A randomized Phase II trial evaluating efficacy, safety, and tolerability of oral BI 409306 in attenuated psychosis syndrome: Design and rationale

Richard S E Keefe, Scott W Woods, Tyrone D Cannon, Stephan Ruhrmann, Daniel H Mathalon, Philip McGuire, Holger Rosenbrock, Kristen Daniels, Daniel Cotton, Dooti Roy, Stephane Pollentier, Michael Sand, Richard S E Keefe, Scott W Woods, Tyrone D Cannon, Stephan Ruhrmann, Daniel H Mathalon, Philip McGuire, Holger Rosenbrock, Kristen Daniels, Daniel Cotton, Dooti Roy, Stephane Pollentier, Michael Sand

Abstract

Aim: Attenuated psychosis syndrome (APS), a condition for further study in the Diagnostic and Statistical Manual of Mental Disorders-5, comprises psychotic symptoms that are qualitatively similar to those observed in schizophrenia but are less severe. Patients with APS are at high risk of converting to first-episode psychosis (FEP). As evidence for effective pharmacological interventions in APS is limited, novel treatments may provide symptomatic relief and delay/prevent psychotic conversion. This trial aims to investigate the efficacy, safety, and tolerability of BI 409306, a potent and selective phosphodiesterase-9 inhibitor, versus placebo in APS. Novel biomarkers of psychosis are being investigated.

Methods: In this Phase II, multinational, double-blind, parallel-group trial, randomized (1:1) patients will receive BI 409306 50 mg or placebo twice daily for 52 weeks. Patients (n = 300) will be enrolled to determine time to remission of APS, time to FEP, change in everyday functional capacity (Schizophrenia Cognition Rating Scale), and change from baseline in Brief Assessment of Cognition composite score and Positive and Negative Syndrome Scale scores. Potential biomarkers of psychosis under investigation include functional measures of brain activity and automated speech analyses. Safety is being assessed throughout.

Conclusions: This trial will determine whether BI 409306 is superior to placebo in achieving sustainable remission of APS and improvements in cognition and functional capacity. These advances may provide evidence-based treatment options for symptomatic relief in APS. Furthermore, the study will assess the effect of BI 409306 on psychotic conversion and explore the identification of patients at risk for conversion using novel biomarkers.

Trial registration: ClinicalTrials.gov NCT03230097.

Keywords: cognition; early intervention; phosphodiesterase; psychotic disorders; schizophrenia.

Conflict of interest statement

The authors met the criteria for authorship as recommended by the International Committee of Medical Journal Editors. R. S. E. K. is a paid consultant to Boehringer Ingelheim and several other pharmaceutical companies, and is the owner of VeraSci, which received paid services for this trial. R. S. E. K. also receives royalties for the tablet‐based Brief Assessment of Cognition (BAC) and the Brief Assessment of Cognition in Schizophrenia (BACS) symbol coding, which is part of the MATRICS battery. S. W. W., T. D. C., S. R., D. H. M., and P. M. are paid consultants to Boehringer Ingelheim International GmbH. T. D. C. has received grants from the National Institutes of Health. S. R. has received grants from the German Research Foundation, the European Commission, the Federal Ministry of Education and Research, and the Federal Institute for Drugs and Medical Devices, and has received speaker's honorarium from Boehringer Ingelheim International GmbH. D. H. M. is also a paid consultant to Alkermes, and has received grants from the National Institute of Mental Health, and honorarium from Alkermes. H. R. and S. P. are employees of Boehringer Ingelheim Pharma GmbH & Co KG and Boehringer Ingelheim International GmbH, respectively; M. S., D. C., D. R., and K. D. are employees of Boehringer Ingelheim Pharmaceuticals, Inc. None of the authors received direct compensation related to the development of this manuscript.

© 2020 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.

