- Email: [email protected]
Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment
SCHRES-06543; No of Pages 6 Schizophrenia Research xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment Robin Emsley a,⁎, Laila Asmal a, Stéfan du Plessis a, Bonginkosi Chiliza a, Martin Kidd b, Jonathan Carr c, Matthijs Vink d a
Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa Centre for Statistical Consultation, Stellenbosch University, South Africa Division of Neurology, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa d Department of Psychiatry, University Medical Centre Utrecht, The Netherlands b c
a r t i c l e
i n f o
Article history: Received 1 June 2015 Received in revised form 6 September 2015 Accepted 8 September 2015 Available online xxxx Keywords: Striatum Caudate Putamen Antipsychotics Schizophrenia
a b s t r a c t Background: Studies of pre-and post-treatment striatal volume in schizophrenia have reported conflicting results. Materials and methods: We assessed dorsal striatal (caudate and putamen) volumes bilaterally in 22 nevertreated, non-substance-abusing patients with first-episode schizophrenia or schizophreniform disorder and 23 healthy controls matched for age, sex and educational status. Patients received either risperidone or flupenthixol long acting injection and were compared by structural MRI with controls at weeks 0, 4 and 13. T1-weighted data on a 3T MRI scanner were obtained and images were reconstructed using FreeSurfer. Treatment outcome was assessed by changes in psychopathology, insight, functionality, cognitive performance and motor symptoms. Results: Caudate, but not putamen volumes was significantly larger in patients bilaterally at baseline (P = 0.01). Linear mixed effects repeated measures found no significant group × time interactions for any of the regions. Caudate volume was not significantly associated with improvements in psychotic symptoms. Also, the findings of a regression model were inconsistent insofar as larger caudate volume was associated with less improvement in depression scores, greater improvement in functionality and greater improvement in verbal learning but less improvement in reasoning and problem solving (left caudate) and composite cognitive score (right caudate). Conclusions: The increased caudate volumes prior to treatment are contrary to previous reports in never-treated patients with first-episode schizophrenia, and together with our failure to demonstrate volume changes related to acute treatment, call into question previous proposals that enlarged caudate volume is a consequence of antipsychotic treatment. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Striatal dysfunction is a fundamental component of the neurobiology of schizophrenia, with elevated striatal dopamine synthesis considered the best replicated dopaminergic abnormality in schizophrenia (Howes and Kapur, 2009). Structural imaging studies of striatal volume have however reported inconsistent results, although systematic reviews have concluded that striatal volume is likely decreased in unmedicated patients with first-episode schizophrenia, whereas studies in chronic, medicated samples mostly report striatal volume increases (Brandt and Bonelli, 2008; Ellison-Wright et al., 2008). Also, results from longitudinal studies suggest that antipsychotic treatment may be associated with striatal volume increases (Brandt and Bonelli, 2008; Haijma et al., 2013) although this is equivocal, and does not seem to be not specific ⁎ Corresponding author at: Department of Psychiatry, Faculty of Medicine and Health Sciences, PO Box 19063, Tygerberg 7505, South Africa. E-mail address: [email protected] (R. Emsley).
to first generation antipsychotics, as originally proposed (Ebdrup et al., 2013). In this study, we investigated dorsal striatal (caudate and putamen) volumes in a sample of 22 never-treated patients with first-episode schizophrenia at baseline, and after 4 and 13 weeks of antipsychotic treatment. A healthy control group (n = 23) matched for age, sex and educational status was included. We selected treatment naïve patients with a first-episode of schizophrenia to avoid the potential confounding influences of disease chronicity and previous antipsychotic usage. Moreover, by using depot antipsychotics we avoided the confounding effect of covert non-adherence. We also took care to exclude patients with substance abuse and comorbid psychiatric and general medical conditions. Based on previous literature, we hypothesised that patients would have smaller caudate volumes and normal putamen volumes at baseline and that these volumes would increase during the course of antipsychotic treatment. We further hypothesised that striatal volumes would be associated with changes in psychopathology, cognitive performance and functional outcome during the treatment period.
http://dx.doi.org/10.1016/j.schres.2015.09.014 0920-9964/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Emsley, R., et al., Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.09.014
2
R. Emsley et al. / Schizophrenia Research xxx (2015) xxx–xxx
2. Materials and methods
at two-weekly intervals. SOFAS, and BIS were performed at weeks 0 and 13.
2.1. Study design 2.4. Treatment This was a single-site study conducted over 13 weeks of standardised treatment in antipsychotic-naive patients with a first-episode of schizophrenia. The study was initially conducted as a randomised, doubleblinded, controlled trial to compare risperidone long acting injection and flupenthixol decanoate. However, no treatment x group effects were demonstrated in any of the MRI measures so treatment groups were pooled, and compared with the healthy controls for all of the subsequent analyses. 2.2. Participants Patients were recruited from in- and outpatient facilities at Stikland and Tygerberg Hospitals and surrounding community clinics, in Cape Town, South Africa. They were carefully screened and those who met inclusion criteria were invited to participate in the study. Written, informed consent was obtained from participants and if available, from a family member after complete description of the study. In the case of minors, written assent was obtained as well as parental consent. Inclusion criteria were: male or female; in- or outpatients; aged 16 to 45 years; Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, text revision (DSM-IV) (American Psychiatric Association, 2000) diagnosis of schizophreniform disorder or schizophrenia; no previous exposure to antipsychotic medication; and right handedness. Exclusion criteria were: substance abuse in the previous 6 months (ascertained by patient and carer interrogation, or a positive urine test at baseline or any of the subsequent visits), significant general medical condition, and mental retardation (IQ b 70). A group of healthy controls was also recruited for the MRI scans and cognitive testing. They were matched to the patients by age, sex, ethnicity and educational status. They were recruited from nonmedical staff in the hospital and their relatives and acquaintances, and from independent sources in the community. They were excluded if they reported a history of mental illness, previous treatment with psychotropic medication or substance abuse, or were not right handed. The study was approved by the Committee for Human Research, Faculty of Health Sciences, University of Stellenbosch. The study was registered at the South African National Clinical Trials Register (DOH-27–0710– 1808) and was conducted in accordance with International Conference on Harmonisation guidelines on good clinical practise (International Conference on Harmonization., 1996). 2.3. Assessments Investigators were physicians who were trained in the use of the key assessment instruments, and inter-rater reliability testing was conducted periodically (intraclass correlation 0.7 or greater). Patients and controls were assessed by means of the Structured Clinical Interview for DSM-IV (SCID) (First et al., 1994). Diagnosis was made by one of the psychiatrists and confirmed by consensus at regular team meetings including several experienced psychiatrists. Efficacy assessments included the PANSS (Kay et al., 1987), Calgary Depression Scale for Schizophrenia (CDSS) (Addington et al., 1993), Social and Occupational Functioning Assessment Scale (SOFAS) (American Psychiatric Association, 2000), and the Birchwood Insight Scale (BIS) (Birchwood et al., 1994). For cognitive assessments, we used the MATRICS Consensus Cognitive Battery (MCCB) (Nuechterlein and Green, 2006), which was administered by trained M-level psychologists. Motor side-effects were assessed by the Extrapyramidal Symptom Rating Scale (ESRS) (Chouinard and Margolese, 2005). A physical examination was conducted at baseline and urine screening tests for amphetamines, cannabis and methaqualone were performed at each visit. Participants underwent imaging at weeks 0 (prior to antipsychotic administration), 4 and 13. PANSS, CGI, CDSS and ESRS were assessed
