Is the Hedgehog Pathway Involved in the Pathophysiology of Schizophrenia? A Systematic Review of Current Evidence of Neural Molecular Correlates and Perspectives on Drug Development.

Among the pathophysiological correlates of schizophrenia, recent research suggests a potential role for the Hedgehog (Hh) signalling pathway, which has been traditionally studied in embryonic development and oncology. Its dysregulation may impact brain homeostasis, neuroplasticity, and potential involvement in neural processes. This systematic review provides an overview of the involvement of Hh signalling in the pathophysiology of schizophrenia and antipsychotic responses. We searched the PubMed and Scopus databases to identify peer-reviewed scientific studies focusing on Hh and schizophrenia, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, finally including eight studies, including three articles focused on patients with schizophrenia, two animal models of schizophrenia, two animal embryo studies, and one cellular differentiation study. The Hh pathway is crucial in the development of midbrain dopaminergic neurons, neuroplasticity mechanisms, regulating astrocyte phenotype and function, brain-derived neurotrophic factor expression, brain glutamatergic neural transmission, and responses to antipsychotics. Overall, results indicate an involvement of Hh in the pathophysiology of schizophrenia and antipsychotic responses, although an exiguity of studies characterises the literature. The heterogeneity between animal and human studies is another main limitation. Further research can lead to better comprehension and the development of novel personalised drug treatments and therapeutic interventions.

Frequencies of Combined Dysfunction of Cytochromes P450 2C9, 2C19, and 2D6 in an Italian Cohort: Suggestions for a More Appropriate Medication Prescribing Process.

Improper drug prescription is a main cause of both drug-related harms (inefficacy and toxicity) and ineffective spending and waste of the healthcare system's resources. Nowadays, strategies to support an improved, informed prescription process may benefit from the adequate use of pharmacogenomic testing. Using next-generation sequencing, we analyzed the genomic profile for three major cytochromes P450 (CYP2C9, CYP2C19, CYP2D6) and studied the frequencies of dysfunctional isozymes (e.g., poor, intermediate, or rapid/ultra-rapid metabolizers) in a cohort of 298 Italian subjects. We found just 14.8% of subjects with a fully normal set of cytochromes, whereas 26.5% of subjects had combined cytochrome dysfunction (more than one isozyme involved). As improper drug prescription is more frequent, and more burdening, in polytreated patients, since drug-drug interactions also cause patient harm, we discuss the potential benefits of a more comprehensive PGX testing approach to support informed drug selection in such patients.

Grey Matter Volume Reductions of the Left Hippocampus and Amygdala in PTSD: A Coordinate-Based Meta-Analysis of Magnetic Resonance Imaging Studies.

INTRODUCTION: In recent years, research on posttraumatic stress disorder (PTSD) focused on the description of different biological correlates of illness. Morphological changes of different brain regions were involved in PTSD neurophysiopathology, being related to trauma or considered a resilience biomarker. In this meta-analysis, we aimed to investigate the grey matter changes reported in magnetic resonance imaging (MRI) studies on patients who have developed PTSD compared to exposed subjects who did not show a clinical PTSD onset. METHODS: We meta-analysed eight peer-reviewed MRI studies conducted on trauma-exposed patients and reported results corrected for false positives. We then conducted global and intergroup comparisons from neuroimaging data of two cohorts of included subjects. The included studies were conducted on 250 subjects, including 122 patients with PTSD and 128 non-PTSD subjects exposed to trauma. RESULTS: Applying a family-wise error correction, PTSD subjects compared to trauma-exposed non-PTSD individuals showed a significant volume reduction of a large left-sided grey matter cluster extended from the parahippocampal gyrus to the uncus, including the amygdala. CONCLUSIONS: These volumetric reductions are a major structural correlate of PTSD and can be related to the expression of symptoms. Future studies might consider these and other neural PTSD correlates, which may lead to the development of clinical applications for affected patients.

Decisional capacity to consent to treatment and research in patients affected by Mild Cognitive Impairment. A systematic review and meta-analysis.

