Connectome dysfunction in patients at clinical high risk for psychosis and modulation by oxytocin.

Abnormalities in functional brain networks (functional connectome) are increasingly implicated in people at Clinical High Risk for Psychosis (CHR-P). Intranasal oxytocin, a potential novel treatment for the CHR-P state, modulates network topology in healthy individuals. However, its connectomic effects in people at CHR-P remain unknown. Forty-seven men (30 CHR-P and 17 healthy controls) received acute challenges of both intranasal oxytocin 40 IU and placebo in two parallel randomised, double-blind, placebo-controlled cross-over studies which had similar but not identical designs. Multi-echo resting-state fMRI data was acquired at approximately 1 h post-dosing. Using a graph theoretical approach, the effects of group (CHR-P vs healthy control), treatment (oxytocin vs placebo) and respective interactions were tested on graph metrics describing the topology of the functional connectome. Group effects were observed in 12 regions (all pFDR < 0.05) most localised to the frontoparietal network. Treatment effects were found in 7 regions (all pFDR < 0.05) predominantly within the ventral attention network. Our major finding was that many effects of oxytocin on network topology differ across CHR-P and healthy individuals, with significant interaction effects observed in numerous subcortical regions strongly implicated in psychosis onset, such as the thalamus, pallidum and nucleus accumbens, and cortical regions which localised primarily to the default mode network (12 regions, all pFDR < 0.05). Collectively, our findings provide new insights on aberrant functional brain network organisation associated with psychosis risk and demonstrate, for the first time, that oxytocin modulates network topology in brain regions implicated in the pathophysiology of psychosis in a clinical status (CHR-P vs healthy control) specific manner.

Microglial large extracellular vesicles propagate early synaptic dysfunction in Alzheimer's disease.

Synaptic dysfunction is an early mechanism in Alzheimer's disease that involves progressively larger areas of the brain over time. However, how it starts and propagates is unknown. Here we show that amyloid-ß released by microglia in association with large extracellular vesicles (Aß-EVs) alters dendritic spine morphology in vitro, at the site of neuron interaction, and impairs synaptic plasticity both in vitro and in vivo in the entorhinal cortex-dentate gyrus circuitry. One hour after Aß-EV injection into the mouse entorhinal cortex, long-term potentiation was impaired in the entorhinal cortex but not in the dentate gyrus, its main target region, while 24 h later it was also impaired in the dentate gyrus, revealing a spreading of long-term potentiation deficit between the two regions. Similar results were obtained upon injection of extracellular vesicles carrying Aß naturally secreted by CHO7PA2 cells, while neither Aß42 alone nor inflammatory extracellular vesicles devoid of Aß were able to propagate long-term potentiation impairment. Using optical tweezers combined to time-lapse imaging to study Aß-EV-neuron interaction, we show that Aß-EVs move anterogradely at the axon surface and that their motion can be blocked through annexin-V coating. Importantly, when Aß-EV motility was inhibited, no propagation of long-term potentiation deficit occurred along the entorhinal-hippocampal circuit, implicating large extracellular vesicle motion at the neuron surface in the spreading of long-term potentiation impairment. Our data indicate the involvement of large microglial extracellular vesicles in the rise and propagation of early synaptic dysfunction in Alzheimer's disease and suggest a new mechanism controlling the diffusion of large extracellular vesicles and their pathogenic signals in the brain parenchyma, paving the way for novel therapeutic strategies to delay the disease.

T1AM/TAAR1 System Reduces Inflammatory Response and ß-Amyloid Toxicity in Human Microglial HMC3 Cell Line.

