Antipsychotic drugs (APs) have profoundly changed the treatment landscape for psychiatric disorders, yet their impact on neuroplasticity and neurotrophism remains only partially understood. While second-generation antipsychotics (SGAs) are associated with a better side effect profile than their predecessors, the emergence of third-generation antipsychotics (TGAs)—such as brexpiprazole, cariprazine, lurasidone, iloperidone, lumateperone, pimavanserin, and roluperidone—has prompted renewed interest in their potential neuroprotective and pro-cognitive effects. This review attempts to carefully examine the evidence on the neurotrophic properties of TGAs and their role in modulating brain plasticity by analyzing studies published between 2010 and 2024. Although data remain limited and focused primarily on earlier SGAs, emerging findings suggest that some TGAs may exert positive effects on neuroplastic processes, including the modulation of brain-derived neurotrophic factors (BDNFs) and synaptic architecture. However, robust clinical data on their long-term effects and comparative efficacy are lacking; therefore, further research is necessary to validate their role in preventing neurodegenerative changes and improving cognitive outcomes in patients with psychiatric conditions.

Background/Objectives: Obsessive–compulsive disorder (OCD) is a complex psychiatric condition often associated with alterations in cognitive processes, including memory. Although memory dysfunction has been proposed as a contributing factor to the onset and maintenance of OCD symptoms, it remains debated whether these deficits reflect genuine cognitive impairments or maladaptive metacognitive processes, such as pathological doubt and memory distrust. This review aims to synthesize current findings on memory functioning in OCD, focusing on distinct memory systems and the role of metacognition. Methods: A comprehensive literature search was conducted across five databases (PubMed, Scopus, Embase, PsycINFO, and Google Scholar), covering studies up to April 2025. Search terms included “Obsessive-compulsive disorder”; “OCD”; “Memory dysfunction”; “Episodic memory”; “Working memory impairment”; “Prospective memory deficits”; “Checking compulsions”; “Memory confidence”; “Cognitive biases”. Results: Short-term memory appears generally preserved in OCD. Working memory deficits are consistently reported, especially in the visuospatial domain, and they are associated with difficulties in updating and clearing irrelevant information. Episodic memory impairments are common and often linked to inefficient encoding strategies and heightened cognitive self-consciousness. Prospective memory is frequently compromised under neutral conditions. Individuals with checking symptoms tend to show intact objective memory performance, despite reporting low memory confidence, supporting the concept of memory distrust. Conclusions: Memory dysfunction in OCD is multifaceted, involving both cognitive and metacognitive alterations. The evidence supports a model in which executive dysfunctions and memory-related beliefs contribute to compulsive behaviors more than objective memory failure. These insights highlight the need for integrative assessment protocols and personalized interventions targeting both cognitive performance and metacognitive appraisals.

Background/Objectives: Sensory deprivation, defined as a reduction or absence of external sensory input across one or more modalities, has long been investigated in extreme and experimental settings. More recently, its relevance has expanded to clinical contexts and environmental conditions. The present narrative review aims to synthesize current evidence on the neurobiological mechanisms, psychological effects, and clinical implications of sensory deprivation, with particular attention to its dual role as both a risk factor and, under controlled conditions, a potential therapeutic tool. Methods: A narrative literature search was conducted using PubMed, Scopus, and PsycINFO, covering studies published up to August 2025. Search terms included sensory deprivation, neuroplasticity, neurotransmitters, HPA axis, neuro-inflammation, circadian rhythms, psychopathology, extreme environments, and spaceflight. Preclinical and clinical studies examining biological, cognitive, and psychological consequences of reduced sensory stimulation were included. Data were synthesized thematically without quantitative meta-analysis. Results: Evidence indicates that sensory deprivation induces widespread neurobiological adaptations involving neurotransmitter systems (particularly dopaminergic pathways), dysregulation of the hypothalamic–pituitary–adrenal axis, neuroimmune activation, circadian rhythm disruption, and structural and functional brain changes, notably affecting the hippocampus. These alterations are associated with increased vulnerability to depression, anxiety, hallucinations, dissociative symptoms, and cognitive impairment. Duration, voluntariness, and individual differences (e.g., baseline vulnerability/resilience, trait anxiety, and prior psychiatric history) critically modulate outcomes. However, short-term and voluntary sensory restriction, such as Floatation-REST, may promote relaxation and emotional regulation under specific conditions. Conclusions: Sensory deprivation exerts complex, context-dependent effects on brain function and mental health. Duration, individual vulnerability, and voluntariness critically modulate outcomes. Understanding these mechanisms is increasingly relevant for clinical practice and for developing preventive strategies in extreme environments, including future long-duration space missions.

