Dissertationen zum Thema „Manic depressive illness“

Many international studies have been conducted on paediatric bipolar disorder, but few research studies have been conducted on parenting a child diagnosed with bipolar disorder, both on an international and national level. The researcher utilised Bronfenbrenner’s Ecological Systems Theory as the theoretical framework in exploring and describing this research field. The study has been conducted by means of a systematic review and all of the articles included in the review examined some aspect of parenting and paediatric bipolar disorder. The articles were systematically assessed, and six themes emerged which include: paediatric bipolar on the rise; the effects of paediatric bipolar disorder, post-paediatric bipolar disorder; managing paediatric bipolar disorder is a family responsibility; foundations for effective parenting; and supporting parents of a paediatric bipolar patient.

If mania and depression are part of the same pathological processes, one would predict that episodes of one prospectively increase the odds of episodes of the other. The aim of the present study was to test this hypothesis. For comparison purposes, their relationship was contrasted to the relationship between mania and periods of psychosis. Exploratory analyses also tested the degree to which episodes of each occur with greater frequency over time (i.e., kindling). Participants for the present study came from the Suffolk County Mental Health Project (N = 628), a study of first-admission patients with psychosis. Of these participants, 144 met diagnostic criteria for bipolar I disorder and were analyzed for the current study. Results indicated that mania in a given month predicted depression the following month, even after controlling for other symptoms. The reverse, however, was not the case. Mania and psychosis, in contrast, were found to be robust predictors of one another from month to month. Effects were not due to treatment or demographic differences. These findings provide evidence that mania and depression are weakly related. In contrast, mania and psychosis are more closely linked. Findings are consistent with suggestions that psychiatric nosology regroup mania more closely with thought disorders rather than with internalizing or depressive ones. They also alert clinicians to the strong, longitudinal persistence and comorbidity among these syndromes.

This dissertation examines how bipolar disorder, a common and disabling psychiatric condition, is made relevant as a participants' concern in a site of massively consequential psychological business - the psychotherapy session. As its central thesis is the claim that the practices by which bipolar disorder gets done as bipolar disorder are invariably absent in most formal accounts of the disorder. In this regard, the dissertation provides an empirically grounded description of a range of discursive practices associated with the doing of bipolar disorder in psychotherapy. This is undertaken from a discursive psychological orientation that draws extensively from ethnomethodology, conversation analysis, and Wittgensteinian philosophy. Following a review of bipolar disorder as a diagnostic psychiatric category, consideration is given to alternate conceptualisations which suggest the category is constructed in-and-through complex socio-historical practices which are often occluded and considered irrelevant to the category's situated deployment. This notion is used to provide a more sustained examination of how one might 'get at' such practices in situ by way of conducting ethnomethodological and conversation analytically informed investigations. In consideration of how one might approach psychological categorisation practices in talk-in-interaction, a discursive psychological orientation is developed which stresses the social, public nature of psychological categories in use. The empirical materials examined in the dissertation are drawn from a corpus of audio recordings of seven 'naturally occurring' psychotherapy sessions involving a clinical psychologist and five clients for whom the category 'bipolar disorder' has demonstrable relevance. Practices examined include those relating to the production and recognition of what might count as a bipolar disorder 'symptom', the manner in which 'moods' operate as account production devices, and the methods by which psychological terms (such as 'thought' and 'feel') operate in-and-as situated practices involved in psychotherapeutic business.

This dissertation examines how bipolar disorder, a common and disabling psychiatric condition, is made relevant as a participants' concern in a site of massively consequential psychological business - the psychotherapy session. As its central thesis is the claim that the practices by which bipolar disorder gets done as bipolar disorder are invariably absent in most formal accounts of the disorder. In this regard, the dissertation provides an empirically grounded description of a range of discursive practices associated with the doing of bipolar disorder in psychotherapy. This is undertaken from a discursive psychological orientation that draws extensively from ethnomethodology, conversation analysis, and Wittgensteinian philosophy. Following a review of bipolar disorder as a diagnostic psychiatric category, consideration is given to alternate conceptualisations which suggest the category is constructed in-and-through complex socio-historical practices which are often occluded and considered irrelevant to the category's situated deployment. This notion is used to provide a more sustained examination of how one might 'get at' such practices in situ by way of conducting ethnomethodological and conversation analytically informed investigations. In consideration of how one might approach psychological categorisation practices in talk-in-interaction, a discursive psychological orientation is developed which stresses the social, public nature of psychological categories in use. The empirical materials examined in the dissertation are drawn from a corpus of audio recordings of seven 'naturally occurring' psychotherapy sessions involving a clinical psychologist and five clients for whom the category 'bipolar disorder' has demonstrable relevance. Practices examined include those relating to the production and recognition of what might count as a bipolar disorder 'symptom', the manner in which 'moods' operate as account production devices, and the methods by which psychological terms (such as 'thought' and 'feel') operate in-and-as situated practices involved in psychotherapeutic business.

Thesis (M.S.W.)--Smith College School for Social Work, Northampton, Mass., 2007<br>Thesis submitted in partial fulfillment for the degree of Master of Social Work. Includes bibliographical references (leaves 65-67).

It has been six decades since the discovery of lithium for the treatment of bipolar disorder. There is, as yet, no conclusive evidence as to how lithium produces this therapeutic effect, since it is known to interact with multiple cellular targets. One of the most credible targets is the enzyme, inositol monophosphatase (lMPase), which plays a crucial role in cell signalling. My aim was to find a novel IMPase inhibitor and evaluate it as a possible lithium-like mood stabiliser by using enzyme, cell and whole animal experiments. To achieve this, I created recombinant human and mouse IMPase enzymes and then used these for screening and crystallisation. I used two different approaches for the small-molecule screening: substrate-based virtual screening and drug repositioning using a library of compounds with clinically proven safety. I identified ebselen as a novel IMPase inhibitor suitable for drug repositioning. I determined thatebselen inhibited IMPase noncompetitively, likely through a covalent modification on a cysteine. In cell cultures, ebselen was found to inhibit not just IMPase but other steps that resulted in accumulation of higher inositol phosphates. When injected intraperitoneally into mice, ebselen crossed the blood- brain barrier and exhibited inhibition of IMPase ex vivo. Moreover, in mice, ebselen simulates some, but not all, of the behavioural effects of lithium. I have determined that ebselen inhibits IMPase and acts as a partial lithium mimetic. Given that ebselen is safe in man, it warrants clinical testing for the treatment of bipolar disorder.

Aim To determine the neural correlates of Bipolar Disorder (BD) using functional Magnetic Resonance Imaging (fMRI) in different phases of the illness. Methods Five fMRI studies were conducted in adult female BD patients and healthy matched comparison subjects. The first two studies examined patients with bipolar depression and hypomania using captioned-pictures to characterize mood-state related patterns of activation. The subsequent three studies investigated BD euthymia using emotional words and faces to identify a potential trait-marker. Results During depression, bipolar patients demonstrated additional subcortical activation in the thalamus, amygdala, hypothalamus and medial globus pallidus. In hypomania, patients again had additional subcortical activation involving the caudate and the thalamus. In both studies patients had prefrontal cortex activation, but the pattern differed from that in healthy subjects. These studies suggested a pattern of mood-state related subcortical recruitment for emotional processing in BD. The next set of studies examined euthymic BD patients to partition trait and state-markers. The first study used implicit positive and negative word-associated affect and found diminished responses to positive and negative affective words as compared to healthy subjects in both cortical and subcortical brain regions, in particular the cingulate, thalamus and caudate. The second study used the emotional Stroop task to elicit implicit affective processing and euthymic patients had less cortical and subcortical activation in response to affect, in particular decreased left ventral prefrontal cortex (BA47) activation. The final study used explicit emotional processing of fear and disgust to examine affective responses, and showed that patients were generally less responsive to disgust, but had comparatively greater activations to fear. Conclusions BD patients have a likely deficit in the ventral prefrontal cortex that is evident in euthymia. Prefrontal cognitive appraisal of emotions is constrained in euthymic, depressed and hypomanic phases, reflected in subcortical changes that suggest additional processing. The likely cause for this is a functional prefrontal cortex deficit that results in compensatory changes in emotional processing systems. Treatment probably stabilizes these systems without normalizing them. Our studies demonstrate the benefits of examining BD in its different phases, and future studies should attempt to emulate this in medication-free patients.

Bipolar disorder is a psychiatric condition which affects up to 1% of the general population and results in episodes of mania and depression. Molecular biological studies have shown that several components of the signal transduction pathways are affected in bipolar illness. However, the precise systems and components involved in the disorder still remain unknown. Our goal was to identify some of the differences in signal transduction pathways of B-lymphocytes. Using cultured lymphocytes obtained from bipolar patients, we found that there exist no difference in the levels of protein kinase C, Galphas and Galphai proteins, and tubulin between control and bipolar cell lines following stimulation of the PI pathway with the 5-HT 2 receptor agonist, alpha-methyl serotonin. These data are not consistent with previous findings. The lack of a significant difference between control and bipolar with respect to PKC might be due to the fact that we studied a different cell type or to poor stimulation conditions, and/or possibly to a high PKC content in the membrane of these cells, thereby masking the effect of stimulation. The results obtained for the G proteins can be attributed to a lack of effect of the agonist on these proteins which are associated with the adenylate cyclase pathway.

Bipolar disorder is characterized by episodes of mania and depression and serious suicidal risks. Recent studies reported high mental imagery susceptibility (general use of imagery in daily life and emotional impact of prospective imagery) in euthymic bipolar patients. This thesis aims to: a) replicate these findings in patients at different phases of bipolar disorder and with varying degrees of bipolarity, and b) explore how mental imagery susceptibility, ruminative processing, and behavioural approach system (BAS) sensitivity interact to amplify mood symptoms. Chapter 1 provides an overview of current theories of mood amplification and recurrence in bipolar disorders. Chapter 2 details the local validation of scales used in the thesis. Chapter 3 (Study 1) investigated whether mental imagery susceptibility, positive rumination and BAS sensitivity were elevated in remitted bipolar I disorder compared with major depressive disorder and non-psychiatric controls. Results suggested that these cognitive variables were elevated in remitted bipolar I disorder. Positive rumination also interacted with positive prospective images to predict bipolarity. Chapter 4 (Study 2) found that these cognitive variables were elevated in bipolar I disorder during manic and euthymic phases, compared to major depression. Further, the number of positive prospective images predicted recovery status and manic symptom severity. Chapters 5, 6 and 7 report that, compared with people without bipolar spectrum conditions, these cognitive characteristics were elevated in sub-threshold bipolar disorder (Study 3), individuals with high bipolar risks based on a behavioural paradigm (Study 4), and individuals with high familial risk (Study 5). Studies 3-5 confirmed that positive and negative prospective images interacted with rumination to amplify hypomanic and depressive symptoms respectively. Chapter 8 (Study 6) showed that suicidal flash-forwards function as a psychological escape from perceived entrapment and defeat in suicidality. Based on these findings, Chapter 9 proposes novel imagery-based techniques for targeting problematic imagery in bipolar disorders.

