Elske Vrieze

Dimensions in Major Depressive Disorder and their Relevance for Treatment Outcome

BACKGROUND Major depressive disorder (MDD) is a heterogeneous disease. More homogeneous psycho(patho)logical dimensions would facilitate MDD research as well as clinical practice. The first aim of this study was to find potential dimensions within a broad psychopathological assessment in depressed patients. Second, we aimed at examining how these dimensions predicted course in MDD. METHODS Ten psychopathological variables were assessed in 75 MDD inpatients. Factor and regression analyses assessed putative relations between psychopathological factors and depression severity and outcome after 8 weeks of treatment. RESULTS A 3-factor model (eigenvalue: 54.4%) was found, representing a psychomotor change, anhedonia and negative affect factor. Anhedonia and negative affect predicted depression severity (R(2)=0.37, F=20.86, p<0.0001). Anhedonia predicted non-response (OR 6.00, CI 1.46-24.59) and both negative affect (OR 5.69, CI 1.19-27.20) and anhedonia predicted non-remission (OR 9.28, CI 1.85-46.51). LIMITATIONS The sample size of the study was relatively modest, limiting the number of variables included in the analysis. CONCLUSIONS Results confirm that psychomotor change, anhedonia and negative affect are key MDD dimensions, two of which are related to treatment outcome.

Optimized In Vivo Detection of Dopamine Release Using 18F-Fallypride PET

The high-affinity D2/3 PET radioligand 18F-fallypride offers the possibility of measuring both striatal and extrastriatal dopamine release during activation paradigms. When a single 18F-fallypride scanning protocol is used, task timing is critical to the ability to explore both striatal and extrastriatal dopamine release simultaneously. We evaluated the sensitivity and optimal timing of task administration for a single 18F-fallypride PET protocol and the linearized simplified reference region kinetic model in detecting both striatal and extrastriatal reward-induced dopamine release, using human and simulation studies. Methods: Ten healthy volunteers underwent a single-bolus 18F-fallypride PET protocol. A reward responsiveness learning task was initiated at 100 min after injection. PET data were analyzed using the linearized simplified reference region model, which accounts for time-dependent changes in 18F-fallypride displacement. Voxel-based statistical maps, reflecting task-induced D2/3 ligand displacement, and volume-of-interest–based analysis were performed to localize areas with increased ligand displacement after task initiation, thought to be proportional to changes in endogenous dopamine release (γ parameter). Simulated time–activity curves for baseline and hypothetical dopamine release functions (different peak heights of dopamine and task timings) were generated using the enhanced receptor-binding kinetic model to investigate γ as a function of these parameters. Results: The reward task induced increased ligand displacement in extrastriatal regions of the reward circuit, including the medial orbitofrontal cortex, ventromedial prefrontal cortex, and dorsal anterior cingulate cortex. For task timing of 100 min, ligand displacement was found for the striatum only when peak height of dopamine was greater than 240 nM, whereas for frontal regions, γ was always positive for all task timings and peak heights of dopamine. Simulation results for a peak height of dopamine of 200 nM showed that an effect of striatal ligand displacement could be detected only when task timing was greater than 120 min. Conclusion: The prefrontal and anterior cingulate cortices are involved in reward responsiveness that can be measured using 18F-fallypride PET in a single scanning session. To measure both striatal and extrastriatal dopamine release, the height of dopamine released and task timing need to be considered in designing activation studies depending on regional D2/3 density.

The influence of maternal cortisol and emotional state during pregnancy on fetal intrauterine growth

Background:This exploratory study investigates the influence of maternal cortisol and emotional state during pregnancy on fetal intrauterine growth (IUG). We expected higher basal cortisol levels, or more depressive and anxious complaints during pregnancy, to be associated with slower IUG and lower birth weight.Methods:A total of 91 pregnant women were recruited from the antenatal clinic and were seen once each trimester. In addition to psychological assessments, a diurnal cortisol profile was derived from saliva samples. IUG was evaluated using ultrasound.Results:In mid-pregnancy (trimester (T)2), basal cortisol levels significantly predicted the variance of weight (proportion of variance in growth variable explained (PVE) = 11.6%) and body mass index (BMI) at birth (PVE = 6.8%). In late pregnancy (T3) emotional state, particularly depressive symptoms (BMI at birth: PVE = 6.9%; ponderal index (PI) at birth: PVE = 8.2%; head circumference at T3: PVE = 10.3%; head circumference at birth PVE = 9.1%) and attachment (BMI at birth: PVE = 6.9%; PI at birth: PVE = 7.2%) had an influence on growth. Analysis of growth between T2 and T3 showed that attachment and cortisol in T3 had an influence on the variation in increase in estimated fetal weight (PVE = 12.5–8.6%).Conclusion:These data indicate basal cortisol levels were more important in T2 whereas emotional state was more important in T3.

