P.3.007 Abnormalities in reward prediction error signals in depression and schizophrenia

Clinical neuropsychopharmacology serotoninergic tonus affects neurogenesis [1]. However, not every depressed patient have smaller HCVs as it is shown in our sample, a finding which is in line with the literature [2]. Therefore, we suggest that with the contribution of the risk allele of 5-HTTLPR, a more prominent decline in neurogenesis may cause defects in the cellular integrity of hippocampal neurons which leads to smaller HCVs. 5-HTTLPR polymorphism has an effect on HCVs of depressed patients which is apparent only in S/S genotype, a finding to be investigated regarding its clinical and therapeutic effects.

Variables Age Sex (M/F) Age at onset (years) Duration all episodes (weeks) last episode (weeks) Number of episodes HDRS# scores Genotype distribution L/L L/S S/S Hippocampal volume* Right Total L/L L/S S/S Left Total L/L L/S S/S

Depressed patients (n = 44)

Controls (n = 43)

Statistics

Mean±SD 33.6±9.5 11/33 30.87±8.4

Mean±SD 30.4±6.7 t = 1.77 df = 85 p>0.05 16/27 X2 = 1.51 df = 1 P>0.05 NA NA

42.3±36.0 29.3±37.1 1.4±0.6 25.0±5.0 N (%) 11 (25.0%) 22 (50.0%) 11 (25.0%) cc

NA NA NA NA N (%) 10 (18.6%) 25 (58.1%) 8 (23.3%) cc

NA NA NA NA

3.18 (0.347) 3.37 (0.398) 3.19 (0.354) 2.98 (0.131)

3.13 (0.301) 3.164 (0.149) 3.070 (0.314) 3.250 (0.383)

F = 0.78; df = 1,78; p>0.05a F = 4.05; df = 2,78; p = 0.021b F = 4.34; df = 1, 16; p = 0.053c F = 2.61; df = 1, 42; p>0.05c

3.31 (0.341) 3.49 (0.353) 3.33 (0.354) 3.08 (0.140)

3.35 (0.358) 3.40 (0.213) 3.28 (0.368) 3.507 (0.443)

F = 1.48, df = 1,78; p>0.05a F = 4.63, df = 2,78; p = 0.013b F = 1.45; df = 1,16; p>0.05c

X2 = 0.7 df = 2 p>0.05

F = 15.7; df = 1, 14; p = 0.01c

F = 0.55; df = 1,42; p>0.05c F = 22.8; df = 1,14; p < 0.001c

#

HDRS, Hamilton Depression Rating Scale. *Cofactors: total brain volume, age and gender. a Group comparison. b Disease–genotype interaction. c Univariate analysis.

Reference(s) [1] Martinowich K, Lu B. 2008 Interaction between bdnf and serotonin: Role in mood disorders. Neuropsychopharmacology 33:73−83. [2] Eker C, Gonul AS. 2009 Volumetric MRI studies of the hippocampus in major depressive disorder: Meanings of inconsistency and directions for future

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research. World J Biol Psychiatry Jun 10:1−17. [Epub ahead of print]. [3] Frodl T et al. 2008 Reduced gray matter brain volumes are associated with variants of the serotonin transporter gene in major depression. Mol Psychiatry 13: 1093–101.

P.3.007 Abnormalities in reward prediction error signals in depression and schizophrenia V.B. Gradin1 ° , P. Kumar2 , G. Waiter3 , T. Ahearn3 , I. Reid4 , C. Stickle5 , M. Milders6 , J. Hall7 , J.D. Steele8 . 1 University of Aberdeen, Mental health, Aberdeen, United Kingdom; 2 University of Oxford, Psychiatry, Oxford, United Kingdom; 3 University of Aberdeen, Medical Physics, Aberdeen, United Kingdom; 4 University of Aberdeen, Mental Health, Aberdeen, United Kingdom; 5 Cornhill Hospital, Mental Health, Aberdeen, United Kingdom; 6 University of Aberdeen, Psychology, Aberdeen, United Kingdom; 7 University of Edinburgh, Psychiatry, Edinburgh, United Kingdom; 8 University of Dundee, Centre for Neuroscience, Dundee, United Kingdom Abnormal functioning of the dopamine (DA) system has been associated with anhedonia in depression and negative plus positive symptoms in schizophrenia. It remains unclear though, how a DA dysfunction could mechanistically account for anhedonia or psychosis. “Phasic” DA signals code a reward prediction error: increased (decreased) firing rate if rewards are better (worse) than expected and no change if rewards are as expected. These signals may mediate learning of stimulusresponse-outcomes associations and/or attribution of incentive salience to reward related stimuli. Temporal difference (TD) models from reinforcement learning theory provide a mathematical description of these signals. In this study, we explored hypothesized abnormalities of phasic DA signals in depression and schizophrenia. Abnormal phasic DA signals in depression/schizophrenia could relate to anhedonia/negative symptoms, and also to psychotic symptoms by contributing to abnormal associations. A depression (15/15 on antidepressant medication), a schizophrenia (14/14 on antipsychotic and 4/14 on antidepressant medication) and a control (n = 15) group, were scanned using functional magnetic resonance imaging (fMRI) during an instrumental rewardlearning task. Controls participated on a medicated state, after receiving the antidepressant citalopram at a dose of 20 mg/day for 3 days to account for the patient’s antidepressant medication. On each trial of the paradigm, subjects had to choose between two pictures. If they chose the “correct” one they got two drops of water