The overarching aim of this thesis was to use an experimental psychopathology approach to investigate mood, stress and mental imagery in the Broad Bipolar Phenotype (BPP), defined by the experience of elevated lifetime hypomania. Daily mood reactions to stress have been well explored in psychosis, but the limited research in BD has produced mixed findings. Holmes, Geddes, Colom and Goodwin (2008) hypothesised that mental imagery in BD may amplify emotion and worsen day to day mood extremes. This thesis investigates volunteers ranging across the continuum ofthe BPP in relation to key variables from the Holmes et al (2008) model: mood, stress and mental imagery, and brings new methodology to this area. The Mood Disorder Questionnaire (MDQ; Hirschfeld et ai, 2000) was used to identify groups with high (N=50; ~ 7 symptoms) and low (N=60; :s 6 symptoms) rates of hypomanic experience i.e. high MDQ and low MDQ. A single investigation was conducted for this thesis (N=IIO) which is divided into four studies. Study I and 2 tested the hypothesis that high MDQ volunteers would report higher levels of mental imagery compared to low MDQ volunteers. Study I (N=61) found that high MDQ volunteers had higher levels of trait mental imagery and intrusive imagery of the future, replicating patient findings. Study 2 (N=49) extended these findings to additional imagery measures. In a laboratory study, study 3 tested the hypothesis that after an experimental stressor (a traumatic film) high MDQ volunteers would experience more image-based flashback memories to the film than low MDQ volunteers. Volunteers reported any flashback memories to the film via mobile phone Short Message Service (SMS) prompts for six days, plus convergent measures at follow-up. As predicted, compared to the low MDQ group, the high MDQ group experienced significantly more flashback memories to the stressor (on all measures). Study 4 used an Experience Sampling Method (ESM; momentary assessment sampling over time) to frequently monitor mood and its event-related stress context. Thus, in the context of daily life study 4 sought to explore the role of bipolarity in exacerbating mood reactions, in comparison to other hypothesised contributors: neuroticism and intrusive imagery of the future. SMS mobile-phone messages were sent 10 times a day for 6 days to capture event-related stress ratings and mood ratings. Higher bipolarity (MDQ), neuroticism (EPQN) and intrusive imagery of the future (IFES) were each associated with increased mood reactions over six days, compared to lower levels of these characteristics. In understanding which of these characteristics best accounted for mood reactions, bipolarity (MDQ) best accounted for elated mood reactions, neuroticism did not best account for any moods, intrusive imagery of the future (lFES) best accounted for sad, depressed and anxious mood reactions and both bipolarity and intrusive imagery of the future best accounted for fearful mood reactions. In summary, the aim of this thesis was to investigate volunteers ranging across the continuum of the BPP in relation to key variables from the Holmes et al (2008) model: mood, stress and mental imagery. As predicted, compared to low MDQ volunteers, the high MDQ group had higher levels of I) self-reported use of mental imagery, 2) negative flashback memory imagery after an experimental stressor and 3) daily life negative mood reactions to stress. Critically, repeatedly imaging future scenes (lFES), which flash to mind unbidden, was found to show the greatest impact on negative mood reactions in daily life. Mental imagery offers a psychological characteristic which is elevated in volunteers at the higher end of the BPP continuum and also has the potential to be a novel cognitive treatment target in clinical BD samples. For example, targeting flashback memories after a stressor or targeting intrusive imagery of the future may help regulate mood reactions in daily life. This warrants further investigation in patients with BD.

A study was conducted in which a computerized battery of information processing tasks (called the COGLAB) was administered to three subject groups: patients with schizophrenia, patients with bipolar disorder, and normal controls. The tasks included Mueller-Lyer illusion, reaction time, size estimation, Wisconsin Card Sort, backward masking. and Asarnow Continuous Performance.

El trastorn bipolar és una malaltia altament discapacitant i que té un gran impacte en la vida dels pacients. L’any 2007, el Programa de Trastorn Bipolar de l’Hospital Clínic juntament amb la col•laboració d’altres centres internacionals, va crear una escala anomenada Functioning Assessment Short Test (FAST). Aquest instrument va surgir com a resposta a la necessitat que existia, tant en la pràctica clínica com en la recerca, d’una escala clínica que avalués el funcionament psicosocial dels pacients amb trastorn bipolar. Existeixen moltes escales per mesurar el funcionament psicosocial en les poblacions psiquiàtriques però cap d’elles és específica pel trastorn bipolar. A més la utilització de diferents instruments de mesura i paràmetres de discapacitat al llarg de la literatura fan difícil la comparació entre estudis. A més, la FAST com a escala de mesura quantitativa del funcionament psicosocial té molts avantatges respecte les que s’han utilitzat fins al moment: a) està dissenyada per experts en trastorn bipolar; per tant, els ítems que s’exploren reflecteixen realment les àrees on els pacients presenten més dificultats; b) l’avaluació és clínica, per tant no només es basa en les respostes del pacient sinó també es complementa la información amb altres fonts (curs clínic, avaluació del psiquiatre, informació dels familiars...). D’aquesta manera es superen moltes fonts de biaix típiques dels instruments d’autoavaluació, com per exemple l’estat d’ànim concomitant a l’avaluació que pot afectar positiva o negativament les respostes que dóna el pacient; c) finalment, una altra avantatge és la facilitat i rapidesa en la seva aplicació que la fa idònia per ser utilitzada tant en context de recerca com en la pràctica clínica diària. Amb la validació de la FAST, l’any 2007 , coincidint amb la meva incorporació a l’equip, es va obrir un nou horitzó per explorar el funcionament en el trastorn bipolar amb aquesta nova escala i respondre preguntes que fins ara no quedaven clares en la literatura. Així doncs, el primer pas va ser vincular-me en un estudi que ja estava iniciat, on s’avaluava el funcionament dels pacients amb trastorn bipolar en els tres estats diferents de la malaltia: eutímia, depressió i (hipo)mania en comparació amb un grup de controls sans. En aquest estudi, es va comprovar que la simptomatologia depressiva era més discapacitant que la maníaca però també es va observar que els pacients eutímics presentaven dificultats en el funcionament psicosocial. Amb el segon estudi (es va comparar una mostra de pacients eutímics dividits en funció de la tipologia diagnòstica (subtipus I vs. subtipus II) ja que revisant la literatura no quedava clar fins a quin punt aquest factor podria influenciar el funcionament psicosocial dels pacients eutímics. Finalment i aprofitant que l’escala FAST permet avaluar tant el funcionament global com també l’estudi de dominis específics del funcionament psicosocial, es va portar a terme un tercer estudi per tal d’analitzar quines variables clíniques i neurocognitives podrien ser les que impacten en el funcionament psicosocial dels pacients amb trastorn bipolar. Aquest estudi, respecte als dos anteriors introdueix com a novetat les variables neurocognitives així com també un disseny longitudinal amb un seguiment als Quatre anys.

Bipolar disorder is a serious illness affecting approximately 2-4% of the population and is one of the world’s leading causes of disability. In individuals with bipolar disorder, medical comorbidity associated with cardiovascular, respiratory and endocrine disorders is related to increased rates of mortality. Recent updates to multi-system inflammatory related conceptualizations of bipolar disorder focus on the unique power that medical illness and biological processes may play as factors associated with course and outcome in bipolar disorder. The current study examined medical comorbidity and its associations with various demographic and psychological variables in individuals with bipolar disorder, schizophrenia, and major depressive disorder with psychotic features followed for 10 years from their first hospital admission. When compared to an age, gender and race-matched control sample from the population, those with bipolar disorder had significantly higher medical comorbidity across a range of medical diagnoses both at 6 months and 10 years after first hospital admission. Ten years following initial hospitalization, individuals in all three diagnostic groups reported increased rates of diabetes (OR: 2.0 – 3.7), stroke (OR: 4.6 – 7.0) and asthma (OR: 1.9 - 3.1), and individuals with bipolar disorder reported increased rates of cancer (OR = 2.1). A number of psychological and demographic symptoms were examined for their ability to predict the development of medical illness across the assessment interval. Overall rates of medical illness were elevated both early in illness course and 10 years after diagnosis, suggesting that broad sequelae of multi-system inflammation are present early and progress over time.

Bipolar disorder is characterized by disruptions in mood and affect that occur not only during mood episodes, but during euthymic periods as well. At the same time, sensitivity of the behavioral activation system (BAS) has been implicated in the disorder and is a risk marker for it. Less clear is the relationship between BAS sensitivity and positive affect, particularly lower level facets of positive affect. The aim of the present study was to examine the relationship between positive affect and vulnerability for mania as assessed using BAS sensitivity. Specifically, the link between daily levels and fluctuations of positive affect and baseline BAS sensitivity was examined. Following the hierarchical model of affect, this study also assessed the relationship between BAS sensitivity and the distinct facets of positive affect. Finally, this study examined whether BAS sensitivity moderates associations between daily rewards and positive affect. Undergraduates (N = 265) from a large university in the South were recruited to complete measures of BAS sensitivity, affect, and mood symptoms at baseline. Using ecological momentary assessment (EMA), participants completed daily surveys assessing affect and engagement with rewarding situations. An exploratory factory analysis revealed a four factor structure of positive affect, consisting of Serenity, Joviality, Attentiveness, and Self-Assurance. Greater daily levels of overall positive affect, as well as the lower order facets of Joviality, Self-Assurance, and Attentiveness, were predicted by heightened BAS sensitivity. In contrast, the facet of Serenity demonstrated minimal associations with BAS sensitivity. The study findings support a multi-faceted structure of positive affect and suggest that certain facets may be more closely related to risk for bipolar disorder. Specifically, Joviality and Self-Assurance may represent maladaptive forms of positive affect, whereas Serenity may function as a protective element against bipolar disorder.

The aims of the current research program were to examine the social-cognitive and sociological models of stigma in relation to student attitudes towards an individual experiencing a mood disorder. Two experiments (Studies 1 and 2) sought to empirically distinguish between controllability and responsibility, both constructs of the attribution model which is subsidiary to the social-cognitive model of stigma. Despite manipulating controllability, participants were reluctant to attribute controllability of cause to individuals experiencing depression or bipolar disorder. The stability of beliefs about the controllability of cause for condition onset was consistent with research suggesting that the Australian public increasingly conceptualise mental disorders in terms of biochemical and genetic causal factors. These findings, in combination with past research linking biogenetic beliefs to negative attitudes, resulted in a change in focus of investigation in Studies 3, 4, 5 and 6 to explain why, contrary to the prediction of the attribution model, biogenetic explanations of mental disorders are associated with the proliferation of stigma. To measure causal beliefs, the Causal Belief Inventory (CBI) was developed in Study 3 and refined in Study 4. The correlational results examined in Studies 4, 5 and 6 found that genetic and biochemical causal beliefs were associated with a number of positive attitudes towards individuals experiencing a mood disorder and that genetic cause was associated with a reduced implicit bias against major depression. Furthermore, each study pointed to the centrality of judgments of differentness in determining affective responses and direct and proxy measures of behaviour. In contrast, manipulation of genetic and psychosocial cause in Study 5 found that causal condition largely failed to impact upon student attitudes. Mediator analysis did, however, find that beliefs about the stability of the vignette actor's condition fully mediated the relationship between the negative influence of genetic cause on proxy helping behaviour. Manipulation of psychosocial, genetic and biochemical cause with the inclusion of a non-depressed control in Study 6 resulted in more ambiguous findings. The combination of findings from Studies 1 to 6 suggest that focusing on the impact of the controllability of cause of depression onset on student attitudes is unwarranted. Instead researchers and public health educators should be examining models which facilitate the examination of the cognitive factors that mediate these relationships. Two such models, namely the social-cognitive and sociological models of stigma, were found to adequately fit the data. Recommendations for integrating these two models of stigma are discussed.

