Reduced dorso-lateral prefrontal cortex in treatment resistant schizophrenia

SCHRES-05417; No of Pages 6 Schizophrenia Research xxx (2013) xxx–xxx

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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, Brazil PROESQ: Schizophrenia Program, Federal University of São Paulo, São Paulo, Brazil Center of Mathematics, Computation and Cognition, Federal University of ABC, Santo André, Brazil d Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil e Department of Psychiatry, Federal University of São Paulo, São Paulo, Brazil b c

a r t i c l e

i n f o

Article history: Received 16 January 2013 Received in revised form 30 April 2013 Accepted 2 May 2013 Available online xxxx Keywords: Cortical thickness Schizophrenia Treatment resistant Refractory MRI

a b s t r a c t Background: Treatment resistance affects up to one third of patients with schizophrenia (SCZ). A better understanding of its biological underlying processes could improve treatment. The aim of this study was to compare cortical thickness between non-resistant SCZ (NR-SCZ), treatment-resistant SCZ (TR-SCZ) patients and healthy controls (HC). Methodology: Structural MRI scans were obtained from 3 groups of individuals: 61 treatment resistant SCZ individuals, 67 non-resistant SCZ and 80 healthy controls. Images were analyzed using cortical surface modelling (implemented in freesurfer package) to identify group differences in cortical thickness. Statistical significant 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 frontal cortex and left caudal middle frontal cortex). TR-SCZ group also showed decreased thickness in the left dorsolateral prefrontal cortex (DLPFC) when compared with patients from NR-SCZ group. Conclusions: The reduction in cortical thickness in DLPFC indicates a more severe form of the disease or a specific finding for this group. Alterations in this region should be explored as a putative marker for treatment resistance. Prospective studies, with individuals being followed from first episode psychosis until refractoriness is diagnosed, are needed to clarify these hypotheses. © 2013 Elsevier B.V. All rights reserved.

1. Introduction Schizophrenia (SCZ) is a chronic psychotic disorder associated with significant impairment in social and occupational functioning that is estimated to affect 0.3 to 1.6% of the population (Kessler et al., 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 male than female, patients with poorer premorbid functioning, and earlier age of onset (Meltzer, 1997). After the robust evidence of the superiority in efficacy of clozapine over other antipsychotics (Kane et al., 1988; Wahlbeck et al., 1999; ⁎ Corresponding author at: Interdiciplinary Laboratory in Clinical Neuroscience (LiNC), Department of Psychiatry, UNIFESP, Edifício de Pesquisas II, Rua Pedro de Toledo, 669, 3rd floor, Vila Clementino, Unmarked definida por andrezugman, 04039-032 São Paulo, SP. Tel.: +55 11 5576 4845. E-mail address: [email protected] (A. Zugman).

Chakos et al., 2001; Iqbal et al., 2003), there was a recent trend to move to broader definitions of treatment resistance so that more patients are offered treatment with clozapine (Bondolfi et al., 1998; Pantelis and Lambert, 2003; The British Psychological Society and The Royal College of Psychiatrists, 2010). In fact, clozapine appears to have a positive effect even in symptoms traditionally considered resistant, such as negative symptoms and cognitive disturbances, particularly in domains of attention, verbal fluency and executive functions (Meltzer and McGurk, 1999). Nevertheless, due to its severe adverse effects clozapine prescription is recommended only after the patient being considered as treatment resistant (i.e.: failure to two adequate trial with antipsychotics) (Moore et al., 2007; The British Psychological 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 correlates or consequences of lack of response to neuroleptic agents. To date there are no putative biological marker that could help clinicians to propose an earlier introduction of clozapine. Regarding structural abnormalities in SCZ, one of the most replicated findings is that individuals with this disease show reductions

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Please cite this article as: Zugman, A., et al., Reduced dorso-lateral prefrontal cortex in treatment resistant schizophrenia, Schizophr. Res. (2013), http://dx.doi.org/10.1016/j.schres.2013.05.002

