Clinical correlates and prognostic implications of severe suicidal ideation in major depressive disorder

Suicidal ideation (SI) is a risk factor for suicidal behaviour. To ascertain the clinical correlates and prognostic impact of severe SI, we analysed 249 outpatients with major depressive disorder (MDD) and suicidal thoughts included in the COmbining Medications to Enhance Depression outcome (CO-MED) trial. Patients with severe SI (36%) were younger at disease onset (P = 0.0033), more severely depressed (P = 0.0029), had more lifetime suicidal behaviour (P < 0.0001) and psychiatric comorbidities (panic disorder: P = 0.0025; post-traumatic stress disorder: P = 0.0216), and a history of childhood maltreatment (neglect: P = 0.0054; emotional abuse: P = 0.0230; physical abuse: P = 0.0076; sexual abuse: P = 0.0016) than those experiencing low-moderate SI. After controlling for depression score, severe SI was positively correlated with lifetime suicidal behaviour (OR [95% CI]: 1.26 [1.12-1.41]), panic disorder (1.05 [1.00-1.12]), and childhood maltreatment (neglect: 1.93 [1.13-3.30]; physical abuse: 2.00 [1.11-3.69]; sexual abuse: 2.13 [1.17-3.88]), and inversely correlated with age of onset (0.97 [0.95-0.99]) and sleep-onset insomnia (0.76 [0.61-0.96]). Finally, the occurrence of serious lifetime suicidal behaviour was predicted by SI severity (2.18 [1.11-4.27]), bipolar score (1.36 [1.02-1.81]), and childhood sexual abuse (2.35 [1.09-5.05]). These results emphasise the importance of assessing childhood maltreatment and bipolar liability in MDD to estimate suicidal behaviour risk

Challenging sequential approach to treatment resistant depression: Cost-utility analysis based on the Sequenced Treatment Alternatives to Relieve Depression (STAR⁎D) trial

In major depression, when a first antidepressant does not cause remission of symptoms (60%–75%), there are several options for continuing treatment in the next step. This study is a cost-utility analysis (CUA) of different second-line approaches. In a simulated trial outpatients with MDD were treated with citalopram for 13 weeks (level 1), then based on two alternative algorithms implemented from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Algorithm A: citalopram was continued until study endpoint (week 26). Algorithm B: patients who remitted during level 1 continued citalopram. Those who did not remit could opt for switching to another antidepressant (venlafaxine; sertraline) (b1) or adding bupropion to citalopram treatment (augmentation; b2). Algorithm B increased remission rate by 10.6% over Algorithm A (number needed to treat: 9.9; sensitivity range: 9.1–12.5). As a comparison, differences between active antidepressants and placebo are associated with NNT values of 6 to 8. In CUA Algorithm B was dominant with an ICER of $11,813 (sensitivity range=$1783 – $21,784), which is <1GDP per capita cost-effectiveness threshold (USA=$47,193). Among Algorithm B options, switching (b1) dominated Algorithm A with a smaller number of responders than augmentation approach (b2) (NNT 11 vs. 7.7), whereas ICER values were similar (b1: $14,738; b2:$15,458). However we cannot exclude a bias in selecting second treatment. This cost-utility analysis shows (in line with current guidelines) a benefit in modifying antidepressant treatment if response to first-line agent does not occur within 3 months, but not a clear-cut evidence in terms of NNT

A model to incorporate genetic testing (5-HTTLPR) in pharmacological treatment of major depressive disorders.

none5Objective. To evaluate the benefit of pharmacogenetics in antidepressant treatment. Methods. In a simulated trial 100,000 subjects in a current episode of major depressive disorder (MDD) received citalopram or bupropion based on the clinician's decision (algorithm A) or following indications from 5-HTTLPR genetic testing (algorithm B), which effect size of was estimated from a meta-analysis of pharmacogenetic trials. A and B were compared in a cost-utility analysis (12 weeks). Costs (international $, 2010) were drawn from official sources. Treatment effects were expressed as quality-adjusted life weeks (QALWs). Outcome was incremental cost-effectiveness ratio (ICER). Results. Under base-case conditions, genetic test use was associated with increases in antidepressant response (0.062 QALWs) and tolerability (0.016 QALWs) but cost benefit was not acceptable (ICER =$2,890; $1,800-$4,091). However, when the joint effect on antidepressant response and tolerability was analyzed in two recurrent episodes, ICER dropped to $1,392 ($837-$1,982). Cost-effectiveness acceptability curve (CEAC) showed a >80% probability that ICER value fell below the commonly accepted 3 times Gross Domestic Product (GDP) threshold (World Health Organization) and therefore suggesting cost-effectiveness. Conclusion. Notwithstanding some caveats (exclusion of gene-gene and gene-environment interactions; simple 5-HTTLPR architecture), this simulation is favourable to incorporate pharmacogenetic test in antidepressant treatment.openA. Serretti; P. Olgiati; E. Bajo; M. Bigelli; D. De RonchiA. Serretti; P. Olgiati; E. Bajo; M. Bigelli; D. De Ronch

