Biological profiling of prospective antidepressant response in major depressive disorder: Associations with (neuro)inflammation, fatty acid metabolism, and amygdala-reactivity.

BACKGROUND: A better understanding of factors underlying antidepressant non-response may improve the prediction of which patients will respond to what treatment. Major depressive disorder (MDD) is associated with alterations in fatty acid metabolism, (neuro)inflammation and amygdala-reactivity. However, their mutual relations, and the extent to which they are associated with prospective antidepressant-response, remain unknown. PURPOSE: To test (I) alterations in (neuro)inflammation and its associations with fatty acid metabolism and amygdala-reactivity in MDD-patients compared to controls, and (II) whether these alterations are associated with prospective paroxetine response. METHODS: We compared 70 unmedicated MDD-patients with 51 matched healthy controls at baseline, regarding erythrocyte membrane omega-6 arachidonic acid (AA), inflammation [serum (high-sensitivity) C-reactive protein (CRP)], and in a subgroup amygdala-reactivity to emotional faces using functional magnetic resonance imaging (fMRI) (N=42). Subsequently, we treated patients with 12 weeks paroxetine, and repeated baseline measures after 6 and 12 weeks to compare non-responders, early-responders (response at 6 weeks), and late-responders (response at 12 weeks). RESULTS: Compared to controls, MDD-patients showed higher CRP (p=0.016) and AA (p=0.019) after adjustment for confounders at baseline. AA and CRP were mutually correlated (p=0.043). In addition, patients showed a more negative relation between AA and left amygdala-reactivity (p=0.014). Moreover, AA and CRP were associated with antidepressant-response: early responders showed lower AA (p=0.018) and higher CRP-concentrations (p=0.008) than non-responders throughout the study. CONCLUSION: Higher observed CRP and AA, their mutual association, and relation with amygdala-reactivity, are corroborative with a role for (neuro)inflammation in MDD. In addition, observed associations of these factors with prospective antidepressant-response suggest a potential role as biomarkers. Future studies in independent samples are needed to replicate and test the clinical applicability of these biological predictors for treatment response to result in a precision/personalized medicine approach for treatment.

Visuospatial planning in unmedicated major depressive disorder and bipolar disorder: distinct and common neural correlates.

BACKGROUND: Cognitive impairments are an important feature of both remitted and depressed major depressive disorder (MDD) and bipolar disorder (BD). In particular, deficits in executive functioning may hamper everyday functioning. Identifying the neural substrates of impaired executive functioning would improve our understanding of the pathophysiology underlying these disorders, and may eventually aid in discriminating between MDD and BD, which is often difficult during depression and remission. To date, mostly medicated MDD and BD subjects have been investigated, which may have influenced results. Therefore, we investigated executive functioning in medication-free depressed and remitted MDD and BD subjects. METHOD: We used the Tower of London (ToL) visuospatial planning task to assess behavioural performance and blood oxygen-level dependent responses in 35 healthy controls, 21 remitted MDD, 23 remitted BD, 19 depressed MDD and nine depressed BD subjects. RESULTS: Visuospatial planning per se was associated with increased frontostriatal activity in depressed BD compared to depressed MDD. In addition, post-hoc analyses indicated that visuospatial planning load was associated with increased parietal activity in depressed compared to remitted subjects, and BD compared to MDD subjects. Task performance did not significantly differ between groups. CONCLUSIONS: More severely affected, medication-free mood disorder patients require greater parietal activity to perform in visuospatial planning, which may be compensatory to maintain relatively normal performance. State-dependent frontostriatal hyperactivity during planning may be a specific BD characteristic, providing clues for further characterization of differential pathophysiology in MDD v. BD. This could potentially provide a biomarker to aid in the differentiation of these disorders.

Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder.