Patients were randomised to either risperidone or flupenthixol treatment. There was a one week lead-in period of oral risperidone or flupenthixol 1 to 3 mg/day followed by long acting injections every 2 weeks for 12 weeks. Oral risperidone was continued for 3 weeks after the first injection due to its delayed time to attainment of therapeutic levels. The starting doses were 25 mg 2-weekly for long-acting risperidone and 10 mg 2-weekly for flupenthixol decanoate. Additional oral antipsychotic medication was permitted at the discretion of the investigator. Permitted concomitant treatment included medication for general medical conditions, lorazepam for sedation, orphenadrine or biperiden for extrapyramidal symptoms and propranolol for akathisia. No benzodiazepines, propranolol or anticholinergics were permitted in the 12 h prior to assessments. Medications not permitted included other antipsychotics, mood stabilisers and psychostimulants. 2.5. Imaging methods 2.5.1. MRI-acquisition We acquired high-resolution T1-weighted data on a researchdedicated 3T Siemens Allegra MRI scanner (Erlangen, Germany) with the following acquisition parameters: MPRAGE sequence, 2080 ms repetition time; 4.88 ms echo time, Field of view: 230 mm, 176 slices, 0.9 mm X 0.9 mm X 1 mm voxel size. All of the scans were screened for intracranial pathology by a radiologist and inspected for motion artefacts. 2.5.2. MRI preprocessing Scans were processed and analysed using FreeSurfer stable release version 5.1. (http://surfer.nmr.mgh.harvard.edu/) to measure a priori regions of interests (ROIs), namely left and right caudate and putamen volumes. Details of these procedures have been previously described (Dale et al., 1999). Briefly, slices were resampled to a threedimensional image with 1 mm isotropic voxels. Non-uniform intensity normalisation was then performed and images were registered to the Montreal Neurological Institute space. A second normalisation step was performed with a different algorithm in which control points were automatically identified and normalised to a standard intensity value. This was followed by an automated skull strip procedure. Global brain anatomy was then delineated into cortical and subcortical labels. Reconstructions were performed with custom batching scripts, on the Centre for High Performance Computing, Rosebank, Cape Town, Sun Intel Nehalem cluster (http://www.chpc.ac.za/). All data were visually inspected for errors in Talairach transformation, skull strip, final segmentations as well as the within subject-registrations. We undertook detailed quality checking. Any errors were corrected manually and re-inspected. 2.6. Statistical methods Analyses were performed on a modified intent-to-treat basis, meaning that participants were included in the analysis if they had a baseline and at least one post-baseline MRI measure. We employed linear mixed effect models for continuous repeated measures (MMRM) to compare changes in striatal volumes over time between the patients and controls. Visit-wise changes in caudate and putamen volumes bilaterally were compared between patients and controls using a model that included fixed terms of age, gender, intracranial volume, group, time and all interaction effects. Comparisons between patients and controls for baseline caudate and putamen volumes were derived from the post-hoc Fisher's Least Significant Difference (LSD) tests. We applied false discovery rate (FDR) adjustment of significance value according
Please cite this article as: Emsley, R., et al., Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.09.014
R. Emsley et al. / Schizophrenia Research xxx (2015) xxx–xxx
to the method of Benjamini and Hochberg (1995) to correct for multiple comparisons. FDR has been recommended as a less stringent alternative to the control of Type I errors compared to familywise error rate controlling procedures such as the Bonferroni correction (Glickman et al., 2014). The corrected significance level was 0.025. To explore whether baseline caudate volumes were related to changes in psychopathology, functionality, cognitive performance and motor disorders during the treatment period, we conducted linear regression using left and right baseline caudate volumes as dependent variables and change scores for the following clinical and cognitive outcome measures as independent predictors: PANSS total and positive, negative, disorganised, excited and depression/anxiety factor scores; BIS total score; CDSS total; CGI SOFAS; and the eight MCCB cognitive domain scores of Speed of Processing, Attention and Vigilance, Working Memory, Verbal Learning, Visual Learning, Rapid Processing Speed, Social Cognition and Composite score; and ESRS total score. The change scores were calculated by subtracting the baseline score from the week 13 score. The only exception was for ESRS total scores where we calculated the change from baseline to maximum score at any time-point, as symptoms had usually resolved at week 13 with anticholinergic medication. We did not conduct linear regression analyses for baseline putamen volumes as they did not differ from controls. 3. Results The demographic and baseline data for the patients and controls are provided in Table 1. There were no significant differences between patients and controls regarding age, gender, ethnicity and educational
Table 1 Demographic and baseline clinical characteristics for the patients and healthy controls.
Sex (Male/Female) Ethnicity (Mixed/Black) Educational level Elementary Secondary Tertiary Axis 1 diagnosis Schizophreniform disorder Schizophrenia
Age (years) MCCB score: Speed of processing Attention and vigilance Working memory Verbal learning Visual learning Reasoning and problem solving Social cognition Composite score DUP (weeks) BIS CDSS SOFAS PANSS Positive subscale PANSS Negative subscale PANSS General subscale PANSS Total score ESRS Total score
Patients N = 22
Controls N = 23
N
%
N
19/3 14/8
86/14 15/8 64/36 16/7
0 19 3
0 86 14
9
41
13
59
1 20 2
%
Chi square df
65/35 2.7 70/30 .18 2 4 87 9
1 1 4
Pa .1 .67 .74
Mean SD 24.6 6.1
Mean SD 27.8 8.9
t-value −1.42
df Pa 43 .16
25.3 29.4 26.2 37.4 36.2 34.7
12.4 10.6 14.9 8.5 13.7 7.3
30.7 36.4 29.2 38.4 39.5 38.7
13 9.7 14.6 8.4 16.9 10.7
−1.4 −2.2 −.66 −.37 −.7 −1.4
40 40 40 40 40 40
27.1 19.9 40.7 6.3 4.9 52 22 21.6 41.5 85 1.52
17.3 14.7 40.3 2.0 5.3 11.9 5.3 6.3 8.6 16 2.91
32.5 24.5
16.9 15.2
−1 −.9
37 .34 37 .35
.18 .03 .51 .71 .49 .18
DUP = duration of untreated psychosis; BIS = Birchwood Insight Scale; CDSS = Calgary depression scale for schizophrenia; SOFAS = social and occupational functioning assessment scale, severity; PANSS = positive and negative syndrome scale; ESRS = extrapyramidal symptom rating scale. a t-test or Chi square.
3
status. Twenty-eight patients were randomised, of whom 22 had at least one post-baseline scan and were included in the analysis. Twenty patients completed the study. Reasons for dropout were: consent withdrawal (n = 2), absconded (n = 3), lack of response (n = 1), relocation (n = 1) and protocol violation (n = 1). Mean (SD) endpoint doses were 31.66 (6.45) mg 2-weekly for long-acting risperidone and 13.07 (2.53) mg 2-weekly for flupenthixol decanoate. (These doses correspond to chlorpromazine equivalents of 126.64 mg/day for risperidone and 65.35 mg/day for flupenthixol (Bazire, 2010)). Thirty healthy controls were recruited, of whom 10 absconded. Twenty-three had at least one post-baseline scan and were included in the analysis. Table 2 provides mean baseline values for left and right baseline caudate and putamen volumes. Caudate, but not putamen volumes were significantly larger in patients bilaterally (P = 0.01). Scatterplots for the baseline left and right caudate and putamen volume measurements are provided in Fig. 1. MMRM results for the striatal volumes over 13 weeks of antipsychotic treatment are provided in Fig. 2. There were no significant group × time interactions for either the caudate or the putamen bilaterally. Best subsets regression identified CDSS total (P = 0.001), SOFAS (P = 0.003) and MCCB subscales of verbal learning (P = 0.0003) and reasoning and problem solving (P = 0.0001) subscales as independent predictors of left caudate baseline volume (R2 = 0.82) and CDSS total (P = 0.04), SOFAS (P = 0.05), MCCB verbal learning subscale (P = 0.001) and MCCB composite score (P = 0.0009) as independent predictors of right caudate baseline volume (R2 = 0.71). 4. Discussion This study provides evidence of increased caudate volumes bilaterally in a sample of never-treated patients with first-episode schizophrenia relative to matched healthy controls. These findings were unanticipated. Previous MRI studies comparing unmedicated, or minimally medicated patients with first-episode schizophrenia with controls reported either no differences (DeLisi et al., 1991; Chakos et al., 1994; Gur et al., 1998; Lang et al., 2001; Shihabuddin et al., 2001; Gunduz et al., 2002; Cahn et al., 2002; Glenthoj et al., 2007), or smaller caudate volumes (Keshavan et al., 1998; Shihabuddin et al., 1998; Corson et al., 1999). An explanation for our findings is not immediately apparent. Care was taken to exclude potential confounders such as substance abuse, diagnostic uncertainty and co-morbid disorders. Perhaps, our results reflect heterogeneity of the illness, not only in symptom expression but also in its underlying neurobiology. It is interesting to note however that never-treated patients with schizotypal personality disorder were found to have larger striatal size, with larger putamen size being proposed as a marker for favourable prognosis (Chemerinski et al., 2013) although two other studies found significantly smaller caudate nucleus volumes in never-medicated subjects with schizotypal personality disorder than in normal subjects (Levitt et al., 2002; Koo et al., 2006). Also, our results are consistent with reports of increased striatal dopamine function in the schizophrenia prodrome and during acute psychotic exacerbations (Howes et al., 2009). Furthermore, a study in a sample of largely medicated patients with chronic schizophrenia utilising the same FreeSurfer automated segmentation technique as we did reported Table 2 Mean and 95% CI baseline volumes of the left and right caudate and putamen.a Patients N = 22
Left caudate (mm3) Right caudate (mm3) Left putamen (mm3) Right putamen (mm3) a
Controls N = 23
Mean
95% CI
4082 4103 5840 5698
3771 3802 5372 5243
4393 4403 6307 6153
Mean
95% CI
3573 3614 5997 5702
3344 3392 5653 5366
Pa 3802 3836 6342 6037
0.01 0.01 0.6 0.9
LSD tests.