OBJECTIVES: To perform a meta-analysis of clinical studies on the differences in treatment or research decision-making capacity among patients with Mild Cognitive Impairment (MCI), Alzheimer's disease (AD), and healthy comparisons (HCs). DESIGN: A systematic search was conducted on Medline/Pubmed, CINAHL, PsycINFO, Web of Science, and Scopus. Standardized mean differences and random-effects model were used in all cases. SETTING: The United States, France, Japan, and China. PARTICIPANTS: Four hundred and ten patients with MCI, 149 with AD, and 368 HCs were included. MEASUREMENTS: The studies we included in the analysis assessed decisional capacity to consent by the MacArthur Competence Assessment Tool for Treatment (MAcCAT-T), MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR), Capacity to Consent to Treatment Instrument (CCTI), and University of California Brief Assessment of Capacity to Consent (UBACC). RESULTS: We identified 109 potentially eligible studies from 1672 records, and 7 papers were included in the meta-analysis. The meta-analysis showed that there was significant impairment in a decision-making capacity in MCI patients compared to the HCs group in terms of Understanding (SMD = -1.04, 95% CI: -1.31 to -0.77, P < 0.001; I2 = 52%, P = 0.07), Appreciation (SMD = -0.51, 95% CI: -0.66 to -0.36, P < 0.001; I2 = 0%, P = 0.97), and Reasoning (SMD = -0.62, 95% CI: -0.77, -0.47, P < 0.001; I2=0%, P =0.46). MCI patients scored significantly higher in Understanding (SMD = 1.50, 95% CI: 0.91, 2.09, P = 0.01, I2 = 78%, P = 0.00001) compared to patients affected by AD. CONCLUSIONS: Patients affected by MCI are at higher risk of impaired capacity to consent to treatment and research compared to HCs, despite being at lower risk compared to patients affected by AD. Clinicians and researchers need to carefully evaluate decisional capacity in MCI patients providing informed consent.

Are Affective Temperaments, Emotional Abuse, and Neglect Involved in Mentalization Abilities in Patients With Psychiatric Disorders?

ABSTRACT: Patients who have experienced emotional abuse and neglect often develop psychiatric disorders in adulthood. However, whether emotional abuse, neglect, and mentalization abilities relate to one another and the role of possible mediators of this relationship in psychiatric patients are still unknown. We evaluated the potential role of affective temperament as a mediator of the relationship between emotional abuse and neglect and mentalization. We performed a cross-sectional study of 252 adult psychiatric inpatients. The Childhood Trauma Questionnaire, Mentalization Questionnaire, and Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A) were administered. Results showed a significant indirect effect of emotional abuse and neglect on scores on the Mentalization Questionnaire through the TEMPS-A (b = 0.25, 95% confidence interval [0.143-0.375]), demonstrating that affective temperament mediates the relationship among emotional abuse, neglect, and mentalization impairment in psychiatric patients. A careful evaluation of mentalization abilities in patients with psychiatric disorders and who have a history of emotional abuse and neglect is necessary for a better understanding of psychopathology and for the choice of therapeutic strategies.

Calls to the anti-violence number in Italy during COVID-19 pandemic: correlation and trend analyses of violence reports during 2020.

PURPOSE: We hypothesized that during the 2020 pandemic there has been a significant change along the year, depending on the SARS-CoV-2 impact on the population and varying difficulties implied in the norms that were adopted to embank the pandemic. Our objectives were to verify how the phenomenon of domestic violence has evolved and changed along 2020, and to clarify if these changes were correlated to the evolution of the pandemic. METHODS: Though the analysis of the number of daily calls from women to the national anti-violence number and the parameters related to COVID-19 pandemic (daily cases, deaths, hospitalizations, and admissions in ICU), a positive correlation was found between daily deaths due to COVID-19 and the number of calls to the anti-violence number, while daily hospitalizations and admissions in ICU negatively correlated with calls of women reporting at the national anti-violence number. RESULTS: The number of daily calls from women reporting at the national anti-violence number positively correlated with the number of quarantined people shifted of 30 days from the beginning of isolation at home, as well. We also analyzed temporal trends of daily calls from women to the national anti-violence number from 25th of February 2020 to 31st of December 2020. CONCLUSIONS: These findings demonstrate the importance of an active anti-violence telephone service and may help in developing a strategy to improve anti-violence facilities, especially during crises, such as specific sources of psychological support for women who have survived violence episodes.

