Há poucos estudos voltados para a heterogeneidade do transtorno de déficit de atenção/hiperatividade (TDAH) em adultos, apesar de ser um transtorno psiquiátrico comum. As freqüentes associações do TDAH com outros problemas psiquiátricos aumentam a sua morbidade. Dentre essas comorbidades, destacase o transtorno depressivo maior (TDM), que além de ser freqüente influencia o impacto e a abordagem terapêutica do TDAH. Foram avaliados 320 adultos em atendimento ambulatorial para TDAH. O diagnóstico seguiu os critérios do DSM-IV. As entrevistas foram realizadas com a versão em português do K-SADS-E para TDAH e transtorno opositor desafiante (TOD), e com o SCID-IV de transtornos do eixo I para as comorbidades psiquiátricas. Os diagnósticos foram confirmados por avaliação clínica. Modelos de regressão foram aplicados para testar a associação entre a ocorrência de TDM e os desfechos clínicos e demográficos avaliados. Os indivíduos com TDAH e TDM apresentaram maior freqüência de diagnóstico de transtornos de ansiedade e experiência de tratamento prévio (tanto psicoterápico quanto farmacológico) quando comparados a indivíduos com TDAH, sem TDM. Por outro lado, apresentaram menos freqüentemente diagnóstico de dependência de drogas e histórico escolar de repetência ou suspensões de classe. Não houve diferença significativa entre os grupos com ou sem TDM quanto à idade do diagnóstico de TDAH. Os achados sugerem uma utilidade do diagnóstico de TDM como um indicador relevante de determinadas características clínicas em adultos com TDAH. A maior procura por tratamento relacionada ao TDM não foi acompanhada de um diagnóstico mais precoce do TDAH, como seria esperado. Se confirmados, esses dados apontam para a necessidade de pesquisas e educação médica voltadas para um reconhecimento mais eficiente e precoce do TDAH em pacientes que buscam atendimento em saúde mental por outras causas. / There are few studies on the heterogeneity of adult ADHD, despite it is a common psychiatric disorder. The frequent comorbidity between ADHD and other psychiatric problems, increases the morbidity of the disorder. Major depressive disorder (MDD) stands out between other ADHD comorbidities, since it is frequent and influences ADHD outcomes and therapeutic approach. Three hundred and twenty adult outpatients were evaluated for ADHD. Diagnosis followed DSM-IV criteria. Interviews to evaluate ADHD and oppositional defiant disorder (ODD) were performed based on the Portuguese-language version of K-SADS-E and Psychiatric comorbidities were evaluated using SCID-IV for axis I disorders. Diagnoses were confirmed by clinical interview. Regression models were applied to test MDD association with clinical and demographic outcomes. Subjects presenting ADHD and MDD had a higher frequency of anxiety diagnosis and prior experience of psychotherapy and/or pharmacological treatment when compared to ADHD subjects free of MDD. On the other hand, they reported less often drug dependence diagnosis, grade repetition and school suspensions. There was no significant difference between groups with or without MDD on the age at ADHD diagnosis. These findings suggest that the MDD diagnosis may be useful as an important indicator of certain clinical characteristics in adults with ADHD. The more frequent search for treatment attributable to MDD diagnosis was not accompanied by an earlier ADHD diagnosis, as expected. If confirmed, the present data point to the need for research and medical education towards an earlier and more efficient ADHD diagnosis in patients who search for mental health care for other reasons.

