Towards achieving remission in the treatment of depression

The burden of depressive illness constitutes a major public health issue. Despite real progress and better tolerance of new antidepressant medications, a significant number of depressed patients still suffer from rather severe residual depressive symptoms.This relative lack of efficacy clearly interferes with their psychosocial functioning and their quality of life. In addition, it is now well-recognized that the failure to reach full clinical remission after antidepressant treatment involves a high risk of relapse or recurrence in patients suffering from major depression. This paper reviews the concept of remission across different definitions, and the potential risk factors associated with the failure to reach clinical remission. The identification of specific residual symptoms in nonremitted patients is also of great importance, in order to assess the predictive value of those symptoms in relation to relapse and recurrence. Some methodological issues are also discussed, as well as various therapeutic strategies aimed at relieving residual depressive symptoms. Clinical remission remains a qold standard and a primary objective of modem antidepressant therapy

El cerco trascendental de la Metafísica. Acerca del pensamiento metafísico de José Gómez Caffarena

La proposta metafísica de José Gómez Caffarena no s'entén sense l'intent de J. Maréchal de coordinar en un mateix discurs l'especulació metafísica tomista i l'esperit de la crítica kantiana a través de l'explicitació dels temes clàssics de la metafísica de l'Aquinat a la llum de les convergències que, al seu parer, aquesta manté amb l'obra de Kant.El treball d'investigació que es presenta té per objectiu calibrar fins a quin punt l'obra especulativa de Caffarena suposa una continuació articulada des de l'esquema bàsic de tal 'tomisme transcendental'. La tesi que es defensa és que la seva proposta, de tonalitats marcadament més kantianes que la d'altres pensadors transcendentals, suposa no només un pas legítim, i potser més coherent amb el transcendentalisme kantià, sinó també una pedra de toc crítica per a l'abast últim de tota metafísica transcendental. El fet de remuntar la raó metafísica a l'àmbit antropològic fa que el fenomenisme epistemològic, el discurs asimptòtic sobre l'Absolut i la reducció formal de la seva nota 'personal' ('Déu') hagin de ser, estrictament, la darrera paraula d'aquesta metafísica. Davant d'això respon Caffarena amb una assumpció racional-vitalista del 'sentit de la vida' per dotar de vigència i veritat les afirmacions realitzades. Un 'haver de ser' que omple de contingut l'estructura conceptual erigida fent del primat de la raó pràctica i el seu interès l'eix vertebrador de la seva proposta metafísica.L'anàlisi pren com a principal punt de referència les tres obres metafísiques de l'autor (Metafísica Fundamental, Metafísica Trascendental, Metafísica Religiosa) i el seu últim gran treball, El Enigma y el Misterio, que en la investigació és tinguda com una revisió de la trilogia anterior. Atenent al seu contingut, es corrobora la darrera modèstia crítica en la qual queda la reflexió metafísica de Caffarena, amb la consegüent obertura a una raó més apofàtica que propositiva pel que fa a la 'darrera qüestió' metafísica. Donat que la desigual relació entre l'àmbit del teòric i el primat del pràctic, lluny d'equilibrar-se és cada vegada més notòria, distanciant-se així de la intenció de l'obra de Maréchal, en la investigació s'assumeix com a darrera conclusió que l'obra de Caffarena llega, precisament en tant que límit de la pretensió de dur a terme una metafísica transcendental, la necessitat de repensar el mètode de la Metafísica.La propuesta metafísica de José Gómez Caffarena no se comprende sin el intento de J. Maréchal de coordinar en un mismo discurso la especulación metafísica tomista y el espíritu de la crítica kantiana a través de una explicitación de los temas clásicos de la metafísica del Aquinate a la luz de las convergencias que, a su parecer, ésta mantiene con la obra de Kant. El trabajo de investigación que se presenta tiene por objetivo calibrar hasta qué punto la obra especulativa de Caffarena supone una continuación articulada desde el esquema básico de tal 'tomismo trascendental'. La tesis que se defiende es que su propuesta, de tintes y rasgos marcadamente más kantianos que la de otros pensadores trascendentales, supone no solamente un paso legítimo, y quizá más coherente con el trascendentalismo kantiano, sino también una piedra de toque crítica para el alcance último de toda metafísica trascendental. El retrotraimiento de la razón metafísica a lo antropológico hace que el fenomenismo epistemológico, el discurso asintótico sobre lo Absoluto y la reducción formal de su nota 'personal' ('Dios') deban ser, estrictamente, la última palabra de esta metafísica. Ante ello responde Caffarena con una asunción racional-vitalista del 'sentido de la vida' para dotar de vigencia y verdad las afirmaciones realizadas. Un 'deber ser' que llena de contenido la estructura conceptual erigida haciendo del primado de la razón práctica y su interés el eje vertebrador de su propuesta metafísica.El análisis toma como principal punto de referencia las tres obras metafísicas del autor (Metafísica Fundamental, Metafísica Trascendental, Metafísica Religiosa) y su último gran trabajo, El Enigma y el Misterio, que en la investigación es tenida como una revisión de la trilogía anterior. Atendiendo a su contenido, se corrobora la postrera modestia crítica en que queda la reflexión metafísica de