Please cite this article as: Emsley, R., et al., Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.09.014
4
R. Emsley et al. / Schizophrenia Research xxx (2015) xxx–xxx
Fig. 1. Scatterplots for the baseline left and right caudate and putamen volume measurements for patients and controls.
volumetric increases in the caudate, as well as the putamen and globus pallidus (Goldman et al., 2008). While these authors attributed their findings to the effects of antipsychotic medication, our results suggest that this may not be the case and that larger caudate volumes may be more directly related to the illness itself. Indeed, most volumetric studies in schizophrenia have reported enlargement of the striatum — although this has been regarded as a consequence of neuroleptic treatment, as most of these studies included medicated patients (Corson et al., 1999). Our failure to demonstrate changes in striatal volume during 13 weeks of treatment also counts against antipsychotic treatment being responsible for increased striatal volume. Additionally, the absence of differential effects between long acting risperidone injection and flupenthixol decanoate, while possibly due to the small sample and the relative “atypicality” of flupenthixol (Hertling et al., 2003), is consistent with the findings of Glenthoj et al. (Glenthoj et al., 2007) who did not observe changes in caudate volume after 12 weeks of treatment with either zuclopenthixol or risperidone, although they found a significant increase in putamen volume in the patients treated with risperidone. They postulated that antipsychotic dose and the degree of D2-receptor occupancy may be important in determining whether or not striatal volumes increase during treatment (Glenthoj et al., 2007). They cited two studies investigating the effects of risperidone on basal ganglia volumes in first episode schizophrenia. The first, with a mean dose of 2.7 mg/day found no increase after 1 year of treatment (Lang et al., 2001), while the other, with a mean dose of 6.05 mg/day reported
significant volume increases in the caudate nucleus and the nucleus accumbens after 3 months of treatment (Massana et al., 2005). This hypothesis would explain our negative finding, as we prescribed the lowest possible doses of antipsychotics. On the other hand, a recent systematic review of volumetric changes in basal ganglia after antipsychotic monotherapy found that, contrary to previous reports (Scherk and Falkai, 2006; Vita and DePeri, 2007; Navari and Dazzan, 2009) no studies found that conventional antipsychotics induce basal ganglia volume increases, and with second generation antipsychotics both volumetric increases and decreases have been reported (Ebdrup et al., 2013). While brain volume increases are more difficult to explain than decreases, they may reflect structural plasticity which could be due to remodelling of neuronal processes rather than neurogenesis, or to an increase in the number of non-neuronal cells, whose progenitor cells retain the ability to divide in the adult brain (Zatorre et al., 2012). Of interest is that caudate enlargement has also been found in children with autism spectrum disorders where it has been suggested to be due to failure of maturational pruning (Voelbel et al., 2006). Similarly, failure of maturational pruning has been proposed to be important in the pathogenesis of schizophrenia (Feinberg, 1982). One other possible explanation for our findings is that the larger pre-treatment caudate volumes represent a compensatory response to the underlying illness. In this respect, recent interest in neuroinflammation as an important component of the disease process may be relevant (Doorduin et al.,
Please cite this article as: Emsley, R., et al., Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.09.014
R. Emsley et al. / Schizophrenia Research xxx (2015) xxx–xxx
5
Fig. 2. MMRM results for the left and right caudate and putamen volumes over 13 weeks of antipsychotic treatment and for the healthy controls over the same time period.
2009). Neuroinflammation may be detrimental when excessive or persistent. On the other hand, it may be beneficial — an adaptive process for restoring tissue homeostasis. In the latter case, it is a physiological defence process that attempts to limit the disease progression, to repair damage and to regenerate tissues (Jacobs and Tavitian, 2012). It involves increased local blood flow and vascular permeability, cytokine production, activation of microglia and infiltration of mobile cells of the immune system (Graeber et al., 2011). In this regard, endothelial cell activation related to inflammation has been found to be significantly correlated with basal ganglia volume (particularly the right globus pallidus) in a sample of patients with schizophrenia and affective disorders (Dieset et al., 2015). It could be speculated that caudate volumes change throughout the course of the illness, and that caudate enlargement, perhaps due to inflammatory response, occurs soon after onset of psychosis. In this regard, it is of note that the mean DUP of our patients (40.7 weeks) was considerably shorter than that of the studies reporting smaller caudate volumes in which DUP was reported (301 weeks (Keshavan et al., 1998) and 3.75 years (Corson et al., 1999)). As the illness progresses, caudate shrinkage may occur, and finally, if patients are exposed to high doses of potent dopamine D2 receptor antagonists, caudate enlargement may once again occur. Baseline caudate volume was not related to treatment response in terms of PANSS symptom reductions, insight improvement or emergence of motor symptoms. Also, the findings of the regression model were inconsistent insofar as larger caudate volume is associated with less improvement in depression scores, greater improvement in functionality and greater improvement in verbal learning but less improvement in reasoning and problem solving (left caudate) and composite cognitive score (right caudate). While a considerable amount of
variability is explained in the regression models, these results should be interpreted with caution, with the inconsistent results possibly being due to the small sample size. As hypothesised, we did not find any volume differences in the putamen between patients and controls. This is consistent with other studies (Keshavan et al., 1998; Gur et al., 1998; Lang et al., 2001; Shihabuddin et al., 2001; Gunduz et al., 2002; Glenthoj et al., 2007). Strengths of our study include the carefully selected sample and matched controls; exclusion of substance abuse; standardised treatment with assured adherence; and multiple assessment points. Limitations are the small sample which means that the study is underpowered to detect smaller effects, particularly when comparing the two treatment groups; our treatment period of 13 weeks may have been too short — it is possible that changes related to treatment may occur more gradually; and because we used low doses we cannot rule out an effect for antipsychotics on striatal volume when prescribed in higher doses. Also, although we matched controls for age, sex, ethnicity and educational status, it is possible that the groups may have differed in other respects. Finally, we restricted our analysis to the dorsal striatum in view of the fact that FreeSurfer has some difficulty with measuring and parcellating the nucleus accumbens. In conclusion, to the best of our knowledge this is the first report of enlarged caudate volumes in never-treated first-episode schizophrenia. Together with our failure to demonstrate striatal volume changes over time, our results call into question previous proposals that enlarged caudate volume is a consequence of antipsychotic treatment. Future studies would do well to track longitudinal changes in striatal volume in relation to the stage of illness and medication status including antipsychotic dose. These studies should also include markers of neuroinflammation at these different stages.
Please cite this article as: Emsley, R., et al., Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.09.014
6
R. Emsley et al. / Schizophrenia Research xxx (2015) xxx–xxx
Role of funding source This study was supported by the Medical Research Council of South Africa and the New Partnership for Africa's Development (NEPAD) initiative through the Department of Science and Technology of South Africa (Grant number #65174). Risperidone medication was provided by Janssen South Africa. Funding sources were not involved in the study design, collection, analysis and interpretation of data, writing the manuscript or the decision to submit the paper for publication. Contributors Dr. Emsley designed the study and wrote the protocol. Dr. du Plessis performed the MRI analyses. Dr. Kidd conducted the statistical analyses. All authors contributed to and have approved the final manuscript.
Conflicts of interest Dr. Emsley has received honoraria from AstraZeneca, Janssen, Lundbeck, Servier and Otsuka for participating in advisory boards and speaking at educational meetings, and has received research funding from Janssen and Lundbeck. Dr. Chiliza has received honoraria from Sandoz, Lundbeck and Janssen for speaking at educational meetings. Drs. du Plessis, Kidd, Carr and Vink report no conflicts of interest. Acknowledgement We thank the Centre for High Performance Computing, Council for Scientific and Industrial Research, Cape Town for storage, processing and technical support.