Figures

FIGURE 1
FIGURE 1
Mode of action for PDE9 and BI 409306. Ca2+, calcium; cGMP, cyclic guanosine 3′,5′‐monophosphate; GTP, guanosine triphosphate; LTP, long‐term potentiation; NMDA‐R, N‐methyl‐D‐aspartate receptor; NO, nitric oxide; NOS, nitric oxide synthase; PDE9, phosphodiesterase‐9; sGC, soluble guanylate cyclase. Figure adapted from reference Moschetti et al. (2016) Copyright © 2016 Boehringer Ingelheim. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution‐Non‐Commercial License
FIGURE 2
FIGURE 2
Overview of trial design

References

    1. Addington, J., Cornblatt, B. A., Cadenhead, K. S., Cannon, T. D., McGlashan, T. H., Perkins, D. O., Seidman, L. J., Tsuang, M. T., Walker, E. F., Woods, S. W., & Heinssen, R. (2011). At clinical high risk for psychosis: Outcome for nonconverters. The American Journal of Psychiatry, 168(8), 800–805. 10.1176/appi.ajp.2011.10081191.
    1. American Psychiatric Association . (2013). Diagnostic and statistical manual of mental disorders, 5th Edition: DSM‐5. American Psychiatric Association.
    1. Amminger, G. P., Schäfer, M. R., Schlögelhofer, M., Klier, C. M., & McGorry, P. D. (2015). Longer‐term outcome in the prevention of psychotic disorders by the Vienna omega‐3 study. Nature Communications, 6, 7934. 10.1038/ncomms8934.
    1. Atkins, A. S., Tseng, T., Vaughan, A., Twamley, E. W., Harvey, P., Patterson, T., Narasiman, M., & Keefe, R. S. E. (2017). Validation of the tablet‐administered brief assessment of cognition (BAC app). Schizophrenia Research, 181, 100–106. 10.1016/j.schres.2016.10.010.
    1. Bedi, G., Carrillo, F., Cecchi, G. A., Slezak, D. F., Sigman, M., Mota, N. B., Ribeiro, S., Javitt, D. C., Copelli, M., & Corcoran, C. M. (2015). Automated analysis of free speech predicts psychosis onset in high‐risk youths. NPJ Schizophrenia, 1, 15030. 10.1038/npjschz.2015.30. .
    1. Bodatsch, M., Brockhaus‐Dumke, A., Klosterkotter, J., & Ruhrmann, S. (2015). Forecasting psychosis by event‐related potentials‐systematic review and specific meta‐analysis. Biological Psychiatry, 77(11), 951–958. 10.1016/j.biopsych.2014.09.025.
    1. Boland, K., Moschetti, V., Dansirikul, C., Pichereau, S., Gheyle, L., Runge, F., Zimdahl‐Gelling, H., & Sand, M. (2017). A phase I, randomized, proof‐of‐clinical‐mechanism study assessing the pharmacokinetics and pharmacodynamics of the oral PDE9A inhibitor BI 409306 in healthy male volunteers. Human Psychopharmacology, 32(1), e2569. 10.1002/hup.2569.
    1. Brown, D., Daniels, K., Zhang, S., Pichereau, S., & Sand, M. (2015). Safety, tolerability, pharmacokinetics and pharmacodynamics of BI 409306 folm‐coated tablets given orally QD for 14 days in patients with schizophrenia. Schizophrenia Bulletin, 41(Suppl), S304.
    1. Brown, D., Nakagome, K., Cordes, J., Brenner, R., Grunder, G., Keefe, R. S. E., Riesenberg, R., Walling, D. P., Daniels, K., Wang, L., McGinniss, J., & Sand, M. (2018). Evaluation of the efficacy, safety, and tolerability of BI 409306, a novel phosphodiesterase 9 inhibitor, in cognitive impairment in schizophrenia: A randomized, double‐blind, placebo‐controlled, phase II trial. Schizophrenia Bulletin, 45, 350–359. 10.1093/schbul/sby049.
