One-year follow-up of a randomized controlled trial of sertraline and cognitive behavior group therapy in depressed primary care patients (MIND study).

BACKGROUND: The long-term course of symptoms in patients with mild-to-moderate depression is not well understood. A 12-month-follow-up analysis was performed on those participants from a randomized controlled 10-week trial (RCT, MIND-study), who had received either treatment with an antidepressant (sertraline) or a psychotherapeutic intervention (group cognitive-behavioral therapy (CBT)). METHODS: The longitudinal interval follow-up evaluation (LIFE) was applied to 77 patients with mild-to moderate depression. The primary outcome was the number of weeks in the one-year follow-up period spent completely recovered from all depressive symptoms. Functional outcome was measured with the Global Assessment of Functioning (GAF) scale. Further outcomes were relapse and remission rates based on weekly psychiatric rating scales (PSR) and the number of weeks in the follow-up period during which patients had a depressive disorder or subthreshold symptoms of depression. RESULTS: Patients with acute treatment (10 weeks) with SSRI and those with acute treatment with CBT (also 10 weeks) did not differ significantly concerning the number of weeks in the follow-up period in which they were completely recovered (primary outcome) (SSRI: 31.6 weeks (standard deviation (SD): 23.7), CBT: 27.8 weeks (SD: 24.3)). Sertraline was superior to CBT regarding GAF scores by trend (p = 0.06). LIMITATIONS: The generalizability of the findings is limited by the moderate sample size and missing values (LIFE). CONCLUSIONS: Sertraline and group CBT have similar anti-depressive effects in the long-term course of mild-to-moderate depression. Regarding long-term global functioning, sertraline seems to be slightly superior to CBT.

Study design features affecting outcome in antidepressant trials.

BACKGROUND: A key issue in the approval process of antidepressants is the inconsistency of results between antidepressant clinical phase III trials. Identifying factors influencing efficacy data is needed to facilitate interpretation of the results. METHODS: We reviewed data packages submitted as new drug applications to Swissmedic focusing on pivotal, short-term antidepressant trials. Included studies used HAMD-17 or HAMD-21 as primary measures and enrolled patients aged 18-65 years with a diagnosis of major depression. Due to the hierarchical structure of the data a mixed-effect regression model has been applied with responder rates as primary outcome criterion. Random intercepts were estimated for the different trials, while study design factors were assigned as explanatory fixed effects. RESULTS: The final dataset was based upon 35 study reports with a total of N=10,835 patients. Significant results were found for study arm (placebo vs. active compound, p<0.001), sample size (p=0.002), duration of treatment (p=0.024), two or more active treatment arms (p=0.022) and the individual drug (p=0.029). Furthermore, a tendency to an association with the outcome was observed for baseline disease severity (p=0.077) and possibility of dosing adaptation (p=0.076). LIMITATIONS: Due to strict confidentiality agreements, individual drugs are not reported here. Further research should consider additional variables that might have an impact on the results of antidepressant trials. CONCLUSIONS: Efficacy data in antidepressant trials is significantly affected by various factors. These factors and their potentially confounding role have to be considered in the interpretation of the results.

Can effects of antidepressants in patients with mild depression be considered as clinically significant?

BACKGROUND: How to define clinical significance of antidepressants has become a matter of far-reaching clinical and regulatory consequences. A mean difference of at least 3 points on the Hamilton Depression Rating Scale (HAMD-17) between active treatment and placebo has been proposed as cut-off score for clinical significance in antidepressant trials. OBJECTIVE: We aimed to present arguments that this, and other commonly used related approaches to establish clinical significance are likely to be misleading and risky depriving patients with mild depression of efficient treatments. METHODS: These problems are exemplified with the data from a randomized placebo-controlled five-arm clinical trial with primary care patients with milder depressive syndromes (MIND-study). RESULTS AND CONCLUSIONS: Designs for studying clinical significance have to be distinguished from those assessing efficacy. Moreover, evaluation of the clinical significance of psychotherapy as a possible alternative to antidepressants faces the problem of how to define a valid control group where blinding of neither therapists nor patients is possible.