Are Demoralization and Insight Involved in Suicide Risk? An Observational Study on Psychiatric Inpatients.

INTRODUCTION: Several features contribute to determining suicide risk. This study was designed with the aim of evaluating whether insight into illness and demoralization are involved in suicide risk (active suicidal ideation or behavior). METHODS: For this purpose, in a sample of 100 adult psychiatric inpatients, we used the Columbia Suicide Severity Rating Scale to assess suicide risk, the Demoralization Scale for demoralization symptoms, and the Insight Scale to assess illness insight. We also investigated several demographic and clinical features, including gender, age, duration of untreated illness, previous suicide attempts, and nonsuicidal self-injurious behavior. RESULTS: The results demonstrated that patients with higher scores on the insight-high dimension had 1.35 greater odds of having a higher suicide risk, and those with lifetime suicide attempts had 7.45 greater odds of having a higher suicide risk. Among the various clinical factors, the study indicated that only nonsuicidal self-harm behaviors in the last 3 months was a risk factor for suicide risk. CONCLUSIONS: The results indicated that greater illness insight is involved in suicide risk regardless of demoralization.

Quetiapine Abuse Fourteen Years Later: Where Are We Now? A Systematic Review.

Background: Quetiapine, an atypical antipsychotic endowed with weak dopamine antagonist, potent 5-HT2A-blocking, partial 5-HT1A-agonist, anti-H1 histamine, adrenolytic, and sigma1 receptor agonist activities, since an original 2004 report is increasingly misused. Although some of its pharmacodynamics might explain some motives for voluptuary use, most of its actions are directed at setting-off those motives. Hence, it is possible that its popularity in special populations is due to the fact that the unpleasant or unwanted effects of addiction substances are somehow soothed by quetiapine. Currently, quetiapine is tested in substance use disorders, showing some promise, but it is likely to be misused in certain contexts. Objectives: To review the evidence for the use of quetiapine as addiction substance and investigate the characteristics of populations involved in such addiction. Methods: A systematic review of literature on various databases retrieved on September 7, 2018 87 records to comment. Results. We reviewed the evidence for quetiapine's addictive potential in the light of its pharmacodynamics properties and presented two cases of recreational quetiapine use, by a 35-year old male patient with past addictive behavior and by a 50-year-old woman with major depressive disorder and conversion disorder. We found quetiapine to be abused mainly by addict populations and people with law involvement. Conclusions/Importance: There is no reason to include quetiapine among regulated substances, but monitoring of its use in selected populations is warranted. Psychiatrists and physicians working in the penitentiary system should be aware of the addictive potential of quetiapine and adopt measures restricting its use.

Predictive factors of overall functioning improvement in patients with chronic schizophrenia and schizoaffective disorder treated with paliperidone palmitate and aripiprazole monohydrate.

BACKGROUND: Long-acting injectable (LAI) antipsychotics can improve medication adherence and reduce hospitalisation rates compared with oral treatments. Paliperidone palmitate (PAL) and aripiprazole monohydrate (ARI) LAI treatments were associated with improvements in global functioning in patients with schizophrenia. OBJECTIVE: The objective of this study was to assess the predictive factors of better overall functioning in patients with chronic schizophrenia and schizoaffective disorder treated with PAL and ARI. METHOD: Enrolled were 143 (97 males, 46 females, mean age 38.24 years, SD = 12.65) patients with a diagnosis of schizophrenia or schizoaffective disorder, whom we allocated in two groups (PAL and ARI treatments). We assessed global functioning, amount of oral medications, adherence to oral treatment, and number of hospitalisations before LAI introduction and at assessment time point. RESULTS: Longer treatment time with LAIs (p < .001), lower number of oral drugs (p < .001), and hospitalisations (p = .002) before LAI introduction, and shorter duration of illness (p = .038) predicted better Global Assessment of Functioning scores in the whole sample (R2  = 0.337). CONCLUSION: Early administration and longer duration of ARI or PAL treatments could play a significant role in improving global functioning of patients with schizophrenia and schizoaffective disorder. Better improvement in functioning could be achieved with ARI in young individuals with recent illness onset and PAL in patients at risk for recurrent hospitalisations.

