Overcoming treatment-resistant depression with machine-learning based tools: a study protocol combining EEG and clinical data to personalize glutamatergic and brain stimulation interventions (SelecTool Project).

Treatment-Resistant Depression (TRD) poses a substantial health and economic challenge, persisting as a major concern despite decades of extensive research into novel treatment modalities. The considerable heterogeneity in TRD's clinical manifestations and neurobiological bases has complicated efforts toward effective interventions. Recognizing the need for precise biomarkers to guide treatment choices in TRD, herein we introduce the SelecTool Project. This initiative focuses on developing (WorkPlane 1/WP1) and conducting preliminary validation (WorkPlane 2/WP2) of a computational tool (SelecTool) that integrates clinical data, neurophysiological (EEG) and peripheral (blood sample) biomarkers through a machine-learning framework designed to optimize TRD treatment protocols. The SelecTool project aims to enhance clinical decision-making by enabling the selection of personalized interventions. It leverages multi-modal data analysis to navigate treatment choices towards two validated therapeutic options for TRD: esketamine nasal spray (ESK-NS) and accelerated repetitive Transcranial Magnetic Stimulation (arTMS). In WP1, 100 subjects with TRD will be randomized to receive either ESK-NS or arTMS, with comprehensive evaluations encompassing neurophysiological (EEG), clinical (psychometric scales), and peripheral (blood samples) assessments both at baseline (T0) and one month post-treatment initiation (T1). WP2 will utilize the data collected in WP1 to train the SelecTool algorithm, followed by its application in a second, out-of-sample cohort of 20 TRD subjects, assigning treatments based on the tool's recommendations. Ultimately, this research seeks to revolutionize the treatment of TRD by employing advanced machine learning strategies and thorough data analysis, aimed at unraveling the complex neurobiological landscape of depression. This effort is expected to provide pivotal insights that will promote the development of more effective and individually tailored treatment strategies, thus addressing a significant void in current TRD management and potentially reducing its profound societal and economic burdens.

COVID-19 and psychiatric disorders among young people: a cross-sectional study.

During the COVID-19 pandemic, a significant rise in mental health issues was observed. Particularly, children and adolescents have shown a higher risk of developing mental disorders than adults. This study aimed to describe the evolving features of the requests for psychiatric emergency interventions during the COVID-19 pandemic in young people. We conducted a cross-sectional study comparing the number, characteristics, and symptoms of people aged between 12 and 18 years old attending one Emergency Department (ED) for psychiatric issues, considering three different periods: T0 (8 March 2019-7 March 2020), T1 (8 March 2020-7 March 2021), and T2 (8 March 2021-7 March 2022). Total admissions were 220: 99 (45%) during T0, 40 (18.1%) for T1, and 81 (36.8%) for T2 ( P  < 0.001). A significant decrease in the mean age from T0 to T1 was found ( P  < 0.01). Admissions for psychomotor agitation decreased, while admission due to anxiety disorder and nonsuicidal self-injury raised significantly ( P  < 0.05), as for first psychiatric presentation ( P  < 0.01). Regarding substance use, a significant reduction was observed ( P  < 0.05). The rates of eating disorders ( P  < 0.001) and early insomnia ( P  < 0.01) increased from T0. These findings highlight the worsening of psychiatric symptoms in the young population during the COVID-19 pandemic.

The Impact of COVID-19 on Neuropsychological and Emotional-Behavioural Development in a Group of 8- and 9-Year-Old Children.

