Introduction
Psychotic disorders such as schizophrenia, schizo-affective disorder and bipolar disorder are severe mental illnesses along a psychosis continuum, with great clinical heterogeneity within each diagnostic group. Recent genetic (Andreassen et al. Reference Andreassen, Thompson, Schork, Ripke, Mattingsdal, Kelsoe, Kendler, O'Donovan, Rujescu, Werge, Sklar, Roddey, Chen, McEvoy, Desikan, Djurovic and Dale2013), imaging (Rimol et al. Reference Rimol, Hartberg, Nesvag, Fennema-Notestine, Hagler, Pung, Jennings, Haukvik, Lange, Nakstad, Melle, Andreassen, Dale and Agartz2010, Reference Rimol, Nesvag, Hagler, Bergmann, Fennema-Notestine, Hartberg, Haukvik, Lange, Pung, Server, Melle, Andreassen, Agartz and Dale2012; Haukvik et al. Reference Haukvik, Westlye, Morch-Johnsen, Jorgensen, Lange, Dale, Melle, Andreassen and Agartz2015), neuropathological (Wang et al. Reference Wang, Lohmann, Yang, Zimmerman, Pantazopoulos, Herring, Berretta, Heckers and Konradi2011) and epidemiological (Lichtenstein et al. Reference Lichtenstein, Yip, Bjork, Pawitan, Cannon, Sullivan and Hultman2009) studies suggest shared pathophysiological traits along the psychosis continuum, although the exact mechanisms are not known.
There is an ongoing debate as to whether the psychotic disorders are progressive brain disorders or not (Vita et al. Reference Vita, De Peri, Deste and Sacchetti2012; Fusar-Poli et al. Reference Fusar-Poli, Smieskova, Kempton, Ho, Andreasen and Borgwardt2013; Zipursky et al. Reference Zipursky, Reilly and Murray2013). Increasingly sophisticated magnetic resonance imaging (MRI) techniques have facilitated studies of longitudinal brain changes in psychotic disorders. The results are mixed, with some studies showing significant brain volume loss over time in chronic schizophrenia (Veijola et al. Reference Veijola, Guo, Moilanen, Jaaskelainen, Miettunen, Kyllonen, Haapea, Huhtaniska, Alaraisanen, Maki, Kiviniemi, Nikkinen, Starck, Remes, Tanskanen, Tervonen, Wink, Kehagia, Suckling, Kobayashi, Barnett, Barnes, Koponen, Jones, Isohanni and Murray2014), first-episode schizophrenia (Andreasen et al. Reference Andreasen, Nopoulos, Magnotta, Pierson, Ziebell and Ho2011), first-episode psychosis (FEP) (Gutiérrez-Galve et al. Reference Gutiérrez-Galve, Chu, Leeson, Price, Barnes, Joyce and Ron2015) and the psychosis prodromal state (Cannon et al. Reference Cannon, Chung, He, Sun, Jacobson, van Erp, McEwen, Addington, Bearden, Cadenhead, Cornblatt, Mathalon, McGlashan, Perkins, Jeffries, Seidman, Tsuang, Walker, Woods and Heinssen2015), whereas other studies report a lack of longitudinal changes (Schaufelberger et al. Reference Schaufelberger, Lappin, Duran, Rosa, Uchida, Santos, Murray, McGuire, Scazufca, Menezes and Busatto2011). Some authors argue that antipsychotic medication may cause or moderate the longitudinal changes (Ho et al. Reference Ho, Andreasen, Ziebell, Pierson and Magnotta2011; Vita et al. Reference Vita, De Peri, Deste and Sacchetti2012; Fusar-Poli et al. Reference Fusar-Poli, Smieskova, Kempton, Ho, Andreasen and Borgwardt2013), whereas others report no such associations (Cannon et al. Reference Cannon, Chung, He, Sun, Jacobson, van Erp, McEwen, Addington, Bearden, Cadenhead, Cornblatt, Mathalon, McGlashan, Perkins, Jeffries, Seidman, Tsuang, Walker, Woods and Heinssen2015). Some studies have analysed changes in a priori selected cortical or subcortical regions (Roiz-Santianez et al. Reference Roiz-Santianez, Ayesa-Arriola, Tordesillas-Gutierrez, Ortiz-Garcia de la Foz, Perez-Iglesias, Pazos, Sanchez and Crespo-Facorro2014; Gutiérrez-Galve et al. Reference Gutiérrez-Galve, Chu, Leeson, Price, Barnes, Joyce and Ron2015), others in regional gray and white matter or total brain volume (Andreasen et al. Reference Andreasen, Nopoulos, Magnotta, Pierson, Ziebell and Ho2011; Boonstra et al. Reference Boonstra, Cahn, Schnack, Hulshoff