Resumen de Neurotoxicity of major depressive disorder: A neuroimaging and neuropsychological study
Introduction Major depressive disorder (MDD) is characterized by feelings of sadness and/or apathy, physical disturbances and cognitive impairment. After the first episode, 50% of patients relapse and up to 20% become chronic. Current aetiological theories, which consider brain structure and function as part of MDD pathophysiology, postulate that structural alterations and cognitive impairments would ease recurrence and chronicity. However, the brain areas implied are inconsistent between studies, hindering the characterization of MDD pathophysiological models and slowing the finding of new treatments. In addition, therapeutic strategies for patients with treatment resistant depression (TRD) are scarce and generally have a negative impact on cognition, preventing them from a complete recovery. Thus, new studies are needed to determine individual variables predicting clinical trajectories such as chronicity.
Objectives E1: To investigate structural brain abnormalities at different stages of the illness and to determine the effect of clinical characteristics on brain GMV.
E2: To determine the cerebral metabolism changes during a switch-off of electrical stimulation in implanted patients with TRD who had achieved clinical improvement.
E3: To evaluate cognitive function of TRD patients before and after DBS of the SCG.
E4: To examine the prognostic potential of clinical and sMRI data in the long-term clinical outcomes of MDD.
Methods Voxel-based morphometry (VBM) was used to compare 66 MDD patients at different illness stages with 32 healthy controls. GMV were also correlated with patients¿clinical characteristics (E1). 66 MDD patients were contacted at 5 years after MRI scan and split in 4 groups depending on their clinical trajectories during that time (n=49). Regression analysis with clinical and neuroimaging data as predictive variables and clinical outcomes as dependent variable was carried out (E4). Finally, a neuropsychological battery was administered before and after DBS of subgenual cingulate gyrus (SCG) in TRD patients, with a control group of first episode patients (E3). In addition, clinically stable TRD patients underwent a positron emission tomography (PET) analysis comparing active versus inactive DBS (E2).
Results VBM showed a significant group effect in right superior frontal gyrus, left medial frontal gyrus and left cingulate gyrus. Patients whose condition was treatment resistant/chronic exhibited the smallest volumes in frontotemporal areas. Longer illness duration was negatively correlated with decreases in right medial frontal cortex and left insula (E1). The fourth study showed that GMV explained a 20% more of variance when added to clinical characteristics predicting long-term clinical outcomes. Anterior cingulate gyrus was the area adding more value to the prediction. In addition, such cingulate area showed a metabolic decrease in TRD patients who were clinically stable when the stimulation was stopped. Finally, neuropsychological assessment of TRD patients show no impairment of cognitive functioning after DBS, but a memory improvement (E2).
Conclusions Frontotemporolimbic areas were smaller in the patients with severe depression and were associated with duration of illness, but not with medication patterns, suggesting negative effects of long-lasting MDD on grey matter. In addition, GMV demonstrate an added value to clinical information of depressive patients in terms of predicting their long-term clinical outcome (E4). Right dorsal anterior cingulate gyrus seems to be closely related to treatment response (E2). Finally, neuropsychological performance of patients after DBS (E3) supported the cognitive safety of this new technique adding valuable information for its future implementation as a therapeutic alternative for TRD patients.
Limitations A longitudinal study would be more appropriate to ascertain whether volume reductions in chronic patients are a result of enduring MDD effects or the cause of a more severe disorder. Regarding the follow-up study, differences in illness stage at baseline could lead to confusion. The results of second and third study should be interpreted with caution given the small sample size and the fact that some TRD patients received ECT before implantation. However, the results are promising as provide strong evidence of the pernicious effects that depression exert on brain, specially when treatment is unsuccessful. In addition, findings point to key brain areas as future biological markers to guide new treatments for major depression.