    1. Calkins, M. E., Moore, T. M., Merikangas, K. R., Burstein, M., Satterthwaite, T. D., Bilker, W. B., Ruparel, K., Chiavacci, R., Wolf, D. H., Mentch, F., Qiu, H., Connolly, J. J., Sleiman, P. A., Hakonarson, H., Gur, R. C., & Gur, R. E. (2014). The psychosis spectrum in a young U.S. community sample: Findings from the Philadelphia Neurodevelopmental Cohort. World Psychiatry, 13(3), 296–305. 10.1002/wps.20152.
    1. Cannon, T. D., Cadenhead, K., Cornblatt, B., Woods, S. W., Addington, J., Walker, E., Seidman, L. J., Perkins, D., Tsuang, M., McGlashan, T., & Heinssen, R. (2008). Prediction of psychosis in youth at high clinical risk: A multisite longitudinal study in North America. Archives of General Psychiatry, 65(1), 28–37. 10.1001/archgenpsychiatry.2007.3.
    1. Cannon, T. D., Chung, Y., He, G., Sun, D., Jacobson, A., van Erp, T. G., McEwan, S., Addington, J., Bearden, C. E., Cadenhead, K., Cornblatt, B., Mathalon, D. H., McGlashan, T., Perkins, D., Jeffries, C., Seidman, L. J., Tsuang, M., Walker, E., Woods, S. W., Heinssen, R., & North American Prodrome Longitudinal Study Consortium . (2015). Progressive reduction in cortical thickness as psychosis develops: A multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biological Psychiatry, 77(2), 147–157. 10.1016/j.biopsych.2014.05.023.
    1. Cannon, T. D., Yu, C., Addington, J., Bearden, C. E., Cadenhead, K. S., Cornblatt, B. A., Heinssen, R., Jeffries, C. D., Mathalon, D. H., McGlashan, T. H., Perkins, D. O., Seidman, L. J., Tsuang, M. T., Walker, E. F., Woods, S. W., & Kattan, M. W. (2016). An individualized risk calculator for research in prodromal psychosis. The American Journal of Psychiatry, 173(10), 980–988. 10.1176/appi.ajp.2016.15070890.
    1. Clark, S. R., Baune, B. T., Schubert, K. O., Lavoie, S., Smesny, S., Rice, S. M., Schäfer, M. R., Benninger, F., Feucht, M., Klier, C. M., McGorry, P. D., & Amminger, G. P. (2016). Prediction of transition from ultra‐high risk to first‐episode psychosis using a probabilistic model combining history, clinical assessment and fatty‐acid biomarkers. Translational Psychiatry, 26(9), e897. 10.1038/tp.2016.170.
    1. Cornblatt, B. A., Carrió, R. E., Auther, A., McLaughlin, D., Olsen, R. H., John, M., & Correll, C. U. (2015). Psychosis prevention: A modified clinical high risk perspective from the recognition and prevention (RAP) program. The American Journal of Psychiatry, 172(10), 986–994. 10.1176/appi.ajp.2015.13121686.
    1. Cornblatt, B. A., Lencz, T., Smith, C., Olsen, R., Auther, A. M., Nakayama, E., Lesser, M. L., Tai, J. Y., Shah, M. R., Foley, C. A., Kane, J. M., & Correll, C. U. (2007). Can antidepressants be used to treat the schizophrenia prodrome? Results of a prospective, naturalistic treatment study of adolescents. The Journal of Clinical Psychiatry, 68(4), 546–557.
    1. Craddock, N., & Owen, M. J. (2007). Rethinking psychosis: The disadvantages of a dichotomous classification now outweigh the advantages. World Psychiatry, 6(2), 84–91.
    1. Davies, C., Cipriani, A., Ioannidis, J. P. A., Radua, J., Stahl, D., Provenzani, U., McGuire, P., & Fusar‐Poli, P. (2018). Lack of evidence to favor specific preventive interventions in psychosis: A network meta‐analysis. World Psychiatry, 17(2), 196–209. 10.1002/wps.20526.
    1. Devoe, D. J., Peterson, A., & Addington, J. (2018). Negative symptom interventions in youth at risk of psychosis: A systematic review and network meta‐analysis. Schizophrenia Bulletin, 44(4), 807–823. 10.1093/schbul/sbx139.