Relationship between cognitive avoidant coping and changes in overgeneral autobiographical memory retrieval following an acute stressor

According to the functional avoidance hypothesis, overgeneral autobiographical memory, the tendency to retrieve personal memories in a less specific format, might serve an affect-regulating function. Reducing the specificity of memories of negative events may prevent individuals from re-experiencing the associated painful emotions. This cognitive avoidance strategy might not only be employed by depressed and traumatized patients, but also by healthy individuals. In the present study we tested the hypothesis that the increase in memory overgenerality induced by an acute stressor is positively correlated with habitual (cognitive) avoidant coping. Participants (N = 32) were exposed to a Trier Social Stress Test. Cognitive avoidant coping was measured at the start of the experiment by means of the Mainz Coping Inventory. Before, immediately after, and 40 min after the Trier Social Stress Test, autobiographical memory specificity was assessed by means of the Autobiographical Memory Test. Cognitive avoidant coping was significantly correlated with an increase in categoric memories from pre to immediately post stressor, but not with change in overgeneral memories from pre to 40 min post stressor. The results of the present experiment provide further support for functional avoidance as one of the mechanisms underlying overgeneral memory.

Repeated stress hormone measurements after a social stressor in major depressive disorder: Association patterns and predictive ability

Stress Test (TSST) was administered to induce an endocrine stress response. Both tests were administered at study inclusion, after 8 weeks, and 1-year follow up. Relations between stress hormone responses and reward learning were separately probed in MDD and control subjects. Further, we evaluated whether HPA axis dysregulation predicted reward responsiveness at follow up in MDD. Results: At baseline, a negative correlation between ACTH release and reward learning emerged among depressed women (R2 = 0.23, F = 7.91, p = 0.009). Conversely, among depressed women, blunted baseline ACTH sensitivity predicted reduced reward learning ability one year later (R2 = 0.18, F = 5.0, p = 0.04). Conclusions: Among depressed women, potentiated ACTH release in response to TSST was associated with reduced reward learning. In addition, HPA dysregulation prospectively predicted blunted reward learning one year later making the current finding the first prospective evidence that HPA dysregulation predicts blunted reward learning ability in MDD over time.

P01-299 Reward sensitivity and response to treatment in major depression

Rationale Anhedonia, or the lack of reactivity to a pleasurable stimuli is expressed as reduced reward sensitivity in patients with major depressive disorder (MDD) (1) . Reward experience might discriminate between depressed patients who respons to treatment and those who do not (2) . Objective The purpose of this study was to test the hypothesis that patients non-responsive to treatment show reduced reward sensitivity compared to responsive patients. Method A probabilistic computer task was used to measure reward sensitivity objectively (3) . Twenty-eight medicated inpatients meeting DSM-IV criteria for MDD performed the reward task within the first week after submission and again after eight weeks. The response to treatment was assessed with the Hamilton Depression rating Scale (HDRS). Patients with scores less that ten or a fifty percent reduction on the HDRS after 8 weeks were considered responders to treatment. Sixteen healthy subjects were recruited as controls. Results When considering reward sensitivity at baseline, the control group was significantly more sensitive to reward than the responders group and the non-responders group, who were the least reward sensitive (F = 11.88; p Conclusion These results support the hypothesis that impairment of reward responsiveness might influence response to treatment in patients with MDD.

P.1.e.00l A dynamic [18F]-fally pride PET study: measuring dopamine neuromodulation in the extrastriatal reward circuit

Introduction: Animal research indicates the mesocorticolimbic pathway as the central circuit of the brain reward system, with dopamine (DA) as the most important neurotransmitter (1). Previous studies propose that the extrastriatal part of the reward circuit plays a role in the ability to experience pleasure (liking the reward), but also in behaviours like motivation and drive (wanting the reward and learning). It is hypothesized that these psychological subcomponents of reward correspond with specific neural areas in the extrastriatal reward pathway in the brain. Purpose: The purpose of this study was first to examine presynaptic DA release in extrastriatal regions of the reward circuit, in particular the prefrontal cortex (PFC) and anterior cingulate cortex (ACC), by measuring the high affinity D 2 /D 3 radioligand [ 18 F]-fallypride binding potential in response to a monetary reward challenge and second to identify the specific neural subcomponents in this part of the reward system in the brain. Methods: 10 healthy volunteers underwent a single [ 18 F]fallypride injection Positron Emission tomography imaging session (2) while executing a computerized probabilistic reward task (3). DA-release in the extrastriatal reward areas of the brain was statistically tested by measuring time-dependent alterations in the kinetics of [18F]fallypride using the linearized simplified reference region model (LSRRM). Statistic images, reflecting DA changes, were calculated and correlated with reward responsiveness, and feedbackrelated behaviour (learning and reward anticipation) by trail by trail probabilistic reward analysis . Results: Voxel-based analysis revealed a significant inverse correlation between reward capacity and DArelease in the ventralmedial PFC (BA 10), orbitofrontal PFC (BA 11) and ACC (BA 32). Furthermore, the ACC and thalamic DA-displacement showed a significant positive correlation with the impaired tendency to modulate behavior as a function of prior reinforcements. Conclusion: These findings support the hypothesis that several extrastriatal areas of the brain are involved in reward capacity. Individuals with a lower reward responsiveness show a higher DA release in prefrontal areas and the ACC during a reward challenge. Furthermore, integration of reinforcement history over time inversely correlates with thalamic and ACC DA release BACKGROUND