[Downloaded free from http://www.indianjpsychiatry.org on Saturday, April 17, 2021, IP: 117.251.52.

169]

ORIGINAL ARTICLE

A comparative diffusion tensor imaging study of patients with and without

treatment‑resistant schizophrenia
Anisha Aggarwal, Sandeep Grover, Chirag Ahuja1, Subho Chakrabarti, Niranjan Khandelwal1, Ajit Avasthi
Department of Psychiatry and 1Radiodiagnosis and Neuroimaging, Postgraduate Institute of Medical Education and Research,
Chandigarh, India

ABSTRACT

Aim: The aim was to study the brain connectivity using diffusion tensor imaging  (DTI) among patients with
treatment‑resistant schizophrenia (TRS) and compare the same with a group of patients without TRS.
Methods: Twenty‑three patients with TRS and 15 patients without TRS underwent DTI using a 3T magnetic resonance
imaging machine. DTI data were processed with the calculation of fractional anisotropy (FA) and apparent diffusion
coefficient. Patients were also assessed on Brief Psychiatric Rating Scale, Positive and Negative Symptom Scale, Global
Assessment of Functioning Scale, and Clinical Global Impression severity scale.
Results: Patients with TRS and non‑TRS differed significantly in the FA values in the region of right superior longitudinal
fasciculus and right uncinate fasciculus, with more integrity of tracts in the non‑TRS group. However, these differences
disappeared when Bonferroni correction was used for multiple comparisons.
Conclusion: The present study suggests lack of significant difference in DTI findings between patients with TRS and
non‑TRS.

Key words: Diffusion tensor imaging, schizophrenia, treatment resistance

INTRODUCTION respond to adequate treatment and are known to be suffering

Schizophrenia is arguably the most puzzling of psychiatric
syndromes and one of the most debilitating psychiatric
disorders. Despite the numerous studies aimed at
understanding the disorder, its pathophysiology is largely
unknown, with available treatments showing only partial
efficacy in treating this disorder.[1] Available data suggest
that about one‑third of patients with schizophrenia do not
Address for correspondence: Dr. Sandeep Grover,
Department of Psychiatry, Postgraduate Institute
Medical Science, Rohtak ‑ 124 001, Haryana, India.
E‑mail: drsandeepg2002@yahoo.com
Submitted: 23‑Feb‑2020,  Revised: 14‑Jun‑2020,
Accepted: 17‑Sep‑2020,  Published: 14-Apr-2021
Access this article online
Quick Response Code
Website:
www.indianjpsychiatry.org
DOI:
10.4103/psychiatry.IndianJPsychiatry_147_20
from treatment‑resistant schizophrenia (TRS).[2] Patients with
TRS are found to be highly symptomatic, require extensive
periods of hospitalization, and are responsible for the high
share of total cost toward treating schizophrenia.[3,4]
As one‑third of patients do not respond or show minimal
response to available treatments, clinicians and investigators
have attempted to predict nonresponse to treatment as
early as possible, with an aim to possibly start clozapine
before the treatment resistance evolves. One of the ways
via which this prediction has been made in literature is
This is an open access journal, and articles are distributed under the terms of
the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License,
which allows others to remix, tweak, and build upon the work non‑commercially,
as long as appropriate credit is given and the new creations are licensed under
the identical terms.
For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com
How to cite this article: Aggarwal A, Grover S, Ahuja C,
Chakrabarti S, Khandelwal N, Avasthi A. A comparative
diffusion tensor imaging study of patients with and without
treatment-resistant schizophrenia. Indian J Psychiatry
2021;63:146-51.