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Clinical neuropsychopharmacology

as a “reward”. By trial and error, subjects had to learn which of the two pictures would more likely deliver the water. Each subject’s sequence of choices and rewards was entered into a TD model to generate a TD rewardlearning signal that was used as a parametric modulation for image analysis. Patients with depression demonstrated a reduced TD signal strength in the midbrain, striatum and right amygdala-hippocampal complex compared to controls. Schizophrenic patients demonstrated reduced activation in the midbrain, right amygdala-hippocampal complex and right insula compared to controls. Depressive patients showed reduced/increased activation in the left ventral striatum/insula compared to schizophrenic patients (differences between groups are significant at a cluster extent threshold of p < 0.05 corrected for multiple comparisons across the whole brain). In schizophrenia, decreased activation of the midbrain and insula correlated with increased severity of positive symptoms (r = −0.70, p < 0.01; r = 0.83, p < 0.01). Diminished reward-related DA signals in depression/schizophrenia implies reduced attribution of salience to rewarding events, consistent with anhedonia/negative symptoms. While a “truly” diminished functioning of phasic DA signals might occur in depression [1] a similar imaging observation in schizophrenia may be due to a reduced signal/noise in the reward circuitry [2]. In schizophrenia, abnormal DA signals in the midbrain and insula may be associated with psychotic symptoms, related to DA signals attributing aberrant salience to external and internal objects [3]. In the striatum, abnormalities in DA signals seem more marked in schizophrenia than in depression. This is the first study to compare phasic signals in both depression and schizophrenia. These results may help to bridge the gap between the biology and phenomenology of the illnesses and highlight the potential role of abnormalities of phasic signals as biomarkers of psychiatric disorders.

Region Controls > Depression Left putamen Midbrain Right amygdala–hippocampal complex Controls > Schizophrenia Midbrain Right amygdala–hippocampal complex Right insula Depression > Schizophrenia Right insula Schizophrenia > Depression Left ventral striatum

Talairach (x,y,z)

Z

(−24,14,4) (−6,−8,−12) (26,−22,−22)

3.15 3.36 3.09

(−8,−16,−14) (30,−22,−8) (38,−4,0)

2.69 3.46 3.02

(36,6,8)

3.01

(−16,12,−12)

3.16

Coordinates reported refer to the most statistically significant voxel within an area.

Reference(s) [1] Juckel, G., Schlagenhauf, F., Koslowski, M., W¨ustenberg, T., Villringer, A., Knutson B., Wrase J., Heinz A., 2006 Dysfunction of ventral striatal reward prediction in schizophrenia. Neuroimage 29, 409–416. [2] Kumar, P., Waiter, G., Ahearn, T., Milders, M., Reid, I., Steele, J.D., 2008 Abnormal temporal difference reward-learning signals in major depression Brain IF 8.5, 130 (9), 2367−74. [3] Kapur, S., 2003 Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 160, 13−23. P.3.008 Acute tryptophan depletion increases cingulate cortex reactivity in recovered depressed patients J. Horder1 ° , P. Cowen1 , M. Browning1 , S. McTavish1 , C.J. Harmer1 . 1 University of Oxford, Psychiatry, Oxford, United Kingdom Introduction: Acute tryptophan depletion (ATD) is used experimentally to reduce human central serotonin levels. Full dose ATD (100 g) often causes acute return of depressive symptoms in patients with a history of depression, but not in never-depressed controls. Lowdose ATD (31.5 g) does not alter mood, and hence allows neural and cognitive effects of ATD to be dissociated from mood changes. Low dose ATD has been shown to affect cognition in several studies e.g. Munafo et al, Hayward et al found increased interference effects in an emotional Stroop task in recovered depressives [1,2]. Two fMRI studies, Horacek et al and Evers et al, showed that ATD increases neural response to conflict in Stroop tasks in healthy volunteers [3]. However, no neuroimaging studies have been conducted in recovered depressives. We used fMRI to investigate the effects of low-dose ATD on neural response in a Stroop task in recovered depressives, in order to compare these effects to those seen in healthy volunteers. Participants: We recruited 21 currently unmedicated, recovered unipolar depressed patients (10 female), with at least one past DSM-IV Major Depressive Episode, who had been euthymic for >6 months. Exclusion criteria included: current Axis I disorder; not being fluent in English. Methods: We used a randomized, double-blind, parallel-groups design. Subjects were assigned low-dose ATD, or a balanced mixture containing tryptophan (BAL) as a control. Studies have shown that the same depleting mixture reduces plasma tryptophan by 60−70% while