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Brain Sciences
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Advanced Clinical Diagnosis, Evaluation, and Treatment of Psychosis
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Advanced Clinical Diagnosis, Evaluation, and Treatment of Psychosis

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Neuropsychiatry".

Deadline for manuscript submissions: closed (31 January 2026) | Viewed by 21781

Special Issue Editors

Dr. Giulia Menculini

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Guest Editor
Department of Psychiatry, University of Perugia, 06132 Perugia, Italy
Interests: psychotic disorders; affective psychoses; schizophrenia; antipsychotic drugs; psychosocial treatments; at-risk mental states; biomarkers; early intervention; prevention; social psychiatry
Dr. Gaia Sampogna

E-Mail Website
Guest Editor
Department of Psychiatry, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Interests: psychotic disorders; affective psychoses; schizophrenia; antipsychotic drugs; psychosocial treatments; at-risk mental states; biomarkers; early intervention; prevention; social psychiatry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Psychotic disorders represent the most prevalent psychiatric conditions with a significant impact on quality of life and functioning. The treatment of these conditions has historically been based on therapeutic strategies acting on the dopaminergic and serotonergic systems, with the main target of symptom remission. 

During the last decades, a precision approach to the diagnosis of affective and non-affective psychosis has been implemented, supported by research in the field of neuroimaging and biomarkers, possibly helping with the characterization of different clinical phenotypes that are beyond diagnostic boundaries. This has also led to the introduction of novel pharmacological and non-pharmacological interventions directed not only towards symptom resolution but also targeting the functioning dimension, with the major objective of full-functional recovery. Moreover, the “at-risk mental state” paradigm has promoted the new challenge of early diagnosis and intervention of psychotic disorders. 

All these topics will be addressed in this Special Issue, and thus all papers focusing on novel diagnostic and treatment approaches to psychotic disorders in different periods of life are welcome.

Dr. Giulia Menculini
Dr. Gaia Sampogna
Guest Editors

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Keywords

  • psychotic disorders
  • affective psychoses
  • schizophrenia
  • antipsychotic drugs
  • psychosocial treatments
  • at-risk mental states
  • biomarkers
  • early intervention, prevention, social psychiatry

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Published Papers (9 papers)

