Progressive disability and prefrontal shrinkage in schizophrenia patients with poor outcome: A 3-year longitudinal study

SCHRES-06966; No of Pages 8 Schizophrenia Research xxx (2016) xxx–xxx

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Progressive disability and prefrontal shrinkage in schizophrenia patients with poor outcome: A 3-year longitudinal study N. Dusi a, M. Bellani a, C. Perlini b, L. Squarcina c, V. Marinelli c, L. Finos d, C.A. Altamura e, M. Ruggeri c, P. Brambilla e,f,⁎ a

UOC Psychiatry, Policlinico G.B. Rossi, Azienda Ospedaliera-Universitaria Integrata, Verona, Italy Section of Clinical Psychology, University of Verona, Verona, Italy Section of Psychiatry, University of Verona, Verona, Italy d Department of Developmental Psychology and Socialization, University of Padova, Padova, Italy e Department of Neurosciences and Mental Health, Psychiatric Clinic, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy f Department of Psychiatry and Behavioural Sciences, University of Texas Health Science Center at Houston, TX, USA b c

a r t i c l e

i n f o

Article history: Received 25 November 2015 Received in revised form 5 September 2016 Accepted 5 September 2016 Available online xxxx Keywords: Psychosis Dorsolateral prefrontal cortex Orbitofrontal cortex Prefrontal cortex Magnetic resonance Disability Follow-up

a b s t r a c t Introduction: Schizophrenia is a severe disabling disorder with heterogeneous illness courses. In this longitudinal study we characterized schizophrenia patients with poor and good outcome (POS, GOS), using functional and imaging metrics. Patients were defined in accordance to Keefe's criteria (i.e. Kraepelinian and non-Kraepelinian patients). Methods: 35 POS patients, 35 GOS patients and 76 healthy controls (H) underwent clinical, functioning and magnetic resonance imaging (MRI) assessments twice over three years of follow-up. Information on psychopathology, treatment, disability (using the World Health Organization Disability Assessment Scale II, WHO-DAS-2) and prefrontal morphology was collected. Dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) were manually traced. Results: At baseline, subjects with POS showed significantly decreased right dorsolateral prefrontal cortex (DLPFC) white matter volumes (WM) compared to healthy controls and GOS patients (POS VS HC, p b 0.001; POS vs GOS, p = 0.03), with shrinkage of left DLPFC WM volumes at follow up (t = 2.66, p = 0.01). Also, POS patients had higher disability in respect to GOS subjects both at baseline and after 3 years at the WHO-DAS-2 (p b 0.05). Discussion: Our study supports the hypothesis that POS is characterized by progressive deficits in brain structure and in “real-life” functioning. These are particularly notable in the DLPFC. © 2016 Elsevier B.V. All rights reserved.

1. Introduction Schizophrenia is a severe and disabling disorder with heterogeneous manifestations and clinical course (Mueser and McGurk, 2004). In order to achieve a narrower definition of the diagnosis, Keefe and colleagues proposed to distinguish two groups of patients with different illness course (Keefe et al., 1987). A first sub-group, labeled poor outcome schizophrenia (POS, i.e. kraepelinian) group, are characterized by clinical and social deterioration, with needs of institutional and informal financial support and constant care in day-life activity (van Os and Kapur, 2009). A second, labeled good outcome schizophrenia (GOS, i.e. non-kraepelinian), achieves periods of clinical remission, can conduct a fairly independent life, and receives hospitalization for short periods of time over years (Frese et al., 2009). This differentiation is not only related to clinical aspects of the disease, but can also facilitate biological ⁎ Corresponding author: Dipartimento di Neuroscienze e Salute Mentale, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy. E-mail address: [email protected] (P. Brambilla).

and genetic research on schizophrenia by offering more homogenous illness phenotypes (Agarwal et al., 2008; Bellani et al., 2013; Brambilla et al., 2014; Dusi et al., 2015a). Therefore, there is an increasing interest of neural morphometric markers of POS and GOS, to confirm from a neurobiological point of view the distinction between these two groups of patients. Early morphometric studies reported that patients with POS tend to have larger ventricular size than GOS patients (DeLisi et al., 1992; Pearlson et al., 1984). Recently, gray matter alterations in POS patients were reported, particularly in prefrontal cortices (Horga et al., 2011; Mitelman et al., 2005a; Mitelman et al., 2005b; Mitelman et al., 2005c; Staal et al., 2001). Lower white matter volumes have been shown in prefrontal fibers (Andreone et al., 2007), particularly dorsolateral prefrontal cortex (DLPFC), in POS patients relative to GOS ones and healthy controls (Buchsbaum et al., 2009; Mitelman et al., 2005a; Mitelman et al., 2007). Moreover, it has been suggested that these alterations undergo a worsening progression over time (Cahn et al., 2002a; DeLisi et al., 2004; Mathalon et al., 2001), being particularly associated to more severe positive symptoms (Mathalon et al., 2001), longer hospitalizations (Mathalon et al., 2001; van Haren et al., 2007), poorer cognitive

http://dx.doi.org/10.1016/j.schres.2016.09.013 0920-9964/© 2016 Elsevier B.V. All rights reserved.

Please cite this article as: Dusi, N., et al., Progressive disability and prefrontal shrinkage in schizophrenia patients with poor outcome: A 3-year longitudinal study, Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.09.013

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N. Dusi et al. / Schizophrenia Research xxx (2016) xxx–xxx

performance (Baiano et al., 2008; Ho et al., 2003; Perlini et al., 2012) and lower global functioning (Brambilla et al., 2007; Cahn et al., 2002b; Lieberman et al., 2001; van Haren et al., 2008). These observations suggest the existence of a distinct subpopulation of poor outcome patients with progressive deterioration causing selfcare dysfunctions, refractory symptomatology and cognitive impairment (Keefe et al., 1988). Interestingly enough, this definition is in line with the early descriptions by Emil Kraepelin of dementia praecox (Kraepelin, 1896). Indeed, Kraepelin first formulated in a systematic manner the concept of dementia praecox and stated how patients with non-affective psychosis underwent a progressive cognitive deterioration during early adulthood, which resembled demential syndromes (Saugstad, 2009). Accordingly, Keefe and colleagues proposed a definition of POS, which was called Kraepelinian, under the following criteria: continuous hospitalizations for five years previous to assessment or, living outside the hospital, need of continuous assistance, unemployment and lack of remission of symptoms (Keefe et al., 1987). However, some studies failed to demonstrate progressive prefrontal alterations in POS (DeLisi et al., 1997; DeLisi et al., 1995), Also, the underlying mechanistic processes and the functioning impact of prefrontal alterations are still under debate (Bellani et al., 2010; Elvevag and Goldberg, 2000; Tournikioti et al., 2007). The aim of our study was to delineate the longitudinal course of prefrontal anatomy and “real-life” functioning in POS and GOS (based on the Keefe criteria). 2. Methods 2.1. Subjects We recruited 35 patients with POS and 35 patients with GOS, according to Keefe's criteria (Keefe et al., 1987) from the South-Verona Psychiatric Case Register (Amaddeo et al., 2009), a community-based mental health register, which refers to the four Psychiatry Services of the city of Verona. Diagnoses were obtained using the Item Group Checklist of the Schedule for Clinical Assessment in Neuropsychiatry (IGC-SCAN) (Tansella and Nardini, 1996; Wing, 1992), administered by two trained clinical research psychologists with experience in this measure (having administered at least ten previous IGC-SCAN assessments with a trained senior investigator). The psychopathological item groups completed by the two raters were compared, to discuss any discrepancies in the assessment of major symptoms. Diagnoses of schizophrenia were corroborated by the clinical consensus of two staff psychiatrists according to DSM-IV criteria. We also ensured the reliability of the IGC-SCAN diagnoses by holding regular consensus meetings with the psychiatrists treating the patients and a senior investigator. Patients' clinical information was retrieved from psychiatric interviews, the attending psychiatrist and medical charts. At the time of scanning, all patients were receiving antipsychotic medication. As most patients were undertaking both first and second generation antipsychotics at the time of scanning, we applied two reliable measures of standardized antipsychotic dosage (Nose et al., 2008). Chlorpromazine equivalents (CPZ-equivalents) and prescribed daily dose/defined daily dose (PDD/DDD) of typical antipsychotics, atypical antipsychotics, overall antipsychotic medication and the duration of antipsychotic treatment were calculated for each patient. Clinical symptoms were characterized using the Brief Psychiatric Rating Scale (BPRS 24-item version) (Ventura et al., 2000) and the impairment in day life activities with the World Health Organization Disability Assessment Scale 2 (WHO-DAS-2, 2001). Patients were divided in two outcome groups, according to Keefe and colleagues criteria (Keefe et al., 1987). Exclusion criteria were Comorbid Axis I psychiatric disorders, alcohol or substance abuse within the 6 months previous to MR, history of traumatic head injury with loss of consciousness, major neurological medical illness, and mental retardation. Seventy-six normal controls were also recruited. They had no history of DSM-IV axis I disorders, as determined by a modified interview

deriving from the SCID-IV non-patient version (SCID-NP) (First et al., 2000), of psychiatric disorders among first-degree relatives, of alcohol or substance abuse, and had no current major neurological or medical illnesses. The study was approved by the Ethics Committee of the Azienda Ospedaliera Universitaria Integrata of Verona. All individuals provided signed informed consent. 2.2. World Health Organization-Disability Assessment Schedule-2 (WHODAS-2) The WHO-DAS-2 assesses the activity limitations and participation restrictions experienced by a person, irrespective of diagnosis. It has six major domains, which include activities that are considered important in many cultures. These are: (1) understanding and communicating with the world, (2) moving and getting around, (3) self-care, (4) getting along with people, (5) life activities, (6) participation in society. The instrument encompasses 32 questions and the answers rate the degree of difficulty on a 1 to 5 points scale. The evaluation pertains the previous 30 days. 2.3. MRI procedure MRI scans were acquired with a 1.5-T Siemens Magnetom Symphony Maestro Class, Syngo MR 2002B at the Borgo Roma University Hospital of Verona. Scans were obtained between 2002 and 2012 and scan software has been updated in 2004 and 2009. All participants were provided with earplugs to reduce acoustic noise and the participant was comfortably placed in a head holder and maintained stable, in order to minimize movement artifacts. Initially, exploratory T1- weighted images (TR = 450 ms, TE = 14 ms, flip angle = 90°, FOV = 230 × 230, slice thickness = 5 mm, matrix size =384 × 512) were obtained to verify subject's head position and image quality. A sequence of DP/T2weighted images were then obtained (TR = 2500 ms, TE = 24/ 121 ms, flip angle = 180°, FOV = 230 × 230, slice thickness = 5 mm, and matrix size = 410 × 512) according to an axial plane parallel to the anterior–posterior commissures (AC–PC), to exclude focal lesions. Subsequently, a coronal 3D MPR sequence was acquired (TR = 2060 ms, TE = 3.9 ms, flip angle = 15°, FOV = 176 × 235, slice thickness = 1.25 mm, matrix size = 270 × 512, TI = 1100) to obtain 144 images covering the entire brain. 2.4. Image analysis All imaging data were transferred to a PC workstation and analyzed using the BRAINS2 software developed at the University of Iowa (http:// www.psychiatry.uiowa.edu/mhcrc/IPLpages/BRAINS.htm). Two regions of interest (ROIs) were selected, namely the dorsolateral prefrontal cortex (DLPFC) and the orbitofrontal cortex (OFC). The DLPFC was defined in accordance with prior tracing methods (Gilbert et al., 2001) to include all slices anterior to the posterior border of the genu till the anterior border of the Sylvian horizontal ramus. The superior border of the area was defined by the superior frontal sulcus, the inferior border by the upper border of the Sylvian fissure, posteriorly, and by the horizontal ramus of the Sylvian fissure, anteriorly; the lateral boundary was delineated by the edge of the brain, and the medial boundary was represented by the line connecting the most medial point of the superior frontal sulcus and the Sylvian fissure/horizontal ramus. The OFC was traced consistent with published methods (Lacerda et al., 2003). The region's posterior boundary was defined by the tip of the genu of corpus callosum, and the last slice traced was the most anterior coronal slice where brain tissue could be identified. The superior boundary was represented by the inferior border of the anterior cingulate. More anteriorly, the superior limit was represented by a midpoint placed on the intercommissural line. The inferior border was traced following the inferior surface of the frontal lobes.

Please cite this article as: Dusi, N., et al., Progressive disability and prefrontal shrinkage in schizophrenia patients with poor outcome: A 3-year longitudinal study, Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.09.013

N. Dusi et al. / Schizophrenia Research xxx (2016) xxx–xxx

Intracranial volume (ICV) was traced in the coronal plane along the border of the brain and included the cerebrospinal fluid, dura mater, sinus, optic chiasma, brainstem, and cerebral and cerebellar matter. The inferior border did not extended below the base of the cerebellum. The first and last 10 slices including brain matter were traced; afterwards 1 slice on every 5 was traced. Tracing was performed by a rater blind to subjects' identity and sociodemo- graphic and clinical variables. Two raters achieved high reliability, as defined by intraclass correlation coefficients (ICCs) of 0.90 for the DLPFC, OFC and ICV, established by blindly tracing 10 randomly selected scans. 2.5. Statistical analysis All statistical analyses were conducted using IBM SPSS Statistic for Mac software, version 21.0 and R statistical analyses package 3.2.5 version for PC (http://www.r-project.org/). A two-tailed significance level of p = 0.05 corrected for multiple comparisons was adopted. Demographic and clinical variables were compared using Student's t-test, Pearson's chi-square and one-way analysis of variance (ANOVA), as appropriate. For the analysis of prefrontal volumes, we used a multiple testing correction method for structured hypotheses, called the Inheritance procedure, which has been previously reported thoroughly (Goeman and Finos, 2012). As first step, the procedure applied a multivariate analysis of variance (MANOVA) test, using DLPFC and OFC total volumes as response and diagnostic groups (i.e. GOS, POS, and HC), age, gender, intracranial volume (ICV) and body mass index (BMI) as covariates. If the multivariate analyses for diagnostic groups were significant at significance level of p = 0.05, two linear models were then fitted, one for DLPFC and one for OFC. Significance level for the two following tests for diagnostic groups was set at p = 0.05/2 = 0.025. When any area was significant, each sub-area (i.e. gray matter, and white matter) was tested at a corrected (i.e. reduced) significance level. Finally, for each significant model a post-hoc analysis for multiples comparisons was performed for the three diagnostic groups. We applied Holm method with Shaffer logical implications. In all models, we considered the log

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transformation, which provides better residuals distribution (i.e. better respect of the assumption underling linear models). For the longitudinal changes in volumes between T0 and T1, we used paired t-tests for each area, applying the same hierarchical method (i.e. Inheritance procedure) to select significant chances in volumes. To better communicate the volume decrease in areas with a significant pvalue, we computed a Percentage Change (PC) score defined as the percentage of volume reduction per year relative to the baseline (i.e. PC = (VolumeT1 − VolumeT0) / (T1 − T0) / VolumeT0 ∗ 100) (Haukvik et al., 2016). This score is reported together with the t- and the p-value. We also evaluated associations between medications' and volumes' change. We used correlation tests between each area and medication variables (“atypical antipsychotics PDD/DDD”, typical antipsychotics PDD/DDD. total antipsychotics PDD/DDD, CPZ-equivalents atypical antipsychotics, CPZ-equivalents typical antipsychotics, CPZ-equivalents total antipsychotics) and we corrected p-values using Holm methods. 3. Results 3.1. Baseline assessment 3.1.1. Clinical variables (Table 1) Both groups of patients had a higher BMI compared to healthy controls (F2,0.145 = 6.89, p = 0.01). POS were older than GOS (t = 2.21, p = 0.03). Therefore, BMI and age were included as covariates in the GLM analyses comparing volumes across diagnostic groups, in order to control for these possible confounders. POS patients, compared to GOS ones, reported higher disability at WHO-DAS-2 (“getting around”: t = − 3.39, p b 0.02; “getting along with people”: t = − 2.31, p = 0.02) and longer duration of antipsychotic medication (p = 0.05). No differences were observed between GOS and POS at the BPRS. 3.1.2. Prefrontal volumes (Fig. 1) At first, a multivariate analysis of variance (MANOVA) test with multiple testing correction for structured hypotheses (Inheritance procedure), using DLPFC and OFC total volume as response and groups (i.e.

Table 1 descriptive statistics of baseline sample.

Age (years) Gender: M/F Ethnicity BMI Handedness (% right) BPRS total score Negative symptoms Positive symptoms WHO-DAS total score Domain 1 Domain 2 Domain 3 Domain 4 Domain 5 Domain 6 Antipsychotic medication CPZ eq. total CPZ eq. typical CPZ eq. atypical Antipsychotic medication PDD/DDD total PDD/DDD typical PDD/DDD atypical Treatment Duration (years)

Healthy controls (N = 76)

Good outcome patients (N = 35)

Poor outcome patients (N = 35)

39.28 ± 11.57 36/40 Caucasian 23.52 ± 3.57 75.0%

36.51 ± 10.18 25/10 Caucasian 26.08 ± 5.15 88.6% 43.82 ± 21.39 10.96 ± 5.87 11.36 ± 7.03 19.18 ± 5.67 3.07 ± 1.38 2.50 ± 1.26 2.25 ± 0.84 3.71 ± 1.90 2.89 ± 1.19 4.75 ± 1.93

42.66 ± 12.86 21/14 Caucasian 26.71 ± 6.28 80. 0% 45.41 ± 18.36 12.25 ± 4.18 11.55 ± 6.54 22.13 ± 6.71 3.87 ± 1.18 3.77 ± 1.58 2.29 ± 0.69 3.55 ± 1.74 3.77 ± 1.66 4.87 ± 1.60

223.21 ± 167.65 14.88 ± 23.44 208.33 ± 182.42 1.04 ± 0.75 0.13 ± 0.31 0.93 ± 0.83 9.81 ± 9.27

Statistics HC vs GO vs PO

GO vs PO

p

F2.145 = 2.58 χ2 = 5.91

t = −2.21

0.79/0.03 N0.05

F2.145 = 6.89

t = −0.46

0.01/0.64

t = −0.31 t = −0.99 t = −0.10 t = −1.81 t = −1.87 t = −3.39 t = −0.20 t = −0.34 t = −2.31 t = −2.62

0.75 0.32 0.91 0.07 0.06 b0.02 0.84 0.72 0.02 0.79

207.55 ± 170.97 25.29 ± 46.19 182.85 ± 190.73

t = 0.38 t = 0.5 t = −1.18

0.70 0.57 0.23

1.15 ± 0.74 0.39 ± 0.69 0.76 ± 0.80 14.43 ± 10.63

t = −0.60 t = −1.99 t = 0.88 t = −2.14

0.54 0.05 0.38 0.05

Legend: BMI, body mass index, CPZ-Eq, Clorpromazine-Equivalents, HC, healthy controls, GO, good outcome patients, PO, poor outcome patients, PDD/DDD, prescribed daily dosage/defined daily dosage, WHO-DAS: domain 1, understanding & communicating, Domain 2, getting around, Domain 3, self-care, Domain 4, getting along with people, Domain 5, life activities, Domain 6, participation in society. Bold values indicate significance at (P b 0.05).

Please cite this article as: Dusi, N., et al., Progressive disability and prefrontal shrinkage in schizophrenia patients with poor outcome: A 3-year longitudinal study, Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.09.013

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N. Dusi et al. / Schizophrenia Research xxx (2016) xxx–xxx

GOS, POS, and HC) age, gender, intracranial volume (ICV), handedness and body mass index (BMI) as covariates, reported a significant effect for DLPFC (F2.139 = 4.11, p = 0.01). Post-hoc analyses, revealed lower DLPFC volumes in POS (but not GOS) patients compared to healthy controls (p b 0.01). A MANOVA following the same procedure was conducted for OFC but we did not find significant effects. In this set of analyses, significance threshold was set at a level of p b 0.025 in accordance to Inheritance procedure for multiple testing correction. Then, we conducted a MANOVA on four DLPFC subdivisions (left-right, white matter-gray matter) using age, gender, ICV, handedness and BMI as covariates, showing a significant difference in right white matter DLPFC volumes (F2.139 = 7.25, p b 0.01). Post-hoc analyses revealed lower right white matter DLPFC volumes in POS patients compared to healthy controls (p b 0.001) and GOS (p = 0.03). In this latter set of analyses, significance threshold level was set at p b 0.00625, thus the difference between POS and GOS did not survive the correction for multiple testing. Finally, Pearson's correlation matrix between volumes and age, BPRS positive and negative symptoms, WHO-DAS-2, CPZ-equivalents and duration of treatment did not find any significant correlations that survived Bonferroni correction for multiple comparisons.

3.2. Follow up assessment 3.2.1. Clinical variables (Table 2) Twenty-three healthy controls, 13 GOS patients and 16 POS patients were re-evaluated (average years between assessments: 3.35 years; SD = 2.11, median 3.00, range 1–9 years). Compared to GOS, POS had more severe BPRS negative symptoms (t = − 2.25, p = 0.03), higher disability (WHO-DAS-2 “getting around”: t = −2.20, p = 0.03), longer duration of antipsychotics' administration (p b 0.01), and compared to both GOS and healthy subjects higher BMI (F2. 49 = 5.49, p b 0.01). No differences were observed for age and gender composition of the sample. 3.2.2. Prefrontal volumes (Fig. 2) A paired sample t-test between baseline and follow-up values and percentage longitudinal change scores were calculated for OFC and DLPFC volumes across the three groups of subjects, revealing a statistically significant difference between baseline and follow-up only on DLPFC volumes (but not OFC) among poor outcome patients (PC = −5.85, t = 2.16, p = 0.04). Successively, a second paired sample

Fig. 1. a: baseline comparison of dorsolateral prefrontal cortex (DLPFC) volume across groups. b: baseline comparison of right dorsolateral prefrontal cortex (DLPFC) white matter volume across groups. MANOVA with age, gender, ICV and BMI as covariates and post-hoc analysis with Inheritance procedure for multiple testing correction. *p b 0.025; **p b 0.00625. HC, healthy controls, GOS good outcome patients, POS poor outcome patients.

Please cite this article as: Dusi, N., et al., Progressive disability and prefrontal shrinkage in schizophrenia patients with poor outcome: A 3-year longitudinal study, Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.09.013

N. Dusi et al. / Schizophrenia Research xxx (2016) xxx–xxx

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Table 2 descriptive statistics of follow-up sample. Healthy controls (N = 23)

Age (years) Gender: M/F Ethnicity BMI Handedness (% right) BPRS total score Negative symptoms Positive symptoms WHO-DAS-2 total score Domain 1 Domain 2 Domain 3 Domain 4 Domain 5 Domain 6 Antipsychotic medication CPZ eq. total CPZ eq. typical CPz eq. atypical Antipsychotic medication PDD/DDD total PDD/DDD typical PDD/DDD atypical Treatment Duration (years)

42.17 ± 11.90 13/10 Caucasian 23.68 ± 2.67 56.0%

GOS patients (N = 13)

POS patients (N = 16)

Statistics HC vs GOS vs POS

GOS vs POS

p

38.77 ± 9.47 10/3

46.81 ± 12.86 10/6

F2.51 = 1.75 χ2 = 1.50

t = −1.87

0.18/0.07 0.47

29.28 ± 7.09 100% 34.18 ± 5.38 8.55 ± 2.16 7.55 ± 2.46 21.45 ± 6.66 3.73 ± 1.90 2.45 ± 0.68 2.27 ± 0.90 4.27 ± 2.00 3.73 ± 1.61 5.00 ± 2.04

26.24 ± 5.24 81.3% 39.66 ± 9.85 10.92 ± 2.81 9.17 ± 3.88 22.92 ± 10.56 3.58 ± 2.27 3.58 ± 1.56 3.33 ± 1.72 3.58 ± 2.02 4.08 ± 2.46 4.75 ± 2.17

F2.51 = 5.49

t = 1.38

b0.01/0.19

t = −1.63 t = −2.25 t = −1.18 t = −0.39 t = 0.16 t = −2.20 t = −1.82 t = −0.82 t = −0.40 t = 0.28

0.11 0.03 0.25 0.69 0.87 b0.03 0.83 0.42 0.68 0.78

215.06 ± 128.93 18.52 ± 35.08 203.23 ± 147.35

280.93 ± 207.08 34.06 ± 54.79 246.86 ± 190.73

t = −0.99 t = −0.88 t = −0.57

0.32 0.38 0.57

0.68 ± 0.56 0.13 ± 0.27 0.72 ± 0.63 9.85 ± 5.129

0.78 ± 1.03 0.28 ± 0.61 1.01 ± 0.78 20.94 ± 7.94

t = −0.32 t = −0.83 t = −0.32 t = −4.34

0.75 0.41 0.75 b0.01

Legend: BMI, body mass index, CPZ-Eq, Clorpromazine-Equivalents, HC, healthy controls; GOS, good outcome schizophrenia; POS, poor outcome schizophrenia; PDD/DDD, prescribed daily dosage/defined daily dosage, WHO-DAS-2: Domain 1, understanding & communicating, Domain 2, getting around, Domain 3, self-care, Domain 4, getting along with people, Domain 5, life activities, Domain 6, participation in society. Bold values indicate significance at (P b 0.05).

t-test for DLPFC subdivisions (left, right, white matter, gray matter) was performed, showing smaller left DLPFC white matter in POS (PC = −8.57, t = 2.66, p = 0.01). No statistically significant associations were found between DLPFC and OFC volumes, age, clinical scales (BPRS, WHO-DAS).

3.2.3. Medication effect No statistically significant correlation was found between any prefrontal area volume and CPZ-equivalents or PDD/DDD of antipsychotic medication and duration of treatment (Pearson's correlations), for any group.

Fig. 2. longitudinal comparison within poor outcome patients for left dorsolateral prefrontal cortex (DLPFC) white matter volumes. Paired sample t-test. *(t = 2.66, p = 0.01). HC, healthy controls, GOS good outcome patients, POS poor outcome patients.

Please cite this article as: Dusi, N., et al., Progressive disability and prefrontal shrinkage in schizophrenia patients with poor outcome: A 3-year longitudinal study, Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.09.013

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4. Discussion In this study we conducted longitudinal analyses of poor and good outcome patients with schizophrenia (POS, GOS), i.e. kraepelinians and non kraepelinians, as per Keefe's criteria (Keefe et al., 1987). At baseline, as expected, patients with POS had higher disability compared to GOS and lower DLPFC whole volume and right DLPFC white matter volume than healthy controls. At follow-up, POS presented a significant decrease of left DLPFC white matter volume, confirming the presence of disrupted prefrontal cortex connectivity in Kraepelinian schizophrenia (Dusi et al., 2012; Mitelman et al., 2006), with more severe negative symptoms, longer treatment duration and higher disability. GOS did not present volumetric alterations either at baseline or at follow-up. This result was not expected as it is expected that GOS would have lower prefrontal volumes than healthy controls. However, it is consistent with previous literature on krepelinian vs non krepaelinian patients (Buchsbaum et al., 2009; Mitelman et al., 2005a; Mitelman et al., 2007). DLPFC is involved in circuits related to executive functions and reward behaviors, which are relevant to social behavior (Lawrence et al., 1998; Weinberger et al., 2001; Zald et al., 2014). In this line, two prior studies found that lower prefrontal cortex volumes predicted poor psychosocial outcome in schizophrenia (Chemerinski et al., 2002; Prasad et al., 2005). In a sample of first episode schizophrenia and schizoaffective disorder patients, Prasad and colleagues found low left DLPFC gray matter volume as a predictor of poor social functioning at 1 but not 2 years follow up (Prasad et al., 2005). This observation was not confirmed in our study, where DLPFC alteration was found in POS after 3 years, involving white matter, indicating a stable marker of outcome in chronic patients. Furthermore, in a sample of chronic patients, Chemerinski and colleagues found frontal gray matter areas' volume correlating with social dysfunction (Chemerinski et al., 2002). However, in their study it appeared that white matter volume was not included in the analysis. These conflicting results among studies on this topic, probably reflect the difference of the samples included in these studies, i.e. first episode vs poor outcome chronic patients, representing different stages of the disease. Hypothetically, potential resilience processes of prefrontal areas occurring early in the illness are lost as the disease progresses, whereas, in parallel, degenerative mechanisms take place over time, affecting prefrontal circuitry and cortical connectivity. These results suggest that poor psychosocial outcome in patients with schizophrenia is related to altered prefrontal fibers relevant to cognitive properties such as attention, associative learning, and working memory, as consistently confirmed by diffusion tensor imaging studies (Andreone et al., 2007; Bellani and Brambilla, 2011; Kubicki et al., 2005); according to this hypothesis, white matter, rather than gray matter, alteration and degeneration could be more relevant to illness pathology and poor functioning in schizophrenia. In conclusion, our study confirms and reinforces the hypothesis of progressive disability and prefrontal degeneration of POS over time, which may be sustained by altered connectivity mainly involving the DLPFC (Mitelman et al., 2005a; Mitelman et al., 2005b). However, it should be noted that, even though the sample at baseline was relatively consistent, the study suffers from attrition at follow-up, where a smaller number of subjects were evaluated. Also, neuropsychological and genetic assessments would help in better defining the relationships between psychosocial functioning and prefrontal morphology, ultimately allowing a more complete characterization of POS vs GOS patients (Prasad et al., 2005). Future studies should therefore replicate our findings in larger longitudinal studies involving first-episode patients, coupling imaging with neuropsychological and genetic characterization (Ruggeri et al., 2012). This will definitely help research isolating subgroups of poor/ good outcome patients who can differently benefit from tailored therapeutic (Bellani et al., 2011; Dusi et al., 2015b; Ostuzzi et al., 2013) and rehabilitation strategies (Cheng and Jones, 2013; Ruggeri and Tansella, 2013; Vita et al., 2013).

Contributors PB designed the study and wrote the protocol. ND worked on imaging post-processing and wrote the first draft of the manuscript, along with MB. ND and LF run statistical analyses. CP and VM recruited the subjects and administered clinical assessment. All authors contributed to the interpretation of the data, revised the manuscript and agreed with the final content of the manuscript.

Funding body agreements and policies PB and MB were partly supported by the Italian Ministry of Health (RF-2011-02352308 to Dr. Brambilla and GR-2010-2319022 to Dr. Bellani). Conflict of interest No authors of this manuscript have fees and grants from, employment by, consultancy for, shared ownership in, or any close relationship with an organization whose interests, financial or otherwise, may by affected by the publication of the paper. Acknowledgments PB and MB were partly supported by the Italian Ministry of Health (RF-201102352308 to Dr. Brambilla and GR-2010-2319022 to Dr. Bellani). We thank Prof. Vaibhav Diwadkar for thoughtful suggestions and careful linguistic correction of the manuscript and Gianluca Rambaldelli for helping with the management of the dataset for the earlier versions of the manuscript.

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Please cite this article as: Dusi, N., et al., Progressive disability and prefrontal shrinkage in schizophrenia patients with poor outcome: A 3-year longitudinal study, Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.09.013

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Please cite this article as: Dusi, N., et al., Progressive disability and prefrontal shrinkage in schizophrenia patients with poor outcome: A 3-year longitudinal study, Schizophr. Res. (2016), http://dx.doi.org/10.1016/j.schres.2016.09.013