José Antonio Monreal

Increased adrenocorticotropin suppression following dexamethasone administration in sexually abused adolescents with posttraumatic stress disorder.

Evidence suggests that individuals with posttraumatic stress disorder (PTSD) have an enhanced sensitization of the hypothalamic--pituitary--adrenocortical (HPA) axis. However, few studies in adolescents have been performed. Fourteen sexually abused adolescent inpatients with DSM-IV PTSD (12 female, two male; mean +/- SD age, 16.2 +/- 1.9 years) were compared with 14 adolescent hospitalized controls (11 female, three male; mean age, 15.7 +/- 2.0 years). All subjects underwent a standard dexamethasone suppression test (DST, 1 mg given orally at 2300 h) five days after admission. Baseline blood samples were obtained at 0800 h, and the following day, adrenocorticotropin (ACTH) and cortisol levels were measured at 0800, 1600, and 2300 h. Clinical assessment included the Impact of Event Scale, Stanford Acute Stress Reaction Questionnaire, Beck Depression Inventory, and Coping Inventory for Stressful Situations. Post-DST ACTH levels were significantly lower in PTSD than in control adolescents (at 0800 h: P < 0.005; at 1600 h: P < 0.001; at 2300 h: P < 0.05). In patients, post-DST cortisol levels were reduced but not significantly. No correlations were found between ACTH and cortisol levels and time elapsed since trauma. These results demonstrate that sexually abused adolescents with PTSD show ACTH hypersuppression to DST suggesting enhanced glucocorticoid receptor sensitivity in the pituitary.

Lack of effect of HPA axis hyperactivity on hormonal responses to d-fenfluramine in major depressed patients: implications for pathogenesis of suicidal behaviour.

There is evidence for inhibitory effects of adrenocorticosteroids on serotonergic (5-HT) activity. However, in depression the relationship between altered cortisol levels and brain 5-HT function remains to be clarified. The aim of this study was to investigate whether hypothalamic-pituitary-adrenal (HPA) axis hyperactivity is associated with 5-HT dysfunction in depressed patients, especially in those with suicidal behaviour. Cortisol levels following the dexamethasone suppression test (DST, 1 mg PO) and prolactin, corticotropin and cortisol responses to the d-fenfluramine test (d-FEN, 45 mg PO) - a specific 5-HT releaser/uptake inhibitor - were measured in 71 drug-free DSM-IV major depressed inpatients (40 with a history of suicide attempt, 31 without) and 34 hospitalized healthy control subjects. Depressed patients showed higher post-DST cortisol levels but similar responses to d-FEN compared with control subjects. Hormonal responses to d-FEN were not correlated with cortisol levels (basal or post-DST). Among the depressed patients, DST suppressors and DST nonsuppressors exhibited no significant difference in endocrine responses to d-FEN. However, patients with a history of suicide attempt, when compared with patients without such a history, showed lower hormonal responses to d-FEN but comparable basal and post-DST cortisol levels. Taken together these results suggest that, in depression, HPA axis hyperactivity is not responsible for the reduced 5-HT activity found in patients with a history of suicidal behavior.

Increased adrenocorticotropin suppression after dexamethasone administration in sexually abused adolescents with posttraumatic stress disorder.

Abstract: Evidence suggests that individuals with posttraumatic stress disorder (PTSD) have enhanced sensitization of the hypothalamic‐pituitary‐adrenocortical (HPA) axis. Fourteen adolescent inpatients with DSM‐IV PTSD were compared with 14 adolescent hospitalized controls without current axis I diagnoses. All patients were drug‐naive. The causative trauma had been sexual abuse in all cases. Dexamethasone, 1 mg orally, was given at 11 PM, 5 days after admission. Baseline blood samples were obtained at 8 AM, and on the following day, adrenocorticotropin (ACTH) and cortisol levels were measured at 8 AM, 4 PM, and 11 PM. Clinical assessment included the Impact of Event Scale, Stanford Acute Stress Reaction Questionnaire, Beck Depression Inventory, and Coping Inventory for Stressful Situations. Post‐DST ACTH levels were significantly lower in PTSD than in control adolescents (at 8 AM, P <0.005; at 4 PM, P <0.001; and at 11PM, P <0.05). In patients, post‐DST cortisol levels were reduced but not significantly. No correlations were found between ACTH and cortisol levels and time elapsed since trauma. These results demonstrate that sexually abused adolescents with PTSD show ACTH hypersuppression to DST, suggesting enhanced glucocorticoid receptor sensitivity in the pituitary.