Introduction: The rapid spread of the COVID-19 pandemic has had a significant impact on the psychological well-being of millions of people around the world, and even more so among children. Contracting SARS-CoV-2, resulting in home confinement and restrictions on daily and school activities, led to negative effects on the mental health of the paediatric population. Although children suffering from COVID-19 had milder general symptoms compared to adults, impairments in cognitive, neuropsychological, and emotional-behavioural development were noted. Objective: The main aim of the present study was to detect possible changes in the neuropsychological and emotional-behavioural development of children after infection with the SARS-CoV-2 virus. The second aim was to investigate possible relationships between cognitive abilities and psychosocial characteristics. Methods: A total of 40 patients aged 8-9 years were recruited and divided into two groups: children who contracted (CG) and did not contract (NCG) SARS-CoV-2. The BVN 5-11 (Neuropsychological evaluation battery for developmental age from 5 to 11 years) instrument was administered to assess attention, memory, verbal recall, planning, phonemics, and categorical fluency domains in the paediatric population. Data on changes in emotional-behavioural profile and daily activities were collected through a questionnaire to parents. Results: The Wilcoxon signed-rank test revealed a significant change in mood after the COVID-19 period only in the CG participants (p = 0.019). However, the neuropsychological performance of the two identified groups on BVN 5-11 sub-items was below the cutoff of clinical significance. Correlations were found between sub-items of the BVN 5-11 battery, extracurricular activities, and children's psycho-motor development. Significant positive correlations were observed between Naming on visual presentation and Reading time (p = 0.006), backward digit span and time of motor activity (p = 0.009), Visual attention and Reading time (p = 0.048), and Phonemic fluency and time observed using devices (p = 0.030). Positive statistically significant correlations were also found between Mood and Free behaviour (p = 0.000), between Mood and Structured behaviour (p = 0.005), and between Mood and peer Interaction (p = 0.013). Conclusions: SARS-CoV-2 infection negatively affected the emotional development of children contracting the virus. The neuropsychological functioning of the paediatric population was influenced by psychosocial variables and time spent on daily activities, which played a protective role in children's cognitive development.

The progression trajectory of Bipolar Disorder: results from the application of a staging model over a ten-year observation.

BACKGROUND: Trying to better define Bipolar Disorder (BD) progression, different staging models have been conceptualized, each one emphasizing different aspects of illness. In a previous article we retrospectively applied the main staging models to a sample of 100 bipolar patients at four time points over a ten-year observation. In the present study, focusing on Kupka & Hillegers's model, we aimed to assess the transition of the same sample through the different stages of illness and to explore the potential role of clinical variables on the risk of progression. METHODS: Multistate Model using the mstate package in R and Markov model with stratified hazards were used for statistical analysis. RESULTS: A high hazard of transition from stage 2 to 3 emerged, with a probability of staying in stage 2 decreasing to 14 % after 3 years. BD II was significantly associated with transition from stage 1 to 2, whereas the number of lifetime episodes >3 and the elevated predominant polarity with transition from stage 3 to 4. CONCLUSION: Our results corroborated the evidence on BD progression and contributed to outline its trajectory over time. Further effort may help to define a standardized staging approach towards ever increasing tailored interventions.

The clinical utility and relevance in clinical practice of DSM-5 specifiers for major depressive disorder: A Delphi expert consensus study.

Major depressive disorder (MDD) is a heterogeneous syndrome, associated with different levels of severity and impairment on the personal functioning for each patient. Classification systems in psychiatry, including ICD-11 and DSM-5, are used by clinicians in order to simplify the complexity of clinical manifestations. In particular, the DSM-5 introduced specifiers, subtypes, severity ratings, and cross-cutting symptom assessments allowing clinicians to better describe the specific clinical features of each patient. However, the use of DSM-5 specifiers for major depressive disorder in ordinary clinical practice is quite heterogeneous. The present study, using a Delphi method, aims to evaluate the consensus of a representative group of expert psychiatrists on a series of statements regarding the clinical utility and relevance of DSM-5 specifiers for major depressive disorder in ordinary clinical practice. Experts reached an almost perfect agreement on statements related to the use and clinical utility of DSM-5 specifiers in ordinary clinical practice. In particular, a complete consensus was found regarding the clinical utility for ordinary clinical practice of using DSM-5 specifiers. The use of specifiers is considered a first step toward a "dimensional" approach to the diagnosis of mental disorders.

Bipolar disorder staging and the impact it has on its management: an update.

INTRODUCTION: The longitudinal course of bipolar disorder (BD) is associated with an active process of neuroprogression, characterized by structural brain alterations and progressive functional impairment. In the last decades, a growing need of a standardized staging model for BD arose, with the aim of a more appropriate definition of stage-specific clinical manifestations and the identification of more customized therapeutic tools. AREAS COVERED: The authors review the literature on clinical aspects, neurobiological correlates and treatment issues related to BD progression. Thereafter, they address the definition, constructs, and evolution of the staging concept, focusing on the clinical applications of BD staging models available in literature. EXPERT OPINION: Although several staging models for BD have been proposed to date, their application in clinical practice is still relatively scant. This may have a detrimental impact on the clinical and therapeutic management of BD, in terms of early and proper diagnosis as well as tailored treatment interventions according to the different stages of illness. Future research efforts should tend to the integration of recent insights on neuroimaging and epigenetic markers, toward a standardized and multidimensional staging model.