References Addington, D., Addington, J., Maticka-Tyndale, E., 1993. Assessing depression in schizophrenia: the calgary depression scale. Br. J. Psychiatry Suppl. 22, S39–S44. American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders. 4 Text revision ed. American Psychiatric Association, Washington, DC. Bazire, S., 2010. Psychotropic Drug Directory. HealthComm UK Ltd, A Schofield Healthcare Media Company, Suite 3.1, 36 Upperkirkgate, Aberdeen. Benjamini, Y., Hochberg, Y., 1995. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57 (1), 289–300. Birchwood, M., Smith, J., Drury, V., Healy, J., Macmillan, F., Slade, M., 1994. A self-report Insight Scale for psychosis: reliability, validity and sensitivity to change. Acta Psychiatr. Scand. 89 (1), 62–67. Brandt, G.N., Bonelli, R.M., 2008. Structural neuroimaging of the basal ganglia in schizophrenic patients: a review. Wien. Med. Wochenschr. 158, 84–90. Cahn, W., Hulshoff Pol, H.E., Bongers, M., Schnack, H.G., Mandl, R.C., van Haren, N.E., Durston, S., Koning, H., Van Der Linden, J.A., Kahn, R.S., 2002. Brain morphology in antipsychoticnaive schizophrenia: a study of multiple brain structures. Br. J. Psychiatry Suppl. 43, s66–s72. Chakos, M.H., Lieberman, J.A., Bilder, R.M., Borenstein, M., Lerner, G., Bogerts, B., Wu, H., Kinon, B., Ashtari, M., 1994. Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. Am. J. Psychiatry 151, 1430–1436. Chemerinski, E., Byne, W., Kolaitis, J.C., Glanton, C.F., Canfield, E.L., Newmark, R.E., Haznedar, M.M., Novakovic, V., Chu, K.W., Siever, L.J., Hazlett, E.A., 2013. Larger putamen size in antipsychotic-naive individuals with schizotypal personality disorder. Schizophr. Res. 143, 158–164. Chouinard, G., Margolese, H.C., 2005. Manual for the extrapyramidal symptom rating scale (ESRS). Schizophr. Res. 76, 247–265. Corson, P.W., Nopoulos, P., Andreasen, N.C., Heckel, D., Arndt, S., 1999. Caudate size in first-episode neuroleptic-naive schizophrenic patients measured using an artificial neural network. Biol. Psychiatry 46, 712–720. Dale, A.M., Fischl, B., Sereno, M.I., 1999. Cortical surface-based analysis. I. Segmentation and surface reconstruction. NeuroImage 9, 179–194. DeLisi, L.E., Hoff, A.L., Schwartz, J.E., Shields, G.W., Halthore, S.N., Gupta, S.M., Henn, F.A., Anand, A.K., 1991. Brain morphology in first-episode schizophrenic-like psychotic patients: a quantitative magnetic resonance imaging study. Biol. Psychiatry 29, 159–175. Dieset, I., Haukvik, U.K., Melle, I., Røssberg, J.I., Ueland, T., Hope, S., Dale, A.M., Djurovic, S., Aukrust, P., Agartz, I., Andreassen, O.A., 2015. Association between altered brain morphology and elevated peripheral endothelial markers—implications for psychotic disorders. Schizophr. Res. 161 (2–3), 222–228. Doorduin, J., de Vries, E.F., Willemsen, A.T., de Groot, J.C., Dierckx, R.A., Klein, H.C., 2009. Neuroinflammation in schizophrenia-related psychosis: a PET study. J. Nucl. Med. 50, 1801–1807. Ebdrup, B.H., Norbak, H., Borgwardt, S., Glenthoj, B., 2013. Volumetric changes in the basal ganglia after antipsychotic monotherapy: a systematic review. Curr. Med. Chem. 20, 438–447. Ellison-Wright, I., Glahn, D.C., Laird, A.R., Thelen, S.M., Bullmore, E., 2008. The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis. Am. J. Psychiatry 165, 1015–1023. Feinberg, I., 1982. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J. Psychiatr. Res. 17, 319–334.
First, M.B., Spitzer, R.L.G.M., Williams, L.B.W., 1994. Structured Clinical Interview for DSMIV Axis I Disorders, Patient Edition (SCID-P). 2nd. New York, New York State Psychiatric Institute. Biom. Res. Glenthoj, A., Glenthoj, B.Y., Mackeprang, T., Pagsberg, A.K., Hemmingsen, R.P., Jernigan, T.L., Baare, W.F., 2007. Basal ganglia volumes in drug-naive first-episode schizophrenia patients before and after short-term treatment with either a typical or an atypical antipsychotic drug. Psychiatry Res. 154, 199–208. Glickman, M.E., Rao, S.R., Schultz, M.R., 2014. False discovery rate control is a recommended alternative to bonferroni-type adjustments in health studies. J. Clin. Epidemiol. 67 (8), 850–857. Goldman, A.L., Pezawas, L., Mattay, V.S., Fischl, B., Verchinski, B.A., Zoltick, B., Weinberger, D.R., Meyer-Lindenberg, A., 2008. Heritability of brain morphology related to schizophrenia: a large-scale automated magnetic resonance imaging segmentation study. Biol. Psychiatry 63, 475–483. Graeber, M.B., Li, W., Rodriguez, M.L., 2011. Role of microglia in CNS inflammation. FEBS Lett. 585, 3798–3805. Gunduz, H., Wu, H., Ashtari, M., Bogerts, B., Crandall, D., Robinson, D.G., Alvir, J., Lieberman, J., Kane, J., Bilder, R., 2002. Basal ganglia volumes in first-episode schizophrenia and healthy comparison subjects. Biol. Psychiatry 51, 801–808. Gur, R.E., Maany, V., Mozley, P.D., Swanson, C., Bilker, W., Gur, R.C., 1998. Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia. Am. J. Psychiatry 155, 1711–1717. Haijma, S.V., Van, H.N., Cahn, W., Koolschijn, P.C., Hulshoff Pol, H.E., Kahn, R.S., 2013. Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. Schizophr. Bull. 39, 1129–1138. Hertling, I., Philipp, M., Dvorak, A., Glaser, T., Mast, O., Beneke, M., Ramskogler, K., SaletuZyhlarz, G., Walter, H., Lesch, O.M., 2003. Flupenthixol versus risperidone: subjective quality of life as an important factor for compliance in chronic schizophrenic patients. Neuropsychobiology 47, 37–46. Howes, O.D., Kapur, S., 2009. The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr. Bull. 35, 549–562. Howes, O.D., Montgomery, A.J., Asselin, M.C., Murray, R.M., Valli, I., Tabraham, P., BramonBosch, E., Valmaggia, L., Johns, L., Broome, M., McGuire, P.K., Grasby, P.M., 2009. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch. Gen. Psychiatry 66, 13–20. International Conference on Harmonization., 1996. ICH Harmonised Tripartite Guidelines for Good Clinical Practice. Brookwood Medical Publications Ltd, Surrey. Jacobs, A.H., Tavitian, B., 2012. Noninvasive molecular imaging of neuroinflammation. J. Cereb. Blood Flow Metab. 32, 1393–1415. Kay, S.R., Fizbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261–267. Keshavan, M.S., Rosenberg, D., Sweeney, J.A., Pettegrew, J.W., 1998. Decreased caudate volume in neuroleptic-naive psychotic patients. Am. J. Psychiatry 155, 774–778. Koo, M.S., Levitt, J.J., McCarley, R.W., Seidman, L.J., Dickey, C.C., Niznikiewicz, M.A., Voglmaier, M.M., Zamani, P., Long, K.R., Kim, S.S., Shenton, M.E., 2006. Reduction of caudate nucleus volumes in neuroleptic-naive female subjects with schizotypal personality disorder. Biol. Psychiatry 60, 40–48. Lang, D.J., Kopala, L.C., Vandorpe, R.A., Rui, Q., Smith, G.N., Goghari, V.M., Honer, W.G., 2001. An MRI study of basal ganglia volumes in first-episode schizophrenia patients treated with risperidone. Am. J. Psychiatry 158, 625–631. Levitt, J.J., McCarley, R.W., Dickey, C.C., Voglmaier, M.M., Niznikiewicz, M.A., Seidman, L.J., Hirayasu, Y., Ciszewski, A.A., Kikinis, R., Jolesz, F.A., Shenton, M.E., 2002. MRI study of caudate nucleus volume and its cognitive correlates in neuroleptic-naive patients with schizotypal personality disorder. Am. J. Psychiatry 159, 1190–1197. Massana, G., Salgado-Pineda, P., Junque, C., Perez, M., Baeza, I., Pons, A., Massana, J., Navarro, V., Blanch, J., Morer, A., Mercader, J.M., Bernardo, M., 2005. Volume changes in gray matter in first-episode neuroleptic-naive schizophrenic patients treated with risperidone. J. Clin. Psychopharmacol. 25, 111–117. Navari, S., Dazzan, P., 2009. Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings. Psychol. Med. 39, 1763–1777. Nuechterlein, K.H., Green, M.F., 2006. MATRICS Consensus Battery Manual. MATRICS Assessment Inc, Los Angeles. Scherk, H., Falkai, P., 2006. Effects of antipsychotics on brain structure. Curr. Opin. Psychiatry 19, 145–150. Shihabuddin, L., Buchsbaum, M.S., Hazlett, E.A., Haznedar, M.M., Harvey, P.D., Newman, A., Schnur, D.B., Spiegel-Cohen, J., Wei, T., Machac, J., Knesaurek, K., Vallabhajosula, S., Biren, M.A., Ciaravolo, T.M., Luu-Hsia, C., 1998. Dorsal striatal size, shape, and metabolic rate in never-medicated and previously medicated schizophrenics performing a verbal learning task. Arch. Gen. Psychiatry 55, 235–243. Shihabuddin, L., Buchsbaum, M.S., Hazlett, E.A., Silverman, J., New, A., Brickman, A.M., Mitropoulou, V., Nunn, M., Fleischman, M.B., Tang, C., Siever, L.J., 2001. Striatal size and relative glucose metabolic rate in schizotypal personality disorder and schizophrenia. Arch. Gen. Psychiatry 58, 877–884. Vita, A., DePeri, L., 2007. The effects of antipsychotic treatment on cerebral structure and function in schizophrenia. Int. Rev. Psychiatry 19, 429–436. Voelbel, G.T., Bates, M.E., Buckman, J.F., Pandina, G., Hendren, R.L., 2006. Caudate nucleus volume and cognitive performance: are they related in childhood psychopathology? Biol. Psychiatry 60, 942–950. Zatorre, R.J., Fields, R.D., Johansen-Berg, H., 2012. Plasticity in gray and white: neuroimaging changes in brain structure during learning. Nat. Neurosci. 15, 528–536.