146 © 2021 Indian Journal of Psychiatry | Published by Wolters Kluwer - Medknow

[Downloaded free from http://www.indianjpsychiatry.org on Saturday, April 17, 2021, IP: 117.251.52.169]
Aggarwal, et al.: DTI study of patients with and without TRS
through neuroimaging, which highlights the structural
or functional changes in brain, possibly contributing to
etiopathogenesis of treatment resistance in schizophrenia.
Most of the available studies have focused on patients with
chronic schizophrenia using techniques such as computed
tomography (CT), magnetic resonance imaging (MRI), or
functional MRI, with meager data on studying cases of TRS
using diffusion tensor imaging (DTI).[4,5] Among the various
neuroimaging techniques, DTI can be considered as more
useful than CT and MRI in schizophrenia as it provides
direct information about the white‑matter neuroanatomical
connectivity between different areas of the brain. These
neuroanatomical connections could, therefore, be directly
studied to understand the etiopathogenesis of schizophrenia
and the etiopathogenesis of treatment resistance as well.
A recent systematic review evaluated the neuroimaging
findings of patients refractory to treatment and compared
the available data with healthy controls and those
responding to treatment.[4] In contrast to healthy controls,
patients with TRS showed gray‑matter reductions, which is
consistent with findings seen in schizophrenia in general.
When patients with treatment resistance/refractoriness
were compared with those responding to treatment, the
finding, which was most, replicated included a greater
reduction in gray matter in resistant patients, predominantly
in the frontal areas. However, none of the studies included
in the review, compared patients with treatment resistance
with treatment responders or healthy controls, was based
on DTI.[4] Another systematic review published in 2015,
also dealt with neuroimaging findings in patients with
TRS.[5] CT‑based studies showed prefrontal atrophy in
patients with TRS.[5] MRI studies showed that compared to
healthy controls, patients with TRS have more widespread
reduction in cortical thickness in all the lobes of brain than
patients with non‑TRS, who had reduced cortical thickness
only in frontal area of the brain.[5] As per this review, only one
study was based on DTI, which compared patients with TRS
and healthy controls. This study showed that compared to
healthy controls, patients with TRS showed lower fractional
anisotropy (FA) in multiple white‑matter bundles. The areas
involved included the genu, body, and splenium of the
corpus callosum; inferior longitudinal fasciculus; superior
longitudinal fasciculus (SLF); external capsule; uncinate
fasciculus (UF); posterior limb of the internal capsule; the
left anterior limb of internal capsule; fornix; cerebellar
peduncles; and the corticospinal tract at the level of the
brainstem. There was no voxel of increased FA in patients
compared with controls.[5] A recently published study based
on 1.5 T, voxel‑based statistical analysis using the tract‑based
spatial statistics (TBSSv1.2) approach compared patients
with treatment refractory schizophrenia and nonrefractory
schizophrenia. This study showed no differences in FA of
white‑matter integrity between the two groups.[6]
Considering the limited DTI data for patients with TRS, this
study aimed to compare the brain connectivity using DTI
Indian Journal of Psychiatry Volume 63, Issue 2, March-April 2021
among patients with and without TRS. It was hypothesized
that individuals with TRS would not differ significantly in
terms of brain circuitry involving the white matter compared
to patients with non‑TRS.
METHODS
This study was carried out in a tertiary care teaching
hospital in North India. The ethics committee of the
institute approved the study, and all the study participants