Dopamine and serotonin function in untreated schizophrenia: clinical correlates of the apomorphine and d-fenfluramine tests.

This study examined the prolactin (PRL), adrenocorticotropin (ACTH) and cortisol responses to the direct DA receptor agonist apomorphine (APO) and the selective 5HT-releasing agent d-fenfluramine (d-FEN) in 20 untreated inpatients with DSM-IV schizophrenia and without a history of suicide attempt, compared to 23 hospitalized healthy controls. We hypothesized that different patterns of responsiveness of the DA and 5-HT systems might be associated with specific schizophrenic symptom clusters. A positive correlation was observed between pituitary-adrenal response to APO and d-FEN tests (i.e. deltaACTH and deltacortisol) in the overall population and in schizophrenic patients. Pituitary-adrenal response to APO was lower in patients than in normal controls. Moreover, lower pituitary-adrenal response to APO and d-FEN was associated with increased severity of BPRS thought disturbance score. Lower pituitary-adrenal responses to APO (and to a lesser degree to d-FEN) differentiated paranoid from disorganized schizophrenic patients. Neither PRL suppression to APO, nor PRL stimulation to d-FEN were altered in schizophrenic patients. Our results suggest that decreased hypothalamic DA receptor activity (possibly secondary to increased presynaptic DA release) together with relatively decreased 5-HT tone characterize paranoid SCH, while normal hypothalamic DA receptor activity together with relatively increased 5-HT tone characterize the disorganized SCH subtype.

Targeting hypothalamic-pituitary-adrenal axis hormones and sex steroids for improving cognition in major mood disorders and schizophrenia: a systematic review and narrative synthesis

Cognitive deficits are a core feature of serious mental illnesses such as schizophrenia, major depressive disorder (MDD) and bipolar disorder (BD) and are a common cause of functional disability. There is limited efficacy of pharmacological interventions for improving the cognitive deficits in these disorders. As pro-cognitive pharmacological treatments are lacking, hormones or drugs that target the endocrine system may become potential candidates for repurposing trials aiming to improve cognition. We aimed to study whether treatment with drugs targeting the hypothalamic-pituitary-adrenal (HPA) axis and sex steroids can improve cognition in patients with schizophrenia, MDD or BD. A systematic search was performed using PubMed (Medline), PsychInfo and clinicaltrials.gov, and a narrative synthesis was included. The systematic review identified 12 studies dealing with HPA-related drugs (mifepristone [nu202f=u202f3], cortisol synthesis inhibitors [ketoconazole, nu202f=u202f2], dehydroepiandrosterone [nu202f=u202f5], fludrocortisone [nu202f=u202f2]) and 14 studies dealing with sex steroids (oestradiol [nu202f=u202f2], selective oestrogen receptor modulators [raloxifene, nu202f=u202f7], pregnenolone [nu202f=u202f5]). Positive trials were found for BD (mifepristone), MDD (dehydroepiandrosterone and fludrocortisone) and schizophrenia (dehydroepiandrosterone, raloxifene and pregnenolone). A replication of positive findings by at least two clinical trials was found for mifepristone in BD and raloxifene and pregnenolone in schizophrenia. The use of drugs targeting hormones related to the HPA axis and sex steroids is a promising field of research that might help to improve the cognitive outcome of patients with schizophrenia, bipolar disorder and major depressive disorder in the near future.

F82. COGNITIVE BIASES IN PATIENTS WITH SCHIZOPHRENIA AND HIGH SCHOOL STUDENTS: ASSOCIATION WITH PSYCHOPATHOLOGICAL SYMPTOMS

