F. Bayle

Morningness–eveningness and treatment response in major depressive disorder

In a large, prospective, 8-week open study of 721 outpatients receiving agomelatine treatment for a current major depressive episode (MDE), morningness–eveningness (Composite Scale of Morningness) was assessed before and after treatment to investigate possible changes in morningness–eveningness after treatment and evaluate whether morningness–eveningness at baseline predicted treatment response. A change towards morningness was observed after treatment. This change was greater in responders than non-responders. Moreover, being a morning type at baseline was an independent predictor of response to treatment. Once thought to be a trait variable, morningness–eveningness is a potential treatment target that should be systematically assessed in MDE patients.

Is it worth assessing progress as early as week 2 to adapt antidepressive treatment strategy? Results from a study on agomelatine and a global meta-analysis.

CONTEXT A delay of 4-8weeks before modifying the prescribed antidepressant treatment is usually proposed when incomplete treatment response is observed. A number of studies nevertheless proposed that the lack of early improvement (usually 20% decrease of severity at week 2) is predictive of the absence of subsequent treatment response, potentially saving weeks of inadequate treatment, but with no information for non-interventional studies devoted to outpatients. METHOD Two thousand nine hundred and thirty-eight outpatients with major depressive disorder were included in a multicentre, non-interventional study, assessing at inclusion, week 2 and week 6, mood (QIDS-C, CGI, PGI and VAS) sleep (LSEQ) and functionality (SDS). All metrics at week 2 were tested for their capacity to predict response (and then remission) at week 6, all patients being treated by agomelatine. A meta-analysis of all studies (n=12) assessing the predictive role of improvement at week 2 was also performed, assessing specific effect size of published studies and the weight of the different parameters they used. RESULTS The QIDS-C and the CGI-I were the only instruments with an area under the curve over 0.7, with different cut-offs for treatment response and remission. A decrease of more than five points at the QIDS-C had the highest positive predictive value for treatment response, and a CGI-I over three had the highest negative predictive value, which would favour relying on the clinicians for warning (too high CGI-I), and on instruments for confidence (favourable decrease of the QIDS-C). The meta-analysis of all studies also detected a large effect size of early improvement, stressing how rating week 2 severity could be beneficial in clinical practice. CONCLUSIONS Previous reports stressing the interest of an assessment at week 2 were reinforced by the present results, which also defined more accurately what could be the most appropriate cut-offs, and how combining these early results could be more effective.

Time-stability of the “Functional Remission of General Schizophrenia” (FROGS) scale

Functional remission in schizophrenia is an important treatment goal, particularly for patients who have achieved symptomatic remission. The Functional Remission of General Schizophrenia (FROGS) scale has recently been developed, with the FROGS total score being reported as reliable in a cross-sectional study, with an exploratory factor analysis showing three oblique meaningful factors. As such an instrument should have a stable structure over time, but also be able to detect improvement of functioning with time, we have further analysed the validity of the FROGS scale, specifically assessing time-stability. We re-evaluated the initial patient sample around 1.5 years after the first evaluation (mean=17.1 months, standard deviation=1.9), restricting the analyses to patients who were still being followed-up and in clinical remission (n=140 patients). The mean (standard deviation) FROGS total score was 75.82 (10.85) at the second evaluation, showing a significant improvement with time (3.84; P<0.0001 versus the first evaluation). The internal consistency/reliability of the FROGS scale was still very high (Cronbachs α=0.919). Significant improvements between the first and second evaluations were also apparent for all the individual items in the FROGS scale (P<0.01) as well as for the subscores for the three extracted factors (P<0.0001). Statistically significant correlations were observed between the FROGS scale and other indices, including the Global Assessment of Functioning (r=0.58; P<0.0001). These results provide further evidence of the solid psychometric properties of the FROGS scale.