Sensitivity to changes during antidepressant treatment: a comparison of unidimensional subscales of the Inventory of Depressive Symptomatology (IDS-C) and the Hamilton Depression Rating Scale (HAMD) in patients with mild major, minor or subsyndromal depression.

In the efficacy evaluation of antidepressant treatments, the total score of the Hamilton Depression Rating Scale (HAMD) is still regarded as the 'gold standard'. We previously had shown that the Inventory of Depressive Symptomatology (IDS) was more sensitive to detect depressive symptom changes than the HAMD17 (Helmreich et al. 2011). Furthermore, studies suggest that the unidimensional subscales of the HAMD, which capture the core depressive symptoms, outperform the full HAMD regarding the detection of antidepressant treatment effects. The aim of the present study was to compare several unidimensional subscales of the HAMD and the IDS regarding their sensitivity to changes in depression symptoms in a sample of patients with mild major, minor or subsyndromal depression (MIND). Biweekly IDS-C28 and HAMD17 data from 287 patients of a 10-week randomised, placebo-controlled trial comparing the effectiveness of sertraline and cognitive-behavioural group therapy in patients with MIND were converted to subscale scores and analysed during the antidepressant treatment course. We investigated sensitivity to depressive change for all scales from assessment-to-assessment, in relation to depression severity level and placebo-verum differences. The subscales performed similarly during the treatment course, with slight advantages for some subscales in detecting treatment effects depending on the treatment modality and on the items included. Most changes in depressive symptomatology were detected by the IDS short scale, but regarding the effect sizes, it performed worse than most subscales. Unidimensional subscales are a time- and cost-saving option in judging drug therapy outcomes, especially in antidepressant treatment efficacy studies. However, subscales do not cover all facets of depression (e.g. atypical symptoms, sleep disturbances), which might be important for comprehensively understanding the nature of the disease depression. Therefore, the cost-to-benefit ratio must be carefully assessed in the decision for using unidimensional subscales.

Clinical predictors of response and remission in inpatients with depressive syndromes.

BACKGROUND: Most predictor analyses search for single predictors or rely on data from randomized controlled trials. We aimed at detecting a set of clinical baseline variables for prediction of response and remission in 1014 naturalistically treated inpatients with major depressive episode treated for 53.62 ± 47.5 days. METHODS: A three-staged procedure was implemented. First, univariate tests were used for finding associations with baseline variables. Second, logistic regression and third-CART analyses were used to determine predictors of response to inpatient treatment. RESULTS: Presence of suicidality, a higher initial HAMD-21 total score, an episode length <24 months, fewer previous hospitalizations, and absence of any ICD-10F4 comorbidity predicted response in 2 different statistical models. Remission was predicted by lower HAMD-21 baseline score, episode length <24 months and fewer previous hospitalizations in both models. LIMITATION: Results were assessed by a post-hoc analysis, based on prospectively collected data. No controlled study design. CONCLUSION: Contrary to current beliefs, baseline suicidality might be associated with higher chances for response. In addition, baseline severity might impact outcome depending on which criterion (remission or response) used.

Are treatment preferences relevant in response to serotonergic antidepressants and cognitive-behavioral therapy in depressed primary care patients? Results from a randomized controlled trial including a patients' choice arm.

BACKGROUND: Little is known about the influence of depressed patients' preferences and expectations about treatments upon treatment outcome. We investigated whether better clinical outcome in depressed primary care patients is associated with receiving their preferred treatment. METHODS: Within a randomized placebo-controlled single-centre 10-week trial with 5 arms (sertraline; placebo; cognitive-behavioral group therapy, CBT-G; moderated self-help group control; treatment with sertraline or CBT-G according to patients' choice), outcomes for 145 primary care patients with mild-to-moderate depressive disorders according to DSM-IV criteria were investigated. Preference for medication versus psychotherapy was assessed at screening using a single item. Post-baseline difference scores for the Hamilton Depression Rating Scale (HAMD-17) were used to assess treatment outcome (mixed-model repeated-measures regression analysis). RESULTS: Depressed patients receiving their preferred treatment (n = 63), whether sertraline or CBT-G, responded significantly better than those who did not receive their preferred therapy (n = 54; p = 0.001). The difference in outcome between both groups was 8.0 points on the HAMD-17 for psychotherapy and 2.9 points on the HAMD-17 for treatment with antidepressants. Results were not explained by differences in depression severity or dropout rates. CONCLUSIONS: Patients' relative preference for medication versus psychotherapy should be considered when offering a treatment because receiving the preferred treatment conveys an additional and clinically relevant benefit (HAMD-17: +2.9 points for drugs; +8.0 points for CBT-G) in outcome.