La aparición de los antipsicóticos atípicos o de segunda generación ha supuesto un gran cambio en el manejo de los pacientes con trastorno bipolar. Los ensayos controlados han demostrado la eficacia de prácticamente todos los antipsicóticos atípicos en la manía aguda. Además, la mayor parte de ellos disponen de datos positivos para el tratamiento de mantenimiento del trastorno bipolar, lo que sugiere propiedades normotímicas. E incluso algunos de ellos han mostrado datos positivos en la depresión bipolar. Sin embargo, apenas existen estudios independientes comparando la acción de los atípicos con la de los clásicos, mas allá del uso de haloperidol como comparador activo en algunos estudios de manía aguda. En este contexto, esta tesis tiene como objetivo evaluar el comportamiento de los antipsicóticos atípicos en las fases de manía aguda y depresión, en comparación con el de los antipsicóticos clásicos (haloperidol) y placebo respectivamente, para testar las posibles propiedades normoreguladoras en los episodios agudos. Se utilizaron para ello las técnicas de metanálisis, estructurándose la tesis en dos metanálisis separados. El primero en manía aguda, comparando antipsicóticos atípicos con antipsicóticos clásicos. Dentro de este metanálisis se escogieron dos variables principales: la velocidad de inicio de acción, operativizada como la disminución en la puntuación en la escala de manía a la primera semana, y el viraje depresivo. En los dos casos, se trata de variables de interés clínico, escasamente estudiadas hasta la actualidad, y que señalan el perfil de acción de los fármacos. En segundo lugar, se llevó a cabo un segundo metanálisis comparando la acción de los antipsicóticos atípicos con la del placebo (no existían estudios comparativos con antipsicóticos clásicos) en depresión bipolar. Los resultados de la primera variable del metanálisis en manía aguda, que dan lugar al primer artículo de esta tesis, confirman que el haloperidol muestra un inicio de acción más rápido que los antipsicóticos atípicos. El tamaño del efecto fue pequeño (SMD = 0,17 [0,01 - 0,32] tal como cabria esperar entre dos grupos de eficacia demostrada. Sin embargo, este resultado sugiere que el haloperidol puede seguir siendo un tratamiento de primera línea en la manía aguda en casos graves en los que se requiere una mejoría sintomática urgente, siempre y cuando el riesgo de efectos adversos extrapiramidales y de viraje depresivo sea bajo. El segundo artículo de la tesis analiza las diferencias en el riesgo de viraje depresivo tras el tratamiento de la manía aguda con antipsicóticos atípicos en comparación con haloperidol. El resultado del metanálisis es que los atípicos conllevan un 42% menos de riesgo de viraje que el haloperidol. No obstante, se observa heterogeneidad en este análisis y las diferencias entre grupos son atribuibles especialmente a la acción de tres de los atípicos: olanzapina, quetiapina, y ziprasidona. El segundo metanalisis, que da lugar al tercer lugar de la tesis, observa que existe un efecto positivo en la depresión bipolar, en comparacion con placebo, pero que solo es atribuible a algunos de los antipsicóticos atípicos, concretamente, a la olanzapina y la quetiapina. De modo que se concluye que no se trata de un efecto de clase de la familia. Analizando los resultados de los dos metanálisis en conjunto se observa que se puede establecerse un gradiente en función de la afinidad por el receptor dopaminergico D2, modulado por la acción sobre otros receptores, en el que la mayor afinidad y selectividad antiD2 supondría mayor potencia antimaníaca, inicio de acción antimaníaca más rápido, mayor riesgo de viraje depresivo, e ineficacia y/o agravamiento de la depresión bipolar. Haloperidol se situaría en el extremo izquierdo del gradiente y se propone la siguiente ubicación para los antipsicóticos atípicos: Risperidona – Aripiprazol – Ziprasidona – Olanzapina – Quetiapina. Además, este gradiente coincide con el de los valores del Índice de Polaridad obtenidos en los estudios de prevención de recurrencias con los antipsicóticos atípicos, de lo que se desprende que los efectos en los episodios agudos tiende a perdurar durante el tratamiento de mantenimiento.<br>Introduction of atypical antipsychotics has involved a great change in the management of bipolar disorder during last decade. Not only they show efficacy in mania, but also for recurrence prevention, and some of them have also been shown to work in bipolar depression. However, comparisons with classical neuroleptics to assess advantages and disadvantages are scarce. In this context, the goal of this thesis was to assess the behavior of atypical antipsichotics in the acute phases of mania and depression, compared to classical antipsychotics in the former and with placebo in the latter, and study their possible normothymic properties. Metanalysis techniques were used. The thesis was structured in two different metanalysis. The first one in acute mania, comparing atypical and classical antipyschotics. Two different outcomes were assessed: speed of onset of action and switch to depression. The second metanalysis studied the efficacy of atypical antipsychotics in bipolar depression versus placebo. The first article of the thesis shows that haloperidol has a faster onset of action than atypical antipsychotics in acute mania. The size of the effect was small (SMD = 0,17 [0,01 - 0,32] but could still be clinically significant in the subset of severe manic patients who require an urgent relief of symtpoms. On the other hand, as it is shown in the second paper of the thesis, treatment with atypicals involves a 42% reduction in the risk of switch to depression compared to haloperidol. However, heterogeneity was present which could be due to differences in the group of atypicals, as three of them (olanzapine, quetiapine, and ziprasidone) could explain the effect. The third article, corresponding to the second metanálisis, shows only some atypicals, namely olanzapine and quetiapine, are efficacious in bipolar depression. Therefore, there is no class effect. A global view of both metanalysis shows that dopaminergic D2 affinity is likely to be the most important factor over the different profile of antipsychotics, with lower affinity involving more clear normothymic actions.

Felip V d’Espanya va presentar, des de la joventut, símptomes que avui dia la psiquiatria reconeix com una entitat nosològica específica. La present tesi, interdisciplinària història i medicina, contextualitza en el seu moment històric els episodis més significatius de la malaltia d’aquest rei, alhora que elabora la seva historia psiquiàtrica, a partir de correspondència diplomàtica i altres testimonis coetanis. Es basa en el DSM-5 (Manual Diagnòstic i Estadístic dels Trastorns Mentals, 5th Edició) per emetre un diagnòstic de presumpció del trastorn mental que, de manera inevitable, va condicionar el seu regnat (1701-1746)<br>From the time of his youth, Philip V of Spain displayed symptoms which psychiatry now recognises as a specific diagnostic condition. This interdisciplinary thesis, drawing on both history and medicine, contextualise the principal episodes of the King’s illness tracing his psychiatric history, through diplomatic correspondence and other contemporary resources. Based on the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) the thesis presents a presumptive diagnosis of Philip’s mental condition, which inevitably had an impact on his entire reign (1701-1746)

Objective: The aim of the current study was to investigate the differences in baseline characteristics and three-year outcomes between two diagnostic categories with presentation of first-episode psychosis: bipolar affective disorder (mania with psychotic features) and schizophrenia. The comparison was based on pre-treatment characteristics, clinical presentation, symptomatic and functional outcomes, and engagement in risk behaviours. Methods:461 schizophrenic patients and 54 bipolar affective disorder (BAD) patients between the ages of 15 to 25 years from a local first-episode psychosis treatment program within the years2001 to 2003 were studied. Researchers collected detailed data on baseline and three-year follow up variables from systematic medical file review for statistical analyses. Results: At service entry, compared to schizophrenic patients, bipolar affective disorder(BAD)patients exhibited more prominent positive symptoms (p = 0.01), were younger at first presentation and had a higher unemployment rate (p < 0.01), were more likely to have acute onset of psychosis, shorter duration of untreated psychosis (DUP), a higher rate of hospital admission within first month after initial contact, and lower pre-treatment functioning (Social and Occupational Functioning Assessment Scale (SOFAS), p < 0.001). There was no significant difference in gender, education level, age of onset and pre-treatment risk taking behaviours. After applying univariate analysis of variance (ANCOVA)by controlling baseline variables that showed significant differences, the three year follow up reveals that schizophrenic patients displayed fewer numbers of hospitalization (p <0.01)with no difference in the total length (days) of hospitalization, more prominent positive symptoms(p < 0.01), poorer functioning at year 3 (p <0.05), and consistently significant lower employment rate at 12 month (p < 0.001), 24 month (p < 0.001) and 36 month (p < 0.01). Finally, more schizophrenic patients received social benefits (p < 0.05). Conclusion: The outstanding baseline poorer functioning level of bipolar affective disorder patients have progressively made a modest improvement in functional outcomes at the end of three-year follow up. BAD patients also displayed a marked improvement with fewer positive symptoms in the follow up. The results suggest a differentiation in symptomatology and the course of illness between bipolar affective disorder and schizophrenia with first-episode psychosis. In coherence with other scholastic literature, duration of untreated psychosis (DUP) associates with remission(Crumlish et al., 2009;Chang et al., 2012a), positive symptoms(Barnes et.al., 2008; Chang et.al., 2012b; Clarke et al., 2006; Crumlish et.al., 2009;), and functional outcomes(Barnes et al., 2008; Chang et al., 2012b; Clarke et.al., 2006; Crumlish et.al, 2009; Fusar-Poli et al., 2009). Moreover, further exploration about the diagnostic-specific therapeutic window for early intervention, symptoms management, and rehabilitation strategies in occupational training are in demand.<br>published_or_final_version<br>Psychological Medicine<br>Master<br>Master of Psychological Medicine

Cognitive impairment is a key characteristic of schizophrenia and is a clear predictor of functional outcome. This thesis explores the relationship between cognitive ability relating to social and non-social processing. Schizophrenia patients demonstrate an impaired ability to recognise, label and discriminate emotional expression within the face. The underlying mechanisms behind this social cognitive impairment are not yet fully understood. This thesis explores the notion that a basic perceptual impairment in processing facial information adversely impacts on the perception of more complex information derived from faces, such as emotional expression. Face perception relies on processing the featural characteristics of a face as well as the relationship between these features. Information pertaining to the spatial distances between features is referred to as configural information.<br>A group of schizophrenia patients and healthy control participants completed a battery of tasks that assessed basic neurocognition, facial emotion processing and configural face processing. A model of face processing was proposed and used to systematically pinpoint specific deficits that may contribute to impaired face processing in schizophrenia. The results indicated that schizophrenia patients show impairments on three broad constructs; basic neurocognition, facial emotion processing, and most pertinently, deficits in configural processing. It was revealed that although neurocognitive and face processing both explained a significant proportion of the variance in facial emotion processing, the effect of neurocognition was indirect and mediated by face processing.<br>To investigate the diagnostic specificity of these findings, a group of bipolar disorder patients was also tested on the task battery. The results indicated that bipolar disorder patients also show social and non-social cognitive impairments, however, not as severe as that demonstrated by the schizophrenia patients. Furthermore, the effect of neurocognitive performance on facial emotion processing appeared more direct for bipolar disorder patients compared to schizophrenia patients. Although deficits in face processing were observable in bipolar, they were not specific to configural processing. Thus, deficits in emotion processing were more associated to neurocognitive ability in bipolar disorder patients, and more associated to configural face processing in schizophrenia patients. The configural processing deficits in schizophrenia are discussed as a lower-order perception problem. In conclusion, the results of this thesis are discussed in terms of their implication for treatment.