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A. Zugman et al. / Schizophrenia Research xxx (2013) xxx–xxx

in brain volume and cortical thickness in several regions (e. g.: prefrontal 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; Schultz et al., 2010). Disease duration, severity and medication use (Staal et al., 2001; Woods et al., 2005; Haijma et al., 2012) have been associated with these reductions. In addition, poorer treatment response has been linked to gray matter reduction (Harvey et al., 1993; Lieberman, 1999), but there are no studies evaluating brain thickness in treatment resistant SCZ and in comparison to non-treatment resistant patients. Cortical thickness is thought to better represent an endophenotype for a disorder than volume (which is cortical thickness and area measures combined) (Panizzon et al., 2009). The objective of this study is to compare cortical thickness between non-resistant schizophrenia, treatment-resistant schizophrenia and healthy controls. We hypothesize that TR-SCZ group will have greater reduction in cortical thickness, which would be compatible 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 participated in this study. Subjects were recruited from an outpatient unit for treatment of SCZ. Diagnosis was confirmed according to DSM-IV criteria using The Structured Clinical Interview for DSM-IV (SCID I). Trained psychiatrists conducted all interviews. All patients were being followed for at least one year. Healthy controls were recruited from a governmental employment agency, among individuals without any current or lifetime psychiatric diagnosis or 1st degree relative with a major psychiatric condition. Subjects in the NR-SCZ and TR-SCZ were also assessed with the positive and negative syndrome scale (PANSS) (Kay et al., 1987) and global assessment of functioning (GAF) (Jones et al., 1995). Medication doses were standardized using defined daily dose (DDD), following the guidelines available in http://www.whocc.no/atc_ddd_index. Treatment resistance was defined as a failure to respond to 4–6 week trials of at least two different antipsychotic medications in adequate doses (equivalent to at least 400 mg/day of chlorpromazine or 5 mg/day of risperidone). Additionally, 6 month period without remission was required (i.e.: score of 4 or more in eight PANSS items: delusions, unusual thought content, hallucinatory behavior, mannerisms/posturing, blunted affect, social withdrawal, and lack of spontaneity). These criteria follow the recommendation of the International Psychopharmacological Algorithm Project [www.ipap.org]. This study was approved by the Research Ethics Committee of UNIFESP [CEP No. 0661/11], and a written informed consent was obtained from all recruited participants. Clinical and laboratory

investigations were strictly conducted according to the principles expressed in the Declaration of Helsinki. 2.2. MRI Protocol Images were acquired in a Siemens 1.5 T scanner using a 3DSPGR sequence 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 segmentation were performed with the Freesurfer image analysis suite, which is documented and freely available for download online (http://surfer.nmr.mgh.harvard.edu/). The technical 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 to identify the main effect of group (TR-SCZ vs SCZ; TR-SCZ vs control; SCZ vs control), controlling for age and gender and a surface Gaussian smoothing (FWHM = 15 mm). Statistical significant differences were identified using Monte-Carlo simulation method with a corrected p-cluster b 0.01 (vertex-z-threshold = 2.0). For the comparison between patient groups we used the PANSS total score as a nuisance factor in order to reduce the influences of symptom severity. Additional analyses were carried out with duration of illness and DDD as nuisance factor. In patients receiving clozapine, DDD was correlated to thickness co-varied for age and gender. For demographics and clinical characteristics we used one-way ANOVA or chi-square test (when appropriated) using SPSS 20.0 for Mac. Statistical significance was set in 0.05. 3. Results Demographics and clinical characteristics of the sample are described in Table 1. All subjects with schizophrenia from both treatment groups were receiving antipsychotic medication. The majority of patients in TR-SCZ group were receiving clozapine (clozapine: 72.1%, olanzapine: 19.7%, quetiapine: 3.3%, haloperidol: 1%, risperidone: 1% and aripriprazole: 1%). NR-SCZ received olanzapine more frequently (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 frontal cortex (Fig. 1) (coordinates (x,y,z): − 11, 19.2, 35.4, cluster size: 1222 mm 2, 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).

Table 1 Clinical and demographic characteristics of the sample.

Age in years (mean/SD) Male (%) PANSS positive (mean/SD) PANSS negative (mean/SD) PANSS general (mean/SD) PANSS total (mean/SD) GAF (mean/SD) Duration of illness in years (mean/SD) DDD (mean/SD)

HC (n = 80)

TR-SCZ (n = 61)

NTR-SCZ (n = 67)

Test-value

P

33.46/8.67 66 – – – – – – –

33.80/8.54 65 14.10/4.52 18.67/5.75 30.39/7.62 63.41/14.82 47.77/10.95 12.9/6.72 1.71/.68

35.81/8.76 67 11.61/3.66 15.39/4.68 27.73/6.84 54.58/12.63 55.42/12.88 12.21/7.29 1.34/0.63

F X2 F F F F F F F

0.229 0.914 0.001⁎ 0.001⁎ 0.03⁎ b0.001⁎ b0.001⁎

= = = = = = = = =

1.48 0.80 11.99 12.63 4.33 13.21 12.63 0.310 10.43

0.57 0.002⁎

PANSS: positive and negative syndrome scale; GAF: global assessment of functioning scale; DDD: antipsychotic defined daily dose. ⁎ p b 0.05.