The Inventory Of Depressive Symptomatology (IDS-C(28)) is more sensitive to changes in depressive symptomatology than the Hamilton Depression Rating Scale (HAMD(17)) in patients with mild major, minor or subsyndromal depression.

Depression rating scales play a decisive role in the assessment of the severity of depression and the evaluation of the efficacy of antidepressant treatments. The Hamilton Depression Rating Scale (HAMD) is regarded as the 'gold standard'; nevertheless, studies suggest that the Inventory of Depressive Symptomatology (IDS) is more sensitive to detect symptom changes. The aim of the present study was to investigate whether the IDS is more sensitive in detecting changes in depression symptoms in patients with mild major, minor or subsyndromal depression (MIND). Biweekly IDS-C(28) and HAMD(17) data from 340 patients of a 10-week randomized, placebo-controlled trial comparing the effectiveness of sertraline and cognitive-behavioural therapy in patients with MIND were analysed. We investigated sensitivity to change for both scales (1) from assessment-to-assessment, (2) in relation to depression severity level, and (3) in relation to DSM-IV depression criterion symptoms. The IDS-C(28) was more sensitive in detecting changes in depression symptomatology over the treatment course as well as for different severity levels, especially in patients with a low depression severity. It assesses the DSM-IV criteria more thoroughly, is better able to track the change of cognitive symptoms and to identify residual symptoms. Both scales are well able to assess depressive symptomatology. However, the IDS-C(28) surpasses the HAMD(17) in detecting small changes especially in the core symptoms of depression. This is important for an optimal treatment by capturing early improvements, enabling prompt reactions and detecting residual symptoms.

Do efficacy and effectiveness samples differ in antidepressant treatment outcome? An analysis of eligibility criteria in randomized controlled trials.

BACKGROUND: Because of strict inclusion and exclusion criteria, results drawn from placebo-controlled randomized antidepressant efficacy trials may not be transferable to real-world patients. METHOD: This study was performed from March 2000 to September 2005 as a prospective, multicenter follow-up. Patients were recruited from February 2000 to June 2005. All patients were hospitalized (N = 1,014) and met DSM-IV criteria for major depressive episode. Assessments with the 21-item Hamilton Depression Rating Scale were conducted biweekly until discharge. According to the most commonly applied exclusion criteria in randomized controlled antidepressant efficacy trials, patients were retrospectively divided into 2 groups: (1) patients not fulfilling exclusion criteria and therefore eligible for a randomized placebo-controlled trial, referred to as "efficacy sample," and (2) patients fulfilling at least 1 exclusion criterion, not being eligible for inclusion in an efficacy trial ("nonefficacy sample"). The efficacy sample was compared with the nonefficacy sample in terms of sociodemographic and clinical baseline variables and outcome measures, such as remission and response rates, 17-item Hamilton Depression Rating Scale mean scores, time to remission, and time to response. RESULTS: Significant differences were found, with the efficacy sample being older (P = .03) and being more often treated at a university hospital (P = .02). The efficacy sample demonstrated superior outcome only in significantly higher mean Global Assessment of Functioning scores at discharge (P = .03). There were no differences regarding remission (P = .68) and response (P = .06) rates, length of hospital stay (P = .49), 17-item Hamilton Depression Rating Scale total score at discharge (P = .13), or time to response (P = .39) or remission (P = .16). CONCLUSIONS: Both groups differed significantly in several baseline measures and final Global Assessment of Functioning scores but not in any other outcome measure. Challenging current beliefs, our findings show that results from efficacy antidepressant trials might be more generalizable than previously thought.