Omega-3 polyunsaturated fatty acid (PUFA) supplementation has been proposed as (adjuvant) treatment for major depressive disorder (MDD). In the present meta-analysis, we pooled randomized placebo-controlled trials assessing the effects of omega-3 PUFA supplementation on depressive symptoms in MDD. Moreover, we performed meta-regression to test whether supplementation effects depended on eicosapentaenoic acid (EPA) or docosahexaenoic acid dose, their ratio, study duration, participants' age, percentage antidepressant users, baseline MDD symptom severity, publication year and study quality. To limit heterogeneity, we only included studies in adult patients with MDD assessed using standardized clinical interviews, and excluded studies that specifically studied perinatal/perimenopausal or comorbid MDD. Our PubMED/EMBASE search resulted in 1955 articles, from which we included 13 studies providing 1233 participants. After taking potential publication bias into account, meta-analysis showed an overall beneficial effect of omega-3 PUFAs on depressive symptoms in MDD (standardized mean difference=0.398 (0.114-0.682), P=0.006, random-effects model). As an explanation for significant heterogeneity (I(2)=73.36, P<0.001), meta-regression showed that higher EPA dose (ß=0.00037 (0.00009-0.00065), P=0.009), higher percentage antidepressant users (ß=0.0058 (0.00017-0.01144), P=0.044) and earlier publication year (ß=-0.0735 (-0.143 to 0.004), P=0.04) were significantly associated with better outcome for PUFA supplementation. Additional sensitivity analyses were performed. In conclusion, present meta-analysis suggested a beneficial overall effect of omega-3 PUFA supplementation in MDD patients, especially for higher doses of EPA and in participants taking antidepressants. Future precision medicine trials should establish whether possible interactions between EPA and antidepressants could provide targets to improve antidepressant response and its prediction. Furthermore, potential long-term biochemical side effects of high-dosed add-on EPA supplementation should be carefully monitored.

Net gain analysis, an addition to responder analysis--The case of antipsychotic treatment of acute mania.

Net Gain Analysis (NGA) is proposed as an alternative to Responders Analysis (RA) as a more comprehensive method to tap clinical relevance of the effect of treatment. NGA is the group difference in responders minus the group difference in deteriorators; while RA is the group difference in responders. We examined the performance of these two methods in a dataset consisting of individual patient data from 10 randomized controlled trials (N = 2666) of five different antipsychotics in patients with acute mania by comparing the rank ordering of the five compounds according to both systems (NGA and RA). The rank order did not differ between the 2 systems but the inferiority of one compound was revealed more evidently by the NGA in comparison to the RA.

DHEAS and cortisol/DHEAS-ratio in recurrent depression: State, or trait predicting 10-year recurrence?

BACKGROUND: Major depressive disorder (MDD) has been associated with low dehydroepiandrosterone-sulphate (DHEAS), - particularly relative to high cortisol - although conflicting findings exist. Moreover, it is unclear whether low DHEAS is only present during the depressive state, or manifests as a trait that may reflect vulnerability for recurrence. Therefore, we longitudinally tested whether low DHEAS and high cortisol/DHEAS-ratio in recurrent MDD (I) reflects a trait, and/or (II) varies with depressive state. In addition, we tested associations with (III) previous MDD-episodes, (IV) prospective recurrence, and (V) effects of cognitive therapy. METHODS: At study-entry, we cross-sectionally compared morning and evening salivary DHEAS and molar cortisol/DHEAS-ratio of 187 remitted recurrent MDD-patients with 72 matched controls. Subsequently, patients participated in an 8-week randomized controlled cognitive therapy trial. We repeated salivary measures after 3 months and 2 years. We measured clinical symptoms during a 10-year follow-up. RESULTS: Remitted patients showed steeper diurnal DHEAS-decline (p<.005) and a flatter diurnal profile of cortisol/DHEAS-ratio (p<.001) than controls. We found no state-effect in DHEAS or cortisol/DHEAS-ratio throughout follow-up and no association with number of previous episodes. Higher morning cortisol/DHEAS-ratio predicted shorter time till recurrence over the 10-year follow-up in interaction with the effects of cognitive therapy (p<.05). Finally, cognitive therapy did not influence DHEAS or cortisol/DHEAS-ratio. CONCLUSIONS: Diurnal profiles of DHEAS and cortisol/DHEAS-ratio remain equally altered in between depressive episodes, and may predict future recurrence. This suggests they represent an endophenotypic vulnerability trait rather than a state-effect, which provides a new road to understand recurrent depression and its prevention. TRIAL REGISTRATION: www.isrctn.com/ISRCTN68246470.

Efficacy of drug treatment for acute mania differs across geographic regions: An individual patient data meta-analysis of placebo-controlled studies.

