Euthymic bipolar disorder (euBD) patients exhibit deficits in neurocognitive and social cognitive functioning compared to healthy controls (HCs). Our prior research has shown that the excitatory/inhibitory (E/I) imbalance in the default mode network (DMN) is linked to executive function in euBD. Neurocognitive impairments are associated with social cognition deficits in individuals with mental disorders. Given this connection, this study posits E/I imbalance within the DMN is associated with social cognition, with executive function as a mediator.

Seventy-five HCs and 49 euBD individuals were recruited. Using the emotion recognition task, Diagnostic Analysis of Nonverbal Accuracy 2-Taiwan version (DANVA-2-TW) and cognitive flexibility task, Wisconsin Card Sorting Test (WCST), we assessed emotion recognition and prefrontal function. Proton magnetic resonance spectroscopy (1H-MRS) measured metabolites in the posterior cingulate cortex (PCC) and medial prefrontal cortex/anterior cingulate cortex (mPFC/ACC), quantifying excitatory glutamate+glutamine (Glx) and inhibitory GABA to calculate the E/I ratio.

euBD patients showed poorer emotion recognition (p = 0.020) and poorer cognitive flexibility (fewer WCST categories completed, p = 0.002). A negative association was found between emotion recognition and the E/I ratio in the mPFC/ACC of the BD patients (r = −0.30, p = 0.034), which was significantly mediated by cognitive flexibility (Z = −2.657, p = 0.007).

The BD patients demonstrate deficits in emotion recognition, linked to an altered E/I balance in the prefrontal cortex, and the cognitive flexibility, a key aspect of executive function, mediates the impact of the E/I ratio on emotion recognition accuracy in euBD patients.

To examine and record the clinical antidepressant effect of exogenous agmatine, an amino acid derived central glutamaergic modulator in endogenously depressed subjects. It was also the author's intention to examine the effects of parachlorophenylalanine (PCPA)in therapeutic responders to determine if serotonergic mechanisms mediate agmatine's antidepressant effect.

Exogenous agmatine was ingested in doses of 2‐3mg/day by depressed subjects with Major Depresssive Disorder (MDD), clinically assessed using the 21 item Hamilton Rating Scale for Depression (HAM‐D), the Clinical Global Impression (CGI) and the Brief Psychiatric Rating Scale (BPRS). Antidepressant responders volunteered to concommittantly ingest parachlorophenylalanine (PCPA) at starting doses of 250mg/day, and increased until depressive relapse, mitigating side effects, or a maximum dosage of 1250mg/day.

Three depressed subjects showing total illness remission with exogenous agmatine did not relapse after concomitantly adding PCPA. Effective in relieving both psychomotor agitation and retardation, the antidepressant effect was free of physical or behavioural side effects: gastrointestinal discomfort and loose stools in one subject resolved spontaneously within days. All three subjects refused to risk depressive relapse by temporarily stopping agmatine after PCPA was stopped.

The antidepressant effect of exogenous agmatine was documented in a small number of MDD subjects, and was not reversed/modified by PCPA confirming findings in animals that therapeutic response is not mediated by serotonergic mechanisms. A NAMDA (N‐methyl‐D‐aspartate) receptor antagonist, agmatine's recognized function in brain as inhibitory modulator of excitatory glutamatergic transmission suggests a pivotal role for brain glutamate, contributing to the ripening glutamatergic basis of depression, and a rational basis for future antidepressant pharmacotherapy.