O Transtorno da Depressão Maior (MDD) é uma doença muito difundida em todo mundo e com uma alta prevalência, principalmente em mulheres. Transtornos de humor são recorrentes e ameaçam a vida, devido ao risco de suicídio. Apesar disso, a etiologia do MDD ainda é pouco entendida e diversas hipóteses foram desenvolvidas na tentativa de explicá-la. Uma delas está ligada ao estresse. Distúrbios no eixo hipotálamo-hipófiseadrenal (HPA) estão presentes em cerca 70% de pacientes com depressão. Ao buscar um melhor modelo animal para estudo do impacto do estresse no desenvolvimento da depressão, chegamos ao estresse leve crônico (CMS). Em estudos prévios desenvolvidos neste laboratório, observamos que há diferenças entre tipos de estressores e os mediadores secretados na resposta do eixo HPA, isto é, durante o estresse físico é secretado o mediador vasopressina, enquanto que no estresse psicológico, é secretado o mediador CRF; já nos estresses considerados mistos (como nado forçado), ambos os mediadores estão presentes. Assim, propusemos estabelecer protocolos de CMS baseados no protocolo original de Paul Willner, pesquisador que desenvolveu este modelo, empregando estressores do tipo físico ou psicológico, separadamente. O que observamos foi que nenhum dos dois tipos de estressores conseguiu levar os animais à anedonia (queda na preferência por sacarose). No entanto, ao observar o ganho de peso dos animais ao longo do tempo e o mapeamento cerebral com citocromo c oxidase, notamos que o estresse teve seu impacto no animais. Comparados a outros modelos de depressão, o CMS tem a premissa de desenvolver um estado depressivo nos animais antes do teste com drogas antidepressivas, fazendo com que tenha uma alta validade preditiva. Ele também pode incorporar outros endpoints para avaliar outros comportamentos, além da anedonia, que possam demonstrar o estado depressivo no animal. Por exemplo, observamos no mapeamento cerebral que a substância negra e a PAG estiveram mais ativas no estresse físico e elas podem estar implicadas na busca por recompensa e na modulação de dor, respectivamente. Concluímos que o modelo de CMS é apropriado, embora ainda necessite de estudos quanto à equivalência de intensidade de estressores / Major Depressive Disorder (MDD) is a widespread disease all over the world with a high prevalence, especially among women. Mood disorders are recurrent and life threatening, due to suicide risk. Despite those, MDD etiology is poorly understood and several hypotheses have been developed to try and explain it. One of them is connected to stress. Disorders on the hypothalamus-pituitary-adrenal (HPA) axis are present in up to 70% of patients with depression. While searching for a better animal model to study the impact that stress might have on depression onset, we came across the Chronic Mild Stress (CMS) model. During previous studies developed in this lab, weve observed that there are differences between types of stressors and mediators involved in the HPA axis response, i.e. during physical stress, the mediator secreted is vasopressin, whereas during psychological stress, the mediator is CRF; on mixed stress (like forced swim), both mediators are present. That way, we proposed to set up CMS protocols based on Paul Willner (the researcher who developed this model)s original one, employing physical or psychological stressors separately. None of the types of stressors were able to induce anhedonia (decrease in sucrose preference) in the animals. However, noticing the animals weight gain over time, and cerebral mapping with cytochrome c oxidase, we could see that stress had impact over the animals. Compared to other depression models, CMS has the presupposition of leading the animals to a depressive-like state before testing antidepressant drugs, which gives it a high predictive validity. The model can also incorporate different endpoints to assess other behaviors, besides anhedonia, that may show the animals depressive-like state. For instance, we observed in the brain mapping that substantia nigra and PAG were more activated in physical stress and they can be implicated in reward seeking and pain modulation, respectively. So, we conclude that the CMS model is appropriate, although it still needs more research regarding the intensity of stressors equivalence

Only one third of depressed patients experience a beneficial therapeutic effect after using a first-line medication, leaving two-thirds of patients without effective treatment. It has been shown that a combination of two drugs with different modes of action result in an increase in the number of patients responding to treatment. One of the most effective strategies is the addition of low doses of an atypical antipsychotic. In depth evaluation of the neurobiological properties of atypical antipsychotics have revealed that these agents produce antidepressant effects and enhance the therapeutic response of first-line medications through antagonism of the 5-HT2A, 5-HT2C, 5-HT1B/D, 5-HT7 receptors and NET; agonism of the 5-HT1A receptor; and/or D2/3 partial agonism. The present experiments focused on determining the mode of action of this combination of drugs to help design better antidepressant treatment in the future. A series of electrophysiological experiments were proposed to assess 5-HT and NE neurotransmission in the rat hippocampus, as well as DA transmission in the rat forebrain.