Please cite this article as: Emsley, R., et al., Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.09.014
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment Robin Emsley a,⁎, Laila Asmal a, Stéfan du Plessis a, Bonginkosi Chiliza a, Martin Kidd b, Jonathan Carr c, Matthijs Vink d a
Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa Centre for Statistical Consultation, Stellenbosch University, South Africa Division of Neurology, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa d Department of Psychiatry, University Medical Centre Utrecht, The Netherlands b c
a r t i c l e
i n f o
Article history: Received 1 June 2015 Received in revised form 6 September 2015 Accepted 8 September 2015 Available online xxxx Keywords: Striatum Caudate Putamen Antipsychotics Schizophrenia
a b s t r a c t Background: Studies of pre-and post-treatment striatal volume in schizophrenia have reported conflicting results. Materials and methods: We assessed dorsal striatal (caudate and putamen) volumes bilaterally in 22 nevertreated, non-substance-abusing patients with first-episode schizophrenia or schizophreniform disorder and 23 healthy controls matched for age, sex and educational status. Patients received either risperidone or flupenthixol long acting injection and were compared by structural MRI with controls at weeks 0, 4 and 13. T1-weighted data on a 3T MRI scanner were obtained and images were reconstructed using FreeSurfer. Treatment outcome was assessed by changes in psychopathology, insight, functionality, cognitive performance and motor symptoms. Results: Caudate, but not putamen volumes was significantly larger in patients bilaterally at baseline (P = 0.01). Linear mixed effects repeated measures found no significant group × time interactions for any of the regions. Caudate volume was not significantly associated with improvements in psychotic symptoms. Also, the findings of a regression model were inconsistent insofar as larger caudate volume was associated with less improvement in depression scores, greater improvement in functionality and greater improvement in verbal learning but less improvement in reasoning and problem solving (left caudate) and composite cognitive score (right caudate). Conclusions: The increased caudate volumes prior to treatment are contrary to previous reports in never-treated patients with first-episode schizophrenia, and together with our failure to demonstrate volume changes related to acute treatment, call into question previous proposals that enlarged caudate volume is a consequence of antipsychotic treatment. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Striatal dysfunction is a fundamental component of the neurobiology of schizophrenia, with elevated striatal dopamine synthesis considered the best replicated dopaminergic abnormality in schizophrenia (Howes and Kapur, 2009). Structural imaging studies of striatal volume have however reported inconsistent results, although systematic reviews have concluded that striatal volume is likely decreased in unmedicated patients with first-episode schizophrenia, whereas studies in chronic, medicated samples mostly report striatal volume increases (Brandt and Bonelli, 2008; Ellison-Wright et al., 2008). Also, results from longitudinal studies suggest that antipsychotic treatment may be associated with striatal volume increases (Brandt and Bonelli, 2008; Haijma et al., 2013) although this is equivocal, and does not seem to be not specific ⁎ Corresponding author at: Department of Psychiatry, Faculty of Medicine and Health Sciences, PO Box 19063, Tygerberg 7505, South Africa. E-mail address: [email protected] (R. Emsley).
to first generation antipsychotics, as originally proposed (Ebdrup et al., 2013). In this study, we investigated dorsal striatal (caudate and putamen) volumes in a sample of 22 never-treated patients with first-episode schizophrenia at baseline, and after 4 and 13 weeks of antipsychotic treatment. A healthy control group (n = 23) matched for age, sex and educational status was included. We selected treatment naïve patients with a first-episode of schizophrenia to avoid the potential confounding influences of disease chronicity and previous antipsychotic usage. Moreover, by using depot antipsychotics we avoided the confounding effect of covert non-adherence. We also took care to exclude patients with substance abuse and comorbid psychiatric and general medical conditions. Based on previous literature, we hypothesised that patients would have smaller caudate volumes and normal putamen volumes at baseline and that these volumes would increase during the course of antipsychotic treatment. We further hypothesised that striatal volumes would be associated with changes in psychopathology, cognitive performance and functional outcome during the treatment period.
http://dx.doi.org/10.1016/j.schres.2015.09.014 0920-9964/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Emsley, R., et al., Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.09.014
2
R. Emsley et al. / Schizophrenia Research xxx (2015) xxx–xxx
2. Materials and methods
at two-weekly intervals. SOFAS, and BIS were performed at weeks 0 and 13.
2.1. Study design 2.4. Treatment This was a single-site study conducted over 13 weeks of standardised treatment in antipsychotic-naive patients with a first-episode of schizophrenia. The study was initially conducted as a randomised, doubleblinded, controlled trial to compare risperidone long acting injection and flupenthixol decanoate. However, no treatment x group effects were demonstrated in any of the MRI measures so treatment groups were pooled, and compared with the healthy controls for all of the subsequent analyses. 2.2. Participants Patients were recruited from in- and outpatient facilities at Stikland and Tygerberg Hospitals and surrounding community clinics, in Cape Town, South Africa. They were carefully screened and those who met inclusion criteria were invited to participate in the study. Written, informed consent was obtained from participants and if available, from a family member after complete description of the study. In the case of minors, written assent was obtained as well as parental consent. Inclusion criteria were: male or female; in- or outpatients; aged 16 to 45 years; Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, text revision (DSM-IV) (American Psychiatric Association, 2000) diagnosis of schizophreniform disorder or schizophrenia; no previous exposure to antipsychotic medication; and right handedness. Exclusion criteria were: substance abuse in the previous 6 months (ascertained by patient and carer interrogation, or a positive urine test at baseline or any of the subsequent visits), significant general medical condition, and mental retardation (IQ b 70). A group of healthy controls was also recruited for the MRI scans and cognitive testing. They were matched to the patients by age, sex, ethnicity and educational status. They were recruited from nonmedical staff in the hospital and their relatives and acquaintances, and from independent sources in the community. They were excluded if they reported a history of mental illness, previous treatment with psychotropic medication or substance abuse, or were not right handed. The study was approved by the Committee for Human Research, Faculty of Health Sciences, University of Stellenbosch. The study was registered at the South African National Clinical Trials Register (DOH-27–0710– 1808) and was conducted in accordance with International Conference on Harmonisation guidelines on good clinical practise (International Conference on Harmonization., 1996). 2.3. Assessments Investigators were physicians who were trained in the use of the key assessment instruments, and inter-rater reliability testing was conducted periodically (intraclass correlation 0.7 or greater). Patients and controls were assessed by means of the Structured Clinical Interview for DSM-IV (SCID) (First et al., 1994). Diagnosis was made by one of the psychiatrists and confirmed by consensus at regular team meetings including several experienced psychiatrists. Efficacy assessments included the PANSS (Kay et al., 1987), Calgary Depression Scale for Schizophrenia (CDSS) (Addington et al., 1993), Social and Occupational Functioning Assessment Scale (SOFAS) (American Psychiatric Association, 2000), and the Birchwood Insight Scale (BIS) (Birchwood et al., 1994). For cognitive assessments, we used the MATRICS Consensus Cognitive Battery (MCCB) (Nuechterlein and Green, 2006), which was administered by trained M-level psychologists. Motor side-effects were assessed by the Extrapyramidal Symptom Rating Scale (ESRS) (Chouinard and Margolese, 2005). A physical examination was conducted at baseline and urine screening tests for amphetamines, cannabis and methaqualone were performed at each visit. Participants underwent imaging at weeks 0 (prior to antipsychotic administration), 4 and 13. PANSS, CGI, CDSS and ESRS were assessed