Positive Clinical Psychology (PCP) argues that positive and negative psychological constructs are jointly important for explaining psychological problems. “Positive” constructs have been explicitly focused on by positive psychology researchers and “negative” constructs have been explicitly focused on by mental health researchers. This thesis examines the relationship between positive and negative constructs in relation to four psychological problems: depressive symptoms (Chapter 2), anxiety-problems (Chapter 3), suicide attempts (SAs) (Chapter 4 and 5), and nonsuicidal self-injury (NSSI) (Chapter 4 and 5). Clarifying how psychological problems are most appropriately conceptualised has implications for definitions, diagnostic criteria, measurement, and clinical interventions. This thesis provides evidence that some constructs form bipolar continua, having a positive pole and a negative pole, whilst other constructs do not. Chapters 2 and 3 demonstrate that well-being and calmness respectively form continua with depressive and anxiety symptoms. In contrast, Chapters 4 and 5 demonstrate that SA and NSSI cognitions do not form a continuum with another construct. Results indicate that positive and negative constructs appear to have different relationships to one-another depending on the construct under investigation. Constructs that are common in the general population – such as depressive symptoms, anxiety symptoms, well-being symptoms, and calmness symptoms – appear to be bipolar, having a positive and a negative pole. Psychological constructs that are rare in the general population and which specifically characterise psychological problems (rather than being an extreme manifestation of a common psychological experience) – such as SA and NSSI cognitions – appear to be unipolar. The replication of scientific findings also features strongly throughout this thesis. Each chapter may therefore have a timely bearing on the emerging “replication crisis” literature.

OBJECTIVE: Anxiety disorders are among the most common comorbid conditions in youth with bipolar disorder (BP). We aimed to examine the prevalence, correlates, persistence (>50% of the follow-up time), and the onset of new anxiety disorders in youth with comorbid anxiety disorders and BP. METHODS: As part of the Course and Outcome of Bipolar Youth study (COBY), 446 youth ages 7 to 17, who met DSM-IV criteria for BP-I (n=260), BP-II (n=32) or operationalized criteria for BP not otherwise specified (BP-NOS; n=154) were included. Subjects were evaluated for current and lifetime Axis-I psychiatric disorders at intake using the Schedule for Affective Disorders and Schizophrenia for School-Aged Children–Present and Lifetime version (K-SADS-PL), and standardized instruments to assess functioning and family history. Subjects were followed on average 5 years using the Longitudinal Interval Follow-up Evaluation. RESULTS: Forty-four percent (n=194) of the sample met DSM-IV criteria for at least one lifetime anxiety disorder, most commonly separation anxiety (24%) and generalized anxiety disorders (16%). Nearly 20% met criteria for two or more anxiety disorders. Overall, anxiety disorders predated the onset of BP. BP-II subjects were more likely than BP-I or BP-NOS subjects to have a comorbid anxiety disorder. After adjusting for confounding factors, BP youth with anxiety were more likely to have BP-II, longer duration of mood symptoms, more severe ratings of depression, and family history of depression, hopelessness and somatic complaints during their worst lifetime depressive episode than those without anxiety. Of the 170 youth who had anxiety at intake, 80.6% had an anxiety disorder at any time during the follow-up. Most of the anxiety disorders during the follow-up were of the same type as those present at intake. About 50% of the youth had persistent anxiety, particularly Generalized Anxiety Disorder (GAD). Persistence was associated with multiple anxiety disorders, less follow-up time in euthymia, less conduct disorder, and less treatment with antimanic and antidepressant medications (all p-values≤0.05). Twenty-five percent of the sample who did not have an anxiety disorder at intake developed new anxiety disorders during follow-up, most commonly GAD. New onsets were significantly associated with being female, lower socioeconomic status, presence of attention-deficit/hyperactivity disorder and substance use disorder and more follow-up time with manic or hypomanic symptoms (all p-values≤0.05) CONCLUSIONS: Comorbid anxiety disorders are common in youth with BP, and most often predate BP onset. BP-II, a family history of depression, and more severe lifetime depressive episodes distinguish BP youth with comorbid anxiety disorders from those without. In addition, anxiety disorders in youth with BP tend to persist and new anxiety disorders onset in a substantial proportion of the sample. Careful consideration should be given to the assessment of comorbid anxiety in BP youth. Furthermore, early identification of factors associated with the persistence and onset of new anxiety disorders may enable the development of strategies for treatment and prevention.<br>OBJECTIUS: Els trastorns d'ansietat són les condicions comòrbides més comuns en nens i adolescents amb trastorn bipolar (TB), però fins on sabem, cap estudi ha examinat l'evolució dels trastorns d'ansietat en joves i adults amb TB. L'objectiu de l'estudi va ser examinar els factors associats amb la persistència (>50% del temps de seguiment) i l'aparició de nous trastorns d'ansietat en nens i adolescents amb TB. MÈTODE: Com a part de l’estudi Course and Outcome of Bipolar Youth (COBY), 413 nens i adolescents entre 7 i 17 anys que complien els criteris per el Manual Diagnòstic i Estadístic IV (DSM-IV) pel TB-I (n=244), TB-II (n=28) o el criteri operacionalitzat pel TB no especificat (TB-NOS; n=154) van ser reclutats principalment de consultoris d'atenció ambulatòria. Els subjectes van ser seguits de mitjana durant 5 anys utilitzant el Longitudinal Interval Follow-up Evaluation. RESULTATS: Dels 170 nens i adolescents que presentaven ansietat a l'inici de l’estudi, el 80.6% tenia un trastorn d'ansietat en qualsevol moment durant el seguiment. La majoria dels trastorns d'ansietat durant el seguiment van ser del mateix tipus que els presents a l'inici de l'estudi. Al voltant del 50% dels joves tenien persistència d'ansietat, sobretot trastorn d'ansietat generalitzada (TAG). La persistència es va associar amb trastorns d'ansietat múltiple, menys temps de seguiment en eutimia, menys trastorn de conducta i menor tractament amb medicaments antidepressius i antimaníacs. Vint-cinc per cent de la mostra que no tenien un trastorn d'ansietat a l'inici, va desenvolupar nous trastorns d'ansietat durant el seguiment, en general TAG. L'inici de nous trastorns d'ansietat es va associar significativament amb ser dona, baix nivell socioeconòmic, presència del trastorn per dèficit d'atenció i hiperactivitat, trastorn per consum de substàncies i més temps de seguiment amb símptomes maníacs o hipomaníacs. CONCLUSIONS: Els trastorns d'ansietat en nens i adolescents amb TB tendeixen a persistir i l'ansietat de nou inici apareix en una proporció substancial de la mostra. S'ha de prestar atenció a l'avaluació de l'ansietat comòrbida en nens i adolescents amb TB i la identificació precoç dels factors associats amb la persistència i l'aparició de nous trastorns d'ansietat poden permetre el desenvolupament d'estratègies pel tractament i la seva prevenció.

Introducción. El trastorno bipolar (TB) tiene un gran impacto en las personas que lo padecen y una mortalidad por suicidio hasta 20 veces mayor que el resto de la población. La depresión bipolar es uno de los principales factores de riesgo de suicidio, sin embargo existe escasa evidencia en relación a su tratamiento. Uno de los temas más controversiales es el uso de antidepresivos, que a pesar de ser el tratamiento más utilizado, su eficacia y seguridad han sido puestos en duda. Hipótesis. Los pacientes expuestos a AD vs los no expuestos tienen características clínicas y un curso de enfermedad diferente, presentando un mayor número de complicaciones, entre ellas, una mayor incidencia de suicidabilidad. Objetivos. Caracterizar los factores demográficos y clínicos asociados al uso de antidepresivos en pacientes con depresión bipolar, así como los factores asociados a ideación o actos suicidas. Valorar la asociación entre uso de antidepresivos y conductas suicidas e identificar los factores predictores de riesgo suicida en el trastorno bipolar. Método. Estudio naturalístico de cohorte. Se reclutaron pacientes adultos en seguimiento en la Unidad de Trastorno Bipolar de nuestro hospital. Se recogieron variables clínicas basados en entrevistas semiestructuradas y escalas. Asimismo, se realizó un seguimiento bisemanal de un episodio depresivo index durante 12 semanas y se recogieron variables clínicas, de respuesta al tratamiento y de suicidabilidad. Para el tercer estudio, se reclutaron pacientes con trastorno bipolar en seguimiento sistemático, provenientes de 5 centros en distintos países. Análisis de resultados. Se realizaron análisis bivariados para buscar asociaciones entre factores demográficos y clínicos y uso de antidepresivos. Con los resultados de este análisis preliminar, se realizó un modelo de regresión logística múltiple con uso de AD como variable dependiente. Se utilizó el mismo procedimiento para valorar factores asociados a suicidabilidad y establecer un modelo predictivo de suicidabilidad en depresión bipolar. Resultados/Conclusiones. La prevalencia de uso de antidepresivos para el tratamiento de la depresión bipolar aguda es muy alta (cercana al 80%), incluso en un centro especializado como el nuestro, y está asociado a una historia de depresión más severa. Los virajes fueron 7 veces más altos en el grupo expuesto a antidepresivos, incluso con tratamiento coadyuvante con estabilizadores del ánimo. Los factores de riesgo asociados a la ideación y los actos suicidas en el trastorno bipolar tienen que ver con una mayor severidad de la enfermedad y con la presencia de síntomas mixtos y polaridad predominante depresiva, así como el sexo femenino y la mayor latencia en el diagnóstico. Asimismo, observamos que el riesgo de ideación y conductas suicidas en el trastorno bipolar tipo II es tan alto como en el tipo I, lo que sugiere que éste subtipo no es una variante más leve de la enfermedad, sino clínicamente diferente. La clasificación por polaridad predominante es un buen diferenciador del curso clínico y pronóstico de los pacientes con trastorno bipolar. Destaca la asociación entre polaridad predominante depresiva y el debut de enfermedad con episodios depresivos o mixtos, la presencia de mas episodios mixtos durante la evolución y el aumento del riesgo de actos suicidas. Asimismo, sumar los episodios mixtos a la polaridad predominante depresiva, aumenta significativamente su asociación con los actos suicidas y la capacidad predictiva de morbilidad a largo plazo de los primeros episodios. Por último, esta clasificación permite planificar las intervenciones terapéuticas según las características clínicas de los pacientes, además de abrir la posibilidad de buscar marcadores biológicos a partir de subgrupos con comportamiento clínico diferente. Limitaciones. Los estudios observacionales no permiten establecer relaciones causales. El hecho de haberse realizado en un centro académico especializado podría limitar la generalización de los resultados.<br>Introduction. Suicide accounts for 15-20% of bipolar patients overall mortality. Depression is one of the most important risk factors and its treatment is a matter of controversy, especially regarding antidepressant use. Objective. To characterize clinical and demographic factors associated to suicidality and antidepressant use. In addition, to evaluate the association between antidepressant use and suicidal behaviour. Methods. Naturalistic cohort study. We recruited 290 systematically followed-up bipolar patients from our program at Hospital Clínic (Barcelona, Spain). We assessed them through semistructured clinical interviews and scales during a depressive index episode and followed them for 12 weeks. For the third study, we recruited 928 bipolar I patients from five academic centers in different countries and tested the replicability and usefulness of the predominant polarity concept and its association with suicide. Results/Conclusions. Despite the scarce evidence available, the proportion of patients receiving antidepressants for the treatment of bipolar depression is strikingly high and its use is associated with more severe depressive morbidity. Regarding acute complications associated with treatment, the risk of treatment associated manic switch in the antidepressant group was seven times higher. In addition, risk for suicidal thoughts/behaviour and rapid cycling was two times higher in the antidepressant group, although the difference was not statistically significant. These results suggest that antidepressant use may be related with a higher proportion of adverse outcomes in bipolar depression. Risk factors associated with suicidal thoughts and acts in bipolar disorder, are associated with a more severe illness and depressive morbidity, such as the presence of mixed symptoms, depressive predominant polarity and longer delay between illness onset and the diagnosis of bipolar disorder. Suicidal thoughts and acts in bipolar disorder type II are as prevalent as in type I. This strongly suggests that bipolar type II is not a milder form of disorder, but clinically different. Finally, predominant polarity is a relevant and useful way of classifying bipolar disorder patients, with different clinical course and prognosis. Depressive predominant polarity is associated with a depressive or mixed episode at onset, the presence of more mixed episodes during the clinical course of the disorder and a two-fold increase in suicidal risk, when compared to manic/hypomanic predominant polarity. Including mixed-states with predominant depressions markedly increased association with suicidal risk (two-fold), which confirms mixed symptoms as an important risk factor. Limitations. Causal relationships cannot be established properly through observational studies. Nevertheless, such naturalistic experiences may serve as useful representations of current clinical practices and results. Sampling at a prominent university referral center may not generalize to other sites.