Bipolar disorder (BD) and major depressive disorder (MDD) are characterised by a fundamental disturbance of mood, with strong support for overlapping causal pathways. Structural brain and neurocognitive abnormalities have been associated with mood disorders, but it is unknown whether these reflect early adverse effects predisposing to mood disorders or emerge as a consequence of illness onset. The Bipolar Family Study is well-suited to examine the origin of structural brain and neuropsychological abnormalities in mood disorders further. The volumes of subcortical brain regions, cortical thickness and surface area measures of frontal and temporal regions of interest and neuropsychological performance over a two-year time interval was compared at baseline and longitudinally between three groups: young individuals at high risk of mood disorders who subsequently developed MDD during the follow-up period (HR-MDD), individuals at high risk of mood disorders who remained well (HR-well), and healthy control subjects (HC). The longitudinal analysis of cortical thickness revealed significant group effects for the right parahippocampal and right fusiform gyrus. Cortical thickness in both of these brain regions across the two time points was reduced in both high-risk groups relative to controls, with the HR-MDD group displaying a thinner parahippocampus gyrus than the HR-well group. Moreover, a significant interaction effect was observed for the left inferior frontal and left precentral gyrus. The HR-well subjects had progressive thickness reductions in these brain regions relative to controls, while the HR-MDD group showed cortical thickening of these areas. Finally, longitudinal analyses of neuropsychological performance revealed a significant group effect for long delay verbal memory and extradimensional set-shifting performance. Reduced neurocognitive performance during both tasks across the two time points was found in the HR-well group relative to controls, with the HR-MDD group displaying decreased extradimensional set-shifting abilities as compared to the HC group only. These findings indicate, that reduced left parahippocampal and fusiform thickness constitute a familial trait marker for vulnerability to mood disorders and may thus form potential neuroanatomic endophenotypes. Particularly strong thickness reductions of the parahippocampal gyrus appear be linked to an onset of MDD. Moreover, progressive thickness reductions in the left inferior frontal and precentral gyrus in early adulthood form a familial trait marker for vulnerability to mood disorders, potentially reflecting early neurodegenerative processes. By contrast, an absence of cortical thinning of these brain regions in early adulthood appears to be linked to the onset of MDD, potentially reflecting a lack or delay of normal synaptic pruning processes. Reduced long delay verbal memory and extradimensional set-shifting performance across time constitute a familial trait marker for vulnerability to mood disorders, likely representing disturbances of normal brain development predisposing to illness. These findings advance our understanding of the origin of structural brain and neurocognitive abnormalities in mood disorders.