Pol, Minderhoud, Kahn and van Haren2011; Veijola et al. Reference Veijola, Guo, Moilanen, Jaaskelainen, Miettunen, Kyllonen, Haapea, Huhtaniska, Alaraisanen, Maki, Kiviniemi, Nikkinen, Starck, Remes, Tanskanen, Tervonen, Wink, Kehagia, Suckling, Kobayashi, Barnett, Barnes, Koponen, Jones, Isohanni and Murray2014). Hulshoff Pol & Kahn (Reference Hulshoff Pol and Kahn2008) reported a 0.5% brain volume reduction in schizophrenia spectrum FEP v. 0.2% in controls, and the volume reductions have been associated with poorer clinical outcome in some (Cahn et al. Reference Cahn, van Haren, Hulshoff Pol, Schnack, Caspers, Laponder and Kahn2006; van Haren et al. Reference van Haren, Hulshoff Pol, Schnack, Cahn, Brans, Carati, Rais and Kahn2008) but not all (Roiz-Santianez et al. Reference Roiz-Santianez, Ayesa-Arriola, Tordesillas-Gutierrez, Ortiz-Garcia de la Foz, Perez-Iglesias, Pazos, Sanchez and Crespo-Facorro2014; Gutiérrez-Galve et al. Reference Gutiérrez-Galve, Chu, Leeson, Price, Barnes, Joyce and Ron2015) studies. Meta-analyses have reported progressive changes in FEP and schizophrenia (Vita et al. Reference Vita, De Peri, Deste and Sacchetti2012; Fusar-Poli et al. Reference Fusar-Poli, Smieskova, Kempton, Ho, Andreasen and Borgwardt2013). The meta-analyses include subjects across the life span with different brain developmental trajectories and studies with a variety of different image acquisition parameters and scan processing methods.
Patients with FEP display great symptom heterogeneity. Acute symptoms may fluctuate and new affective and psychosis symptoms may emerge. Hence early diagnosis within the psychosis spectrum is challenging, and re-evaluation and change of diagnosis may occur in up to 40% of FEP patients (Salvatore et al. Reference Salvatore, Baldessarini, Tohen, Khalsa, Sanchez-Toledo, Zarate, Vieta and Maggini2011, Reference Salvatore, Baldessarini, Khalsa, Amore, Di Vittorio, Ferraro, Maggini and Tohen2013). Previous valuable and important longitudinal studies in FEP have tended to include psychoses within the schizophrenia spectrum and other non-affective psychoses such as brief psychotic disorder and psychosis not otherwise specified (NOS), but not the affective psychoses in bipolar disorder and psychotic depression (for a review, see Morgan et al. Reference Morgan, Lappin, Heslin, Donoghue, Lomas, Reininghaus, Onyejiaka, Croudace, Jones, Murray, Fearon, Doody and Dazzan2014). This may have led to a bias toward a poor outcome or brain characteristics that are not representative of the broad FEP group. In order to give FEP patients accurate and cautious information of expected illness prognosis, longitudinal studies of brain changes and their association with clinical characteristic in broad FEP samples are crucial.
The aim of the present study was two-fold: (1) to explore if FEP patients showed a different pattern of brain structural change over a 1-year period compared with healthy controls; and (2) to investigate if putative longitudinal brain changes correlated with measures of clinical characteristics and outcome.
We hypothesized: (1) that FEP patients would show greater subcortical volume decline and ventricular volume enlargement, and more pronounced cortical thinning than healthy controls; and (2) that higher percentage longitudinal brain change would correlate with medication use, longer duration of untreated psychosis (DUP), lower age at illness onset and a more severe outcome.
We studied a wide range of distinct surface-based measures of cortical area and thickness across the whole cortical mantle, and volumes of subcortical structures including the ventricles, the basal ganglia (caudate, putamen accumbens, pallidum), the limbic structures (hippocampus, amygdala, thalamus) and the cerebellum to get a comprehensive overview of patterns of longitudinal brain changes, not restricted to a priori selected regions.