La recerca en els darrers anys ha demostrat que el pacient amb trastorn bipolar (TB) no està lliure d'afectació neurocognitiva i que aquesta pot tenir una repercussió important en el seu funcionament quotidià. Pel que fa al trastorn bipolar tipus II (TB-II), atès que ha patit una manca d'atenció i durant molt de temps ha estat un subtipus infradiagnosticat, els treballs dirigits a aspectes neuropsicològics han estat escassos amb resultats discrepants i no concloents. Per tant, cal dur a terme estudis centrats en aquesta població específica per tal d'establir de manera adequada el seu perfil neurocognitiu donades les implicacions clíniques i terapèutiques que se'n poden derivar. En aquesta tesi es du a terme una revisió sistemàtica (primer estudi) de la literatura existent per a veure quin és l'estat actual d'aquesta temàtica. A partir d'aquesta s'estableixen les bases per a la recerca posterior, amb l'objectiu de determinar els principals dèficits neurocognitius associats al TB-II avaluant pacients amb criteris rigorosos d'eutímia. Amb el segon estudi es va detectar que els pacients TB-II en remissió presenten un rendiment neurocognitiu inferior als subjectes sans tant en el domini d'atenció com en els de memòria verbal, memòria de treball i funció executiva. En segon lloc s'intentaven identificar possibles predictors del funcionament psicosocial a partir de l'estudi de variables clíniques, sociodemogràfiques i neurocognitives. Es va observar que les disfuncions executives i la presència de simptomatologia subclínica de caire depressiu podrien ser útils com a predictors d'un major deteriorament funcional en aquest grup. Posteriorment, ens varem proposar estudiar si existeix heterogeneïtat neurocognitiva entre aquesta subpoblació amb un tercer estudi. Es va observar que existeixen diversos subgrups amb perfils neurocognitius diferenciats entre els pacients; pacients amb un rendiment neurocognitiu totalment preservat, pacients amb alteracions moderades-greus en tots els dominis cognitius (amb excepció de la memòria verbal amb dèficit lleu) i pacients amb un rendiment intermedi amb alteracions (leus. Més d'un 50% dels pacients TB-II presentaven dificultats neurocognitives. Cap variable clínica relacionada amb la severitat o cronicitat de la malaltia podia explicar les diferències entre subgrups. Aquells pacients amb un rendiment neurocognitiu deficitari global presentaven un QI més baix, un pitjor funcionament psicosocial global i majors dificultats per a realitzar i gaudir de les activitats de lleure. En darrer lloc, cal tenir present que és necessari oferir als pacients un tractament integral de la malaltia on es contemplin també les dificultats neurocognitives i de funcionalitat, oferint, per tant, noves estratègies d’intervenció que permetin millorar aquests aspectes. D’aquesta manera, amb el darrer estudi (quart estudi) s’avaluava l’eficàcia d’una nova estratègia d’intervenció neurocognitiva, la rehabilitació funcional, específicament en un grup de pacients TB‐II també eutímics, valorant l’impacte que aquesta intervenció podia exercir sobre el funcionament psicosocial dels pacients. La rehabilitació funcional va mostrar ser efectiva no només millorant el funcionament general sinó també reduint la simptomatologia subclínica depressiva dels pacients TB‐II.<br>Patients with Bipolar Disorder (BD) show broad cognitive impairments that persist during euthymia despite remission of mood symptoms. Cognitive deficits in BD are associated with impairments in functional outcome and quality of life. Thus, improving cognitive functioning is an important treatment goal in people with BD. Bipolar II disorder subtype (BD-II) has been underdiagnosed in clinical practice, therefore, many aspects of BD-II are still understudied such as neurocognitive functioning. In the present thesis, a systematic review of literature regarding neurocognition in BD-II was carried out. Then, we assessed a sample of strictly defined BD-II euthymic patients to compare it with a sample of healthy controls (HC) to elucidate the neuropsychological profile of this bipolar subtype. A second objective was to study the relationship between neurocognitive performance and functional outcome. BD-II patients showed a significantly lower performance on several measures of attention, learning and verbal memory, and executive function compared with HC. The presence of subthreshold depressive symptomatology and one measure related to executive function and working memory were the variables that best predicted psychosocial functioning. After that, we attempted to analyse cognitive variability also in a sample of euthymic BD-II patients, using a cluster analysis to provide groups of different neurocognitive patterns. Three clusters were detected: an intact neurocognitive group, an intermediate or selectively impaired and a globally impaired group. Approximately one-half of the patients were cognitively impaired. The 3 clusters statistically differed in the premorbid intelligence quotient, the global functional outcome and leisure activities. The globally impaired cluster showed the lowest attainments concerning these 3 variables, which are considered proxies of cognitive reserve. No differences in other clinical characteristics were found among the groups. Taking all these data into account, it seems necessary to implement therapies focused on enhancing functional outcome in bipolar II disorder patients. Hence, we carried out a subanalysis aimed to assess the efficacy of an intervention called Functional Remediation specifically in a sample of BD-II patients. Our results suggest that the Functional remediation appears to be effective in improving the overall functional outcome in BPII, as well as in reducing subclinical depressive symptoms.

Severe mental disorders, such as Major Depressive Disorder (MDD), Bipolar Disorder (BD) and Schizophrenia (SCZ), represent a huge burden to society, reflecting the limited efficacy of current drug treatments. Although the progress in development of pharmacological treatments is one of the great successes of modern psychiatry, it should not be forgotten that a very high percentage of patients do not receive and/or seek the proper treatment for their disease. Individual differences in clinical response to psychotropic drugs have long been recognized as a fundamental problem in the treatment of the seriously mentally ill patient. This variability in individual response ranges from patients who experience complete symptom remission to a subset of patients often describes as “treatment refractory”, as well as a marked variability in susceptibility to adverse drug effects. In this sense, the overall objective of pharmacogenetics is to determine the genetic basis of the variability in drug efficacy and safety, and to use this information to benefit the patient detecting a priori those patients that could not respond to a drug and/or present drug side effects. The present dissertation hypothesizes that lack of response to psychotropic drugs will be associated to genetic variability at genes coding for proteins involved directly or indirectly in the mechanism of action of these drugs. In this sense three different studies have been carried out. The first study analyses genetic variability at genes of the endocannabinoid system in clinical response and/or remission to citalopram treatment in MDD patients. The second study analyses genetic variability at genes related to phosphoinositide (PI), glycogen synthetase kinase-3 (GSK3), hypothalamic-pituitary-adrenal (HPA) and glutamatergic pathways in clinical response to lithium in BD patients. The third study analyses genetic variability at genes related to neurotrophic factors and HPA in clinical response to clozapine in patients with SCZ. Our results focused in the analyses of genetic variability at genes coding for proteins involved in the mechanism of action of psychotropic drugs let us to detect some minor and moderate effects of genetic variants that could explain, at least, part of the lack of response to these drugs. The results of our study in relation to citalopram response in MDD showed that genetic variability at genes related to the endocannabinoid system could play a role in the understanding of clinical response to this drug treatment. Specifically, we found an association between CNR1 gene and clinical remission at 12th week and an effect of CNR1 gene on longitudinal response (along the 12th week follow-up). The results of our study in relation to lithium response in BD showed that genetic variability at INPP1, IMPA2, GSK3B and GRIK2 genes could play a role in the understanding of lithium response. Finally, the results in relation to clozapine response in SCZ showed that genetic variants at FKBP5 and NTRK2 genes may play a role in clozapine response. The detection of individual genetic differences in the response to psychotropic drugs may provide new strategies for the treatment of mental disorders, as well as, new knowledge about the aetiology of these disorders.<br>Los trastornos mentales graves, como son la depresión mayor (DM), el trastorno bipolar (TB) y la esquizofrenia (SCZ), se han convertido en los últimos años en un importante problema de salud en los países desarrollados. Aunque el avance alcanzado en el desarrollo de tratamientos farmacológicos ha constituido uno de los grandes logros de la psiquiatría moderna, no debemos olvidar que hay un porcentaje muy alto de pacientes que no reciben el tratamiento adecuado para su enfermedad. En este sentido, la farmacogenética tiene como objetivo identificar y caracterizar los factores genéticos que se encuentran en la base de las diferencias existentes entre individuos en la respuesta clínica al tratamiento farmacológico. La presente tesis pretende estudiar variación genética basada en genes que codifican para moléculas implicadas directamente o indirectamente en los mecanismos de acción del tratamiento con citalopram (DM), carbonato de litio (TB) y clozapina (SCZ) que nos explicará parte del riesgo para la no respuesta clínica y la no remisión del episodio tratado farmacológicamente. Los resultados nos permitieron identificar variación genética asociada a la respuesta al tratamiento. Concretamente, nuestros resultados indicaron que variabilidad genética relacionada con el sistema endocannabinoide se asociaba con la respuesta a citalopram en DM. Por otro lado, genes involucrados con el sistema de fosfoinositoles podrían explican parte de la variación en la respuesta al litio en el TB. En referencia al estudio de la respuesta a clozapina en pacientes con SCZ, los resultados sugieren que variantes genéticas en los genes FKBP5 y NTRK2 pueden jugar un papel en la respuesta. En este sentido, nuestro estudio proporciona evidencia de la implicación del eje hipotálamo-pituitario-adrenal (HPA) y de factores neurotróficos en la modulación de la respuesta a clozapina. La detección de diferencias genéticas individuales en la respuesta a los fármacos psicotrópicos puede proporcionar nuevas estrategias para el tratamiento de trastornos mentales, así como, nuevos conocimientos sobre la etiología de estos trastornos.

