- Email: [email protected]
High FSH:LH ratio may be associated with poor response of negative symptoms in postmenopausal schizophrenia women
S538
P.3.d. Psychotic disorders and treatment − Treatment (clinical)
and concerns about long-term safety, mortality and increased cost exist [5]. There are two strategies to combining antipsychotics: co-initiation of two agents at the same time, or augmentation with a second antipsychotic to the baseline agent. To date, no metaanalysis exists regarding antipsychotic co-initiation strategies. Therefore, we conducted a meta-analysis of the available randomized controlled evidence regarding the efficacy, effectiveness and safety of antipsychotic co-initiation in schizophrenia. Methods: Systematic PubMed/Medline, PsycInfo, CJN, WangFan and CBM search from database inception until 05/25/2015 for randomized controlled trials comparing antipsychotic co-initiation with antipsychotic monotherapy in 20 adults with schizophrenia. Two independent investigators extracted data for a random effects meta-analysis to calculate standardized mean differences (SMD) or risk ratios (RRs) +/− their 95% confidence intervals (CIs) for continuous and categorical outcomes, respectively. Co-primary outcomes were overall symptom reduction and study-defined response. Secondary outcomes included all-cause and specificcause discontinuation, psychopathology and adverse effects. Prespecified subgroup and meta-regression analyses (for all studies combined and for blinded studies reporting last-observationcarried-forward (LOCF) data separately. Results: Meta-analyzing 79 studies (n = 6,173, duration = 10.5±6.2 weeks), antipsychotic co-initiation was superior to monotherapy regarding overall symptom reduction (studies = 59, n = 4,391, SMD = −0.673, 95% CI = −0.878 to −0.468, p < 0.001) as well as study-defined response (studies = 58, n = 4,159, RR = 1.101, 95% CI = 1.063 to 1.141, p < 0.001). However, superiority was driven by open label/observed-cases studies and was not apparent in blinded/LOCF studies (symptom severity: studies = 4, n = 279, SMD = −0.062, 95% CI = −0.359 to 0.235, p = 0.681; response: studies = 13, n = 805, RR = 0.993, 95% CI = 0.920 to 1.070, p = 0.845). Non-superiority of antipsychotic coinitiation vs monotherapy in blinded/LOCF studies was replicated regardless of individual antipsychotics, dosage, and treatment setting. In meta-regression analyses, a higher baseline symptom severity (PANSS) was associated with less symptom improvement (studies = 49, n = 3,758, Coefficient = 0.022, 95% CI = 0.002 to 0.043, p = 0.033), while longer illness duration was associated with more response (studies = 47, n = 3,519, Coefficient = 0.008, 95% CI = 0.002 to 0.015, p = 0.010). Again, these results were not replicated in blinded/LOCF studies. No between-group differences emerged regarding all-cause and specific-cause discontinuation, positive, general and depressive symptoms. Nevertheless, coinitiation was superior to monotherapy regarding negative symptoms (studies = 43, n = 3,143, SMD = −0.691, 95% CI = −1.008 to −0.375, p<0001) and global impression (studies = 4, n = 269, SMD = −2.266, 95% CI = −4.194 to 0.337, p = 0.221), but again both outcomes were not significant in blinded/LOCF studies. No difference emerged regarding adverse effect (AE)-related discontinuation (p = 0.371), whereas 1 AE occurred less often with co-initiation (studies = 16, n = 1,138, RR = 0.779, 95% CI = 0.649 to 0.934, p = 0.007). Partial D2-agonist (aripiprazole)– D2-antagonist-co-initiation compared to D2-antagonist monotherapy was associated with less constipation (p = 0.004), prolactin elevation (p < 0.001) and body weight change (p = 0.015). However, none of the AE results were replicated in blinded/LOCF studies. Conclusion: This first meta-analysis of randomized controlled trials investigating antipsychotic co-initiation versus monotherapy in schizophrenia indicates that antipsychotic co-initiation lacks blinded/LOCF evidence for superior efficacy. Co-initiation of a
