FULL PAPER 3-T Proton Magnetic Spectroscopy in Unmedicated First Episode Psychosis: A Focus on Creatine Philip G. Tibbo, 1,2 * Denise Bernier, 1 Christopher C. Hanstock, 3 Peter Seres, 3 Bonnie Lakusta, 2 and Scot E. Purdon 2 Different lines of evidence suggest an abnormal cerebral energy metabolism as being critical to the pathophysiology of schizophrenia. However, it is unknown as to whether levels of creatine (Cr) would be involved in these anomalies. The study involved 33 unmedicated first episode psychosis patients and 41 healthy controls. Proton magnetic resonance spectroscopy ( 1 H-MRS) was performed at 3 T using a long TE (TE/TM/TR of 240/27/3000 ms) such that within the total phosphocreatine (PCr) plus Cr signal (tCr 240 ), mainly Cr was detectable. The target region was an 18 cm 3 prefrontal volume. A negative association was found between age of patients and tCr 240 lev- els referenced to internal water, with 20% of the variance in tCr 240 accounted for by Age. A secondary finding revealed 16% reduction of tCr 240 levels in patients, solely when com- paring participants older than the median age of patients. No association existed between tCr 240 levels and clinical varia- bles. These findings support previous data reporting abnor- malities in brain creatine kinase isoenzymes involved with the maintenance of energy pools in schizophrenia. The implica- tions of using a long TE are discussed in terms of the relative proportions of Cr and PCr within the tCr 240 signal, and of potential group differences in T 2 times. Magn Reson Med 000:000–000, 2012. V C 2012 Wiley Periodicals, Inc. Key words: schizophrenia; phosphocreatine; creatine; adenosine triphosphate; internal reference; long time of echo Independent lines of evidence support the hypothesis that in schizophrenia there is an abnormal cerebral energy metabolism, which might be critical to the patho- physiology of this illness. Empirical data are provided by phosphorus magnetic resonance spectroscopy studies (1) reporting abnormal concentration levels of phospho- creatine (PCr) in unmedicated patients with schizophre- nia in the regions of the frontal lobes (2) and basal gan- glia (3,4), with the latter region normalizing over time after successful treatment (5). Evidence also comes from proton magnetic resonance spectroscopy ( 1 H-MRS) stud- ies reporting abnormal levels of tCr, the combined signal from PCr plus creatine (Cr), in frontal (6–8) and hippo- campal regions (9,10) of medicated patients with estab- lished schizophrenia (for the most part of the samples). One other line of evidence is provided by positron emis- sion tomography studies: decreased perfusion (an index of tissue metabolic activity) was found relative to a nor- mative sample, in the regions of medial frontal and basal ganglia, with a sample size of 70 patients medication- free for at least 4 weeks (11), as well as in the prefrontal region of neuroleptic-naive early schizophrenia patients (12). In vivo 1 H-MRS can detect signals from two guani- dino compounds that play an important role in energy homeostasis in the brain: PCr and Cr, both together yielding an overall tCr peak observed at 3.03 ppm from their methyl protons; other peaks from their methylene protons can also be observed at 3.91 ppm for Cr and 3.93 ppm for PCr (13). Creatine is transported through the blood into tissues with high energy demands by the specific creatine transporter CrT. Creatine kinase (CK) isoenzymes in the tissue then produce PCr from adeno- sine triphosphate (ATP) and Cr, in the following equi- librium reaction: PCr þ ADP (adenosine diphosphate) þ H þ <¼> Cr þ ATP (adenosine triphosphate) (14). ATP plays a critical role in the brain as an energy source and also during energy transfer within the cells; to meet high and fluctuating demands of metabolic activity in the brain, ATP is continuously regenerated from the large cellular pools of PCr via the action of the CK iso- enzymes (15,16). In schizophrenia, there is evidence that these molecu- lar conversions that occur via the action of the CK isoen- zymes (for both the breakdown and synthesis of ATP) might be markedly compromised. Important reductions (independent of age) exist in the activity of the CK isoen- zymes in brain tissue of patients relative to a normative sample, in several brain regions. In the anterior cingulate cortex, the activity of isoenzymes is lower by a factor of 2.8; in the cerebellum, this factor is 5.5 (17). One could, therefore, hypothesize that previous findings in schizo- phrenia of abnormal regional levels of tCr (6–8) and of PCr (2–4) would be linked to an altered Cr:PCr equilib- rium which involved the CK isoenzymes. Impairments in the efficiency of these molecular conversions in schiz- ophrenia would detrimentally impact on ATP levels available for brain function, which could in part explain (18) the reports of lower perfusion in these brain regions in patients with schizophrenia (11,12). The two contributing components of the 1 H-MRS tCr signal have different T 2 relaxations times, PCr having a markedly shorter T 2 time than Cr (19). When the signal 1 Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada. 2 Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada. 3 Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada. Grant sponsors: Alberta Heritage Foundation for Medical Research, Canadian Institutes of Health Research Neurosciences Mental Health and Addiction Institute. *Correspondence to: Philip G. Tibbo, M.D., Nova Scotia Early Psychosis Program, 5909 Veterans’ Memorial Lane, Abbie J. Lane Building, Room 3030, Halifax, Nova Scotia, Canada, B3H 2E2. E-mail: phil.tibbo@cdha. nshealth.ca Received 21 December 2011; accepted 22 March 2012. DOI 10.1002/mrm.24291 Published online in Wiley Online Library (wileyonlinelibrary.com). Magnetic Resonance in Medicine 000:000–000 (2012) V C 2012 Wiley Periodicals, Inc. 1