Recent studies have reported positive effects of Intermittent Fasting (IF) on metabolic parameters, cognition, and mood. However, regarding depressive symptoms, the effect of IF is not clear. The purpose of this review was to assess the available evidence on IF interventions for depression in both clinical and preclinical studies. Of the 23 included studies, 15 were performed on humans and 8 on animal models. The studies on rodents suggested that IF acts as a circadian regulator, improving neurotransmitter availability and increasing the levels of neurotrophic factors in the brain. However, the investigations on humans mainly evaluated healthy volunteers and showed a great heterogeneity regarding both the IF regimen studied and the observed effects on mood. Most available clinical trials have specific limitations, such as small sample sizes and uncontrolled designs. A comprehensive systematic review was conducted on five databases, PubMed, Cochrane, the Central Register of Controlled Trials, Web of Science databases, BVS and Scopus, identifying 23 relevant studies up to 6 October 2022. IF has potentially relevant physiological effects for the treatment of mood disorders, but better designed studies and controlled evaluations are needed to evaluate its efficiency in the treatment of major depression.

The hippocampus has been highly implicated in the pathophysiology of bipolar disorder (BD). Nevertheless, no study has longitudinally evaluated hippocampal metabolite levels in bipolar depression under treatment with lithium. Nineteen medication-free BD patients (78.9% treatment-naïve and 73.7% with BD type II) presenting an acute depressive episode and 17 healthy controls were studied. Patients were treated for 6 weeks with lithium in an open-label trial. N-acetyl aspartate (NAA), creatine, choline, myo-Inositol, and glutamate levels were assessed in the left hippocampus before (week 0) and after (week 6) lithium treatment using 3T proton magnetic resonance spectroscopy (1H-MRS). The metabolite concentrations were estimated using internal water as reference and voxel segmentation for partial volume correction. At baseline, acutely depressed BD patients and healthy controls exhibited similar hippocampal metabolites concentrations, with no changes after 6 weeks of lithium monotherapy. A significant correlation between antidepressant efficacy and increases in NAA concentration over time was observed. Also, there was a significant positive correlation between the changes in glutamate concentrations over follow-up and plasma lithium levels at endpoint. Mixed effects model analysis revealed a bimodal effect of lithium plasma levels in hippocampal glutamate concentrations: levels of 0.2 to 0.49mmol/L (n=9) were associated with a decrease in glutamate concentrations, whereas the subgroup of BD subjects with “standard” lithium levels (≥0.50 mmol/L; n = 10) showed an overall increase in glutamate concentrations over time. These preliminary results suggest that lithium has a bimodal action in hippocampal glutamate concentration depending on the plasma levels.

Recent advances on the understanding about brain processes from structural to molecular mechanisms have provided a new picture on the complex etiological basis of bipolar disorder (BD). However, a considerable number of our patients do not benefit from currently available treatments. This chapter discusses potential therapeutic targets for the development of new treatments for BD. These include molecular systems, neurotransmitters and cellular signaling circuits implicated in neuroplasticity, cellular energy production, and neuronal excitability that have been found to be altered in the acute phases of BD by proof of concept clinical studies. Still, while relapse prevention is one of the most important aims in the treatment of BD, very little is known about the underlying mechanisms of mood switching, an area that should be considered of high priority for future investigations.