Predice la mejoría precoz inducida por los antidepresivos la respuesta/remisión? Análisis de los datos de un estudio naturalista en una muestra a gran escala de pacientes hospitalizados con depresión mayor / Does early improvement triggered by antidepressants predict response/remission? - Analysis of data from a naturalistic study on a large sample of inpatients with major depression

El inicio lento de acción de los antidepresivos y la elevada proporción de pacientes con una respuesta insuficiente, o no respondedores, son retos clínicos bien conocidos. Por esta razón, parece necesario identificar las variables predictoras de la respuesta e incluso, lo que es más importante, de la remisión. Se ha sugerido que la reducción de los síntomas depresivos en un estadio precoz del tratamiento antidepresivo podría predecir su resultado. El objetivo del presente estudio fue examinar si en un estudio naturalista a mayor escala, efectuado en una cohorte de pacientes hospitalizados con depresión mayor, se confirmaría esta hipótesis derivada de los ensayos aleatorizados y controlados (EAC), efectuados en pacientes ambulatorios. Los pacientes fueron tratados con diversos antidepresivos y medicación concomitante de acuerdo con el protocolo desarrollado a partir de las directrices clínicas basadas en la evidencia. Métodos La presente investigación fue un estudio naturalista prospectivo, a gran escala. Todos los pacientes (n=795) fueron hospitalizados y cumplían los criterios DSM-IV de depresión mayor de acuerdo con la structured clinical interview (SCID, ‘entrevista clínica estructurada’). Las evaluaciones se efectuaron cada 2 semanas. En dos visitas diferentes se examinaron diversas definiciones de mejoría precoz (reducción del 20, 25 y 30% en las puntuaciones totales basales obtenidas en la escala de depresión de Hamilton [HAMD-21]). Para las diferentes definiciones de mejoría precoz se calcularon la sensibilidad, especificidad y los valores predictivos. Se efectuaron análisis ROC (curva de eficacia diagnóstica), al igual que modelos de regresión logística. La respuesta se definió como una mejoría del 50% de la puntuación basal total obtenida en la escala HAMD-21 y la remisión como una puntuación ≤7 en el momento del alta. Además, se analizó el tiempo transcurrido hasta la respuesta calculando las estimaciones de supervivencia de Kaplan-Meier para la definición de la mejoría precoz «óptima» en comparación con ninguna. Se efectuaron análisis de subgrupo para examinar si los resultados eran homogéneos a través de los subgrupos de tratamiento. Resultados: El 48,8% de pacientes de la muestra del presente estudio manifestó remisión. La tasa de respuesta global fue del 79,6%. Una disminución del 20% en la puntuación basal total obtenida en la escala HAMD-21 en el día 14 proporcionó una sensibilidad del 75% y una especificidad del 59% para la predicción de la respuesta. Esta definición de mejoría precoz fue una variable predictora incluso más sensible de remisión (80%), con una especificidad limitada (43%). Un valor de la AUC de alrededor de 0,68 de la respuesta precoz (mejoría del 20%) indica una «predictividad» satisfactoria para ambos intervalos de tiempo examinados (día 14 y 28) y solo cambió ligeramente con los porcentajes más altos en la reducción de la puntuación (AUC=0,71 y 0,73, respectivamente). Más de un tercio (37%) de todos los pacientes que no habían mostrado mejoría en el día 14 seguían sin manifestarla en el curso tardío del tratamiento (casi la mitad de todos los pacientes [43%] en el día 28). Se obtuvieron resultados similares mediante los análisis de supervivencia de Kaplan-Meier. La prueba del log-rank reveló un tiempo significativamente más prolongado hasta la respuesta en pacientes sin mejoría precoz (p<0,0001). Limitaciones: Los resultados se evaluaron mediante un análisis post-hoc basado en datos obtenidos prospectivamente. Es preciso mencionar diversos problemas del diseño naturalista, en especial la ausencia de un grupo de control y que tan solo pudo considerarse un número limitado de factores de estratificación. Conclusión: Los resultados respaldan los hallazgos previos de que la mejoría precoz en las 2 primeras semanas puede predecir con una elevada sensibilidad la respuesta y la remisión posterior, incluso en pacientes hospitalizados que presentan una depresión más grave. Puesto que empleamos un diseño de estudio naturalista, los datos pueden considerarse la replicación de los resultados previos extraídos de los EAC en un contexto naturalista. Encontramos un efecto antidepresivo global que fue constante a través de los subgrupos de tratamiento con respecto a los valores de sensibilidad. No obstante, somos conscientes de la imposibilidad de los estudios sobre efectividad para extraer relaciones causales del tratamiento a partir de una estrategia no controlada. Sin embargo, es posible que la replicación de los estudios previos indique que durante el tratamiento, en caso de ausencia de mejoría precoz, puede acelerarse un cambio de fármaco (AU)

