Cascadas de la plasticidad neuronal: desde los genes a la conducta en la patofisiología y el tratamiento del trastorno bipolar /Cellular Plasticity Cascades: Genes to Behavior Pathways in the Pathophysiology and Treatment of Bipolar Disorder

The “molecular medicine revolution” has brought to bear the power of sophisticated cellular and molecular biologic methodologies to tackle many of society’s most devastating illnesses. This has allowed the study of a variety of human diseases which are caused by abnormalities in cell to cell communication; studies of such diseases are offering unique insights into the physiologic and pathophysiologic functioning of many cellular signaling pathways. It is clear that bipolar disorder is a disorder of “synapses and circuits,” not “too much/too little” of individual neurotransmitter systems. A major defect is in the ability to regulate neuroplastic adaptations to perturbations (both physiological and pathophysiological) without failing or invoking compensatory adaptations that overshoot and predispose to oscillations. Many of the very same “plasticity regulators” also play a critical role in cell survival, cell atrophy, and cellular resilience. New genomics and proteomics technologies are also being utilized to facilitate the identification of genes that are regulated by mood stabilizers, and have led to novel and completely unexpected targets, most notably neurotrophic signaling cascades. Optimal long term treatment for these devastating disorders may only be attained by providing both trophic and neurochemical support; the trophic support would be envisioned as enhancing and maintaining normal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. There are a number of pharmacologic “plasticity enhancing” strategies being investigated which may be of considerable utility in the treatment of mood disorders; this research hold much promise for the development of novel therapeutics for the treatment of Bipolar Disorder.

La vulgarización del término depresión ha conllevado a una borrosidad del término que parece haberse extendido a los médicos no especialistas en Psiquiatría. Por otra parte la respuesta terapéutica a los síntomas depresivos inducidos por situaciones adaptativas al tratamiento con los modernos fármacos antidepresivos es percibido por los médicos de familia y lamentado, injustificadamente, por algunos responsables de la gestión de la salud pública.
La situación contrasta con la claridad y estabilidad diagnóstica de la depresión desde el punto de vista de la Psiquiatría en relación a los síntomas depresivos reactivos, el temperamento depresivo o simplemente la tristeza como emoción básica.
En esta presentación se intentará clarificar la situación y relacionar las distintas situaciones comentadas sin detrimento de mantener la necesidad de un diagnostico claro y estable para las enfermedades depresivas. La metodología utilizada es la consideración de la depresión según el modelo médico, sus bases bioquímicas y la acción de los fármacos antidepresivos.

The conventional definitions of a favorable outcome in a randomized clinical trial of an antidepressant medication were established in the 1960s and 1970s. Typically, patients were considered to have responded when there was at least a 50% decline in a standardized depression score after four to six weeks of therapy. Alternatively, the treating clinician's global judgment that there had been “much” or “very much” improvement was sometimes utilized. Although response so defined is a valid indicator of therapeutic benefit, it was never intended to represent an optimal therapeutic outcome. There is, for example, ample evidence that patients who have responded, but who continue to manifest residual depressive symptoms, have persistent psychosocial impairments and a greater risk of relapse. It is also possible for patients with very severe depressive episodes to improve sufficiently enough to be declared responders, yet still meet syndromal criteria for a major depressive episode. As a result of these limitations, there has been growing interest in the use of a more complete level of improvement, for example, remission of the depressive episode as the primary indicator of antidepressant efficacy. This presentation will review the evidence from both naturalistic and controlled studies that supports the validity of the remission definition.

Depression is a major concern for the European health systems, employers and families. The economic burden of depression has been estimated at €120 billion per year, exceeding those of all other disorders in CNS. Research investments into affective disorders only make up a couple of percentage of the societal cost of the disease. This demands new efforts at a European level, in order to save the minds of Europe.

Although research on the neurobiology of behavioral differences, such as emotionality, is still in its infancy, several milestones have already been reached: Variation in gene expression were confirmed to play a predominant role in individual differences in emotionality; gene x environment interaction were established in humans as well as the nonhuman primate and rodent model; gene-phenotype correlations were substantiated by functional neuroimaging; as well as the notion that both genes and environmental factor impact on brain development and thus set the stage for emotion regulation is increasingly appreciated. Investigation of subtle alterations in the expression of genes of the serotonergic pathway, such as the serotonin transporter (5HTT), of correlations between 5HTT genotype and brain activity, and of environmental variables interacting with 5HTT variants currently strengthen research on the genetics and epigenetics of emotionality.

Major depression runs in families. The familial transmission is (almost exclusively) genetic. Close to half the cause of the development of major depression is explained by heredity. A higher genetic liability seems to result from twin studies of clinical samples compared to common population samples. Major depression seems to be genetically related to anxiety disorder (especially generalized anxiety disorder) on the one side, and bipolar disorders on the other side. Genetic factors may have a direct effect on the experience of depressive affects and thoughts. However, they may also act through personality traits, causing negative events that it its turn release clinical depression.

