The dissociative effects of ketamine and psychedelics might be associated with their rapid antidepressant properties, raising questions about whether these effects are necessary for their therapeutic action. Additionally, the distinct dissociative experiences often reported by patients in clinical trials may reveal whether they receive an active treatment or a placebo, potentially introducing bias into the results. In this viewpoint, we propose administering ketamine/psychedelics to patients during sleep, offering a novel approach to address and explore these challenges.

From a neuroscientific point of view, one of the unique archetypes of substance use disorders is its road to relapse, in which the reward system plays a crucial role. Studies on the neurobiology of substance use disorders have highlighted the central role of a protein belonging to the Fos family of transcription factors, ΔFosB. Relying on the roles ΔFosB plays in the pathophysiology of substance use disorders, we endeavour to present some evidence demonstrating that N-acetylcysteine, a low-cost and well-tolerated over-the-counter medicine, may influence the downstream pathway of ΔFosB, thereby serving as a treatment strategy to mitigate the risk of relapse in cases of substance use.

Here, we have utilised the concept of fuzzy logic and Karl Popper’s notion of verisimilitude to advocate navigating the complexity of psychiatric nosology, emphasising that psychiatric disorders defy Boolean logic. We underscore the importance of embracing imprecision and collecting extensive data for a more nuanced understanding of psychiatric disorders, asserting that falsifiability is crucial for scientific progress. We encourage the advancement of personalised psychiatric taxonomy, urging the continual accumulation of data to inform emerging advancements like artificial intelligence in reshaping current psychiatric nosology.

We address the unconsciously biased perception of psychiatric disorders, highlighting a hierarchical perspective that favours certain diagnoses over others. We aim to uncover reasons for these inequities, emphasising the need for a shift toward pathophysiology-based nomenclature that can promote equal support for each disorder, enhance treatment adherence and encourage open discussions.

Prenatal stress is believed to increase the risk of developing neuropsychiatric disorders, including major depression. Adverse genetic and environmental impacts during early development, such as glucocorticoid hyper-exposure, can lead to changes in the foetal brain, linked to mental illnesses developed in later life. Dysfunction in the GABAergic inhibitory system is associated with depressive disorders. However, the pathophysiology of GABAergic signalling is poorly understood in mood disorders. Here, we investigated GABAergic neurotransmission in the low birth weight (LBW) rat model of depression. Pregnant rats, exposed to dexamethasone, a synthetic glucocorticoid, during the last week of gestation, yielded LBW offspring showing anxiety- and depressive-like behaviour in adulthood. Patch-clamp recordings from dentate gyrus granule cells in brain slices were used to examine phasic and tonic GABAA receptor-mediated currents. The transcriptional levels of selected genes associated with synaptic vesicle proteins and GABAergic neurotransmission were investigated. The frequency of spontaneous inhibitory postsynaptic currents (sIPSC) was similar in control and LBW rats. Using a paired-pulse protocol to stimulate GABAergic fibres impinging onto granule cells, we found indications of decreased probability of GABA release in LBW rats. However, tonic GABAergic currents and miniature IPSCs, reflecting quantal vesicle release, appeared normal. Additionally, we found elevated expression levels of two presynaptic proteins, Snap-25 and Scamp2, components of the vesicle release machinery. The results suggest that altered GABA release may be an essential feature in the depressive-like phenotype of LBW rats.

With almost one-third of patients with major depression not adequately responsive to treatments, the management of treatment-resistant depression (TRD) has continued to be challenging. Recently, an essential step was taken to replace TRD with difficult-to-treat depression (DTD), pointing to some drawbacks associated with this terminology and identifying addressable barriers. In line with the DTD concept, we discuss why terming this population of patients as TRD could be semantically and clinically misleading. We then suggest replacing TRD with quasi-tenacious depression (QTD), a model and terminology that are derived from a potentially measurable outcome, the tenacity index (TI). QTD predicts that in theory remission is achievable by providing suitable treatments at hand. QTD states that every patient with major depression (even those who respond well) has some degree of tenacity that needs to be overcome by the use of proper treatment modalities. Ergo, in patients with a higher TI, due to the dearth of available armamentaria, one might suffice to achieve a partial resolution of symptoms balanced with an optimal quality of life. However, QTD calls for an incessant pursuit of novel treatments and the identification of contributing factors leading to high TI. On a track toward personalized psychiatry, and in harmony with DTD, QTD embraces all key barriers leading to a failure to treatment response and tries to provide a measurable entity for a better clinical decision while conveying a dynamic positive outlook of the disorder for both patients and health care providers.

The Wistar Hannover rat (WHR) is a strain commonly used for toxicity studies but rarely used in studies investigating depression neurobiology. In this study, we aimed to characterise the behavioural responses of WHR to acute and repeated antidepressant treatments upon exposure to the forced swim test (FST) or learned helplessness (LH) test. WHR were subjected to forced swimming pre-test and test with antidepressant administration (imipramine, fluoxetine, or escitalopram) at 0, 5 h and 23 h after pre-test. WHR displayed high immobility in the test compared to unstressed controls (no pre-swim) and failed to respond to the antidepressants tested. The effect of acute and repeated treatment (imipramine, fluoxetine, escitalopram or s-ketamine) was then tested in animals not previously exposed to pre-test. Only imipramine (20 mg/kg, 7 days) and s-ketamine (acute) reduced the immobility time in the test. To further investigate the possibility that the WHR were less responsive to selective serotonin reuptake inhibitors, the effect of repeated treatment with fluoxetine (20 mg/kg, 7 days) was investigated in the LH model. The results demonstrated that fluoxetine failed to reduce the number of escape failures in two different protocols. These data suggest that the WHR do not respond to the conventional antidepressant treatment in the FST or the LH. Only s-ketamine and repeated imipramine were effective in WHR in a modified FST protocol. Altogether, these results indicate that WHR may be an interesting tool to investigate the mechanisms associated with the resistance to antidepressant drugs and identify more effective treatments.

Behavioural animal experimentation is an inseparable part of research trying to understand the biological underpinnings of human behaviour, diseases and disorders. Working with animals comes with great responsibility to achieve reliable and reproducible results of highest scientific quality. In a simple step-by-step fashion, we highlight some common issues that may occur along the path to conducting behavioural animal experimentations and posit some solutions and grounds to ensure the excellence of work done in this research area while aspiring to improve conditions for laboratory animals. It entails topics of study design, animal and experimenter welfare, experimental considerations and frequentist biostatistics. At the end, we direct to some guidelines and manuals that may prove valuable to researchers in this field. Our ten simple tips and traps are meant for students who are learning about important concepts for the first time; graduates whose statistics training all too often has neglected the concept of power in experimental design; and researches who would like a light-hearted refresher on these topics. With this perspective, we hope that you will avoid falling into traps and find answers to what you always wanted to know about conducting behavioural animal experimentation.