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Sub-optimal response in schizophrenia is frequent, warranting augmentation strategies over treatment-as-usual (TAU). We assessed nutraceuticals/phytoceutical augmentation strategies via network meta-analysis. Randomized controlled trials in schizophrenia/schizoaffective disorder were identified via the following databases: PubMed, MEDLINE, EMBASE, Scopus, PsycINFO, CENTRAL, and ClinicalTrials.gov. Change (Standardized Mean Difference = SMD) in total symptomatology and acceptability (Risk Ratio = RR) were co-primary outcomes. Secondary outcomes were positive, negative, cognitive, and depressive symptom changes, general psychopathology, tolerability, and response rates. We conducted subset analyses by disease phase and sensitivity analyses by risk of bias and assessed global/local inconsistency, publication bias, risk of bias, and confidence in the evidence. The systematic review included 49 records documenting 50 studies (n = 2384) documenting 22 interventions. Citicoline (SMD =-1.05,95%CI = -1.85; -0.24), L-lysine (SMD = -1.04,95%CI = -1.84; -0.25), N-acetylcysteine (SMD = -0.87, 95%CI = -1.27; -0.47) and sarcosine (SMD = -0.5,95%CI = -0.87-0.13) outperformed placebo for total symptomatology. High heterogeneity (tau2 = 0.10, I2 = 55.9%) and global inconsistency (Q = 40.79, df = 18, p = 0.002) emerged without publication bias (Egger's test, p = 0.42). Sarcosine improved negative symptoms (SMD = -0.65, 95%CI = -1.10; -0.19). N-acetylcysteine improved negative symptoms (SMD = -0.90, 95%CI = -1.42; -0.39)/general psychopathology (SMD = -0.76, 95%CI = -1.39; -0.13). No compound improved total symptomatology within acute phase studies (k = 7, n = 422). Sarcosine (SMD = -1.26,95%CI = -1.91; -0.60), citicoline (SMD = -1.05,95%CI = -1.65;-0.44), and N-acetylcysteine (SMD = -0.55,95%CI = -0.92,-0.19) outperformed placebo augmentation in clinically stable participants. Sensitivity analyses removing high-risk-of-bias studies confirmed overall findings in all phases and clinically stable samples. In contrast, the acute phase analysis restricted to low risk-of-bias studies showed a superior effect vs. placebo for N-acetylcysteine (SMD = -1.10, 95%CI = -1.75,-0.45), L-lysine (SMD = -1.05,95%CI = -1.55, -0.19), omega-3 fatty acids (SMD = -0.83,95%CI = -1.31, -0.34) and withania somnifera (SMD = -0.71,95%CI = -1.21,-0.22). Citicoline (SMD = -1.05,95%CI = -1.86,-0.23), L-lysine (SMD = -1.04,95%CI = -1.84,-0.24), N-acetylcysteine (SMD = -0.89,95%CI = -1.35,-0.43) and sarcosine (SMD = -0.61,95%CI = -1.02,-0.21) outperformed placebo augmentation of TAU ("any phase"). Drop-out due to any cause or adverse events did not differ between nutraceutical/phytoceutical vs. placebo+TAU. Sarcosine, citicoline, and N-acetylcysteine are promising augmentation interventions in stable patients with schizophrenia, yet the quality of evidence is low to very low. Further high-quality trials in acute phases/specific outcomes/difficult-to-treat schizophrenia are warranted.