Please cite this article as: Zugman, A., et al., Reduced dorso-lateral prefrontal cortex in treatment resistant schizophrenia, Schizophr. Res. (2013), http://dx.doi.org/10.1016/j.schres.2013.05.002

A. Zugman et al. / Schizophrenia Research xxx (2013) xxx–xxx

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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 group and healthy control group corrected for multiple comparison. Blue area represents thinner cortical areas in non-resistant schizophrenia group. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

3.2. Treatment resistant schizophrenia vs healthy control The analysis between TR-SCZ and HC showed difference in six clusters in the left hemisphere and four clusters in the right hemisphere for a corrected p-cluster b 0.01. Clusters' locations are summarized in Table 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-SCZ group. This difference remained significant when DDD and disease duration were considered as nuisance factor (coordinates (x,y,z): −30, 44, 4.5, cluster size: 1168 mm 2, p b 0.01) (Fig. 3). There was no association between clozapine (n = 44) DDD and thickness. 4. Discussion The results of this study showed that TR-SCZ group presented a more widespread cortical thickness reduction, with 10 clusters in both hemispheres. NR-SCZ group showed 2 clusters in the left hemisphere with decreased thickness. In addition, a significant reduction in the left DLPFC of TR-SCZ was found as compared to NR-SCZ. Although cortical thickness could be related to other markers of illness severity, our analysis showed that this difference was not due to higher scores in PANSS.

Table 2 Cluster coordinate sizes and significance for comparison treatment resistant schizophrenia group and healthy control group. Cluster

X

Left hemisphere 1 −22 2 −48 3 −28 4 −25 5 −54 6 −16

Y

Z

Size (mm2)

P

Region

31 3 −76 13 −44 67

−10.3 −28.5 −3 42 12 4

9615 3312 1170 4003 2458 831

0.001 0.001 0.001 0.001 0.001 0.001

Lateral orbitofrontal Middle temporal Fusiform Caudal middle frontal Superior temporal gyrus Lingual

14 −6 −26 −3

6400 2515 3903 1134

0.001 0.001 0.001 0.001

Precentral Parstriangularis Middle temporal Lateral occipital

Right hemisphere 1 47 5 2 41 29 3 49 4 4 28 −78

Global gray matter reduction has been found to be a marker of poorer outcome in SCZ (Mitelman et al., 2003; Molina et al., 2010). The reduction in only two areas in NR-SCZ group could be related to this fact. The NR-SCZ group, indeed have GAF and PANSS scores that indicate less severe symptomatology. In fact in the TR-SCZ group there was a significant decrease in thickness in frontal, parietal, temporal and occipital regions. This could reflect an overlap between treatment resistance criteria and the worse outcome. Patients with worse outcome exhibit larger decrease in volume on follow-up (van Haren et al., 2008). Interestingly, prior reports of structural findings in SCZ with poor outcome described posterior gray matter deficits (Mitelman and Buchsbaum, 2007). Whereas good outcome and bad outcome schizophrenia exhibited gray matter deficits in frontotemporal regions what differentiated patients with bad or good outcome were deficits in the temporal and occipital regions (Mitelman et al., 2007). NR-SCZ in fact exhibited reduced thickness in left frontal lobe, and no thickness reduction in other lobes. However, when comparing both SCZ groups, TR-SCZ showed a significance reduction in thickness in the DLPFC. Moreover, structural and functional (Minzenberg et al., 2009) neuroimaging studies demonstrate alteration in the DLPFC of schizophrenia patients. Further, the left frontal cortex had been previously showed to relate to prognosis in longitudinal studies. For instance worse BPRS symptoms correlated with faster decline in volume of left frontal gray matter (Mathalon, 2011). Additionally poor outcome schizophrenia was associated with weaker correlation between left prefrontal areas and medial and prefrontal cortices, as compared to good outcome and healthy subjects, indicating a disrupted connection between these areas (Mitelman et al., 2005). The DLPFC area was related to working memory function (Petrides et al., 1993; Friedman and Goldman-Rakic, 1994) and deficits in this function were well described in SCZ (Park et al., 1999; Barch et al., 2001; Manoach, 2003). There is evidence that structural network related to working memory might be impaired in SCZ. A study by Ehrlich et al. (2012) found association between lateral prefrontal cortex thickness and working memory in healthy controls, while subjects in the schizophrenia group showed this association with right middle and superior temporal gyrus. Cognitive deficits are thought to reflect cortical neuropathology (Ehrlich et al., 2012); thus it is possible that our finding reflects a more specific pathological process that leads to treatment resistance. Interestingly, DLPFC functioning at baseline predicted poor treatment response to antipsychotic medication after 10 weeks (van Veelen et al.,