Method
Subjects
The subject sample consisted of patients with FEP (n = 79) and healthy controls (n = 82) from the on-going multicenter Thematically Organized Psychosis (TOP) Research Study at the University of Oslo and collaborating hospitals in Oslo, Norway. The formal inclusion criteria were: age between 18 and 65 years (but the oldest included FEP patient was 48 years); no head trauma leading to loss of consciousness; and absence of previous or current somatic illness that might affect brain morphology. FEP was defined as patients who had received less than 1 year of adequate treatment for psychotic disorders within the schizophrenia spectrum [n = 44; schizophrenia (DSM-IV 295.1, 295.3, 295.6, 295.9) (n = 37), schizophreniform disorder (DSM-IV 295.4) (n = 2), or schizo-affective disorder (DSM-IV 295.7) (n = 5)], the bipolar spectrum [n = 18; bipolar I disorder (DSM-IV 296.0–7) (n = 15), bipolar II disorder (DSM-IV 296.89) (n = 2), or bipolar disorder NOS (DSM-IV 296.80) (n = 1)], and other psychoses [n = 17; depressive psychosis (n = 5), paranoid psychosis (n = 2), or psychotic disorder NOS (n = 10)]. All patients had a previous or current episode of psychosis defined as a score of 4 or above on the Positive and Negative Syndrome Scale (PANSS) items P1 (delusions), P3 (hallucinatory behavior), P5 (grandiosity), P6 (suspiciousness/persecution) and G9 (unusual thought content).
The healthy control subjects were randomly selected from the national population register. They were resident in the same catchment area and were within the same age range as the patients. Baseline scans from the current subject sample have been included in previous larger studies of brain structure differences between schizophrenia, bipolar disorder and healthy controls (Rimol et al. Reference Rimol, Hartberg, Nesvag, Fennema-Notestine, Hagler, Pung, Jennings, Haukvik, Lange, Nakstad, Melle, Andreassen, Dale and Agartz2010, Reference Rimol, Nesvag, Hagler, Bergmann, Fennema-Notestine, Hartberg, Haukvik, Lange, Pung, Server, Melle, Andreassen, Agartz and Dale2012; Haukvik et al. Reference Haukvik, Westlye, Morch-Johnsen, Jorgensen, Lange, Dale, Melle, Andreassen and Agartz2015).
The study was approved by the Regional Committee for Medical Research Ethics and the Norwegian Data Inspectorate, and was conducted in accordance with the Helsinki declaration. After complete description of the study to the subjects, written informed consent was obtained from all participating subjects.
Clinical assessments
All patients underwent thorough clinical investigation by specially trained psychologists and physicians at baseline and at 1-year follow-up. At baseline 217 FEP patients underwent MRI scanning. Of the 93 patients who met for a second scanning, 14 subjects were excluded because of poor scan quality or segmentation errors. As such, 79 patients were included in this study. The included patients had longer DUP (t 116 = 2.1, p = 0.036), used less second-generation antipsychotics (SGA) at baseline (t 159 = −2.2, p = 0.031) and had a smaller proportion of women (χ2 1 = 4.65, p = 0.031). The other demographic and clinical variables at baseline did not differ between follow-up and non-follow-up patients (Table 1).
Demographic and clinical characteristics of FEP patients included at baseline and follow-up
Data are given as mean (s.d.) and range unless otherwise indicated.
FEP, First-episode psychosis; s.d., standard deviation; n.s., not significant; n.a., not applicable; DUP, duration of untreated psychosis; YMRS, Young Mania Rating Scale; CDSS, Calgary Depression Scale for Schizophrenia; GAF, Global Assessment of Function split version; PANSS, Positive and Negative Syndrome Scale; DDD, defined daily dosage; FGA, first-generation antipsychotics; SGA, second-generation antipsychotics.
a χ2 Test for categorical variables; t test or Mann–Whitney non-parametric test for continuous variables.
b n = 207.
Clinical diagnoses were assessed using the Structured Clinical Interview for DSM Axis I disorders (SCID-I) module A-E (Spitzer et al. Reference Spitzer, Williams, Gibbon and First1992) at baseline and follow-up, with an overall agreement for diagnostic categories of 82%, κ = 0.77 (95% confidence interval 0.60–0.94) between raters. Current psychosocial function was assessed with the Global Assessment of Function scale, split version. Affective state was assessed with the Young Mania Rating Scale and the Calgary Depression Scale for Schizophrenia, and current psychotic symptoms were rated by the PANSS (Kay et al. Reference Kay, Fiszbein and Opler1987), with high intraclass coefficients (Engh et al. Reference Engh, Friis, Birkenaes, Jonsdottir, Klungsoyr, Ringen, Simonsen, Vaskinn, Opjordsmoen and Andreassen2010). All symptom scales were administered at both time points. Remission at follow-up was defined as no positive symptoms within a week of follow-up assessment as measured by a score of 3 or below on all of the PANSS items P1, P3, P5, P6 and G9. Current use of medication [first-generation antipsychotics (FGA), SGA, lithium, and antiepileptics] was converted into standard defined daily dosages (DDD) in accordance with the guidelines from the World Health Organization Collaborating Center for Drug Statistics Methodology (hhtp:// www.whocc.no/atcdd).
