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Original Article |

Prediction of Functional Outcome 18 Months After a First Psychotic Episode:  A Proton Magnetic Resonance Spectroscopy Study FREE

Stephen J. Wood, PhD; Gregor E. Berger, MD; Martin Lambert, MD; Phillipe Conus, MD; Dennis Velakoulis, FRANZCP; Geoffrey W. Stuart, PhD; Patricia Desmond, MD; Patrick D. McGorry, PhD; Christos Pantelis, MD
[+] Author Affiliations

Author Affiliations: Melbourne Neuropsychiatry Centre, University of Melbourne (Drs Wood, Velakoulis, Stuart, and Pantelis); Brain Research Institute (Dr Wood); ORYGEN Research Centre (incorporating the Early Psychosis Prevention and Intervention Centre) (Drs Berger, Lambert, Conus, and McGorry); and Department of Radiology, Royal Melbourne Hospital (Dr Desmond), Melbourne, Australia.


Arch Gen Psychiatry. 2006;63(9):969-976. doi:10.1001/archpsyc.63.9.969.
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Context  Recent magnetic resonance imaging studies have attempted to relate volumetric brain measurements in early schizophrenia to clinical and functional outcome some years later. These studies have generally been negative, perhaps because gray and white matter volumes inaccurately assess the underlying dysfunction that might be predictive of outcome.

Objective  To investigate the predictive value of frontal and temporal spectroscopy measures for outcome in patients with first-episode psychoses.

Design  Left prefrontal cortex and left mediotemporal lobe voxels were assessed using proton magnetic resonance spectroscopy to provide the ratio of N-acetylaspartate (NAA) and choline-containing compounds to creatine and phosphocreatine (Cr) (NAA/Cr ratio). These data were used to predict outcome at 18 months after admission, as assessed by a systematic medical record audit.

Setting  Early psychosis clinic.

Participants  Forty-six patients with first-episode psychosis.

Main Outcome Measures  We used regression models that included age at imaging and duration of untreated psychosis to predict outcome scores on the Global Assessment of Functioning Scale, Clinical Global Impression scales, and Social and Occupational Functional Assessment Scale, as well as the number of admissions during the treatment period. We then further considered the contributions of premorbid function and baseline level of negative symptoms.

Results  The only spectroscopic predictor of outcome was the NAA/Cr ratio in the prefrontal cortex. Low scores on this variable were related to poorer outcome on all measures. In addition, the frontal NAA/Cr ratio explained 17% to 30% of the variance in outcome.

Conclusions  Prefrontal neuronal dysfunction is an inconsistent feature of early psychosis; rather, it is an early marker of poor prognosis across the first years of illness. The extent to which this can be used to guide treatment and whether it predicts outcome some years after first presentation are questions for further research.

Figures in this Article

Psychotic disorders often begin in adolescence or early adulthood and can cause significant and chronic cognitive and psychosocial impairment. The illness course is variable, with as many patients tending to improve in the long term as those who show further deterioration.14 There are many predictors of outcome in schizophrenia, which include age, sex, family history of schizophrenia, early treatment response,5 subjective treatment response,6 recovery style,7 severity of symptoms, negative symptoms, cognitive performance,8 shorter rapid eye movement latency,9 structural brain abnormalities, neurological soft signs, tardive dyskinesia, adverse life events, premorbid vocational functioning, premorbid social withdrawal, and duration of untreated psychosis (DUP).1018 However, most of these associations were established retrospectively and in populations with chronic schizophrenia, which has made outcome prediction from the first psychotic episode difficult, although such a tool would be useful in determining treatment options.

It is well accepted that patients with schizophrenia have abnormal brain morphologic structure, which is already present at the time of the first psychotic episode, particularly in cortical areas.19,20 However, it is unclear when these structural brain changes emerge, and few studies have attempted to relate them to future clinical outcome. Most investigators have used computed tomography,21 with some reporting an inverse correlation between the ventricle-brain ratio and outcome,22,23 and not others.24 Some investigations were retrospective in nature or were restricted to particular subgroups of patients (eg, inpatients); therefore, it is unclear whether these relationships are the result of selection bias.

Some studies (mainly using magnetic resonance imaging) have attempted to examine the prediction of outcome in a prospective design. One study, by Milev et al,25 investigated 123 patients with a DSM-IV diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder and attempted to predict outcome during 5 years (measured as psychosocial function, time spent as an inpatient, and duration of clinically significant symptoms) using 7 volumetric measures obtained at baseline (frontal and temporal tissue, frontal and temporal cerebrospinal fluid, cerebral and cerebellar tissue, and ventricular cerebrospinal fluid). Only temporal lobe tissue volume significantly predicted outcome, with smaller temporal volume at baseline predicting greater persistence of psychotic symptoms. However, this only explained 5.8% of the variance in persistence of hallucinations, indicating that its prognostic value was low. An additional investigation was a multicenter European study26 of 109 patients with recent-onset schizophrenia followed up 2 years later. Outcome (measured in terms of need for care and social functioning) was predicted using 7 baseline volumetric measures (intracranium, total brain, cerebral gray and white matter, lateral and third ventricles, and cerebellum), but no significant relationship was found.

Assessment of outcome in both studies,25,26 was methodologically good and included a structured interview with the patient at follow-up. This implies that the failure of these studies to find clinically significant relationships between baseline structural imaging data and outcome at least 2 years later is either because there is no such relationship to find or because of the relative insensitivity of volumetric methods to the functional integrity of the brain. An imaging tool that might have better predictive power for outcome in psychotic disorders is magnetic resonance spectroscopy (MRS). This technique assesses the concentration of various brain metabolites in vivo and as such is able to give more detailed information about the integrity of the region of interest at the cellular and metabolic levels compared with the relatively gross volumetric estimates. This is especially true for a disorder such as schizophrenia, in which the cellular abnormalities remain unclear.27 However, to date there have been no studies using this technique to predict outcome from a first psychotic episode, to our knowledge.

One metabolite that has been of particular interest in schizophrenia is N-acetylaspartate (NAA), which has long been considered a marker of neuronal integrity.28 Although it is agreed that NAA is present both intraneuronally and extraneuronally (eg, as demonstrated by Bhakoo and Pearce29), it is reduced in conditions in which there is persistent or reversible neuronal loss.30 In schizophrenia, reduction in NAA level is most consistently found in the prefrontal cortex of patients with established illness,31 where it is associated with poorer cognition,32 longer duration of illness,33 and greater levels of negative symptoms.34 These findings suggest that the level of prefrontal NAA may be associated with poor outcome, but it is unknown if this relationship is present at first onset or if it develops during the disorder. There have been some investigations indicating prefrontal reductions in NAA in schizophreniform disorder,35 but others have not shown this.36

In this study, we aimed to explore the predictive value of baseline measures that included symptoms and NAA/creatine (Cr) ratios in the left hippocampus and prefrontal cortex for 18-month clinical and functional outcome from the earliest phase of a first episode of psychosis.

PARTICIPANTS

Forty-six patients with first-episode psychosis (63% male) were recruited from the Early Psychosis Prevention and Intervention Centre (part of ORYGEN Research Centre), Melbourne.37 Study inclusion criteria were (1) age at onset of 15 to 29 years (inclusive) and (2) currently psychotic as reflected by the presence of at least 1 of the following 4 symptoms: (a) delusions, (b) hallucinations, (c) disorder of thinking or speech other than simple acceleration or retardation, and (d) disorganized, bizarre, or markedly inappropriate behavior. The DMS-IV diagnoses were derived from a retrospective medical record audit (described in the “Outcome Data” subsection). The mean ± SD age of the group was 21.6 ± 3.2 years, with a median DUP of 46 days (range, 0-3317 days). Diagnoses included schizophrenia (n = 18), schizophreniform psychosis (n = 6), schizoaffective disorder (n = 7), bipolar disorder with psychotic symptoms (n = 9), major depression with psychotic symptoms (n = 2), delusional disorder (n = 1), and psychosis not otherwise specified (n = 3). All patients were being treated with atypical antipsychotic medication at the time of imaging (mainly 2-4 mg of risperidone or 5-10 mg of olanzapine). Six of the patients were also treated with lithium carbonate (500-1500 mg/d).