were recruited after obtaining written informed consent.
The study followed a cross‑sectional design, in which all
the patients were assessed only once. The study sample
comprised of two groups, that is, Group I comprised of
23 patients with TRS, whereas Group II comprised of
15 patients who did not fulfill the criteria of TRS (non‑TRS
Group). Both the study groups were matched for age,
gender, and total duration of illness. For this study, TRS
was defined on the basis of: (i) insufficient response to two
clinical trials of two different antipsychotics for at least
6 weeks’ duration and no period of good functioning in
the previous 2 years as determined by Global Assessment
for Functional Scale (GAF)[7] score of <59, score of ≥4 on
2 of the 4 Brief Psychiatric Rating Scale (BPRS)[8] items of
conceptual disorganization, suspiciousness, hallucinatory
behavior, and unusual thought content, total BPRS‑18
score  ≥45, and Clinical Global Impression  (CGI)[9] score
of ≥4 at the time of assessment. To be included in the study,
the participants were required to be aged 18–65 years and
fulfill the diagnosis of schizophrenia as per the Diagnostic
and Statistical Manual, fourth revision (DSM‑IV) criteria, as
confirmed by using the Mini International Neuropsychiatric
Interview (MINI).[10] Additionally, to be considered for
the non‑TRS group, participants were required to have
a period of good functioning in the previous 2 years and
total BPRS‑18 item scale score  ≤35, CGI score of  ≤3,
score of <4 on 2 of the 4 BPRS items of conceptual
disorganization, suspiciousness, hallucinatory behavior,
and unusual thought content. Patients with the presence
of organic brain syndrome, intellectual disability, comorbid
drug dependence (other than tobacco dependence), history
of any brain disorder (e.g., head injury, stroke, epilepsy, and
Parkinson’s disease), history of any illness which can cause
white‑matter damage (e.g., multiple sclerosis), comorbid
severe medical conditions which could influence the
neuroimaging findings (e.g., poorly controlled diabetes or
symptomatic coronary artery disease), and those receiving
clozapine for more than 1 week just prior to assessment or
have received clozapine in the past were excluded from the
study. Similarly, patients with contraindication for MRI (i.e.,
those with pacemakers, aneurysm clip, cochlear implants,
claustrophobia) were also excluded from the study. All the
patients were assessed on CGI Severity scale, BPRS, Positive
and Negative Symptom Scale (PANSS),[11] and GAF scale. In
addition, using a semi‑structured interview, all the patients
147
[Downloaded free from http://www.indianjpsychiatry.org on Saturday, April 17, 2021, IP: 117.251.52.169]
Aggarwal, et al.: DTI study of patients with and without TRS
were evaluated for the presence or absence of auditory
hallucinations in their lifetime.
Premorbid personality prior to onset of illness was assessed
by a semi‑structured interview conducted with the patient
and family members and a review of treatment records.
Presence of personality disorder was defined as per the
ICD‑10 criteria.
DTI data were acquired using 3T MRI machine (60 slices;
TE = 100 ms; TR = 15000 ms; 30 directions; voxel size:
2.4 × 2.4 × 2.4; time of accuracy: 8.32 min; and slice
thickness = 2.4 mm). The DTI images were processed and
analyzed on the Siemens work station (software Numaris,
version syngo MR B17). Motion and Eddy current‑induced
geometric distortions were corrected automatically.
DTI data were processed by a qualified neuroradiologist,
and the following steps were followed: (i) correction for
motion and Eddy current‑induced geometric distortions
with rotation of the b‑matrix to preserve the orientation
information was ensured, (ii) diffusion tensor using a robust
nonlinear regression method was estimated, and (iii) FA
and apparent diffusion coefficient (ADC) were calculated.