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17 pages, 789 KB  
Article
Dissociative Bipolar At-Risk Phenotype: Traumatic Burden and Subthreshold Affective Psychopathology in a Help-Seeking Youth Sample
by Francesca Scopetta, Marta Barbi, Gianmarco Cinesi, Filippo De Giorgi, Alfonso Tortorella and Giulia Menculini
Brain Sci. 2026, 16(4), 349; https://doi.org/10.3390/brainsci16040349 - 25 Mar 2026
Viewed by 507
Abstract
Background: Youth mental health services increasingly encounter adolescents and young adults with complex affective presentations and trauma histories. Dissociation has been proposed as a clinically relevant marker within bipolar vulnerability pathways but remains underrecognized in early-intervention settings. This pilot study investigated the prevalence [...] Read more.
Background: Youth mental health services increasingly encounter adolescents and young adults with complex affective presentations and trauma histories. Dissociation has been proposed as a clinically relevant marker within bipolar vulnerability pathways but remains underrecognized in early-intervention settings. This pilot study investigated the prevalence and clinical correlates of bipolar at-risk (BAR) status in a help-seeking youth sample, with specific focus on dissociative symptoms in this vulnerable population. Methods: A pilot study with a cross-sectional design was conducted in a specialized outpatient clinic for 14–25-year-olds. Seventy-six participants without Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision bipolar disorder completed a multidimensional assessment, including dissociative (Dissociative Experiences Scale version 2 [DES-II], Adolescent-DES [A-DES], Structured Clinical Interview for DSM Dissociative Disorders [SCID-D]), affective, anxiety, impulsivity, and prodromal symptom measures. BAR status (BAR+) was determined via clinical interview according to Bechdolf criteria. Clinically significant dissociation (DES+) was defined by established cut-offs at the DES-II and A-DES scales. Group comparisons, binary logistic regression and exploratory mediation analysis were performed. Results: In our sample, 44.7% of the participants met BAR+ criteria and 42.9% displayed clinically significant dissociation. Patients with BAR+ status more frequently reported familiar history of affective disorders, previous antidepressant use, loneliness, and non-suicidal self-injury. They displayed more severe depressive symptoms and impulsivity, as well as higher scores at all the affective temperament subscale except for hyperthymic. BAR+ patients displayed higher prevalence of dissociative symptoms than BAR− (51.6% vs. 24.2%; p = 0.045). Among the BAR+ subgroup, DES+ youths showed greater traumatic burden, depressive symptoms, and anxious temperament scores. Dissociation was associated with BAR+ status (OR 3.2) after adjusting for age, gender, and loneliness, while attentional impulsivity did not mediate this relationship. Conclusions: Dissociative symptomatology is highly prevalent among help-seeking youths and is directly associated with subthreshold bipolar-spectrum vulnerability. A dissociative BAR phenotype, marked by emotional instability and trauma exposure, may delineate a clinically complex subgroup, supporting the integration of dissociation-focused assessment into youth bipolar-risk staging and early-intervention protocols. Full article
(This article belongs to the Special Issue Advanced Clinical Diagnosis, Evaluation, and Treatment of Psychosis)
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14 pages, 567 KB  
Article
Psychotic Spectrum Symptoms in Adults with Autism Spectrum Disorder and in Their First-Degree Relatives
by Benedetta Nardi, Francesca Parri, Stefano Pini, Federico Giovannoni, Cristiana Pronestì, Silvia Tarantino, Gabriele Massimetti, Ivan Mirko Cremone, Liliana Dell’Osso and Barbara Carpita
Brain Sci. 2026, 16(3), 307; https://doi.org/10.3390/brainsci16030307 - 13 Mar 2026
Viewed by 850
Abstract
Objectives: Autism Spectrum Disorder (ASD) and psychotic disorders have long been considered separate diagnostic entities, yet increasing evidence highlights shared neurodevelopmental mechanisms and symptom overlap. Psychotic-like experiences have been frequently reported in individuals with ASD, while subthreshold autistic traits (ATs) in first-degree [...] Read more.