Background: Delayed onset of efficacy of antidepressants and a high proportion of depressed patients being poor or non-responders to antidepressants are well known clinical challenges. Therefore, it seems to be necessary to identify predictors for response and –even more important – for remission. It has been suggested that reduction of depressive symptoms at an early stage of antidepressant treatment may predict treatment outcome. Our objective was to test, if this hypothesis derived from randomized controlled studies (RCTs) in outpatients, would be confirmed in a large naturalistic study in a cohort of inpatients with major depression. Patients were treated with various antidepressants and co-medication according to the protocol based on evidence based clinical guidelines. Methods: This was a large naturalistic prospective study. All patients (N=795) were hospitalized and met DSM-IV criteria for major depression according to a structured clinical interview (SCID). Assessments were conducted biweekly. Several definitions of early improvement (20%, 25% and 30% reduction in HAMD-21 baseline total scores) at two different visits were tested. Sensitivity, specificity and predictive values were calculated for the different definitions of early improvement. ROC-analyses as score and remission as a score of ≤7 at discharge. Additionally, time to response was analyzed by computing Kaplan–Meier survival estimates for the "best" early improvement definition in comparison to non early improvement. Subgroup analyses were conducted to test whether the results were consistent across treatment subgroups. Results: In total, 48.8% of patients in our sample were remitters. The overall response rate was 79.6%. A 20% reduction of HAMD-21 total baseline score at Day 14 provided a sensitivity of 75% and a specificity of 59% for response prediction. This definition of early improvement was an even more sensitive predictor for remission (80%) with a limited specificity (43%). The AUC value of about 0.68 for early response (20% improvement) indicates good predictability for both time intervals tested (Day 14 and Day 28) and changed only marginally with increased percentages in score reduction (AUC=0.71 and 0.73, respectively). More than one third (37%) of all patients who had not improved at Day 14 showed not response in the later treatment course (this was the case for nearly half of all patients (43%) at Day 28). Similar results were obtained by Kaplan–Meier survival analyses. Log-rank test showed significantly longer time to response in patients with non-early improvement (pb0.0001). Limitations: Results were assessed by a post-hoc analysis based on prospectively collected data. Several caveats of a naturalistic design must be mentioned, especially there was no control group and only a limited number of stratification factors could be considered. Conclusion: The results support earlier findings that early improvement in the first two weeks may predict with high sensitivity later response and remission, even in hospitalized patients suffering from a more severe degree of depression. Since we used a naturalistic study design, the data may be considered as a replication of previous results drawn from RCTs in a naturalistic environment. We found a global antidepressant effect which was consistent across treatment subgroups regarding sensitivity values. However, we are aware of the inability of effectiveness studies to draw causal treatment relationships from the uncontrolled approach. Nevertheless, the replication of previous results might indicate that a drug switch during treatment in case of lack of early improvement could be accelerated (AU)

A 12-month-old boy with a localized verrucous tumor.

A 12-month-old boy was admitted suffering from a localized pad-like thickening of tissue affecting the area of his right hand joint. First affection of skin was detected at age of 6 months, when a red macula was noted. The parents were now afraid of a viral or malignant disorder. The lesion completely resolved by the second birthday without medical intervention.

Does early improvement in major depression protect against treatment emergent suicidal ideation?