D2 antagonist with aripiprazole might ameliorate constipation, prolactin elevation and body weight compared to monotherapy. However, more blinded and high quality trials are needed to confirm/extend these results. References [1] Hasan, A., Falkai, P., Wobrock, T., et al., 2012. World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry 13(5), 318–378. [2] Gallego, J.A., Bonetti, J., Zhang, J., Kane, J.M., Correll, C.U., 2012. Prevalence and correlates of antipsychotic polypharmacy: a systematic review and meta-regression of global and regional trends from the 1970s to 2009. Schizophr Res 138(1), 18−28. [3] Kuipers, E., Yesufu-Udechuku, A., Taylor, C., Kendall, T., 2014. Management of psychosis and schizophrenia in adults: summary of updated NICE guidance. BMJ 348, 1173. [4] Correll, C.U., Rummel-Kluge, C., Corves, C., Kane, J.M., Leucht, S., 2009. Antipsychotic Combinations vs Monotherapy in Schizophrenia: A Meta-analysis of Randomized Controlled Trials. Schizophr Bull 35(2), 443–457. [5] Gallego, J.A., Nielsen, J., De Hert, M., Kane, J.M., Correll, C.U., 2012. Safety and tolerability of antipsychotic polypharmacy. Expert Opin Drug Saf 11(4), 527–542.
P.3.d.016 High FSH:LH ratio may be associated with poor response of negative symptoms in postmenopausal schizophrenia women A. Gonz´alez Rodr´ıguez1 ° , R. Catal´an2 , R. Penad´es2 , V. Ruiz Cort´es3 , M. Torra4 , M. Bernardo2 1 Barcelona Clinic Schizophrenia Unit BCSU. Neuroscience Institute, Hospital Clinic of Barcelona. Department of Psychiatry and Clinical Psychobiology. University of Barcelona, Barcelona, Spain; 2 Barcelona Clinic Schizophrenia Unit BCSU. Neurosciences Institute, Hospital Clinic of Barcelona. Department of Psychiatry and Clinical Psychobiology. University of Barcelona. CIBERSAMIDIBAPS, Barcelona, Spain; 3 Neurosciences Institute, Hospital Clinic of Barcelona, Barcelona, Spain; 4 Pharmacology and Toxicology. Biochemistry and Molecular Genetics Department, Hospital Clinic of Barcelona, Barcelona, Spain Introduction: Menopause is defined as a permanent hypergonadotrophic hypogonadism and amenorrhea that determines a follicular depletion and an absence of ovarian secretion of estradiol (E2) [1]. Age-related changes of ovarian function are also characterized by parallel changes of Follicle-stimulating (FSH) and Luteinizing Hormone (LH) levels, being the last less predictive of poor ovarian reserve [2], and providing single FSH measurement little information regarding the menopausal status [2]. Within postmenopausal schizophrenia women, several authors have reported the possibility that psychotic symptoms may worsen at this period of time and higher doses of antipsychotics may be required [3]; however, few studies have investigated potential associations between hormone levels and antipsychotic response in this population. Aims: The main goal of this study was to assess the relationship between gonadal and pituitary gonadotropin hormone levels and antipsychotic response in postmenopausal schizophrenia women. Methods: Participants and study design: Thirty-one acutely postmenopausal schizophrenia women (DSM-IV-TR) were included in a 12-week prospective observational study. The following measurements were undertaken: (1) Psychopathological
