Sanne Wulff

Alterations of the Brain Reward System in Antipsychotic Naïve Schizophrenia Patients

BACKGROUND Various schizophrenic symptoms are suggested to be linked to a dysfunction of the brain reward system. Several studies have found alterations in the reward processing in patients with schizophrenia; however, most previous findings might be confounded by medication effects. METHODS Thirty-one antipsychotic-naïve schizophrenia patients and 31 age- and gender-matched healthy control subjects were examined with functional magnetic resonance imaging while playing a variant of the monetary incentive delay task. The task variant made it possible to separate overall salience (defined as arousing events) into behavioral salience (events where a predicted reward requires performance) and valence anticipation (the anticipation of a monetarily significant outcome). Furthermore, the evaluation of monetary gain and loss was assessed. RESULTS During reward anticipation, patients had a significant attenuation of the activation in ventral tegmentum, ventral striatum, and anterior cingulate cortex during presentation of salient cues. This signal attenuation in ventral striatum was correlated with the degree of positive symptoms. Signal attenuation was most pronounced for behavioral salience and nonsignificant for value anticipation. Furthermore, patients showed a changed activation pattern during outcome evaluation in right prefrontal cortex. CONCLUSION Our results suggest that changes during reward anticipation in schizophrenia are present from the beginning of the disease. This supports a possible involvement of reward disturbances in the pathophysiology of schizophrenia. The most pronounced changes were seen in relation to overall salience. In ventral striatum these changes were associated with the degree of positive symptoms.

Improvement of Brain Reward Abnormalities by Antipsychotic Monotherapy in Schizophrenia

CONTEXT Schizophrenic symptoms are linked to a dysfunction of dopamine neurotransmission and the brain reward system. However, it remains unclear whether antipsychotic treatment, which blocks dopamine transmission, improves, alters, or even worsens the reward-related abnormalities. OBJECTIVE To investigate changes in reward-related brain activations in schizophrenia before and after antipsychotic monotherapy with a dopamine D2/D3 antagonist. DESIGN Longitudinal cohort study. SETTING Psychiatric inpatients and outpatients in the Capital Region of Denmark. PARTICIPANTS Twenty-three antipsychotic-naive patients with first-episode schizophrenia and 24 healthy controls initially matched on age, sex, and parental socioeconomic status were examined with functional magnetic resonance imaging while playing a variant of the monetary incentive delay task. INTERVENTIONS Patients were treated for 6 weeks with the antipsychotic compound amisulpride. Controls were followed up without treatment. MAIN OUTCOME MEASURES Task-related blood oxygen level-dependent activations as measured by functional magnetic resonance imaging before and after antipsychotic treatment. RESULTS At baseline, patients, as compared with controls, demonstrated an attenuation of brain activation during reward anticipation in the ventral striatum, bilaterally. After 6 weeks of treatment, patients showed an increase in the anticipation-related functional magnetic resonance imaging signal and were no longer statistically distinguishable from healthy controls. Among the patients, there was a correlation between the improvement of positive symptoms and normalization of reward-related activation. Those who showed the greatest clinical improvement in positive symptoms also showed the greatest increase in reward-related activation after treatment. CONCLUSIONS To our knowledge, this is the first controlled, longitudinal study of reward disturbances in schizophrenic patients before and after their first antipsychotic treatment. Our results demonstrate that alterations in reward processing are fundamental to the illness and are seen prior to any treatment. Antipsychotic treatment tends to normalize the response of the reward system; this was especially seen in the patients with the most pronounced treatment effect on the positive symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01154829.

Striatal Reward Activity and Antipsychotic-Associated Weight Change in Patients With Schizophrenia Undergoing Initial Treatment

