Aquesta tesi es planteja com a objectiu principal identificar, en pacients amb trastorn depressiu major (TDM), característiques neuroanatòmiques, tant a nivell neuroestructural com neurofuncional, que es puguin relacionar amb variables clíniques, d'evolució i de resposta a tractament i per tant, constituir fenotips de neuroimatge. Amb aquesta finalitat hem estudiat la relació entre les dades obtingudes mitjançant ressonància magnètica (RM) i variables com el subtipus depressiu (depressió amb malenconia i depressió comòrbida a trastorn obsessiu-compulsiu (TOC)), el nombre de recaigudes, el temps fins a la remissió o la resposta a tractament. Aquesta tesis doctoral consta de tres estudis principals: PRIMER ESTUDI: Es va estudiar un grup de pacients amb TDM que apareixia en el decurs d'un TOC, comparant-los amb un grup de pacients amb TOC pur. Es va deteminar que els primers presentaven una major reducció de l'escorça orbito-frontal medial (EOFm) i un patró de correlacions amb altres estructures que els diferenciava clarament dels subjectes amb TOC pur. Publicació: N Cardoner, C Soriano-Mas, J Pujol, P Alonso, B Harrison, J Deus, R Hernández-Ribas, JM Menchón, J Vallejo. Brain structural correlates of depressive comorbidity in obsessive-compulsive disorder. Neuroimage 2007; 38: 413-421 Factor d’impacte = 5,937. JCR 2010 = 1r quartil, 1r decil, número 1/14 (Neuroimatge). SEGON ESTUDI: Es va estudiar de forma transversal un grup de 70 pacients amb depressió malenconiosa, comparant-los amb una mostra de controls sans. Es van trobar reduccions de substància gris (SG) en l'ínsula esquerra i increment de la substància blanca (SB) en l'àrea troncoencefálica superior. Posteriorment es va realitzar el seguiment longitudinal d'aquests pacients, obtenint-se, en 30 dels 70 pacients inclosos en l'estudi transversal, una segona RM al cap de 7 anys. La SB de l'àrea troncoencefálica superior va mostrar una evolució temporal diferencial entre els pacients depressius i els controls sans, mostrant una disminució de volum en els primers i un increment en els segons. El decrement de SG en ambdues ínsules es va relacionar amb el nombre de recaigudes durant el seguiment. Publicació: C Soriano-Mas, R Hernández-Ribas, J Pujol, M Urretavizcaya, J Deus, B Harrison, H Ortiz, M López-Solà, JM Menchón, N Cardoner. Cross-Sectional and Longitudinal Assessment of Structural Brain Alterations in Melancholic Depression. Biological Psychiatry 2011; 69:318-325 Factor d’impacte = 8,674. JCR 2010 = 1r quartil, 1r decil, número 4/128 (Psiquiatria). TERCER ESTUDI: Es va estudiar mitjançant RM funcional (RMf) una mostra de pacients amb TDM amb la finalitat de determinar els correlats neurofuncionals de la resposta al tractament actiu mitjançant estimulació magnètica transcranial repetitiva (EMTr), comparant-lo amb un grup de subjectes que rebien EMTr placebo. Es va relacionar la resposta clínica a EMTr amb l'activitat en l'escorça cingulada anterior (CCA), l’EOFm esquerra, l'escorça frontal medial (EFm) dreta i el putamen ventro-caudal esquerre. Publicació: R Hernández-Ribas, J Deus, J Pujol, C Segalàs, J Vallejo, JM Menchón, N Cardoner, C Soriano-Mas. Identifying Brain Imaging Correlates of Clinical Response to Repetitive Transcranial Magnetic Stimulation (rTMS) in Major Depression. Brain Stimulation (en premsa) Factor de impacto = 4,964. JCR 2010 = 1r quartil, número 41/239 (Neurociències). VALORACIÓ GLOBAL: En concordança amb les hipòtesis i els objectius del present treball, s’han descrit un conjunt d’alteracions neuroestructurals i neurofuncionals que es poden considerar correlats neurals d’aspectes clínics com el subtipus depressiu, d’aspectes evolutius com el nombre de recurrències clíniques, o d’aspectes relacionats amb la resposta al tractament antidepressiu. Aquests correlats es podrien considerar, segons el nostre criteri, com a fenotips de neuroimatge, ja que s’associen a característiques concretes del trastorn depressiu major i ens permeten diferenciar entre grups/subgrups de pacients. / MAGNETIC RESONANCE IMAGING STUDY OF NEURAL BASIS OF MAJOR DEPRESSIVE DISORDER: FOCUS ON SYMPTOMS, LONGITUDINAL COURSE AND RESPONSE TO TREATMENT SUMMARY: Main objective: To identify brain imaging correlates of clinical, outcome and treatment response variables in patients with major depressive disorder (MDD). FIRST STUDY 72 obsessive-compulsive patients (OCD) with (n=33) or without (n=39) MDD, and 72 control subjects (CS) were assessed. OCD with MDD showed a larger reduction of medial orbitofrontal cortex (mOFC) gray matter (GM) volume. Both OCD groups showed distinct correlations of mOFC GM volume with other brain regions. Publication: N Cardoner, C Soriano-Mas, J Pujol, P Alonso, B Harrison, J Deus, R Hernández-Ribas, JM Menchón, J Vallejo. Brain structural correlates of depressive comorbidity in obsessive-compulsive disorder. Neuroimage 2007; 38: 413-421 SECOND STUDY Whole-brain magnetic resonance images (MRI) were collected from 70 melancholic inpatients and 40 CS. A subset of 30 patients and 20 CS were rescanned after a 7-year period. In cross-sectional assessment, melancholic patients showed GM reductions in the left insula and white matter (WM) increases in the upper brainstem tegmentum. In longitudinal assessment, WM of the upper brainstem tegmentum showed a different temporal evolution between groups. Bilateral GM insulae reductions were associated with the number of relapses. Publication: C Soriano-Mas, R