Telephone-administered psychotherapy in combination with antidepressant medication for the acute treatment of major depressive disorder

BACKGROUND Telephone-administered psychotherapies (T-P) provided as an adjunct to antidepressant medication may improve response rates in major depressive disorder (MDD). The goal of this study was to compare telephone-administered social rhythm therapy (T-SRT) and telephone-administered intensive clinical management (T-ICM) as adjuncts to antidepressant medication for MDD. A secondary goal was to compare T-P with Treatment as Usual (TAU) as adjunctive treatment to medication for MDD. METHODS 221 adult out-patients with MDD, currently depressed, were randomly assigned to 8 sessions of weekly T-SRT (n=110) or T-ICM (n=111), administered as an adjunct to agomelatine. Both psychotherapies were administered entirely by telephone, by trained psychologists who were blind to other aspects of treatment. The 221 patients were a posteriori matched with 221 depressed outpatients receiving TAU (controls). The primary outcome measure was the percentage of responders at 8 weeks post-treatment. RESULTS No significant differences were found between T-SRT and T-ICM. But T-P was associated with higher response rates (65.4% vs 54.8%, p=0.02) and a trend toward higher remission rates (33.2% vs 25.1%; p=0.06) compared to TAU. LIMITATIONS Short term study. CONCLUSIONS This study is the first assessing the short-term effects of an add-on, brief, telephone-administered psychotherapy in depressed patients treated with antidepressant medication. Eight sessions of weekly telephone-delivered psychotherapy as an adjunct to antidepressant medication resulted in improved response rates relative to medication alone.

An increase in joy after two weeks is more specific of later antidepressant response than a decrease in sadness

BACKGROUND Early improvement in positive emotions-more than decreases in negative emotions-was highly predictive of treatment response in an ecologically valid prospective manner. This result needs replication with simpler assessments to determine whether it can be translated into clinical practice. METHODS 2049 adult depressed outpatients receiving agomelatine were assessed at inclusion, week 2, and week 6 using the clinician-rated Quick Inventory of Depressive Symptomatology, Sheehan Disability Scale, Clinical Global Impression scale, and Multidimensional Assessment of Thymic States (MATHYS), an auto-questionnaire rating the frequency of emotions, including sadness and joy, over the previous week. RESULTS Joy and sadness had a relatively low correlation coefficient at baseline (r=-0.277), joy (r=-0.160) being less correlated with clinical severity than sadness (r=0.317). An increase in joy at week 2 had higher specificity (85.04%) and positive predictive value (70.55%) for treatment response than decreased sadness (57.92% and 66.04%, respectively), and the global capacity of the former to predict remission, either clinical (Yule Q coefficient, 39.96%) or functional (44.35%), was even better compared to the prediction of clinical response (37.38%). LIMITATIONS MATHYS retrospectively assesses emotions, with five possible ratings only, relying on self-rated frequencies. With only a 6-week follow-up, conclusions are limited to short-term aspects of clinical and functional remission. CONCLUSIONS Early improvement in joy during the first 2 weeks of treatment is strongly specific for treatment response and remission. The frequency of joy captures the predictivity and may deserve further study regarding inclusion in depressive rating scales.

Validation of a four items version of the Functional Remission of General Schizophrenia scale (the mini-FROGS) to capture the functional benefits of clinical remission

OBJECTIVES We previously developed the Functional Remission Of General Schizophrenia (FROGS) scale demonstrating first, reliable assessment in a cross-sectional study and second, good time-stability. The purpose of the present analysis was to propose a shorter version (mini-FROGS), more compatible with the limited time available in a psychiatric visit, focusing on the functional domains that have higher likelihood of being improved with higher and/or longer symptomatic remission in different cultural backgrounds. METHODS We used multiple regressions to find the most informative items explaining increased length of symptomatic remission, using prospective data from a national observational multicenter survey. Then, the mini-FROGS was used in different European countries to test its between-center reliability, compared to other scales. RESULTS Four domains were retained as capturing the maximum of symptomatic remission, namely (1) travel and communication, (2) management of illness and treatment, (3) self-esteem and sense of independence and (4) respect of biological rhythms. First, the mini-FROG was evaluated in 443 French patients with clinical remission and 22 without, and 12/18 months later in 140 patients still in clinical remission and 23 in relapse. In Europe, 295 schizophrenia patients were assessed with the mini-FROGS and other scales devoted to functional remission, allowing comparisons. The mini-FROGS showed good correlations with other scales in different countries and demonstrated good psychometric properties. CONCLUSION These results give evidence that a 4 items-only version of the FROGS scale may be useful to assess important aspects of functional remission, tightly linked to the length of clinical remission.