    1. Dorner‐Ciossek, C., Giovannini, R., & Rosenbrock, H. (2015). BI 409306, a novel phosphodiesterase 9A inhibitor, part I: Potency, selectivity and in‐vitro functional characterization on synaptic plasticity. Schizophrenia Bulletin, 41, S31.
    1. European Medicines Agency . (2012). Guideline on clinical investigation of medicinal products, including depot preparations in the treatment of schizophrenia.
    1. Fusar‐Poli, P., Bonoldi, I., Yung, A. R., Borgwardt, S., Kempton, M. J., Valmaggia, L., Barale, F., Caverzasi, E., & McGuire, P. (2012). Predicting psychosis: Meta‐analysis of transition outcomes in individuals at high clinical risk. Archives of General Psychiatry, 69(3), 220–229. 10.1001/archgenpsychiatry.2011.1472.
    1. Fusar‐Poli, P., Borgwardt, S., Bechdolf, A., Addington, J., Riecher‐Rössler, A., Schultze‐Lutter, F., Keshavan, M., Wood, S., Ruhrmann, S., Seidman, L. J., Valmaggia, L., Cannon, T., Velthorst, E., De Haan, L., Cornblatt, B., Bonoldi, I., Birchwood, M., McGlashan, T., & Yung, A. (2013). The psychosis high‐risk state: A comprehensive state‐of‐the‐art review. JAMA Psychiatry, 70(1), 107–120. 10.1001/jamapsychiatry.2013.269.
    1. Fusar‐Poli, P., Rocchetti, M., Sardella, A., Avila, A., Brandizzi, M., Caverzasi, E., Politi, P., Ruhrmann, S., & McGuire, P. (2015). Disorder, not just state of risk: Meta‐analysis of functioning and quality of life in people at high risk of psychosis. The British Journal of Psychiatry, 207(3), 198–206. 10.1192/bjp.bp.114.157115.
    1. Hastrup, L. H., Kronborg, C., Bertelsen, M., Jeppesen, P., Jorgensen, P., Petersen, L., Thorup, A., Simonsen, E., & Nordentoft, M. (2013). Cost‐effectiveness of early intervention in first‐episode psychosis: Economic evaluation of a randomised controlled trial (the OPUS study). The British Journal of Psychiatry, 202(1), 35–41. 10.1192/bjp.bp.112.112300.
    1. Hawkins, K. A., Keefe, R. S., Christensen, B. K., Addington, J., Woods, S. W., Callahan, J., Zipursky, R. B., Perkins, D. O., Tohen, M., Breier, A., & McGlashan, T. H. (2008). Neuropsychological course in the prodrome and first episode of psychosis: Findings from the PRIME North America Double Blind Treatment Study. Schizophrenia Research, 105(1–3), 1–9. 10.1016/j.schres.2008.07.008.
    1. Hutton, P., & Taylor, P. J. (2014). Cognitive behavioural therapy for psychosis prevention: A systematic review and meta‐analysis. Psychological Medicine, 44(3), 449–468. 10.1017/s0033291713000354.
    1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use . (1996). ICH harmonised tripartite guideline: guideline for good clinical practice E6(1).
    1. Kay, S. R., Fiszbein, A., & Opler, L. A. (1987). The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13(2), 261–276.
    1. Keefe, R. S., Davis, V. G., Spagnola, N. B., Hilt, D., Dgetluck, N., Ruse, S., Patterson, T. D., Narasimhan, M., & Harvey, P. D. (2015). Reliability, validity and treatment sensitivity of the schizophrenia cognition rating scale. European Neuropsychopharmacology, 25(2), 176–184. 10.1016/j.euroneuro.2014.06.009.
    1. Mathalon, D. H. (2014). Impaired synaptic plasticity, synapti over‐pruning, inflammation, and stress: A pathogenic model of the transition to psychosis in clinical high risk youth. Biological Psychiatry, 75(Suppl), 1S–401S.