IMPORTANCE Weight gain is a common and serious adverse effect of antipsychotic treatment. A variable individual predisposition to development of metabolic disturbances calls for predictive biological markers. OBJECTIVES To investigate whether attenuated striatal activity during reward anticipation is associated with amisulpride-induced weight change in antipsychotic-naive patients with schizophrenia undergoing initial treatment and to examine the association between weight change and changes in reward anticipation activity after treatment. DESIGN, SETTING, AND PARTICIPANTS Sixty-nine antipsychotic-naive inpatients and outpatients with schizophrenia were included in a multimodal longitudinal cohort study from December 16, 2008, to December 11, 2013. Fifty-eight patients underwent functional magnetic resonance imaging (fMRI) while performing a monetary reward task. After 6 weeks of treatment with amisulpride, a relatively selective dopamine D2 antagonist, 39 patients underwent a second fMRI scan and measurement of change in body weight. Final follow-up was completed on January 14, 2014, and data were analyzed from October 25, 2014, to June 15, 2015 and August 31 to September 19, 2015. EXPOSURES Six weeks of individually dosed amisulpride treatment. MAIN OUTCOMES AND MEASURES Reward-anticipation activity in the striatum before and after treatment and weight change. RESULTS Of the 69 patients who consented to the study, 39 underwent the follow-up fMRI and weight measurement (age range, 18-45 years; 17 women and 22 men). The mean (SD) daily dose of amisulpride was 272 (168; range, 50-800) mg, and patients gained a mean (SD) of 2.3 (2.8; range, -4 to 8) kg in body weight. Improvement from baseline to follow-up was found on the mean (SD) positive (19.9 [4.1] to 14.3 [3.8]), general (39.7 [7.7] to 30.5 [7.7]), and total (78.5 [15.3] to 63.2 [13.9]) scores on the Positive and Negative Syndrome Scale (P < .001). Weight gain was predicted by low mean (SD) baseline reward-related activity in the right-sided putamen (0.20 [0.93]; F35,3 = 5.64; P = .003). After 6 weeks, weight gain was associated with an increase in mean (SD) reward activity in the same region during treatment (0.28 [0.74]; F37,1 = 4.48; P = .04). CONCLUSIONS AND RELEVANCE Activity in striatal regions of the reward system appears to be associated with the individual variability in the predisposition for antipsychotic-associated weight gain. Moreover, pharmacologic modulation of the reward system may play a role in antipsychotic-associated weight gain.

Striatal D2/3 Binding Potential Values in Drug-Naïve First-Episode Schizophrenia Patients Correlate With Treatment Outcome

One of best validated findings in schizophrenia research is the association between blockade of dopamine D2 receptors and the effects of antipsychotics on positive psychotic symptoms. The aim of the present study was to examine correlations between baseline striatal D2/3 receptor binding potential (BPp) values and treatment outcome in a cohort of antipsychotic-naïve first-episode schizophrenia patients. Additionally, we wished to investigate associations between striatal dopamine D2/3 receptor blockade and alterations of negative symptoms as well as functioning and subjective well-being. Twenty-eight antipsychotic-naïve schizophrenia patients and 26 controls were included in the study. Single-photon emission computed tomography (SPECT) with [123I]iodobenzamide ([123I]-IBZM) was used to examine striatal D2/3 receptor BPp. Patients were examined before and after 6 weeks of treatment with the D2/3 receptor antagonist amisulpride. There was a significant negative correlation between striatal D2/3 receptor BPp at baseline and improvement of positive symptoms in the total group of patients. Comparing patients responding to treatment to nonresponders further showed significantly lower baseline BPp in the responders. At follow-up, the patients demonstrated a negative correlation between the blockade and functioning, whereas no associations between blockade and negative symptoms or subjective well-being were observed. The results show an association between striatal BPp of dopamine D2/3 receptors in antipsychotic-naïve first-episode patients with schizophrenia and treatment response. Patients with a low BPp have a better treatment response than patients with a high BPp. The results further suggest that functioning may decline at high levels of dopamine receptor blockade.

Negative Symptoms and Reward Disturbances in Schizophrenia Before and After Antipsychotic Monotherapy

Background. Negative symptoms (NS) are a central part of the symptomatology of schizophrenia, which is highly correlated to the functional outcome. Disturbances of the brain reward system are suggested to be central in the pathogenesis of NS by decreasing motivation and hedonic experiences. In this study, we compared reward-related brain activity in patients improving and not improving in NS after treatment with amisulpride. Methods. Thirty-nine antipsychotic-naive patients and 49 healthy controls completed functional magnetic resonance imaging with a modified monetary incentive delay task. Psychopathology of the patients was characterised with Positive and Negative Syndrome Scale (PANSS), and they were treated with individual doses of amisulpride (mean 271 mg) for 6 weeks, after which the examinations were repeated. Results. Patients improved on positive, general, and total PANSS score after treatment (P < .001). Fourteen patients had ≥20% improvement of NS, whereas 25 patients improved <20%. At baseline, one-way analysis of variance showed group difference bilaterally in the caudate nucleus and in the right nucleus accumbens (all P < .002), which was caused by decreased reward anticipation activity in the nonimproving patients compared to healthy controls. There was a significant group × time interaction, with the healthy controls and the improvers decreasing and the nonimprovers increasing in reward anticipation activity after treatment, most pronounced in the left caudate nucleus (P = .001). Discussion. Patients improving in NS score had a less aberrant reward system at baseline, but reward related activity was reduced over time. Patients not improving in NS showed decreased striatal reward-activity at baseline, which improved over time. Whether this is associated with alteration in working memory and reward learning or with pronounced symptoms within specific domains of NS may be addressed in future studies.