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Impairment of insulin action and metabolic dysregulation have traditionally been associated with schizophrenia, although the molecular basis of such association remains still elusive. The present meta-analysis aims to assess the impact of insulin action manipulations (i.e., hyperinsulinemia, hypoinsulinemia, systemic or brain insulin resistance) on glutamatergic, dopaminergic, γ-aminobutyric acid (GABA)ergic, and serotonergic pathways in the central nervous system. More than one hundred outcomes, including transcript or protein levels, kinetic parameters, and other components of the neurotransmitter pathways, were collected from cultured cells, animals, or humans, and meta-analyzed by applying a random-effects model and adopting Hedges'g to compare means. Two hundred fifteen studies met the inclusion criteria, of which 180 entered the quantitative synthesis. Significant impairments in key regulators of synaptic plasticity processes were detected as the result of insulin handlings. Specifically, protein levels of N-methyl-D-aspartate receptor (NMDAR) subunits including type 2A (NR2A) (Hedges' g = -0.95, 95%C.I. = -1.50, -0.39; p = 0.001; I2 = 47.46%) and 2B (NR2B) (Hedges'g = -0.69, 95%C.I. = -1.35, -0.02; p = 0.043; I2 = 62.09%), and Postsynaptic density protein 95 (PSD-95) (Hedges'g = -0.91, 95%C.I. = -1.51, -0.32; p = 0.003; I2 = 77.81%) were found reduced in insulin-resistant animal models. Moreover, insulin-resistant animals showed significantly impaired dopamine transporter activity, whereas the dopamine D2 receptor mRNA expression (Hedges'g = 3.259; 95%C.I. = 0.497, 6.020; p = 0.021; I2 = 90.61%) increased under insulin deficiency conditions. Insulin action modulated glutamate and GABA release, as well as several enzymes involved in GABA and serotonin synthesis. These results suggest that brain neurotransmitter systems are susceptible to insulin signaling abnormalities, resembling the discrete psychotic disorders' neurobiology and possibly contributing to the development of neurobiological hallmarks of treatment-resistant schizophrenia.
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Esquizofrenia , Humanos , Animales , Esquizofrenia/metabolismo , Insulina/metabolismo , Neurobiología , Homólogo 4 de la Proteína Discs Large/metabolismo , Receptores de N-Metil-D-Aspartato , Ácido gamma-Aminobutírico , NeurotransmisoresRESUMEN
PURPOSE: Although dalbavancin is currently approved for the treatment of ABSSIs, several studies suggest its efficacy and tolerance as long-term therapy for other off-label indications requiring prolonged intravenous antibiotic administration. METHODS: We conducted a prospective nationwide study of dalbavancin use in real-life settings for both approved and off-label indications analysing for each case the clinical and microbiological characteristics of infection the efficacy and safety of treatments. RESULTS: During the study period (from December 2018 to July 2021), the ID specialists from 14 different centres enrolled 223 patients treated with dalbavancin [141 males (63%) and 82 females (37%); male/female ratio 1.72; mean age 59 (SD 17.2) years, (range 15-96). Most patients in the study population (136/223; 61.0%) came from community rather than health care facilities and most of them were visited in Infectious Diseases wards (93/223; 41.7%) and clinics (55/223; 24.7%) even though some patients were cured in other settings, such as surgery wards (18/223; 8.1%), orthopaedic wards (11/223; 4.9%), Emergency Rooms (7/223; 3.1%) and non-surgical other than ID wards (6/223; 2.7%). The most common ID diagnoses were osteomyelitis (44 cases/223; 19.7%; of which 29 acute and 15 chronic osteomyelitis), cellulitis (28/223; 12.5%), cutaneous abscess (23/223; 10.3%), orthopaedic prosthesis-associated infection (22/223; 9.9%), surgical site infection (20/223; 9.0%) and septic arthritis (15/223; 6.7%). CONCLUSION: In conclusion, by virtue of its PK/PD properties, dalbavancin represents a valuable option to daily in-hospital intravenous or outpatient antimicrobial regimens also for off-label indications requiring a long-term treatment of Gram-positive infections.