All subjects were screened for comorbid medical and psychiatric conditions by clinical assessment and by physical and neurological examinations. Exclusion criteria were seizures, polydipsia, neurological diseases, impaired thyroid function, corticosteroid use, a history of significant head injury, electroconvulsive therapy during the 6 months before imaging, or a DSM-IV diagnosis of alcohol or other substance dependence. The North Western Health Care Network/University of Melbourne research and ethics committees approved the research protocol, and all subjects provided written informed consent.

PROSPECTIVE DATA
Psychopathology

Levels of psychopathology were assessed at the time of imaging using the Positive and Negative Syndrome Scale38 in all but 4 patients. Rather than using the total or subscale scores, we used a 5-factor model (negative syndrome, delusions and hallucinations, cognitive disturbance, antisocial tendency, and affective syndrome) that best approximates the underlying structure of the instrument, similar to the model described by White et al.39 In particular, we used a summary score composed of emotional withdrawal, blunted affect, lack of spontaneity, passive/apathetic social withdrawal, poor rapport, motor retardation, and active social avoidance to represent the negative syndrome.40

Magnetic Resonance Spectroscopy

Proton spectra were acquired from all subjects using a 1.5-T scanner (GE Medical Systems, Milwaukee, Wis) at the Royal Melbourne Hospital, Melbourne, Australia. Two volumes of interest (dimensions, 15 × 15 × 15 mm) were obtained from the left hemisphere in each patient, one in the mediotemporal lobe and one in the middle frontal gyrus. These were localized on the T1-weighted coronal images obtained for volumetric purposes; the midpoint of the mediotemporal voxel was positioned 4.5 mm posterior to the amygdala, and the midpoint of the middle frontal voxel was positioned 7.5 mm anterior to the genu of the corpus callosum (Figure 1). The mediotemporal voxel was positioned so that the hippocampus touched the bottom and the left-hand side of the box, and the middle frontal voxel was placed as far laterally as possible without including the skull in the region of interest. Shimming was performed by an automated global shim, and water-suppressed spectra were acquired using a point-resolved spectroscopy sequence (repetition time, 1500 milliseconds; echo time, 135 milliseconds; and number of signals acquired, 128). Spectra were analyzed using the LCModel method,41 and data are reported as the ratio of the NAA (2.01 ppm) and choline-containing compounds (3.20 ppm) peaks to the Cr peak (3.02 ppm). The output from LCModel includes the Cramer-Rao lower bounds, which are a measure of reliability. For the hippocampal region, the mean Cramer-Rao lower bounds for each metabolite were as follows: Cr, 11.2; NAA, 8.0; and choline-containing compounds, 9.1. For the frontal region, the same metabolites had mean Cramer-Rao lower bounds as follows: Cr, 10.8; NAA, 5.7; and choline-containing compounds, 9.9. Sample spectra for both regions of interest are shown in Figure 2.

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Figure 1.

Magnetic resonance images showing the location of the midpoint of the mediotemporal voxel (A) and the dorsolateral prefrontal voxel (B). The images are presented in radiological format, with the left hemisphere on the right.

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Figure 2.

Sample spectra and LCModel41 fits (heavy line) from the mediotemporal voxel (A) and the dorsolateral prefrontal voxel (B).

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OUTCOME DATA

Outcome data were derived from the First Episode Psychosis Outcome Study,42 a systematic medical record audit of all patients consecutively accepted and subsequently treated at the Early Psychosis Prevention and Intervention Centre between January 1998 and December 2000. Treatment included a standardized initial psychiatric assessment (including psychiatric history and a detailed mental state examination), outpatient case management, cognitive behavioral therapy, low-dose antipsychotic therapy, an inpatient unit for acute care during crisis admissions, a mobile crisis intervention and community treatment team, acute and recovery group programs, family work, and specialized consultations to treat enduring positive psychotic symptoms, if necessary, for an episode of care of 18 months. Details of the medical record review methods, including comprehensive quality assurance strategies, are fully described elsewhere.42

Demographic and illness-related details were assessed using the Early Psychosis File Questionnaire, a comprehensive instrument that consists of questions from the Royal Park Multidiagnostic Instrument for Psychosis,43,44 the Drug and Alcohol Assessment Schedule,43,44 the DUP Scale,45 a modified version of the Brief Psychiatric Rating Scale,46 the Clinical Global Impression (CGI)–Schizophrenia Scale,47,48 the CGI–Bipolar Illness Scale,49 the Global Assessment of Functioning (GAF) Scale,45 the Social and Occupational Functional Assessment Scale (SOFAS),45 the Premorbid Adjustment Scale,50 the Vocation and Location Index,51 a modified version of the Udvalg for Kliniske Undersogelser Adverse Effect Scale,52 and measures of level of engagement (score range, 1-5), compliance (on a 4-point scale ranging from 0 [total noncompliance] to 3 [full compliance] with antipsychotic treatment), current drug use (type of substance and modification of use), and traumatic life events. The North Western Health Care Network/University of Melbourne approved the study.

Interrater reliability was established for all primary and secondary outcome scales used in the study by randomly selecting 40 medical records stratified by time. Each of these medical records was assessed independently by the 2 main investigators (M.L. and P.C.), who gave ratings related to the situation at enrollment in the Early Psychosis Prevention and Intervention Centre on the following scales: CGI–Schizophrenia, CGI–Bipolar Illness, GAF, SOFAS, Premorbid Adjustment, and Insight. Analysis revealed good to very good interrater reliability, with κ values ranging from 0.82 to 0.92 (CGI–Schizophrenia, 0.87; CGI–Bipolar Illness mania severity, 0.89; CGI–Bipolar Illness depression severity, 0.87; GAF, 0.88; SOFAS, 0.92; Premorbid Adjustment, 0.82; and Insight, 0.89).

Concurrent validity was examined by assessing the correlation between CGI–Schizophrenia, GAF, and SOFAS scores at baseline and at discharge or loss to follow up. Correlation coefficients between those scales were high (>0.78), and scores on the scales were all significantly correlated with one another (P<.001).

Validity of the diagnosis was also examined. Between 1998 and 2000, 230 patients at the Early Psychosis Prevention and Intervention Centre were included in prospective trials and were assessed using a Structured Clinical Interview for DSM-IV Axis I disorders for psychotic and comorbid diagnoses soon after entry to the service (weeks 2-4). In 115 medical records randomly selected from the 230 medical records, the assessed diagnoses were compared with those given in the First Episode Psychosis Outcome Study.42 The κ values revealed good concordance for psychosis diagnoses (κ=0.795) and for comorbid substance abuse diagnoses (κ=0.736).

In this study, outcome data included GAF, SOFAS, and CGI scores at discharge, and the number of inpatient admissions during the 18-month treatment period. The number of inpatient admissions was selected (rather than a measure such as the number of days hospitalized during the treatment period) because it represented a measure of successive psychotic exacerbations.

STATISTICAL ANALYSIS

The statistical analyses were conducted in similar fashion to those of Milev et al.25 We first tested if there was an effect of each regional metabolite ratio on the outcome variables as a whole (discharge GAF, CGI, and SOFAS scores, and the number of acute admissions). For each of the 4 metabolite ratios, we performed a joint omnibus multivariate regression test, which assessed the effect of the metabolite ratio on all 4 outcome variables simultaneously. For ratios in which this test was significant at P = .05, follow-up analyses were performed with each outcome variable independently. Duration of untreated psychosis and age at the time of MRS imaging were entered as covariates in all analyses (it was previously shown that there is no effect of DUP on spectroscopy variables in this cohort36). Within the regression-based analysis, we introduced model terms that represented the interaction between diagnostic group and regional metabolite ratios.53 In effect, this amounted to fitting separate regression lines (between metabolite ratio and outcome) for each diagnostic group and then testing whether the slopes of those regression lines were the same.

Outcome variables for the sample at discharge are summarized in Table 1, along with the same variables at intake. There were no significant sex or diagnostic (schizophrenia spectrum vs nonschizophrenia spectrum) differences for any of the 4 outcome measures or on covariates such as age at MRS, CGI scores at intake, GAF scores at intake, or any of the 5 symptom scale scores. However, DUP significantly differed between the diagnostic groups (Mann-Whitney test, 144.5; P = .04), with the nonschizophrenia spectrum group having a median DUP of 30 days compared with 61 days in the schizophrenia spectrum group.