Subsequently, using the region of interest (ROI) approach,
data were analyzed.
The tensor data were loaded on the Neuro 3D platform
to derive the FA and ADC maps. The FA/ADC maps were
subsequently fused with the 3D T1 MPRAGE high‑resolution
images for better depiction and confirmation of the
white‑matter tracts. The tracts were identified as per the
different cut sections, that is, sagittal, axial, or coronal
depending on the best visibility of the tract. Thereafter,
ROI‑based analysis was performed on the desired tracts. Up
to five ROIs were chosen to enclose tracts’ cross‑sections, and
a mean of the ROIs was calculated to improve the specificity
of the data. The radius of each ROI varied between 2 mm
and 10 mm, depending on the thickness of the white‑matter
bundle. Following this, a set of 22 values each depicting the
FA values and ADC values were obtained for further analysis.
Data were analyzed by using SPSS Inc. Released 2007.
SPSS for Windows, Version 16.0. (Chicago, SPSS Inc.). The
mean and standard deviation with range were calculated
for continuous variables and frequency and percentages
were calculated for categorical variables. Comparisons
were done by using Student’s t‑test, Mann–Whitney test,
and Chi‑square test. Bonferroni correction was applied to
address multiple comparisons, and P = 0.002 (0.05/22) was
considered statistically significant.
RESULTS
The demographic profile of the study sample is shown in
Table 1. Compared to non‑TRS group, patients with TRS
148
had significantly longer duration of untreated psychosis,
had significantly higher BPRS and PANSS total scores, had
higher scores in all the domains of BPRS and PANSS, had
significantly higher CGI severity score, had significantly higher
impairment in the level of functioning as assessed by GAF,
and had received significantly higher number of adequate
antipsychotic trials [Table 1]. Most of the patients in the TRS
group had continuous symptoms in the last 5 years.
Only two patients (one borderline and one anxious avoidant
personality disorder) in the TRS group had evidence to
suggest the presence of personality disorder prior to the
onset of the schizophrenia, whereas only one patient had
personality disorder (schizoid personality disorder) in the
non‑TRS group. Overall, majority of the patients in both the
groups had no diagnosable personality disorder prior to
onset of schizophrenia. In the TRS group, 30.4% (n = 7) of
the patients had lifetime diagnosis of tobacco dependence,
of which 21.7% were still using tobacco in the dependence
pattern at the time of assessment for the study. About
one‑fifth (21.7%; n = 5) of the patients in the TRS group
had lifetime diagnosis of alcohol dependence, of which 8.7%
fulfilled the diagnosis of alcohol dependence in the last
2 years too. However, no patient was using alcohol in the
dependent pattern at the time of assessment for the study.
When patients with and without TRS were compared, no
significant difference was seen in terms of substance use
pattern in the lifetime, last 5 years, and last 2 years.
Diffusion tensor imaging findings
As is evident from Table 2, in terms of FA values, significant
difference between the two groups was noted only in the
right superior longitudinal fasciculus (SLF) and right uncinate
Figure 1: The tract superior longitudinal fasciculus (yellow
arrowhead), an association fiber tract well represented in
the color green. Uncinate fibers  (blue arrow) are forming a
loop and turning around the lateral sulcus; in turn connecting
inferior frontal and temporal lobes. The ellipsoids depict
anisotropy in both the tracts, with higher fractional anisotropy
in the right superior longitudinal fasciculus and right uncinate
fasciculus in the control group
Indian Journal of Psychiatry Volume 63, Issue 2, March-April 2021
[Downloaded free from http://www.indianjpsychiatry.org on Saturday, April 17, 2021, IP: 117.251.52.169]