Please cite this article as: Zugman, A., et al., Reduced dorso-lateral prefrontal cortex in treatment resistant schizophrenia, Schizophr. Res. (2013), http://dx.doi.org/10.1016/j.schres.2013.05.002

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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 schizophrenia 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 interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

2011). There is evidence that higher DLPFC volume predicts response to clozapine (Molina et al., 2003). Our finding combined with those of previous studies might reflect that an alteration in the DLPFC could be a marker of worse treatment response to antipsychotic medication, leading to worse prognosis in SCZ patients. A possible confound is the overlap of subjects in TR-SCZ group and those receiving clozapine. However there was no correlation between clozapine DDD and cortical thickness. This is in line with previous report of lack of effect of clozapine and olanzapine in brain development in child onset schizophrenia (Mattai et al., 2010). Furthermore altered frontal lobe in drug-naïve first episode patients suggests that it is not induced by medication (Hazlett et al., 2008; Venkatasubramanian et al., 2008). This is a cross-sectional study, and it, is not possible to confirm if the reduced cortical area associated with TR-SCZ was already present at earlier stages of the disease. Additionally PANSS scores refer to the current clinical presentation. This may not reflect global disease severity. Another factor that limits interpretation of the result is the exposure to different medications between groups. On the other hand, the main strength of this study is that we used the same criteria used to recommend a trial with clozapine in clinical setting (Moore et al., 2007; The British Psychological Society and The Royal College of Psychiatrists, 2010).

5. Conclusion In this study, a reduction in the left DLPFC was suggested as a neuroimaging marker for treatment resistance. If this finding is confirmed in further studies with longitudinal design, it opens new avenues for investigation of neurobiological substrates of refractoriness. The development of novel strategies for early identification of treatment resistance might help to develop algorithms for earlier use of specific treatments (such as clozapine). Role of funding source This work was supported by São Paulo Research Foundation (FAPESP; 2011/ 50740-5) to RAB.

Contributors Author Andre Zugman wrote the first draft of the manuscript and analyzed MRI data. Author Ary Gadelha designed the study and managed literature searches. Idaiane Assunção was responsible for MRI acquisition and reviewed the manuscript. João Sato analyzed MRI data and reviewed the manuscript. Authors Vanessa Kiyomi Ota and Deyvis Loureiro Rocha were responsible for patient recruitment and clinical interviews. Jair de Jesus Mari, Sintia Iole Belangero, Rodrigo A. Bressan and Elisa Brietzke reviewed the initial manuscript and conducted literature searches. Andrea P. Jackowski designed the study, analyzed MRI data and reviewed the manuscript. All authors contributed to and approved the final draft of the manuscript.

Fig. 3. Group effect between treatment resistant schizophrenia and non-resistant schizophrenia. Statistical map of reduced thickness in treatment-resistant schizophrenia group related to non-resistant schizophrenia group corrected for multiple comparisons.

Please cite this article as: Zugman, A., et al., Reduced dorso-lateral prefrontal cortex in treatment resistant schizophrenia, Schizophr. Res. (2013), http://dx.doi.org/10.1016/j.schres.2013.05.002

A. Zugman et al. / Schizophrenia Research xxx (2013) xxx–xxx Conflict of interest Dr. 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 JanssenCilag, Pfizer and Lundbeck. All other authors declare no conflict of interest inherent to this article. Acknowledgments None.

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Please cite this article as: Zugman, A., et al., Reduced dorso-lateral prefrontal cortex in treatment resistant schizophrenia, Schizophr. Res. (2013), http://dx.doi.org/10.1016/j.schres.2013.05.002

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Please cite this article as: Zugman, A., et al., Reduced dorso-lateral prefrontal cortex in treatment resistant schizophrenia, Schizophr. Res. (2013), http://dx.doi.org/10.1016/j.schres.2013.05.002