Table Graphic Jump LocationTable 1. Outcome Measures at Intake and Discharge, Negative Syndrome at Intake, and Premorbid Global Assessment of Functioning Scale (GAF) Score

Left mediotemporal MRS data were available from all but 1 patient, whose data were unusable (because of poor shim, broad line widths, and a signal-noise ratio of 1), and left prefrontal MRS data were available from all but 5 patients (unusable in 1 patient [failed water suppression] and not performed in 4 patients). The 6 patients for whom complete MRS data were unavailable were significantly older than the remaining 40 patients (24.1 vs 21.3 years; t44 = −2.1, P = .04) and had significantly higher scores on the antisocial tendency syndrome (14.3 vs 10.3; t40 = −2.6, P = .01). However, they were not receiving significantly higher doses of antipsychotic medication.

Four joint omnibus tests for effects of each metabolite ratio in each region of interest on all 4 outcome measures were performed. Duration of untreated psychosis and age at MRS were included in the analyses. Of all spectroscopy measures, only the NAA/Cr ratio in the left frontal region of interest was significantly related to outcome (F4,34 = 4.30, P = .006; P>.2 for all other measures). Each outcome measure was then individually tested using the left frontal NAA/Cr ratio. There were statistically significant effects of the NAA/Cr ratio on CGI scores at discharge (F1,40 = 5.67, P = .02), GAF scores at discharge (F1,40 = 7.94, P = .008), SOFAS scores at discharge (F1,40 = 13.27, P = .001), and the number of admissions during the treatment period (F1,40 = 10.73, P = .002). Figure 3 shows the relationship between the frontal NAA/Cr ratio and the GAF score at discharge.

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Figure 3.

Scattergraph of the relationship between the frontal N-acetylaspartate–creatine and phosphocreatine (NAA/Cr) ratio and the Global Assessment of Functioning (GAF) Scale score at discharge.

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Because negative symptoms at baseline assessment and premorbid functioning (assessed by GAF score) have previously been related to outcome in studies5456 of schizophrenia, both factors were entered as additional covariates in the omnibus regression test. Table 1 gives the mean values for both of these variables. The frontal NAA/Cr ratio continued to have a significant effect on GAF scores at discharge (F1,36 = 5.99, P = .02), SOFAS scores at discharge (F1,36 = 8.97, P = .005), and the number of admissions (F1,36 = 5.11, P = .03). The frontal NAA/Cr ratio no longer significantly predicted CGI scores at discharge, but this effect was still a trend (F1,36 = 3.21, P = .08). Together, the 5 predictive factors (frontal NAA/Cr ratio, baseline negative symptoms, premorbid GAF score, age at imaging, and DUP) explained more than 60% of the variance in GAF scores at discharge, 63% of the variance in SOFAS scores at discharge, 38% of the variance in CGI scores at discharge, and 54% of the variance in the number of admissions, with the frontal NAA/Cr ratio alone explaining 17%, 17%, 24%, and 30%, respectively (Table 2).

Table Graphic Jump LocationTable 2. Regression Variables for the Prediction of the Outcome Measures

There were no diagnostic subgroup (schizophrenia spectrum vs nonschizophrenia spectrum) effects in the relationships between the frontal NAA/Cr ratio and outcome variables (P>.75 for all). Adding the remaining 4 symptom factors from the Positive and Negative Syndrome Scale (cognitive disturbance, delusions and hallucinations, affective syndrome, and antisocial tendency) did not alter our findings, and none of these factors significantly predicted any outcome variable. Furthermore, the results were unchanged when the 6 patients treated with lithium were excluded from the analyses.

To our knowledge, this is the first study to use proton MRS data, acquired early in the first episode of a psychotic illness, to predict functional outcome after 18 months of optimal treatment. We demonstrated that the NAA/Cr ratio in the left prefrontal cortex is related to clinical severity and to global function at the end of the treatment phase and is predictive of the number of acute inpatient admissions during the same period. These findings are independent of baseline levels of negative symptoms, age, and DUP, suggesting a primary role of prefrontal neuronal dysfunction in patients with poor outcome.

These data suggest that a lower frontal NAA/Cr ratio (presumably a result of lower NAA) may be a marker of an intermediate phenotype of patients with first-episode psychosis with poor response to optimal treatment. This may explain the more consistent MRS findings in chronic illness and the considerable variability in studies of first-episode patients.31,36 In the absence of differences when compared with controls, there is an association between greater prefrontal NAA reductions and greater symptom severity (and poorer social functioning) in deficit schizophrenia.57 A similar result was obtained in inpatients.34 Both studies34,57 and the present findings implicate prefrontal neuronal or synaptic dysfunction as a potential component of poor outcome. The results of our study further suggest that this association can be identified early on with the emergence of frank psychotic symptoms. Therefore, patients included in most imaging studies of chronic schizophrenia may have more severe illness and poorer prognosis, characterized by prominent negative symptoms and neuropsychological deficits implicating frontal systems (eg, as demonstrated by Pantelis et al58). It is likely that such patients at onset of illness showed more prominent negative symptoms and had compromised frontal lobe integrity. One study has suggested a decline in the frontal NAA/Cr ratio with continued illness on the basis of cross-sectional data from a few patients.59 However, close examination of those data reveals that the patient with chronic schizophrenia did not have NAA/Cr ratios that fell below the range of the recent-onset group; instead, they were equal to the bottom 30% to 40%, suggesting that poor outcome is associated with lower NAA/Cr ratios early in the course of illness. Previous work from our group identified poorer prefrontal cortical function in prodromal patients who later become psychotic, suggesting that poor outcome and poor prefrontal cortex integrity are linked before frank psychosis.60,61

The lack of association between mediotemporal metabolite ratios and outcome may reflect a lesser degree of impairment in this region early in the course of illness. Although mediotemporal lobe structures, including the hippocampus, have been reported as being reduced in volume from illness onset,62,63 recent work among our large cohort suggests that such abnormalities are not found at the earliest phases of the illness.64,65 Instead, mediotemporal lobe abnormalities may arise over time with continued illness.

It is unclear what a lower NAA/Cr ratio is signaling in terms of underlying neuronal function. The rate of NAA production seems to be tightly coupled to the rate of glucose metabolism,66 which has led to the suggestion that it may be an osmolyte that prevents the buildup of intraneuronal water.67 Therefore, a possibility is that a lower NAA/Cr ratio is a proxy for reduced resting metabolism.36 An alternative hypothesis might be based on the presumed role of NAA in myelin synthesis,68 implicating a failure of normal white matter maturation associated with poor prognosis.69 In addition, there may be alterations in the chemical environment of the brains of patients with schizophrenia, changing the T2-weighted relaxation time of NAA and further complicating the interpretation of the findings.70,71

Awareness of an association between lower NAA/Cr ratios soon after onset of frank psychotic symptoms and poor clinical and functional outcome after 18 months may allow a more tailored treatment of patients with early psychosis. By combining frontal NAA/Cr ratios with negative symptoms, premorbid functioning, DUP, and age at presentation, as much as half of the variance in outcome could be explained. This could lead to more aggressive management of patients with early psychosis on the basis of these measurements, such as more intensive case management, additional neuroprotective treatments, and early prescription of newer atypical neuroleptic drugs. The newer atypical neuroleptic drugs have proven efficacy in targeting negative symptoms and functional outcome7274 and may have positive effects on neuropsychological function and brain imaging parameters.75,76 Future research is required to establish which of these therapeutic strategies has the most effect on functional outcome in this patient group.

