Major depression disease (MDD) is associated with the dysfunction of multinode brain networks. However, converging evidence implicates the reciprocal interaction between midline limbic regions (typified by the ventral anterior cingulate cortex, vACC) and the dorso-lateral prefrontal cortex (dlPFC), reflecting interactions between emotions and cognition. Furthermore, growing evidence suggests a role for abnormal glutamate metabolism in the vACC, while serotonergic treatments (selective serotonin reuptake inhibitor, SSRI) effective for many patients implicate the serotonin system. Currently, no mechanistic framework describes how network dynamics, glutamate, and serotonin interact to explain MDD symptoms and treatments. Here, we built a biophysical computational model of 2 areas (vACC and dlPFC) that can switch between emotional and cognitive processing. MDD networks were simulated by slowing glutamate decay in vACC and demonstrated sustained vACC activation. This hyperactivity was not suppressed by concurrent dlPFC activation and interfered with expected dlPFC responses to cognitive signals, mimicking cognitive dysfunction seen in MDD. Simulation of clinical treatments (SSRI or deep brain stimulation) counteracted this aberrant vACC activity. Theta and beta/gamma oscillations correlated with network function, representing markers of switch-like operation in the network. The model shows how glutamate dysregulation can cause aberrant brain dynamics, respond to treatments, and be reflected in EEG rhythms as biomarkers of MDD.

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Background: Bipolar disorder is a disabling disease characterized by the recurrence of mood episodes. Successful strategies for the acute treatment of bipolar depression are still a matter of controversy. Total sleep deprivation (TSD) has shown acute antidepressant effect; however, the prompt relapse of depressive symptoms after sleep recovery has been reported. Taking this into consideration, we aimed to address a twofold research question: what are the acute effects of adding TSD to pharmacological treatment and what are the acute and chronic effects of adding medications to TSD. Methods: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched for clinical trials assessing bipolar depression and TSD. Two independent reviewers selected and classified 90 abstracts. The outcomes we assessed were change in Hamilton Depression Rating Scale (HDRS) or Montgomery-Asberg Depression Rating Scale (MADRS), sustained long-term response rate, treatment-emergent mania or hypomania, and tolerability (using dropout rates as a proxy). The compared groups were: TSD alone versus TSD plus medications and medications alone versus medications plus TSD. Data was analyzed using Stata 16.0. Results: Patients treated with TSD plus medications compared with medications alone showed a significant decrease in depressive symptomatology after one week (SMD −0.584 [95% CI −1.126 to −0.042], p = 0.03. Also, a significant decrease in depressive symptomatology (SMD −0.894 [95% CI −1.388 to −0.399], p < 0.001) was found in the group with TSD plus medications compared with TSD alone, at the 10 th day of treatment. We meta-analyzed the long-term effect of the TSD. It showed a sustained antidepressant effect (log OR = 2.365 (95% CI 0.95 to 3.779, p < 0.001) in the group where TSD was combined with medication when compared with patients treated only with TSD. Finally, no differences in tolerability (log OR = 0.234 (95% CI −1.164 to 1.632, p = 0.74) or affective switch were found.

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