OBJECTIVE: To investigate the association of early improvement and treatment emergent suicidal ideation in a large sample (N=705) of naturalistically treated inpatients with major depressive disorder. METHOD: In line with previous reports early improvement was defined as a 20% HAMD improvement within the first two weeks of antidepressant treatment. Treatment emergent suicidal ideation was defined by a sudden increase from 0 or 1 to at least 3 on HAMD item 3 and from 0.1 to at least 4 on MADR item 10 for suicidal ideation. Early improvers were compared with non-early improvers with respect to the occurrence of treatment emergent suicidality during treatment. RESULTS: Early improvers were 3 (MADRS) to 3.4 (HAMD) times less likely to experience new emergence of suicidal ideation during the treatment course than non-improvers. In addition, early improvement was associated with significantly less pessimistic thoughts. LIMITATIONS: The analysis is based on secondary analysis of prospectively collected data. No controlled study design. CONCLUSION: Early improvement is associated with significantly less treatment emergent suicidal ideation for it may provide rapid symptom relief and reduce hopelessness.

Effects of pharmacotherapy and psychotherapy in depressed primary-care patients: a randomized, controlled trial including a patients' choice arm.

Mild depressive syndromes are highly prevalent among primary-care patients. Evidence-based treatment recommendations need to be derived directly from this diagnostically heterogeneous group. The primary aim was to assess the efficacy of sertraline and cognitive-behavioural group therapy for treatment of depressed primary-care patients, the secondary aim was to evaluate if receiving treatment according to free choice is associated with a better outcome than randomization to a particular treatment. We conducted a randomized, placebo-controlled, single-centre, 10-wk trial with five arms: sertraline (flexible dosages up to 200 mg/d) (n = 83); placebo (n = 83); manual-guided cognitive-behavioural group therapy (one individual session and nine group sessions per 90 min) (n = 61); guided self-help group (control condition, n = 59); and treatment with sertraline or cognitive-behavioural group therapy according to patients' choice (n = 82). From 1099 consecutively screened adult patients, 368 formed the intent-to-treat population with milder forms of depression. Primary outcome was a global efficacy measure combining z-converted Hamilton Depression Rating Scale and clinician-rated Inventory for Depressive Symptomatology scores. Sertraline was superior to placebo (p = 0.03). Outcome for guided self-help groups was worse compared to cognitive-behavioural group therapy (p = 0.002) and compared to all other treatment arms including pill placebo (secondary analyses). Outcome in the patients' choice arm was similar to that in the sertraline and cognitive-behavioural group therapy. Overall, sertraline is efficacious in primary-care patients with milder forms of depression. The superiority of cognitive-behavioural group therapy over guided self-help groups might partly be explained by 'nocebo' effects of the latter.

Early improvement is a predictor of treatment outcome in patients with mild major, minor or subsyndromal depression.

BACKGROUND: There is substantial evidence that early improvement (EI) under antidepressant treatment is a clinically useful predictor of later treatment outcome in patients with major depressive disorders. The aim of this study was to test whether EI can also be used as a predictor for treatment outcome in patients with mild major, minor or subsyndromal depression, i.e. patients, who are typically treated by general practitioners. METHODS: Analyses were carried out using data from 223 patients of a 10-weeks randomized, placebo-controlled trial comparing the effectiveness of sertraline and cognitive-behavioural therapy (CBT) in patients with mild major, minor or subsyndromal depression. EI was defined as a reduction of > or =20% on the 17-item Hamilton Rating Scale for Depression (HAMD-17) compared with baseline within the first 2 weeks of treatment. The predictive value of EI for stable response at week 8 and 10 (> or =50% HAMD-17 sum score reduction at weeks 8 and 10) and stable remission (HAMD-17 sum score < or =7 at weeks 8 and 10) was evaluated. RESULTS: In both the sertraline- and CBT-treatment group, EI was a highly sensitive predictor for later stable response (76% and 82%, respectively) and stable remission (70% and 75%, respectively). In patients without EI, only a small proportion of sertraline or CBT-treated patients achieved stable response (20.9% and 5.9%, respectively) or stable remission (18.6% and 8.8%, respectively). Patients with EI were by far more likely to achieve stable response or stable remission than patients without as indicated by high odds ratios (95% confidence interval) of 8.1 (3.0-21.8) and 3.8 (1.4-10.1) for sertraline, and 11.1 (2.1-58.4) and 7.2 (1.7-30.8) for CBT-treated patients, respectively. LIMITATIONS: Sample sizes were relatively low in different treatment groups. CONCLUSION: The identification of early improvement might be useful in clinical decision making in the early course of treatment of patients with mild major, minor and subthreshold depression.