Treatment adherence rates across different psychiatric disorders and settings: findings from a large patient cohort.

Approximately 50% of patients with psychiatric disorders do not fully adhere to the prescribed psychopharmacological therapy, significantly impacting the progression of the disorder and the patient's quality of life. The present study aimed to assess potential differences in terms of rates and clinical features of treatment adherence in a large cohort of psychiatric patients with different diagnoses attending various psychiatric services. The study included 307 psychiatric patients diagnosed with a primary major depressive disorder, bipolar disorder, anxiety disorder, schizophrenic spectrum disorder, or personality disorder. Patient's adherence to treatment was evaluated using the Clinician Rating Scale, with a cutoff of at least five defining adherence subgroups. One-third of the sample reported poor medication adherence. A lower rate of adherence emerged among patients with schizophrenic spectrum disorder and bipolar disorder. Subjects with poor adherence were more frequently inpatients and showed higher current substance use, a greater number of previous hospitalizations, and more severe scores at psychopathological assessment compared with patients with positive adherence. Poor adherence was associated with symptom severity and increased rates of relapses and rehospitalizations. In addition, substance use appears to be an unfavorable transdiagnostic factor for treatment adherence.

Long COVID in Children, Adults, and Vulnerable Populations: A Comprehensive Overview for an Integrated Approach.

Long COVID affects both children and adults, including subjects who experienced severe, mild, or even asymptomatic SARS-CoV-2 infection. We have provided a comprehensive overview of the incidence, clinical characteristics, risk factors, and outcomes of persistent COVID-19 symptoms in both children and adults, encompassing vulnerable populations, such as pregnant women and oncological patients. Our objective is to emphasize the critical significance of adopting an integrated approach for the early detection and appropriate management of long COVID. The incidence and severity of long COVID symptoms can have a significant impact on the quality of life of patients and the course of disease in the case of pre-existing pathologies. Particularly, in fragile and vulnerable patients, the presence of PASC is related to significantly worse survival, independent from pre-existing vulnerabilities and treatment. It is important try to achieve an early recognition and management. Various mechanisms are implicated, resulting in a wide range of clinical presentations. Understanding the specific mechanisms and risk factors involved in long COVID is crucial for tailoring effective interventions and support strategies. Management approaches involve comprehensive biopsychosocial assessments and treatment of symptoms and comorbidities, such as autonomic dysfunction, as well as multidisciplinary rehabilitation. The overall course of long COVID is one of gradual improvement, with recovery observed in the majority, though not all, of patients. As the research on long-COVID continues to evolve, ongoing studies are likely to shed more light on the intricate relationship between chronic diseases, such as oncological status, cardiovascular diseases, psychiatric disorders, and the persistent effects of SARS-CoV-2 infection. This information could guide healthcare providers, researchers, and policymakers in developing targeted interventions.

Impact of Benzodiazepines and Illness Duration on Obsessive-Compulsive Disorder during COVID-19 in Italy: Exploring Symptoms' Evolutionary Benefits.

Obsessive-compulsive disorder (OCD) is believed to follow a waxing and waning course, often according to environmental stressors. During the COVID-19 pandemic, pre-existing OCD symptoms were reported to increase and to change from checking to washing behaviors, while new-onset symptoms were predominantly of the hoarding type. In the present study, we followed the evolution of OCD symptoms, anxiety, depression, and insights of illness in forty-six OCD patients throughout the pandemic. Clinical measures were collected at four different time points before and during the COVID-19 pandemic in Italy. Within-subject comparisons were used to compare clinical scale scores across time, and correlations were examined between patients' baseline characteristics and changes in clinical scores. We found that all clinical measures increased during the first Italian lockdown with respect to the pre-pandemic values. Anxiety decreased during the temporary elimination of restriction provisions, whereas the severity of OCD symptoms and insight returned to pre-pandemic values during the second mandatory lockdown. These results were observed only in two sub-groups of patients: those taking benzodiazepines and those with shorter illness duration. Our findings suggest the need for additional clinical attention to these specific sub-groups of OCD patients in case of particularly distressing circumstances while pointing to a possible adaptive role of their OCD symptoms when the environment requires a higher care of hygiene and an extraordinary supply of essential resources.