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Antibacterianos , Uso Fuera de lo Indicado , Sistema de Registros , Teicoplanina , Humanos , Teicoplanina/análogos & derivados , Teicoplanina/uso terapéutico , Teicoplanina/efectos adversos , Teicoplanina/administración & dosificación , Persona de Mediana Edad , Masculino , Femenino , Adulto , Anciano , Antibacterianos/uso terapéutico , Antibacterianos/efectos adversos , Antibacterianos/administración & dosificación , Adolescente , Uso Fuera de lo Indicado/estadística & datos numéricos , Anciano de 80 o más Años , Adulto Joven , Estudios Prospectivos , Resultado del TratamientoRESUMEN
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, ß-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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Antipsicóticos , Esquizofrenia , Humanos , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Dopamina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Esquizofrenia Resistente al Tratamiento , beta-ArrestinasRESUMEN
Although antipsychotics' mechanisms of action have been thoroughly investigated, they have not been fully elucidated at the network level. We tested the hypothesis that acute pre-treatment with ketamine (KET) and administration of asenapine (ASE) would modulate the functional connectivity of brain areas relevant to the pathophysiology of schizophrenia, based on transcript levels of Homer1a, an immediate early gene encoding a key molecule of the dendritic spine. Sprague-Dawley rats (n = 20) were assigned to KET (30 mg/kg) or vehicle (VEH). Each pre-treatment group (n = 10) was randomly split into two arms, receiving ASE (0.3 mg/kg), or VEH. Homer1a mRNA levels were evaluated by in situ hybridization in 33 regions of interest (ROIs). We computed all possible pairwise Pearson correlations and generated a network for each treatment group. Acute KET challenge was associated with negative correlations between the medial portion of cingulate cortex/indusium griseum and other ROIs, not detectable in other treatment groups. KET/ASE group showed significantly higher inter-correlations between medial cingulate cortex/indusium griseum and lateral putamen, the upper lip of the primary somatosensory cortex, septal area nuclei, and claustrum, in comparison to the KET/VEH network. ASE exposure was associated with changes in subcortical-cortical connectivity and an increase in centrality measures of the cingulate cortex and lateral septal nuclei. In conclusion, ASE was found to finely regulate brain connectivity by modelling the synaptic architecture and restoring a functional pattern of interregional co-activation.
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Antipsicóticos , Conectoma , Ketamina , Ratas , Animales , Antipsicóticos/farmacología , Ratas Sprague-Dawley , Densidad Postsináptica , Genes Inmediatos-Precoces , Ketamina/farmacologíaRESUMEN
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.
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COVID-19 , Trastornos Mentales , Femenino , Humanos , Salud Mental , Estudios Prospectivos , PandemiasRESUMEN
Pilonidal Sinus is a benign, chronic disease that affects the hair follicles of the natal cleft of the sacrococcygeal area. Its ideal treatment is controversial, especially in complex or recurrent cases. The aim of this study is to evaluate the use of minimally invasive endoscopic approach in this setting. We enrolled patients affected by complex or recurrent sacrococcygeal pilonidal sinus from January 2015 through December 2020 who underwent Video-Assisted Ablation of Pilonidal Sinus. All patients enrolled were re-evaluated once a year with a standard physical examination. The patients included were 38. Recurrence rate at 1-, 3- and 5-years follow-ups were 28.9%, 22.2% and 38.1% respectively. Of interest, the mean (SD) distance from the most lateral orifice to the midline was higher in group of patients with recurrence and the multivariate analysis demonstrated that it was the limiting factor, which influences the recurrence rate. In complex or recurrent pilonidal sinus disease with pits off the midline the endoscopic approach should not be the first choice. This makes us think that these cases should have their own classification to be identified and guide surgeons in choosing the appropriate approach.
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Seno Pilonidal , Humanos , Seno Pilonidal/cirugía , Seno Pilonidal/diagnóstico , Estudios Retrospectivos , Enfermedad Crónica , Recurrencia , Resultado del TratamientoRESUMEN
BACKGROUND: 3D rendering (3DR) represents a promising approach to plan surgical strategies. The study aimed to compare the results of minimally invasive liver resections (MILS) in patients with 3DR versus conventional 2D CT-scan. METHODS: We performed 118 3DR for various indications; the patients underwent a preoperative tri-phasic CT-scan and rendered with Synapse3D® Software. Fifty-six patients undergoing MILS with pre-operative 3DR were compared to a similar cohort of 127 patients undergoing conventional pre-operative 2D CT-scan using the propensity score matching (PSM) analysis. RESULTS: The 3DR mandated pre-operative surgical plan variations in 33.9% cases, contraindicated surgery in 12.7%, providing a new surgical indication in 5.9% previously excluded cases. PSM identified 39 patients in both groups with comparable results in terms of conversion rates, blood loss, blood transfusions, parenchymal R1-margins, grade ≥3 Clavien-Dindo complications, 90-days mortality, and hospital stay respectively in 3DR and conventional 2D. Operative time was significantly increased in the 3DR group (402 vs. 347 min, p = 0.020). Vascular R1 resections were 25.6% vs 7.7% (p = 0.068), while the conversion rate was 0% vs 10.2% (p = 0.058), respectively, for 3DR group vs conventional 2D. CONCLUSION: 3DR may help in surgical planning increasing resectability rate while reducing conversion rates, allowing the precise identification of anatomical landmarks in minimally invasive parenchyma-preserving liver resections.