Genetics of Late-Onset Alzheimer's Disease: Update from the Alzgene Database and Analysis of Shared Pathways

The genetics of late-onset Alzheimer's disease (LOAD) has taken impressive steps forwards in the last few years. To date, more than six-hundred genes have been linked to the disorder. However, only a minority of them are supported by a sufficient level of evidence. This review focused on such genes and analyzed shared biological pathways. Genetic markers were selected from a web-based collection (Alzgene). For each SNP in the database, it was possible to perform a meta-analysis. The quality of studies was assessed using criteria such as size of research samples, heterogeneity across studies, and protection from publication bias. This produced a list of 15 top-rated genes: APOE, CLU, PICALM, EXOC3L2, BIN1, CR1, SORL1, TNK1, IL8, LDLR, CST3, CHRNB2, SORCS1, TNF, and CCR2. A systematic analysis of gene ontology terms associated with each marker showed that most genes were implicated in cholesterol metabolism, intracellular transport of beta-amyloid precursor, and autophagy of damaged organelles. Moreover, the impact of these genes on complement cascade and cytokine production highlights the role of inflammatory response in AD pathogenesis. Gene-gene and gene-environment interactions are prominent issues in AD genetics, but they are not specifically featured in the Alzgene database

Using DRG to analyze hospital production: a re-classification model based on a linear tree-network topology

Background: Hospital discharge records are widely classified through the Diagnosis Related Group (DRG) system; the version currently used in Italy counts 538 different codes, including thousands of diagnosis and procedures. These numbers reflect the considerable effort of simplification, yet the current classification system is of little use to evaluate hospital production and performance. Methods: As the case-mix of a given Hospital Unit (HU) is driven by its physicians’ specializations, a grouping of DRGs into a specialization-driven classification system has been conceived through the analysis of HUs discharging and the ICD-9-CM codes.&nbsp;We propose a three-folded classification, based on the analysis of 1,670,755 Hospital Discharge Cards (HDCs) produced by Lombardy Hospitals in 2010; it consists of 32 specializations (e.g. Neurosurgery), 124 sub-specialization (e.g. skull surgery) and 337 sub-sub-specialization (e.g. craniotomy). Results: We give a practical application of the three-layered approach, based on the production of a Neurosurgical HU; we observe synthetically the profile of production (1,305 hospital discharges for 79 different DRG codes of 16 different MDC are grouped in few groups of homogeneous DRG codes), a more informative production comparison (through process-specific comparisons, rather than crude or case-mix standardized comparisons) and a potentially more adequate production planning (considering the Neurosurgical HUs of the same city, those produce a limited quote of the whole neurosurgical production, because the same activity can be realized by non-Neurosugical HUs). Conclusion: Our work may help to evaluate the hospital production for a rational planning of available resources, blunting information asymmetries between physicians and managers.&nbsp

Influence of postpartum onset on the course of mood disorders

BACKGROUND: To ascertain the impact of postpartum onset (PPO) on the subsequent time course of mood disorders. METHODS: This retrospective study compared per year rates of excited (manic or mixed) and depressive episodes between fifty-five women with bipolar (N = 22) or major depressive (N = 33) disorders with first episode occurring postpartum (within four weeks after childbirth according to DSM-IV definition) and 218 non-postpartum onset (NPPO) controls. Such patients had a traceable illness course consisting of one or more episodes alternating with complete symptom remission and no additional diagnoses of axis I disorders, mental retardation or brain organic diseases. A number of variables reported to influence the course of mood disorders were controlled for as possible confounding factors RESULTS: Bipolar women with postpartum onset disorder had fewer excited episodes (p = 0.005) and fewer episodes of both polarities (p = 0.005) compared to non-postpartum onset subjects. No differences emerged in the rates of depressive episodes. All patients who met criteria for rapid cycling bipolar disorder (7 out of 123) were in the NPPO group. Among major depressives, PPO patients experienced fewer episodes (p = 0.016). With respect to clinical and treatment features, PPO-MDD subjects had less personality disorder comorbidity (p = 0.023) and were less likely to be on maintenance treatment compared to NPPO comparison subjects (p = 0.002) CONCLUSION: Such preliminary findings suggest that PPO mood disorders may be characterized by a less recurrent time course. Future research in this field should elucidate the role of comorbid personality disorders and treatment. Moreover it should clarify whether PPO disorders are also associated with a more positive outcome in terms of social functioning and quality of life