Caffarena, con la consiguiente apertura a una razón más apofática que propositiva en lo que concierne a la 'última cuestión' metafísica. Puesto que la desigual relación entre el ámbito de lo teórico y el primado de lo práctico, lejos de equilibrarse, es cada vez más notoria, distanciándose así de la intención de la obra de Maréchal, se asume como última conclusión de la investigación que la obra de Caffarena arroja, precisamente en tanto que límite de la pretensión de llevar a cabo una metafísica trascendental, la necesidad de repensar el método de la Metafísica.It is not possible to understand José Gómez Caffarena's metaphysical proposal without J. Maréchal's attempt to coordinate, in the same discourse, the thomistic metaphysical speculation and Kantian criticism's spirit, by means of making explicit Aquinas' classic metaphysical themes in view of the convergences that, according to him, it keeps with Kant's work. The research work here presented seeks to evaluate to what extent Caffarena's speculative work represents a continuation of the basic scheme of such 'transcendental thomism'. The defended thesis is that his proposal, which evidences features more markedly Kantian than other transcendental thinkers, is not only a legitimate step, and perhaps even more consistent with Kantian transcendentalism, but also a critical touchstone of any transcendental metaphysics. The fact that metaphysical reason goes back to the anthropological scope determines that the epistemological phenomenalism, the asymptotic discourse about the Absolute and the formal reduction of his 'personal' attributes ( 'God') must be, strictly speaking, the last word of this metaphysics. In response to this, Caffarena adopts a rational-vitalistic approach to the 'meaning of life' in order to provide his assertions with validity and truth. A 'must be' that supplies the erected conceptual structure with content, turning the primacy of practical reason and its importance into the cornerstone of his metaphysics. The analysis takes as its main reference points our author's three metaphysical works (Metafísica Fundamental, Metafísica Trascendental, Metafísica Religiosa) and his last major work, El Enigma y el Misterio, which in this research is considered as a revision of the previous trilogy. Taking its content into account, it is possible to confirm that Caffarena's metaphysical reflection remains in a critical modesty, which entails the beginning of a more apophatic than propositive consideration about the 'last question' in metaphysics. Bearing in mind that the uneven relationship between the scope of the theoretical reason and the primacy of the practical one, far from reaching a balance, becomes more noticeable, thus moving away from Maréchal's work intentions, it is assumed as the ultimate conclusion of the investigation that Caffarena's proposal leaves, precisely because it sets a limit to the aim of developing a transcendental metaphysics, the need to rethink Metaphysics' method.La proposta metafisica di José Gómez Caffarena non si comprende senza il tentativo di J. Maréchal di unire tra loro il discorso metafisico tomista e lo spirito della critica kantiana, ovvero di esplicitare i temi classici della metafisica di Tommaso d'Aquino alla luce delle convergenze che, secondo il parere del filosofo belga, questa presenta con l'opera di Kant. Il lavoro di ricerca che presentiamo si propone di valutare in quale misura l'opera speculativa di Caffarena è una continuazione articolata sulla base strutturale di tale 'tomismo trascendentale'. La tesi che presentiamo è che la sua opera, dalle caratteristiche nettamente più kantiane rispetto ad altri pensatori della corrente trascendentale, non è soltanto un passo legittimo, e forse più coerente con il trascendentalismo kantiano, ma anche un contrappunto critico sulla portata ultima di una metafisica trascendentale. Volgendosi la ragione metafisica all'ambito antropologico, ne consegue che il fenomenismo epistemologico, il discorso asintotico sull'Assoluto e la riduzione formale della caratteristica 'personale' ('Dio') divengono, logicamente (rigorosamente), l'ultima parola di una tale metafisica. A tutto ciò Caffarena risponde con una affermazione razionale-vitalistica del 'senso della vita' per dotare di validità e verità le sue affermazioni. Un 'dover essere' che riempia di contenuto la struttura concettuale eretta facendo del primato della ragione pratica e dell'importanza di questa la pietra angolare della sua metafisica. L'analisi prende come punto di riferimento principale le tre opere metafisiche dell'autore (Metafísica Fundamental, Metafísica Trascendental, Metafísica Religiosa) nonché l'ultima importante da lui realizzata, El Enigma y el Misterio, che nella ricerca che presentiamo viene letta come una revisione della trilogia precendente. Il suo contenuto conferma la modestia critica a cui giunge da ultimo la riflessione metafisica di Caffarena con la conseguente apertura a una ragione più apofatica che assertiva per quanto concerne 'la questione ultima' della metafisica. Poichè il rapporto disuguale tra il campo d'applicazione teorico e il primato della ragione pratica si accentua sempre di più, invece di equilibrarsi, allontanandosi così dallo spirito dell'opera di Maréchal, la conclusione ultima della nostra ricerca sulla proposta di Caffarena, proprio perché questa rappresenta il limite alla pretensione di costruire una metafisica trascendentale, è la necessità di ripensare il metodo della Metafisica

Molecular changes associated with escitalopram response in a stress-based model of depression