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Laparoscopía , Neoplasias Hepáticas , Humanos , Hepatectomía/efectos adversos , Hepatectomía/métodos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Tomografía Computarizada por Rayos X , Estudios Retrospectivos , Complicaciones Posoperatorias/cirugía , Procedimientos Quirúrgicos Mínimamente Invasivos/métodosRESUMEN
INTRODUCTION: Despite progressive improvements in technical skills and instruments that have facilitated surgeons performing intracorporeal gastro-jejunal and jejuno-jejunal anastomoses, one of the big challenging tasks is handsewn knot tying. We analysed the better way to fashion a handsewn intracorporeal enterotomy closure after a stapled anastomosis. METHODS: All 579 consecutive patients from January 2009 to December 2019 who underwent minimally invasive partial gastrectomy for gastric cancer were retrospectively analysed. Different ways to fashion intracorporeal anastomoses were investigated: robotic versus laparoscopic approach; laparoscopic high definition versus three-dimensional versus 4K technology; single-layer versus double-layer enterotomies. Double-layer enterotomies were analysed layer by layer, comparing running versus interrupted suture; the presence versus absence of deep corner suture; and type of suture thread. RESULTS: Significantly lower rates of bleeding (p = 0.011) and leakage (p = 0.048) from gastro-jejunal anastomosis were recorded in the double-layer group. Barbed suture thread was significantly associated with reduced intraluminal bleeding and leakage rates both in the first (p = 0.042 and p = 0.010) and second layer (p = 0.002 and p = 0.029). CONCLUSIONS: Double-layer sutures using barbed suture thread both in first and second layer to fashion enterotomy closure result in lower intraluminal bleeding and anastomotic leak rates.
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Laparoscopía , Técnicas de Sutura , Humanos , Estudios Retrospectivos , Anastomosis Quirúrgica/efectos adversos , Anastomosis Quirúrgica/métodos , Intestinos , Laparoscopía/efectos adversos , Laparoscopía/métodos , Gastrectomía/efectos adversos , Gastrectomía/métodos , SuturasRESUMEN
BACKGROUND: During pancreatic resections assessing tumour boundaries and identifying the ideal resection margins can be challenging due to the associated pancreatic gland inflammation and texture. This is particularly true in the context of minimally invasive surgery, where there is a very limited or absent tactile feedback. Indocyanine green (ICG) fluorescence imaging can assist surgeons by simply providing valuable real-time intraoperative information at low cost with minimal side effects. This meta-analysis summarises the available evidence on the use of near-infrared fluorescence imaging with ICG for the intraoperative visualization of pancreatic tumours (PROSPERO ID: CRD42021247203). METHODS: MEDLINE, Embase, and Web Of Science electronic databases were searched to identify manuscripts where ICG was intravenously administered prior to or during pancreatic surgery and reporting the prevalence of pancreatic lesions visualised through fluorescence imaging. RESULTS: Six studies with 7 series' reporting data on 64 pancreatic lesions were included in the analysis. MINOR scores ranged from 6 to 10, with a median of 8. The most frequent indications were pancreatic adenocarcinoma and neuroendocrine tumours. In most cases (67.2%) ICG was administered during surgery. ICG fluorescence identified 48/64 lesions (75%) with 81.3% accuracy, 0.788 (95%CI 0.361-0.961) sensitivity, 1 (95%CI 0.072-1) specificity and positive predictive value of 0.982 (95%CI 0.532-1). In line with the literature, ICG fluorescence identified 5/6 (83.3%) of pancreatic lesions during robotic pancreatic resections performed at our Institution. CONCLUSION: This meta-analysis is the first summarising the results of ICG immunofluorescence in detecting pancreatic tumours during surgery, showing good accuracy. Additional research is needed to define optimal ICG administration strategies and fluorescence intensity cut-offs.