    1. McGlashan, T. H., Walsh, B. C., & Woods, S. W. (2010). The psychosis‐risk syndrome: Handbook for diagnosis and follow‐up. Oxford University Press.
    1. McGlashan, T. H., Zipursky, R. B., Perkins, D., Addington, J., Miller, T., Woods, S. W., Hawkins, K. A., Hoffman, R. E., Preda, A., Epstein, I., Addington, D., Lindborg, S., Trzaskoma, Q., Tohen, M., & Breier, A. (2006). Randomized, double‐blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. The American Journal of Psychiatry, 163(5), 790–799. 10.1176/ajp.2006.163.5.790.
    1. McGorry, P. D., Nelson, B., Markulev, C., Yuen, H. P., Schafer, M. R., Mossaheb, N., Schlögelhofer, M., Smesny, S., Hickie, I. B., Berger, G. E., Chen, E. Y. H., de Haan, L., Nieman, D. H., Nordentoft, M., Riecher‐Rössler, A., Verma, S., Thompson, A., Yung, A. R., & Amminger, G. P. (2017). Effect of omega‐3 polyunsaturated fatty acids in young people at ultrahigh risk for psychotic disorders: The NEURAPRO randomized clinical trial. JAMA Psychiatry, 74(1), 19–27. 10.1001/jamapsychiatry.2016.2902.
    1. Mechelli, A., Lin, A., Wood, S., McGorry, P., Amminger, P., Tognin, S., McGuire, P., Young, J., Nelson, B., & Yung, A. (2017). Using clinical information to make individualized prognostic predictions in people at ultra high risk for psychosis. Schizophrenia Research, 184, 32–38. 10.1016/j.schres.2016.11.047.
    1. Michel, C., Ruhrmann, S., Schimmelmann, B. G., Klosterkotter, J., & Schultze‐Lutter, F. (2018). Course of clinical high‐risk states for psychosis beyond conversion. European Archives of Psychiatry and Clinical Neuroscience, 268(1), 39–48. 10.1007/s00406-016-0764-8.
    1. Miller, T. J., McGlashan, T. H., Rosen, J. L., Cadenhead, K., Cannon, T., Ventura, J., McFarlane, W., Perkins, D. O., Pearlson, G. D., & Woods, S. W. (2003). Prodromal assessment with the structured interview for prodromal syndromes and the scale of prodromal symptoms: Predictive validity, interrater reliability, and training to reliability. Schizophrenia Bulletin, 29(4), 703–715.
    1. Miller, T. J., Zipursky, R. B., Perkins, D., Addington, J., Woods, S. W., Hawkins, K. A., Hoffman, R., Preda, A., Epstein, I., Addington, D., Lindborg, S., Marquez, E., Tohen, M., Breier, A., & McGlashan, T. H. (2003). The PRIME North America randomized double‐blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis. II. Baseline characteristics of the "prodromal" sample. Schizophrenia Research, 61(1), 19–30.
    1. Moschetti, V., Boland, K., Feifel, U., Hoch, A., Zimdahl‐Gelling, H., & Sand, M. (2016). First‐in‐human study assessing safety, tolerability and pharmacokinetics of BI 409306, a selective phosphodiesterase 9A inhibitor, in healthy males. British Journal of Clinical Pharmacology, 82(5), 1315–1324. 10.1111/bcp.13060.
    1. Moschetti, V., Boland, K., Hoch, A., Timmer, W., Zimdahl‐Gelling, H., Borta, A., & Sand, M. (2015). Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of BI 409306 film‐coated tablets given orally once‐ or twice‐daily for 14 days in young and elderly healthy volunteers. Alzheimer's & Dementia, 11(Suppl), 468–469.