S250. RELATION BETWEEN PSYCHOPATHOLOGY AND QUALITY OF LIFE IN SCHIZOPHRENIA PATIENTS BEFORE AND AFTER FIRST ANTIPSYCHOTIC TREATMENT

Abstract Background It is common knowledge that antipsychotic treatment improves the symptomatology in schizophrenia, especially for the psychotic and general symptoms. It is also a fact that patients with schizophrenia often report a reduced quality of life compared to healthy controls. In this study we aim at examining the relation between self-reported quality of life (QLS), psychopathological symptoms and level of function before and after antipsychotic treatment. We hypothesize that there will be a correlation between QLS and severity of symptoms before treatment. Further we expect an improvement in QLS after treatment and that this improvement will correlate with improvement in symptomatology. Methods As a part of a large multimodal study on antipsychotic naïve patients with schizophrenia, 69 patients were recruited. Their psychopathology was measured with the Positive and Negative Syndrome Scale (PANSS), level of function was estimated using Global Assessment of Function (GAF), and QLS was reported by answering a questionnaire. Patients were treated with individual doses of Amisulpride for six weeks, after which they were reexamined. The questionnaire regarding QLS counts 21 questions, divided into four domains: Self and present life (i.e. “how satisfied are you with your present life”), social relations (“how satisfied are you with your current social life”), Living situation (“how much do you like the place you live”) and Work situation (“How satisfied are you with the work you do”). Higher scores indicate higher satisfaction within the domain. Since the follow up period was only 6 weeks, we focused on self and present life (SPL) and social relations (SR), as we did not expect the living and work situation to change significantly within this period. Results Baseline data were available on 48 patients, mean age 25 years (6.1), 31 males (65%). Their PANSS total score was 84 (16.0), GAF was 41(9.4), SPL-score was 13 (5.3) SR-score 10(5.3). For SPL as well as SR, there was a negative correlation with PANSS-total, PANSS-negative and PANSS- general (p-values<0.007). Follow-up data were available on 33 patients, mean age 25 years (6.6), 19 males (58%). They received 273 (163.3) mg Amisuplride. PANSS total was 68 (14.4) and GAF was 53 (15.7), SPL-score was 14 (3.9) SR-score 11(4.6). Paired T-test showed a significant improvement in PANSS total, PANSS positive, PANSS general and GAF (all p-values<0.001). There was also an improvement in SR (p=0.003), but no significant improvement in SPL and PANSS negative score (p=0.12 and p=0.5). There were no correlations between neither of the QLS scores and any psychopathology scores at follow up. Likewise, there was no correlation between change in QLS scores and change in psychopathology. However, there was a negative correlation with change in SPL and medication dose (p=0.009) Discussion In this study, we found that antipsychotic naïve patients with most severe symptoms had the lowest self-reported QLS. This relation was only observed for negative and general symptoms, but not for positive symptoms or GAF score. As expected there was a treatment induced improvement in positive and general symptoms as well as GAF score. Likewise, patients improved on QLS, but only on SR and not in the overall measure of SPL. This may partly be because antipsychotic medication primarily improves positive symptoms, which were not correlated with QLS. Additionally, there was even a negative correlation with medication dose, indicating that patients with higher doses had the least improvement I SPL score. The results indicate that there is not a simple relationship between antipsycotic induced improvement in psychopathology and selfreported QLS. High doses of medication may even reduce QLS.

Multiple measures of HPA axis function in ultra high risk and first-episode schizophrenia patients

INTRODUCTION Abnormalities within hypothalamus-pituitary-adrenal (HPA) axis might interact with other neurobiological systems to enhance the risk of psychosis. Most of the neurodevelopmental and HPA axis changes occur in adolescence; this is also the period when prodromal and psychotic symptoms occur for the first time. More knowledge about how various stress components interact can advance understanding of the link between psychosis and the HPA axis. METHOD We examined 41 ultra high-risk (UHR) patients and 40 antipsychotic-naïve first-episode schizophrenia (FES) patients and compared them with 47 matched controls. The Perceived Stress Scale and the Recent Life Events Questionnaire were used to assess the stress levels. Day-time saliva samples were taken to measure cortisol. The pituitary gland volume was measured manually on the structural MRI using stereology. RESULTS Only the UHR patients, had a higher cortisol increase just after awakening (p = 0.009) compared to healthy controls. In UHR patients, we found a negative correlation between cortisol increase after awakening and symptom severity (p = 0.008). Pituitary gland volume and diurnal cortisol were not significantly different among the three groups. There was no correlation between pituitary gland volume, perceived stress/recent life events and any of the cortisol measures or symptoms. CONCLUSION Symptom severity during the very early phase of illness (UHR) seems to be associated with altered cortisol increase. Longitudinal studies in UHR patients would be useful to examine how stress levels affect the course of the illness.