Objectives: Autism Spectrum Disorder (ASD) and psychotic disorders have long been considered separate diagnostic entities, yet increasing evidence highlights shared neurodevelopmental mechanisms and symptom overlap. Psychotic-like experiences have been frequently reported in individuals with ASD, while subthreshold autistic traits (ATs) in first-degree relatives may also confer vulnerability to psychotic symptoms. This cross-sectional study aimed to compare psychotic spectrum manifestations among adults with ASD, their first-degree relatives (BAP), and controls (HCs), to explore associations between psychotic and ATs, and to evaluate whether psychotic symptoms predict diagnostic group membership. Methods: 22 adults with ASD, 22 BAP, and 24 HCs were evaluated with the Psychotic Spectrum–Self Report (PSY-SR) and the Adult Autism Subthreshold Spectrum (AdAS Spectrum). Results: ASD participants scored significantly higher on the PSY-SR. BAP individuals showed higher PSY-SR total scores compared to HCs, though less severe than in ASD. All PSY-SR domains positively correlated with all AdAS Spectrum domains, with few exceptions. Multinomial regressions showed that higher PSY-SR total scores significantly predicted ASD and BAP membership, and that the PSY-SR Paranoid domain score specifically predicted inclusion in both groups in relation to HCs. Conclusions: Psychotic spectrum symptoms are elevated not only in individuals with ASD but also among first-degree relatives, supporting a continuum linking autistic and psychotic vulnerabilities. The strong association between paranoid symptoms and ATs highlights a dimension of potential clinical relevance for early identification and assessment. These findings reinforce shared neurodevelopmental pathways between the autism and psychosis spectra and underscore the importance of dimensional approaches across diagnostic categories. Full article
(This article belongs to the Special Issue Advanced Clinical Diagnosis, Evaluation, and Treatment of Psychosis)
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9 pages, 213 KB  
Article
Managing Dual Diagnosis Patients and the Importance of Assessing Capacity: Data from London Inpatient Services
by Iain Hyndman, Angelo Ricciardi, Olesya Ajnakina, Christian Lowe, Cemile Kalkan, Sofia Mota, Christos Theleritis, Stefano Ferracuti, Stefania Bonaccorso and Fabrizio Schifano
Brain Sci. 2025, 15(12), 1259; https://doi.org/10.3390/brainsci15121259 - 24 Nov 2025
Viewed by 1038
Abstract
Objective: Substance use in patients with mental disorders is often associated with worse outcomes, increased risks, and impaired decision-making. Therefore, the evaluation of mental capacity in patients with coexisting mental illness and substance use disorder (dual diagnosis) is necessary to improve clinical outcomes [...] Read more.
Objective: Substance use in patients with mental disorders is often associated with worse outcomes, increased risks, and impaired decision-making. Therefore, the evaluation of mental capacity in patients with coexisting mental illness and substance use disorder (dual diagnosis) is necessary to improve clinical outcomes and mitigate risks to self and others. Design: A retrospective inspection of electronic records for patients admitted between March 2017 and August 2020 in two London inpatient facilities was conducted. Capacity was assessed using the principles set out in the Mental Capacity Act 2005. Results: A capacity assessment was recorded in 34.9% of admissions. Only 6.2% of admissions whose primary diagnosis was mental and behavioral changes due to the use of substances had a recorded mental capacity assessment. Capacity to understand the negative impact of substances was assessed in 2.1% of total admissions. Conclusions: This study indicates very low rates of mental capacity assessment across acute psychiatric admissions, with very few relating to capacity to understand the risks associated with using substances. Further research on the capacity of patients with dual diagnosis is needed. This may help to manage certain risks in this patient population. Full article
(This article belongs to the Special Issue Advanced Clinical Diagnosis, Evaluation, and Treatment of Psychosis)
17 pages, 575 KB  
Article
The Mediating Role of Social Camouflaging on the Relationship Between Autistic Traits and Orthorexic Symptoms
by Barbara Carpita, Benedetta Nardi, Cristiana Pronestì, Gianluca Cerofolini, Matilde Filidei, Chiara Bonelli, Gabriele Massimetti, Ivan Mirko Cremone, Stefano Pini and Liliana Dell’Osso
Brain Sci. 2025, 15(5), 503; https://doi.org/10.3390/brainsci15050503 - 14 May 2025
Cited by 5 | Viewed by 2071
Abstract
Background/Objectives: Recent lifestyle and dietary changes, driven by health awareness and ecological concerns, have led to the rise in numerous type of diets, which can promote well-being but may also contribute to Orthorexia Nervosa (ON), which have been suggested to be linked [...] Read more.