Erectile dysfunction in patients taking psychotropic drugs and treated with phosphodiesterase-5 inhibitors.

OBJECTIVES: The aim of this study was to assess the prevalence of patients with Erectile Dysfunction (ED) receiving psychotropic drugs, the impact of these drugs on hormonal profile, and the efficacy of PDE5-i in these patients. MATERIALS AND METHODS: We recruited 1872 patients referring for ED to our Andrology Unit. Assessment included serum testosterone, gonadotropins, TSH, prolactin, and PSA, and the IIEF-5 questionnaire for ED diagnosis. Inclusion criteria were age 21-75 years and IIEF-5 total score ≤ 21; exclusion criteria included hypogonadism, diabetes mellitus, previous prostatectomy, other medication intake, and ED diagnosis prior to psychotropic drug treatment. Efficacy was rated with the IIEF-5 (remission: total score ≥ 22). RESULTS: The prevalence of ED patients treated with psychotropic drugs since ≥ 3 months was 9.5% (178/1872), subdivided according to the drugs used into: Group A, 16 patients treated with atypical antipsychotics (9.0%); Group B, 55 patients with benzodiazepines (30.9%); Group C, 33 patients with antidepressant drugs (18.5%); and Group D, 74 patients with multiple psychotropic drugs (41.6%). Patients in Group A were significantly younger than other groups (p < 0.05). The hormonal profile presented only higher prolactin level in patients treated with antipsychotics, alone or in combination (p < 0.05). Overall, 146 patients received PDE5-i. Remission rate, after three months of treatment, was significantly higher in Group B compared to C and D groups (p < 0.05). CONCLUSIONS: A substantial portion of patients receiving psychotropic drugs show ED. Sexual performance in these patients benefits from PDE5-i. Age, effects of psychiatric disorders, psychotropic drugs, and PDE5-i treatment modality accounted for variability of response in this sample.

Depressive symptoms, temperament/character, and attention deficit/hyperactivity disorder traits in medical students seeking counseling.

BACKGROUND: To investigate depressive symptoms, temperament, and attention deficit/hyperactivity disorder traits in medical students, comparing those who sought psychological counseling with those who did not seek it. SUBJECTS AND METHODS: We assessed 49 students seeking counseling (mean age=24.4 years, SD=4.07) and 49 noncounseling controls (mean age=21.7 years, SD=2.6). Participants were assessed for depressive symptoms with the Beck Depression Inventory-II, for temperament/character dimensions using the Temperament and Character Inventory-Revised, and for attention deficit/hyperactivity symptoms using the Adult ADHD Self-Report Scale. RESULTS: Counseling-seeking students were more likely to have attention deficit/hyperactivity symptoms, scored higher on the Beck Depression Inventory-II and on the Temperament and Character Inventory-Revised Harm avoidance, and lower on the Temperament and Character Inventory-Revised Self-Directedness, compared to controls. CONCLUSIONS: Medical students applying for counseling should be carefully assessed for depressive symptoms, attention deficit/hyperactivity symptoms, and temperament characteristics; depressive and attention deficit/hyperactivity symptoms could be the focus of counseling interventions.

Functional Magnetic Resonance Imaging Correlates of First-Episode Psychoses during Attentional and Memory Task Performance.

BACKGROUND: The nature of the alteration of the response to cognitive tasks in first-episode psychosis (FEP) still awaits clarification. We used activation likelihood estimation, an increasingly used method in evaluating normal and pathological brain function, to identify activation changes in functional magnetic resonance imaging (fMRI) studies of FEP during attentional and memory tasks. METHODS: We included 11 peer-reviewed fMRI studies assessing FEP patients versus healthy controls (HCs) during performance of attentional and memory tasks. RESULTS: Our database comprised 290 patients with FEP, matched with 316 HCs. Between-group analyses showed that HCs, compared to FEP patients, exhibited hyperactivation of the right middle frontal gyrus (Brodmann area, BA, 9), right inferior parietal lobule (BA 40), and right insula (BA 13) during attentional task performances and hyperactivation of the left insula (BA 13) during memory task performances. CONCLUSIONS: Right frontal, parietal, and insular dysfunction during attentional task performance and left insular dysfunction during memory task performance are significant neural functional FEP correlates.