Patients were randomised to either risperidone or flupenthixol treatment. There was a one week lead-in period of oral risperidone or flupenthixol 1 to 3 mg/day followed by long acting injections every 2 weeks for 12 weeks. Oral risperidone was continued for 3 weeks after the first injection due to its delayed time to attainment of therapeutic levels. The starting doses were 25 mg 2-weekly for long-acting risperidone and 10 mg 2-weekly for flupenthixol decanoate. Additional oral antipsychotic medication was permitted at the discretion of the investigator. Permitted concomitant treatment included medication for general medical conditions, lorazepam for sedation, orphenadrine or biperiden for extrapyramidal symptoms and propranolol for akathisia. No benzodiazepines, propranolol or anticholinergics were permitted in the 12 h prior to assessments. Medications not permitted included other antipsychotics, mood stabilisers and psychostimulants. 2.5. Imaging methods 2.5.1. MRI-acquisition We acquired high-resolution T1-weighted data on a researchdedicated 3T Siemens Allegra MRI scanner (Erlangen, Germany) with the following acquisition parameters: MPRAGE sequence, 2080 ms repetition time; 4.88 ms echo time, Field of view: 230 mm, 176 slices, 0.9 mm X 0.9 mm X 1 mm voxel size. All of the scans were screened for intracranial pathology by a radiologist and inspected for motion artefacts. 2.5.2. MRI preprocessing Scans were processed and analysed using FreeSurfer stable release version 5.1. (http://surfer.nmr.mgh.harvard.edu/) to measure a priori regions of interests (ROIs), namely left and right caudate and putamen volumes. Details of these procedures have been previously described (Dale et al., 1999). Briefly, slices were resampled to a threedimensional image with 1 mm isotropic voxels. Non-uniform intensity normalisation was then performed and images were registered to the Montreal Neurological Institute space. A second normalisation step was performed with a different algorithm in which control points were automatically identified and normalised to a standard intensity value. This was followed by an automated skull strip procedure. Global brain anatomy was then delineated into cortical and subcortical labels. Reconstructions were performed with custom batching scripts, on the Centre for High Performance Computing, Rosebank, Cape Town, Sun Intel Nehalem cluster (http://www.chpc.ac.za/). All data were visually inspected for errors in Talairach transformation, skull strip, final segmentations as well as the within subject-registrations. We undertook detailed quality checking. Any errors were corrected manually and re-inspected. 2.6. Statistical methods Analyses were performed on a modified intent-to-treat basis, meaning that participants were included in the analysis if they had a baseline and at least one post-baseline MRI measure. We employed linear mixed effect models for continuous repeated measures (MMRM) to compare changes in striatal volumes over time between the patients and controls. Visit-wise changes in caudate and putamen volumes bilaterally were compared between patients and controls using a model that included fixed terms of age, gender, intracranial volume, group, time and all interaction effects. Comparisons between patients and controls for baseline caudate and putamen volumes were derived from the post-hoc Fisher's Least Significant Difference (LSD) tests. We applied false discovery rate (FDR) adjustment of significance value according
Please cite this article as: Emsley, R., et al., Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.09.014
R. Emsley et al. / Schizophrenia Research xxx (2015) xxx–xxx
to the method of Benjamini and Hochberg (1995) to correct for multiple comparisons. FDR has been recommended as a less stringent alternative to the control of Type I errors compared to familywise error rate controlling procedures such as the Bonferroni correction (Glickman et al., 2014). The corrected significance level was 0.025. To explore whether baseline caudate volumes were related to changes in psychopathology, functionality, cognitive performance and motor disorders during the treatment period, we conducted linear regression using left and right baseline caudate volumes as dependent variables and change scores for the following clinical and cognitive outcome measures as independent predictors: PANSS total and positive, negative, disorganised, excited and depression/anxiety factor scores; BIS total score; CDSS total; CGI SOFAS; and the eight MCCB cognitive domain scores of Speed of Processing, Attention and Vigilance, Working Memory, Verbal Learning, Visual Learning, Rapid Processing Speed, Social Cognition and Composite score; and ESRS total score. The change scores were calculated by subtracting the baseline score from the week 13 score. The only exception was for ESRS total scores where we calculated the change from baseline to maximum score at any time-point, as symptoms had usually resolved at week 13 with anticholinergic medication. We did not conduct linear regression analyses for baseline putamen volumes as they did not differ from controls. 3. Results The demographic and baseline data for the patients and controls are provided in Table 1. There were no significant differences between patients and controls regarding age, gender, ethnicity and educational
Table 1 Demographic and baseline clinical characteristics for the patients and healthy controls.
Sex (Male/Female) Ethnicity (Mixed/Black) Educational level Elementary Secondary Tertiary Axis 1 diagnosis Schizophreniform disorder Schizophrenia
Age (years) MCCB score: Speed of processing Attention and vigilance Working memory Verbal learning Visual learning Reasoning and problem solving Social cognition Composite score DUP (weeks) BIS CDSS SOFAS PANSS Positive subscale PANSS Negative subscale PANSS General subscale PANSS Total score ESRS Total score
Patients N = 22
Controls N = 23
N
%
N
19/3 14/8
86/14 15/8 64/36 16/7
0 19 3
0 86 14
9
41
13
59
1 20 2
%
Chi square df
65/35 2.7 70/30 .18 2 4 87 9
1 1 4
Pa .1 .67 .74
Mean SD 24.6 6.1
Mean SD 27.8 8.9
t-value −1.42
df Pa 43 .16
25.3 29.4 26.2 37.4 36.2 34.7
12.4 10.6 14.9 8.5 13.7 7.3
30.7 36.4 29.2 38.4 39.5 38.7
13 9.7 14.6 8.4 16.9 10.7
−1.4 −2.2 −.66 −.37 −.7 −1.4
40 40 40 40 40 40
27.1 19.9 40.7 6.3 4.9 52 22 21.6 41.5 85 1.52
17.3 14.7 40.3 2.0 5.3 11.9 5.3 6.3 8.6 16 2.91
32.5 24.5
16.9 15.2
−1 −.9
37 .34 37 .35
.18 .03 .51 .71 .49 .18
DUP = duration of untreated psychosis; BIS = Birchwood Insight Scale; CDSS = Calgary depression scale for schizophrenia; SOFAS = social and occupational functioning assessment scale, severity; PANSS = positive and negative syndrome scale; ESRS = extrapyramidal symptom rating scale. a t-test or Chi square.
3
status. Twenty-eight patients were randomised, of whom 22 had at least one post-baseline scan and were included in the analysis. Twenty patients completed the study. Reasons for dropout were: consent withdrawal (n = 2), absconded (n = 3), lack of response (n = 1), relocation (n = 1) and protocol violation (n = 1). Mean (SD) endpoint doses were 31.66 (6.45) mg 2-weekly for long-acting risperidone and 13.07 (2.53) mg 2-weekly for flupenthixol decanoate. (These doses correspond to chlorpromazine equivalents of 126.64 mg/day for risperidone and 65.35 mg/day for flupenthixol (Bazire, 2010)). Thirty healthy controls were recruited, of whom 10 absconded. Twenty-three had at least one post-baseline scan and were included in the analysis. Table 2 provides mean baseline values for left and right baseline caudate and putamen volumes. Caudate, but not putamen volumes were significantly larger in patients bilaterally (P = 0.01). Scatterplots for the baseline left and right caudate and putamen volume measurements are provided in Fig. 1. MMRM results for the striatal volumes over 13 weeks of antipsychotic treatment are provided in Fig. 2. There were no significant group × time interactions for either the caudate or the putamen bilaterally. Best subsets regression identified CDSS total (P = 0.001), SOFAS (P = 0.003) and MCCB subscales of verbal learning (P = 0.0003) and reasoning and problem solving (P = 0.0001) subscales as independent predictors of left caudate baseline volume (R2 = 0.82) and CDSS total (P = 0.04), SOFAS (P = 0.05), MCCB verbal learning subscale (P = 0.001) and MCCB composite score (P = 0.0009) as independent predictors of right caudate baseline volume (R2 = 0.71). 4. Discussion This study provides evidence of increased caudate volumes bilaterally in a sample of never-treated patients with first-episode schizophrenia relative to matched healthy controls. These findings were unanticipated. Previous MRI studies comparing unmedicated, or minimally medicated patients with first-episode schizophrenia with controls reported either no differences (DeLisi et al., 1991; Chakos et al., 1994; Gur et al., 1998; Lang et al., 2001; Shihabuddin et al., 2001; Gunduz et al., 2002; Cahn et al., 2002; Glenthoj et al., 2007), or smaller caudate volumes (Keshavan et al., 1998; Shihabuddin et al., 1998; Corson et al., 1999). An explanation for our findings is not immediately apparent. Care was taken to exclude potential confounders such as substance abuse, diagnostic uncertainty and co-morbid disorders. Perhaps, our results reflect heterogeneity of the illness, not only in symptom expression but also in its underlying neurobiology. It is interesting to note however that never-treated patients with schizotypal personality disorder were found to have larger striatal size, with larger putamen size being proposed as a marker for favourable prognosis (Chemerinski et al., 2013) although two other studies found significantly smaller caudate nucleus volumes in never-medicated subjects with schizotypal personality disorder than in normal subjects (Levitt et al., 2002; Koo et al., 2006). Also, our results are consistent with reports of increased striatal dopamine function in the schizophrenia prodrome and during acute psychotic exacerbations (Howes et al., 2009). Furthermore, a study in a sample of largely medicated patients with chronic schizophrenia utilising the same FreeSurfer automated segmentation technique as we did reported Table 2 Mean and 95% CI baseline volumes of the left and right caudate and putamen.a Patients N = 22
Left caudate (mm3) Right caudate (mm3) Left putamen (mm3) Right putamen (mm3) a
Controls N = 23
Mean
95% CI
4082 4103 5840 5698
3771 3802 5372 5243
4393 4403 6307 6153
Mean
95% CI
3573 3614 5997 5702
3344 3392 5653 5366
Pa 3802 3836 6342 6037
0.01 0.01 0.6 0.9
LSD tests.