Background/Objectives: Recent lifestyle and dietary changes, driven by health awareness and ecological concerns, have led to the rise in numerous type of diets, which can promote well-being but may also contribute to Orthorexia Nervosa (ON), which have been suggested to be linked to autism spectrum disorder. This study aimed to explore the relationship between autistic traits, social camouflaging, and orthorexic tendencies in female university students, focusing on how these factors intersect with specific dietary habits. Methods: 554 female students were recruited via an online survey and assessed with the Adult Autism Subthreshold (AdAS) Spectrum, the Camouflaging Autistic Traits Questionnaire (CAT-Q), and the ORTO-R. Participants were categorized into four groups based on AdAS Spectrum and CAT-Q quartiles. Results: Vegans and vegetarians exhibited higher orthorexic tendencies and specific autistic traits. High scorers on the AdAS Spectrum and CAT-Q also showed higher ORTO-R scores, with both AdAS Spectrum and CAT-Q total scores, as well as certain domains, serving as significant positive predictors of higher ORTO-R scores. Notably, the AdAS Spectrum total score had a significant direct and indirect effect (through the CAT-Q) on the ORTO-R total score. Conclusions: The study found significant associations between autistic traits, social camouflaging behaviors, and orthorexic tendencies in female university students. These findings suggest that the strict dietary behaviors and rigid thinking characteristic of orthorexia may be influenced by underlying autistic features, highlighting the need for further research into the intersection of autism and eating disorders. Full article
(This article belongs to the Special Issue Advanced Clinical Diagnosis, Evaluation, and Treatment of Psychosis)
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16 pages, 499 KB  
Article
Mental Health, Emotional Regulation, and Psychosocial Work Factors Among Scientific Researchers: A Cross-Sectional Study from Paraguay
by Julio Torales, Anthon Torres-Romero, Iván Barrios, Marcelo O’Higgins, Tomás Caycho-Rodríguez, João Mauricio Castaldelli-Maia and Antonio Ventriglio
Brain Sci. 2025, 15(1), 65; https://doi.org/10.3390/brainsci15010065 - 13 Jan 2025
Cited by 2 | Viewed by 4891
Abstract
Background: This study examined the prevalence of mental health issues among Paraguayan researchers and their relationships with emotional regulation and psychosocial factors. Methods: A cross-sectional survey of 235 researchers was conducted using validated instruments: the Depression, Anxiety, and Stress Scale (DASS-21); the Job [...] Read more.
Background: This study examined the prevalence of mental health issues among Paraguayan researchers and their relationships with emotional regulation and psychosocial factors. Methods: A cross-sectional survey of 235 researchers was conducted using validated instruments: the Depression, Anxiety, and Stress Scale (DASS-21); the Job Content Questionnaire (JCQ); and the Difficulties in Emotion Regulation Scale (DERS). Sociodemographic, academic, and behavioral variables were also analyzed. Results: Findings revealed significant rates of depression (26.4%), anxiety (30.6%), and stress (32.3%), with female researchers reporting nearly twice the rates of anxiety and stress compared to males. Researchers with doctoral degrees exhibited lower anxiety levels, emphasizing the protective role of advanced academic qualifications. Conversely, younger and early-career researchers were more vulnerable to psychological distress. High job demands and emotional dysregulation were strongly associated with poorer mental health outcomes, while hazardous alcohol consumption and low physical activity further exacerbated risks. Conclusions: These findings highlight the urgent need for institutional reforms to prioritize mental health and well-being in academic environments. By advancing the understanding of occupational health in resource-limited settings, this study provides actionable recommendations to improve the working conditions and mental health of researchers in Paraguay and beyond. Full article
(This article belongs to the Special Issue Advanced Clinical Diagnosis, Evaluation, and Treatment of Psychosis)
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15 pages, 338 KB  
Article
Altered Rhythmicity, Depressive Ruminative Thinking and Suicidal Ideation as Possible Correlates of an Unrecognized Autism Spectrum in Patients with Borderline Personality Disorder
by Ivan Mirko Cremone, Liliana Dell’Osso, Benedetta Nardi, Federico Giovannoni, Francesca Parri, Cristiana Pronestì, Chiara Bonelli, Gabriele Massimetti, Stefano Pini and Barbara Carpita
Brain Sci. 2024, 14(12), 1297; https://doi.org/10.3390/brainsci14121297 - 23 Dec 2024
Cited by 6 | Viewed by 2671
Abstract