The findings of this study are limited by several factors. First, the MRS voxel was fairly large, and we did not control for the gray matter–white matter ratio. Because the concentration of NAA differs between gray and white matter, it is possible that tissue atrophy in the prefrontal voxel might lead to lower NAA/Cr ratios, although to date frontal atrophy has not been shown to predict clinical outcome in early psychosis, to our knowledge. Second, the NAA/Cr ratio may be merely a proxy for clinical symptoms at baseline. However, adding baseline symptom levels maintained the significant effect of the NAA/Cr ratio, suggesting that the degree of shared variance is small. Third, because we used a ratio rather than an absolute quantification of metabolites, a poor outcome might be associated with an increased Cr peak rather than lower NAA. However, this would likely reflect a hypermetabolic state,77 which is an uncommon finding in schizophrenia research. Fourth, because the outcome data were obtained by medical record audit, the measures obtained using the GAF Scale and SOFAS are global and do not capture the many dimensions of functioning. However, the use of more detailed scales would have been inappropriate in the context of a medical record audit. Fifth, all the analyses assume a linear relationship between outcome and the predictive variables, which may not be the case for DUP.18 Sixth, given recent reports of progressive brain change in the disorder,64,78,79 the relationship we identified may have an association with the degree of change. Within-subject longitudinal studies are needed to adequately address this issue.

In summary, we have shown that prefrontal neuronal and synaptic integrity early in a first psychotic episode, as assessed by the NAA/Cr ratio, is predictive of functional outcome 18 months later. This has a high degree of relevance to our understanding of the variability in outcome from first-episode psychosis, suggesting that impaired prefrontal function is associated with poor prognosis. It also opens the way for possible clinical applications of in vivo brain MRS in the treatment of psychotic disorders.

Correspondence: Stephen J. Wood, PhD, Melbourne Neuropsychiatry Centre, University of Melbourne, c/o National Neuroscience Facility, 161 Barry St, Carlton 3053, Victoria, Australia (sjwood@unimelb.edu.au).

Submitted for Publication: May 9, 2005; final revision received December 20, 2005; accepted January 20, 2006.

Author Contributions: Dr Wood takes responsibility for the integrity of the data and the accuracy of the data analysis for this study. All authors had full access to all the data in the study.

Funding/Support: This study was supported by project grant 981112 from the National Health and Medical Research Council. Dr Wood is supported by a Clinical Career Development Award from the National Health and Medical Research Council and is the recipient of a National Alliance for Research on Schizophrenia and Depression Young Investigator Award.

Previous Presentation: This study was presented in part at the 12th Scientific Meeting and Exhibition of the International Society for Magnetic Resonance in Medicine; May 17, 2004; Kyoto, Japan.

Acknowledgment: We thank Sue Cotton, PhD, for assistance with data verification.