For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic ‘fashions’, and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health,lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts<br>Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

Los pacientes bipolares presentan tasas muy elevadas de conductas suicidas. Dado que el litio, uno de los fármacos más ampliamente utilizado para tratar el trastorno bipolar, ha demostrado presentar ciertas propiedades antisuicidas y antiimpulsivas, pretendemos analizar el impacto que la variabilidad genética en algunos de los genes implicados en algunas de las vías relacionadas con el mecanismo de acción del litio ejerce sobre la conducta suicida, así como en los niveles de impulsividad, dimensión considerada tradicionalmente como un potencial endofenotipo de la conducta suicida. Además, habiéndose establecido una asociación entre un peor nivel de funcionamiento y la historia de conducta suicida en este grupo de pacientes, también nos propusimos estudiar el rol que la impulsividad podría desempeñar en el nivel de deterioro funcional que los pacientes bipolares presentan. Para analizar el efecto de la variabilidad genética en las vías vinculadas al mecanismo de acción del litio tanto en la emergencia de la conducta suicida, como en el nivel de impulsividad de los pacientes bipolares se llevaron a cabo dos estudios de asociación genética. En el primero de ellos, los resultados mostraron que los portadores del genotipo AA para el SNP rs669838 perteneciente al gen IMPA2 (OR= 2.92; IC95% [1.20-7.15]; χ²= 7.015; p=0.008) y el genotipo GG del rs4853694 del gen INPP1 (OR= 3.69; IC95% [1.05-14.56]; χ²=5.66; p=0.02) presentaban un riesgo de cometer tentativas suicidas, aproximadamente, 3 veces mayor en comparación con aquellos que presentaban un genotipo diferente. En el caso del gen GSK3β, los portadores del alelo T (T/T o T/-) del SNP rs1732170 (OR= 2.05; IC95% [1.02-4.16]; χ²= 7.7; p=0.029) y los portadores del alelo A (A/A o A/-) del rs11921360 (OR= 3.2; IC95% [1.03-13.49]; χ²=4.7; p=0.02) presentaban también el doble y el triple de riesgo de presentar conductas suicidas, respectivamente. Respecto a los niveles de impulsividad, los resultados obtenidos indicaron que los pacientes portadores del alelos T para el SNP rs1732170 (18.95 vs. 17.38; F=9.470; p=.002; η2 parcial=5.1%; Poder observado=86.4 %) y los del alelo G del SNP rs334558 (19.37 vs. 17.88; F=5.715; p=.018; η2 parcial =3.2%; Poder observado=66.2%), ambos pertenecientes al gen GSK3β, presentaban mayores puntuaciones en la subescala de impulsividad cognitiva. En el tercero de los estudios, cuyo objetivo era analizar la potencial relación entre la impulsividad y el nivel de funcionamiento global de los pacientes bipolares, se halló mostraron que los niveles de impulsividad y funcionamiento no eran independientes, mostrando una correlación positiva (r pearson=0.300; p<0.001), esto es, a mayor impulsividad, mayor deterioro funcional. Respecto al análisis multivariante, destacar que de entre todas las variables analizadas, tan solo la presencia de sintomatología depresiva (β=1.580; p<0.001), el número de hospitalizaciones previas (β=0.837;p=0.019) y los niveles de impulsividad (β=0.319;p=0.004) se asociaron significativamente a un peor funcionamiento global. En resumen, nuestros resultados parecen confirmar que la variabilidad genética en genes implicados tanto en la vía de los fosfoinositoles como de la Wnt/β-catenina se asociaría tanto una mayor vulnerabilidad para la emergencia de conductas de tipo suicida en el caso del trastorno bipolar y, en el caso específico del gen GSK3β, también se asocia niveles incrementados de impulsividad cognitiva. Por otro lado, nuestros resultados sugieren que la impulsividad, del mismo modo que la sintomatología depresiva y el número de hospitalizaciones, se asocia fuertemente al deterioro funcional en el trastorno bipolar, especialmente en los dominios de funcionamiento cognitivo, manejo de las finanzas y autonomía personal.<br>Bipolar patients are at high risk of suicide. Bearing in mind that lithium, one of the mainstays of the treatment of BP, presents antisuicidal and antiimpulsive properties, our aims was to analyze the impact of genetic variability at genes involved in its putative mechanism of action such on the emergence of suicidal behaviour as well on increased impulsivity, which in turn has been traditionally considered as a potential endophenotype of suicidality. In addition, considering that it has been established a link between history of suicidal behaviour and a poor functional outcome, we also investigated the functional impact of trait-impulsivity in bipolar disorder. Our results showed that genetic variability at both the phosphoinositol and the Wnt/β-catenin pathways increases the risk of suicidal behavior in bipolar patients and, in the specific case of GSK3 gene, it is also associated with increased levels of cognitive impulsivity. Furthermore, our results suggest that impulsivity, as well as depressive symptoms and hospitalizations, is strongly associated with functional impairment in bipolar disorder, especially in the domains of cognitive functioning, finance and autonomy domains.

Los estudios de neuroimagen funcional en el trastorno bipolar han descrito un patrón de activación reducida de regiones prefrontales junto con hiperactivación en estructuras subcorticales. Una cuestión que está sin resolver es la determinación de los cambios dependientes del "estado" vs "rasgo", es decir, si existen diferencias entre los episodios maníacos y depresivos, y hasta qué punto los cambios observados persisten en eutimia. Además, los estudios hasta la fecha se han centrado principalmente en el estudio de las activaciones, y poco se sabe acerca de los cambios en la desactivación. Dado que los cambios funcionales cerebrales en eutimia no están directamente relacionados con los síntomas agudos de la manía o depresión, parece probable que reflejen otros aspectos del trastorno. Una posibilidad es que reflejen la vulnerabilidad a la enfermedad y, dado que uno de los principales factores de riesgo es la genética, se plantea la cuestión de si los cambios cerebrales funcionales en eutimia también se puedan detectar en los familiares de pacientes que no han desarrollado el trastorno. Por otro lado, es posible que el deterioro cognitivo presente en eutimia se relacione con los cambios funcionales y/o estructurales cerebrales encontrados, pero hasta la fecha los resultados han sido inconsistentes. El objetivo de este trabajo es, por tanto, examinar los cambios en el funcionamiento cerebral en cada una de las tres fases del trastorno bipolar; determinar qué cambios en el funcionamiento cerebral están presentes en familiares sanos de primer grado de los pacientes; y determinar si, y en qué medida, el deterioro cognitivo en pacientes eutímicos se asocia con cambios cerebrales funcionales y/o estructurales. Nuestros resultados indican que los cambios funcionales cerebrales en el trastorno bipolar se pueden dividir en aquellos que están relacionados con el estado y los que son marcadores rasgo. La corteza parietal mostró evidencia de pertenecer a la primera categoría mientras que la corteza prefrontal dorsolateral mostró una combinación de ambas características: exhibe una activación reducida en ambas fases agudas de la enfermedad, pero sin normalizarse completamente en la eutimia. El fallo en la desactivación en la corteza frontal medial, correspondiente con el nodo anterior de la red neuronal por defecto, mostró una clara evidencia de ser un marcador rasgo para el trastorno. Esta alteración, se observó igualmente, pero de forma menos marcada, en los hermanos no afectados. Sin embargo, su disfunción no parece ser responsable del deterioro cognitivo presente en el trastorno, que en cambio sí que se relaciona con una activación reducida en la corteza prefrontal dorsolateral derecha. En conclusión, estos resultados ponen de relieve la implicación de la red neuronal por defecto en el trastorno bipolar. Sin embargo, la naturaleza de esta disfunción y su relación con la sintomatología de este trastorno es aún desconocida.<br>Findings from functional imaging studies in bipolar disorder provide only an incomplete answer to the question of what changes characterise bipolar disorder and the ‘state’ vs. ‘trait‘ characteristics of functional imaging abnormalities, whether there are differences between patients in manic and depressed episodes and to what extent changes seen in both phases of illness persist into euthymia. Since brain functional changes in euthymia are unrelated to the acute phases of the disorder, the question arises of whether brain functional changes can reflect vulnerability to the disorder and/or can be related to the cognitive impairment present in euthymia. Also, studies to date have mainly focused on activation changes and the importance not only of task-related activation but also deactivations has become increasingly recognised following the discovery of the default mode network. Thus, the aims of the thesis are to examine patterns of activation and deactivation during performance of a working memory task in bipolar patients in different phases of illness: mania, depression and euthymia; to examine brain functional changes in a group of first-degree relatives of euthymic bipolar patients; and to examine the relationship between brain structural and functional changes and the cognitive impairment of euthymic bipolar patients. The results provide evidence that bipolar disorder is characterised by both mood-state-dependent and mood-state-independent functional imaging abnormalities and highlight the involvement of the default mode network dysfunction in the disorder. Failure of deactivation in the medial frontal cortex was seen in all three illness phases and, to a lesser extent, in the unaffected first- degree relatives and so seems to represent a trait-like abnormality. However it does not seem to be relevant to cognitive impairment in euthymia, since medial frontal failure of deactivation did not distinguish cognitively preserved from cognitively impaired euthymic patients. According to these results, dorsolateral prefrontal cortex activation does not fully normalise in euthymia and reduced activation in that region may be associated with cognitive impairment in euthymic bipolar patients.