Given globalization trends in the conduct of clinical trials, the external validity of trial results across geographic regions is questioned. The objective of this study was to examine the efficacy of treatment in acute mania in bipolar disorder across regions and to explain potential differences by differences in patient characteristics. We performed a meta-analysis of individual patient data from 12 registration studies for the indication acute manic episode of bipolar disorder. Patients (n = 3207) were classified into one of three geographic regions: Europe (n = 981), USA (n = 1270), and other regions (n = 956). Primary outcome measures were mean symptom change score on the Young Mania Rating Scale (YMRS) from baseline to endpoint and responder status (50% improvement form baseline). Effect sizes were significantly smaller in the USA (g = 0.203, 95% confidence interval (CI) 0.062-0.344; odds ratio (OR) 1.406, 95% CI 0.998-1.980) than in Europe (g = 0.476, 95% CI 0.200-0.672; OR 2.380, 95% CI 1.682-3.368) or other regions (g = 0.533, 95% CI 0.399-0.667; OR 2.300, 95% CI 1.800-2.941). Regional differences in age, gender, initial severity, body mass index, placebo response, discontinuation rate, and type of compound could not explain the geographic differences in effect. Less severe symptoms at baseline in the US patients did explain some of the difference in responder status between patients in Europe and the USA. These findings suggest that the results of studies involving patients with acute mania cannot be extrapolated across geographic regions. Similar findings have been identified in schizophrenia, contraceptive, and in cardiovascular trials. Therefore, this finding may indicate a more general problem regarding the generalizability of pharmacological trials over geographic regions.

Placebo response in antipsychotic trials of patients with acute mania: Results of an individual patient data meta-analysis.

We examined the role of placebo response in acute mania trials. Specifically, whether placebo response: (1) predicts treatment effect, (2) can be predicted by patient and study characteristics, and (3) can be predicted by a parsimonious model. We performed a meta-analysis of individual patient data from 10 registration studies (n=1019) for the indication acute manic episode of bipolar disorder. We assessed the effect of 14 determinants on placebo response. Primary outcome measures were mean symptom change score (MCS) on the Young Mania Rating Scale (YMRS) and response rate (RR), defined as ≥ 50% YMRS symptom improvement from baseline to endpoint. The overall placebo response was 8.5 points improvement on the YMRS (=27.9%) with a RR of 32.8%. Placebo response was significantly associated with the overall treatment response. Five determinants significantly (p<0.05) predicted the placebo response. The multivariate prediction model, which consisted of baseline severity, psychotic features at baseline, number of geographic regions, and region, explained 10.4% and 5.5% of the variance in MSC and RR, respectively. Our findings showed that the placebo response in efficacy trials of antipsychotics for acute mania is substantial and an important determinant of treatment effect. Placebo response is influenced by patient characteristics (illness severity and presence of psychotic features) and by study characteristics (study year, number of geographic regions and region). However, the prediction model could only explain the placebo response to a limited extent. Therefore, limiting trials to certain patients in certain geographic regions seems not a viable strategy to improve assay sensitivity.

Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: systematic review and meta-analysis.

OBJECTIVE: To perform a meta-analysis on studies reporting prevalence of Toxoplasma gondii (T. gondii) infection in any psychiatric disorder compared with healthy controls. Our secondary objective was to analyze factors possibly moderating heterogeneity. METHOD: A systematic search was performed to identify studies into T. gondii infection for all major psychiatric disorders versus healthy controls. Methodological quality, publication bias, and possible moderators were assessed. RESULTS: A total of 2866 citations were retrieved and 50 studies finally included. Significant odds ratios (ORs) with IgG antibodies were found in schizophrenia (OR 1.81, P < 0.00001), bipolar disorder (OR 1.52, P = 0.02), obsessive-compulsive disorder (OR 3.4, P < 0.001), and addiction (OR 1.91, P < 0.00001), but not for major depression (OR 1.21, P = 0.28). Exploration of the association between T. gondii and schizophrenia yielded a significant effect of seropositivity before onset and serointensity, but not IgM antibodies or gender. The amplitude of the OR was influenced by region and general seroprevalence. Moderators together accounted for 56% of the observed variance in study effects. After controlling for publication bias, the adjusted OR (1.43) in schizophrenia remained significant. CONCLUSION: These findings suggest that T. gondii infection is associated with several psychiatric disorders and that in schizophrenia reactivation of latent T. gondii infection may occur.