Selective Serotonin Reuptake Inhibitors (SSRIs) are the most widely used antidepressant drugs (AD), due to their excellent safety and tolerability. However, as with other AD, they have a limited efficacy and slow onset of clinical action. Preclinical research has identified a number of cellular mechanisms potentially responsible for the suboptimal therapeutic action of SSRIs. The talk will review the role of several 5-HT receptors (5-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2C and 5-HT₃) as potential therapeutic targets to accelerate or enhance the clinical action of SSRIs.

Brian E Leonard. Pharmacology Department, National University of Ireland, Galway, Ireland

For over 50 years, antidepressants have been developed based on the assumption that the primary disorder in depression is related to a dysfunctional noradrenergic and/or serotonergic system. This has resulted in a plethora of modestly effective drugs that are presumed to enhance the activity of these biogenic amines. However, a substantial minority of depressed patients show inadequate response to treatment. As there is now evidence that effective treatment is associated with repair of damaged neuronal networks, perhaps it is timely to consider how improvements may be made to existing, and future, antidepressants.

Sidney H. Kennedy. Bipolar Guidelines Group, Canadian Network for Mood and Anxiety Treatments, Department of Psychiatry, University of Toronto, Can

Results from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) series of studies indicate that even after 4 consecutive trials under “real world” conditions, approximately 50% of patients have not achieved remission. These findings support the need to differentiate sub-populations, whether on the basis of symptomatology, neurobiology or other variables to deliver optimally matched treatments.
This presentation will focus on Deep Brain Stimulation (DBS) to cingulate area 25 as a hypothesis driven investigational procedure for Treatment Resistant Depression (TRD). Comparison of outcomes between DBS and other neuromodulation therapies including Transcranial Magnetic Stimulation and Vagus Nerve Stimulation will also be addressed.

Gerard Marek. Neuroscience Discovery Research, LRL, Lilly Corporate Center, Indianapolis, USA

All currently used antipsychotic drugs used in schizophrenia block dopamine receptors. Based on preclinical models (PCP-induced hyperactivity,CAR), mGlu2/3 receptor agonists have been suggested as potential antipsychotic drugs. A recent phase II study assessed the therapeutic potential of a prodrug for a mGlu2/3 agonist schizophrenic patients. This mGlu receptor agonist prodrug significantly improved both the negative and positive symptoms of schizophrenic patients. This work builds upon the previous demonstration for anxiolytic effects of mGlu2/3 receptor agonists.

Peter McGuffin. Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College, London, UK

Genética de los trastornos bipolares / Genetics of Bipolar Disorder

There is strong evidence from family and twin studies, supported by some adoption data of an important genetic contribution to bipolar disorder. The mode of transmission is complex and almost certainly involves multiple genes of small effect, even though the overall heritability is high at around 80%. Recent twin analysis suggests overlapping effects with both unipolar depression and schizophrenia. Recent molecular studies confirm the overlap with schizophrenia involving at least two different chromosomal regions and a number of positional candidate genes. Results are also beginning to emerge from a very large scale whole genome association study suggesting new susceptibility loci that were previously undetected by linkage or candidate gene approaches.

Kiki Chang. Stanford University, School of Medicine, Department of Psychiatry and Behavioral Sciences, Division of Child Psychiatry and Child Development, California, USA

Anomalías cerebrales previas al desarrollo del trastorno bipolar / Brain abnormalities prior to the development of bipolar disorder

Studying populations at high-risk for developing bipolar disorder allows for identification of characteristics that may present risk factors (bipolar traits or endophenotypes) for bipolar development. This presentation will review brain imaging findings in patients already with bipolar disorder and discuss the emerging literature in morphometric, spectroscopic, and functional imaging findings in at-risk populations. These findings point to abnormalities in prefrontal-subcortical circuits that may underlie the pathophysiology of bipolar disorder.

Mary L. Phillips. Department of Psychiatry, University of Pittsburgh, PA, USA

Anomalías cerebrales que distinguen el trastorno bipolar de la depresión unipolar / Brain abnormalities that distinguish bipolar disorder from unipolar depression

My research has focused on examination of specific functional abnormalities in neural systems underlying emotion processing and emotion regulation that may be present as biomarkers of disorder in individuals with major psychiatric disorders, including bipolar disorder and unipolar depression. The identification of these biomarkers is, I believe, a crucially important step toward the long-term goal of improving diagnostic accuracy in individuals presenting in the early stages of psychiatric illness. I have also begun to focus on examination of the extent to which markers of dysfunction in neural systems underlying emotion processing may act as predictors of response to specific treatments in individuals suffering from affective disorders, and may be present in individuals at high genetic risk of future development of these disorders.

Conferencia de Clausura / Closure Conference
Moderador /Chairman: Steven Paul Lilly Research Laboratories, Eli Lilly Company, Indianapolis, USA

Mario Maj. Department of Psychiatry, University of Naples SUN, Italy

La ‘folie circulaire’ de Falret como variación del trastorno bipolar: antiguas y recientes evidencias / Falret’s ‘folie circulaire’ as a distinct variety of bipolar disorder: old and new evidence

The origin of the concept of bipolar disorder is commonly traced back to the mid-1800 contributions by Falret on “la folie circulaire” (“circular insanity”) (1) and Baillarger on “la folie à double forme” (“dual form insanity”) (2). The continuity between these contributions and Kraepelin’s description of manic-depressive insanity is correctly pointed out. One aspect, however, is usually overlooked: both Falret and Baillarger, contrary to Kraepelin, described a specific variety of bipolar disorder: the one characterized by the direct, regular transition from mania to depression or vice versa. Both of them regarded this “circular” form as distinct from those cases in which manic and depressive episodes occur separately and both considered this distinction as significant. Falret reported that “circular insanity is very hereditary” and “infinitely more frequent in females than in males”, and stated that “mania and melancholia, when they occur in isolation, are more treatable than when they occur together in circular insanity”. Modern generations of psychiatrists have not ignored Falret and Baillarger’s teaching completely. In fact, some scholars of manic-depressive illness have explicitly distinguished a “circular” form of the disease, having a poor prognosis (e.g., 3), while others have reported that the tendency to switch is a predictor of a worse outcome (e.g., 4-6). Turvey et al. (7) reported that “polyphasic episodes” (i.e., episodes including at least two switches in polarity) are associated with a poor prognosis, concluding that “it is more likely that patients who switch have a more severe form of bipolar disorder which manifests as affective instability”. We found that a polyphasic index episode, especially if starting with depression, was associated with a poor outcome in bipolar disorder (8). Thus, currently available research provides some evidence that Falret and Baillarger were actually right: i.e., that the regular switch from one polarity of mood to the other may identify a variety of bipolar disorder with a characteristic prognosis, treatment response and perhaps pathophysiology. This pattern may represent a significant target for new pharmacological and psychosocial treatment strategies.

Despedida y Clausura / Farewel & Closure

Ponente: César Soutullo
Depart. of Psychiatry and Medical Psychology, Clínica Universitaria de Navarra, Pamplona, Sp
Miércoles 11, 13:00 h y Miércoles 11, 17:30 h

TRASTORNO BIPOLAR EN NIÑOS Y ADOLESCENTES / BIPOLAR DISORDER IN CHILDREN AND ADOLESCENTS

Bipolar disorder (BD) is a chronic, highly genetic psychiatric disorder, that usually begins in adolescence or early adulthood associated with significant morbidity and mortality, with similar gender and cross-cultural prevalence. Pepubertal-onset BD frequently has a phenotype that includes non-episodic, chronic, rapid-cycling, mixed manic state, that may be comorbid with attention-deficit hyperactivity disorder (ADHD), and Conduct Disorder (CD), or have features of ADHD and/ or CD as initial manifestations. In this seminar we will review data on the phenomenology, clinical course, and treatment of pediatric BP that will help participants to better identify this condition in children & adolescents.

DEPRESIÓN REFRACTARIA / REFRACTIVE DEPRESSION

Despite refinements to the existing therapeutic modalities, there remains a significant subpopulation of severely ill patients with refractory mood disorders who fail to achieve a clinical response. The therapeutic approach to these cases has relied on pharmacotherapy in various sequences and combinations, electroconvulsive therapy and other stimulation techniques. This presentation reviews the evidences, benefits and risks of all known therapies.

LA PSICO-EDUCACIÓN COMO FACTOR PRNÓSTICO EN EL TRASTORNO BIPOLAR / PSYCHO-EDUCATION AS PROGNOSIS FACTOR IN BIPOLAR DISORDER

Group psychoeducation has shown its efficacy on prevention of all sort of bipolar recurrences, including mania/hypomania, mixed episodes and depression. At the conclusion of this workshop the participant should be able to acknowledge the impact of psychoeducation in the prophylaxis of recurrences in bipolar disorder, with special emphasis on long-term outcome.

  Ponencias de 20 minutos / 20-minute talks
  10 minutos de discusión después de cada ponencia / 10-minute discussion after each talk
  Seminarios: Duración, 1 hora: Exposición, 20 min; Coloquio con los asistentes, 40 min.
Grupos reducidos

Fundación Lilly

ENGLISH <> SPANISH : TRADUCCIÓN SIMULTANEA <> SIMULTANEOUS TRANSLATION PROVIDED