Please cite this article as: Emsley, R., et al., Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.09.014
4
R. Emsley et al. / Schizophrenia Research xxx (2015) xxx–xxx
Fig. 1. Scatterplots for the baseline left and right caudate and putamen volume measurements for patients and controls.
volumetric increases in the caudate, as well as the putamen and globus pallidus (Goldman et al., 2008). While these authors attributed their findings to the effects of antipsychotic medication, our results suggest that this may not be the case and that larger caudate volumes may be more directly related to the illness itself. Indeed, most volumetric studies in schizophrenia have reported enlargement of the striatum — although this has been regarded as a consequence of neuroleptic treatment, as most of these studies included medicated patients (Corson et al., 1999). Our failure to demonstrate changes in striatal volume during 13 weeks of treatment also counts against antipsychotic treatment being responsible for increased striatal volume. Additionally, the absence of differential effects between long acting risperidone injection and flupenthixol decanoate, while possibly due to the small sample and the relative “atypicality” of flupenthixol (Hertling et al., 2003), is consistent with the findings of Glenthoj et al. (Glenthoj et al., 2007) who did not observe changes in caudate volume after 12 weeks of treatment with either zuclopenthixol or risperidone, although they found a significant increase in putamen volume in the patients treated with risperidone. They postulated that antipsychotic dose and the degree of D2-receptor occupancy may be important in determining whether or not striatal volumes increase during treatment (Glenthoj et al., 2007). They cited two studies investigating the effects of risperidone on basal ganglia volumes in first episode schizophrenia. The first, with a mean dose of 2.7 mg/day found no increase after 1 year of treatment (Lang et al., 2001), while the other, with a mean dose of 6.05 mg/day reported
significant volume increases in the caudate nucleus and the nucleus accumbens after 3 months of treatment (Massana et al., 2005). This hypothesis would explain our negative finding, as we prescribed the lowest possible doses of antipsychotics. On the other hand, a recent systematic review of volumetric changes in basal ganglia after antipsychotic monotherapy found that, contrary to previous reports (Scherk and Falkai, 2006; Vita and DePeri, 2007; Navari and Dazzan, 2009) no studies found that conventional antipsychotics induce basal ganglia volume increases, and with second generation antipsychotics both volumetric increases and decreases have been reported (Ebdrup et al., 2013). While brain volume increases are more difficult to explain than decreases, they may reflect structural plasticity which could be due to remodelling of neuronal processes rather than neurogenesis, or to an increase in the number of non-neuronal cells, whose progenitor cells retain the ability to divide in the adult brain (Zatorre et al., 2012). Of interest is that caudate enlargement has also been found in children with autism spectrum disorders where it has been suggested to be due to failure of maturational pruning (Voelbel et al., 2006). Similarly, failure of maturational pruning has been proposed to be important in the pathogenesis of schizophrenia (Feinberg, 1982). One other possible explanation for our findings is that the larger pre-treatment caudate volumes represent a compensatory response to the underlying illness. In this respect, recent interest in neuroinflammation as an important component of the disease process may be relevant (Doorduin et al.,
Please cite this article as: Emsley, R., et al., Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.09.014
R. Emsley et al. / Schizophrenia Research xxx (2015) xxx–xxx
5
Fig. 2. MMRM results for the left and right caudate and putamen volumes over 13 weeks of antipsychotic treatment and for the healthy controls over the same time period.
2009). Neuroinflammation may be detrimental when excessive or persistent. On the other hand, it may be beneficial — an adaptive process for restoring tissue homeostasis. In the latter case, it is a physiological defence process that attempts to limit the disease progression, to repair damage and to regenerate tissues (Jacobs and Tavitian, 2012). It involves increased local blood flow and vascular permeability, cytokine production, activation of microglia and infiltration of mobile cells of the immune system (Graeber et al., 2011). In this regard, endothelial cell activation related to inflammation has been found to be significantly correlated with basal ganglia volume (particularly the right globus pallidus) in a sample of patients with schizophrenia and affective disorders (Dieset et al., 2015). It could be speculated that caudate volumes change throughout the course of the illness, and that caudate enlargement, perhaps due to inflammatory response, occurs soon after onset of psychosis. In this regard, it is of note that the mean DUP of our patients (40.7 weeks) was considerably shorter than that of the studies reporting smaller caudate volumes in which DUP was reported (301 weeks (Keshavan et al., 1998) and 3.75 years (Corson et al., 1999)). As the illness progresses, caudate shrinkage may occur, and finally, if patients are exposed to high doses of potent dopamine D2 receptor antagonists, caudate enlargement may once again occur. Baseline caudate volume was not related to treatment response in terms of PANSS symptom reductions, insight improvement or emergence of motor symptoms. Also, the findings of the regression model were inconsistent insofar as larger caudate volume is associated with less improvement in depression scores, greater improvement in functionality and greater improvement in verbal learning but less improvement in reasoning and problem solving (left caudate) and composite cognitive score (right caudate). While a considerable amount of
variability is explained in the regression models, these results should be interpreted with caution, with the inconsistent results possibly being due to the small sample size. As hypothesised, we did not find any volume differences in the putamen between patients and controls. This is consistent with other studies (Keshavan et al., 1998; Gur et al., 1998; Lang et al., 2001; Shihabuddin et al., 2001; Gunduz et al., 2002; Glenthoj et al., 2007). Strengths of our study include the carefully selected sample and matched controls; exclusion of substance abuse; standardised treatment with assured adherence; and multiple assessment points. Limitations are the small sample which means that the study is underpowered to detect smaller effects, particularly when comparing the two treatment groups; our treatment period of 13 weeks may have been too short — it is possible that changes related to treatment may occur more gradually; and because we used low doses we cannot rule out an effect for antipsychotics on striatal volume when prescribed in higher doses. Also, although we matched controls for age, sex, ethnicity and educational status, it is possible that the groups may have differed in other respects. Finally, we restricted our analysis to the dorsal striatum in view of the fact that FreeSurfer has some difficulty with measuring and parcellating the nucleus accumbens. In conclusion, to the best of our knowledge this is the first report of enlarged caudate volumes in never-treated first-episode schizophrenia. Together with our failure to demonstrate striatal volume changes over time, our results call into question previous proposals that enlarged caudate volume is a consequence of antipsychotic treatment. Future studies would do well to track longitudinal changes in striatal volume in relation to the stage of illness and medication status including antipsychotic dose. These studies should also include markers of neuroinflammation at these different stages.
Please cite this article as: Emsley, R., et al., Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.09.014
6
R. Emsley et al. / Schizophrenia Research xxx (2015) xxx–xxx
Role of funding source This study was supported by the Medical Research Council of South Africa and the New Partnership for Africa's Development (NEPAD) initiative through the Department of Science and Technology of South Africa (Grant number #65174). Risperidone medication was provided by Janssen South Africa. Funding sources were not involved in the study design, collection, analysis and interpretation of data, writing the manuscript or the decision to submit the paper for publication. Contributors Dr. Emsley designed the study and wrote the protocol. Dr. du Plessis performed the MRI analyses. Dr. Kidd conducted the statistical analyses. All authors contributed to and have approved the final manuscript.
Conflicts of interest Dr. Emsley has received honoraria from AstraZeneca, Janssen, Lundbeck, Servier and Otsuka for participating in advisory boards and speaking at educational meetings, and has received research funding from Janssen and Lundbeck. Dr. Chiliza has received honoraria from Sandoz, Lundbeck and Janssen for speaking at educational meetings. Drs. du Plessis, Kidd, Carr and Vink report no conflicts of interest. Acknowledgement We thank the Centre for High Performance Computing, Council for Scientific and Industrial Research, Cape Town for storage, processing and technical support.