The one-carbon-cycle and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in recurrent major depressive disorder; influence of antidepressant use and depressive state?

BACKGROUND: An important biological factor suggested in the pathophysiology of (recurrent) Major Depressive Disorder (MDD) concerns a polymorphism in a gene encoding for the MTHFR-enzyme of the one-carbon (1-C)-metabolism. Integratively investigating key 1-C-components (folate, homocysteine, vitamin B6 and B12), including the possible effects of antidepressant medication and depressive state, could provide more insight in the possible association between the MTHFR-polymorphism and recurrent MDD. METHODS: We compared the MTHFR C677T-polymorphism together with the key 1-C-components in clinically ascertained patients with recurrent MDD (n=137) to age- and gender-matched healthy controls (n=73). RESULTS: First, patients had lower folate (t=2.25; p=.025) as compared to controls; a difference that resolved after correction for demographics (t=1.22; p=.223). Second, patients that were depressed during sampling had lower vitamin B6 (t=-2.070; p=.038) and higher homocysteine (t=2.404; p=.016) compared to those in remission. Finally, current use of antidepressants had no influence on the 1-C-components. CONCLUSIONS: Despite investigation of a specific recurrently depressed patient population, we found no clear associations with the 1-C-cycle, except for higher homocysteine and lower vitamin B6 during the depressed state. This suggests that 1-C-cycle alterations in MDD are state-associated, possibly resulting from high levels of acute (psychological) stress, and may provide a treatment target to reduce cardiovascular risk in this population.

Interaction between the MTHFR C677T polymorphism and traumatic childhood events predicts depression.

Childhood trauma is associated with the onset and recurrence of major depressive disorder (MDD). The thermolabile T variant of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) is associated with a limited (oxidative) stress defense. Therefore, C677T MTHFR could be a potential predictor for depressive symptomatology and MDD recurrence in the context of traumatic stress during early life. We investigated the interaction between the C677T MTHFR variant and exposure to traumatic childhood events (TCEs) on MDD recurrence during a 5.5-year follow-up in a discovery sample of 124 patients with recurrent MDD and, in an independent replication sample, on depressive symptomatology in 665 healthy individuals from the general population. In the discovery sample, Cox regression analysis revealed a significant interaction between MTHFR genotype and TCEs on MDD recurrence (P=0.017). Over the 5.5-year follow-up period, median time to recurrence was 191 days for T-allele carrying patients who experienced TCEs (T+ and TCE+); 461 days for T- and TCE+ patients; 773 days for T+ and TCE- patients and 866 days for T- and TCE- patients. In the replication sample, a significant interaction was present between the MTHFR genotype and TCEs on depressive symptomatology (P=0.002). Our results show that the effects of TCEs on the prospectively assessed recurrence of MDD and self-reported depressive symptoms in the general population depend on the MTHFR genotype. In conclusion, T-allele carriers may be at an increased risk for depressive symptoms or MDD recurrence after exposure to childhood trauma.

Cannabis and cognitive performance in psychosis: a cross-sectional study in patients with non-affective psychotic illness and their unaffected siblings.

BACKGROUND: The relationship between cannabis use and cognitive functioning in patients with psychosis has yielded contradictory findings. In individuals at genetic high risk for psychosis, information is sparse. The aim of this study was to assess the association between recency and frequency of cannabis use and cognitive functioning in patients with psychosis and their unaffected siblings. METHOD: We conducted a cross-sectional study in 956 patients with non-affective psychosis, 953 unaffected siblings, and 554 control subjects. Participants completed a cognitive test battery including assessments of verbal learning, set shifting, sustained attention, processing speed, working memory, acquired knowledge, reasoning and problem solving and social cognition. Cannabis use was assessed by urinalysis and by the Composite International Diagnostic Interview. Using random-effect regression models the main effects of cannabis (recency and frequency) and the interaction with status (patient, sibling, control) on cognitive functioning were assessed. RESULTS: Current cannabis use was associated with poorer performance on immediate verbal learning, processing speed and working memory (Cohen's d -0.20 to -0.33, p<0.005). Lifetime cannabis use was associated with better performance on acquired knowledge, facial affect recognition and face identity recognition (Cohen's d+0.17 to +0.33, p<0.005). There was no significant interaction between cannabis and status on cognitive functioning. CONCLUSIONS: Lifetime cannabis-using individuals might constitute a subgroup with a higher cognitive potential. The residual effects of cannabis may impair short-term memory and processing speed.