P.3.d. Psychotic disorders and treatment − Treatment (clinical) assessment (at baseline and 12-week): the Positive and Negative Syndrome Scale (PANSS) for psychotic symptoms, the Personal and Social Performance Scale (PSP) for functionality, and the Clinical Global Impression Scale (CGI-SCH); (2) Laboratory: Follicle-stimulating Hormone (FSH), Luteinizing Hormone (LH), estradiol (E2), progesterone, testosterone, free testosterone index, and Sex Hormone-Binding Globulin (SHBG) were measured. Immunoassays were used. FSH:LH ratio was also calculated, as it has been considered an early biomarker of poor ovarian response [4]. Statistical Procedures: To determine the association between hormone serum levels and psychopathological improvement, the bivariate and partial Pearson correlation coefficients were performed. Results: The correlation analysis between hormone levels and mean changes in assessment scales was performed in two steps. First, the bivariate Pearson correlational analysis revealed no relationship between FSH, LH, estradiol, progesterone and other hormone levels and mean changes in assessment scales and subscales. FSH:LH ratio was not correlated with an improvement in the five symptomatic domains. Subsequently, to investigate whether duration of illness, antipsychotic equivalent doses, body mass index (BMI) and smoking were involved in the relationship between hormone levels and psychopathological improvement, partial correlational analysis were conducted. After adjustment, FSH:LH ratio was negatively associated with improvement in negative symptoms (r = 0.987, p = 0.013). No other associations were found between hormone serum levels and psychopathological changes. Conclusions: High FSH:LH ratio was significantly associated with lower improvement in negative symptoms, suggesting that negative symptoms seem to worsen when FSH levels rise and vice versa. Our findings indicate that postmenopausal hormone changes involving ovarian changes (i.e. estradiol levels), as well as central hypothalamic pituitary alterations, may modulate antipsychotic response in postmenopausal schizophrenia women. Further studies are needed to confirm these results, and may be focused on the study of the impact of hypothalamic-pituitary-gonadal system on the antipsychotic response in schizophrenia women. References [1] Riecher-R¨ossler, A., 2009. Psychotic disorders and menopause: the untold story, in: Soares, C.N., Warren, M., The Menopausal Transition: Interface between Gynecology and Psychiatry. Karger, Basel, Switzerland, pp. 115–126. [2] Hall, J.E., 2015. Endocrinology of the Menopause. Endocrinol Metab Clin North Am 44, 485–496. [3] Seeman, M.V., 2012. Treating schizophrenia at the time of menopause. Maturitas 72, 117–120. [4] Barroso, G., Oehninger, S., Monz´o, A., et al., 2001. High FSH:LH ratio and low LH levels in basal cycle day 3: impact on follicular development and IVF outcome. J Assit Reprod Genet 18, 499–450. Disclosure statement: Prof. Miquel Bernardo has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of ABBiotics, Adamed, Boehringer, Eli Lilly, Ferrer, Forum Pharmaceuticals, Janssen-Cilag, Lundbeck, Otsuka, Pfizer. Alexandre Gonz´alez-Rodr´ıguez have received honoraria or paid for travels from Pfizer, Janssen, Lundbeck-Otsuka and Ferrer. Rosa Catal´an has received honoraria or has been paid for travels from Lilly, Lundbeck, Janssen, Ferrer, Pfizer and Bristol. Rafael Penad´es have received honoraria or paid for travels from Otsuka-Lundbeck. Victoria Ruiz-Cort´es has been paid for registration at congresses from Janssen-Cilag.
S539
P.3.d.017 Predictors of multiple treatment failure of antipsychotics in early-onset psychosis L. Pina-Camacho1,2 ° , H. Dean3 , S. Lechler3 , N. Sears3 , R. Patel3 , I. Kartoglu3 , H. Shetty3 , M. Hotopf3 , T. Ford4 , M. Kyriakopoulos1 , C. Arango2 , J. MacCabe3 , R. Hayes3 , J. Downs3 1 Department of Child and Adolescent Psychiatry Institute of Psychiatry Psychology and Neuroscience, King’s College London, London, United Kingdom; 2 Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Mara˜no´ n IiSGM School of Medicine Universidad Complutense CIBERSAM, Madrid, Spain; 3 Institute of Psychiatry Psychology and Neuroscience King’s College London, NIHR South London and Maudsley Biomedical Research Centre, London, United Kingdom; 4 University of Exeter, Medical School, Exeter, United Kingdom Background: In adult-onset psychosis, a