Healthy controls were interviewed for symptoms of severe mental illness by trained clinical psychologists and examined with the Primary Care Evaluation of Mental Disorders (Spitzer et al. Reference Spitzer, Williams, Kroenke, Linzer, deGruy, Hahn, Brody and Johnson1994) to ensure no current or previous severe psychiatric disorders. Control subjects with current or previous somatic illness, or substance misuse disorder including alcohol overuse that could affect brain morphology were excluded.
MRI acquisition and processing
All participants underwent MRI scanning at baseline and follow-up on the same 1.5 T Siemens Magnetom Sonata scanner (Siemens Medical Solutions). Two sagittal T1-weighted magnetization prepared rapid gradient echo (MPRAGE) volumes were acquired at each time point with the Siemens tfl3d1_ns pulse sequence (echo time = 3.93 ms, repetition time = 2730 ms, inversion time = 1000 ms, flip angle = 7°, field of view = 24 cm, voxel size = 1.33 × 0.94 × 1 mm3, number of partitions = 160) and subsequently averaged together, after rigid-body registration, to increase the signal:noise ratio. There was no major scanner upgrade during the study period, and patients and controls were scanned interchangeably to avoid the possibility for across-time scanner drifting to confound diagnostic differences. A neuroradiologist evaluated all scans, and subjects with scans showing minor brain pathology were excluded from the study.
The FreeSurfer software (version 5.3.0) (http://surfer.nmr.mgh.harvard.edu/) was used to estimate volumes of subcortical structures (Fischl et al. Reference Fischl, Salat, Busa, Albert, Dieterich, Haselgrove, van der Kouwe, Killiany, Kennedy, Klaveness, Montillo, Makris, Rosen and Dale2002, Reference Fischl, Salat, van der Kouwe, Makris, Segonne, Quinn and Dale2004) and cortical surface area and thickness (Dale et al. Reference Dale, Fischl and Sereno1999; Fischl et al. Reference Fischl, Sereno and Dale1999); see the online Supplementary material and Haukvik et al. (Reference Haukvik, McNeil, Lange, Melle, Dale, Andreassen and Agartz2014, Reference Haukvik, Westlye, Morch-Johnsen, Jorgensen, Lange, Dale, Melle, Andreassen and Agartz2015) for details. To extract reliable volume and thickness estimates of longitudinal changes, images were automatically processed with the FreeSurfer longitudinal stream (Reuter et al. Reference Reuter, Schmansky, Rosas and Fischl2012). Specifically, an unbiased within-subject template space and image are created using robust, inverse consistent registration (Reuter et al. Reference Reuter, Rosas and Fischl2010). Several processing steps, such as skull stripping, Talairach transforms, atlas registration as well as spherical surface maps and parcellations are then initialized with common information from the within-subject template, significantly increasing reliability and statistical power (Reuter et al. Reference Reuter, Schmansky, Rosas and Fischl2012). Quality control and editing were performed by a trained research assistant supervised by an experienced FreeSurfer user. All volumes were visually inspected for segmentation errors. If found, segmentation errors were corrected using manual editing and/or control points (http://freesurfer.net/fswiki/Tutorials).
Statistical analyses
Statistical analyses were performed by the use of the statistical package SPSS version 20 (IBM, USA), and with the FreeSurfer statistical tools. Demographic and clinical variables were evaluated by t tests, non-parametric Mann–Whitney tests and χ2 analysis as applicable. All statistical tests were two-tailed.
At first, baseline differences in brain structural measures between patients and controls were tested using analysis of covariance (ANCOVA) with the brain as the dependent variable, diagnosis as fixed factor, and age and intracranial volume as covariates for the subcortical measures. Bonferroni correction was applied to adjust for multiple comparisons of 12 subcortical structures (10 bilateral structures – amygdala, hippocampus, thalamus, accumbens, pallidum, caudatus, putamen, cerebellum white matter and cortex, lateral ventricle and lateral inferior ventricle, and in addition the 3rd and 4th ventricles). Diagnostic differences in cortical thickness and area were analysed over 300 000 points across the whole cortical mantle with a general linear model within the FreeSurfer software. A false discovery rate (FDR) of 5% was applied to the α threshold of 0.05 to adjust for multiple comparisons. The analyses were repeated, with inclusion of FEP within schizophrenia spectrum only (n = 44) and healthy controls.