El término de Patología Dual (PD) hace referencia a la coexistencia o concurrencia de, al menos, un Trastorno por Uso de Sustancias (TUS) y un Trastorno Mental (TM) en una misma persona. Si bien existe una amplia variedad de combinaciones posibles dada la naturaleza heterogénea de esta condición, en este trabajo se ha considerado la comorbilidad de los TM severos esquizofrenia, trastorno bipolar y depresión mayor. La relevancia de la PD se relaciona con su etiología y expresión fenotípica compleja en la que intervienen múltiples factores de riesgo y de protección junto a su elevada prevalencia, gravedad clínica y psicosocial, difícil manejo terapéutico y peor pronóstico funcional. La evidencia científica y la práctica clínica demuestran que en pacientes duales existen variaciones neurocognitivas y de ritmicidad circadiana asociadas al tipo de TM comórbido que derivan en implicaciones clínicas y funcionales de diferente impacto. El objetivo de la presente tesis doctoral consistió en explorar tales diferencias y la interrelación con otras variables sociodemográficas y clínicas atendiendo al tipo de diagnóstico psiquiátrico comórbido. Con ello se pretende contribuir al conocimiento de un perfil cognitivo y circadiano diferencial en pacientes duales que pueda trasladarse al desarrollo de posibles intervenciones preventivas y de estrategias terapéuticas más dirigidas a sus necesidades individuales y recuperación. La investigación abarcó tres áreas de estudio. En la primera se analizaron las variables sociodemográficas y clínicas de los tres grupos de pacientes duales en tratamiento, permitiendo definir y precisar características asociadas al diagnóstico psiquiátrico y su riesgo o influencia en el inicio y desarrollo del trastorno comórbido. La segunda consistió en la evaluación del rendimiento neurocognitivo, el análisis del efecto que la inteligencia premórbida tiene en el mismo y la interrelación de ambos con variables clínicas. Las alteraciones cognitivas se consideran endofenotipos de algunos TM y, en los últimos años, diferencias individuales en la actividad cerebral y un buen funcionamiento premórbido se han relacionado con el mejor rendimiento cognitivo y funcional. Por último, se exploraron las diferencias en la expresión rítmica circadiana ─temperatura corporal periférica (TCP), horarios de sueño-vigilia y tipología circadiana─ incluyendo la comparación con un grupo de controles sanos (CS) y la influencia del tipo de tratamiento ambulatorio o residencial (mayoritariamente en comunidad terapéutica). Se ha señalado que las alteraciones rítmicas circadianas, tanto en pacientes TUS como en algunos TM, podrían ser una característica clínica significativa que afecta la aparición y el curso del trastorno comórbido. Los datos en pacientes duales, aunque muy escasos, apuntan la existencia de recuperación rítmica asociada al tiempo de abstinencia y al tipo de tratamiento. Se evaluó un total de 114 participantes varones de edades comprendidas entre 20 y 50 años. Todos ellos con diagnóstico de PD en tratamiento ambulatorio o residencial (mayoritariamente en comunidad terapéutica). Los participantes fueron divididos en tres grupos atendiendo al diagnóstico psiquiátrico comórbido de esquizofrenia (SZ+=38), bipolar (BP+=37) o depresión mayor (DM+=39). Fueron criterios de inclusión al estudio la vinculación regular al tratamiento y estabilidad clínica, remisión inicial del TUS (no inducido) y abstinencia mínima de tres meses y hasta un año. Los resultados indicaron que los pacientes con SZ+ presentaron indicadores de mayor riesgo para el inicio y mantenimiento del trastorno comórbido así como de mayor gravedad social y clínica, como inactividad laboral por discapacidad/incapacidad, nivel más bajo de estudios, una edad de inicio tanto del TM como del TUS más temprana, más antecedentes familiares de consumo, uso simultáneo de más sustancias y más consumo de nicotina. A diferencia de éstos, los pacientes con DM+ mostraron una edad media superior, mayor probabilidad de estar separado/divorciado y de tener hijos, desempleo por paro o baja laboral, edad de inicio del TM más tardía, pauta más reducida de fármacos y menor consumo de nicotina. Además, la mitad de ellos se encontraba realizando tratamiento intensivo en comunidad terapéutica. Los BP+ se situaron en una posición intermedia en la mayoría de variables, si bien presentaron más años de estudios y menor dependencia de la adicción. Respecto al rendimiento cognitivo, el funcionamiento premórbido estuvo conservado en los tres grupos, así como las habilidades visuoconstructivas y espaciales, y el span atencional. El aprendizaje y memoria verbal estuvieron afectados en SZ+ y relativamente conservados en DM+ y BP+, exceptuando la evocación inmediata. Destacó un buen procesamiento de la información en DM+, con algunas dificultades en SZ+ y BP+. El funcionamiento ejecutivo de los tres grupos fue adecuado excepto en la tarea TMT, donde SZ+ y BP+ mostraron déficits en la inhibición cognitiva de secuencias automáticas y flexibilidad mental. La inteligencia premórbida influyó en casi todos los dominios cognitivos evaluados y, en menor medida, también la edad de los pacientes, la duración de la abstinencia, la estabilidad clínica y la edad de inicio tanto del TUS como del TM. En cuanto a la expresión rítmica circadiana, los pacientes SZ+, seguidos de BP+, mostraron una acrofase más tardía y un mínimo y mesor más elevados que DM+ y CS. Los pacientes DM+ presentaron mayor amplitud y estabilidad del ritmo respecto a los otros grupos de pacientes y a CS. Además, DM+ fueron predominantemente matutinos, dormían menos horas al día y se levantaban más temprano. Todos los grupos diagnóstico aportaron una menor fragmentación del ritmo comparados con CS. El índice de circadianidad fue menor en SZ+ y DM+ que el observado en CS y según el rango normativo. Por otra parte, respecto a los pacientes residenciales, aquellos ambulatorios presentaron un valor mínimo, mesor y L10 más elevado, una acrofase más tardía y un retraso de la hora central del periodo de vigilia. También refirieron mayor duración de sueño diario, horas más tardías de levantarse y acostarse así como una tipología intermedia. Junto al tipo de tratamiento las variables de edad, abstinencia y consumo de nicotina fueron factores indicativos de afectación o recuperación rítmica. Tales hallazgos apuntan la importancia de la preservación o recuperación cognitiva y circadiana en la funcionalidad de los pacientes duales, siendo indicadores la inteligencia premórbida y el tratamiento residencial respectivamente. Entre las implicaciones preventivas y clínicas que se derivan destaca el incluir en primeros episodios y a edades más avanzadas evaluaciones neuropsicológicas y del CI premórbido e incorporar intervenciones para enriquecer la reserva cognitiva en caso necesario. Así mismo, evaluar el estado rítmico circadiano antes y a lo largo del tratamiento, incorporando estrategias cronoterapéuticas en los pacientes ambulatorios. En conclusión, la consideración de las alteraciones neurocognitivas y circadianas y el impacto en ellas del TM comórbido contribuirá a la detección de posibles marcadores de vulnerabilidad y pueden ser predictores de pronóstico y adherencia al tratamiento junto al establecimiento de objetivos y estrategias de tratamiento más precisas orientadas a la prevención o rehabilitación así como a mantener cambios de comportamiento y hábitos saludables a medio y largo plazo para la evitación de recaídas.<br>The term Dual Pathology (DP) refers to the coexistence or concurrence of at least one Substance Use Disorder (SUD) and a Mental Disorder (MD) in the same person. Although there is a wide variety of possible combinations given the heterogeneous nature of this condition, this work has considered the comorbidity of three very prevalent severe MDs in DP (schizophrenia, bipolar disorder and major depression). The relevance of DP seems to be related to its etiology and complex phenotypic expression in which multiple risk and protection factors are involved. Added to this is the high prevalence, clinical and psychosocial severity, difficult therapeutic management and worse overall functional prognosis. Today, the correct detection, diagnosis and therapeutic intervention in DP is a difficult task and a pending challenge among professionals and researchers in the fields of mental health and addictions. Scientific evidence and clinical practice show that in dual patients there are cognitive and circadian rhythmic variations associated with the type of comorbid MD, which may result in clinical and functional implications of different impact. Therefore, the objective of the present doctoral thesis was to explore such differences and the interrelation with other sociodemographic and clinical variables based on the type of comorbid psychiatric diagnosis. Our purpose is to try to contribute to the knowledge of a differential profile in dual patients according to the comorbid pathology that could be transferred to the development of possible preventive interventions and therapeutic strategies especially directed to their individual needs. This research covered three areas of study. First, the sociodemographic and clinical variables of the three groups of dual patients under treatment were analyzed, allowing to define and specify characteristics associated with the psychiatric diagnosis and their risk or influence on the onset and development of the comorbid disorder. Secondly, was the evaluation of neurocognitive performance, the analysis of the effect that premorbid intelligence has on it and the interrelation of both with clinical variables. Cognitive alterations are considered as endophenotypes of some MD and, in recent years, individual differences in brain activity and good premorbid functioning have been linked to a better cognitive and functional performance. Finally, differences in circadian rhythmic expression - peripheral body temperature (PBT), sleep-wake time and circadian typology- were explored, including a comparison with a group of healthy controls (HC) and the influence of the type of outpatient treatment or residential (mostly in therapeutic community). The evidence indicates the existence of circadian rhythmic alterations in both SUD and in some MD, suggesting that these alterations could be a significant clinical feature that affects the onset and course of comorbid disorder. Data in dual patients, although scarce, suggest the existence of rhythmic recovery associated with withdrawal time and the type of treatment. A total of 114 male participants aged 20 to 50 years were evaluated, all of them with diagnosis of DP in outpatient or residential treatment (most in the therapeutic community). The participants were divided into three groups based on the comorbid psychiatric diagnosis of schizophrenia (SZ+=38), bipolar disorder (BP+=37) or major depression (MD+=39). Inclusion criteria to the study were regular treatment adherence and clinical stability, initial remission of SUD (not induced), and minimum abstinence period of three months and up to one year. The results indicated that patients with SZ+ presented indicators of a greater risk for the onset and maintenance of the comorbid disorder as well as greater social and clinical severity, such as inactivity due to disability, lower level of studies, and an earlier age of onset for both MD and SUD, more family history of substance use, simultaneous use of more substances, and more nicotine consumption. In contrast to these, patients with MD+ exhibited an older average age, greater probability of being separated/divorced and having children, unemployment due to work stoppage or work leave, age of onset of the latest MD, reduced pattern of drugs, and lower consumption of nicotine. In addition, half of them were undergoing an intensive treatment in a therapeutic community. The BP+ patients were placed in an intermediate position in the majority of the variables, although the group highlighted a higher level of education and a lower severity of addiction. Regarding the cognitive performance, premorbid functioning was conserved in the three groups, as well as visoconstructive and spatial skills, and attention span. Learning and verbal memory were affected in SZ+ and relatively conserved in MD+ and BP+, except for immediate memory. Thus, we observed a good processing of information for MD+, and some difficulties for SZ+ and BP+. The executive functioning of the three groups was adequate except in the TMT task, in which SZ+ and BP+ showed deficits in the cognitive inhibition of automatic sequences and mental flexibility. Moreover, premorbid intelligence influenced almost all cognitive domains evaluated and, to a lesser extent also the age of the patients, the abstinence period, clinical stability, and the age of onset for both SUD and MD+. Regarding the circadian rhythmic expression, the SZ+ patients, followed by BP+, showed a late acrophase and a higher mesor than MD+ and HC. The MD+ patients presented greater amplitude and stability of the rhythm compared with the other groups of patients and HC. In addition, patients MD+ were predominantly within a morning typology, slept less hours a day and got up earlier. All the diagnostics groups exhibited less fragmentation of the rhythm compared to HC. The circadianity index was lower in SZ+ and MD+ than that observed for HC, and according to the normative range. On the other hand, regarding residential patients, those outpatients had a higher minimum, mesor and L10 value, a late acrophase and a delay in the central time of the waking period. They also reported a longer duration of daily sleep, later hours of getting up and going to bed, as well as an intermediate typology. Together with the type of treatment, age, abstinence period and nicotine consumption were indicative factors of rhythmic involvement or recovery. Our findings point out the importance of the cognitive preservation and circadian recovery in the functionality of dual patients; being indicators of these aspects the premorbid intelligence and the residential treatment, respectively. Among the preventive and clinical implications that arise from such findings, it is worth mentioning the inclusion of neuropsychological and premorbid IC assessment in early episodes and at older ages, also incorporating interventions to enrich the cognitive reserve if necessary. Likewise, other clinical implications from our observations are to evaluate the circadian rhythmic state before and throughout the SUD treatment, incorporating chronotherapeutic strategies for outpatients. In conclusion, the consideration of neurocognitive and circadian alterations and the posible impact on them of comorbid MD will contribute to the detection of possible markers of vulnerability and can be predictors of prognosis and adherence to treatment together with the establishment of more precise goals and strategies; oriented to prevention or rehabilitation as well as to maintaining changes in behavior and healthy habits in the medium and long term to avoid relapses.