Carpenter  WT  JrStrauss  JS The prediction of outcome in schizophrenia, IV: eleven-year follow-up of the Washington IPSS cohort. J Nerv Ment Dis 1991;179517- 525
PubMed Link to Article
Thara  RHenrietta  MJoseph  ARajkumar  SEaton  WW Ten-year course of schizophrenia: the Madras longitudinal study. Acta Psychiatr Scand 1994;90329- 336
PubMed Link to Article
Harrison  GHopper  KCraig  TLaska  ESiegel  CWanderling  JDube  KCGanev  KGiel  Ran der Heiden  WHolmberg  SKJanca  ALee  PWLeon  CAMalhotra  SMarsella  AJNakane  YSartorius  NShen  YSkoda  CThara  RTsirkin  SJVarma  VKWalsh  DWiersma  D Recovery from psychotic illness: a 15- and 25-year international follow-up study. Br J Psychiatry 2001;178506- 517
PubMed Link to Article
Henry  LPHarris  MGSchwartz  OS  et al.  The 8 year functional and symptomatic outcome of first episode psychosis (FEP) [abstract]. Schizophr Bull 2005;31224
May  PRVan Putten  TYale  C Predicting outcome of antipsychotic drug treatment from early response. Am J Psychiatry 1980;1371088- 1089
PubMed
Van Putten  TMay  PR Subjective response as a predictor of outcome in pharmacotherapy: the consumer has a point. Arch Gen Psychiatry 1978;35477- 480
PubMed Link to Article
Thompson  KNMcGorry  PDHarrigan  SM Recovery style and outcome in first-episode psychosis. Schizophr Res 2003;6231- 36
PubMed Link to Article
Verdoux  HLiraud  FAssens  FAbalan  Fvan Os  J Social and clinical consequences of cognitive deficits in early psychosis: a two-year follow-up study of first-admitted patients. Schizophr Res 2002;56149- 159
PubMed Link to Article
Goldman  MTandon  RDeQuardo  JRTaylor  SFGoodson  JMcGrath  M Biological predictors of 1-year outcome in schizophrenia in males and females. Schizophr Res 1996;2165- 73
PubMed Link to Article
Beiser  MBean  GErickson  DZhang  JIacono  WGRector  NA Biological and psychosocial predictors of job performance following a first episode of psychosis. Am J Psychiatry 1994;151857- 863
PubMed
Johnstone  ECMacmillan  JFFrith  CDBenn  DKCrow  TJ Further investigation of the predictors of outcome following first schizophrenic episodes. Br J Psychiatry 1990;157182- 189
PubMed Link to Article
Robinson  DWoerner  MGAlvir  JMBilder  RGoldman  RGeisler  SKoreen  ASheitman  BChakos  MMayerhoff  DLieberman  JA Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry 1999;56241- 247
PubMed Link to Article
Lieberman  JAPhillips  MGu  HStroup  SZhang  PKong  LJi  ZKoch  GHamer  RM Atypical and conventional antipsychotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. Neuropsychopharmacology 2003;28995- 1003
PubMed
Malla  AKNorman  RMManchanda  RAhmed  MRScholten  DHarricharan  RCortese  LTakhar  J One year outcome in first episode psychosis: influence of DUP and other predictors. Schizophr Res 2002;54231- 242
PubMed Link to Article
Murray  RMvan Os  J Predictors of outcome in schizophrenia. J Clin Psychopharmacol 1998;18 ((suppl 1)) 2S- 4S
PubMed Link to Article
Altamura  ACBassetti  RSassella  FSalvadori  DMundo  E Duration of untreated psychosis as a predictor of outcome in first-episode schizophrenia: a retrospective study. Schizophr Res 2001;5229- 36
PubMed Link to Article
Larsen  TKMoe  LCVibe-Hansen  LJohannessen  JO Premorbid functioning versus duration of untreated psychosis in 1 year outcome in first-episode psychosis. Schizophr Res 2000;451- 9
PubMed Link to Article
Harrigan  SMMcGorry  PDKrstev  H Does treatment delay in first-episode psychosis really matter? Psychol Med 2003;3397- 110
PubMed Link to Article
Shenton  MEDickey  CCFrumin  MMcCarley  RW A review of MRI findings in schizophrenia. Schizophr Res 2001;491- 52
PubMed Link to Article
Wright  ICRabe-Hesketh  SWoodruff  PWRDavid  ASMurray  RMBullmore  ET Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000;15716- 25
Staal  WGHulshoff Pol  HEKahn  RS Outcome of schizophrenia in relation to brain abnormalities. Schizophr Bull 1999;25337- 348
PubMed Link to Article
Tandon  RDeQuardo  JRTaylor  SFMcGrath  MJibson  MEiser  AGoldman  M Phasic and enduring negative symptoms in schizophrenia: biological markers and relationship to outcome. Schizophr Res 2000;45191- 201
PubMed Link to Article
Williams  AOReveley  MAKolakowska  TArdern  MMandelbrote  BM Schizophrenia with good and poor outcome, II: cerebral ventricular size and its clinical significance. Br J Psychiatry 1985;146239- 246
PubMed Link to Article
Wilms  Gvan Ongeval  CBaert  ALClaus  ABollen  Jde Cuyper  HEneman  MMalfroid  MPeuskens  JHeylen  S Ventricular enlargement, clinical correlates and treatment outcome in chronic schizophrenic inpatients. Acta Psychiatr Scand 1992;85306- 312
PubMed Link to Article
Milev  PHo  BCArndt  SNopoulos  PAndreasen  NC Initial magnetic resonance imaging volumetric brain measurements and outcome in schizophrenia: a prospective longitudinal study with 5-year follow-up. Biol Psychiatry 2003;54608- 615
PubMed Link to Article
van Haren  NEMCahn  WHulshoff Pol  HESchnack  HGCaspers  ELemstra  ASitskoorn  MMWiersma  Dvan den Bosch  RJDingemans  PMSchene  AHKahn  RS Brain volumes as predictor of outcome in recent-onset schizophrenia: a multi-center MRI study. Schizophr Res 2003;6441- 52
PubMed Link to Article
Harrison  PJ The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999;122(pt 4)593- 624Review
PubMed Link to Article
Urenjak  JWilliams  SRGadian  DGNoble  M Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 1993;13981- 989
Bhakoo  KKPearce  D In vitro expression of N-acetyl aspartate by oligodendrocytes: implications for proton magnetic resonance spectroscopy signal in vivo. J Neurochem 2000;74254- 262
PubMed Link to Article
Birken  DLOldendorf  WH N-acetyl-l-aspartic acid: a literature review of a compound prominent in 1H-NMR spectroscopic studies of the brain. Neurosci Biobehav Rev 1989;1323- 31
Link to Article
Keshavan  MSStanley  JAPettegrew  JW Magnetic resonance spectroscopy in schizophrenia: methodological issues and findings: part II. Biol Psychiatry 2000;48369- 380
Link to Article
Bertolino  AEsposito  GCallicott  JHMattay  VSvan Horn  JDFrank  JABerman  KFWeinberger  D Specific relationship between prefrontal neuronal N-acetylaspartate and activation of the working memory cortical network in schizophrenia. Am J Psychiatry 2000;15726- 33
Stanley  JAWilliamson  PCDrost  DRylett  RJCarr  TJMalla  AThompson  RT An in vivo proton magnetic resonance spectroscopy study of schizophrenia patients. Schizophr Bull 1996;22597- 609
PubMed Link to Article
Callicott  JHBertolino  AEgan  MMattay  VSLangheim  FJPWeinberger  DR Selective relationship between prefrontal N-acetylaspartate measures and negative symptoms in schizophrenia. Am J Psychiatry 2000;1571646- 1651
Link to Article
Bertolino  ASciota  DBrudaglio  FAltamura  MBlasi  GBellomo  AAntonucci  NCallicott  JHGoldberg  TEScarabino  TWeinberger  DRNardini  M Working memory deficits and levels of N-acetylaspartate in patients with schizophreniform disorder. Am J Psychiatry 2003;160483- 489
PubMed Link to Article
Wood  SJBerger  GVelakoulis  DPhillips  LJMcGorry  PDYung  ARDesmond  PPantelis  C Proton magnetic resonance spectroscopy in first episode psychosis and ultra high-risk individuals. Schizophr Bull 2003;29831- 843
PubMed Link to Article
McGorry  PDEdwards  JMihalopoulos  CHarrigan  SMJackson  HJ EPPIC: an evolving system of early detection and optimal management. Schizophr Bull 1996;22305- 326
Link to Article
Kay  SRFiszbein  AOpler  LA The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987;13261- 276
PubMed Link to Article
White  LHarvey  PDOpler  LLindenmayer  JP Empirical assessment of the factorial structure of clinical symptoms in schizophrenia: a multisite, multimodel evaluation of the factorial structure of the Positive and Negative Syndrome Scale. Psychopathology 1997;30263- 274
PubMed Link to Article
Stuart  GWSmith  DPantelis  C Syndromes of psychosis and the Positive and Negative Syndrome Scale (PANSS): lack of support for the three-syndrome model of psychotic symptoms [abstract]. Schizophr Res 2001;49 ((suppl 1)) 23
Provencher  SW Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 1993;30672- 679
PubMed Link to Article