Certain electrophysiological markers hold promise in distinguishing individuals with major depressive disorder (MDD) and in predicting antidepressant response, thereby assisting with assessment and optimizing treatment, respectively. This thesis examined resting brain activity via electroencephalographic (EEG) recordings, as well as EEG-derived event-related potentials (ERPs) to auditory stimuli and facial expression presentations in individuals with MDD and controls. Additionally, the utility of resting EEG as well as auditory ERPs (AEPs), and the associated loudness-dependence of AEPs (LDAEP) slope, were assessed in predicating outcome to chronic treatment with one of three antidepressant regimens [escitalopram (ESC); bupropion (BUP); ESC+BUP]. Relative to controls, depressed adults had lower pretreatment cortical activity in regions implicated in approach motives/positive processing. Increased anterior cingulate cortex (ACC)-localized theta was observed, possibly reflecting emotion/cognitive regulation disturbances in the disorder. AEPs and LDAEPs, putative indices of serotonin activity (implicated in MDD etiology), were largely unaltered in MDD. Assessment of ERPs to facial expression processing indicated slightly blunted late preconscious perceptual processing of expressions, and prolonged processing of intensely sad faces in MDD. Faces were rated as sadder overall in MDD, indicating a negative processing bias. Treatment responders (vs. non-responders) exhibited baseline cortical hypoactivity; after a week of treatment, cortical arousal emerged in responders. Increased baseline left fronto-cortical activity and early shifts towards this profile were noted in responders (vs. non-responders). Responders exhibited a steep, and non-responders shallow, baseline N1 LDAEP derived from primary auditory cortex activity. P2 LDAEP slopes (primary auditory cortex-derived) increased after a week of treatment in responders and decreased in non-responders. Consistent with overall findings, ESC responders displayed baseline cortical hypoactivity and steep LDAEP-sLORETA slopes (vs. non-responders). BUP responders also exhibited steep baseline slopes and high ACC theta. These results indicate that specific resting brain activity profiles appear to distinguish depressed from non-depressed individuals. Subtle ERP modulations to simple auditory and emotive processing also existed in MDD. Resting alpha power, ACC theta activity and LDAEP slopes predicted antidepressant response in general, but were limited in predicting outcome to a particular treatment, which may be associated with limited sample sizes.

Previous magnetic resonance imaging (MRI) studies have demonstrated brain atrophy in major depressive disorder (MDD) that is progressive with continuing illness and may be reversible with antidepressant treatment. What remains unclear is whether brain structure can be positively affected by pharmacological intervention even if patients fail to remit on the treatment. The primary aim of this thesis was to prospectively track changes in brain structure in patients with treatment-resistant depression while they underwent pharmacotherapy with the goal of attaining remission. There is evidence that gene variants associated with poorer antidepressant response also confer greater risk of volume reduction in the hippocampus. A secondary aim of the thesis was to investigate the effects of monoaminergic-related gene variants on hippocampal volume in patients and controls at baseline imaging. Outpatients with treatment-resistant MDD underwent structural MRI scans at baseline and after either 6-months of sustained remission or 12-months of failure to remit. Matched controls were scanned once to provide comparison data for patients’ baseline scans. Participants also provided blood samples for genetic analyses. Imaging outcome measures included longitudinal changes in whole-brain volume, and gray matter volume and mean cortical thickness within specific cortico-limbic regions of interest (ROIs). Over follow-up, remitted patients had an increase in whole-brain volume, while nonremitted patients lost brain volume despite receiving more treatment strategies. Remitters and nonremitters also showed subtle changes in volume and thickness over time in several ROIs in opposing directions, with increasing hippocampal volume and cortical thickness in the rostral middle frontal gyrus and orbitofrontal cortex in remitters, and decreasing volume or thickness in these regions in nonremitters. Genetic imaging analyses revealed that polymorphisms in certain norepinephrine- and serotonin-related genes have similar effects on hippocampal volume in patients and controls, while the serotonin transporter polymorphism differentially affects hippocampal volume in the presence of depression. Given the observations of volume increase in remitted patients and continuing atrophy in nonremitters, pharmacotherapy in the absence of sustained remission is likely insufficient to elicit structural recovery in depression. This finding is important since the restoration of brain structure in patients with treatment-resistant depression may have positive implications for their future prognosis.