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Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Adenocarcinoma/cirugía , Verde de Indocianina , Imagen Óptica/métodos , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/cirugía , Espectroscopía Infrarroja Corta/métodosAsunto(s)
Laparoscopía , Proctectomía , Neoplasias del Recto , Humanos , Perineo , Neoplasias del Recto/cirugía , Recto/cirugíaRESUMEN
Insomnia represents a significant public health burden, with a 10% prevalence in the general population. Reduced sleep affects social and working functioning, productivity, and patient's quality of life, leading to a total of $100 billion per year in direct and indirect healthcare costs. Primary insomnia is unrelated to any other mental or medical illness; secondary insomnia co-occurs with other underlying medical, iatrogenic, or mental conditions. Epidemiological studies found a 40-50% comorbidity prevalence between insomnia and psychiatric disorders, suggesting a high relevance of mental health in insomniacs. Sleep disturbances also worsen the outcomes of several psychiatric disorders, leading to more severe psychopathology and incomplete remission, plausibly contributing to treatment-resistant conditions. Insomnia and psychiatric disorder coexistence can lead to polypharmacy, namely, the concurrent use of two or more medications in the same patient, regardless of their purpose or rationale. Polypharmacy increases the risk of using unnecessary drugs, the likelihood of drug interactions and adverse events, and reduces the patient's compliance due to regimen complexity. The workup of insomnia must consider the patient's sleep habits and inquire about any medical and mental concurrent conditions that must be handled to allow insomnia to be remitted adequately. Monotherapy or limited polypharmacy should be preferred, especially in case of multiple comorbidities, promoting multipurpose molecules with sedative properties and with bedtime administration. Also, non-pharmacological interventions for insomnia, such as sleep hygiene, relaxation training and Cognitive Behavioral Therapy may be useful in secondary insomnia to confront behaviors and thoughts contributing to insomnia and help optimizing the pharmacotherapy. However, insomnia therapy should always be patient-tailored, considering drug indications, contraindications, and pharmacokinetics, besides insomnia phenotype, clinical picture, patient preferences, and side effect profile.
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Trastornos Mentales , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiología , Trastornos del Inicio y del Mantenimiento del Sueño/complicaciones , Salud Mental , Calidad de Vida , Polifarmacia , Trastornos Mentales/complicaciones , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/epidemiología , SueñoRESUMEN
Early life stress may induce synaptic changes within brain regions associated with behavioral disorders. Here, we investigated glutamatergic functional connectivity by a postsynaptic density immediate-early gene-based network analysis. Pregnant female Sprague-Dawley rats were randomly divided into two experimental groups: one exposed to stress sessions and the other serving as a stress-free control group. Homer1 expression was evaluated by in situ hybridization technique in eighty-eight brain regions of interest of male rat offspring. Differences between the perinatal stress exposed group (PRS) (n = 5) and the control group (CTR) (n = 5) were assessed by performing the Student's t-test via SPSS 28.0.1.0 with Bonferroni correction. Additionally, all possible pairwise Spearman's correlations were computed as well as correlation matrices and networks for each experimental group were generated via RStudio and Cytoscape. Perinatal stress exposure was associated with Homer1a reduction in several cortical, thalamic, and striatal regions. Furthermore, it was found to affect functional connectivity between: the lateral septal nucleus, the central medial thalamic nucleus, the anterior part of the paraventricular thalamic nucleus, and both retrosplenial granular b cortex and hippocampal regions; the orbitofrontal cortex, amygdaloid nuclei, and hippocampal regions; and lastly, among regions involved in limbic system. Finally, the PRS networks showed a significant reduction in multiple connections for the ventrolateral part of the anteroventral thalamic nucleus after perinatal stress exposure, as well as a decrease in the centrality of ventral anterior thalamic and amygdaloid nuclei suggestive of putative reduced cortical control over these regions. Within the present preclinical setting, perinatal stress exposure is a modifier of glutamatergic early gene-based functional connectivity in neuronal circuits involved in behaviors relevant to model neurodevelopmental disorders.