Abstract Background Some cognitive biases, mainly the “jumping to conclusions” and attributional styles, play a key role in the formation and maintenance of delusions. Other thinking errors include dichotomous thinking, emotionally based reasoning, and catastrophising. The aim of our study was to assess the relationship between cognitive biases and psychopathological symptoms (positive, negative, depressive) in a clinical sample of patients with schizophrenia and a population sample of high school students. Methods The clinical sample included 35 patients with schizophrenia (35.6 ± 10.8 years, 40% women) attending to the Department of Mental Health from Parc Taulí Hospital Universitari (Sabadell, Spain) and 45 high school students (16.6 ± 0.9 years) located in the same province. Cognitive biases were assessed with the Cognitive Biases Questionnaire, that covers 5 types of biases (intentionalising [I]; catastrophizing [C]; dichotomous thinking [DT]; jumping to conclusions [JTC]; and emotional reasoning [ER]) and also gives a total score. Psychopathological symptoms in patients were assessed with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS). Psychopathological symptoms in high school students were assessed with the Community Assessment of Psychic Experiences (CAPE). Statistical analyses were performed with SPSS version 21.0. CBQ scores between groups were compared with Student’s T-test. The association between dimensions of the CBQ and scores of psychopathological scales was tested with Spearman’s correlations. Significance level was set at p<0.05 (two-tailed). Results CBQ total scores did not differed between patients with schizophrenia (45.3 ± 8.2) and high school students (44.2 ± 6.7). No significant differences between groups were found in any of the five cognitive biases. When exploring the relationship between cognitive biases and psychopathological symptoms in patients with schizophrenia, total CBQ scores were associated with CDSS scores (r= 0.65, p<0.001). In relation to particular cognitive biases, depressive symptoms were associated with all cognitive biases (I: r= 0.43, p= 0.017; C: r= 0.62, p<0.001; DT: r= 0.42, p= 0.020; JTC: r= 0.46, p= 0.012; ER: r= 0.57, p= 0.001), positive symptoms with ER (r= 0.43, p= 0.009) and general psychopathology symptoms of the PANSS with C (r= 0.34, p= 0.044), DT (r= 0.35, p= 0.041) and ER (r= 0.45, p= 0.007). In high school students, CBQ total scores were associated with positive (r= 0.43, p= 0.003) and depressive (r= 0.35, p= 0.020) symptoms. In relation to particular cognitive biases, depressive symptoms were associated with DT (r= 0.47, p= 0.001) whereas positive symptoms were associated with DT (r= 0.31, p= 0.036) and ER (r= 0.30, p= 0.047). Discussion Although we did not find significant differences in the presence of cognitive biases when comparing two different samples, similar associations were found when exploring the relationship between cognitive biases and psychopathology symptoms. Our results are in accordance previous studies reporting the role of some cognitive biases on the risk of developing psychotic symptoms. On the other hand, a clear association between cognitive biases was found for depressive symptoms in both patients with schizophrenia and high school students. Our study highlights the importance of identifying and treating cognitive biases with appropriate therapies (e.g. metacognitive training) for improving the outcome of psychoses in both patients and people at risk for developing a psychotic disorder in the future.