number of factors are associated with poor clinical outcomes, which include the severity of negative symptoms at illness onset, the presence of premorbid difficulties, and a family history of psychotic disorder [1]. If and how these factors effect psychosis prognosis in children and adolescents is unclear [2]. Objective: Using a retrospective cohort design and data from a large electronic case register, we sought to investigate, in a sample of children and adolescents with first-episode psychosis (FEP), the prospective association of demographic and clinical variables at first presentation to services with reduced antipsychotic effectiveness. We used multiple treatment failure (MTF) as a proxy for reduced treatment effectiveness, defined as the initiation of a third trial of novel antipsychotic as a result of insufficient response, nontolerable adverse effects or non-adherence. We hypothesized that presence of premorbid difficulties (e.g. comorbid neurodevelopmental disorders), baseline negative symptoms and family history of psychosis would be positively associated with MTF. Methods: Data were obtained from a clinical cohort of 638 children (51% male) with FEP, aged 10−17 years, referred to inpatient and community-based services in South London, UK, using the Clinical Record Interactive Search (CRIS) system. Age, sex, ethnicity, adaptive function, inpatient status, presence of negative symptoms at first presentation, first degree family history of psychosis, co-morbid neurodevelopmental disorders (autism spectrum disorders [ASD], intellectual disability [ID], and hyperkinetic disorders), unique antipsychotic medications prescribed in a 5-year observation period, and reasons for MTF were extracted from electronic patient records. The effect of neurodevelopmental comorbidity, presenting with two or more Marder Negative Symptoms, and family history of psychosis, on the development of MTF over a 5-year period was modelled using Cox regression. Results: One hundred and twenty-four children with FEP (19.3% of the sample) developed MTF prior to the age of eighteen. Of those, 10.5% (n = 13) showed a persistently insufficient response to two consecutive trials of different antipsychotics, 14.5% (n = 18) experienced persistently non-tolerable adverse effects, 4% (n = 5) showed persistent non-adherence, and 78% (n = 77) showed a combination of these reasons. After controlling for a range of potential confounders, a fully adjusted cox proportional hazards model found that co-morbid ASD (adjusted hazard ratio [aHR] 1.89; 95% CI 1.03–3.46; p < 0.05) was significantly associated with MTF. The presence of two or more NS around the first episode (aHR 2.00; 1.16– 3.42; p < 0.05), family history of psychosis (aHR 2.08; 1.15–3.75;
P.3.d. Psychotic disorders and treatment − Treatment (clinical)
and concerns about long-term safety, mortality and increased cost exist [5]. There are two strategies to combining antipsychotics: co-initiation of two agents at the same time, or augmentation with a second antipsychotic to the baseline agent. To date, no metaanalysis exists regarding antipsychotic co-initiation strategies. Therefore, we conducted a meta-analysis of the available randomized controlled evidence regarding the efficacy, effectiveness and safety of antipsychotic co-initiation in schizophrenia. Methods: Systematic PubMed/Medline, PsycInfo, CJN, WangFan and CBM search from database inception until 05/25/2015 for randomized controlled trials comparing antipsychotic co-initiation with antipsychotic monotherapy in 20 adults with schizophrenia. Two independent investigators extracted data for a random effects meta-analysis to calculate standardized mean differences (SMD) or risk ratios (RRs) +/− their 95% confidence intervals (CIs) for continuous and categorical outcomes, respectively. Co-primary outcomes were overall symptom reduction and study-defined