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.

Obsessive-Compulsive Disorder as an Epiphenomenon of Comorbid Bipolar Disorder? An Updated Systematic Review.

BACKGROUND: Bipolar disorder (BD) and obsessive-compulsive disorder (OCD) comorbidity is an emerging condition in psychiatry, with relevant nosological, clinical, and therapeutic implications. METHODS: We updated our previous systematic review on epidemiology and standard diagnostic validators (including phenomenology, course of illness, heredity, biological markers, and treatment response) of BD-OCD. Relevant papers published until (and including) 15 October 2023 were identified by searching the electronic databases MEDLINE, Embase, PsychINFO, and Cochrane Library, according to the PRISMA statement (PROSPERO registration number, CRD42021267685). RESULTS: We identified 38 new articles, which added to the previous 64 and raised the total to 102. The lifetime comorbidity prevalence ranged from 0.26 to 27.8% for BD and from 0.3 to 53.3% for OCD. The onset of the two disorders appears to be often overlapping, although the appearance of the primary disorder may influence the outcome. Compared to a single diagnosis, BD-OCD exhibited a distinct pattern of OC symptoms typically following an episodic course, occurring in up to 75% of cases (vs. 3%). Notably, these OC symptoms tended to worsen during depressive episodes (78%) and improve during manic or hypomanic episodes (64%). Similarly, a BD course appears to be chronic in individuals with BD-OCD in comparison to patients without. Additionally, individuals with BD-OCD comorbidity experienced more depressive episodes (mean of 8.9 ± 4.2) compared to those without comorbidity (mean of 4.1 ± 2.7). CONCLUSIONS: We found a greater likelihood of antidepressant-induced manic/hypomanic episodes (60% vs. 4.1%), and mood stabilizers with antipsychotic add-ons emerging as a preferred treatment. In line with our previous work, BD-OCD comorbidity encompasses a condition of greater nosological and clinical complexity than individual disorders.

Beyond imagination: Sorting out and treating psychosis in the context of autism spectrum disorder.

In the last decades, growing caseness for Autism Spectrum Disorder (ASD) has been observed, owing to the diagnostic accretion of low-impairment forms, over and above other possible causes. Unrecognized ASD is likely to be mislabeled as a psychotic disorder (PD), as people in the spectrum may show 'pseudopsychotic' symptoms, resembling both negative and positive symptoms. On the other hand, PDs are likely to be overlooked when they arise in people with ASD, due to the 'diagnostic overshadowing' of new-onset conditions by lifelong core autistic symptoms. The three available metanalyses on the occurrence of psychosis in adults with ASD convergently reported a rate of PDs that is at least ten times higher than in the general population. Therefore, the lack of literature addressing risk factors, outcomes, and treatment options for psychosis in the context of ASD is utterly concerning. The present review aims to summarize up-to-date knowledge of PDs with comorbid ASD in terms of clinical features, course, and treatment.

Evaluating the 6-month formulation of paliperidone palmitate: a twice-yearly injectable treatment for schizophrenia in adults.

INTRODUCTION: Paliperidone Palmitate is the only antipsychotic that has been developed in three different intramuscular long-acting injectable (LAI) dosing regimen: monthly (PP1M), quarterly (PP3M), and from 2020 also twice-yearly (PP6M). The latter was approved for the maintenance treatment of adults with schizophrenia and clinically stabilized with PP1M or PP3M. AREAS COVERED: Data from studies evaluating efficacy in the maintenance treatment of schizophrenia with PP6M are reviewed. Since no post-marketing safety studies are currently available, data from spontaneous reporting system databases, FAERS and Eudravigilance, are analyzed and the reported treatment-emergent adverse events of PP6M are discussed. EXPERT OPINION: The efficacy of PP6M is comparable to that of PP3M in terms of relapses prevention in patients with schizophrenia previously stabilized on PP3M or PP1M. Also, the maintenance of clinical efficacy in the long term has been demonstrated. Data from pharmacovigilance analyses, as well as from phase 3 studies, show that PP6M is generally well tolerated, consistently with PP3M safety data. PP6M allows a longer dosing interval than any other LAI antipsychotics, potentially reducing nonadherence and disease relapses. In future, an increase in the prescription rates of PP6M is expected and real-world efficacy and tolerability studies will be conducted.

