Although monoaminergic-targeted drugs have prompted great advances in the development of treatments for depression, the need for new options persists, since these drugs still have a delayed clinical effect and most patients do not respond properly to them. Recently, the observation of the antidepressant effects of ketamine brought on a new wave of studies regarding the comprehension of the neurobiology of depression and the development of new and more effective antidepressant drugs.

Thus, in this paper, we present a historical review of the development of monoaminergic antidepressant drugs and the role of ketamine as the introductory agent of a new era in the research of the neurobiology of depression.

Firstly, we review how the pharmacological treatment for major depression started, and we point out the main drugs discovered, the researchers involved, and how the studies developed have contributed to the understanding of the neurobiology of depression. Secondly, the major problems regarding the clinical efficacy and acceptance of these drugs are discussed, and the introduction of the glutamatergic system as a target for antidepressant drugs is presented. Finally, we review how ketamine revealed itself as an exciting option towards obtaining pharmacological agents to treat depression, through the understanding of biological markers.

Ketamine contributed to confirm that different targets of the glutamatergic system and neurotrophic pathways are strictly related to the neurobiology of depression. There are several antidepressant drugs based on ketamine’s mechanism of action already in the pipeline, and glutamatergic-targeted antidepressants may be on the market in the near future.

l-theanine, an amino acid uniquely contained in green tea (Camellia sinensis), has been suggested to have various psychotropic effects. This study aimed to examine whether l-theanine is effective for patients with major depressive disorder (MDD) in an open-label clinical trial.

Subjects were 20 patients with MDD (four males; mean age: 41.0±14.1 years, 16 females; 42.9±12.0 years). l-theanine (250 mg/day) was added to the current medication of each participant for 8 weeks. Symptoms and cognitive functions were assessed at baseline, 4, and 8 weeks after l-theanine administration by the 21-item version of the Hamilton Depression Rating Scale (HAMD-21), State-Trait Anxiety Inventory (STAI), Pittsburgh Sleep Quality Index (PSQI), Stroop test, and Brief Assessment of Cognition in Schizophrenia (BACS).

HAMD-21 score was reduced after l-theanine administration (p=0.007). This reduction was observed in unremitted patients (HAMD-21>7; p=0.004) at baseline. Anxiety-trait scores decreased after l-theanine administration (p=0.012) in the STAI test. PSQI scores also decreased after l-theanine administration (p=0.030) in the unremitted patients at baseline. Regarding cognitive functions, response latency (p=0.001) and error rate (p=0.036) decreased in the Stroop test, and verbal memory (p=0.005) and executive function (p=0.016) were enhanced in the BACS test after l-theanine administration.

Our study suggests that chronic (8-week) l-theanine administration is safe and has multiple beneficial effects on depressive symptoms, anxiety, sleep disturbance and cognitive impairments in patients with MDD. However, since this is an open-label study, placebo-controlled studies are required to consolidate the effects.

Paediatric bipolar disorder – bipolar disorder occurring in prepubertal children – is a diagnosis subject to considerable controversy. Whilst historically considered to be very rare, proponents since the 1990s have argued that mania can present differently in children and, as such, is much more common than previously thought. Such proposals raise questions about the validity of proposed phenotypes and potential risks of iatrogenic harm.

I critically examine the construct of paediatric bipolar disorder using Robins and Guze’s (1970, American Journal of Psychiatry 126, 983–987) influential criteria for the validity of a psychiatric diagnosis. I review, in turn, evidence relating to its clinical description, delimitation from other conditions, follow-up studies, family studies, laboratory studies, and treatment response.

Across domains, existing research highlights significant challenges establishing the diagnosis. This includes significant heterogeneity in operationalising criteria for children; variable or poor inter-rater reliability; difficulty distinguishing paediatric bipolar disorder from other conditions; large differences in rates of diagnosis between the United States of America and other countries; limited evidence of continuity with adult forms; and a lack of evidence for proposed paediatric phenotypes in children at genetic high-risk of the condition. Laboratory and treatment studies are limited, but also do not provide support for the construct.

Evidence for the more widespread existence of paediatric bipolar disorder and its various proposed phenotypes remains weak. The ongoing popularity of the diagnosis, most evident in America, may reflect social pressures and broader limitations in psychiatric nosology. The uncertainty around the diagnosis highlights the need for careful longitudinal assessment of children potentially affected.

Chronic stress responses can lead to physical and behavioural health problems, often experienced and observed in the care of people with intellectual disabilities or people with dementia. Electrodermal activity (EDA) is a bio-signal for stress, which can be measured by wearables and thereby support stress management. However, the how, when and to what extent patients and healthcare providers can benefit is unclear. This study aims to create an overview of available wearables enabling the detection of perceived stress by using EDA.

Following the PRISMA-SCR protocol for scoping reviews, four databases were included in the search of peer-reviewed studies published between 2012 and 2022, reporting detection of EDA in relation to self-reported stress or stress-related behaviours. Type of wearable, bodily location, research population, context, stressor type and the reported relationship between EDA and perceived stress were extracted.

Of the 74 included studies, the majority included healthy subjects in laboratory situations. Field studies and studies using machine learning (ML) to predict stress have increased in the last years. EDA is most often measured on the wrist, with offline data processing. Studies predicting perceived stress or stress-related behaviour using EDA features, reported accuracies between 42% and 100% with an average of 82.6%. Of these studies, the majority used ML.

Wearable EDA sensors are promising in detecting perceived stress. Field studies with relevant populations in a health or care context are lacking. Future studies should focus on the application of EDA-measuring wearables in real-life situations to support stress management.

To examine associations between IgA responses to Gram-negative gut commensal bacteria and peri-menstrual symptoms and sex hormone levels during the menstrual cycle in women with and without premenstrual symptoms.

Forty women aged 18–45 years completed the Daily Record of Severity of Problems (DRSP) during all 28 consecutive days of the menstrual cycle. We assayed, in plasma, IgA responses to six Gram-negative bacteria, that is, Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii, Klebsiella pneumoniae, Pseudomonas putida and Citobacter koseri, progesterone and oestradiol at days 7, 14, 21 and 28 of the menstrual cycle.

Significant changes in Δ (actual − 1 week earlier) IgA to lipopolysaccharides (LPS) of the six Gram-negative bacteria during the menstrual cycle were observed with peak IgA levels at T4 (day 28) and lows at T1 or T2 (day 7 or 14). The ΔIgA changes in H. alvei, M. Morganii, P. putida during the menstrual cycle were significantly and positively associated with changes in the total DRSP score, and severity of physio-somatic, anxiety and breast-craving, but not depressive, symptoms. The changes in IgA responses to LPS were largely predicted by changes in progesterone and steady-state levels of progesterone averaged over the luteal phase.

Menstrual cycle-associated changes in IgA directed against LPS and by inference bacterial translocation may be driven by the effects of progesterone on transcellular, paracellular and vascular pathways (leaky gut) thereby contributing to the severity of physio-somatic and anxiety symptoms as well as fatigue, breast swelling and food cravings.