Background/Objectives: Recent research has explored the presence of subthreshold autistic traits (ATs) in individuals with borderline personality disorder (BPD), suggesting that these traits may contribute to the severity of BPD symptoms and increase the risk of other mental health issues, including suicidal behaviors. [...] Read more.
Background/Objectives: Recent research has explored the presence of subthreshold autistic traits (ATs) in individuals with borderline personality disorder (BPD), suggesting that these traits may contribute to the severity of BPD symptoms and increase the risk of other mental health issues, including suicidal behaviors. This study aims to investigate the relationship between ATs and affective symptoms, such as mood instability and suicidality, in people diagnosed with BPD. Methods: A total of 48 subjects with BPD were assessed with self-report questionnaires including the Adult Autism Subthreshold Spectrum (AdAS Spectrum), the mood spectrum self-report version (MOODS-SR) and the ruminative response scale (RRS). Results: Subjects with significant ATs scored higher than BPD subjects in all domains and in the total score of AdAS Spectrum, RRS, and MOODS-SR, as well as in the items investigating suicidality. RRS total score, its depression domain, and the MOODS-SR rhythmicity domain, as well as suicidality, were predictors of the presence of ATs. Conclusions: Our data confirm the relationship between the presence of clinically significant ATs and affective symptoms, ruminative thinking, and suicidality in patients with BPD. Full article
(This article belongs to the Special Issue Advanced Clinical Diagnosis, Evaluation, and Treatment of Psychosis)
18 pages, 11109 KB  
Article
Effects of Sarcosine (N-methylglycine) on NMDA (N-methyl-D-aspartate) Receptor Hypofunction Induced by MK801: In Vivo Calcium Imaging in the CA1 Region of the Dorsal Hippocampus
by Yi-Tse Hsiao, Ching-Yuan Chang, Ting-Yen Lee, Wan-Ting Liao, Wen-Sung Lai and Fang-Chia Chang
Brain Sci. 2024, 14(11), 1150; https://doi.org/10.3390/brainsci14111150 - 16 Nov 2024
Cited by 2 | Viewed by 5045
Abstract
Background: Hypofunction of the glutamate system in the brain is one of the pathophysiological hypotheses for schizophrenia. Accumulating animal and clinical studies show that sarcosine (N-methylglycine), a glycine transporter-1 inhibitor, is effective in ameliorating the negative and cognitive symptoms of schizophrenia. The aims [...] Read more.
Background: Hypofunction of the glutamate system in the brain is one of the pathophysiological hypotheses for schizophrenia. Accumulating animal and clinical studies show that sarcosine (N-methylglycine), a glycine transporter-1 inhibitor, is effective in ameliorating the negative and cognitive symptoms of schizophrenia. The aims of the present study were to observe the effects of sarcosine on neuronal activity in the dorsal CA1 (dCA1) hippocampal neurons within an NMDA receptor hypofunction model induced by MK801. Methods: We applied in vivo calcium imaging to observe the dynamics of fluorescence from the dCA1 hippocampal neurons when the mice were exploring in an open field. Using this tool, we directly measured and compared neuronal properties between sarcosine-treated and untreated mice. At the same time, the physiological function of the neurons was also quantified by measuring their place fields. Results: Our data demonstrated that MK-801 (0.2 mg/kg) diminished the fluorescence intensity of dCA1 neurons that had been genetically modified with a calcium indicator. MK-801 also significantly increased the correlation coefficient between the fluorescence dynamics of pairs of cells, a feature that may be linked to the symptom of disorganization in human patients with schizophrenia. The spatial correlations of place fields in the mice were impaired by MK-801 as well. Injected sarcosine (500 mg or 1000 mg/kg) significantly alleviated the abovementioned abnormalities. Conclusions: Our data provide evidence to support the use of sarcosine to alleviate symptoms of schizophrenia, especially hippocampus-related functions. Full article
(This article belongs to the Special Issue Advanced Clinical Diagnosis, Evaluation, and Treatment of Psychosis)
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17 pages, 586 KB  
Systematic Review
Orexins, Psychosis, and Antipsychotics: A Systematic Review of Studies of Orexin Levels and the Effects of Dual Orexin Receptor Antagonists (DORAs)
by Stella Margoni, Senad Hasaj, Guglielmo Donofrio, Georgios D. Kotzalidis, Tommaso Callovini, Mario Pinto, Camilla Scialpi, Matteo Bucci, Maria Benedetta Anesini, Gabriele Sani, Lorenzo Moccia and Delfina Janiri
Brain Sci. 2026, 16(4), 361; https://doi.org/10.3390/brainsci16040361 - 27 Mar 2026
Viewed by 978
Abstract
