relationship status was linked to younger mean age, earlier mean age of onset, and current suicidal risk. Being separated was related to older mean age, unemployment, greater symptom severity, current suicidal risk, and add-on treatment strategies. Partnered relationship status was associated with less frequent current suicidal risk. LIMITATIONS: The retrospective assessment of treatment response that was exclusively based on psychopharmacotherapeutic strategies should be critically considered and weighed while interpreting the present results providing novel insights into the complex interaction of relationship status with the clinical phenotype of MDD. CONCLUSIONS: Although MDD patients living in relationships do not seem to be omitted from the evolution of MDD, they may be spared from chronicity and suicidality. Hence, being aware of the current relationship status might support clinicians in the diagnostic and therapeutic process towards optimized management of such challenging clinical phenomena and their negative consequences.

Melancholic features in major depression - a European multicenter study.

There is still a debate, if melancholic symptoms can be seen rather as a more severe subtype of major depressive disorder (MDD) or as a separate diagnostic entity. The present European multicenter study comprising altogether 1410 MDD in- and outpatients sought to investigate the influence of the presence of melancholic features in MDD patients. Analyses of covariance, chi-squared tests, and binary logistic regression analyses were accomplished to determine differences in socio-demographic and clinical variables between MDD patients with and without melancholia. We found a prevalence rate of 60.71% for melancholic features in MDD. Compared to non-melancholic MDD patients, they were characterized by a significantly higher likelihood for higher weight, unemployment, psychotic features, suicide risk, inpatient treatment, severe depressive symptoms, receiving add-on medication strategies in general, and adjunctive treatment with antidepressants, antipsychotics, benzodiazepine (BZD)/BZD-like drugs, low-potency antipsychotics, and pregabalin in particular. With regard to the antidepressant pharmacotherapy, we found a less frequent prescription of selective serotonin reuptake inhibitors (SSRIs) in melancholic MDD. No significant between-group differences were found for treatment response, non-response, and resistance. In summary, we explored primarily variables to be associated with melancholia which can be regarded as parameters for the presence of severe/difficult-to treat MDD conditions. Even if there is no evidence to realize any specific treatment strategy in melancholic MDD patients, their prescribed medication strategies were different from those for patients without melancholia.

Reducing antipsychotic drugs in stable patients with chronic schizophrenia or schizoaffective disorder: a randomized controlled pilot trial.

As the course of schizophrenic disorders is often chronic, treatment guidelines recommend continuous maintenance treatment to prevent relapses, but antipsychotic drugs can cause many side effects. It, therefore, seems reasonable to try to reduce doses in stable phases of the illness or even try to stop medication. We conducted a 26 weeks, randomized, rater blind, feasibility study to examine individualized antipsychotic dose reduction versus continuous maintenance treatment (Register Number: NCT02307396). We included chronic, adult patients with schizophrenia or schizoaffective disorder, who were treated with any antipsychotic drug except clozapine, who had not been hospitalized in the last 3 years and who were in symptomatic remission at baseline. The primary outcome was relapse of positive symptoms. Symptom severity, social functioning and side effects were also examined as secondary outcomes. 20 patients were randomized. Relapse rates in the two groups were not significantly different. No patient had to be hospitalized. One patient in the control group dropped out. The mean reduction of antipsychotic dose in the individualized dose-reduction group was 42%, however only one patient discontinued drug completely. There were no significant differences in efficacy or safety outcomes. This randomized trial provides evidence, that reduction of antipsychotic medication in chronic stable schizophrenic patients may be feasible. The results need to be confirmed in a larger trial with a longer follow-up period.

Combining machine learning algorithms for prediction of antidepressant treatment response.

OBJECTIVES: Predictors for unfavorable treatment outcome in major depressive disorder (MDD) applicable for treatment selection are still lacking. The database of a longitudinal multicenter study on 1079 acutely depressed patients, performed by the German research network on depression (GRND), allows supervised and unsupervised learning to further elucidate the interplay of clinical and psycho-sociodemographic variables and their predictive impact on treatment outcome phenotypes. EXPERIMENTAL PROCEDURES: Treatment response was defined by a change of HAM-D 17-item baseline score ≥50% and remission by the established threshold of ≤7, respectively, after up to eight weeks of inpatient treatment. After hierarchical symptom clustering and stratification by treatment subtypes (serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotic, and lithium augmentation), prediction models for different outcome phenotypes were computed with random forest in a cross-center validation design. In total, 88 predictors were implemented. RESULTS: Clustering revealed four distinct HAM-D subscores related to emotional, anxious, sleep, and appetite symptoms, respectively. After feature selection, classification models reached moderate to high accuracies up to 0.85. Highest accuracies were observed for the SSRI and TCA subgroups and for sleep and appetite symptoms, while anxious symptoms showed poor predictability. CONCLUSION: Our results support a decisive role for machine learning in the management of antidepressant treatment. Treatment- and symptom-specific algorithms may increase accuracies by reducing heterogeneity. Especially, predictors related to duration of illness, baseline depression severity, anxiety and somatic symptoms, and personality traits moderate treatment success. However, prospectives application of machine learning models will be necessary to prove their value for the clinic.