Aggarwal, et al.: DTI study of patients with and without TRS

Table 1: Comparison of demographic and clinical variables of treatment‑resistant schizophrenia and

nontreatment‑resistant schizophrenia group
Parameters TRS group I (n=23) Non‑TRS group II (n=15) T‑test/χ2 (P)
Age in years 35.26 (10.85) 33.47 (8.74) t=0.54 (0.59)
Sex, male (%) 11 (47.8) 6 (40) χ2=0.22 (0.63)
Education in years, mean (SD); range 11.65 (4.02) 11.87 (2.90) t=−0.18 (0.86)
Marital status ‑ currently single (%) 13 (56.5) 5 (33.3) χ2=1.96 (0.17)
Occupation ‑ on paid employment (%) 3 (13) 3 (20) F.E=0.44
Type of schizophrenia ‑ paranoid (%) 19 (82.6) 11 (73.3) FE=0.38
Age of onset (in years) 24.65 (8.81) 22.67 (6.31) t=0.75 (0.46)
Duration of untreated psychosis (in days) 1262.35 (1682.43) 234.60 (396.8) U=97.5 (0.02)*
Total duration of illness (in years) 11.17 (8.12) 11.93 (5.92) t=−0.31 (0.76)
Comorbid physical illness ‑ presenta 5 (21.74%) 4 (26.67%) χ2b=0.0 (1)
Comorbid psychiatric illnessb 9 (39.13%) 2 (13.3%) χ2b=1.82 (0.18)
PANSS
Positive subscale score 27.13 (7.21) 7.27 (0.59) t=10.59 (<0.001)***
Negative subscale score 28.22 (11.83) 10.8 (2.57) t=5.59 (<0.001)***
General Psychopathology subscale score 49.70 (10.88) 21.07 (2.60) t=9.96 (<0.001)***
Total PANSS Score 105.04 (23.07) 39.13 (4.60) t=10.87 (<0.001)***
Insight score as assessed from PANSS (G12) 5.56 (1.37) 2.27 (1.10) t=6.69 (<0.001)***
Depression as per PANSS‑D 12.43 (5.95) 6 (1.51) t=4.08 (<0.001) ***
Depression as per PANSS‑D ‑ present (%) 19 (82.60) 5 (33.33) χ2=9.47 (0.002)**
BPRSc
Depression/anxiety/affect 9.70 (5.90) 4.2 (0.56) t=3.58 (0.001)***
Psychosis/thinking disorder 18.04 (3.76) 5.67 (0.90) t=12.46 (<0.001)***
Negative symptoms/withdrawal/retardation 9.17 (6.03) 3.6 (1.40) t=3.50 (0.001)***
Activation 6.65 (3.01) 3.87 (0.83) t=3.48 (<0.001)***
Resistance 10 (3.27) 3.27 (0.46) t=5.84 (<0.001)***
Total BPRS score 53.56 (10.68) 20.6 (2.03) t=11.76 (<0.001)***
GAF
GAF score 21 (11.27) 79.73 (7.36) t=−17.81 (<0.001)***
CGI
CGI severity 5.48 (0.59) 1.13 (0.35) t=25.52 (<0.001)***
Number of adequate trials received 3.78 (1.594) 1.73 (0.59) t=4.75 (<0.001)***
Course of illness in the last 5 years
Continuous illness with no improvement in symptoms (%) 14 (60.87) 0 χ2=14.46 (<0.001***)
Continuous illness with no or minimal symptoms 0 1 (6.7%) FE=0.39
Episodic illness in lifetime with no improvement in symptoms in last 5 years (%) 9 (39.13) 0 χ2b=0.02*
*P≤0.05; **P≤0.01; ***P≤0.001. AComorbid physical illnesses in TRS: diabetes mellitus (n=2), asthma (n=1), anemia (n=1), Acomorbid physical illnesses in
non‑TRS: diabetes mellitus (n=2), hypothyroidism (n=1), hypertension (n=1), Marfan syndrome (n=1); Bcomorbid psychiatric illnesses in TRS: moderate depressive
episode (n=4), tobacco dependence, currently using (n=6); Bcomorbid psychiatric Illnesses in non‑TRS: Moderate depressive episode (n=1), Tobacco dependence,
currently using (n=1); cItems of Brief Psychiatric Rating Scale were categorized into various domains as per.[12] χ2 – Chi‑square value; χ2b – Chi‑square value
with Yate’s correction; U – Mann-Whitney value; t – T test; SD – standard deviation; FE – Fisher’s exact value; PANSS – Positive and Negative Syndrome Scale,
BPRS – Brief Psychiatric Rating Scale; GAF – Global Assessment of Functioning; CGI – Clinical Global Impression; TRS – Treatment‑resistant schizophrenia

fasciculus (UF), with higher FA values for the right SLF and
right UF for the non‑TRS group [Figures 1 and 2]. However,
when duration of untreated psychosis was used as a covariate,
only significant difference persisted for right UF. Lack of
significant difference persisted even after using duration of
untreated psychosis as a covariate. However, when we used
the Bonferroni correction, no significant difference was seen.
In terms of ADC values, no significant difference emerged
between both the groups on any of the tracts [Table 2].
DISCUSSION
Two main schools of thought exist regarding the neurobiology
of TRS. One, which can be characterized as the continuum
hypothesis, posits that the same pathophysiological
processes underlie symptoms in both treatment‑responsive
and ‑resistant patients, but that these processes occur to a
greater degree in patients with TRS, which leads to poor
response to treatment. The other hypothesis, which can be
considered, is the categorical hypothesis, which suggests
that patients with TRS have a fundamentally different
pathophysiology compared to those showing response
to treatment, and thus current treatments are ineffective
as they target the wrong processes.[12] The present study
attempted to understand the etiopathogenesis of TRS on
the basis of these hypotheses.
In the present study, in terms of FA values, when the
comparison was done without statistical correction,
significant difference between the two groups was noted
only in the right SLF and right UF, with higher FA values
for the non‑TRS group. However, this disappeared when
the Bonferroni correction was applied. In terms of ADC
findings of white‑matter tracts, no significant difference
emerged between the two groups on any of the tracts.
There is only one study in the existing literature, which has

