Research conducted on individuals with depression reveals that major depressive disorders (MDDs) coincide with diminished levels of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the brain, as well as modifications in the subunit composition of the primary receptors (GABA_A receptors) responsible for mediating GABAergic inhibition. Furthermore, there is substantial evidence supporting the significant role of GABA in regulating stress within the brain, which is a pivotal vulnerability factor in mood disorders. GABA is readily available and approved as a food supplement in many countries. Although there is substantial evidence indicating that orally ingested GABA may affect GABA receptors in peripheral tissues, there is comparatively less evidence supporting its direct action within the brain. Emerging evidence highlights that oral GABA intake may exert beneficial effects on the brain and psyche through the gut–brain axis. While GABA enjoys wide consumer acceptance in Eastern Asian markets, with many consumers reporting favorable effects on stress regulation, mood, and sleep, rigorous independent research is still largely lacking. Basic research, coupled with initial clinical findings, makes GABA an intriguing neuro-nutritional compound deserving of clinical studies in individuals with depression and other psychological problems.

We recently indicated that four-week probiotic supplementation significantly reduced depression along with microbial and neural changes in people with depression. Here we further elucidated the biological modes of action underlying the beneficial clinical effects of probiotics by focusing on immune-inflammatory processes. The analysis included a total of N = 43 participants with depression, from which N = 19 received the probiotic supplement and N = 24 received a placebo over four weeks, in addition to treatment as usual. Blood and saliva were collected at baseline, at post-intervention (week 4) and follow-up (week 8) to assess immune-inflammatory markers (IL-1β, IL-6, CRP, MIF), gut-related hormones (ghrelin, leptin), and a stress marker (cortisol). Furthermore, transcriptomic analyses were conducted to identify differentially expressed genes. Finally, we analyzed the associations between probiotic-induced clinical and immune-inflammatory changes. We observed a significant group x time interaction for the gut hormone ghrelin, indicative of an increase in the probiotics group. Additionally, the increase in ghrelin was correlated with the decrease in depressive symptoms in the probiotics group. Transcriptomic analyses identified 51 up- and 57 down-regulated genes, which were involved in functional pathways related to enhanced immune activity. We identified a probiotic-dependent upregulation of the genes ELANE, DEFA4 and OLFM4 associated to immune activation and ghrelin concentration. These results underscore the potential of probiotic supplementation to produce biological meaningful changes in immune activation in patients with depression. Further large-scale mechanistic trials are warranted to validate and extend our understanding of immune-inflammatory measures as potential biomarkers for stratification and treatment response in depression. Trial Registration: www.clinicaltrials.gov, identifier: NCT02957591.

Research conducted on individuals with depression reveals that major depressive disorders (MDDs) coincide with diminished levels of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the brain, as well as modifications in the subunit composition of the primary receptors (GABAA receptors) responsible for mediating GABAergic inhibition. Furthermore, there is substantial evidence supporting the significant role of GABA in regulating stress within the brain, which is a pivotal vulnerability factor in mood disorders. Although there is substantial evidence indicating that GABA may be affecting GABA receptors in peripheral tissues, there is comparatively less evidence supporting its direct action within the brain. Emerging evidence highlights that GABA may exert beneficial effects on the brain and psyche through the gut-brain axis. GABA is readily available and approved as a food supplement in many countries. While GABA enjoys wide consumer acceptance in Eastern Asian markets, with many consumers reporting favorable effects on stress regulation, mood, and sleep, rigorous independent research is still largely lacking. Basic research, coupled with initial clinical findings, makes GABA an intriguing neuro-nutritional compound deserving of clinical studies in individuals with depression and other psychological problems.

Electroconvulsive therapy (ECT) is a neuromodulation procedure that uses short electrical pulses causing a brief generalized seizure to treat depression, mania, schizophrenia, and catatonia. Achieving sufficient seizure length is crucial for maintaining therapeutic efficacy, as it influences treatment response. However, over successive sessions, seizure length becomes shorter requiring an increased energy set to generate a sufficient seizure, potentially causing more side effects. Caffeine augmentation offers a promising tool by enhancing neuronal excitability via adenosine receptor modulation. This retrospective study assessed the effects of intravenous caffeine citrate (200 mg) on seizure quality during ECT. Data from 276 ECT sessions across 69 patients at the University Psychiatric Clinics Basel were analyzed. We examined seizure indicators—EEG seizure length, peak heart rate, and energy set— by comparing the last two ECT sessions before caffeine administration with the first two sessions after, controlling for anesthetic effects and their interactions. Caffeine augmentation significantly increased EEG seizure length (t (67) = 8.20, p < 0.001, d = 1.23) and significantly reduced the required energy (t (67) = 4.42, p < 0.001, d = 0.65). There was no significant change in peak heart rate (t (45) = 1.66, p = 0.17, d = 0.17) or other seizure quality metrics or side effects. Type of anesthesia did not affect outcomes, except for energy set where we observed a significant interaction—etomidate combined with caffeine resulted in a smaller energy increase compared to propofol (F (198) = 0.04, η² = 0.04). Our findings suggest that intravenous caffeine augmentation safely enhances seizure length and slows energy set increases in ECT without affecting cardiovascular markers, supporting its use as an effective augmentation strategy to improve ECT efficacy.

Episodic memory is the memory for experienced events. A peak competence of episodic memory is the mental combination of experienced events to infer commonalities. This enables adequate interpretation and behavior. Inferring commonalities in episodic memory may proceed with and without consciousness of events. Yet, what distinguishes conscious from unconscious event encoding? This question inspired nine experiments that featured strongly and weakly masked cartoon clips presented for unconscious and conscious encoding and inference. Each clip featured a scene with a visually impenetrable hiding place. Five animals crossed the scene one-by-one consecutively. One animal trajectory represented one event. The animals moved through the hiding place, where they might linger or not. Participants’ task was to observe the animals’ entrances and exits to maintain a mental record of which animals hid simultaneously. We manipulated information load to explore capacity limits of conscious/unconscious encoding. Memory of inferences was tested immediately or 3.5 or 6 minutes following encoding. Participants retrieved inferences well when encoding was conscious. When encoding was unconscious, participants needed to give retrieval responses intuitively. Only habitually intuitive decision-makers exhibited significant delayed retrieval of inferences drawn unconsciously. Hippocampal activity increased with correct retrieval responses and correlated with retrieval success at both consciousness levels. With increasing information load, delayed retrieval performance remained only stable when encoding had been unconscious. A strong hippocampal-neocortical functional connectivity hallmarked conscious memories. A sparse coding hallmarked unconscious memories. Sparse coding may have enlarged memory capacity. Hence, levels of consciousness influenced the memories’ behavioral impact, representational code, and memory capacity.