Microglial dysfunction is one of the hallmarks and leading causes of common neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD). All these pathologies are characterized by aberrant aggregation of disease-causing proteins in the brain, which can directly activate microglia, trigger microglia-mediated neuroinflammation, and increase oxidative stress. Inhibition of glial activation may represent a therapeutic target to alleviate neurodegeneration. Recently, 3-iodothyronamine (T1AM), an endogenous derivative of thyroid hormone (TH) able to interact directly with a specific GPCR known as trace amine-associated receptor 1 (TAAR1), gained interest for its ability to promote neuroprotection in several models. Nevertheless, T1AM's effects on microglial disfunction remain still elusive. In the present work we investigated whether T1AM could inhibit the inflammatory response of human HMC3 microglial cells to LPS/TNFα or ß-amyloid peptide 25-35 (Aß25-35) stimuli. The results of ELISA and qPCR assays revealed that T1AM was able to reduce microglia-mediated inflammatory response by inhibiting the release of proinflammatory factors, including IL-6, TNFα, NF-kB, MCP1, and MIP1, while promoting the release of anti-inflammatory mediators, such as IL-10. Notably, T1AM anti-inflammatory action in HMC3 cells turned out to be a TAAR1-mediated response, further increasing the relevance of the T1AM/TAAR1 system in the management of NDDs.

Effect of Combined Levothyroxine (L-T4) and 3-Iodothyronamine (T1AM) Supplementation on Memory and Adult Hippocampal Neurogenesis in a Mouse Model of Hypothyroidism.

Mood alterations, anxiety, and cognitive impairments associated with adult-onset hypothyroidism often persist despite replacement treatment. In rodent models of hypothyroidism, replacement does not bring 3-iodothyronamine (T1AM) brain levels back to normal. T1AM is a thyroid hormone derivative with cognitive effects. Using a pharmacological hypothyroid mouse model, we investigated whether augmenting levothyroxine (L-T4) with T1AM improves behavioural correlates of depression, anxiety, and memory and has an effect on hippocampal neurogenesis. Hypothyroid mice showed impaired performance in the novel object recognition test as compared to euthyroid mice (discrimination index (DI): 0.02 ± 0.09 vs. 0.29 ± 0.06; t = 2.515, p = 0.02). L-T4 and L-T4+T1AM rescued memory (DI: 0.27 ± 0.08 and 0.34 ± 0.08, respectively), while T1AM had no effect (DI: -0.01 ± 0.10). Hypothyroidism reduced the number of neuroprogenitors in hippocampal neurogenic niches by 20%. L-T4 rescued the number of neuroprogenitors (mean diff = 106.9 ± 21.40, t = 4.99, pcorr = 0.003), while L-T4+T1AM produced a 30.61% rebound relative to euthyroid state (mean diff = 141.6 ± 31.91, t = 4.44, pcorr = 0.004). We performed qPCR analysis of 88 genes involved in neurotrophic signalling pathways and found an effect of treatment on the expression of Ngf, Kdr, Kit, L1cam, Ntf3, Mapk3, and Neurog2. Our data confirm that L-T4 is necessary and sufficient for recovering memory and hippocampal neurogenesis deficits associated with hypothyroidism, while we found no evidence to support the role of non-canonical TH signalling.

T1AM-TAAR1 signalling protects against OGD-induced synaptic dysfunction in the entorhinal cortex.

Abnormalities in thyroid hormones (TH) availability and/or metabolism have been hypothesized to contribute to Alzheimer's disease (AD) and to be a risk factor for stroke. Recently, 3-iodothyronamine (T1AM), an endogenous amine putatively derived from TH metabolism, gained interest for its ability to promote learning and memory in the mouse. Moreover, T1AM has been demonstrated to rescue the ß-Amyloid dependent LTP impairment in the entorhinal cortex (EC), a brain area crucially involved in learning and memory and early affected during AD. In the present work, we have investigated the effect of T1AM on ischemia-induced EC synaptic dysfunction. In EC brain slices exposed to oxygen-glucose deprivation (OGD), we demonstrated that the acute perfusion of T1AM (5 µM) was capable of preventing ischemia-induced synaptic depression and that this protective effect was mediated by the trace amine-associated receptor 1 (TAAR1). Moreover, we demonstrated that activation of the BDNF-TrkB signalling is required for T1AM action during ischemia. The protective effect of T1AM was more evident when using EC slices from transgenic mutant human APP (mhAPP mice) that are more vulnerable to the effect of OGD. Our results confirm that the TH derivative T1AM can rescue synaptic function after transient ischemia, an effect that was also observed in a Aß-enriched environment.

Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies.

