Structural and functional features of treatment-resistant depression: A systematic review and exploratory coordinate-based meta-analysis of neuroimaging studies

Alessandro Miola

A third of people suffering from major depressive disorder do not experience a significant improvement in their symptoms even after adequate treatment with two different antidepressant medications.

This common condition, termed treatment-resistant depression (TRD), severely affects the quality of life of millions of people worldwide. TRD is of utmost clinical relevance given the impact of residual depressive symptoms on functioning, the higher risk of recurrence, the lower chances of remission, and the risk of suicide (which is at least twice the rate of those with nonresistant depression), causing long-lasting interpersonal problems and social costs. Given its epidemiological and clinical relevance and the little consensus on whether the neurobiological underpinnings of TRD differ from treatment-sensitive depression (TSD), we aimed to highlight the convergent morphometric and functional neuroimaging correlates of TRD.

Fabio Sambataro
Giulia Perini

We systematically reviewed the published literature on structural and resting-state functional neuroimaging of TRD compared to TSD and healthy controls (HC) and performed exploratory coordinate-based meta-analyses of significant results separately for each modality and multimodally (“all-effects”). Out of the initial 1929 studies, only eight involving 555 participants (189 patients with TRD, 156 with TSD, and 210 HC) were included. In all-effects coordinate-based meta-analyses, precentral/superior frontal gyrus showed a significant difference between TRD and HC. Functional and structural imaging meta-analyses did not yield statistically significant results. A marginally significant cluster of altered intrinsic activity was found between TRD and HC in the cerebellum/pons. Frontal, cerebellar, and brainstem functions can be involved in the pathophysiology of TRD.

Although the high clinical heterogeneity of TRD and the different methodological approaches used to study the functional neuroimaging of this condition, we highlighted that the cerebellum/pons could be a candidate brain region for identifying TRD. Further studies using multimodal and task-based approaches are warranted to better characterize the role of this region in treatment resistance to depression.

Brain regions altered in Treatment-Resistant Depression (TRD) in each neuroimaging modality. The results of morphometric (A, B) and resting functional magnetic resonance (C, D) studies are displayed on the Desikan–Killiany atlas. On the leftmost side, the lateral and medial cortical surfaces are displayed for each hemisphere (A, C); on the rightmost side, the coronal and sagittal projections are shown (B, D). Significantly altered morphometry (gray matter volume) in cortical (A; caudal anterior cingulate cortex, rostral middle frontal gyrus, superior frontal gyrus, insula, parahippocampal gyrus, transverse, superior and middle temporal gyrus) and subcortical (B; amygdalae, caudate nuclei, and cerebellum) regions in TRD relative to treatment sensitive depression (TSD) and healthy controls (HC) in the included studies, respectively (here reported in orange). Significantly altered resting-state activity (low-frequency oscillations, regional homogeneity) in the cortical (C; right superior and middle temporal gyrus, right inferior frontal gyrus pars triangularis, right middle and inferior occipital gyrus, right supramarginal gyrus, right insula, left middle cingulate, left inferior frontal gyrus, left cuneus, left precentral and postcentral gyrus, left paracentral lobule, left fusiform gyrus, bilateral inferior parietal lobule, bilateral precuneus, bilateral superior frontal gyrus, bilateral anterior cingulate cortex/medial frontal gyrus) and subcortical (D; the thalamic nuclei and cerebellum) regions in TRD relative to HC in the included studies, respectively (reported in blue). The renderings were created using the R-package ggseg.

Miola A, Meda N, Perini G, Sambataro F. Structural and functional features of treatment-resistant depression: A systematic review and exploratory coordinate-based meta-analysis of neuroimaging studies. Psychiatry Clin Neurosci. 2023 Jan 15. doi: 10.1111/pcn.13530. Epub ahead of print. PMID: 36641802.

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