References Addington, D., Addington, J., Maticka-Tyndale, E., 1993. Assessing depression in schizophrenia: the calgary depression scale. Br. J. Psychiatry Suppl. 22, S39–S44. American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders. 4 Text revision ed. American Psychiatric Association, Washington, DC. Bazire, S., 2010. Psychotropic Drug Directory. HealthComm UK Ltd, A Schofield Healthcare Media Company, Suite 3.1, 36 Upperkirkgate, Aberdeen. Benjamini, Y., Hochberg, Y., 1995. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57 (1), 289–300. Birchwood, M., Smith, J., Drury, V., Healy, J., Macmillan, F., Slade, M., 1994. A self-report Insight Scale for psychosis: reliability, validity and sensitivity to change. Acta Psychiatr. Scand. 89 (1), 62–67. Brandt, G.N., Bonelli, R.M., 2008. Structural neuroimaging of the basal ganglia in schizophrenic patients: a review. Wien. Med. Wochenschr. 158, 84–90. Cahn, W., Hulshoff Pol, H.E., Bongers, M., Schnack, H.G., Mandl, R.C., van Haren, N.E., Durston, S., Koning, H., Van Der Linden, J.A., Kahn, R.S., 2002. Brain morphology in antipsychoticnaive schizophrenia: a study of multiple brain structures. Br. J. Psychiatry Suppl. 43, s66–s72. Chakos, M.H., Lieberman, J.A., Bilder, R.M., Borenstein, M., Lerner, G., Bogerts, B., Wu, H., Kinon, B., Ashtari, M., 1994. Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. Am. J. Psychiatry 151, 1430–1436. Chemerinski, E., Byne, W., Kolaitis, J.C., Glanton, C.F., Canfield, E.L., Newmark, R.E., Haznedar, M.M., Novakovic, V., Chu, K.W., Siever, L.J., Hazlett, E.A., 2013. Larger putamen size in antipsychotic-naive individuals with schizotypal personality disorder. Schizophr. Res. 143, 158–164. Chouinard, G., Margolese, H.C., 2005. Manual for the extrapyramidal symptom rating scale (ESRS). Schizophr. Res. 76, 247–265. Corson, P.W., Nopoulos, P., Andreasen, N.C., Heckel, D., Arndt, S., 1999. Caudate size in first-episode neuroleptic-naive schizophrenic patients measured using an artificial neural network. Biol. Psychiatry 46, 712–720. Dale, A.M., Fischl, B., Sereno, M.I., 1999. Cortical surface-based analysis. I. Segmentation and surface reconstruction. NeuroImage 9, 179–194. DeLisi, L.E., Hoff, A.L., Schwartz, J.E., Shields, G.W., Halthore, S.N., Gupta, S.M., Henn, F.A., Anand, A.K., 1991. Brain morphology in first-episode schizophrenic-like psychotic patients: a quantitative magnetic resonance imaging study. Biol. Psychiatry 29, 159–175. Dieset, I., Haukvik, U.K., Melle, I., Røssberg, J.I., Ueland, T., Hope, S., Dale, A.M., Djurovic, S., Aukrust, P., Agartz, I., Andreassen, O.A., 2015. Association between altered brain morphology and elevated peripheral endothelial markers—implications for psychotic disorders. Schizophr. Res. 161 (2–3), 222–228. Doorduin, J., de Vries, E.F., Willemsen, A.T., de Groot, J.C., Dierckx, R.A., Klein, H.C., 2009. Neuroinflammation in schizophrenia-related psychosis: a PET study. J. Nucl. Med. 50, 1801–1807. Ebdrup, B.H., Norbak, H., Borgwardt, S., Glenthoj, B., 2013. Volumetric changes in the basal ganglia after antipsychotic monotherapy: a systematic review. Curr. Med. Chem. 20, 438–447. Ellison-Wright, I., Glahn, D.C., Laird, A.R., Thelen, S.M., Bullmore, E., 2008. The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis. Am. J. Psychiatry 165, 1015–1023. Feinberg, I., 1982. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J. Psychiatr. Res. 17, 319–334.
First, M.B., Spitzer, R.L.G.M., Williams, L.B.W., 1994. Structured Clinical Interview for DSMIV Axis I Disorders, Patient Edition (SCID-P). 2nd. New York, New York State Psychiatric Institute. Biom. Res. Glenthoj, A., Glenthoj, B.Y., Mackeprang, T., Pagsberg, A.K., Hemmingsen, R.P., Jernigan, T.L., Baare, W.F., 2007. Basal ganglia volumes in drug-naive first-episode schizophrenia patients before and after short-term treatment with either a typical or an atypical antipsychotic drug. Psychiatry Res. 154, 199–208. Glickman, M.E., Rao, S.R., Schultz, M.R., 2014. False discovery rate control is a recommended alternative to bonferroni-type adjustments in health studies. J. Clin. Epidemiol. 67 (8), 850–857. Goldman, A.L., Pezawas, L., Mattay, V.S., Fischl, B., Verchinski, B.A., Zoltick, B., Weinberger, D.R., Meyer-Lindenberg, A., 2008. Heritability of brain morphology related to schizophrenia: a large-scale automated magnetic resonance imaging segmentation study. Biol. Psychiatry 63, 475–483. Graeber, M.B., Li, W., Rodriguez, M.L., 2011. Role of microglia in CNS inflammation. FEBS Lett. 585, 3798–3805. Gunduz, H., Wu, H., Ashtari, M., Bogerts, B., Crandall, D., Robinson, D.G., Alvir, J., Lieberman, J., Kane, J., Bilder, R., 2002. Basal ganglia volumes in first-episode schizophrenia and healthy comparison subjects. Biol. Psychiatry 51, 801–808. Gur, R.E., Maany, V., Mozley, P.D., Swanson, C., Bilker, W., Gur, R.C., 1998. Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia. Am. J. Psychiatry 155, 1711–1717. Haijma, S.V., Van, H.N., Cahn, W., Koolschijn, P.C., Hulshoff Pol, H.E., Kahn, R.S., 2013. Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. Schizophr. Bull. 39, 1129–1138. Hertling, I., Philipp, M., Dvorak, A., Glaser, T., Mast, O., Beneke, M., Ramskogler, K., SaletuZyhlarz, G., Walter, H., Lesch, O.M., 2003. Flupenthixol versus risperidone: subjective quality of life as an important factor for compliance in chronic schizophrenic patients. Neuropsychobiology 47, 37–46. Howes, O.D., Kapur, S., 2009. The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr. Bull. 35, 549–562. Howes, O.D., Montgomery, A.J., Asselin, M.C., Murray, R.M., Valli, I., Tabraham, P., BramonBosch, E., Valmaggia, L., Johns, L., Broome, M., McGuire, P.K., Grasby, P.M., 2009. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch. Gen. Psychiatry 66, 13–20. International Conference on Harmonization., 1996. ICH Harmonised Tripartite Guidelines for Good Clinical Practice. Brookwood Medical Publications Ltd, Surrey. Jacobs, A.H., Tavitian, B., 2012. Noninvasive molecular imaging of neuroinflammation. J. Cereb. Blood Flow Metab. 32, 1393–1415. Kay, S.R., Fizbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261–267. Keshavan, M.S., Rosenberg, D., Sweeney, J.A., Pettegrew, J.W., 1998. Decreased caudate volume in neuroleptic-naive psychotic patients. Am. J. Psychiatry 155, 774–778. Koo, M.S., Levitt, J.J., McCarley, R.W., Seidman, L.J., Dickey, C.C., Niznikiewicz, M.A., Voglmaier, M.M., Zamani, P., Long, K.R., Kim, S.S., Shenton, M.E., 2006. Reduction of caudate nucleus volumes in neuroleptic-naive female subjects with schizotypal personality disorder. Biol. Psychiatry 60, 40–48. Lang, D.J., Kopala, L.C., Vandorpe, R.A., Rui, Q., Smith, G.N., Goghari, V.M., Honer, W.G., 2001. An MRI study of basal ganglia volumes in first-episode schizophrenia patients treated with risperidone. Am. J. Psychiatry 158, 625–631. Levitt, J.J., McCarley, R.W., Dickey, C.C., Voglmaier, M.M., Niznikiewicz, M.A., Seidman, L.J., Hirayasu, Y., Ciszewski, A.A., Kikinis, R., Jolesz, F.A., Shenton, M.E., 2002. MRI study of caudate nucleus volume and its cognitive correlates in neuroleptic-naive patients with schizotypal personality disorder. Am. J. Psychiatry 159, 1190–1197. Massana, G., Salgado-Pineda, P., Junque, C., Perez, M., Baeza, I., Pons, A., Massana, J., Navarro, V., Blanch, J., Morer, A., Mercader, J.M., Bernardo, M., 2005. Volume changes in gray matter in first-episode neuroleptic-naive schizophrenic patients treated with risperidone. J. Clin. Psychopharmacol. 25, 111–117. Navari, S., Dazzan, P., 2009. Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings. Psychol. Med. 39, 1763–1777. Nuechterlein, K.H., Green, M.F., 2006. MATRICS Consensus Battery Manual. MATRICS Assessment Inc, Los Angeles. Scherk, H., Falkai, P., 2006. Effects of antipsychotics on brain structure. Curr. Opin. Psychiatry 19, 145–150. Shihabuddin, L., Buchsbaum, M.S., Hazlett, E.A., Haznedar, M.M., Harvey, P.D., Newman, A., Schnur, D.B., Spiegel-Cohen, J., Wei, T., Machac, J., Knesaurek, K., Vallabhajosula, S., Biren, M.A., Ciaravolo, T.M., Luu-Hsia, C., 1998. Dorsal striatal size, shape, and metabolic rate in never-medicated and previously medicated schizophrenics performing a verbal learning task. Arch. Gen. Psychiatry 55, 235–243. Shihabuddin, L., Buchsbaum, M.S., Hazlett, E.A., Silverman, J., New, A., Brickman, A.M., Mitropoulou, V., Nunn, M., Fleischman, M.B., Tang, C., Siever, L.J., 2001. Striatal size and relative glucose metabolic rate in schizotypal personality disorder and schizophrenia. Arch. Gen. Psychiatry 58, 877–884. Vita, A., DePeri, L., 2007. The effects of antipsychotic treatment on cerebral structure and function in schizophrenia. Int. Rev. Psychiatry 19, 429–436. Voelbel, G.T., Bates, M.E., Buckman, J.F., Pandina, G., Hendren, R.L., 2006. Caudate nucleus volume and cognitive performance: are they related in childhood psychopathology? Biol. Psychiatry 60, 942–950. Zatorre, R.J., Fields, R.D., Johansen-Berg, H., 2012. Plasticity in gray and white: neuroimaging changes in brain structure during learning. Nat. Neurosci. 15, 528–536.
Please cite this article as: Emsley, R., et al., Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.09.014