Trace amine-associated receptor 1 (TAAR1) has emerged as a promising therapeutic target for neuropsychiatric disorders due to its ability to modulate monoaminergic and glutamatergic neurotransmission. In particular, agonist compounds have generated interest as potential treatments for schizophrenia and other psychoses due to TAAR1-mediated regulation of dopaminergic tone. Here, we review unmet needs in schizophrenia, the current state of knowledge in TAAR1 circuit biology and neuropharmacology, including preclinical behavioral, imaging, and cellular evidence in glutamatergic, dopaminergic and genetic models linked to the pathophysiology of psychotic, negative and cognitive symptoms. Clinical trial data for TAAR1 drug candidates are reviewed and contrasted with antipsychotics. The identification of endogenous TAAR1 ligands and subsequent development of small-molecule agonists has revealed antipsychotic-, anxiolytic-, and antidepressant-like properties, as well as pro-cognitive and REM-sleep suppressing effects of TAAR1 activation in rodents and non-human primates. Ulotaront, the first TAAR1 agonist to progress to randomized controlled clinical trials, has demonstrated efficacy in the treatment of schizophrenia, while another, ralmitaront, is currently being evaluated in clinical trials in schizophrenia. Coupled with the preclinical findings, this provides a rationale for further investigation and development of this new pharmacological class for the treatment of schizophrenia and other psychiatric disorders.

Molecular Variants in Human Trace Amine-Associated Receptors and Their Implications in Mental and Metabolic Disorders.

We provide a comprehensive review of the available evidence on the pathophysiological implications of genetic variants in the human trace amine-associated receptor (TAAR) superfamily. Genes coding for trace amine-associated receptors (taars) represent a multigene family of G-protein-coupled receptors, clustered to a small genomic region of 108 kb located in chromosome 6q23, which has been consistently identified by linkage analyses as a susceptibility locus for schizophrenia and affective disorders. Most TAARs are expressed in brain areas involved in emotions, reward and cognition. TAARs are activated by endogenous trace amines and thyronamines, and evidence for a modulatory action on other monaminergic systems has been reported. Therefore, linkage analyses were followed by fine mapping association studies in schizophrenia and affective disorders. However, none of these reports has received sufficient universal replication, so their status remains uncertain. Single nucleotide polymorphisms in taars have emerged as susceptibility loci from genome-wide association studies investigating migraine and brain development, but none of the detected variants reached the threshold for genome-wide significance. In the last decade, technological advances enabled single-gene or whole-exome sequencing, thus allowing the detection of rare genetic variants, which may have a greater impact on the risk of complex disorders. Using these approaches, several taars (especially taar1) variants have been detected in patients with mental and metabolic disorders, and in some cases, defective receptor function has been demonstrated in vitro. Finally, with the use of transcriptomic and peptidomic techniques, dysregulations of TAARs (especially TAAR6) have been identified in brain disorders characterized by cognitive impairment.

3-Iodothyronamine and Derivatives: New Allies Against Metabolic Syndrome?

In the two decades since its discovery, a large body of evidence has amassed to highlight the potential of 3-iodothyronamine (T1AM) as an antiobesity drug, whose pleiotropic signaling actions profoundly impact energy metabolism. In the present review, we recapitulate the most relevant properties of T1AM, including its structural and functional relationship to thyroid hormone, its endogenous levels, molecular targets, as well as its genomic and non-genomic effects on metabolism elicited in experimental models after exogenous administration. The physiological and pathophysiological relevance of T1AM in the regulation of energy homeostasis and metabolism is also discussed, along with its potential therapeutic applications in metabolic disturbances. Finally, we examine a number of T1AM analogs that have been recently developed with the aim of designing novel pharmacological agents for the treatment of interlinked diseases, such as metabolic and neurodegenerative disorders, as well as additional synthetic tools that can be exploited to further explore T1AM-dependent mechanisms and the physiological roles of trace amine-associated receptor 1 (TAAR1)-mediated effects.

Decreased lymphocyte dopamine transporter in romantic lovers.