Lambert  MConus  PLubman  DIWade  DYuen  HMoritz  SNaber  DMcGorry  PDSchimmelmann  BG The impact of substance use disorders on clinical outcome in 643 patients with first-episode psychosis. Acta Psychiatr Scand 2005;112141- 148
Link to Article
McGorry  PDSingh  BSCopolov  DLKaplan  IDossetor  CRvan Riel  RJ Royal Park Multidiagnostic Instrument for Psychosis: part II: development, reliability, and validity. Schizophr Bull 1990;16517- 536
PubMed Link to Article
McGorry  PDCopolov  DLSingh  BS Royal Park Multidiagnostic Instrument for Psychosis: part I: rationale and review. Schizophr Bull 1990;16501- 515
PubMed Link to Article
McGorry  PD Evaluating the importance of reducing the duration of untreated psychosis. Aust N Z J Psychiatry 2000;34 ((suppl)) S145- S149
PubMed Link to Article
Overall  JGorham  D The Brief Psychiatric Rating Scale. Psychol Rep 1962;10799- 812
Link to Article
Guy  W ECDEU Assessment Manual for Psychopharmacology, Revised.  Rockville, Md National Institute of Mental Health1976;DHEW publication (ADM) 76-338
Haro  JMKamath  SAOchoa  SNovick  DRele  KFargas  ARodriguez  MJRele  ROrta  JKharbeng  AAraya  SGervin  MAlonso  JMavreas  VLavrentzou  ELiontos  NGregor  KJones  PBSOHO Study Group, The Clinical Global Impression–Schizophrenia scale: a simple instrument to measure the diversity of symptoms present in schizophrenia. Acta Psychiatr Scand Suppl 2003; ((416)) 16- 23
PubMed
Spearing  MKPost  RMLeverich  GSBrandt  DNolen  W Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Res 1997;73159- 171
PubMed Link to Article
Cannon-Spoor  HEPotkin  SGWyatt  RJ Measurement of premorbid adjustment in chronic schizophrenia. Schizophr Bull 1982;8470- 484
PubMed Link to Article
Tohen  MHennen  JZarate  C  JrBaldessarini  RJStrakowski  SMStoll  ALFaedda  GLSuppes  TGebre-Medhin  PCohen  BM Two-year syndromal and functional recovery in 219 cases of first-episode major affective disorder with psychotic features. Am J Psychiatry 2000;157220- 228
PubMed Link to Article
Lingjaerde  OAhlfors  UGBech  PDencker  SJElgen  K The UKU side effect rating scale: a new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl 1987;3341- 100
PubMed Link to Article
Jaccard  JTurrisi  RWan  CK Interaction Effects in Multiple Regression.  Newbury Park, Calif Sage Publications1990;
Perkins  DLieberman  JGu  HTohen  MMcEvoy  JGreen  AZipursky  RStrakowski  SSharma  TKahn  RGur  RTollefson  GHGDH Research Group, Predictors of antipsychotic treatment response in patients with first episode schizophrenia, schizoaffective and schizophreniform disorders. Br J Psychiatry 2004;18518- 24
Link to Article
Singh  SPBurns  TAmin  SJones  PBHarrison  G Acute and transient psychotic disorders: precursors, epidemiology, course and outcome. Br J Psychiatry 2004;185452- 459
Link to Article
Siegel  SJIrani  FBrensinger  CMKohler  CGBilker  WBRagland  JDKanes  SJGur  RCGur  RE Prognostic variables at intake and long-term level of function in schizophrenia. Am J Psychiatry 2006;163433- 441
Link to Article
Sigmundsson  TMaier  MToone  BKWilliams  SCSimmons  AGreenwood  KRon  MA Frontal lobe N-acetylaspartate correlates with psychopathology in schizophrenia: a proton magnetic resonance spectroscopy study. Schizophr Res 2003;6463- 71
PubMed Link to Article
Pantelis  CStuart  GWNelson  HERobbins  TWBarnes  TRE Spatial working memory deficits in schizophrenia: relationship with tardive dyskinesia and negative symptoms. Am J Psychiatry 2001;1581276- 1285
PubMed Link to Article
Molina  VSánchez  JReig  SSanz  JBenito  CSantamarta  CPascau  JSarramea  FGispert  JDMisiego  JMPalomo  TDesco  M N-acetyl-aspartate levels in the dorsolateral prefrontal cortex in the early years of schizophrenia are inversely related to disease duration. Schizophr Res 2005;73209- 219
PubMed Link to Article
Brewer  WJFrancey  SMWood  SJJackson  HJPantelis  CPhillips  LJYung  ARAnderson  VAMcGorry  PD Memory impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. Am J Psychiatry 2005;16271- 78
PubMed Link to Article
Wood  SJPantelis  CProffitt  TPhillips  LJStuart  GWBuchanan  JAMahony  KBrewer  WSmith  DJMcGorry  PD Spatial working memory ability is a marker of risk-for-psychosis. Psychol Med 2003;331239- 1247
PubMed Link to Article
Velakoulis  DPantelis  CMcGorry  PDDudgeon  PBrewer  WCook  MDesmond  PBridle  NTierney  PMurrie  VSingh  BCopolov  D Hippocampal volume in first-episode psychoses and chronic schizophrenia: a high-resolution magnetic resonance imaging study. Arch Gen Psychiatry 1999;56133- 140
Link to Article
Hirayasu  YShenton  MESalisbury  DFDickey  CCFischer  IAMazzoni  PKisler  TArakaki  HKwon  JSAnderson  JEYurgelun-Todd  DTohen  MMcCarley  RW Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. Am J Psychiatry 1998;1551384- 1391
Pantelis  CVelakoulis  DMcGorry  PDWood  SJSuckling  JPhillips  LJYung  ARBullmore  ETBrewer  WSoulsby  BDesmond  PMcGuire  PK Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 2003;361281- 288
PubMed Link to Article
Velakoulis  DWood  SJWong  MTHMcGorry  PDYung  ARPhillips  LJSmith  DBrewer  WProffitt  TDesmond  PPantelis  C Hippocampal and amygdala volumes according to psychosis stage and diagnosis: a magnetic resonance imaging study of chronic schizophrenia, first-episode psychosis, and ultra-high-risk individuals. Arch Gen Psychiatry 2006;63139- 149Medline 16461856
PubMed Link to Article
Moreno  ARoss  BDBluml  S Direct determination of the N-acetyl-l-aspartate synthesis rate in the human brain by 13C MRS and [1-13C] glucose infusion. J Neurochem 2001;77347- 350
PubMed Link to Article
Baslow  MH N-acetylaspartate in the vertebrate brain: metabolism and function. Neurochem Res 2003;28941- 953
PubMed Link to Article
Chakraborty  GMekala  PYahya  DWu  GLedeen  RW Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase. J Neurochem 2001;78736- 745
PubMed Link to Article
Bartzokis  G Schizophrenia: breakdown in the well-regulated lifelong process of brain development and maturation. Neuropsychopharmacology 2002;27672- 683
PubMed Link to Article
Gorman  JMYurgelun-Todd  DChang  LTang  CYBertolino  A Magnetic resonance spectroscopy: recent findings in understanding the neurochemistry of schizophrenia [abstract]. Schizophr Bull 2005;31443
Ke  YCoyle  JTSimpson  NSGruber  SARenshaw  PFYurgelun-Todd  D Frontal brain NAA T2 values are significantly lower in schizophrenia [abstract]. Schizophr Res 2003;60242
Link to Article
Lambert  MHolzbach  RMoritz  SPostel  NKrausz  MNaber  D Objective and subjective efficacy as well as tolerability of olanzapine in the acute treatment of 120 patients with schizophrenia spectrum disorders. Int Clin Psychopharmacol 2003;18251- 260
PubMed Link to Article
Kivircik Akdede  BBAlptekin  KKitis  AArkar  HAkvardar  Y Effects of quetiapine on cognitive functions in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2005;29233- 238
PubMed Link to Article
Wahlbeck  KCheine  MEssali  AAdams  C Evidence of clozapine's effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials. Am J Psychiatry 1999;156990- 999
PubMed
Lieberman  JATollefson  GDCharles  CZipursky  RSharma  TKahn  RSKeefe  RSGreen  AIGur  REMcEvoy  JPerkins  DHamer  RMGu  HTohen  MHGDH Study Group, Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 2005;62361- 370
PubMed Link to Article
Keefe  RSSeidman  LJChristensen  BKHamer  RMSharma  TSitskoorn  MMLewine  RRYurgelun-Todd  DAGur  RCTohen  MTollefson  GDSanger  TMLieberman  JA Comparative effect of atypical and conventional antipsychotic drugs on neurocognition in first-episode psychosis: a randomized, double-blind trial of olanzapine versus low doses of haloperidol. Am J Psychiatry 2004;161985- 995
PubMed Link to Article
Ke  YCohen  BMLowen  SHirashima  FNassar  LRenshaw  PF Biexponential transverse relaxation (T2) of the proton MRS creatine resonance in human brain. Magn Reson Med 2002;47232- 238
PubMed Link to Article
Ho  BCAndreasen  NCNopoulos  PArndt  SMagnotta  VFlaum  M Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia. Arch Gen Psychiatry 2003;60585- 594
PubMed Link to Article
Wood  SJVelakoulis  DSmith  DBond  DStuart  GWMcGorry  PDBrewer  WJBridle  NEritaia  JDesmond  PSingh  BCopolov  DPantelis  C A longitudinal study of hippocampal volume in first episode psychosis and chronic schizophrenia. Schizophr Res 2001;5237- 46
Link to Article