Introduction: The aim of the project was to investigate the effects of antidepressants on brain networks whilst at rest. My hypothesis was that antidepressants work by reversing persistent activity in the brain’s default mode network (DMN). The DMN is implicated in self-reflection and rumination in MDD. The methodologies and results of studies of resting state networks in MDD and the effects of antidepressants are reviewed in the thesis. Increasing evidence implicates glutamate in the action of antidepressant drugs. Whether there are illness related changes in glutamate function is unresolved, largely because of the lack of techniques for assessing it. Ketamine and other NMDA antagonists have improved MDD symptoms within 24 hours though the effects are short lasting. The molecular neural networks involved in ketamine’s putative antidepressant effects are unclear. The thesis reviews the evidence. Much evidence implicates ACC as a site of action of antidepressant effects but whether this is through its regulation of the DMN or other networks is not known. This thesis compares the effect of ketamine and citalopram on ACC-related systems. Method: The thesis combines two systematic reviews of the effects of MDD and antidepressant drugs on i) resting state networks (53 studies) and ii) glutamate neurotransmission (45 studies of clinical efficacy of ketamine). There are two experimental chapters. The first describes investigation into two rapid acting antidepressant drugs acting via glutamate mechanisms. 54 unmedicated cMDD were scanned across two centres on 3T MRI scanners while being infused with placebo (0.5% saline), 0.5mg/kg ketamine or 100mg AZD6765 over 1 hour. fMRI resting state data between drug treatments was compared for the final 25 minutes of the drug infusion and for a 25 minute resting state scan a day later. The second experimental chapter examines whether these effects were shared by citalopram, a standard antidepressant. 67 unmedicated cMDD, rMDD and HC were administered citalopram 7.5mg i.v. and scanned on a 1.5T MRI scanner. In a second study 63 cMDD and HC were administered i.v. citalopram 7.5mg or placebo (0.5% saline). fMRI resting state data for the final 12 ½ minutes following drug infusion was compared. Independent Component Analysis was performed using the Group ICA for fMRI toolbox. The resting component with the highest spatial correlation to the ACC was used. Brain maps of the intensity of the selected component were constructed for each individual. Group averages were calculated and compared using SPM. Regional analysis was performed using Marseille Boite a Regions d'interet. Results: On day 1 AZD6765 significantly increased mean intensity of ACC resting component in the right insula, right IPL and left cingulate gyrus greater than ketamine or placebo. Ketamine increased mean intensity of ACC resting component greater than placebo in the right lentiform nucleus and left mFG. Significantly decreased mean intensity of ACC resting component in the left insula in the AZD6765 group compared to placebo was noted. On day 2 AZD6765 increased mean intensity of ACC resting component greater than ketamine and placebo in the left and right lentiform nuclei. AZD6765 reduced mean intensity of the ACC resting component in the left and right MFG. The first citalopram study revealed reduced mean intensity of ACC resting component in cMDD compared to rMDD and HC in PCC. rMDD had reduced mean intensity of ACC resting component in the precuneus compared to HC. In the second study, citalopram had no effect in HC but normalised precuneus activity in cMDD producing a significant drug x group interaction. Conclusions: The acute antidepressant effects of citalopram are modulated by changes in the bilateral precuneus. The precuneus is central to connectivity with other regions in MDD. It has a prominent role in the DMN and is linked to rumination. The mechanism of the antidepressant effects of AZD6765 is different from those of ketamine and citalopram. The insula, IPL, MFG, cingulate gyrus and lentiform nuclei are all regions implicated in MDD suggesting antidepressant effects. The rapid antidepressant effects of AZD6765 are possibly due to a resetting of the interface between DMN and salience networks.

In addition to low mood, major depressive disorder (MDD) is characterized by persistent cognitive deficits that impair daily functioning and resist improvement with conventional pharmacotherapies. Repetitive transcranial magnetic stimulation (rTMS) holds promise as an efficacious alternative, offering better outcomes than medication for patients with treatment-resistant depression (TRD). Yet, current rTMS protocols that administer sinusoidal biphasic pulses achieve remission in less than the majority. However, monophasic pulses may yield higher success rates based on greater cortical excitation/neuromodulation strength. MDD is associated with altered P300 event-related potentials (ERPs), indexing decreased attentional resource allocation and slower cortical processing speed. Using a cohort of 20 TRD patients who received high-frequency rTMS, this study aimed to assess the impact of monophasic and biphasic stimulation on attention-related P300 measures and their utility as correlates of clinical/cognitive response. Based on baseline and post-treatment change in P300 components, rTMS-induced increases in automatic attention/passive information processing differed by pulse type and predicted greater clinical improvement in depressed individuals. This study represents an important step towards identifying cognitive changes and underlying cortical mechanisms associated with rTMS response and targeted MDD treatment.