Functional Neuroimaging in Psychopathy.

BACKGROUND AND AIM: Psychopathy is associated with cognitive and affective deficits causing disruptive, harmful and selfish behaviour. These have considerable societal costs due to recurrent crime and property damage. A better understanding of the neurobiological bases of psychopathy could improve therapeutic interventions, reducing the related social costs. To analyse the major functional neural correlates of psychopathy, we reviewed functional neuroimaging studies conducted on persons with this condition. METHODS: We searched the PubMed database for papers dealing with functional neuroimaging and psychopathy, with a specific focus on how neural functional changes may correlate with task performances and human behaviour. RESULTS: Psychopathy-related behavioural disorders consistently correlated with dysfunctions in brain areas of the orbitofrontal-limbic (emotional processing and somatic reaction to emotions; behavioural planning and responsibility taking), anterior cingulate-orbitofrontal (correct assignment of emotional valence to social stimuli; violent/aggressive behaviour and challenging attitude) and prefrontal-temporal-limbic (emotional stimuli processing/response) networks. Dysfunctional areas more consistently included the inferior frontal, orbitofrontal, dorsolateral prefrontal, ventromedial prefrontal, temporal (mainly the superior temporal sulcus) and cingulated cortices, the insula, amygdala, ventral striatum and other basal ganglia. CONCLUSIONS: Emotional processing and learning, and several social and affective decision-making functions are impaired in psychopathy, which correlates with specific changes in neural functions.

Are 5-HT3 antagonists effective in obsessive-compulsive disorder? A systematic review of literature.

OBJECTIVE: The purpose of this literature database search-based review was to critically consider and evaluate the findings of literature focusing on efficacy and safety of 5-HT3 antagonists in the treatment of obsessive-compulsive disorder (OCD), so as to test whether preclinical data match clinical therapeutic trials. DESIGN: The PubMed database has been searched for papers on 5-HT3 antagonists and OCD in humans and for animal models of OCD and 5-HT3 receptors. RESULTS: Of the clinically tested 5-HT3 receptor antagonists, ondansetron has been used to treat OCD in five therapeutic studies, whereas granisetron only in one recent trial. Both showed some efficacy in open studies and superiority to placebo in double-blind studies, along with fair safety. No animal OCD model directly implicated 5-HT3 receptors. CONCLUSIONS: Overall, results indicate some utility, but the available literature is too scanty to allow for valid conclusions to be drawn. The mismatch between animal models of obsessive-compulsive disorder and clinical data with 5-HT3 antagonists needs more clinical data to ensure that it is not an artefact.

Anabolic-androgenic steroid use and psychopathology in athletes. A systematic review.

The use of anabolic-androgenic steroids (AASs) by professional and recreational athletes is increasing worldwide. The underlying motivations are mainly performance enhancement and body image improvement. AAS abuse and dependence, which are specifically classified and coded by the DSM-5, are not uncommon. AAS-using athletes are frequently present with psychiatric symptoms and disorders, mainly somatoform and eating, but also mood, and schizophrenia-related disorders. Some psychiatric disorders are typical of athletes, like muscle dysmorphia. This raises the issue of whether AAS use causes these disorders in athletes, by determining neuroadaptive changes in the reward neural circuit or by exacerbating stress vulnerability, or rather these are athletes with premorbid abnormal personalities or a history of psychiatric disorders who are attracted to AAS use, prompted by the desire to improve their appearance and control their weights. This may predispose to eating disorders, but AASs also show mood destabilizing effects, with longterm use inducing depression and short-term hypomania; withdrawal/discontinuation may be accompanied by depression. The effects of AASs on anxiety behavior are unclear and studies are inconsistent. AASs are also linked to psychotic behavior. The psychological characteristics that could prompt athletes to use AASs have not been elucidated.

A case of rapid conversion to psychosis of delusional misidentification associated with derealisation, verbal memory impairment and FDG-PET imaging abnormalities.