Longitudinal percentage change was estimated for each cortical vertex and subcortical structure volume (V) as annual percentage change (PC) from the baseline (time1) scan, where V PC = [(V time2 − V time1)/(time2 – time1)]/V time1. Then, we used a general linear model with diagnosis as a fixed factor and age as covariate to analyse percentage change for each subcortical structure and vertex-wise across the cortical mantle for each cortical measure (area and thickness). The analyses were repeated after exclusion of all subjects with residual values below −2.5 or above 2.5, to investigate the effects of potential outlier observations on the model. We then analysed longitudinal differences between the schizophrenia spectrum disorder patients (n = 44) and healthy controls.
Associations between longitudinal brain morphological change and clinical characteristics [DUP, age at illness onset, and the use of antipsychotic medication (FGA and SGA) as DDD] in FEP patients were analysed with non-parametric Spearman correlation analyses because of the lack of normal distribution of the clinical variables (also after the logarithmic transformation procedures). Differences between FEP patients with and without SGA medication and the relationship between clinical outcome (remission at follow-up) and longitudinal brain changes were analysed with multiple ANCOVA models with each brain region as the dependent variable, and remitted FEP v. non-remitted FEP patients or SGA users v. non-SGA users as fixed factors. Bonferroni correction was applied to adjust for multiple comparisons of 12 subcortical structures to avoid false-positive results. Since the brain structures are not truly independent, we present nominally significant uncorrected p values in the Results section. The cortical maps were adjusted for multiple comparisons with the FDR.
Results
Demographic and clinical variables
FEP had fewer years of education (t 145 = 4.82, p < 0.0001) and larger scan interval (t 159 = −2.65, p = 0.009) compared with healthy controls (Table 2). The SCID-I-verified diagnoses of 18 (23%) FEP subjects changed from baseline to follow-up: five from schizophreniform disorder and four from psychosis NOS to schizophrenia; one from schizophrenia and two from psychotic depression to schizo-affective disorder; two from psychosis NOS and one from bipolar II disorder to psychotic depression; one from brief psychosis to bipolar I disorder; one from psychosis NOS; and one from psychotic depression to bipolar II disorder. Of the patients, 52 used SGA at baseline, 35 were still using at follow-up, 17 had discontinued use, and seven other patients had started using SGA. At follow-up 42 patients used SGA [risperidone (n = 3), olanzapine (n = 14), aripiprazol (n = 14), quetiapine (n = 10), ziprazidone (n = 1)]. None of the patients received FGA as their primary medication. None of the patients received anticholinergics or central stimulants, one patient received diazepam and one oxazepam daily.
Demographic and clinical characteristics of FEP patients and healthy controls
Data are given as mean (s.d.) and range unless otherwise indicated.
FEP, First-episode psychosis; s.d., standard deviation; n.s., not significant; n.a., not applicable; DUP, duration of untreated psychosis; YMRS, Young Mania Rating Scale; CDSS, Calgary Depression Scale for Schizophrenia; GAF, Global Assessment of Function split version; PANSS, Positive and Negative Syndrome Scale; DDD, defined daily dosage; FGA, first-generation antipsychotics; SGA, second-generation antipsychotics.
a χ2 Test for categorical variables; t test or Mann–Whitney non-parametric test for continuous variables.
b n = 147.
c n = 69.
d n = 6 baseline; n = 1 follow-up.
e n = 52 baseline; n = 42 follow-up.
f n = 10 baseline; n = 10 follow-up.
g n = 1 baseline; n = 4 follow-up.
Clinical characteristics at baseline and follow-up are listed in Table 2.
Baseline MRI characteristics
FEP patients had smaller volumes of the right hippocampus (F 1,158 = 9.82, p = 0.024) and larger volumes of the 3rd ventricle (F 1,158 = 9.48, p = 0.024) compared with healthy controls (online Supplementary Table S1). FEP patients showed regions of cortical thinning and surface area reductions compared with healthy controls, but the differences did not remain significant after FDR correction for multiple comparisons (online Supplementary Fig. S1).