Longitudinal outcomes of a work inclusion program in mental health departments in the city of Milan.

BACKGROUND: Work functioning impairment is a key diagnostic and prognostic criterion in patients with psychiatric disorders and work inclusion is a major goal of their therapeutic pathway. Since 2009, the Regional Innovative Program (PIR) TR106, promoted by ASST Fatebenefratelli-Sacco of Milan in collaboration with other Departments of Mental Health and Addictions (DSMDs) in the town of Milan (Italy), has been developing the employment inclusion of psychiatric patients. AIMS: The objective of this study is to evaluate its outcomes over 8 years of observation. METHOD: We reported the results of a retrospective epidemiologic analysis on 2,142 interventions on 1,066 patients recruited, investigating PIR TR106 outcomes per year focusing on different subgroups. We focused on 'positive', 'negative', and 'other' outcomes. RESULTS: We preliminary calculated job maintenance interventions (5%, 107) and excluded these interventions from the overall. We observed 29 job firing (1.4%) and 15 job resignations (0.7%) as negative results (equal to 2.2% of the total) and 388 job hiring (16.6%), 647 traineeships (31.8%), and 413 work formation (20.3%) as positive outcomes (equal to 68.75%). In other outcomes (29.1%) we found 305 dismissals from PIR TR 106 (15%) and transitory outcomes (14.1%).Job hiring increased from 8.9% in 2012 to 23.8 % in 2019 (p < .001), while the dismissals diminished from 26.7% to 13.3% (p < .001). The effectiveness of traineeships in terms of job hiring increased in the ratio of annual job hiring versus job traineeship (+48.8%). The majority of hired patients (15.1%) were affected by a psychotic disorder. A significant hiring increase was observed in patients with psychotic disorders and personality disorders (p < .005). CONCLUSIONS: PIR-TR106 represents a territorial employment inclusion program with progressively increasing effectiveness and specificity, as suggested by changes in outcomes during the 8-year observation. The adaptive capacity and sustainability of the intervention are worth further investigation.

The use of antipsychotics in obsessive compulsive disorder.

Obsessive-compulsive disorder (OCD) is a chronic disease with a prevalence in the general population of around 2%-3%, generally accompanied by a severe impairment of functioning and quality of life. A consistent subgroup of patients may not achieve adequate symptom remission with first-line treatments (i.e., cognitive behavioral therapy, selective serotonin reuptake inhibitors [SSRIs]). The most validated option for treatment-resistant cases relies on the augmentative use of antipsychotics to SSRIs, preferably of the 'second generation'. Indeed, dopamine appears to be crucially involved in OCD neuropathology due to its implication in systems relating to goal-directed behaviour and maladaptive habits. Nevertheless, the mechanism of action of antipsychotics in OCD symptom improvement is still unclear. Risperidone, aripiprazole, and haloperidol seem to be the most useful medications, whereas 'first generation' antipsychotics may be indicated in case of comorbidity with tics and/or Tourette Syndrome. Antipsychotic augmentation may be also related to side-effects, particularly in the long term (e.g., alteration in metabolic profile, sedation, extrapyramidal symptoms). The present mini-review sought to provide the most updated evidence on augmentative antipsychotic use in treatment-resistant patients with OCD, providing a road map for clinicians in daily practice and shedding light on avenues for further research.

Early-onset obsessive-compulsive disorder: Sociodemographic and clinical characterization of a large outpatient cohort.