Does early improvement triggered by antidepressants predict response/remission? Analysis of data from a naturalistic study on a large sample of inpatients with major depression.

BACKGROUND: Delayed onset of efficacy of antidepressants and a high proportion of depressed patients being poor or non-responders to antidepressants are well known clinical challenges. Therefore, it seems to be necessary to identify predictors for response and - even more important - for remission. It has been suggested that reduction of depressive symptoms at an early stage of antidepressant treatment may predict treatment outcome. Our objective was to test, if this hypothesis derived from randomized controlled studies (RCTs) in outpatients, would be confirmed in a large naturalistic study in a cohort of inpatients with major depression. Patients were treated with various antidepressants and co-medication according to the protocol based on evidence-based clinical guidelines. METHODS: This was a large naturalistic prospective study. All patients (N=795) were hospitalized and met DSM-IV criteria for major depression according to a structured clinical interview (SCID). Assessments were conducted biweekly. Several definitions of early improvement (20%, 25% and 30% reduction in HAMD-21 baseline total scores) at two different visits were tested. Sensitivity, specificity and predictive values were calculated for the different definitions of early improvement. ROC-analyses as well as logistic regression models have been performed. Response was defined as 50% improvement of the total baseline HAMD-21 score and remission as a score of

The controversial link between antidepressants and suicidality risks in adults: data from a naturalistic study on a large sample of in-patients with a major depressive episode.

Some meta-analyses of randomized placebo-controlled trials on antidepressants conclude that there might be an increased risk for suicidal behaviour, especially in children and adolescents but also in adults. Placebo-controlled trials exclude patients with serious suicidality and might therefore underestimate the risk of respective adverse events. The change of suicidal ideation and the prevalence of suicides and non-fatal suicide attempts were therefore analysed in a large naturalistic prospective multicentre study of depressed in-patients. Additionally, specific risk factors for new emergence of suicidal ideation were investigated. The naturalistic prospective study was performed in 12 psychiatric hospitals of the German research network on depression and suicidality (seven psychiatric university hospitals and five district hospitals) in Germany. All patients (n=1014) were hospitalized and had to meet DSM-IV criteria for major depressive disorder. Six events were defined for the purposes of statistical analysis: 'emergence', 'extended emergence', 'improvement' and 'worsening of suicidal ideation', 'suicide attempts' and 'suicides'. Logistic regression analysis and classification and regression trees (CART) analyses were conducted to determine specific risk factors for new emergence of suicidal ideation. The mean HAMD total score decreased from 24.8 at baseline to 10 after 10 wk. An effect on suicidality was evident by week 2 in the sense of a decrease of the mean HAMD item-3 score. Emergence, worsening and improvement of suicidal ideation occurred in 3.2%, 14.74% and 90.79% of patients, respectively. A total of 10 suicide attempts and two suicides were reported. The rate of suicides (13.44/1000 patient-years) was rather low and comparable to the rate observed in randomized controlled antidepressant trials. Five risk factors for emergence of suicidal ideation were determined with two independent statistical methods: age (with higher risk at age <45 yr), treatment resistance, number of hospitalizations, presence of akathisia and comorbid personality disorder. Age <45 yr as one of five risk factors for the emergence of suicidal ideation is in line with the meta-analysis performed for the recent US Food & Drug Administration (FDA) memorandum; although the naturalistic study design does not permit definite conclusions to be made about certain compounds. The rate of suicides was comparable to that seen in randomized controlled trials, as were the rates of emergence and worsening of suicidal ideation, but more improvement was found. Thus, in-patient treatment in a psychiatric care setting, including daily assessments of suicidality by trained psychiatrists adhering to the rules of good clinical practice (e.g. use of specific co-medications, supportive psychotherapy and continuous medical attendance by nursing staff) might be beneficial.