Figures

Place holder to copy figure label and caption
Figure 3.

Scattergraph of the relationship between the frontal N-acetylaspartate–creatine and phosphocreatine (NAA/Cr) ratio and the Global Assessment of Functioning (GAF) Scale score at discharge.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Sample spectra and LCModel41 fits (heavy line) from the mediotemporal voxel (A) and the dorsolateral prefrontal voxel (B).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 1.

Magnetic resonance images showing the location of the midpoint of the mediotemporal voxel (A) and the dorsolateral prefrontal voxel (B). The images are presented in radiological format, with the left hemisphere on the right.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 2. Regression Variables for the Prediction of the Outcome Measures
Table Graphic Jump LocationTable 1. Outcome Measures at Intake and Discharge, Negative Syndrome at Intake, and Premorbid Global Assessment of Functioning Scale (GAF) Score

References

Carpenter  WT  JrStrauss  JS The prediction of outcome in schizophrenia, IV: eleven-year follow-up of the Washington IPSS cohort. J Nerv Ment Dis 1991;179517- 525
PubMed Link to Article
Thara  RHenrietta  MJoseph  ARajkumar  SEaton  WW Ten-year course of schizophrenia: the Madras longitudinal study. Acta Psychiatr Scand 1994;90329- 336
PubMed Link to Article
Harrison  GHopper  KCraig  TLaska  ESiegel  CWanderling  JDube  KCGanev  KGiel  Ran der Heiden  WHolmberg  SKJanca  ALee  PWLeon  CAMalhotra  SMarsella  AJNakane  YSartorius  NShen  YSkoda  CThara  RTsirkin  SJVarma  VKWalsh  DWiersma  D Recovery from psychotic illness: a 15- and 25-year international follow-up study. Br J Psychiatry 2001;178506- 517
PubMed Link to Article
Henry  LPHarris  MGSchwartz  OS  et al.  The 8 year functional and symptomatic outcome of first episode psychosis (FEP) [abstract]. Schizophr Bull 2005;31224
May  PRVan Putten  TYale  C Predicting outcome of antipsychotic drug treatment from early response. Am J Psychiatry 1980;1371088- 1089
PubMed
Van Putten  TMay  PR Subjective response as a predictor of outcome in pharmacotherapy: the consumer has a point. Arch Gen Psychiatry 1978;35477- 480
PubMed Link to Article
Thompson  KNMcGorry  PDHarrigan  SM Recovery style and outcome in first-episode psychosis. Schizophr Res 2003;6231- 36
PubMed Link to Article
Verdoux  HLiraud  FAssens  FAbalan  Fvan Os  J Social and clinical consequences of cognitive deficits in early psychosis: a two-year follow-up study of first-admitted patients. Schizophr Res 2002;56149- 159
PubMed Link to Article
Goldman  MTandon  RDeQuardo  JRTaylor  SFGoodson  JMcGrath  M Biological predictors of 1-year outcome in schizophrenia in males and females. Schizophr Res 1996;2165- 73
PubMed Link to Article
Beiser  MBean  GErickson  DZhang  JIacono  WGRector  NA Biological and psychosocial predictors of job performance following a first episode of psychosis. Am J Psychiatry 1994;151857- 863
PubMed
Johnstone  ECMacmillan  JFFrith  CDBenn  DKCrow  TJ Further investigation of the predictors of outcome following first schizophrenic episodes. Br J Psychiatry 1990;157182- 189
PubMed Link to Article
Robinson  DWoerner  MGAlvir  JMBilder  RGoldman  RGeisler  SKoreen  ASheitman  BChakos  MMayerhoff  DLieberman  JA Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry 1999;56241- 247
PubMed Link to Article
Lieberman  JAPhillips  MGu  HStroup  SZhang  PKong  LJi  ZKoch  GHamer  RM Atypical and conventional antipsychotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. Neuropsychopharmacology 2003;28995- 1003
PubMed
Malla  AKNorman  RMManchanda  RAhmed  MRScholten  DHarricharan  RCortese  LTakhar  J One year outcome in first episode psychosis: influence of DUP and other predictors. Schizophr Res 2002;54231- 242
PubMed Link to Article
Murray  RMvan Os  J Predictors of outcome in schizophrenia. J Clin Psychopharmacol 1998;18 ((suppl 1)) 2S- 4S
PubMed Link to Article
Altamura  ACBassetti  RSassella  FSalvadori  DMundo  E Duration of untreated psychosis as a predictor of outcome in first-episode schizophrenia: a retrospective study. Schizophr Res 2001;5229- 36
PubMed Link to Article
Larsen  TKMoe  LCVibe-Hansen  LJohannessen  JO Premorbid functioning versus duration of untreated psychosis in 1 year outcome in first-episode psychosis. Schizophr Res 2000;451- 9
PubMed Link to Article
Harrigan  SMMcGorry  PDKrstev  H Does treatment delay in first-episode psychosis really matter? Psychol Med 2003;3397- 110
PubMed Link to Article
Shenton  MEDickey  CCFrumin  MMcCarley  RW A review of MRI findings in schizophrenia. Schizophr Res 2001;491- 52
PubMed Link to Article
Wright  ICRabe-Hesketh  SWoodruff  PWRDavid  ASMurray  RMBullmore  ET Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000;15716- 25
Staal  WGHulshoff Pol  HEKahn  RS Outcome of schizophrenia in relation to brain abnormalities. Schizophr Bull 1999;25337- 348
PubMed Link to Article
Tandon  RDeQuardo  JRTaylor  SFMcGrath  MJibson  MEiser  AGoldman  M Phasic and enduring negative symptoms in schizophrenia: biological markers and relationship to outcome. Schizophr Res 2000;45191- 201
PubMed Link to Article
Williams  AOReveley  MAKolakowska  TArdern  MMandelbrote  BM Schizophrenia with good and poor outcome, II: cerebral ventricular size and its clinical significance. Br J Psychiatry 1985;146239- 246
PubMed Link to Article
Wilms  Gvan Ongeval  CBaert  ALClaus  ABollen  Jde Cuyper  HEneman  MMalfroid  MPeuskens  JHeylen  S Ventricular enlargement, clinical correlates and treatment outcome in chronic schizophrenic inpatients. Acta Psychiatr Scand 1992;85306- 312
PubMed Link to Article
Milev  PHo  BCArndt  SNopoulos  PAndreasen  NC Initial magnetic resonance imaging volumetric brain measurements and outcome in schizophrenia: a prospective longitudinal study with 5-year follow-up. Biol Psychiatry 2003;54608- 615
PubMed Link to Article
van Haren  NEMCahn  WHulshoff Pol  HESchnack  HGCaspers  ELemstra  ASitskoorn  MMWiersma  Dvan den Bosch  RJDingemans  PMSchene  AHKahn  RS Brain volumes as predictor of outcome in recent-onset schizophrenia: a multi-center MRI study. Schizophr Res 2003;6441- 52
PubMed Link to Article
Harrison  PJ The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999;122(pt 4)593- 624Review
PubMed Link to Article
Urenjak  JWilliams  SRGadian  DGNoble  M Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 1993;13981- 989
Bhakoo  KKPearce  D In vitro expression of N-acetyl aspartate by oligodendrocytes: implications for proton magnetic resonance spectroscopy signal in vivo. J Neurochem 2000;74254- 262
PubMed Link to Article
Birken  DLOldendorf  WH N-acetyl-l-aspartic acid: a literature review of a compound prominent in 1H-NMR spectroscopic studies of the brain. Neurosci Biobehav Rev 1989;1323- 31
Link to Article
Keshavan  MSStanley  JAPettegrew  JW Magnetic resonance spectroscopy in schizophrenia: methodological issues and findings: part II. Biol Psychiatry 2000;48369- 380
Link to Article
Bertolino  AEsposito  GCallicott  JHMattay  VSvan Horn  JDFrank  JABerman  KFWeinberger  D Specific relationship between prefrontal neuronal N-acetylaspartate and activation of the working memory cortical network in schizophrenia. Am J Psychiatry 2000;15726- 33
Stanley  JAWilliamson  PCDrost  DRylett  RJCarr  TJMalla  AThompson  RT An in vivo proton magnetic resonance spectroscopy study of schizophrenia patients. Schizophr Bull 1996;22597- 609
PubMed Link to Article
Callicott  JHBertolino  AEgan  MMattay  VSLangheim  FJPWeinberger  DR Selective relationship between prefrontal N-acetylaspartate measures and negative symptoms in schizophrenia. Am J Psychiatry 2000;1571646- 1651
Link to Article
Bertolino  ASciota  DBrudaglio  FAltamura  MBlasi  GBellomo  AAntonucci  NCallicott  JHGoldberg  TEScarabino  TWeinberger  DRNardini  M Working memory deficits and levels of N-acetylaspartate in patients with schizophreniform disorder. Am J Psychiatry 2003;160483- 489
PubMed Link to Article
Wood  SJBerger  GVelakoulis  DPhillips  LJMcGorry  PDYung  ARDesmond  PPantelis  C Proton magnetic resonance spectroscopy in first episode psychosis and ultra high-risk individuals. Schizophr Bull 2003;29831- 843
PubMed Link to Article
McGorry  PDEdwards  JMihalopoulos  CHarrigan  SMJackson  HJ EPPIC: an evolving system of early detection and optimal management. Schizophr Bull 1996;22305- 326
Link to Article
Kay  SRFiszbein  AOpler  LA The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987;13261- 276
PubMed Link to Article
White  LHarvey  PDOpler  LLindenmayer  JP Empirical assessment of the factorial structure of clinical symptoms in schizophrenia: a multisite, multimodel evaluation of the factorial structure of the Positive and Negative Syndrome Scale. Psychopathology 1997;30263- 274
