Schizophrenia and Treatment Resistance

Nearly one-third of patients with schizophrenia do not respond to first-line anti-psychotics. This warrants an early diagnosis of this treatment-resistant subset so that drugs like clozapine can be used at an early stage before the psychiatric condition worsens in such patients.

Diffusion tensor imaging (DTI), which can pick up anomalies in white matter connections at an early stage, can test the hypothesis that the brains of patients with treatment-resistant schizophrenia (TRS) are structurally different from those sensitive to usual drugs. In a recently published study in the Indian Journal of Psychiatry by Aggarwal et al., a lack of significant difference in DTI findings between patients with TRS and non-TRS was demonstrated, thus countering the categorical hypothesis for TRS.

Schizophrenia is arguably the most puzzling of psychiatric syndromes and one of the most debilitating psychiatric disorders. Patients with TRS are found to be highly symptomatic and require extensive periods of hospitalization.

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. Prediction has been made previously through neuroimaging, using CT and MRI (mainly), which highlights the structural or functional changes in the brain, possibly contributing to the etiopathogenesis of treatment resistance in schizophrenia.

Among the various neuroimaging techniques, diffusion tensor imaging (DTI) can be considered 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.

On this background, the study aimed to study the brain connectivity using DTI among patients with treatment-resistant schizophrenia (TRS) and compare the same with patients without TRS. It followed a cross-sectional design. The study sample comprised two groups:

• Group I: 23 patients with TRS
• Group II: 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.

DTI data were acquired using a 3T MRI machine. The DTI images were processed and analyzed on the Siemens workstation. DTI data were processed with the calculation of fractional anisotropy (FA) and apparent diffusion coefficient.

It was found that patients with TRS and non‑TRS differed significantly in the fractional anisotropy (FA) values in the region of the 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.

Two main schools of thought exist regarding the neurobiology of TRS:

• 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 categorical hypothesis 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.

The present study demonstrates that white-matter integrity does not significantly differ between the patients with and without TRS, thus refuting the categorical hypothesis.

Source: Indian Journal of Psychiatry 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.