[Speed of onset of depressive episodes: a clinical criterion helpful for separating uni- from bipolar affective disorders]. / Geschwindigkeit des Depressionsbeginns: Ein Unterscheidungsmerkmal hinsichtlich uni- versus bipolarer affektiver Störungen.

OBJECTIVE: Depressive episodes can begin abruptly or start very slowly (over weeks). This relevant clinical feature of affective disorders has not been systematically investigated so far. The aim of this study was to analyze speed of onset of depressive episodes in patients with unipolar depression (UD) and bipolar affective disorders (BD). METHODS: 158 adult patients with UD (N = 108) and BD (N = 50) were examined using the structured "Onset-of-Depression Inventory". Only patients without acute critical life events preceding the onset were included in the study. RESULTS: There was a significant positive correlation between speed of onset of the present and that of the preceding depressive episode (rho = 0.66; p < 0.001). The association between speed of onset and speed of decay of depressive episodes failed to be significant (rho = 0.20; p = 0.09). Patients with bipolar disorder were found to develop depressive episodes significantly faster than patients with major depression (p < 0.001): Whereas depressive episodes started in 58% of patients with bipolar disorder within one week, this was only the case in 7.4% of patients with major depression. CONCLUSIONS: Within subjects, the speed of onset of depression is similar across different episodes. In the absence of acute critical life events, rapid onset of depressive episodes (within one week) is typical for bipolar depression, but not for unipolar depression. A rapid onset of depressive episodes might point to BD in patients with solely depressive episodes in the past and to subgroups with different neurobiological pathogenetic mechanisms.

Onset of depressive episodes is faster in patients with bipolar versus unipolar depressive disorder: evidence from a retrospective comparative study.

OBJECTIVE: Depressive episodes can have a very fast onset (< 1 hour) or start very slowly (> 1 month). This interesting aspect, pointing to different neurophysiological pathomechanisms, has not been systematically evaluated so far. The aim of this study was to describe speed of onset of depressive episodes in a consecutive sample of patients with at least 1 depressive episode and to investigate potential differences between patients with major depression versus bipolar affective disorders concerning this variable. METHOD: We examined 158 consecutive adult patients with major depression (N = 108) and bipolar disorder (N = 50) diagnosed according to criteria of the International Statistical Classification of Diseases, 10th revision, by applying the structured Onset-of-Depression Inventory. Patients with acute critical life events preceding the onset were excluded from final analyses. Data were collected between December 2001 and January 2007. RESULTS: There was a significant positive association between speed of onset of the present depressive episode and that of the preceding depressive episode (rho = 0.66, p < .001). Patients with bipolar disorder developed full-blown depressive episodes significantly faster than patients with major depression (p < .001): Whereas depressive episodes began within 1 week in 58% of patients with bipolar disorder, this was the case in only 7.4% of patients with major depression. CONCLUSION: Intraindividually, the speed of onset of depression is similar across different episodes. In the absence of acute critical life events, fast onset of depressive episodes (within 1 week) is common in bipolar disorder but rare in major depression. This aspect might be useful to identify depressive episodes occurring within a bipolar affective illness and might characterize a subgroup of patients with a distinct neurobiology.

The US FDA 'black box' warning for topical calcineurin inhibitors: an ongoing controversy.

Atopic dermatitis is a chronic inflammatory skin disease characterized by recurrent intense pruritus and a distinctive distribution of skin lesions. The topical calcineurin inhibitors tacrolimus and pimecrolimus were approved in the USA, as an ointment and a cream, respectively, for the treatment of atopic dermatitis in 2000 and 2001, respectively. In 2005, the Pediatric Advisory Committee of the US FDA implemented a 'black box' warning for tacrolimus ointment and pimecrolimus cream due to the lack of long-term safety data and the potential risk of the development of malignancies. This article focuses on the safety aspects of these agents by discussing the findings from preclinical and clinical studies and postmarketing reports with regard to malignancies occurring after the use of tacrolimus ointment and pimecrolimus cream.