response. Secondary outcomes included all-cause and specificcause discontinuation, psychopathology and adverse effects. Prespecified subgroup and meta-regression analyses (for all studies combined and for blinded studies reporting last-observationcarried-forward (LOCF) data separately. Results: Meta-analyzing 79 studies (n = 6,173, duration = 10.5±6.2 weeks), antipsychotic co-initiation was superior to monotherapy regarding overall symptom reduction (studies = 59, n = 4,391, SMD = −0.673, 95% CI = −0.878 to −0.468, p < 0.001) as well as study-defined response (studies = 58, n = 4,159, RR = 1.101, 95% CI = 1.063 to 1.141, p < 0.001). However, superiority was driven by open label/observed-cases studies and was not apparent in blinded/LOCF studies (symptom severity: studies = 4, n = 279, SMD = −0.062, 95% CI = −0.359 to 0.235, p = 0.681; response: studies = 13, n = 805, RR = 0.993, 95% CI = 0.920 to 1.070, p = 0.845). Non-superiority of antipsychotic coinitiation vs monotherapy in blinded/LOCF studies was replicated regardless of individual antipsychotics, dosage, and treatment setting. In meta-regression analyses, a higher baseline symptom severity (PANSS) was associated with less symptom improvement (studies = 49, n = 3,758, Coefficient = 0.022, 95% CI = 0.002 to 0.043, p = 0.033), while longer illness duration was associated with more response (studies = 47, n = 3,519, Coefficient = 0.008, 95% CI = 0.002 to 0.015, p = 0.010). Again, these results were not replicated in blinded/LOCF studies. No between-group differences emerged regarding all-cause and specific-cause discontinuation, positive, general and depressive symptoms. Nevertheless, coinitiation was superior to monotherapy regarding negative symptoms (studies = 43, n = 3,143, SMD = −0.691, 95% CI = −1.008 to −0.375, p<0001) and global impression (studies = 4, n = 269, SMD = −2.266, 95% CI = −4.194 to 0.337, p = 0.221), but again both outcomes were not significant in blinded/LOCF studies. No difference emerged regarding adverse effect (AE)-related discontinuation (p = 0.371), whereas 1 AE occurred less often with co-initiation (studies = 16, n = 1,138, RR = 0.779, 95% CI = 0.649 to 0.934, p = 0.007). Partial D2-agonist (aripiprazole)– D2-antagonist-co-initiation compared to D2-antagonist monotherapy was associated with less constipation (p = 0.004), prolactin elevation (p < 0.001) and body weight change (p = 0.015). However, none of the AE results were replicated in blinded/LOCF studies. Conclusion: This first meta-analysis of randomized controlled trials investigating antipsychotic co-initiation versus monotherapy in schizophrenia indicates that antipsychotic co-initiation lacks blinded/LOCF evidence for superior efficacy. Co-initiation of a
D2 antagonist with aripiprazole might ameliorate constipation, prolactin elevation and body weight compared to monotherapy. However, more blinded and high quality trials are needed to confirm/extend these results. References [1] Hasan, A., Falkai, P., Wobrock, T., et al., 2012. World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry 13(5), 318–378. [2] Gallego, J.A., Bonetti, J., Zhang, J., Kane, J.M., Correll, C.U., 2012. Prevalence and correlates of antipsychotic polypharmacy: a systematic review and meta-regression of global and regional trends from the 1970s to 2009. Schizophr Res 138(1), 18−28. [3] Kuipers, E., Yesufu-Udechuku, A., Taylor, C., Kendall, T., 2014. Management of psychosis and schizophrenia in adults: summary of updated NICE guidance. BMJ 348, 1173. [4] Correll, C.U., Rummel-Kluge, C., Corves, C., Kane, J.M., Leucht, S., 2009. Antipsychotic Combinations vs Monotherapy in Schizophrenia: A Meta-analysis of Randomized Controlled Trials. Schizophr Bull 35(2), 443–457. [5] Gallego, J.A., Nielsen, J., De Hert, M., Kane, J.M., Correll, C.U., 2012. Safety and tolerability of antipsychotic polypharmacy. Expert Opin Drug Saf 11(4), 527–542.