In the schizophrenia spectrum FEP group (n = 44), we found the following baseline differences compared with healthy controls: left hemisphere smaller cerebellar cortex (t 156 = −3.14, p = 0.024); right hemisphere smaller cerebellar cortex (t 156 = −2.97, p = 0.036); and smaller hippocampus (t 156 = −2.90, p = 0.048). Schizophrenia spectrum patients had regional reduced cortical thickness and surface area at baseline compared with healthy controls, in concordance with our previous publications (Rimol et al. Reference Rimol, Hartberg, Nesvag, Fennema-Notestine, Hagler, Pung, Jennings, Haukvik, Lange, Nakstad, Melle, Andreassen, Dale and Agartz2010, Reference Rimol, Nesvag, Hagler, Bergmann, Fennema-Notestine, Hartberg, Haukvik, Lange, Pung, Server, Melle, Andreassen, Agartz and Dale2012) (data not shown).
Baseline subcortical volumes and cortical parameters in FEP patients were not significantly related to DUP, age at illness onset, medication use or remission at follow-up. Remission at follow-up was related to larger cortical area at baseline (p = 0.003).
Trend-level baseline results are listed in the online Supplementary material.
Longitudinal MRI changes
FEP patients and controls did not differ significantly in regional percentage change in cortical thickness, area or volume, or in any of the subcortical structures after strict FDR and Bonferroni correction, respectively. The variation in percentage longitudinal change was largest for the ventricles, ranging from approximately −20% to + 20% of the lateral ventricle volume over a 1-year period, with extreme value outliers at + 75% for the left inferior ventricle (Table 3). For the hippocampus the variation in percentage change was narrower, ranging from approximately −5% to +5% volume change over 1 year. Percentage change within all subcortical structures is listed in Table 3. Age at MRI scanning was not related to percentage longitudinal change for FEP patients or healthy controls.
Longitudinal percentage change in FEP patients (whole group n = 79), FES patients only (n = 44) and HC participants (n = 82)
FEP, First-episode psychosis; FES, first-episode schizophrenia spectrum; HC, healthy control; s.d., standard deviation.
a None of the p values is significant after adjustment for multiple comparisons.
When we repeated the analyses and included only the schizophrenia spectrum FEP, we did not find any significant differences in percentage volume change compared with controls after multiple comparison control (Table 3).
Trend-level longitudinal results are listed in the online Supplementary material.
Longitudinal MRI changes and clinical characteristics
We found no associations that remained significant after adjustment for multiple comparisons between DUP, SGA use, age at illness onset, or remission at follow-up and longitudinal percentage change in any of the subcortical volumes or cortical measures.
Trend-level results are listed in the online Supplementary material.
Discussion
Our main finding was that FEP patients did not show significant longitudinal brain changes over a 1-year period as compared with healthy controls. No significant associations between clinical characteristics, including antipsychotic medication use, and longitudinal brain change were found.
By including affective psychoses (psychotic bipolar disorder and psychotic depression), we studied a FEP group with greater clinical heterogeneity than most of the previous studies (for reviews, see Vita et al. Reference Vita, De Peri, Deste and Sacchetti2012; Fusar-Poli et al. Reference Fusar-Poli, Smieskova, Kempton, Ho, Andreasen and Borgwardt2013; Morgan et al. Reference Morgan, Lappin, Heslin, Donoghue, Lomas, Reininghaus, Onyejiaka, Croudace, Jones, Murray, Fearon, Doody and Dazzan2014). Greater clinical heterogeneity may be related to greater diversity of brain characteristics. Dazzan et al. (Reference Dazzan, Soulsby, Mechelli, Wood, Velakoulis, Phillips, Yung, Chitnis, Lin, Murray, McGorry, McGuire and Pantelis2012) reported that subjects at ultra high-risk for psychosis (UHR) who converted to affective psychoses showed a different pattern of gray matter reduction than UHR subjects who converted to schizophrenia spectrum psychoses. In contrast, Cannon et al. (Reference Cannon, Chung, He, Sun, Jacobson, van Erp, McEwen, Addington, Bearden, Cadenhead, Cornblatt, Mathalon, McGlashan, Perkins, Jeffries, Seidman, Tsuang, Walker, Woods and Heinssen2015) reported that transition from UHR to both affective and schizophrenia spectrum FEP was characterized by common cortical thickness reductions and 3rd ventricle enlargement. Moreover, longitudinal volume reductions specifically in the anterior cingulate cortex have been reported in affective FEP (Koo et al. Reference Koo, Levitt, Salisbury, Nakamura, Shenton and McCarley2008). When we analysed only the schizophrenia spectrum FEP patients, we still did not find any significant longitudinal changes compared with healthy controls. Hence, the lack of longitudinal change cannot be attributed to the inclusion of affective psychoses. The fact that 23% of FEP patients in our cohort changed diagnosis during the follow-up period is in accordance with a previous report of retained psychosis diagnoses in 76.2% (Pope et al. Reference Pope, Joober and Malla2013), and emphasizes the variability in clinical characteristics and course within this group.
Longitudinal MRI studies face particular methodological difficulties regarding alignment of the baseline and follow-up image. We used the FreeSurfer longitudinal pipeline that co-registrates the baseline and follow-up scan of each individual subject and computes an unbiased within-subject template space and image. By this, the statistical power to detect subtle changes over time has been shown to increase significantly (Reuter et al. Reference Reuter, Schmansky, Rosas and Fischl2012). We analysed a wide range of brain volumes and cortical parameters, and applied rigorous multiple comparison control accordingly. This is somewhat in contrast to previous studies analysing selected regions of interest (Roiz-Santianez et al. Reference Roiz-Santianez, Ayesa-Arriola, Tordesillas-Gutierrez, Ortiz-Garcia de la Foz, Perez-Iglesias, Pazos, Sanchez and Crespo-Facorro2014; Gutiérrez-Galve et al. Reference Gutiérrez-Galve, Chu, Leeson, Price, Barnes, Joyce and Ron2015) or more crude measures such as whole-brain or lobar volumes (for a review, see Vita et al. Reference Vita, De Peri, Deste and Sacchetti2012), or studies arguing that less stringent adjustment for multiple tests was required (Andreasen et al. Reference Andreasen, Nopoulos, Magnotta, Pierson, Ziebell and Ho2011; Roiz-Santianez et al. Reference Roiz-Santianez, Ayesa-Arriola, Tordesillas-Gutierrez, Ortiz-Garcia de la Foz, Perez-Iglesias, Pazos, Sanchez and Crespo-Facorro2014). This could explain some of the discrepancies.
Interestingly, by using the exact same FreeSurfer longitudinal pipeline, Cannon et al. (Reference Cannon, Chung, He, Sun, Jacobson, van Erp, McEwen, Addington, Bearden, Cadenhead, Cornblatt, Mathalon, McGlashan, Perkins, Jeffries, Seidman, Tsuang, Walker, Woods and Heinssen2015) found 3rd ventricle volume increase and regional frontal cortical thinning in clinical high-risk subjects (n = 274) who converted (n = 35) to affective or schizophrenia spectrum psychosis. In comparison, we found significantly larger 3rd ventricles in FEP patients at baseline, but no progressive enlargement. This could suggest that some brain changes may occur during transition to psychosis rather than after illness onset. Moreover, we found that patients who were in remission at follow-up had a larger cortical area at baseline. This could reflect subgroups with different illness severity and brain morphological characteristics. These results are intriguing and warrant further investigation.
The pathophysiology of psychotic disorders is heterogeneous, and has been demonstrated to involve, for example, altered dopamine synthesis activity, N-methyl-d-aspartate receptor (NMDAr) hypofunction or pro-inflammatory status (for a review, see Kahn & Sommer, Reference Kahn and Sommer2015). From a functional perspective, FEP with good clinical and functional outcome has been associated with hippocampal volume increase over time (Lappin et al. Reference Lappin, Morgan, Chalavi, Morgan, Reinders, Fearon, Heslin, Zanelli, Jones, Murray and Dazzan2014). We cannot exclude the possibility that the lack of positive findings reflects heterogeneity over several domains.
Medication use may affect brain morphology, especially in the basal ganglia that are rich in dopaminergic neurons. We found less longitudinal reduction of caudate volume in FEP patients who were not in remission at follow-up compared with FEP patients in remission, significant at a trend level. This is partly in line with recent findings of less longitudinal caudate volume reduction in FEP patients (n = 109) compared with healthy controls (n = 76); this finding was, however, independent of clinical outcome among the FEP patients (Roiz-Santianez et al. Reference Roiz-Santianez, Ayesa-Arriola, Tordesillas-Gutierrez, Ortiz-Garcia de la Foz, Perez-Iglesias, Pazos, Sanchez and Crespo-Facorro2014). Longitudinal caudate volume increase in schizophrenia spectrum FEP patients (n = 211) has previously been associated with the use of antipsychotic medication (Ho et al. Reference Ho, Andreasen, Ziebell, Pierson and Magnotta2011). We found no association between longitudinal change and the use of antipsychotics (all non-clozapine SGA) in the caudate or in any other brain region. The directional effects of antipsychotics on basal ganglia volumes may, however, differ not only between FGA and SGA, but also between the different generic compounds within each group (Ebdrup et al. Reference Ebdrup, Norbak, Borgwardt and Glenthoj2013). Olanzapine and risperidone (together used by 17 subjects in our sample) have been associated with basal ganglia volume increase or no change, whereas quetiapine (used by 10 subjects in our sample) has been associated with basal ganglia volume decrease or no change (for a review, see Ebdrup et al. Reference Ebdrup, Norbak, Borgwardt and Glenthoj2013). Accordingly, associations between longitudinal brain changes and SGA use should be interpreted cautiously.
This study has some notable limitations. Since FEP was defined as less than 1 year of adequate treatment, duration of treatment amongst FEP varied from almost 1 year to just a few weeks at baseline inclusion. Second, the time from baseline to follow-up scanning ranged from 9 months to almost 2 years. If there is a decline around transition to psychosis (Cannon et al. Reference Cannon, Chung, He, Sun, Jacobson, van Erp, McEwen, Addington, Bearden, Cadenhead, Cornblatt, Mathalon, McGlashan, Perkins, Jeffries, Seidman, Tsuang, Walker, Woods and Heinssen2015) this might be confounded by the different time points in their early psychosis development when each patient was scanned. We used rigorous statistical adjustment for multiple comparisons to avoid false-positive findings. This might have caused type II errors. For completeness, we reported unadjusted p values for the results that were significant at an α-threshold of 0.05 before multiple comparison adjustment in the online Supplementary material. There was a selection bias between the follow-up- and baseline group, with more men with long duration of untreated illness and less SGA treatment in the follow-up group. Finally, several factors may affect brain structure, including birth complications (Haukvik et al. Reference Haukvik, Schaer, Nesvag, McNeil, Hartberg, Jonsson, Eliez and Agartz2012, Reference Haukvik, McNeil, Lange, Melle, Dale, Andreassen and Agartz2014), exposure to childhood trauma (Aas et al. Reference Aas, Haukvik, Djurovic, Bergmann, Athanasiu, Tesli, Hellvin, Steen, Agartz, Lorentzen, Sundet, Andreassen and Melle2013), alcohol (Agartz et al. Reference Agartz, Shoaf, Rawlings, Momenan and Hommer2003), tobacco (Jorgensen et al. Reference Jorgensen, Skjaervo, Morch-Johnsen, Haukvik, Lange, Melle, Andreassen and Agartz2015) and cannabis use (Malchow et al. Reference Malchow, Hasan, Fusar-Poli, Schmitt, Falkai and Wobrock2013), and exercise (Malchow et al. Reference Malchow, Keeser, Keller, Hasan, Rauchmann, Kimura, Schneider-Axmann, Dechent, Gruber, Ertl-Wagner, Honer, Hillmer-Vogel, Schmitt, Wobrock, Niklas and Falkai2015). Detailed investigations of such effects were beyond the scope of this article, but should be investigated in future studies.
Strengths of the current study include the relatively large subject sample, the thorough clinical characterization of participating subjects, inter-rater reliability testing on clinical instruments, SCID-I-verified diagnoses obtained by specially trained psychiatrists, clinical psychologists or physicians, and the use of the same MRI scanner with no major software or hardware upgrades during the study period.
In summary, by analysing longitudinal change in a wide range of specific subcortical volumes and in cortical parameters across the entire cortical mantle without a priori-selected regions of interest, we found no significant longitudinal brain changes over a 1-year period in FEP patients. Our results add to the mixed literature on progressive brain changes in psychotic disorders. FEP patients should be informed that they do not necessarily have a progressive brain disorder.
Supplementary material
For supplementary material accompanying this paper visit http://dx.doi.org/10.1017/S003329171500210X
Acknowledgements
The study was supported by grants from the Research Council of Norway, the South Eastern Norway Regional Health Authority and the KG Jebsen Foundation.
Declaration of Interest
A.M.D. is a founder and holds equity in CorTechs Labs, and also serves on the Scientific Board. The terms of this arrangement have been reviewed and approved by the University of California, San Diego, in accordance with its conflict of interest policies. All other authors report no conflict of interest.