Indian Journal of Psychiatry Volume 63, Issue 2, March-April 2021 149

 150
Table 2: Comparison of fractional anisotropy and apparent diffusion coefficient (×10‑6mm2/s) findings of white matter tracts of treatment‑resistant
schizophrenia group and nontreatment‑resistant schizophrenia group
Variables TRS group Non‑TRS T‑test/χ2 (P) Covariate TRS group I Non‑TRS group T‑test/χ2 (P) Covariate
I (n=23) group II (n=15) analysisa F (P) (n=23) II (n=15) analysisa F (P)
Fractional anisotropy Apparent diffusion coefficient
Anterior commissure 0.22 (0.10) 0.20 (0.15) t=0.51 (0.610) F=0.058 (0.811) 2078.39 (857.1) 1792.22 (689.65) t=1.08 (0.29) F=0.635 (0.431)
Genu 0.70 (0.21) 0.76 (0.21) t=−0.92 (0.365) F=0.819 (0.372) 1204.53 (1662.14) 734.05 (98.27) t=1.1 (0.28) F=1.494 (0.23)
Splenium 0.87 (0.07) 0.77 (0.26) t=1.6 (0.12) F=2.897 (0.098) 662.29 (106.66) 822.44 (463.64) t=−1.6 (0.12) F=2.852 (0.100)
Corpus callosum 0.70 (0.18) 0.66 (0.20) t=0.67 (0.51) F=0.489 (0.489) 873.52 (358.95) 826.11 (188.22) t=0.47 (0.64) F=0.970 (0.331)
Left anterior limb of internal capsule 0.53 (0.20) 0.48 (0.16) t=0.80 (0.43) F=0.342 (0.563) 653.03 (139.57) 724.97 (98.10) t=−1.73 (0.09) F=4.767 (0.036)
Left genu of internal capsule 0.67 (0.15) 0.68 (0.13) t=−0.88 (0.93) F=0.024 (0.878) 613.4 (90.33) 621.1 (82.68) t=−0.26 (0.79) F=0.299 (0.588)
Left posterior limb of internal capsule 0.72 (0.10) 0.73 (0.12) t=−0.21 (0.84) F=0.111 (0.741) 662.03 (70.42) 664.58 (51.89) t=−0.12 (0.90) F=0.003 (0.960)
Right anterior limb of internal capsule 0.61 (0.19) 0.56 (0.17) t=0.82 (0.41) F=0.044 (0.834) 687.48 (222.14) 725.79 (81.77) t=−0.64 (0.53) F=0.037 (0.849)
Right genu of internal capsule 0.65 (0.16) 0.68 (0.14) t=−0.65 (0.52) F=0.003 (0.958) 639.93 (100.23) 615.29 (96.48) t=0.75 (0.46) F=0.427 (0.518)
Right posterior limb of internal capsule 0.75 (0.12) 0.12 (0.11) t=0.81 (0.42) F=0.397 (0.533) 626.55 (75.10) 663.15 (63.28) t=−1.56 (0.13) F=0.698 (0.409)
Left cingulum 0.71 (0.09) 0.72 (0.07) t=−0.33 (0.75) F=0.141 (0.709) 704.87 (125.37) 701.87 (51.52) t=0.09 (0.93) F=0.456 (0.504)
Right cingulum 0.65 (0.13) 0.66 (0.04) t=−0.12 (0.90) F=1.013 (0.321) 698.62 (86.98) 717.33 (76.53) t=−0.68 (0.50) F=0.006 (0.636)
Left superior occipitofrontal fasciculus 0.44 (0.07) 0.48 (0.05) t=−1.73 (0.09) F=1.254 (0.270) 673.58 (59.34) 644.67 (38.20) t=1.71 (0.10) F=3.114 (0.086)
Right superior occipitofrontal fasciculus 0.44 (0.08) 0.46 (0.06) t=−0.93 (0.36) F=0.266 (0.609) 670.13 (88.63) 653.99 (35.20) t=1.05 (0.30) F=0.179 (0.675)
Left superior longitudinal fasciculus 0.41 (0.06) 0.42 (0.06) t=−0.80 (0.43) F=1.254 (0.270) 665.96 (43.14) 648.82 (33.38) t=1.30 (0.20) F=1.465 (0.234)
Right superior longitudinal fasciculus 0.41 (0.07) 0.45 (0.06) t=−2.05 (0.047)* F=0.266 (0.609) 662.19 (35.55) 653.99 (35.21) t=0.7 (0.49) F=0.718 (0.403)
Left inferior occipitofrontal fasciculus 0.54 (0.09) 0.57 (0.09) t=−1.10 (0.28) F=0.654 (0.424) 789.33 (105.16) 769.85 (86.18) t=0.6 (0.55) F=0.646 (0.427)
Right inferior occipitofrontal fasciculus 0.57 (0.11) 0.51 (0.09) t=1.71 (0.10) F=0.357 (0.067) 750.30 (78.76) 752.98 (56.20) t=−0.11 (0.91) F=0.253 (0.618)
[Downloaded free from http://www.indianjpsychiatry.org on Saturday, April 17, 2021, IP: 117.251.52.169]

