Invited commentary On the brink of precision medicine for psychosis: Treating the patient, not the disease A commentary on: Association between serum levels of glutamate and neurotrophic factors and response to clozapine treatment by Krivoj et al. 2017 Arsime Demjaha Department of Psychosis Studies, Biomedical Research Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK article info Article history: Received 8 August 2017 Accepted 9 August 2017 Available online xxxx Keywords: Treatment resistant schizophrenia Precision medicine Clozapine Psychosis Biomarkers With major scientific developments, precision medicine for psychia- try holds the promise for psychosis prevention and accurate prediction of individual treatment response, bringing hope for much needed effec- tive and safe customized treatments. Although, biologically based and highly personalized treatments have already found their way in several medical specialities, precision medicine remains a challenge to psychia- try (DeLisi and Fleischhacker, 2016); in the absence of accurate diagnos- tic tests or precise biological markers, psychiatrists continue to rely on descriptive psychopathology to diagnose patients and devise corre- sponding treatment plans, which are usually based on ‘trial and error’ method (Keshavan et al., 2017). Thus, seven decades on, since the dis- covery of chlorpromazine, and in a midst of considerable attempts at therapeutic advancement, we are where we are: up to one third of pa- tients with schizophrenia still remain resistant to classic dopamine- blocking antipsychotics, and continue to be exposed to unwanted and often disabling side effects of ineffective treatment (Lindenmayer, 2000). Even clozapine, the only antipsychotic that works in treatment resistant patients, is only efficacious in approximately 50% of cases ex- posing them to potentially serious side effects and little clinical benefit (Chakos et al., 2001; Kane et al., 1988; Lieberman et al., 1994). It is thus of the utmost importance that we develop clinical tools that will enable us to predict accurately and early which specific patient may or may not respond to clozapine, and analogously to the dopamine block- ade, so that clozapine in those deemed to be responsive, is commenced Schizophrenia Research xxx (2017) xxx–xxx E-mail address: arsime.demjaha@kcl.ac.uk. SCHRES-07460; No of Pages 2 at the earliest stage of their illness. However, the success of predicting treatment outcomes will depend largely on identification of precise ge- nomic, neuroimaging and peripheral biomarkers of the treatment re- sponse, which requires studies that in the first instance address rigorously the heterogeneity of the disorder (Demjaha et al., 2009), and that of the response to antipsychotic medication. Direct positron emission tomography (PET) and proton magnetic resonance spectroscopy (H-MRS) evidence indicates that treatment re- sistance in schizophrenia may be associated with normal dopamine function and increased glutamate levels in anterior cingulate cortex (ACC) and putamen (Demjaha et al., 2014; Demjaha et al., 2012; Goldstein et al., 2015). These findings suggest that treatment resistant schizophrenia is neurochemically distinct form of schizophrenic illness and that the neuroimaging measures of dopamine and glutamate may provide means of stratifying patients according to their antipsychotic response. In Schizophrenia Research, Krivoj and colleagues (Krivoy et al., 2017) go further by investigating potential biological predictors of clozapine response. They document that serum brain derived neuro- trophic factor (BDNF) and glutamate levels may distinguish between clozapine responders and non-responders, and suggest that higher glu- tamate levels may be associated with subsequent clozapine response. This led them to consider that treatment resistant patients could further be biologically stratified, according to clozapine treatment response, in those with and without glutamatergic abnormality. Their finding that pre-clozapine high glutamate levels determine response to clozapine is unexpected in light of previous reports that showed ACC glutamate levels to be increased in treatment resistant patients, but decreased in treatment responders (Demjaha et al., 2014; Mouchlianitis et al., 2015; Szulc et al., 2011). Based on this evidence, it would be logical to hypothesise that glutamate levels will be reduced or normalized follow- ing clozapine treatment in a responder group. The authors acknowledge that the cross-sectional design limits their interpretations. It could be that clozapine has indeed reduced glutamate levels, but the lack of pre-clozapine values does not permit any assumptions. Akin to reports from dopamine synthesis capacity studies (in Demjaha et al., 2012), it appears that glutamate levels are not completely normalized following clozapine treatment, but this needs to be determined in future work. Overall, both glutamate and BDNF, have been implicated in pathophys- iology of schizophrenia and constitute plausible candidates for bio- markers of treatment response, (Demjaha et al., 2014; Krebs et al., http://dx.doi.org/10.1016/j.schres.2017.08.011 0920-9964/© 2017 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres Please cite this article as: Demjaha, A., , Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.08.011