OBJECTIVE: The role of dopamine (DA) in romantic love is suggested by different evidence and is supported by the findings of some brain imaging studies. The DA transporter (DAT) is a key structure in regulating the concentration of the neurotransmitter in the synaptic cleft. Given the presence of DAT in blood cells, the present study aimed to explore it in resting lymphocytes of 30 healthy subjects of both sexes in the early stage of romantic love (no longer than 6 months), as compared with 30 subjects involved in a long-lasting relationship. METHODS: All subjects had no physical or psychiatric illness. The DAT was measured by means of the [3H]-WIN 35,428 binding and the [3H]-DA reuptake to resting lymphocytes membranes. Romantic love was assessed by a specific questionnaire developed by us. RESULTS: The results showed that the subjects in the early phase of romantic love had a global alteration of the lymphocyte DAT involving both a decreased number of proteins (Bmax) and a reduced functionality (Vmax). CONCLUSIONS: Taken together, these findings would indicate the presence of increased levels of DA in romantic love that, if paralleled by similar concentrations in the brain, would explain some peculiar features of this human feeling.

Bipolar Disorder With Psychotic Features and Ocular Toxoplasmosis: A Possible Pathogenetic Role of the Parasite?

Recent evidence suggests the involvement of Toxoplasma gondii infection in the emergence of psychotic and affective disorders. In this report, we describe the case of a young Brazilian woman affected by recurrent ocular toxoplasmosis and presenting with a manic episode with psychotic features in the context of a diagnosis of Bipolar Disorder (BD), type I. We observed a relationship between ocular manifestations and the clinical course of bipolar illness, confirmed by molecular analyses (nested-PCR), as well as by the high level of T. gondii specific IgG. This case report is the first showing the presence of circulating parasite DNA at the time of occurrence of psychiatric symptoms, thus providing further support for a possible role of the parasite in the pathogenesis of some cases of BD.

Metabolic syndrome and major depression.

Major depression is associated with a 4-fold increased risk for premature death, largely accounted by cardiovascular disease (CVD). The relationship between depression and CVD is thought to be mediated by the so-called metabolic syndrome (MeS). Epidemiological studies have consistently demonstrated a co-occurrence of depression with MeS components, ie, visceral obesity, dyslipidemia, insulin resistance, and hypertension. Although the exact mechanisms linking MeS to depression are unclear, different hypotheses have been put forward. On the one hand, MeS could be the hallmark of the unhealthy lifestyle habits of depressed patients. On the other, MeS and depression might share common alterations of the stress system, including the hypothalamus-pituitary-adrenal (HPA) axis, the autonomic nervous system, the immune system, and platelet and endothelial function. Both the conditions induce a low grade chronic inflammatory state that, in turn, leads to increased oxidative and nitrosative (O&NS) damage of neurons, pancreatic cells, and endothelium. Recently, neurobiological research revealed that peripheral hormones, such as leptin and ghrelin, which are classically involved in homeostatic energy balance, may play a role in mood regulation. Metabolic risk should be routinely assessed in depressed patients and taken into account in therapeutic decisions. Alternative targets should be considered for innovative antidepressant agents, including cytokines and their receptors, intracellular inflammatory mediators, glucocorticoids receptors, O&NS pathways, and peripheral mediators.

Proton magnetic resonance spectroscopy of N-acetyl aspartate in first depressive episode and chronic major depressive disorder: A systematic review and meta-analysis.

N-acetyl aspartate (NAA) is a marker of neuronal integrity and metabolism. Deficiency in neuronal plasticity and hypometabolism are implicated in Major Depressive Disorder (MDD) pathophysiology. To test if cerebral NAA concentrations decrease progressively over the MDD course, we conducted a pre-registered meta-analysis of Proton Magnetic Resonance Spectroscopy (1H-MRS) studies comparing NAA concentrations in chronic MDD (n = 1308) and first episode of depression (n = 242) patients to healthy controls (HC, n = 1242). Sixty-two studies were meta-analyzed using a random-effect model for each brain region. NAA concentrations were significantly reduced in chronic MDD compared to HC within the frontal lobe (Hedges' g = -0.330; p = 0.018), the occipital lobe (Hedges' g = -0.677; p = 0.007), thalamus (Hedges' g = -0.673; p = 0.016), and frontal (Hedges' g = -0.471; p = 0.034) and periventricular white matter (Hedges' g = -0.478; p = 0.047). We highlighted a gap of knowledge regarding NAA levels in first episode of depression patients. Sensitivity analyses indicated that antidepressant treatment may reverse NAA alterations in the frontal lobe. We highlighted field strength and correction for voxel grey matter as moderators of NAA levels detection. Future studies should assess NAA alterations in the early stages of the illness and their longitudinal progression.