    1. Moschetti, V., Kim, M., Sand, M., Wunderlich, G., Andersen, G., Feifel, U., Jang, I‐J., Timmer, W., Rosenbrock, H., & Boland, K. (2018). The safety, tolerability and pharmacokinetics of BI 409306, a novel and potent PDE9 inhibitor: Overview of three phase I randomised trials in healthy volunteers. European Neuropsychopharmacology, 28(5), 643–655. 10.1016/j.euroneuro.2018.01.003.
    1. National Collaborating Centre for Mental Health . (2014). Psychosis and schizophrenia in adults: The National Institute for Health and Care Excellence (NICE) guideline on treatment and management.
    1. National Institute for Health and Care Excellence (NICE) . (2013). Psychosis and schizophrenia in children and young people: Recognition and management.
    1. National Institute for Health and Care Excellence (NICE) . (2014). Psychosis and schizophrenia in adults: Prevention and management.
    1. Orygen: The National Centre of Excellence in Youth Mental Health . (2016). Australian clinical guidelines for early psychosis.
    1. Perkins, D. O., Jeffries, C. D., Addington, J., Bearden, C. E., Cadenhead, K. S., Cannon, T. D., Cornblatt, B. A., Mathalon, D. H., McGlashan, T. H., Seidman, L. J., Tsuang, M. T., Walker, E. F., Woods, S. W., & Heinssen, R. (2015). Towards a psychosis risk blood diagnostic for persons experiencing high‐risk symptoms: Preliminary results from the NAPLS project. Schizophrenia Bulletin, 41(2), 419–428. 10.1093/schbul/sbu099.
    1. Ruhrmann, S., Schultze‐Lutter, F., Salokangas, R. K., Heinimaa, M., Linszen, D., Dingemans, P., Birchwood, M., Patterson, P., Juckel, G., Heinz, A., Morrison, A., Lewis, S., von Reventlow, H. G., & Klosterkotter, J. (2010). Prediction of psychosis in adolescents and young adults at high risk: Results from the prospective European prediction of psychosis study. Archives of General Psychiatry, 67(3), 241–251. 10.1001/archgenpsychiatry.2009.206.
    1. Salazar de Pablo, G., Catalan, A., & Fusar‐Poli, P. (2019). Clinical validity of DSM‐5 attenuated psychosis syndrome: Advances in diagnosis, prognosis, and treatment. JAMA Psychiatry, 77, 311–320. 10.1001/jamapsychiatry.2019.3561.
    1. Schmidt, F., Gasparoni, N., Gasparoni, G., Gianmoena, K., Cadenas, C., Polansky, J. K., Ebert, P., Nordström, K., Barann, M., Sinha, A., Fröhler, S., Xiong, J., Amirabad, A. D., Ardakani, F. B., Hutter, B., Zipprich, G., Felder, B., Eils, J., & Schulz, M. H. (2017). Combining transcription factor binding affinities with open‐chromatin data for accurate gene expression prediction. Nucleic Acids Research, 45(1), 54–66. 10.1093/nar/gkw1061.
    1. Schmidt, S. J., Schultze‐Lutter, F., Schimmelmann, B. G., Maric, N. P., Salokangas, R. K., Riecher‐Rossler, A., van der Gaag, M., Meneghelli, A., Nordentoft, M., Marshall, M., Morrison, A., Raballo, A., Klosterkötter, K., & Ruhrmann, S. (2015). EPA guidance on the early intervention in clinical high risk states of psychoses. European Psychiatry, 30(3), 388–404. 10.1016/j.eurpsy.2015.01.013.
    1. Schultze‐Lutter, F., Michel, C., Schmidt, S. J., Schimmelmann, B. G., Maric, N. P., Salokangas, R. K. R., Riecher‐Rössler, A., van der Gaag, M., Nordentoft, M., Raballo, A., Meneghelli, A., Marshall, M., Morrison, A., Ruhrmann, S., & Klosterkötter, J. (2015). EPA guidance on the early detection of clinical high risk states of psychoses. European Psychiatry, 30(3), 405–416. 10.1016/j.eurpsy.2015.01.010.