A growing body of work links psychopathology to changes in hedonic capacity following stressors. This was the first experimental study of the effects of stress on hedonic capacity in an analog generalized anxiety disorder (GAD) sample (a high worry group). Specifically, we utilized an experimental manipulation of stress and a behavioral index of anhedonia to test the hypothesis that individuals with GAD, who are at higher risk for developing depression symptoms, exhibit greater stress-related deficits in hedonic capacity than do nonanxious controls. Further, this study assessed whether stress-induced hedonic deficits predicted future depression. Controls exhibited the expected reward learning pattern in the baseline condition, demonstrating intact hedonic responding, as well as the expected pattern of behavioral anhedonia under stress. Contrary to predictions, worriers demonstrated intact hedonic capacity under stress. The stress effect in worriers was modulated by past depression diagnostic status; whereas worriers with no past depression demonstrated blunted baseline hedonic capacity and heightened hedonic capacity under stress, worriers with past depression demonstrated the normative response pattern. Blunted baseline response bias predicted higher future depression in both groups. We discuss the differential stress effects on behavioral hedonic capacity found as a function of worry, the role of past depression as a moderator of stress effects among worriers, and the need for future work to further explicate the mechanisms that may modulate reward response under stress.

Major depressive disorder (MDD) is a relevant condition to consider regarding Work Capacity Evaluation (WCE) because of its high prevalence, strong impact on short-term work disability, and low rate of treatment. The challenge that faces occupational therapists (OTs) is that there is no specific guideline and process to follow when conducting Work Capacity Evaluation with clients suffering from MDD. The researcher had also noted conflicting opinions with regard to the outcome of Work Capacity Evaluation (WCE) and recommendations in occupational therapy reports. The researcher is of the opinion that indeed occupational therapy assessments need to be clear about what to measure, and selection of appropriate standardised measures and non-standardised assessments is needed. Therefore, the research question was, what are the perceptions and practices of occupational therapists in determining work capacity of employees suffering from major depressive disorder? The aim of this study was to describe the perceptions and practices of occupational therapists in determining work capacity of employees suffering from major depressive disorder. The literature showed that Work Capacity Evaluation assists to determine the employee’s returnto- work. The Code of Good Practice: Dismissal contained in the Labour Relations Act of 1998, stipulates that incapacity on the ground of ill health or injury may be either temporary or permanent. The nature of this study was a mixed method design including both qualitative and quantitative approaches. The phenomenological strategy was used. The study had a sample size of 68 participants, practising as occupational therapists. Purposive sampling was used. The data were collected in four distinct phases, referred to as sequential exploratory strategy with elements of embedded design. Phase one, used descriptive open-ended questions; phase two was a close-ended questionnaire to confirm findings in phase one; phase three consisted of focus group interviews and phase four was member checking to confirm findings in phase three. During data analysis, five themes related to employees suffering from MDD emerged and they were identified as: (1) the content of comprehensive assessment for work capacity evaluation, (2) the process of work capacity evaluation, (3) the competency requirements of the occupational therapist, (4) occupational performance and (5) formulating return-to-work decision. Recommendations related to the five themes were formulated and suggestions for future research proffered. The study clarified and confirmed that occupational therapists have a major role to play in performing work capacity of employees suffering from major depressive disorder, and that they need to be competent in performing these evaluations. Copyright / Dissertation (MOccTher)--University of Pretoria, 2011. / Occupational Therapy / unrestricted