Return to work after sick leave due to depression; a conceptual analysis based on perspectives of patients, supervisors and occupational physicians.

OBJECTIVES: This study aims to investigate the most important factors facilitating a return to work after sick leave due to depression from the perspectives of patients, supervisors and occupational physicians. METHODS: Concept mapping was used to develop a conceptual framework. Using purposive sampling, 32 participants representing Employees, supervisors and occupational physicians, were asked to formulate statements on what enables patients with sick leave due to depression to return to work. A total of 41 participants rated and grouped the statements. Data were analyzed using the statistical program Ariadne. RESULTS: The concept mapping yielded 60 statements that consisted of promoting factors for return to work. Based on these statements, three meta-clusters and eight clusters were identified. The three meta-clusters consisted of work-related, person-related and healthcare- related clusters. The work-related meta-cluster comprised of "Adaptation of work", "Understanding and support in the workplace" and "Positive work experiences". The person- related meta-cluster encompassed "Positive and valid self-perception", "Competence in self management", "Positive level of energy", and "Balanced home/work environment". The healthcare-related meta-cluster was composed of "Supportive healthcare". Stakeholder groups differ in opinion, in what they see as most important for return to work. LIMITATIONS: The low number of participants and the high educational level of participants are a limitation for generalization of the findings. CONCLUSIONS: The study generated different statements that stakeholders consider important for return to work after sick leave due to depression. These findings can be used as a checklist for coordination of the return to work process. Differences in opinion regarding what stakeholders see as most important for return to work should receive special consideration during the re-integration process.

Measuring the learning capacity of organisations: development and factor analysis of the Questionnaire for Learning Organizations.

AIMS: To investigate internal consistency and factor structure of a questionnaire measuring learning capacity based on Senge's theory of the five disciplines of a learning organisation: Personal Mastery, Mental Models, Shared Vision, Team Learning, and Systems Thinking. DESIGN: Cross-sectional study. SETTING: Substance-abuse treatment centres (SATCs) in The Netherlands. PARTICIPANTS: A total of 293 SATC employees from outpatient and inpatient treatment departments, financial and human resources departments. MAIN OUTCOME MEASURES: Psychometric properties of the Questionnaire for Learning Organizations (QLO), including factor structure, internal consistency, and interscale correlations. FINDINGS: A five-factor model representing the five disciplines of Senge showed good fit. The scales for Personal Mastery, Shared Vision and Team Learning had good internal consistency, but the scales for Systems Thinking and Mental Models had low internal consistency. CONCLUSIONS: The proposed five-factor structure was confirmed in the QLO, which makes it a promising instrument to assess learning capacity in teams. The Systems Thinking and the Mental Models scales have to be revised. Future research should be aimed at testing criterion and discriminatory validity.

Specific effects of ecstasy and other illicit drugs on cognition in poly-substance users.

BACKGROUND: A large number of studies, reviews and meta-analyses have reported cognitive deficits in ecstasy users. However most ecstasy users are polydrug users, and therefore it cannot be excluded that these deficits are (partly) the result of drugs other than ecstasy. The current study, part of the Netherlands XTC Toxicity (NeXT) study, investigates the specific sustained effects of ecstasy relative to amphetamine, cocaine and cannabis on the brain using neuropsychological examination. METHOD: A stratified sample of 67 subjects with such a variation in type and amount of drug use was included that correlations between the consumption of the various drugs were relatively low allowing stepwise linear multiple regression analyses to differentiate between the effects of ecstasy and those of other substances. Subjects were assessed with neuropsychological tests measuring attention, working memory, verbal and visuospatial memory, and visuospatial ability. RESULTS: Ecstasy use [mean 327 (S.D.=364) tablets in lifetime] had a specific significant dose-related negative effect on verbal delayed recall after adjusting for the use of other drugs. CONCLUSIONS: These findings strongly suggest a specific sustained negative effect of ecstasy use on verbal memory. The clinical relevance is not immediately clear, because test performance generally remained within the normal range. However the magnitude of the effect is substantial (d>0.5) and long-term consequences cannot be excluded.