Emotion dysregulation links pathological eating styles and psychopathological traits in bariatric surgery candidates.

Objectives: Approximately one-third of bariatric surgery patients experience weight regain or suboptimal weight loss within five years post-surgery. Pathological eating styles and psychopathological traits (e.g., emotion dysregulation) are recognized as potential hindrances to sustain weight loss efforts and are implicated in obesity development. A comprehensive understanding of these variables and their interplays is still lacking, despite their potential significance in developing more effective clinical interventions for bariatric patients. We investigate the prevalence of and interactions between pathological eating styles and psychopathological traits in this population. Materials and methods: 110 bariatric surgery candidates were characterized using the Binge Eating Scale (BES), Hamilton Depression/Anxiety Scales (HAM-D/A), Barratt Impulsiveness Scale (BIS-11), Experiences in Close Relationships (ECR), Difficulties in Emotion Regulation Scale (DERS). We analyzed these variables with multiple logistic regression analyses and network analysis. Results: Patients with pathological eating styles showed more pronounced anxiety/depressive symptoms and emotion dysregulation. Network analysis revealed strong connections between BES and DERS, with DERS also displaying robust connections with HAM-A/D and ECR scales. DERS and attention impulsivity (BIS-11-A) emerged as the strongest nodes in the network. Discussion: Our findings demonstrate the mediating role of emotion dysregulation between pathological eating styles and psychopathological traits, supporting existing literature on the association between psychopathological traits, insecure attachment styles, and pathological eating behaviors. This research emphasizes the significance of emotion regulation in the complex network of variables contributing to obesity, and its potential impact on bariatric surgery outcomes. Interventions focusing on emotion regulation may thus lead to improved clinical outcomes for bariatric patients.

Mesostriatal Dopaminergic Circuit Dysfunction in Schizophrenia: A Multimodal Neuromelanin-sensitive MRI and [18F]-DOPA PET Study.

BACKGROUND: Striatal hyperdopaminergia is implicated in the pathoetiology of schizophrenia, but how this relates to dopaminergic midbrain activity is unclear. Neuromelanin-sensitive MRI (NM-MRI) provides a marker of long-term dopamine function. We examined if midbrain NM-MRI contrast-to-noise ratio (NM-CNR) was higher in people with schizophrenia relative to controls and if this correlated with dopamine synthesis capacity. METHODS: N=154 participants (n=74 individuals with schizophrenia and n=80 healthy controls) underwent NM-MRI of the substantia nigra and ventral tegmental area (SN-VTA). A subset of the schizophrenia group (n=38) also received [18F]-DOPA PET to measure dopamine synthesis capacity (Kicer) in the SN-VTA and striatum. RESULTS: SN-VTA NM-CNR was significantly higher in patients with schizophrenia relative to controls (effect size=0.38, p=0.019). This effect was greatest for voxels in the medial and ventral SN-VTA. In patients, SN-VTA Kicer positively correlated with SN-VTA NM-CNR (r=0.44, p=0.005) and striatal Kicer (r=0.71, p<0.001). Voxelwise analysis demonstrated that SN-VTA NM-CNR was positively associated with striatal Kicer (r=0.53, p=0.005) and that this relationship appeared strongest between the ventral SN-VTA and associative striatum in schizophrenia. CONCLUSIONS: Our results suggest that neuromelanin levels are higher in patients with schizophrenia relative to controls, particularly in midbrain regions that project to parts of the striatum which receive innervation from the limbic and association cortices. The direct relationship between measures of neuromelanin and dopamine synthesis suggests that these aspects of schizophrenia pathophysiology are linked. Our findings highlight specific mesostriatal circuits as the loci of dopamine dysfunction in schizophrenia and, thus, potential therapeutic targets.