Left inferior longitudinal fasciculus 0.39 (0.08) 0.40 (0.09) t=−0.19 (0.85) F=0.033 (0.856) 774.82 (94.58) 786.93 (116.79) t=−0.35 (0.73) F=2.045 (0.162)
Aggarwal, et al.: DTI study of patients with and without TRS

Right inferior longitudinal fasciculus 0.38 (0.10) 0.38 (0.11) t=0.12 (0.90) F=0.045 (0.833) 761.38 (96.90) 728.23 (66.70) t=1.16 (0.25) F=0.003 (0.958)
Left uncinate fasciculus 0.38 (0.10) 0.36 (0.10) t=0.64 (0.53) F=0.175 (0.678) 780.97 (102.04) 811.15 (89.13) t=−0.93 (0.36) F=0.403 (0.530)
Right uncinate fasciculus 0.36 (0.09) 0.44 (0.11) t=−2.46 (0.019)* F=6.122 (0.018)* 770.24 (95.71) 775.9 (69.74) t=−0.2 (0.84) F=0.119 (0.732)
*P≤0.05; **P≤0.01; ***P≤0.001. aCovariate: Duration of untreated psychosis. χ2 – Chi‑square value; χ2b – Chi‑square value with Yate’s correction; U – Mann-Whitney value; t – T test; SD – standard deviation;
FE – Fisher’s exact value; TRS – Treatment‑resistant schizophrenia

