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Twenty DSM-IV major depressed patients who had not responded to at least one previous trial of antidepressant therapy at an adequate dose and duration agreed to participate in this study. They were randomly assigned to receive either mirtazapine (30-45mg) alone or in combination with 16 sessions of weekly Interpersonal psychotherapy (IPT). The patients were followed up naturalistically one year, during this time the psychotherapy sessions were delivered monthly Blinded clinician ratings and self ratings were obtained for depression (Hamilton Depression Scale (HamD). Beck Depression Inventory (BD ), anxiety (Hamilton Anxiety Scale (HAS)), and social functioning (Social Adaptation Scale) at baseline, 6, 16, 26 and 52 weeks. I123 Iodobenzamide Single Photon Computed Emission Tomography (IBZM SPECT) scans measured striatal dopamine D2 receptor activity at baseline and after 6 weeks of treatment. A two way repeated measures analysis of variance (ANOVA) detected significant effects measured by the HamD and HAS for time (p= 0.001; p= 0.001 respectively), treatment (p= p= 0.007; p= 0.033) and the interaction between the two (p = 0.007： p = 0.044). Significant differences emerged between the two groups by six months and continued to one year follow up favouring the IPT group (HamD, p= 0.033; HAS, p= 0.003). The only significant effects for the BDI were for time (p= 0.001). There were no statistically significant effects measured by the SAS. A 3-way repeated measures ANOVA on the IBZM SPECT data detected a significant interaction between Time X Hemisphere, demonstrated by a higher IBZM uptake in the striatum in non-responders (p=0.013, agitated patients (p= 0.045) and women (p= 0.012). The same interaction effects were noted in patients with a high level of resistant depression (p= 0.001).This preliminary study shows promising initial results for IPT in resistant depression. There is some evidence to support a role for dopamine in treatment resistant depression.

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Bibliography: leaves 317-350 / 350 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, 1986

L’innovation thérapeutique est limitée en psychiatrie. De nombreux médicaments sélectionnés sur la base de résultats encourageants dans les essais chez l’animal se révèlent décevants lors des essais cliniques. La validité limitée des modèles animaux, et leur utilisation pour tenter de mimer des pathologies définies de façon catégorielle sur la base de regroupement de symptômes de surface sans lien clair avec les processus cérébraux, les mécanismes biologiques ou la génétique, participent à ces difficultés. Une branche des neurosciences cognitives, l’étude de l’apprentissage par renforcement, associée à l’utilisation d’interventions pharmacologiques ciblées chez le sujet malade ou le sujet sain, représente une opportunité de mieux caractériser les processus cérébraux sous-tendant certaines dimensions cardinales des pathologies psychiatriques. Nous illustrons l’utilisation de l’étude de l’apprentissage par renforcement avec intervention pharmacologique dans deux études expérimentales. La première cherche à caractériser l’effet de l’aripiprazole, un antipsychotique atypique, chez des patients atteints du syndrome Gilles de la Tourette, en utilisant une tâche d’apprentissage contrefactuel, évaluant la capacité à apprendre non seulement des conséquences de ses actions, mais également des conséquences hypothétiques d’actions alternatives possibles. La seconde étude, randomisée contrôlée et en double aveugle, étudie l’effet de deux classes différentes d’antidépresseurs, l’escitalopram et l’agomélatine, chez le sujet sain. L’effet de leur administration est évalué à court terme (3 jours) et à long terme (8 semaines) dans deux tâches probabilistes de sélection de stimulus, l’une simple, l’autre avec renversements occasionnels. L’utilisation de cette approche pourrait participer à la définition d’endophénotypes et, en collaboration avec la recherche préclinique, aider à la création de nouveaux modèles animaux pour en améliorer la valeur prédictive. / Successful new drug development has declined in psychiatry in the last decades. This is in part the resut of a high failure rate in translating positive preclinical efficacy results to positive clinical trials. Limitations in the validity of animal models and shortcomings in the usefullnes of the current categorical diagnostic system. Cognitive neurosciences and particularly reinforcement learning and its computational analysis might provide biomarkers required to develop new ways of classifying mental disorders on the basis of both observable behaviour and neurobiological measues. Used in conjunction with pharmacological challenges, it may bring new insights into the physiopahtology and brain mechanisms underlying psychiatric disorders. It may also help design new animal models with imporved predictive validity for the develoment of medications relying on innovative mechanisms of action. We illustrate the use of reinforcement learning and pharmacological challenge in two experimental studies. In the first experiment, we administered a reinforcement learning task that involves both direct learning from obtained outcomes and indirect learning from forgone outcomes to two groups of Gilles de la Tourette patients, one receiving aripiprazole, one unmedicated and to a group of healty subjects. In the second experiment, we administered two probabilistic stimulus selection learning tasks (one simple, one with occasional reversals) to healthy subjects randomly and blindly allocated to either escitalopram, a typical serotonin reuptake inhibitor, agomelatine, an antidepressant with a different mechanism of action, or placebo. The experiment compard the effect of these two classes of antidepressants to placebo after both short term (3 days) and long term (8 weeks) treatment. These experiments bring insights into the understanding of the clinical condition studied, and the effects of the drugs tested. Implications of this approach for the translational approach to drug development is discussed.