Trace amine-associated receptor 1 (TAAR1) agonism as a new treatment strategy for schizophrenia and related disorders.

Schizophrenia remains a major health burden, highlighting the need for new treatment approaches. We consider the potential for targeting the trace amine (TA) system. We first review genetic, preclinical, and clinical evidence for the role of TAs in the aetiopathology of schizophrenia. We then consider how the localisation and function of the trace amine-associated receptor 1 (TAAR1) position it to modulate key brain circuits for the disorder. Studies in rodents using Taar1 knockout (TAAR1-KO) and overexpression models show that TAAR1 agonism inhibits midbrain dopaminergic and serotonergic activity, and enhances prefrontal glutamatergic function. TAAR1 agonists also reduce hyperactivity, attenuate prepulse inhibition (PPI) deficits and social withdrawal, and improve cognitive measures in animal models. Finally, we consider findings from clinical trials of TAAR1 agonists and how this approach may address psychotic and negative symptoms, tolerability issues, and other unmet needs in the treatment of schizophrenia.

Functional correlates of subliminal stimulation in Posttraumatic Stress Disorder: Systematic review and meta-analysis.

Patients with Post-traumatic stress disorder (PTSD) exposed to traumatic reminders show hyperreactivity in brain areas (e.g., amygdala) belonging or related to the Innate Alarm System (IAS), allowing the rapid processing of salient stimuli. Evidence that IAS is activated by subliminal trauma-reminders could shed a new light on the factors precipitating and perpetuating PTSD symptomatology. Thus, we systematically reviewed studies investigating neuroimaging correlates of subliminal stimulation in PTSD. Twenty-three studies were selected from the MEDLINE and Scopus® databases for a qualitative synthesis, 5 of which allowed a further meta-analysis of fMRI data. The intensity of IAS responses to subliminal trauma-related reminders ranged from a minimum in healthy controls to a maximum in the PTSD patients with the most severe (e.g., dissociative) symptoms or the least responsiveness to treatment. Comparisons with other disorders (e.g., phobias) revealed contrasting results. Our findings demonstrate the hyperactivation of areas belonging or related to IAS in response to unconscious threats that should be integrated in diagnostic as well as in therapeutic protocols.

An automatic analysis framework for FDOPA PET neuroimaging.

In this study we evaluate the performance of a fully automated analytical framework for FDOPA PET neuroimaging data, and its sensitivity to demographic and experimental variables and processing parameters. An instance of XNAT imaging platform was used to store the King's College London institutional brain FDOPA PET imaging archive, alongside individual demographics and clinical information. By re-engineering the historical Matlab-based scripts for FDOPA PET analysis, a fully automated analysis pipeline for imaging processing and data quantification was implemented in Python and integrated in XNAT. The final data repository includes 892 FDOPA PET scans organized from 23 different studies. We found good reproducibility of the data analysis by the automated pipeline (in the striatum for the Kicer: for the controls ICC = 0.71, for the psychotic patients ICC = 0.88). From the demographic and experimental variables assessed, gender was found to most influence striatal dopamine synthesis capacity (F = 10.7, p < 0.001), with women showing greater dopamine synthesis capacity than men. Our automated analysis pipeline represents a valid resourse for standardised and robust quantification of dopamine synthesis capacity using FDOPA PET data. Combining information from different neuroimaging studies has allowed us to test it comprehensively and to validate its replicability and reproducibility performances on a large sample size.

Trace amine-associated receptor 1 (TAAR1) agonists for psychosis: protocol for a living systematic review and meta-analysis of human and non-human studies.