    1. Sekar, A., Bialas, A. R., de Rivera, H., Davis, A., Hammond, T. R., Kamitaki, N., Tooley, K., Presumey, J., Baum, M., Van Doren, V., Genovese, G., Rose, S. A., Handsaker, R. E., Daly, M. J., Carroll, M. C., Stevens, B., McCarroll, S. A., & Schizophrenia Working Group of the Psychiatric Genomics Consortium. (2016). Schizophrenia risk from complex variation of complement component 4. Nature, 530, 177–183. 10.1038/nature16549. Retrieved from .
    1. Stone, J. M., Howes, O. D., Egerton, A., Kambeitz, J., Allen, P., Lythgoe, D. J., O'Gorman, R. L., McLean, M. A., Barker, G. J., & McGuire, P. (2010). Altered relationship between hippocampal glutamate levels and striatal dopamine function in subjects at ultra high risk of psychosis. Biological Psychiatry, 68(7), 599–602. 10.1016/j.biopsych.2010.05.034.
    1. Stoneham, E. T., Sanders, E. M., Sanyal, M., & Dumas, T. C. (2010). Rules of engagement: Factors that regulate activity‐dependent synaptic plasticity during neural network development. The Biological Bulletin, 219(2), 81–99. 10.1086/BBLv219n2p81.
    1. Szkultecka‐Debek, M., Miernik, K., Stelmachowski, J., Jakovljevic, M., Jukic, V., Aadamsoo, K., Janno, S., Bitter, I., Tolna, J., Jarema, M., Jankovic, S., Pecenak, J., Vavrusova, L., Tavčar, R., Walczak, J., Talbot, D., & Augustynska, J. (2016). Schizophrenia causes significant burden to patients' and caregivers' lives. Psychiatria Danubina, 28(2), 104–110.
    1. van Tricht, M. J., Nieman, D. H., Koelman, J. H., van der Meer, J. N., Bour, L. J., de Haan, L., & Linszen, D. H. (2010). Reduced parietal P300 amplitude is associated with an increased risk for a first psychotic episode. Biological Psychiatry, 68(7), 642–648. 10.1016/j.biopsych.2010.04.022.
    1. Walker, E. F., Cornblatt, B. A., Addington, J., Cadenhead, K. S., Cannon, T. D., McGlashan, T. H., Perkins, D. O., Seidman, L. J., Tsuang, M. T., Woods, S. W., & Heinssen, R. (2009). The relation of antipsychotic and antidepressant medication with baseline symptoms and symptom progression: A naturalistic study of the North American Prodrome Longitudinal Sample. Schizophrenia Research, 115(1), 50–57. 10.1016/j.schres.2009.07.023.
    1. Wallace, A., Isenberg, K., Barron, J., York, W., Shinde, M., Sidovar, M., Franchino‐Elder, J., & Sand, M. (2018). S252. Health care resource utilisation is higher in patients prior to diagnosis with schizophrenia than non‐schizophrenia comparators in a large commercially‐insured population in the United States. Schizophrenia Bulletin, 44(Suppl 1), S425–S426. 10.1093/schbul/sby018.1039.
    1. World Medical Association . (2013). Declaration of Helsinki—Ethical principles for medical research involving human subjects.
    1. Wunderlich, G., Timmer, W., Andersen, G., Hoch, A., Moschetii, V., Boland, K., Zimdahl‐Gelling, H., Borta, A., & Sand, M. (2015). Phase I studies evaluating the safety, tolerability, and pharmacokinetics of multiple‐rising doses of BI 409306 in young and elderly healthy volunteers. Journal of Prevention of Alzheimer's Disease, 2(4), 324.
    1. Yuen, H. P., Mackinnon, A., & Nelson, B. (2019). Dynamic prediction of transition to psychosis using joint modelling. Schizophrenia Research, S0920‐9964(19), 30566–30563. 10.1016/j.schres.2019.11.059.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner