Reduced dorso-lateral prefrontal cortex in treatment resistant schizophrenia

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Reduced dorso-lateral prefrontal cortex in treatment resistant schizophrenia

André Zugman a,⁎, Ary Gadelha a,b, Idaiane Assunção a, João Sato c, Vanessa K. Ota a,d, Deyvis L. Rocha b,Jair J. Mari a,b,e, Sintia I. Belangero a,d,e, Rodrigo A. Bressan a,b,e,Elisa Brietzke a,e, Andrea P. Jackowski a,e

a Interdiciplinary Laboratory in Clinical Neuroscience (LiNC), Department of Psychiatry, Federal University of São Paulo, São Paulo, Brazilb PROESQ: Schizophrenia Program, Federal University of São Paulo, São Paulo, Brazilc Center of Mathematics, Computation and Cognition, Federal University of ABC, Santo André, Brazild Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazile Department of Psychiatry, Federal University of São Paulo, São Paulo, Brazil

⁎ Corresponding author at: Interdiciplinary LaboratoryDepartment of Psychiatry, UNIFESP, Edifício de Pesquisas Ifloor, Vila Clementino, Unmarked definida por andrezugTel.: +55 11 5576 4845.

E-mail address: [email protected] (A. Zugm

0920-9964/$ – see front matter © 2013 Elsevier B.V. Allhttp://dx.doi.org/10.1016/j.schres.2013.05.002

Please cite this article as: Zugman, A., et al., Rhttp://dx.doi.org/10.1016/j.schres.2013.05.00

a b s t r a c t

a r t i c l e i n f o

Article history:

Received 16 January 2013Received in revised form 30 April 2013Accepted 2 May 2013Available online xxxx

Keywords:Cortical thicknessSchizophreniaTreatment resistantRefractoryMRI

Background: Treatment resistance affects up to one third of patients with schizophrenia (SCZ). A better un-derstanding of its biological underlying processes could improve treatment. The aim of this study was tocompare cortical thickness between non-resistant SCZ (NR-SCZ), treatment-resistant SCZ (TR-SCZ) patientsand healthy controls (HC).Methodology: Structural MRI scans were obtained from 3 groups of individuals: 61 treatment resistant SCZ in-dividuals, 67 non-resistant SCZ and 80 healthy controls. Images were analyzed using cortical surface model-ling (implemented in freesurfer package) to identify group differences in cortical thickness. Statisticalsignificant differences were identified using Monte-Carlo simulation method with a corrected p-cluster b 0.01.Results: Patients in the TR-SCZ group showed a widespread reduction in cortical thickness in frontal, parietal,temporal and occipital regions bilaterally. NR-SCZ group had reduced cortex in two regions (left superior frontalcortex and left caudal middle frontal cortex). TR-SCZ group also showed decreased thickness in the left dorso-

lateral prefrontal cortex (DLPFC) when compared with patients from NR-SCZ group.Conclusions: The reduction in cortical thickness in DLPFC indicates amore severe form of the disease or a specificfinding for this group. Alterations in this region should be explored as a putative marker for treatment resis-tance. Prospective studies, with individuals being followed from first episode psychosis until refractoriness is di-agnosed, are needed to clarify these hypotheses.

© 2013 Elsevier B.V. All rights reserved.

1. Introduction

Schizophrenia (SCZ) is a chronic psychotic disorder associatedwith significant impairment in social and occupational functioningthat is estimated to affect 0.3 to 1.6% of the population (Kessler etal., 2005; Tandon et al., 2008).

In spite of recent advances in development of new antipsychotics,failure to achieve expected response is rather common, and 20–33%of patients with SCZ show limited response to standard medications(Lieberman et al., 1989; Lieberman, 1993; Wiersma et al., 1998).Treatment resistance to neuroleptic agents is more frequent in malethan female, patients with poorer premorbid functioning, and earlierage of onset (Meltzer, 1997).

After the robust evidence of the superiority in efficacy of clozapineover other antipsychotics (Kane et al., 1988; Wahlbeck et al., 1999;

in Clinical Neuroscience (LiNC),I, Rua Pedro de Toledo, 669, 3rdman, 04039-032 São Paulo, SP.

an).

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educed dorso-lateral prefront2

Chakos et al., 2001; Iqbal et al., 2003), there was a recent trend tomove to broader definitions of treatment resistance so that more pa-tients are offered treatment with clozapine (Bondolfi et al., 1998;Pantelis and Lambert, 2003; The British Psychological Society andThe Royal College of Psychiatrists, 2010). In fact, clozapine appearsto have a positive effect even in symptoms traditionally consideredresistant, such as negative symptoms and cognitive disturbances,particularly in domains of attention, verbal fluency and executivefunctions (Meltzer andMcGurk, 1999). Nevertheless, due to its severeadverse effects clozapine prescription is recommended only after thepatient being considered as treatment resistant (i.e.: failure to twoadequate trial with antipsychotics) (Moore et al., 2007; The BritishPsychological Society and The Royal College of Psychiatrists, 2010).In contrast with the significance of refractoriness in clinical setting,there are only few studies investigating possible neurobiological cor-relates or consequences of lack of response to neuroleptic agents. Todate there are no putative biological marker that could help cliniciansto propose an earlier introduction of clozapine.

Regarding structural abnormalities in SCZ, one of the most repli-cated findings is that individuals with this disease show reductions

al cortex in treatment resistant schizophrenia, Schizophr. Res. (2013),

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in brain volume and cortical thickness in several regions (e. g.: pre-frontal and temporal cortices) (Kuperberg et al., 2003; Cotter et al.,2004; Wiegand et al., 2004; Narr et al., 2005; Hamilton et al., 2007;Narayan et al., 2007; Yoon et al., 2007; Nesvag et al., 2008; Schultzet al., 2010). Disease duration, severity and medication use (Staal etal., 2001; Woods et al., 2005; Haijma et al., 2012) have been associatedwith these reductions. In addition, poorer treatment response has beenlinked to gray matter reduction (Harvey et al., 1993; Lieberman, 1999),but there are no studies evaluating brain thickness in treatment resis-tant SCZ and in comparison to non-treatment resistant patients. Corti-cal thickness is thought to better represent an endophenotype for adisorder than volume (which is cortical thickness and area measurescombined) (Panizzon et al., 2009).

The objective of this study is to compare cortical thickness be-tween non-resistant schizophrenia, treatment-resistant schizophre-nia and healthy controls. We hypothesize that TR-SCZ group willhave greater reduction in cortical thickness, which would be compat-ible with a more severe disease process.

2. Methods

2.1. Participants

A total of 208 participants, being 61 TR-SCZ, 67 NR-SCZ, 80 HC par-ticipated in this study. Subjects were recruited from an outpatientunit for treatment of SCZ. Diagnosis was confirmed according toDSM-IV criteria using The Structured Clinical Interview for DSM-IV(SCID I). Trained psychiatrists conducted all interviews. All patientswere being followed for at least one year. Healthy controls wererecruited from a governmental employment agency, among individ-uals without any current or lifetime psychiatric diagnosis or 1stdegree relative with a major psychiatric condition. Subjects in theNR-SCZ and TR-SCZ were also assessed with the positive and negativesyndrome scale (PANSS) (Kay et al., 1987) and global assessment offunctioning (GAF) (Jones et al., 1995). Medication doses were stan-dardized using defined daily dose (DDD), following the guidelinesavailable in http://www.whocc.no/atc_ddd_index.

Treatment resistance was defined as a failure to respond to4–6 week trials of at least two different antipsychotic medicationsin adequate doses (equivalent to at least 400 mg/day of chlorproma-zine or 5 mg/day of risperidone). Additionally, 6 month periodwithout remission was required (i.e.: score of 4 or more in eightPANSS items: delusions, unusual thought content, hallucinatorybehavior, mannerisms/posturing, blunted affect, social withdrawal,and lack of spontaneity). These criteria follow the recommenda-tion of the International Psychopharmacological Algorithm Project[www.ipap.org].

This study was approved by the Research Ethics Committee ofUNIFESP [CEP No. 0661/11], and a written informed consent wasobtained from all recruited participants. Clinical and laboratory

Table 1Clinical and demographic characteristics of the sample.

HC (n = 80) TR-SCZ (n

Age in years (mean/SD) 33.46/8.67 33.80/8.54Male (%) 66 65PANSS positive (mean/SD) – 14.10/4.52PANSS negative (mean/SD) – 18.67/5.75PANSS general (mean/SD) – 30.39/7.62PANSS total (mean/SD) – 63.41/14.82GAF (mean/SD) – 47.77/10.95Duration of illness in years (mean/SD) – 12.9/6.72DDD (mean/SD) – 1.71/.68

PANSS: positive and negative syndrome scale; GAF: global assessment of functioning scale;⁎ p b 0.05.

Please cite this article as: Zugman, A., et al., Reduced dorso-lateral prefronthttp://dx.doi.org/10.1016/j.schres.2013.05.002

investigations were strictly conducted according to the principlesexpressed in the Declaration of Helsinki.

2.2. MRI Protocol

Images were acquired in a Siemens 1.5 T scanner using a 3DSPGRsequence for volumetric analysis (TE = 3.4 ms; TR = 2000 ms;FoV = 256 mm; flip angle: 15°; matrix size: 256 × 256; slice thickness:1 mm).

2.3. Data analysis

Cortical reconstruction and volumetric segmentationwere performedwith the Freesurfer image analysis suite, which is documented and freelyavailable for download online (http://surfer.nmr.mgh.harvard.edu/). Thetechnical details of these procedures are described in prior publications(Fischl and Dale, 2000; Fischl, 2012).

For statistical analysis we used the general linear model in order toidentify the main effect of group (TR-SCZ vs SCZ; TR-SCZ vs control;SCZ vs control), controlling for age and gender and a surface Gaussiansmoothing (FWHM = 15 mm). Statistical significant differenceswere identified using Monte-Carlo simulation method with a correctedp-cluster b 0.01 (vertex-z-threshold = 2.0). For the comparison be-tween patient groupsweused the PANSS total score as a nuisance factorin order to reduce the influences of symptom severity. Additional anal-yses were carried out with duration of illness and DDD as nuisance fac-tor. In patients receiving clozapine, DDD was correlated to thicknessco-varied for age and gender.

For demographics and clinical characteristics we used one-wayANOVA or chi-square test (when appropriated) using SPSS 20.0 forMac. Statistical significance was set in 0.05.

3. Results

Demographics and clinical characteristics of the sample are de-scribed in Table 1. All subjects with schizophrenia from both treat-ment groups were receiving antipsychotic medication. The majorityof patients in TR-SCZ group were receiving clozapine (clozapine:72.1%, olanzapine: 19.7%, quetiapine: 3.3%, haloperidol: 1%, risperi-done: 1% and aripriprazole: 1%). NR-SCZ received olanzapine morefrequently (55.2%) followed by quetiapine (13.4%), risperidone (13.4%),haloperidol (6%), ariprirazole (6%), ziprasidone (1.5%), trifluoperazine(1.5%), paliperidone (1.5%) and, zuclopenthixol (1.5%).

3.1. Non-resistant schizophrenia vs healthy control

NR-SCZ exhibited significant decrease in the left superior frontalcortex (Fig. 1) (coordinates (x,y,z): −11, 19.2, 35.4, cluster size:1222 mm2, p b 0.01) and left caudal middle frontal cortex (coordinates(x,y,z): −38, 13.7, 32.5, cluster size: 1005 mm2, p ≤ 0.01).

= 61) NTR-SCZ (n = 67) Test-value P

35.81/8.76 F = 1.48 0.22967 X2 = 0.80 0.91411.61/3.66 F = 11.99 0.001⁎

15.39/4.68 F = 12.63 0.001⁎

27.73/6.84 F = 4.33 0.03⁎

54.58/12.63 F = 13.21 b0.001⁎

55.42/12.88 F = 12.63 b0.001⁎

12.21/7.29 F = 0.310 0.571.34/0.63 F = 10.43 0.002⁎

DDD: antipsychotic defined daily dose.

al cortex in treatment resistant schizophrenia, Schizophr. Res. (2013),

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Fig. 1. Comparison of non-refractory schizophrenia group with healthy control group. Statistical map of cortical thickness difference between non-resistant schizophrenia groupand healthy control group corrected for multiple comparison. Blue area represents thinner cortical areas in non-resistant schizophrenia group. (For interpretation of the referencesto color in this figure legend, the reader is referred to the web version of this article.)

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3.2. Treatment resistant schizophrenia vs healthy control

The analysis between TR-SCZ and HC showed difference in six clus-ters in the left hemisphere and four clusters in the right hemisphere fora corrected p-cluster b 0.01. Clusters' locations are summarized inTable 2 and Fig. 2.

3.3. Treatment resistant schizophrenia vs non-resistant schizophrenia

A significant reduction in the left dorsolateral prefrontal cortex(DLPF) thickness was observed in TR-SCZ in comparison to NR-SCZgroup. This difference remained significant when DDD and diseaseduration were considered as nuisance factor (coordinates (x,y,z): −30,44, 4.5, cluster size: 1168 mm2, p b 0.01) (Fig. 3). There was no associ-ation between clozapine (n = 44) DDD and thickness.

4. Discussion

The results of this study showed that TR-SCZ group presented amore widespread cortical thickness reduction, with 10 clusters inboth hemispheres. NR-SCZ group showed 2 clusters in the left hemi-sphere with decreased thickness. In addition, a significant reductionin the left DLPFC of TR-SCZ was found as compared to NR-SCZ. Al-though cortical thickness could be related to other markers of illnessseverity, our analysis showed that this difference was not due tohigher scores in PANSS.

Table 2Cluster coordinate sizes and significance for comparison treatment resistant schizo-phrenia group and healthy control group.

Cluster X Y Z Size (mm2) P Region

Left hemisphere1 −22 31 −10.3 9615 0.001 Lateral orbitofrontal2 −48 3 −28.5 3312 0.001 Middle temporal3 −28 −76 −3 1170 0.001 Fusiform4 −25 13 42 4003 0.001 Caudal middle frontal5 −54 −44 12 2458 0.001 Superior temporal gyrus6 −16 67 4 831 0.001 Lingual

Right hemisphere1 47 5 14 6400 0.001 Precentral2 41 29 −6 2515 0.001 Parstriangularis3 49 4 −26 3903 0.001 Middle temporal4 28 −78 −3 1134 0.001 Lateral occipital

Please cite this article as: Zugman, A., et al., Reduced dorso-lateral prefronthttp://dx.doi.org/10.1016/j.schres.2013.05.002

Global gray matter reduction has been found to be a marker ofpoorer outcome in SCZ (Mitelman et al., 2003; Molina et al., 2010).The reduction in only two areas in NR-SCZ group could be related tothis fact. The NR-SCZ group, indeed have GAF and PANSS scores thatindicate less severe symptomatology. In fact in the TR-SCZ groupthere was a significant decrease in thickness in frontal, parietal, tem-poral and occipital regions. This could reflect an overlap betweentreatment resistance criteria and the worse outcome. Patients withworse outcome exhibit larger decrease in volume on follow-up (vanHaren et al., 2008). Interestingly, prior reports of structural findingsin SCZ with poor outcome described posterior gray matter deficits(Mitelman and Buchsbaum, 2007). Whereas good outcome and badoutcome schizophrenia exhibited graymatter deficits in frontotemporalregions what differentiated patients with bad or good outcome weredeficits in the temporal and occipital regions (Mitelman et al., 2007).NR-SCZ in fact exhibited reduced thickness in left frontal lobe, and nothickness reduction in other lobes. However, when comparing bothSCZ groups, TR-SCZ showed a significance reduction in thickness inthe DLPFC.

Moreover, structural and functional (Minzenberg et al., 2009)neuroimaging studies demonstrate alteration in the DLPFC of schizo-phrenia patients. Further, the left frontal cortex had been previouslyshowed to relate to prognosis in longitudinal studies. For instanceworse BPRS symptoms correlated with faster decline in volume ofleft frontal gray matter (Mathalon, 2011). Additionally poor outcomeschizophrenia was associated with weaker correlation between leftprefrontal areas and medial and prefrontal cortices, as comparedto good outcome and healthy subjects, indicating a disrupted connec-tion between these areas (Mitelman et al., 2005). The DLPFC area wasrelated to working memory function (Petrides et al., 1993; Friedmanand Goldman-Rakic, 1994) and deficits in this function were well de-scribed in SCZ (Park et al., 1999; Barch et al., 2001; Manoach, 2003).There is evidence that structural network related to working memorymight be impaired in SCZ. A study by Ehrlich et al. (2012) found asso-ciation between lateral prefrontal cortex thickness and workingmemory in healthy controls, while subjects in the schizophreniagroup showed this association with right middle and superior tempo-ral gyrus. Cognitive deficits are thought to reflect cortical neuropa-thology (Ehrlich et al., 2012); thus it is possible that our findingreflects a more specific pathological process that leads to treatmentresistance.

Interestingly, DLPFC functioning at baseline predicted poor treatmentresponse to antipsychotic medication after 10 weeks (van Veelen et al.,

al cortex in treatment resistant schizophrenia, Schizophr. Res. (2013),

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Fig. 2. Comparison between treatment resistant schizophrenia group and healthy control group. Statistical map of cortical thickness difference between treatment-resistant schizo-phrenia group and healthy control group. Cluster-wise probability (CWP) values (corrected for multiple comparisons) are represented as blue color where CWP b 0.01. (For inter-pretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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2011). There is evidence that higher DLPFC volume predicts response toclozapine (Molina et al., 2003). Our finding combined with those of pre-vious studies might reflect that an alteration in the DLPFC could be amarker of worse treatment response to antipsychotic medication, lead-ing to worse prognosis in SCZ patients.

A possible confound is the overlap of subjects in TR-SCZ group andthose receiving clozapine. However there was no correlation betweenclozapineDDDand cortical thickness. This is in linewith previous reportof lack of effect of clozapine and olanzapine in brain development inchild onset schizophrenia (Mattai et al., 2010). Furthermore alteredfrontal lobe in drug-naïve first episode patients suggests that it is not in-duced by medication (Hazlett et al., 2008; Venkatasubramanian et al.,2008).

This is a cross-sectional study, and it, is not possible to confirm ifthe reduced cortical area associated with TR-SCZ was already presentat earlier stages of the disease. Additionally PANSS scores refer to thecurrent clinical presentation. This may not reflect global disease se-verity. Another factor that limits interpretation of the result is the ex-posure to different medications between groups. On the other hand,the main strength of this study is that we used the same criteriaused to recommend a trial with clozapine in clinical setting (Mooreet al., 2007; The British Psychological Society and The Royal Collegeof Psychiatrists, 2010).

Fig. 3. Group effect between treatment resistant schizophrenia and non-resistant schizophrelated to non-resistant schizophrenia group corrected for multiple comparisons.

Please cite this article as: Zugman, A., et al., Reduced dorso-lateral prefronthttp://dx.doi.org/10.1016/j.schres.2013.05.002

5. Conclusion

In this study, a reduction in the left DLPFC was suggested as a neu-roimaging marker for treatment resistance. If this finding is con-firmed in further studies with longitudinal design, it opens newavenues for investigation of neurobiological substrates of refractori-ness. The development of novel strategies for early identification oftreatment resistance might help to develop algorithms for earlieruse of specific treatments (such as clozapine).

Role of funding sourceThis work was supported by São Paulo Research Foundation (FAPESP; 2011/

50740-5) to RAB.

ContributorsAuthor Andre Zugman wrote the first draft of the manuscript and analyzed MRI

data. Author Ary Gadelha designed the study and managed literature searches. IdaianeAssunção was responsible for MRI acquisition and reviewed the manuscript. João Satoanalyzed MRI data and reviewed the manuscript. Authors Vanessa Kiyomi Ota andDeyvis Loureiro Rocha were responsible for patient recruitment and clinical inter-views. Jair de Jesus Mari, Sintia Iole Belangero, Rodrigo A. Bressan and Elisa Brietzkereviewed the initial manuscript and conducted literature searches. Andrea P. Jackowskidesigned the study, analyzed MRI data and reviewed the manuscript. All authors con-tributed to and approved the final draft of the manuscript.

renia. Statistical map of reduced thickness in treatment-resistant schizophrenia group

al cortex in treatment resistant schizophrenia, Schizophr. Res. (2013),

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Conflict of interestDr. Ary Gadelha has received speaker honoraria from Janseen-Cilag. Dr Rodrigo

Bressan has received honoraria and/or consultations fees from Astra Zeneca, Bristol,Janssen, and Lundbeck; has received research funding from Janssen, Eli Lilly, Lundbeck,Novartis, and Roche. Dr. Elisa Brietzke has received speaker honoraria from Janssen-Cilag, Pfizer and Lundbeck. All other authors declare no conflict of interest inherentto this article.

AcknowledgmentsNone.

Appendix A. Supplementary data

Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.schres.2013.05.002.

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