Background/Objectives: Schizophrenia is a severe psychiatric disorder frequently characterised by sleep and circadian disturbances, which are closely linked to cognitive dysfunction, symptom exacerbation, and poor functional outcomes. A growing body of evidence implicates the orexin (hypocretin) system—an essential regulator of arousal, sleep–wake [...] Read more.
Background/Objectives: Schizophrenia is a severe psychiatric disorder frequently characterised by sleep and circadian disturbances, which are closely linked to cognitive dysfunction, symptom exacerbation, and poor functional outcomes. A growing body of evidence implicates the orexin (hypocretin) system—an essential regulator of arousal, sleep–wake stability, metabolic processes, and motivated behaviour—in the pathophysiology and treatment response of psychotic disorders. We aimed to investigate the relationships between the orexinergic system and psychoses. Methods: On 3 March 2026, we searched the PubMed, Scopus, PsycInfo/Articles and Cinahl databases for studies dealing with the orexin system and psychotic disorders and treatment response. Results: We found 20 eligible studies reporting variable and inconsistent alterations in orexin signalling in patients with schizophrenia. Studies were mostly cross-sectional and heterogeneous in design. Antipsychotic medications interfere with orexin-dependent pathways, potentially contributing to both therapeutic effects and adverse outcomes such as sleep disruption and metabolic dysregulation. Conclusions: While evidence from preclinical studies could point to an influence of dopaminergic activity through orexinergic mechanisms, with possible attenuation of antipsychotic-induced motor side effects and improvement of attentional deficits associated with NMDA receptor hypofunction, the utility of dual orexin receptor antagonists (DORAs) in psychoses is unclear. Despite the high prevalence of insomnia in schizophrenia, its pharmacological management remains suboptimal, with current treatments often limited by reduced efficacy or tolerability concerns. DORAs, which are currently approved medications for the treatment of insomnia, represent a novel and mechanistically distinct therapeutic option that may improve sleep while modulating arousal- and cognition-related circuits relevant to psychosis. Full article
(This article belongs to the Special Issue Advanced Clinical Diagnosis, Evaluation, and Treatment of Psychosis)
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11 pages, 253 KB  
Study Protocol
The Endocannabinoid Activity Remodulation for Psychosis Liability in Youth (EARLY) Study: An Open-Label Feasibility Trial of Ultramicronized-Palmitoylethanolamide Oral Supplementation in Clinical High-Risk State for Psychosis
by Riccardo Bortoletto, Marco Garzitto, Fabiana Piscitelli, Stefano Fornasaro, Claudia Scipioni, Orietta Sepulcri, Martina Fabris, Francesco Curcio, Matteo Balestrieri and Marco Colizzi
Brain Sci. 2024, 14(12), 1230; https://doi.org/10.3390/brainsci14121230 - 7 Dec 2024
Cited by 1 | Viewed by 2300
Abstract
To date, no psychotropic medication has shown to effectively halt progression to psychosis among individuals at Clinical High-Risk for psychosis (CHR), fueling the search for novel therapeutic agents. Recent evidence supports Palmitoylethanolamide (PEA) signaling as a potential psychosis biomarker, also indicating a therapeutic [...] Read more.
To date, no psychotropic medication has shown to effectively halt progression to psychosis among individuals at Clinical High-Risk for psychosis (CHR), fueling the search for novel therapeutic agents. Recent evidence supports Palmitoylethanolamide (PEA) signaling as a potential psychosis biomarker, also indicating a therapeutic role for its supplementation in the treatment of psychotic disorders. Nonetheless, the effect of sustained PEA intake in CHR subjects has never been explored so far. We will assess the feasibility of enrolling 20 CHR young adults presenting with attenuated psychotic symptoms (APS) in a 12-week, open-label, investigator-initiated, proof-of-concept, single-arm trial of ultramicronized-PEA (um-PEA) 600 mg/day. Once completed the 12-week phase, participants will be proposed to enter a 24-week extension phase of the study. We will examine um-PEA ability to reduce APS and psychic distress, um-PEA safety and tolerability, and the biological basis of um-PEA effect in terms of modulation of inflammatory response, endocannabinoid (eCB) signaling, and microbiome composition. Our trial aims to address an unmet clinical need in CHR subjects, providing an initial solid basis for the development of future studies evaluating the efficacy and tolerability of PEA supplementation in this group of patients. Full article
(This article belongs to the Special Issue Advanced Clinical Diagnosis, Evaluation, and Treatment of Psychosis)
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