Hernández-Ribas, J Pujol, M Urretavizcaya, J Deus, B Harrison, H Ortiz, M López-Solà, JM Menchón, N Cardoner. Cross-Sectional and Longitudinal Assessment of Structural Brain Alterations in Melancholic Depression. Biological Psychiatry 2011; 69:318-325 THIRD STUDY Twenty-one MDD patients received active or sham repetitive Transcranial Magnetic Stimulation (rTMS) on the left dorsolateral prefrontal cortex. In the active rTMS group, clinical response was correlated to smaller pre-treatment deactivations in the anterior cingulate, the left medial orbitofrontal and the right middle frontal cortices, and to larger activations in the left ventral-caudal putamen. Publication: R Hernández-Ribas, J Deus, J Pujol, C Segalàs, J Vallejo, JM Menchón, N Cardoner, C Soriano-Mas. Identifying Brain Imaging Correlates of Clinical Response to Repetitive Transcranial Magnetic Stimulation (rTMS) in Major Depression. Brain Stimulation (in press) COMMENT In our research, we found brain imaging changes related to variables such as depressive subtype, number of clinical relapses or response to treatment. These imaging correlates could be considered as neuroimaging phenotypes.

1) Objectives: - To systematically evaluate the effectiveness of pharmacist care compared with usual care (UC) on improving adherence to antidepressants in depressed outpatients. - To evaluate the effectiveness and cost‐effectiveness of a community pharmacist intervention (CPI) compared to UC in the improvement of adherence to antidepressants and patient wellbeing in a primary care population initiating treatment with antidepressants. 2) Methods: A systematic review and meta‐analysis of randomized controlled trials (RCTs) that evaluated the impact of pharmacist interventions on improving adherence to antidepressants was conducted. RCTs were identified through electronic databases and manual search. Methodological quality was assessed and methodological details and outcomes were extracted in duplicate. A RCT comparing patients with depressive disorder receiving a low intensity CPI (87) with patients receiving UC (92) was performed in Barcelona. The intervention consisted of an educational programme focused on improving knowledge about medication, improving patients’ compliance and reducing stigma. Measurements took place at baseline, 3 and 6 months. Adherence was continuously registered from the computerized pharmacy records. Secondary outcomes included clinical severity of depression (PHQ‐9), health‐related quality of life (HRQOL) (EuroQol‐5D) and satisfaction with the treatment received. Direct and indirect costs were assessed using the Client Service Receipt Inventory. Unit costs were derived from official local sources. Quality‐Adjusted Life‐Years (QALYs) were calculated using the EuroQol‐5D Spanish tariffs. 3) Results: Six RCTs were identified in the systematic review; most of them were conducted in the USA. A total of 887 depressed patients who were initiating or maintaining treatment with antidepressants and who received pharmacist care (459 patients) or UC (428 patients) were included in the review. The most commonly reported interventions were patient education and monitoring, monitoring and management of toxicity and side effects and compliance promotion. Overall, no statistical heterogeneity or publication bias was detected. The pooled odds ratio was 1.64 (95% CI 1.24‐2.17). Subgroup analysis showed no statistically significant differences in results. Results from the RCT showed that patients in the CPI group were more likely to remain adherent at 3 and 6‐month follow‐up but the difference was not statistically significant. No statistically significant differences were observed in clinical symptoms or satisfaction with the pharmacy service. However, patients in the CPI group showed greater statistically significant improvement in HRQOL compared to UC patients, both in the ITT and PP analyses. Overall costs were higher in the CPI group than in UC patients, mainly because of differences in productivity losses. There were no statistically significant differences between groups in QALYs. From the societal perspective, the incremental cost‐effectiveness ratio (ICER) for CPI compared with UC was €9,335 per extra adherent patient. The incremental cost‐utility ratio (ICUR) was €38,896 per QALY gained. If willingness to pay (WTP) is €50,000 per one extra adherent patient, per extra remission of symptoms or per QALY, the probability of the CPI being cost‐effective was 0.71, 0.52 and 0.56, respectively. From the healthcare perspective, the ICER was €862 per extra adherent patient. ICUR was €3,542. The probability of the intervention being cost‐effective was 0.75 if WTP is €12,000 for an extra adherent patient and €40,000 for QALY gained. The probability of the CPI being cost‐effective in remission of depressive symptoms was 0.55 for a WTP of €50,000. 4) Conclusions: A pharmacist intervention could be a good strategy to improve patients’ adherence to antidepressants in primary care but evidence supporting the pharmacist intervention in depressed patients is still limited, especially in community pharmacies and outside the USA. A low intensity CPI proved to be ineffective in improving patients’ adherence to antidepressants or clinical symptomatology. However, it was effective in improving the patient’s HRQOL. The CPI was not cost‐effective in comparison with UC in the improvement of adherence, depressive symptoms and QALYs.