EPA-0762 – Beyond depressive symptoms, how agomelatine modifies emotional reactivity, cognitive speed, motivation, psychomotor function and sensory perception?

Introduction Baseline values and early changes of emotional reactivity, cognitive speed, psychomotor function, motivation and sensory perception have been poorly studied in unipolar depression, although they could help to characterize different dimensions harder to capture by clinicians, give new insights on how patients are improved, and offer new markers depicting how early changes testify later treatment response. Methods 1565 adult outpatients with MDD receiving agomelatine completed QIDS-C, CGI and MATHYS scales at inclusion, W2 and W6. The MATHYS includes 20-item self-rated visual analogue scales (from inhibition -0- to activation -10- with -5- representing the usual state) leading to five a priori dimensions (emotional reactivity, cognitive speed, psychomotor function, motivation and sensory perception). Results All dimensions increased from inclusion to W2 and from W2 to W6 (p −3 ). Roughly, improvement was 2-point (out of 10) for motivation, 1.5 for psychomotor function and 0.5 for other dimensions. Motivation: (1) had a trend as being more severe at inclusion in later non-responders (t=1.25, df=1563, p=0.10) (2) displayed the highest difference at W2 in later responders versus non-responders (t=7.98, df=1563, p Conclusions Motivation had the earliest capacity to be improved, the best predictive value for treatment response and the largest global margin of progress in depressed outpatients. Assessing self-reported motivation in MDD could offer an interesting paradigm shift while assessing linear changes of depressive symptoms.

EPA-0601 – The increase of positive emotions after two weeks of agomelatine is more specific to predict later treatment response than the decrease of negative emotions.

Introduction A recent meta-analysis showed that lack of early improvement is able to predict absence of later treatment response in Major Depressive Disorder. Whilst the majority of studies are based on depressive symptoms reduction, early variability of negative and positive emotions could be even more informative. Methods 2938 adult outpatients with MDD were included in this observational study to receive agomelatine. QIDS-C, CGI, and MATHYS scales were completed at inclusion, W2 and W6 for 1565 subjects. The MATHYS rates tonalities of emotions during the previous week, including sadness and happiness, on a Likert Scale with 5 frequencies: from’never’ to’constantly’. Results Responders were 25.72% at W2 (N=402) and 58.02% (N=908) at W6. QIDS-C score decreased from 18.78 at inclusion to 9.28 at W6. At W6, 26.00% patients were remitters (QIDS-C specific (84.78% versus 58.14%), with a better positive predictive value (72.30% versus 67.72%) than the decrease of negative emotions. The global predictive value for positive emotions increase (Yule Q=38.40%, 95%CI[35.99%–40.81%] was overlapping with the one derived from the decrease of negative emotions (Q=41.55, 95%CI[39.10%–43.99%]). Conclusions Beside depressive symptoms, considering early changes in positive and negative emotions could be a relevant choice, as the more specific value for symptoms reduction (QIDS-C) was 72.5% in the same study and the specificity detected for the increase of positive emotions is 84.8% in this analysis.

1311 – Response trajectories during antidepressant treatment of major mood disorder

Context A recent study by Levine and Leucht described several kinetics of treatment response among schizophrenic patients with antipsychotics. We aimed so to test this methodology in a population of depressed patients. Method 2938 outpatients with major depressive disorder were included in a multicentre, non interventional study, assessing at inclusion, week 2 and week 6, mood (QIDS-C, CGI, PGI and VAS) and functionality (SDS). To identify homogeneous groups of patients on the evolution of QIDS criteria over time (D0, W2 and W6), the latent class linear mixed model was used. Then, the groups were described at each time by several clinical characteristics and scores using ANOVA or the chi-square test. All metrics at day 0 and week 2 were tested for their capacity to predict a kinetic of response, all patients being treated by Agomelatine. Results 1200 patients were drug naive for the current episode; 3 types of response kinetics were found: early, intermediate et late responders. The principal factor in relationship with a later response was the number of past episodes. Among the 1700 patients with a previous antidepressant treatment, 6 types of kinetics were distinguished: early response kinetics, intermediate and late response, non response and a singular one with early response at W2 and relapse at W6. The principal factor in relationship with a bad response kinetic was the age at first episode of mood disorder. Conclusions Previous reports stressing the interest of an assessment at week 2 were reinforced by the present results.