Converging evidence points at hypothalamus-pituitary-adrenal (HPA) axis hyperactivity and neuroinflammation as important factors involved in the etiopathogenesis of major depressive disorder (MDD) and in therapeutic efficacy of antidepressants. In this study, we examined the molecular effects associated with a response to a week-long treatment with escitalopram in the chronic escape deficit (CED) model, a validated model of depression based on the induction of an escape deficit after exposure of rats to an unavoidable stress. We confirmed our previous result that a treatment with escitalopram (10 mg/kg) was effective after 7 days in reverting the stress-induced escape deficit in approximately 50% of the animals, separating responders from non-responders. Expression of markers of HPA axis functionality as well as several inflammatory mediators were evaluated in the hypothalamus, a key structure integrating signals from the neuro, immune, endocrine systems. In the hypothalamus of responder animals we observed a decrease in the expression of CRH and its receptors and an increase in GR protein in total and nuclear extracts; this effect was accompanied by a significant decrease in circulating corticosterone in the same cohort. Hypothalamic IL-1\uce\ub2 and TNF\uce\ub1 expression were increased in stressed animals, while CXCL2, IL-6, and ADAM17 mRNA levels were decreased in escitalopram treated rats regardless of the treatment response. These data suggest that efficacy of a one week treatment with escitalopram may be partially mediated by a decrease HPA axis activity, while in the hypothalamus the drug-induced effects on the expression of immune modulators did not correlate with the behavioural outcome

La vida como proyecto y sentido

El propósito de este artículo es aproximarnos al tratamiento que la cuestión del sentido antropológico ha recibido por parte de dos egregios filósofos españoles. El primer gran bloque estará dedicado a explorar —siguiendo a José Ortega y Gasset— cómo la vida auténtica es genuinamente proyectiva, una empresa mediante la cual se despliega el sentido personal. De este modo podremos ahondar en nociones tan relevantes como la vocación, el destino o el fondo insobornable. En la segunda y última parte, José Gómez Caffarena nos ayudará a cuestionar si la experiencia de sentido es indisociable de la gran pregunta por el Sentido, entendido como el horizonte meta-físico de la vida humana

A polygenic predictor of treatment-resistant depression using whole exome sequencing and genome-wide genotyping

Treatment-resistant depression (TRD) occurs in ~30% of patients with major depressive disorder (MDD) but the genetics of TRD was previously poorly investigated. Whole exome sequencing and genome-wide genotyping were available in 1209 MDD patients after quality control. Antidepressant response was compared to non-response to one treatment and non-response to two or more treatments (TRD). Differences in the risk of carrying damaging variants were tested. A score expressing the burden of variants in genes and pathways was calculated weighting each variant for its functional (Eigen) score and frequency. Gene-based and pathway-based scores were used to develop predictive models of TRD and non-response using gradient boosting in 70% of the sample (training) which were tested in the remaining 30% (testing), evaluating also the addition of clinical predictors. Independent replication was tested in STAR*D and GENDEP using exome array-based data. TRD and non-responders did not show higher risk to carry damaging variants compared to responders. Genes/pathways associated with TRD included those modulating cell survival and proliferation, neurodegeneration, and immune response. Genetic models showed significant prediction of TRD vs. response and they were improved by the addition of clinical predictors, but they were not significantly better than clinical predictors alone. Replication results were driven by clinical factors, except for a model developed in subjects treated with serotonergic antidepressants, which showed a clear improvement in prediction at the extremes of the genetic score distribution in STAR*D. These results suggested relevant biological mechanisms implicated in TRD and a new methodological approach to the prediction of TRD.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Polygenic risk scores for neuropsychiatric, inflammatory, and cardio-metabolic traits highlight possible genetic overlap with suicide attempt and treatment-emergent suicidal ideation

Suicide is the second cause of death among youths. Genetics may contribute to suicidal phenotypes and their co-occurrence in other neuropsychiatric and medical conditions. Our study aimed to investigate the association of polygenic risk scores (PRSs) for 24 neuropsychiatric, inflammatory, and cardio-metabolic traits/diseases with suicide attempt (SA) or treatment-worsening/emergent suicidal ideation (TWESI). PRSs were computed based on summary statistics of genome-wide association studies. Regression analyses were performed between PRSs and SA or TWESI in four clinical cohorts. Results were then meta-analyzed across samples, including a total of 688 patients with SA (N-eff = 2,258) and 214 with TWESI (N-eff = 785). Stratified genetic covariance analyses were performed to investigate functionally cross-phenotype PRS associations. After Bonferroni correction, PRS for major depressive disorder (MDD) was associated with SA (OR = 1.24; 95% CI = 1.11-1.38; p = 1.73 x 10(-4)). Nominal associations were shown between PRSs for coronary artery disease (CAD) (p = 4.6 x 10(-3)), loneliness (p = .009), or chronic pain (p = .016) and SA, PRSs for MDD or CAD and TWESI (p = .043 and p = .032, respectively). Genetic covariance between MDD and SA was shown in 86 gene sets related to drugs having antisuicidal effects. A higher genetic liability for MDD may underlie a higher SA risk. Further, but milder, possible modulatory factors are genetic risk for loneliness and CAD