BACKGROUND: There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism. Therefore, we will conduct a living systematic review and meta-analysis to synthesize and triangulate the evidence from preclinical animal experiments and clinical studies on the efficacy, safety, and underlying mechanism of action of TAAR1 agonism for psychosis. METHODS: Independent searches will be conducted in multiple electronic databases to identify clinical and animal experimental studies comparing TAAR1 agonists with licensed antipsychotics or other control conditions in individuals with psychosis or animal models for psychosis, respectively. The primary outcomes will be overall psychotic symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. Two independent reviewers will conduct study selection, data extraction using predefined forms, and risk of bias assessment using suitable tools based on the study design. Ontologies will be developed to facilitate study identification and data extraction. Data from clinical and animal studies will be synthesized separately using random-effects meta-analysis if appropriate, or synthesis without meta-analysis. Study characteristics will be investigated as potential sources of heterogeneity. Confidence in the evidence for each outcome and source of evidence will be evaluated, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, an overall conclusion will be drawn in a triangulation meeting involving a multidisciplinary team of experts. We plan trimonthly updates of the review, and any modifications in the protocol will be documented. The review will be co-produced by multiple stakeholders aiming to produce impactful and relevant results and bridge the gap between preclinical and clinical research on psychosis. PROTOCOL REGISTRATION: PROSPERO-ID: CRD42023451628.

Applications of Mendelian randomization in psychiatry: a comprehensive systematic review.

Psychiatric diseases exact a heavy socioeconomic toll, and it is particularly difficult to identify their risk factors and causative mechanisms due to their multifactorial nature, the limited physiopathological insight, the many confounding factors, and the potential reverse causality between the risk factors and psychiatric diseases. These characteristics make Mendelian randomization (MR) a precious tool for studying these disorders. MR is an analytical method that employs genetic variants linked to a certain risk factor, to assess if an observational association between that risk factor and a health outcome is compatible with a causal relationship. We report the first systematic review of all existing applications and findings of MR in psychiatric disorders, aiming at facilitating the identification of risk factors that may be common to different psychiatric diseases, and paving the way to transdiagnostic MR studies in psychiatry, which are currently lacking. We searched Web of Knowledge, Scopus, and Pubmed databases (until 3 May 2022) for articles on MR in psychiatry. The protocol was preregistered in PROSPERO (CRD42021285647). We included methodological details and results from 50 articles, mainly on schizophrenia, major depression, autism spectrum disorders, and bipolar disorder. While this review shows how MR can offer unique opportunities for unraveling causal links in risk factors and etiological elements of specific psychiatric diseases and transdiagnostically, some methodological flaws in the existing literature limit reliability of results and probably underlie their heterogeneity. We highlight perspectives and recommendations for future works on MR in psychiatry.

Tele-Mental Health for Reaching Out to Patients in a Time of Pandemic: Provider Survey and Meta-analysis of Patient Satisfaction.

BACKGROUND: The COVID-19 pandemic threatened to impact mental health by disrupting access to care due to physical distance measures and the unexpected pressure on public health services. Tele-mental health was rapidly implemented to deliver health care services. OBJECTIVE: The aims of this study were (1) to present state-of-the-art tele-mental health research, (2) to survey mental health providers about care delivery during the pandemic, and (3) to assess patient satisfaction with tele-mental health. METHODS: Document clustering was applied to map research topics within tele-mental health research. A survey was circulated among mental health providers. Patient satisfaction was investigated through a meta-analysis of studies that compared satisfaction scores between tele-mental health and face-to-face interventions for mental health disorders, retrieved from Web of Knowledge and Scopus. Hedges g was used as the effect size measure, and effect sizes were pooled using a random-effect model. Sources of heterogeneity and bias were examined. RESULTS: Evidence on tele-mental health has been accumulating since 2000, especially regarding service implementation, depressive or anxiety disorders, posttraumatic stress disorder, and special populations. Research was concentrated in a few countries. The survey (n=174 respondents from Italy, n=120 international) confirmed that, after the onset of COVID-19 outbreak, there was a massive shift from face-to-face to tele-mental health delivery of care. However, respondents held skeptical views about tele-mental health and did not feel sufficiently trained and satisfied. Meta-analysis of 29 studies (n=2143) showed that patients would be equally satisfied with tele-mental health as they are with face-to-face interventions (Hedges g=-0.001, 95% CI -0.116 to 0.114, P=.98, Q=43.83, I2=36%, P=.03) if technology-related issues were minimized. CONCLUSIONS: Mental health services equipped with tele-mental health will be better able to cope with public health crises. Both providers and patients need to be actively engaged in digitization, to reshape their reciprocal trust around technological innovations.