Indian Journal of Psychiatry Volume 63, Issue 2, March-April 2021

[Downloaded free from http://www.indianjpsychiatry.org on Saturday, April 17, 2021, IP: 117.251.52.169]
Aggarwal, et al.: DTI study of patients with and without TRS
a
b 1. Keshavan MS, Nasrallah HA, Tandon R. Schizophrenia, “Just the Facts”
Figure 2: (a) Fractional anisotropy at a point for the densest
portion of uncinate fasciculus. (b) Fractional anisotropy at a
point for the densest portion of superior longitudinal fasciculus
evaluated the white‑matter integrity in patients with TRS
by using DTI and compared the same with patients without
treatment refractoriness.[6] This study concluded that there
are no differences in FA values/white‑matter integrity
between treatment refractory and nonrefractory groups
following voxel‑wise analysis TBSS approach.[6] The findings
of the present study support the same. As per evidence,
normal controls have asymmetry, with anisotropy on the
left more than right in the UF and patients with chronic
schizophrenia lack the normal left‑greater‑than‑right
anisotropy asymmetry in the UF.[13‑15]
Findings of the present study must be interpreted in light
of its limitations in the form of small sample size and
cross‑sectional assessment. Cross‑sectional comparisons of
treatment‑resistant and ‑responsive patients can potentially
indicate differences that may underlie treatment resistance.
They cannot, however, determine causality. In the present
study, the study participants in the non‑TRS group were in
clinical remission, whereas participants of the TRS group
were symptomatic at the time of the assessment. Have
a non‑TRS symptomatic group, could have been better.
Furthermore, prospective studies will be required to evaluate
whether any neurobiological markers have the potential for
clinically relevant prediction of treatment resistance. The
Indian Journal of Psychiatry Volume 63, Issue 2, March-April 2021
present study did not involve the assessment of cognitive
functions and did not include a healthy control group. DTI
findings were assessed manually rather than using more
sophisticated techniques such as tract‑based spatial statistics.
Future studies must attempt to overcome these limitations.
CONCLUSION
The present study demonstrates that white‑matter integrity
does not significantly differ between the patients with and
without TRS.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
6. Moving ahead with the schizophrenia concept: From the elephant to the
mouse. Schizophr Res 2011;127:3‑13.
2. Molina JD, Jiménez‑González AB, López‑Muñoz F, Cañas F. Evolution of
the concept of treatment‑resistant schizophrenia: Toward a reformulation
for lack of an adequate response. J Exp Clin Med 2012;4:98‑102.
3. McGlashan TH. A selective review of recent North American long‑term
followup studies of schizophrenia. Schizophr Bull 1988;14:515‑42.
4. Mouchlianitis E, McCutcheon R, Howes OD. Brain‑imaging studies of
treatment‑resistant schizophrenia: A systematic review. Lancet Psychiatry
2016;3:451‑63.
5. Nakajima S, Takeuchi H, Plitman E, Fervaha G, Gerretsen P,
Caravaggio F, et al. Neuroimaging findings in treatment‑resistant
schizophrenia: A systematic review: Lack of neuroimaging correlates of
treatment‑resistant schizophrenia. Schizophr Res 2015;164:164‑75.
6. Rodrigues JP, Reis Marques T, Picchioni MM, Ferragamo C, Lawrie S,
Sendt KV, et al. Poster #M178: White matter integrity in treatment-refractory
schizophrenia: a diffusion tensor imaging study. NPJ SCHIZOPHRENIA.
2016;2. 16008. https://doi.org/10.1038/npjschz.2016.8.
7. Aas IH. Guidelines for rating Global Assessment of Functioning (GAF).
Ann Gen Psychiatry 2011;10:2.
8. Hunter EE, Murphy M. Brief Psychiatric Rating Scale. In: Kreutzer JS,
DeLuca J, Caplan B, editors. Encyclopedia of Clinical Neuropsychology.
New York, NY: Springer; 2011.
9. Busner J, Targum SD. The clinical global impressions scale: Applying a
research tool in clinical practice. Psychiatry (Edgmont) 2007;4:28‑37.
10. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E,
et al. The Mini‑International Neuropsychiatric Interview (M.I.N.I.): The
development and validation of a structured diagnostic psychiatric interview
for DSM‑IV and ICD‑10. J Clin Psychiatry 1998;59 Suppl 20:22‑33.
11. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome
scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261‑76.
12. Shafer A. Meta‑analysis of the brief psychiatric rating scale factor structure.
Psychol Assess 2005;17:324‑35.
13. Kubicki M, Westin CF, Maier SE, Frumin M, Nestor PG, Salisbury DF,
et al. Uncinate fasciculus findings in schizophrenia: A magnetic resonance
diffusion tensor imaging study. Am J Psychiatry 2002;159:813‑20.
14. Highley JR, Walker MA, Esiri MM, Crow TJ, Harrison PJ. Asymmetry of the
uncinate fasciculus: A post‑mortem study of normal subjects and patients
with schizophrenia. Cereb Cortex 2002;12:1218‑24.
15. Burns J, Job D, Bastin ME, Whalley H, Macgillivray T, Johnstone EC, et al.
Structural disconnectivity in schizophrenia: A  diffusion tensor magnetic
resonance imaging study. Br J Psychiatry 2003;182:439‑43.
151