F87. SERUM PROLACTIN LEVELS AND COGNITIVE OUTCOME IN FIRST EPISODE PSYCHOSIS: A PROSPECTIVE 1-YEAR FOLLOW-UP STUDY

Abstract Background Recent studies in patients with psychotic disorders or prolactinomas suggest that increased prolactin levels may have negative effects on cognition. Most previous studies including patients with psychotic disorders are cross-sectional, and longitudinal studies are lacking. We aimed to conduct an observational, prospective study to explore whether prolactin levels during the first year of treatment are associated with changes in cognitive tasks. Our hypothesis would be that those patients with increased prolactin levels would show a poorer cognitive outcome than those patients with lower prolactin levels. Methods We studied 60 patients (24.5 ± 6.8 years; 36% women) with a first episode psychosis (FEP) attending the Early Psychosis Programme from two institutions (Parc Taulí Hospital Universitari, Sabadell, Spain; Hospital Universitari Institut Pere Mata). Ethical approval was obtained from the local Ethics Committees of both institutions. Clinical diagnoses for a FEP were generated with the OPCRIT checklist v.4.0 after a semistructured interview by a psychiatrist. The MATRICS Consensus Cognitive Battery (MCCB) was administered to explore neuropsychological functioning at two-time points (baseline, 1 year). The MCCB contains 10 tests to measure cognitive performance in 7 cognitive domains. Three fasting blood samples (baseline, 6 months, 12 months) were obtained in the morning between 8:30 h and 9:30 h in resting conditions, to determine unstimulated plasma prolactin. Serum prolactin levels were determined with immunoassays standardized against the 3rd International Reference Standard 84/500. Statistical analyses were performed with SPSS version 21.0. As prolactin levels might be increased by stress, particularly at the onset of the FEP, we calculated mean prolactin levels over the follow-up period taking into account prolactin values at 6 and 12 months. A general linear model for repeated measures was performed in order to test whether longitudinal changes in cognitive tasks differed by mean prolactin levels. All analyses were adjusted for gender. A p value < 0.05 (two-tailed) was considered to be significant. For descriptive purposes, patients in the fourth quartile for serum prolactin (>47.8 ng/ml for men; >54.3 ng/ml for women) where compared with those with lower prolactin levels. Results Patients improved in all 10 MCCB cognitive tasks one year later (p<0.05 for all tasks). When exploring the interaction between time x prolactin in the GLM analyses, significant interactions were found for three cognitive tasks related with processing speed (BACS-SC [F= 5.9, p= 0.018]; Fluency [F= 5.6, p= 0.022]) and reasoning and problem solving (NAB mazes [F= 4.8, p= 0.033]). Percent change over the follow-up period in these cognitive tasks was greater for patients with lower prolactin levels, when compared to those in the highest quartile: BACS-SC (11.8% vs 0.6%), Fluency (8.5% vs -7.4%) and NAB mazes (10.7% vs -1.1%). Discussion Our study is in accordance with previous cross-sectional studies reporting a negative effect of prolactin levels on cognition and adds new information with a prospective design. A limitation of our study is that patients were treated with different antipsychotics based on the clinical routine practice. Antipsychotic-induced hyperprolactinaemia, which is caused by tuberoinfundibular blockade of D2 receptors, may be reflecting the blockade of D2 receptors in other dopaminergic pathways (striatum and mesocortical pathways) that may also affect cognitive abilities. Further clinical trials are needed to reduce the heterogeneity of the treatment effects and to confirm the potential negative effects of prolactin on cognitive abilities.

T225. OPERATIONAL DEFINITIONS FOR ANTIPSYCHOTIC RESPONSE IN DELUSIONAL DISORDER: A SYSTEMATIC AND CRITICAL REVIEW

Abstract Background Recent research in schizophrenia has revealed that there is no consensus to which is the most appropriate definition for antipsychotic response. Response rates allow the clinician to know how many subjects have responded to a specific treatment. However, once again, levels of response or the cutoff chosen have been subject of controversy, as a high variety of values have been applied in schizophrenia research. This systematic review aimed to examine all the definitions used for antipsychotic response in delusional disorder (DD), to analyze them and provide a discussion of the methodology used. Methods A systematic computerized literature search was performed by using Pubmed, Scopus and PsycINFO databases (1990-September 2017) according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. In addition, reference searches were manually conducted through identified studies in order to obtain other relevant articles not previously found on the initial search strategy. The following search terms were used: [(Antipsychotic response) OR (antipsychotics) OR (treatment response)] AND [(delusional disorder)]. Studies were only included if the met our inclusion criteria: (a) be published in a peer-reviewed journal, (b) prospective or retrospective studies focusing on antipsychotic response, (c) studies assessing response in DD based on clinical judgment or clinical records, (d) studies including a definition of antipsychotic response based on assessment scales and (e) diagnostic criteria based on ICD or DSM. The literature search strategy was conducted independently by two of the authors (A.G. and F.E.). The last search was conducted on 30th October, 2017. Results Seventy-four studies were initially identified. 39 studies were excluded after titles and abstracts were read, as they did not meet our initial inclusion criteria or met any of the exclusion criteria. 22 studies were excluded after reading the full text-document as they failed to meet our inclusion criteria or met any exclusion criteria, and 2 articles were excluded as studies for the assessment were duplicated. After the screening and selection processes, a total of 11 studies met our inclusion criteria, using different methods to define antipsychotic response in DD. Chart review (n=5) and observer-rated scales (n=6), from which 2 of them used the CGI improvement scale for assessing response, 2 studies evaluated it by mean changes from baseline to endpoint scores (PANSS, BPRS), one study combined the CGI improvement scale and mean changes from baseline scores (PANSS), and one study reported responder rates based on a scale-derived cutoff (PANSS). Discussion A lack of consensus in the definitions of antipsychotic response in delusional disorder and a high degree of heterogeneity of the methods used are reflected on this systematic review. Although no consensus for the response definition appears to exist in delusional disorder, there is a need to better quantify the treatment response in terms of percentages of response, and linking these findings with those derived from the CGI. Recommendations from Leucht (2014) in schizophrenia would be a first step in defining response among delusional disorder patients.