INTRODUCTION: Obsessive-compulsive disorder (OCD) is a prevalent and disabling condition characterized by a wide variety of phenotypic expressions. Several studies have reinforced the hypothesis of OCD heterogeneity by proposing subtypes based on predominant symptomatology, course, and comorbidities. Early-onset OCD (EO) could be considered a neurodevelopmental subtype of OCD, with evidence of distinct neurocircuits supporting disease progression. To deepen the heterogeneous nature of the disorder, we analyzed sociodemographic and clinical differences between the EO and late-onset (LO) subtypes in a large outpatient cohort. METHODS: Two hundred and eighty-four patients diagnosed with OCD were consecutively recruited from the OCD Tertiary Clinic at Luigi Sacco University Hospital in Milan. Sociodemographic and clinical variables were analyzed for the entire sample and compared between the two subgroups (EO, age <18 years [n = 117,41.2 %]; LO: late-onset, age ≥18 years [n = 167, 58.8 %]). RESULTS: The EO group showed a higher frequency of male gender (65 % vs 42.5 %, p < .001), and a higher prevalence of Tic and Tourette disorders (9.4 % vs 0 %, p < .001) compared to the LO group. Additionally, in the EO subgroup, a longer duration of untreated illness was observed (9.01 ± 9.88 vs 4.81 ± 7.12; p < .001), along with a lower presence of insight (13.8 % vs. 7.5 %, p < .05). CONCLUSIONS: The early-onset OCD subtype highlights a more severe clinical profile compared to the LO group. Exploring distinct manifestations and developmental trajectories of OCD can contribute to a better definition of homogeneous subtypes, useful for defining targeted therapeutic strategies for treatment.

Selective alterations of endocannabinoid system genes expression in obsessive compulsive disorder.

Obsessive Compulsive Disorder (OCD) is listed as one of the top 10 most disabling neuropsychiatric conditions in the world. The neurobiology of OCD has not been completely understood and efforts are needed in order to develop new treatments. Beside the classical neurotransmitter systems and signalling pathways implicated in OCD, the possible involvement of the endocannabinoid system (ECS) has emerged in pathophysiology of OCD. We report here selective downregulation of the genes coding for enzymes allowing the synthesis of the endocannabinoids. We found reduced DAGLα and NAPE-PLD in blood samples of individuals with OCD (when compared to healthy controls) as well as in the amygdala complex and prefrontal cortex of dopamine transporter (DAT) heterozygous rats, manifesting compulsive behaviours. Also mRNA levels of the genes coding for cannabinoid receptors type 1 and type 2 resulted downregulated, respectively in the rat amygdala and in human blood. Moreover, NAPE-PLD changes in gene expression resulted to be associated with an increase in DNA methylation at gene promoter, and the modulation of this gene in OCD appears to be correlated to the progression of the disease. Finally, the alterations observed in ECS genes expression appears to be correlated with the modulation in oxytocin receptor gene expression, consistently with what recently reported. Overall, we confirm here a role for ECS in OCD at both preclinical and clinical level. Many potential biomarkers are suggested among its components, in particular NAPE-PLD, that might be of help for a prompt and clear diagnosis.

Climate Change Perception and Mental Health. Results from a Systematic Review of the Literature.

Climate change is one of the main global challenges and influences various aspects of human health. Numerous studies have indeed demonstrated an association between extreme climate-related events and physical and mental health outcomes, but little is still known about the association between the perception/awareness of climate change and mental health. In accordance with the PRISMA 2020 guidelines, a search was conducted on PubMed and Scopus. The protocol was registered on PROSPERO. The included studies were original observational studies published in English, reporting the association between the perception/awareness of climate change and mental health. A total of 3018 articles were identified. A total of 10 observational studies were included. The period covered in the included studies ranged between 2012 and 2022. Climate change perception is consistently associated with adverse mental health effects across different types of estimates. In particular, the studies identified an association between a higher level of perception/awareness of climate change and depression, anxiety, eco-anxiety, stress, adjustment disorder, substance use, dysphoria, and even thoughts of suicide. Qualitative data underscore the impact on daily activities, contributing to feelings of loss and suicidal ideation. Moreover, climate change perception correlates with lower well-being and resilience. The association between awareness of climate change and mental health is a complex and still poorly explored phenomenon. The main limitations are the high heterogeneity in terms of exposure assessment and data reporting, which hinders quantitative analysis. These results show that climate change perception impacts mental health. Better understanding the phenomenon represents an opportunity to inform public health interventions that promote mental well-being.