P.3.d.016 High FSH:LH ratio may be associated with poor response of negative symptoms in postmenopausal schizophrenia women A. Gonz´alez Rodr´ıguez1 ° , R. Catal´an2 , R. Penad´es2 , V. Ruiz Cort´es3 , M. Torra4 , M. Bernardo2 1 Barcelona Clinic Schizophrenia Unit BCSU. Neuroscience Institute, Hospital Clinic of Barcelona. Department of Psychiatry and Clinical Psychobiology. University of Barcelona, Barcelona, Spain; 2 Barcelona Clinic Schizophrenia Unit BCSU. Neurosciences Institute, Hospital Clinic of Barcelona. Department of Psychiatry and Clinical Psychobiology. University of Barcelona. CIBERSAMIDIBAPS, Barcelona, Spain; 3 Neurosciences Institute, Hospital Clinic of Barcelona, Barcelona, Spain; 4 Pharmacology and Toxicology. Biochemistry and Molecular Genetics Department, Hospital Clinic of Barcelona, Barcelona, Spain Introduction: Menopause is defined as a permanent hypergonadotrophic hypogonadism and amenorrhea that determines a follicular depletion and an absence of ovarian secretion of estradiol (E2) [1]. Age-related changes of ovarian function are also characterized by parallel changes of Follicle-stimulating (FSH) and Luteinizing Hormone (LH) levels, being the last less predictive of poor ovarian reserve [2], and providing single FSH measurement little information regarding the menopausal status [2]. Within postmenopausal schizophrenia women, several authors have reported the possibility that psychotic symptoms may worsen at this period of time and higher doses of antipsychotics may be required [3]; however, few studies have investigated potential associations between hormone levels and antipsychotic response in this population. Aims: The main goal of this study was to assess the relationship between gonadal and pituitary gonadotropin hormone levels and antipsychotic response in postmenopausal schizophrenia women. Methods: Participants and study design: Thirty-one acutely postmenopausal schizophrenia women (DSM-IV-TR) were included in a 12-week prospective observational study. The following measurements were undertaken: (1) Psychopathological
P.3.d. Psychotic disorders and treatment − Treatment (clinical) assessment (at baseline and 12-week): the Positive and Negative Syndrome Scale (PANSS) for psychotic symptoms, the Personal and Social Performance Scale (PSP) for functionality, and the Clinical Global Impression Scale (CGI-SCH); (2) Laboratory: Follicle-stimulating Hormone (FSH), Luteinizing Hormone (LH), estradiol (E2), progesterone, testosterone, free testosterone index, and Sex Hormone-Binding Globulin (SHBG) were measured. Immunoassays were used. FSH:LH ratio was also calculated, as it has been considered an early biomarker of poor ovarian response [4]. Statistical Procedures: To determine the association between hormone serum levels and psychopathological improvement, the bivariate and partial Pearson correlation coefficients were performed. Results: The correlation analysis between hormone levels and mean changes in assessment scales was performed in two steps. First, the bivariate Pearson correlational analysis revealed no relationship between FSH, LH, estradiol, progesterone and other hormone levels and mean changes in assessment scales and subscales. FSH:LH ratio was not correlated with an improvement in the five symptomatic domains. Subsequently, to investigate whether duration of illness, antipsychotic equivalent doses, body mass index (BMI) and smoking were involved in the relationship between hormone levels and psychopathological improvement, partial correlational analysis were conducted. After adjustment, FSH:LH ratio was negatively associated with improvement in negative symptoms (r = 0.987, p = 0.013). No other associations were found between hormone serum levels and psychopathological changes. Conclusions: High FSH:LH ratio was significantly associated with lower improvement in negative symptoms, suggesting that negative symptoms seem to worsen when FSH levels rise and vice versa. Our findings indicate that postmenopausal hormone changes involving ovarian changes (i.e. estradiol levels), as well as central hypothalamic pituitary alterations, may modulate antipsychotic response in postmenopausal schizophrenia women. Further studies are needed to confirm these results, and may be focused on the study of the impact of hypothalamic-pituitary-gonadal system on the antipsychotic response in schizophrenia women. References [1] Riecher-R¨ossler, A., 2009. Psychotic disorders and menopause: the untold story, in: Soares, C.N., Warren, M., The Menopausal Transition: Interface between Gynecology and Psychiatry. Karger, Basel, Switzerland, pp. 115–126. [2] Hall, J.E., 2015. Endocrinology of the Menopause. Endocrinol Metab Clin North Am 44, 485–496. [3] Seeman, M.V., 2012. Treating schizophrenia at the time of menopause. Maturitas 72, 117–120. [4] Barroso, G., Oehninger, S., Monz´o, A., et al., 2001. High FSH:LH ratio and low LH levels in basal cycle day 3: impact on follicular development and IVF outcome. J Assit Reprod Genet 18, 499–450. Disclosure statement: Prof. Miquel Bernardo has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of ABBiotics, Adamed, Boehringer, Eli Lilly, Ferrer, Forum Pharmaceuticals, Janssen-Cilag, Lundbeck, Otsuka, Pfizer. Alexandre Gonz´alez-Rodr´ıguez have received honoraria or paid for travels from Pfizer, Janssen, Lundbeck-Otsuka and Ferrer. Rosa Catal´an has received honoraria or has been paid for travels from Lilly, Lundbeck, Janssen, Ferrer, Pfizer and Bristol. Rafael Penad´es have received honoraria or paid for travels from Otsuka-Lundbeck. Victoria Ruiz-Cort´es has been paid for registration at congresses from Janssen-Cilag.