For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic ‘fashions’, and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health,lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts.<br>Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

El trastorn bipolar és una malaltia crònica i recurrent, caracteritzada per l’aparició d’episodis d´(hipo)mania i/o estats mixtes, que alternen, de manera irregular, amb episodis de depressió. Tot i que l’elevació i expansió de l’estat d’ànim és la principal característica clínica que permet distingir el trastorn bipolar del trastorn depressiu recurrent, és la depressió, més que la mania, la principal causa de discapacitat i mort en els pacients bipolars. A més, els pacients amb trastorn bipolar passen més temps amb simptomatologia depressiva que amb simptomatologia (hipo)maníaca o mixta. D’altra banda, el tractament de la depressió bipolar és complex i el número d’opcions terapèutiques basades en l’evidència és molt limitat. L’ús d’antidepressius com a tractament de la depressió bipolar és àmpliament debatut. Les dades que recolzen el seu ús són metodològicament pobres i insuficients; i, de la mateixa manera, existeix una extesa creença que els antidepressius poden induir nous episodis d´(hipo)mania (viratges), que estan relacionats amb el desenvolupament de fases mixtes o que poden accelerar la taxa de ciclació, afirmacions que no han estat ni confirmades ni rebutjades per estudis controlats amb placebo. Tot i això, en la pràctica clínica són àmpliament usats, tant associats amb fàrmacs estabilitzadors de l’estat d’ànim com en monoteràpia. Les fases mixtes es caracteritzen per la presència concomitant de símptomes d’ambdós pols afectius i representen un dels principals reptes del maneig dels pacients amb trastorn bipolar tipus I (prevalença del 40% al llarg de la vida, dificultat diagnòstica, alta complexitat terapèutica). Per aportar informació innovadora en la relació entre l’ús d’antidepressius i el desenvolupament de fases mixtes, estudiàrem una mostra de 144 pacients bipolars tipus I, els quals foren seguits durant un període de fins a 20 anys. Tots aquests pacients havien estat tractats, al menys una vegada al llarg de l’evolució de la seva malaltia, amb antidepressius. D’aquesta manera vam poder determinar el percentatge de pacients que desenvolupava una fase mixta i aclarir les característiques clíniques associades a aquest fet, així com el rol dels antidepressius en el curs i l’evolució de la malaltia. L’estudi identificà que prop del 40% dels pacients desenvolupava al menys un episodi mixte al llarg del curs de la malaltia. Així mateix, vam determinar que l’ocurrència d’episodis mixtes està associada a cronicitat, a una pitjor evolució clínica, a un major número d’episodis depressius previs i a un major ús d’antidepressius, especialment Inhibidors de la Recaptació de Serotonina i Noradrenalina. Molt pocs estudis s’han focalitzat en l´impacte dels antidepressius en el curs i l´evolució del trastorn bipolar, especialment pel que es refereix al desenvolupament de viratges, i a les característiques clíniques associades. Per això, vam portar a terme un segon estudi de cohorts, prospectiu, combinat amb avaluacions retrospectives, i amb una mostra de 221 pacients bipolar tipus I i II deprimits. Els pacients van ser seguits des del primer dia de la introducció d’un antidepressiu a la pauta psicofarmacològica prèvia (estabilitzadors de l’estat d’ànim i/o antipsicòtics atípics) i durant sis mesos. L’estudi determinà que una quarta part dels pacients desenvolupava un viratge de depressió a (hipo)mania o a estat mixte associat al tractament antidepressiu, i que els principals factors de risc eren un debut precoç de la malaltia i un curs clínic caracteritzat per baixes taxes de resposta i altes taxes de viratge amb antidepressius. Així mateix, l’estudi no trobà una associació estadísticament significativa entre l’ús d’un nombre elevat d’antidepressius i el desenvolupament de viratges.<br>Treatment of bipolar depression with antidepressants is strongly debated on the basis of the methodologically poor and insufficient data supporting their use and the widely held belief that antidepressants can induce switch into hypomania, mania, or mixed states, or accelerate the rate of cycling. On the other hand, in clinical practice, antidepressants are frequently used either as monotherapy or as adjuncts to mood stabilizing medication for the treatment of bipolar depression, despite the limited evidence of the short- and long-term benefits and potential risks. In fact, the most common treatment of bipolar depression appears to be antidepressant monotherapy. The first study aimed at identifying clinical risk factors for switch into hypomania, mania, or mixed states, within 8 weeks after introduction of an antidepressant or after increasing its dosage, in a prospective, longitudinal design. 221 depressed bipolar I and II disorder patients were treated with antidepressants, which were added to previously prescribed mood stabilizers and/or atypical antipsychotics. Both groups were compared with analysis of variance and χ2 procedures. Treatment-emergent affective switch was detected in 54 patients, while 176 did not. After performing logistic regression analysis, we concluded that bipolar patients with an earlier age at onset and an illness course characterized by lower rate of response to antidepressants and higher rate of switches into mania or hypomania were found to be the ones with higher switch risk. Nevertheless, a greater number of previous antidepressant exposures was not associated with the occurrence of an antidepressant-associated switch. The aim of the second study was to elucidate the factors associated with the occurrence of mixed episodes, characterized by the presence of concomitant symptoms of both affective poles, during the course of illness in bipolar I disorder patients treated with an antidepressant, as well as the role of antidepressants in the course and outcome of the disorder.We enrolled a sample of 144 patients followed for up to 20 years and compared subjects who had experienced at least one mixed episode during the follow-up (n = 60) with subjects who had never experienced a mixed episode (n = 84) regarding clinical variables. Several differences regarding clinical variables were found between the two groups, but after performing logistic regression analysis, we concluded that the occurrence of mixed episodes is associated with a tendency to chronicity, with a poorer outcome, a higher number of depressive episodes, and greater use of antidepressants.

Psychotic disorders including bipolar disorder and schizophrenia are a leading cause of disability across the world but the underlying pathophysiological mechanisms remain poorly understood. Available treatments are inadequate for some sets of symptoms as is the case for negative symptoms in schizophrenia. Alterations in brain connectivity, synaptic plasticity, N-methyl D aspartate receptor (NMDAR) signalling and calcium homeostasis have been suggested to contribute to these disorders. However, the particular transcriptional programmes altered in these disorders are not fully characterised. Previous data suggested that the transcription factors specificity protein 4 (SP4) and SP1 may be involved in the pathophysiology of psychotic disorders. We hypothesized that the expression and/or function of SP4 and SP1 may be altered in psychotic disorders through the regulation of transcriptional programmes involved in neuronal patterning, synaptic plasticity and glutamate signalling. In this doctoral Thesis we aimed to characterise the contribution of SP4 and SP1 transcription factors to the pathophysiology of psychotic disorders. By using real time quantitative RT-PCR and/or immunoblot techniques, we analysed the expression of SP factors, of SP4 S770 phosphorylation and/or of selected SP-regulated gene targets in at least one of the following substrates: (i) rat cerebellar granule neurons (CGNs), (ii) the postmortem brains of bipolar disorder, schizophrenia and control subjects, (iii) peripheral mononuclear blood cells (PMBC) of first-episode psychosis, and (iv) the rodent hippocampus after NMDAR blockade and antipsychotic treatment. We found that membrane depolarisation regulates SP4 protein levels in CGNs by preventing SP4 degradation via the ubiquitin-proteasoma pathway and that lithium prevents SP4 degradation and increases SP1 gene expression in non-depolarising conditions. In postmortem human tissue, we found a reduction in protein but not mRNA expression of SP4 and SP1 in the cerebellum in subjects with bipolar disorder and in subjects with more severe negative symptoms in schizophrenia. We have also found reduced expression of protein and mRNA levels of SP4 in the prefrontal cortex in bipolar disorder and of SP1 in the same region in schizophrenia, suggesting a disorder-specific regulation in this area. In contrast, both SP4 and SP1 protein and mRNA levels were increased in the hippocampus in schizophrenia. Consistent with this, we also observed an increase of SP1 and SP4 protein levels in the hippocampus of a mouse model of psychosis, but not in the hippocampus of a rat model of chronic antipsychotic treatment, suggesting that this upregulation may be present from the early stages of psychosis. We further characterised the phosphorylation of SP4 at serine 770 (S770), which is regulated by membrane depolarisation and NMDAR activity. We found an increase of SP4 S770 phosphorylation in conditions where SP4 protein levels are reduced, namely in the cerebellum of bipolar disorder and of schizophrenia patients with more severe negative symptoms, as well as in PMBC in first-episode psychotic patients. These results suggest that an imbalance in SP4 abundance may be regulated by NMDAR-dependent SP4 phosphorylation in the brain. Moreover, we found that reduced expression of NR2A and DRD2 in the cerebellum of schizophrenia patients correlated with more severe negative symptoms and SP protein levels. Additionally, we show here evidence for an imbalance in the SP4-NWK2-NR1 pathway in the cerebellum of patients with bipolar disorder. This pathway is involved in NR1 subunit availability on the cell surface, suggesting that SP4 could contribute to altered NR1 receptor trafficking in psychotic disorders. Together, the results presented in this Thesis suggest an imbalance in SP4 and SP1 transcription factors in the brains of patients with bipolar disorder and schizophrenia that may contribute to alterations in NMDAR receptor signalling and thereby to the impaired synaptic plasticity and altered brain connectivity observed in psychotic disorders.