Background/Objectives: Major depressive disorder (MDD) represents a leading cause of global disability, with approximately one-third of patients exhibiting treatment resistance (TRD) despite adequate pharmacological interventions. This treatment gap underscores the urgent need for novel therapeutic strategies. Recently, a series of data suggests that botulinum neurotoxin of type A (BoNT-A), traditionally used for neuromuscular and cosmetic indications, could constitute a potential antidepressant tool. This narrative review critically examines the current preclinical and clinical findings of BoNT-A in MDD. Methods: A comprehensive search of PubMed, Scopus, and Web of Science was conducted up to June 2025, including randomized controlled trials, observational studies, animal models, and mechanistic investigations. Search terms included “Botulinum Toxin,” “BoNT type A”, “Depression”, “Major Depressive Disorder”, “Facial Feedback”, and “Neurobiology”. Results: Some randomized and observational studies would indicate that glabellar BoNT-A injections might lead to significant reductions in depressive symptoms in patients with MDD and TRD. Proposed mechanisms include both peripheral modulation of emotional expression and brain effects, such as reduced amygdala hyperactivity, increased BDNF expression, and enhanced monoaminergic transmission. Preclinical studies confirm that BoNT-A modulates limbic and brainstem circuits, possibly implicated in affective regulation. The few comparative studies suggest therapeutic efficacy comparable to that of SSRIs, with a more rapid onset. Preliminary data also support its application in bipolar depression and comorbid anxiety disorders. Conclusions: The available literature would indicate that BoNT-A might constitute a promising candidate at least as an adjunctive treatment in MDD, although the impact of current findings is limited due to the methodological heterogeneity and the small sample sizes of patients examined. Further large-scale, placebo-controlled trials are warranted to elucidate the mode of action of BoNT-A and to validate or not its clinical effectiveness.

Background/Objectives: Major depressive disorder (MDD) represents a leading cause of global disability, with approximately one-third of patients exhibiting treatment resistance (TRD) despite adequate pharmacological interventions. This treatment gap underscores the urgent need for novel therapeutic strategies. Recently, a series of data suggests that botulinum neurotoxin of type A (BoNT-A), traditionally used for neuromuscular and cosmetic indications, could constitute a potential antidepressant tool. This narrative review critically examines the current preclinical and clinical findings of BoNT-A in MDD. Methods: A comprehensive search of PubMed, Scopus, and Web of Science was conducted up to June 2025, including randomized controlled trials, observational studies, animal models, and mechanistic investigations. Search terms included “Botulinum Toxin,” “BoNT,” “major depressive disorder,” “bipolar depression,” and “facial feedback.” Results: Some randomized and observational studies would indicate that glabellar BoNT-A injections might lead to significant reductions of depressive symptoms in patients with MDD and TRD. Proposed mechanisms include both peripheral modulation of emotional expression and brain effects, such as reduced amygdala hyperactivity, increased BDNF expression, and enhanced monoaminergic transmission. Preclinical studies confirm that BoNT-A modulates limbic and brainstem circuits, possibly implicated in affective regulation. The few comparative studies suggest therapeutic efficacy comparable to that of SSRIs, with a more rapid onset. Preliminary data also support its application in bipolar depression and comorbid anxiety disorders. Conclusions: The available literature would indicate that BoNT-A might constitute a promising candidate at least as an adjunctive treatment in MDD, although the impact of current findings is limited due to the methodological heterogeneity and the small sample sizes of patients examined. Further large-scale, placebo-controlled trials are warranted to elucidate the mode of action of BoNT-A and to validate or not its clinical effectiveness.

Background/Objectives: Treatment-resistant depression (TRD) remains one of the most urgent unmet needs in psychiatry, while its therapeutic pipeline is evolving rapidly. To characterize current development trajectories, we conducted a registry-anchored mapping of interventional trials in adults with major depressive disorder and treatment resistance (MDD-TRD), with the aim of defining the distribution of intervention types, endpoint choices, and key design features across the active trial landscape. Methods: We systematically searched ClinicalTrials.gov, the EU Clinical Trials Information System, and ISRCTN for interventional MDD-TRD trials registered up to 18 September 2025. After data cleaning and cross-registry deduplication, 237 unique trials were retained. Interventions were categorized through a taxonomy distinguishing device-based neuromodulation, pharmacological strategies, biologic/novel agents, multimodal non-digital combinations, digital–hybrid programs, psychotherapy, and lifestyle interventions, with classification anchored on structured registry intervention tags and whole-word matching across title and intervention text. Primary endpoints were flagged as standard when they explicitly referenced the Montgomery–Åsberg Depression Rating Scale or Hamilton Depression Rating Scale. We also examined developmental phase, sample size, and recurrent methodological features. Results: Device-based neuromodulation accounted for the largest share of the active pipeline (114/237, 48.1%), followed by pharmacological strategies (86/237, 36.3%), biologic/novel agents (16/237, 6.8%), and multimodal non-digital combinations (11/237, 4.6%). Digital–hybrid programs represented a small but distinctive stratum (5/237, 2.1%), with the remaining records comprising lifestyle interventions (3/237, 1.3%) and psychotherapy (2/237, 0.8%). Standard clinician-rated primary endpoints were used in 63.3% of studies. Trial development was concentrated in mid-phase designs, whereas sample sizes were generally modest (median 49; interquartile range, 19–87). Across modalities, increasing attention was directed to durability of response, functioning, and patient-reported outcomes, with adaptive and enrichment-based designs appearing with greater frequency. Conclusions: The contemporary TRD trial ecosystem is structured around two co-active developmental tracks—device-based neuromodulation and pharmacology with novel mechanisms—accompanied by a smaller but measurably expanding biologic/novel stratum and a still-marginal digital–hybrid presence. This registry-based mapping provides a near-real-time overview of the field and may support future harmonization of trial endpoints and design standards.