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Genes Inmediatos-Precoces , Proteínas de Andamiaje Homer , Efectos Tardíos de la Exposición Prenatal , Ratas Sprague-Dawley , Estrés Psicológico , Animales , Femenino , Embarazo , Proteínas de Andamiaje Homer/metabolismo , Estrés Psicológico/metabolismo , Ratas , Masculino , Densidad Postsináptica/metabolismo , Ácido Glutámico/metabolismo , Encéfalo/metabolismo , Redes Reguladoras de Genes/fisiologíaRESUMEN
Introduction: Schizophrenia (SCZ) and autism spectrum disorder (ASD) are neurodevelopmental diseases characterized by different psychopathological manifestations and divergent clinical trajectories. Various alterations at glutamatergic synapses have been reported in both disorders, including abnormal NMDA and metabotropic receptor signaling. Methods: We conducted a bicentric study to assess the blood serum levels of NMDA receptors-related glutamatergic amino acids and their precursors, including L-glutamate, L-glutamine, D-aspartate, L-aspartate, L-asparagine, D-serine, L-serine and glycine, in ASD, SCZ patients and their respective control subjects. Specifically, the SCZ patients were subdivided into treatment-resistant and non-treatment-resistant SCZ patients, based on their responsivity to conventional antipsychotics. Results: D-serine and D-aspartate serum reductions were found in SCZ patients compared to controls. Conversely, no significant differences between cases and controls were found in amino acid concentrations in the two ASD cohorts analyzed. Discussion: This result further encourages future research to evaluate the predictive role of selected D-amino acids as peripheral markers for SCZ pathophysiology and diagnosis.
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Background: Sub-optimal response in schizophrenia is frequent, warranting augmentation strategies over treatment-as-usual (TAU). Methods: We assessed nutraceuticals/phytoceutical augmentation strategies via network meta-analysis. Randomized controlled trials in schizophrenia/schizoaffective disorder were identified via the following databases: PubMed, MEDLINE, EMBASE, Scopus, PsycINFO, CENTRAL, and ClinicalTrials.gov. Change (Standardized Mean Difference=SMD) in total symptomatology and acceptability (Risk Ratio=RR) were co-primary outcomes. Secondary outcomes were positive, negative, cognitive, and depressive symptom changes, general psychopathology, tolerability, and response rates. We conducted subset analyses by disease phase and sensitivity analyses by risk of bias and assessed global/local inconsistency, publication bias, risk of bias, and confidence in the evidence. Results: The systematic review included 49 records documenting 50 studies (n=2,384) documenting 22 interventions. Citicoline (SMD=-1.05,95%CI=-1.85; -.24), L-lysine (SMD=-1.04,95%CI=-1.84;-.25), N-acetylcysteine (SMD=-.87,95%CI=-1.27;-.47) and sarcosine (SMD=-.5,95%CI=-.87-.13) outperformed placebo for total symptomatology. High heterogeneity (tau2=.10, I2=55.9%) and global inconsistency (Q=40.79, df=18, p=.002) emerged without publication bias (Egger's test, p=.42). Sarcosine improved negative symptoms (SMD=-.65, 95%CI=-1.10; -.19). N-acetylcysteine improved negative symptoms (SMD=-.90, 95%CI=-1.42; -.39)/general psychopathology (SMD=-.76, 95%CI=-1.39; -.13). No compound improved total symptomatology within acute phase studies (k=7, n=422). Sarcosine (SMD=-1.26,95%CI=-1.91; -.60), citicoline (SMD=-1.05,95%CI=-1.65;-.44), and N-acetylcysteine (SMD=-.55,95%CI=-.92,-.19) outperformed placebo augmentation in clinically stable participants. Sensitivity analyses removing high-risk-of-bias studies confirmed overall findings in all phases and clinically stable samples. In contrast, the acute phase analysis restricted to low risk-of-bias studies showed a superior effect vs. placebo for N-acetylcysteine (SMD=-1.10,95%CI=-1.75,-.45), L-lysine (SMD=-1.05,95%CI=-1.55,-.19), omega-3 fatty acids (SMD=-.83,95%CI=-1.31,-.34) and withania somnifera (SMD=-.71,95%CI=-1.21,-.22). Citicoline (SMD=-1.05,95%CI=-1.86,-.23), L-lysine (SMD=-1.04,95%CI=-1.84,-.24), N-acetylcysteine (SMD=-.89,95%CI=-1.35,-.43) and sarcosine (SMD=-.61,95%CI=-1.02,-.21) outperformed placebo augmentation of TAU ("any phase"). Drop-out due to any cause or adverse events did not differ between nutraceutical/phytoceutical vs. placebo+TAU. Conclusions: Sarcosine, citicoline, and N-acetylcysteine are promising augmentation interventions in stable patients with schizophrenia, yet the quality of evidence is low to very low. Further high-quality trials in acute phases/specific outcomes/difficult-to-treat schizophrenia are warranted.