S539
P.3.d.017 Predictors of multiple treatment failure of antipsychotics in early-onset psychosis L. Pina-Camacho1,2 ° , H. Dean3 , S. Lechler3 , N. Sears3 , R. Patel3 , I. Kartoglu3 , H. Shetty3 , M. Hotopf3 , T. Ford4 , M. Kyriakopoulos1 , C. Arango2 , J. MacCabe3 , R. Hayes3 , J. Downs3 1 Department of Child and Adolescent Psychiatry Institute of Psychiatry Psychology and Neuroscience, King’s College London, London, United Kingdom; 2 Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Mara˜no´ n IiSGM School of Medicine Universidad Complutense CIBERSAM, Madrid, Spain; 3 Institute of Psychiatry Psychology and Neuroscience King’s College London, NIHR South London and Maudsley Biomedical Research Centre, London, United Kingdom; 4 University of Exeter, Medical School, Exeter, United Kingdom Background: In adult-onset psychosis, a number of factors are associated with poor clinical outcomes, which include the severity of negative symptoms at illness onset, the presence of premorbid difficulties, and a family history of psychotic disorder [1]. If and how these factors effect psychosis prognosis in children and adolescents is unclear [2]. Objective: Using a retrospective cohort design and data from a large electronic case register, we sought to investigate, in a sample of children and adolescents with first-episode psychosis (FEP), the prospective association of demographic and clinical variables at first presentation to services with reduced antipsychotic effectiveness. We used multiple treatment failure (MTF) as a proxy for reduced treatment effectiveness, defined as the initiation of a third trial of novel antipsychotic as a result of insufficient response, nontolerable adverse effects or non-adherence. We hypothesized that presence of premorbid difficulties (e.g. comorbid neurodevelopmental disorders), baseline negative symptoms and family history of psychosis would be positively associated with MTF. Methods: Data were obtained from a clinical cohort of 638 children (51% male) with FEP, aged 10−17 years, referred to inpatient and community-based services in South London, UK, using the Clinical Record Interactive Search (CRIS) system. Age, sex, ethnicity, adaptive function, inpatient status, presence of negative symptoms at first presentation, first degree family history of psychosis, co-morbid neurodevelopmental disorders (autism spectrum disorders [ASD], intellectual disability [ID], and hyperkinetic disorders), unique antipsychotic medications prescribed in a 5-year observation period, and reasons for MTF were extracted from electronic patient records. The effect of neurodevelopmental comorbidity, presenting with two or more Marder Negative Symptoms, and family history of psychosis, on the development of MTF over a 5-year period was modelled using Cox regression. Results: One hundred and twenty-four children with FEP (19.3% of the sample) developed MTF prior to the age of eighteen. Of those, 10.5% (n = 13) showed a persistently insufficient response to two consecutive trials of different antipsychotics, 14.5% (n = 18) experienced persistently non-tolerable adverse effects, 4% (n = 5) showed persistent non-adherence, and 78% (n = 77) showed a combination of these reasons. After controlling for a range of potential confounders, a fully adjusted cox proportional hazards model found that co-morbid ASD (adjusted hazard ratio [aHR] 1.89; 95% CI 1.03–3.46; p < 0.05) was significantly associated with MTF. The presence of two or more NS around the first episode (aHR 2.00; 1.16– 3.42; p < 0.05), family history of psychosis (aHR 2.08; 1.15–3.75;