Persistent benefits of slow titration of paroxetine in a six-month follow-up

Objective Paroxetine titration may be difficult in older individuals as they are more sensitive to side effects. The current study extends to 6 months our previously published report in which paroxetine was started at 2.5 mg/day and slowly increased by 2.5 mg on alternate days (slow titration) or rapidly titrated to target dose from 10 mg/day (standard titration) in a naturalistic setting. Methods Here, the follow-up period was extended to 26 weeks. We performed an intent-to-treat analysis of 47 subjects from the original sample (major depressive disorder and/or generalized anxiety disorder (GAD); >60 years of age). Missing evaluations were replaced by last observations carried forward. GAD was included as a stratification factor. Results Patients in whom paroxetine was slowly up-titrated were more likely to remit (84.0% vs 54.5%; p = 0.028) and had lower core depression (p = 0.0015) and psychic anxiety levels (p = 0.006) after 26 weeks. Dropout rate was 20% in the slow titration group compared with 77.3% in the standard titration arm (p < 0.001). Patients with GAD accounted for all significant associations. No substantial differences were reported between slow and standard titration groups in the subsample without GAD. Conclusions Despite some limitations, these findings suggest that paroxetine treatment should be started at lower doses in older depressed patients and slowly up-titrated. This strategy would allow to increase antidepressant response and the likelihood of completing treatment cycle in patients with high anxiety levels and GAD comorbidity

Should pharmacogenetics be incorporated in major depression treatment? Economic evaluation in high- and middle-income European countries

none5noThe serotonin transporter 5-HTTLPR polymorphism moderates response to SSRIs and side-effect burden. The aim of this study is to quantify the cost-utility of incorporating 5-HTTLPR genotyping in drug treatment of major depressive disorder (MDD). We previously reported a theoretical model to simulate antidepressant treatment with citalopram or bupropion for 12weeks. The drugs were alternatively selected according to an 'as usual' algorithm or based on response and tolerability predicted by 5-HTTLPR profile. Here we apply this model to conduct a cost-utility analysis in three European regions with high GDP (Euro A), middle GDP (Euro B) and middle-high GDP (Euro C).. In addition we test a verification scenario in which citalopram+bupropion augmentation is administered to individuals with the least favorable 5-HTTLPR genotype. Treatment outcomes are remission and Quality Adjusted-Life Weeks (QALW). Cost data (international $, year 2009) are retrieved from the World Health Organization (WHO) and national official sources. In base-case scenario incremental cost-effectiveness ratio (ICER) values are$1147 (Euro A), $1185 (Euro B) and$1178 (Euro C). From cost-effectiveness acceptability curve (CEAC), the probability of having an ICER value below WHO recommended cost-utility threshold (3 GDP per capita=$1926) is >90$100, pharmacogenetic approach becomes cost-effective in middle-income countries (Euro B). This simulation using data from 27 European states suggests that choosing antidepressant treatment from the results of 5-HTTLPR might be a cost-effective solution in high income countries. Its feasibility in middle income countries needs further research.openP. Olgiati; E. Bajo; M. Bigelli; D. De Ronchi; A. SerrettiP. Olgiati; E. Bajo; M. Bigelli; D. De Ronchi; A. Serrett

SAFECAST Project: Definition and Analysis of the Three-Storey Precast Building

In this paper the activity carried out at the Joint Research Centre of the European Commission (JRC) during the first year of the SAFECAST project is described. After a description of the initial study, focused on the design procedures for precast structures and on the typologies of connections, the results of the predictive analysis performed with simplified models of the three-storey structure that will be tested in ELSA Laboratory are presented. The main results of the analysis are presented in terms of expected ductility demands and a check of the compatibility of the expected response of the structure with the scope of the test programme and with the capabilities of the equipment of the laboratory is performed. In particular, this last check put into evidence some peculiarities of the seismic response which finally will correspond to a modification in the size of the specimen.JRC.DG.G.5-European laboratory for structural assessmen