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Schizophrenia is a worldwide mental illness characterized by alterations at dopaminergic and glutamatergic synapses resulting in global dysconnectivity within and between brain networks. Impairments in inflammatory processes, mitochondrial functions, energy expenditure, and oxidative stress have been extensively associated with schizophrenia pathophysiology. Antipsychotics, the mainstay of schizophrenia pharmacological treatment and all sharing the common feature of dopamine D2 receptor occupancy, may affect antioxidant pathways as well as mitochondrial protein levels and gene expression. Here, we systematically reviewed the available evidence on antioxidants' mechanisms in antipsychotic action and the impact of first- and second-generation compounds on mitochondrial functions and oxidative stress. We further focused on clinical trials addressing the efficacy and tolerability of antioxidants as an augmentation strategy of antipsychotic treatment. EMBASE, Scopus, and Medline/PubMed databases were interrogated. The selection process was conducted in respect of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Several mitochondrial proteins involved in cell viability, energy metabolism, and regulation of oxidative systems were reported to be significantly modified by antipsychotic treatment with differences between first- and second-generation drugs. Finally, antioxidants may affect cognitive and psychotic symptoms in patients with schizophrenia, and although the evidence is only preliminary, the results indicate that further studies are warranted.
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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.
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Antipsicóticos , Trastornos Psicóticos , Esquizofrenia , Humanos , Antipsicóticos/uso terapéutico , Esquizofrenia/metabolismo , Densidad Postsináptica/metabolismo , Receptores de N-Metil-D-AspartatoRESUMEN
Almost 25% of schizophrenia patients suffer from obsessive-compulsive symptoms (OCS) considered a transdiagnostic clinical continuum. The presence of symptoms pertaining to both schizophrenia and obsessive-compulsive disorder (OCD) may complicate pharmacological treatment and could contribute to lack or poor response to the therapy. Despite the clinical relevance, no reviews have been recently published on the possible neurobiological underpinnings of this comorbidity, which is still unclear. An integrative view exploring this topic should take into account the following aspects: (i) the implication for glutamate, dopamine, and serotonin neurotransmission as demonstrated by genetic findings; (ii) the growing neuroimaging evidence of the common brain regions and dysfunctional circuits involved in both diseases; (iii) the pharmacological modulation of dopaminergic, serotoninergic, and glutamatergic systems as current therapeutic strategies in schizophrenia OCS; (iv) the recent discovery of midbrain dopamine neurons and dopamine D1- and D2-like receptors as orchestrating hubs in repetitive and psychotic behaviors; (v) the contribution of N-methyl-D-aspartate receptor subunits to both psychosis and OCD neurobiology. Finally, we discuss the potential role of the postsynaptic density as a structural and functional hub for multiple molecular signaling both in schizophrenia and OCD pathophysiology.
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Trastornos Psicóticos , Esquizofrenia , Humanos , Esquizofrenia/tratamiento farmacológico , Esquizofrenia Resistente al Tratamiento , Dopamina , Neurobiología , Trastornos Psicóticos/tratamiento farmacológico , Ácido GlutámicoRESUMEN
Treatment resistant schizophrenia (TRS) is characterized by a lack of, or suboptimal response to, antipsychotic agents. The biological underpinnings of this clinical condition are still scarcely understood. Since all antipsychotics block dopamine D2 receptors (D2R), dopamine-related mechanisms should be considered the main candidates in the neurobiology of antipsychotic non-response, although other neurotransmitter systems play a role. The aims of this review are: (i) to recapitulate and critically appraise the relevant literature on dopamine-related mechanisms of TRS; (ii) to discuss the methodological limitations of the studies so far conducted and delineate a theoretical framework on dopamine mechanisms of TRS; and (iii) to highlight future perspectives of research and unmet needs. Dopamine-related neurobiological mechanisms of TRS may be multiple and putatively subdivided into three biological points: (1) D2R-related, including increased D2R levels; increased density of D2Rs in the high-affinity state; aberrant D2R dimer or heteromer formation; imbalance between D2R short and long variants; extrastriatal D2Rs; (2) presynaptic dopamine, including low or normal dopamine synthesis and/or release compared to responder patients; and (3) exaggerated postsynaptic D2R-mediated neurotransmission. Future points to be addressed are: (i) a more neurobiologically-oriented phenotypic categorization of TRS; (ii) implementation of neurobiological studies by directly comparing treatment resistant vs. treatment responder patients; (iii) development of a reliable animal model of non-response to antipsychotics.