PubMed Link to Article
Stuart  GWSmith  DPantelis  C Syndromes of psychosis and the Positive and Negative Syndrome Scale (PANSS): lack of support for the three-syndrome model of psychotic symptoms [abstract]. Schizophr Res 2001;49 ((suppl 1)) 23
Provencher  SW Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 1993;30672- 679
PubMed Link to Article
Lambert  MConus  PLubman  DIWade  DYuen  HMoritz  SNaber  DMcGorry  PDSchimmelmann  BG The impact of substance use disorders on clinical outcome in 643 patients with first-episode psychosis. Acta Psychiatr Scand 2005;112141- 148
Link to Article
McGorry  PDSingh  BSCopolov  DLKaplan  IDossetor  CRvan Riel  RJ Royal Park Multidiagnostic Instrument for Psychosis: part II: development, reliability, and validity. Schizophr Bull 1990;16517- 536
PubMed Link to Article
McGorry  PDCopolov  DLSingh  BS Royal Park Multidiagnostic Instrument for Psychosis: part I: rationale and review. Schizophr Bull 1990;16501- 515
PubMed Link to Article
McGorry  PD Evaluating the importance of reducing the duration of untreated psychosis. Aust N Z J Psychiatry 2000;34 ((suppl)) S145- S149
PubMed Link to Article
Overall  JGorham  D The Brief Psychiatric Rating Scale. Psychol Rep 1962;10799- 812
Link to Article
Guy  W ECDEU Assessment Manual for Psychopharmacology, Revised.  Rockville, Md National Institute of Mental Health1976;DHEW publication (ADM) 76-338
Haro  JMKamath  SAOchoa  SNovick  DRele  KFargas  ARodriguez  MJRele  ROrta  JKharbeng  AAraya  SGervin  MAlonso  JMavreas  VLavrentzou  ELiontos  NGregor  KJones  PBSOHO Study Group, The Clinical Global Impression–Schizophrenia scale: a simple instrument to measure the diversity of symptoms present in schizophrenia. Acta Psychiatr Scand Suppl 2003; ((416)) 16- 23
PubMed
Spearing  MKPost  RMLeverich  GSBrandt  DNolen  W Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Res 1997;73159- 171
PubMed Link to Article
Cannon-Spoor  HEPotkin  SGWyatt  RJ Measurement of premorbid adjustment in chronic schizophrenia. Schizophr Bull 1982;8470- 484
PubMed Link to Article
Tohen  MHennen  JZarate  C  JrBaldessarini  RJStrakowski  SMStoll  ALFaedda  GLSuppes  TGebre-Medhin  PCohen  BM Two-year syndromal and functional recovery in 219 cases of first-episode major affective disorder with psychotic features. Am J Psychiatry 2000;157220- 228
PubMed Link to Article
Lingjaerde  OAhlfors  UGBech  PDencker  SJElgen  K The UKU side effect rating scale: a new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl 1987;3341- 100
PubMed Link to Article
Jaccard  JTurrisi  RWan  CK Interaction Effects in Multiple Regression.  Newbury Park, Calif Sage Publications1990;
Perkins  DLieberman  JGu  HTohen  MMcEvoy  JGreen  AZipursky  RStrakowski  SSharma  TKahn  RGur  RTollefson  GHGDH Research Group, Predictors of antipsychotic treatment response in patients with first episode schizophrenia, schizoaffective and schizophreniform disorders. Br J Psychiatry 2004;18518- 24
Link to Article
Singh  SPBurns  TAmin  SJones  PBHarrison  G Acute and transient psychotic disorders: precursors, epidemiology, course and outcome. Br J Psychiatry 2004;185452- 459
Link to Article
Siegel  SJIrani  FBrensinger  CMKohler  CGBilker  WBRagland  JDKanes  SJGur  RCGur  RE Prognostic variables at intake and long-term level of function in schizophrenia. Am J Psychiatry 2006;163433- 441
Link to Article
Sigmundsson  TMaier  MToone  BKWilliams  SCSimmons  AGreenwood  KRon  MA Frontal lobe N-acetylaspartate correlates with psychopathology in schizophrenia: a proton magnetic resonance spectroscopy study. Schizophr Res 2003;6463- 71
PubMed Link to Article
Pantelis  CStuart  GWNelson  HERobbins  TWBarnes  TRE Spatial working memory deficits in schizophrenia: relationship with tardive dyskinesia and negative symptoms. Am J Psychiatry 2001;1581276- 1285
PubMed Link to Article
Molina  VSánchez  JReig  SSanz  JBenito  CSantamarta  CPascau  JSarramea  FGispert  JDMisiego  JMPalomo  TDesco  M N-acetyl-aspartate levels in the dorsolateral prefrontal cortex in the early years of schizophrenia are inversely related to disease duration. Schizophr Res 2005;73209- 219
PubMed Link to Article
Brewer  WJFrancey  SMWood  SJJackson  HJPantelis  CPhillips  LJYung  ARAnderson  VAMcGorry  PD Memory impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. Am J Psychiatry 2005;16271- 78
PubMed Link to Article
Wood  SJPantelis  CProffitt  TPhillips  LJStuart  GWBuchanan  JAMahony  KBrewer  WSmith  DJMcGorry  PD Spatial working memory ability is a marker of risk-for-psychosis. Psychol Med 2003;331239- 1247
PubMed Link to Article
Velakoulis  DPantelis  CMcGorry  PDDudgeon  PBrewer  WCook  MDesmond  PBridle  NTierney  PMurrie  VSingh  BCopolov  D Hippocampal volume in first-episode psychoses and chronic schizophrenia: a high-resolution magnetic resonance imaging study. Arch Gen Psychiatry 1999;56133- 140
Link to Article
Hirayasu  YShenton  MESalisbury  DFDickey  CCFischer  IAMazzoni  PKisler  TArakaki  HKwon  JSAnderson  JEYurgelun-Todd  DTohen  MMcCarley  RW Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. Am J Psychiatry 1998;1551384- 1391
Pantelis  CVelakoulis  DMcGorry  PDWood  SJSuckling  JPhillips  LJYung  ARBullmore  ETBrewer  WSoulsby  BDesmond  PMcGuire  PK Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 2003;361281- 288
PubMed Link to Article
Velakoulis  DWood  SJWong  MTHMcGorry  PDYung  ARPhillips  LJSmith  DBrewer  WProffitt  TDesmond  PPantelis  C Hippocampal and amygdala volumes according to psychosis stage and diagnosis: a magnetic resonance imaging study of chronic schizophrenia, first-episode psychosis, and ultra-high-risk individuals. Arch Gen Psychiatry 2006;63139- 149Medline 16461856
PubMed Link to Article
Moreno  ARoss  BDBluml  S Direct determination of the N-acetyl-l-aspartate synthesis rate in the human brain by 13C MRS and [1-13C] glucose infusion. J Neurochem 2001;77347- 350
PubMed Link to Article
Baslow  MH N-acetylaspartate in the vertebrate brain: metabolism and function. Neurochem Res 2003;28941- 953
PubMed Link to Article
Chakraborty  GMekala  PYahya  DWu  GLedeen  RW Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase. J Neurochem 2001;78736- 745
PubMed Link to Article
Bartzokis  G Schizophrenia: breakdown in the well-regulated lifelong process of brain development and maturation. Neuropsychopharmacology 2002;27672- 683
PubMed Link to Article
Gorman  JMYurgelun-Todd  DChang  LTang  CYBertolino  A Magnetic resonance spectroscopy: recent findings in understanding the neurochemistry of schizophrenia [abstract]. Schizophr Bull 2005;31443
Ke  YCoyle  JTSimpson  NSGruber  SARenshaw  PFYurgelun-Todd  D Frontal brain NAA T2 values are significantly lower in schizophrenia [abstract]. Schizophr Res 2003;60242
Link to Article
Lambert  MHolzbach  RMoritz  SPostel  NKrausz  MNaber  D Objective and subjective efficacy as well as tolerability of olanzapine in the acute treatment of 120 patients with schizophrenia spectrum disorders. Int Clin Psychopharmacol 2003;18251- 260
PubMed Link to Article
Kivircik Akdede  BBAlptekin  KKitis  AArkar  HAkvardar  Y Effects of quetiapine on cognitive functions in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2005;29233- 238
PubMed Link to Article
Wahlbeck  KCheine  MEssali  AAdams  C Evidence of clozapine's effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials. Am J Psychiatry 1999;156990- 999
PubMed
Lieberman  JATollefson  GDCharles  CZipursky  RSharma  TKahn  RSKeefe  RSGreen  AIGur  REMcEvoy  JPerkins  DHamer  RMGu  HTohen  MHGDH Study Group, Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 2005;62361- 370
PubMed Link to Article
Keefe  RSSeidman  LJChristensen  BKHamer  RMSharma  TSitskoorn  MMLewine  RRYurgelun-Todd  DAGur  RCTohen  MTollefson  GDSanger  TMLieberman  JA Comparative effect of atypical and conventional antipsychotic drugs on neurocognition in first-episode psychosis: a randomized, double-blind trial of olanzapine versus low doses of haloperidol. Am J Psychiatry 2004;161985- 995
PubMed Link to Article
Ke  YCohen  BMLowen  SHirashima  FNassar  LRenshaw  PF Biexponential transverse relaxation (T2) of the proton MRS creatine resonance in human brain. Magn Reson Med 2002;47232- 238
PubMed Link to Article
Ho  BCAndreasen  NCNopoulos  PArndt  SMagnotta  VFlaum  M Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia. Arch Gen Psychiatry 2003;60585- 594
PubMed Link to Article
Wood  SJVelakoulis  DSmith  DBond  DStuart  GWMcGorry  PDBrewer  WJBridle  NEritaia  JDesmond  PSingh  BCopolov  DPantelis  C A longitudinal study of hippocampal volume in first episode psychosis and chronic schizophrenia. Schizophr Res 2001;5237- 46
Link to Article

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