Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical–subcortical connections. Antipsychotics are the mainstay of schizophrenia treatment and nearly all share the common feature of dopamine D2 receptor occupancy, whereas glutamatergic abnormalities are not targeted by the presently available therapies. D-amino acids, acting as N-methyl-D-aspartate receptor (NMDAR) modulators, have emerged in the last few years as a potential augmentation strategy in those cases of schizophrenia that do not respond well to antipsychotics, a condition defined as treatment-resistant schizophrenia (TRS), affecting almost 30–40% of patients, and characterized by serious cognitive deficits and functional impairment. In the present systematic review, we address with a direct and reverse translational perspective the efficacy of D-amino acids, including D-serine, D-aspartate, and D-alanine, in poor responders. The impact of these molecules on the synaptic architecture is also considered in the light of dendritic spine changes reported in schizophrenia and antipsychotics’ effect on postsynaptic density proteins. Moreover, we describe compounds targeting D-amino acid oxidase and D-aspartate oxidase enzymes. Finally, other drugs acting at NMDAR and proxy of D-amino acids function, such as D-cycloserine, sarcosine, and glycine, are considered in the light of the clinical burden of TRS, together with other emerging molecules.
Schizophrenia is a severe mental illness characterized by alterations in processes that regulate both synaptic plasticity and functional connectivity between brain regions. Antipsychotics are the cornerstone of schizophrenia pharmacological treatment and, beyond occupying dopamine D2 receptors, can affect multiple molecular targets, pre- and postsynaptic sites, as well as intracellular effectors. Multiple lines of evidence point to the involvement of antipsychotics in sculpting synaptic architecture and remodeling the neuronal functional unit. Furthermore, there is an increasing awareness that antipsychotics with different receptor profiles could yield different interregional patterns of co-activation. In the present systematic review, we explored the fundamental changes that occur under antipsychotics’ administration, the molecular underpinning, and the consequences in both acute and chronic paradigms. In addition, we investigated the relationship between synaptic plasticity and functional connectivity and systematized evidence on different topographical patterns of activation induced by typical and atypical antipsychotics.
Emerging evidence from genomics, post-mortem, and preclinical studies point to a potential dysregulation of molecular signaling at postsynaptic density (PSD) in schizophrenia pathophysiology. The PSD that identifies the archetypal asymmetric synapse is a structure of approximately 300 nm in diameter, localized behind the neuronal membrane in the glutamatergic synapse, and constituted by more than 1000 proteins, including receptors, adaptors, kinases, and scaffold proteins. Furthermore, using FASS (fluorescence-activated synaptosome sorting) techniques, glutamatergic synaptosomes were isolated at around 70 nm, where the receptors anchored to the PSD proteins can diffuse laterally along the PSD and were stabilized by scaffold proteins in nanodomains of 50–80 nm at a distance of 20–40 nm creating “nanocolumns” within the synaptic button. In this context, PSD was envisioned as a multimodal hub integrating multiple signaling-related intracellular functions. Dysfunctions of glutamate signaling have been postulated in schizophrenia, starting from the glutamate receptor’s interaction with scaffolding proteins involved in the N-methyl-D-aspartate receptor (NMDAR). Despite the emerging role of PSD proteins in behavioral disorders, there is currently no systematic review that integrates preclinical and clinical findings addressing dysregulated PSD signaling and translational implications for antipsychotic treatment in the aberrant postsynaptic function context. Here we reviewed a critical appraisal of the role of dysregulated PSD proteins signaling in the pathophysiology of schizophrenia, discussing how antipsychotics may affect PSD structures and synaptic plasticity in brain regions relevant to psychosis.
Few longitudinal studies have so far investigated the impact of sustained COVID‐19 among people with pre‐existing psychiatric disorders. We conducted a prospective study involving people with serious mental illness ( n = 114) and healthy controls ( n = 41) to assess changes in the Perceived Stress Scale, Generalized Anxiety Disorder Scale, Patient Health Questionnaire, and Specific Psychotic Experiences Questionnaire scores 18 months after the COVID‐19 pandemic outset. Subjects underwent interviews with a mental health professional in April 2020 and at the end of the local third wave (October 2021). A significant increase in perceived stress was found in healthy controls, especially females. Psychiatric patients showed a significant worsening of anxiety symptoms compared to baseline records ( t = −2.3, p = 0.036). Patients who rejected vaccination had significantly higher paranoia scores compared to those willing to get vaccinated ( U = 649.5, z = −2.02, p = 0.04). These findings indicate that COVID‐19's sustained emergency may cause enduring consequences on mental health, soliciting further investigations.
Schizophrenia is a severe psychiatric illness affecting almost 25 million people worldwide and is conceptualized as a disorder of synaptic plasticity and brain connectivity. Antipsychotics are the primary pharmacological treatment after more than sixty years after their introduction in therapy. Two findings hold true for all presently available antipsychotics. First, all antipsychotics occupy the dopamine D2 receptor (D2R) as an antagonist or partial agonist, even if with different affinity; second, D2R occupancy is the necessary and probably the sufficient mechanism for antipsychotic effect despite the complexity of antipsychotics’ receptor profile. D2R occupancy is followed by coincident or divergent intracellular mechanisms, implying the contribution of cAMP regulation, β-arrestin recruitment, and phospholipase A activation, to quote some of the mechanisms considered canonical. However, in recent years, novel mechanisms related to dopamine function beyond or together with D2R occupancy have emerged. Among these potentially non-canonical mechanisms, the role of Na2+ channels at the dopamine at the presynaptic site, dopamine transporter (DAT) involvement as the main regulator of dopamine concentration at synaptic clefts, and the putative role of antipsychotics as chaperones for intracellular D2R sequestration, should be included. These mechanisms expand the fundamental role of dopamine in schizophrenia therapy and may have relevance to considering putatively new strategies for treatment-resistant schizophrenia (TRS), an extremely severe condition epidemiologically relevant and affecting almost 30% of schizophrenia patients. Here, we performed a critical evaluation of the role of antipsychotics in synaptic plasticity, focusing on their canonical and non-canonical mechanisms of action relevant to the treatment of schizophrenia and their subsequent implication for the pathophysiology and potential therapy of TRS.
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