F212. IMPROVEMENT IN COGNITIVE BIASES AFTER GROUP PSYCHOEDUCATION AND METACOGNITIVE TRAINING IN RECENT ONSET PSYCHOSIS

Abstract Background Group psychotherapeutic treatments can improve negative symptoms and social functioning deficits in the treatment of schizophrenia. These treatments may include different modalities including group cognitive behavioral therapy, psychoeducation and metacognitive training (MCT). MCT is effective for preventing delusions by modifying the cognitive biases most related to psychosis. Our primary goal was to address whether cognitive biases improve more specifically with MCT when compared to psychoeducation in a sample of patients with recent onset psychosis. Methods Design: a multicenter randomized, pilot clinical trial was performed, in which one group received psychoeducation and the other MCT. Sample 49 patients aged between 18–35 years and with a diagnosis of psychotic disorder according to DSM-IV-TR criteria and less than 3 years of duration of illness. All patients were recruited at two Early Psychosis Programmes in Spain (ParcTaulí Hospital Universitari, Sabadell; Hospital UniversitariInstitut Pere Mata, Reus). Ethical approval was obtained from the local Ethics Committees of both institutions. Outcomes Patients were evaluated at baseline and at the end of each intervention. The primary outcome was cognitive biases, assessed with Cognitive Biases Questionnaire for Psychosis (CBQ). Secondary outcomes included cognitive insight, psychopathological symptoms (positive, negative, depressive) and psychosocial functioning. Interventions The interventions consisted of 8 weekly group sessions of MCT (developed at the University of Hamburg-Eppendorf by Steffen Moritz) or psychoeducation. MCT program included sessions dealing with attributional style, jumping to conclusions, changing beliefs, empathy, memory, and depression and self-esteem. The psychoeducational program included sessions addressing aspects related to psychotic illness (psychotic symptoms, risk factors of relapse, stress management, psychopharmacological treatment, substance use, physical health and social skills). Statistical analysis: A general linear model for repeated measures was performed in order to compare the longitudinal effect of the intervention and to test whether changes in outcome variables differed by treatment group. All analyses were adjusted for gender. A p value < 0.05 (two-tailed) was considered to be significant. Results Of all 49 patients, 38 (77.6%) completed at least 50% of the sessions, and were included in the final analyses. 21 received psychoeducation and 16 MCT. Cognitive biases improved significantly in both psychoeducation (43.8 ± 11.2 vs 40.8 ± 10.4) and MCT groups (44.2 ± 7.6 vs 39.6 ± 5.0). The time effect was significant (F= 18.9, p<0.001) without a different pattern in the change of CBQ scores between groups (interaction time x group, F= 0.63, p= 0.431). An improvement in negative symptoms was also observed after receiving both treatments, without significant differences between groups. No significant changes over time were observed in positive symptoms, depressive symptoms or psychosocial functioning. Discussion Both group psychoeducation and MCT improve cognitive biases in recent onset psychosis. Our study does not support a superiority of one intervention over the other in terms of improving cognitive biases.

Improvement in cognitive biases after group psychoeducation and metacognitive training in recent-onset psychosis: a randomized crossover clinical trial

Metacognitive training (MCT) improves cognitive biases in psychosis. We aimed to explore whether the effectiveness of the combination of psychoeducation and MCT group treatments on cognitive biases differed if the combination was started by psychoeducation or by MCT. Fourty-nine stable patients with a recent-onset psychosis were randomized to two different sequences: MCTu202f+u202fpsychoeducation vs psychoeducationu202f+u202fMCT. Cognitive biases, psychopathology symptoms, insight and functioning were assessed. Cognitive biases and depressive symptoms improved with both group interventions, without differential effects between both sequences. Our study suggests that MCT and psychoeducation are useful in improving cognitive biases and depressive symptoms in recent-onset psychosis.