What patient characteristics make clinicians recommend brief treatment?

OBJECTIVE: Assessing self-rated items that might have an impact on clinicians recommending brief treatment (BT) over unlimited or long-term treatment (ULT). METHOD: On the basis of patient self-report data we compared patients referred by clinicians to BT (n=71) with those referred to ULT (n=145). RESULTS: The final multiple logistic regression model indicates that the chance of being allocated to BT increases with: more satisfaction with support, higher self-esteem, primary education or less, and high desire for support as an intervention. With regard to desire to confess in treatment, low and high scores make the chance of being allocated to BT lower. This is also the case for daily hassles. Finally, some specific target complaints, in particular anxiety, lower the chance of being allocated to BT. CONCLUSION: Using data about patient's complaints and symptoms, stress and support, personality and coping, and request for type of intervention, we built a regression-model that classified 80% of the patients correctly with regard to allocation to BT or ULT.

Quality of life in schizophrenia measured by the MOS SF-36 and the Lancashire Quality of Life Profile: a comparison.

OBJECTIVE: To compare two Quality of Life (QoL) instruments on reliability, feasibility and conceptual overlap in a group of schizophrenic out-patients. METHOD: The Lancashire Quality of Life Profile (LQoLP) and the MOS SF-36 were used to assess the QoL of 143 schizophrenic out-patients. RESULTS: Feasibility and reliability for both instruments were satisfying. Second order factor analysis on 10 LQoLP and eight MOS SF-36 scales resulted in three factors: one health related QoL factor and two general QoL factors; an internal and an external factor. CONCLUSION: QoL measures in schizophrenia studies are not exchangeable. Validity of a specific QoL instrument depends upon the purpose of the study. The LQoLP allows suggestions for specific improvements in mental health care for long-term psychiatric patients. The SF-36 is a good choice when comparison with other patient groups on health related QoL is relevant.

Diagnosing alcoholism in high-risk drinking drivers: comparing different diagnostic procedures with estimated prevalence of hazardous alcohol use.

In several European countries, drivers under influence (DUI), suspected of an alcohol use disorder (AUD, 'alcoholism') are referred for diagnostic examination. The accuracy of diagnostic procedures used in diagnosing AUD in the DUI population is unknown. The aim of this study was to compare three prevalence estimates of AUD based on a structured clinical interview (SCID), a restrictive diagnostic procedure (RDP) and usual clinical diagnostic procedure (CDP), with a prevalence estimate based on sensitivity and specificity data of biological markers of excessive use of alcohol in non-judicial samples. The latter unbiased estimate provides an external yardstick against which the biased patient-based prevalence estimates in this special sample can be evaluated. The unbiased estimate derived from sensitivity and specificity data resulted in a prevalence estimate of excessive use of alcohol between 74 and 82%, which is much higher than the three diagnostic procedures. SCID identified maximally 5% of alcoholics found with the unbiased estimate. RDP identified > or =31% of the unbiased estimate, while CDP identified > or =60% of the unbiased estimate. The high chance of false positive diagnosis, however, makes CDP unacceptable in the legal context of AUD diagnosis in DUI populations.

The Lancashire Quality of Life Profile: modification and psychometric evaluation.

BACKGROUND: Although widely used in Europe, the conceptual and psychometric qualities of the Lancashire Quality of Life Profile (LQoLP) have not been thoroughly examined. Four issues need attention: coverage, scale construction, systematic missing data, and psychometric properties. METHOD: Concept mapping was used to examine the coverage, and exploratory factor analysis to examine the empirical scale structure of the LQoLP. Data of 518 long-term patients from ten different mental health care settings were used. Modifications to the LQoLP were proposed on the basis of these findings, and its psychometric properties were tested. Thirty-one respondents participated in a test-retest reliability study (T1-T2: 2 weeks). RESULTS: The modified LQoLP covers the quality of life-concept in a more comprehensive manner. Internal consistency, test-retest reliability and validity are good. CONCLUSIONS: The modified version of the LQoLP now covers ten domains, paying specific attention to patients' definition of quality of life (autonomy, coping, self-worth). Domains are now based on factor analysis. The problem of systematic missing data is solved. Psychometric properties are good. Because of moderate alphas, two domains need further investigation.