The delusional misidentification syndromes, occurring within the context of different nosological settings, such as schizophrenia, are psychopathological phenomena related to the experience of depersonalisation/derealisation. Extensive research indicates that individuals meeting specific "prodromal" criteria, such as attenuated psychotic symptoms, brief intermittent psychotic symptoms, or functional decline and family history of schizophrenia have increased risk for impending psychosis. Despite depersonalisation and/or derealisation often precede psychotic onset, they are not included among the prodromal criteria of the Australian-American approach. A 17-year-old boy with acute agitation, violent behaviour and aggression, and dissociative amnesia had a mild verbal memory impairment and temporo-limbic hypometabolism on the positron-emission tomography. The patient was assessed with both the ultra-high risk (UHR) and the basic symptom approaches and was not found to be prodromal with imminent risk of transition to psychosis. He was hospitalised briefly and 2 weeks after discharge he developed delusional misidentification. This case shows that even the integration of both UHR and basic symptoms criteria may give false negatives in the prediction of psychosis, especially in those cases in which a long prodromal phase is absent.

Whole-genome sequences of vaginal isolates Lactobacillus crispatus CECT30647 and Lactobacillus gasseri CECT30648.

We present the whole-genome sequences of Lactobacillus crispatus CECT30647 and Lactobacillus gasseri CECT30648, two vaginal isolates with probiotic potential.

The use of prolonged-release melatonin in circadian medicine: a systematic review.

INTRODUCTION: Melatonin, a hormone produced by the pineal gland, regulates the sleep-wake cycle and is effective in restoring biological rhythms. Prolonged-release melatonin (PRM) is designed to mimic the natural physiological pattern of melatonin release. In circadian medicine, PRM can be used to treat sleep and circadian rhythm disorders, as well as numerous organic diseases associated with sleep disorders. EVIDENCE ACQUISITION: This systematic review analyzed 62 studies and adhered to the PRISMA guidelines, examining the effectiveness of PRM in organic pathologies and mental disorders. EVIDENCE SYNTHESIS: The main evidence concerns primary insomnia in subjects over the age of 55, showing significant improvements in sleep quality. In neurodevelopmental disorders, there is evidence of a positive impact on sleep quality and quality of life for patients and their caregivers. PRM shows efficacy in the treatment of sleep disorders in mood disorders, schizophrenia, and neurocognitive disorders, but requires further confirmation. The additional use of PRM is supported for the withdrawal of chronic benzodiazepine therapies. The tolerability and safety of PRM are excellent, with ample evidence supporting the absence of tolerance and dependence. CONCLUSIONS: Overall, PRM in circadian medicine is an effective chronopharmaceutical for restoring the sleep-wake rhythm in patients with insomnia disorder. This efficacy may also extend to sleep disorders associated with mood, neurodevelopmental and neurocognitive disorders, suggesting a further potential role in insomnia associated with various organic diseases.

A coordinate-based meta-analysis of grey matter volume differences between adults with obsessive-compulsive disorder (OCD) and healthy controls.

According to the cortico-striato-thalamo-cortical (CSTC) model of obsessive-compulsive disorder (OCD), the striatum plays a primary role in its neuropathophysiology. Hypothesising that volumetric alterations are more pronounced in subcortical areas of patients within the CSTC circuit compared to healthy controls (HCs), we conducted a coordinate-based meta-analysis of magnetic resonance imaging (MRI) studies. We included 26 whole-brain MRI studies, comprising 3,010 subjects: 1,508 patients (788 men, 720 women; mean age: 30.26 years, SD = 8.16) and 1,502 HCs (801 men, 701 women; mean age: 29.47 years, SD = 7.88). This meta-analysis demonstrated significant grey matter volume increases in the bilateral putamen, lateral globus pallidus, left parietal cortex, right pulvinar, and left cerebellum in adults with OCD, alongside decreases in the right hippocampus/caudate, bilateral medial frontal gyri, and other cortical regions. Volume increases were predominantly observed in subcortical areas, with the exception of the left parietal cortex and cerebellar dentate, while volume decreases were primarily cortical, aside from the right hippocampus/caudate. Further exploration of these neuropathophysiological correlates could inform specific prevention and treatment strategies, advancing precision mental health in clinical applications.

Recognizing and preventing unacknowledged prescribing errors associated with polypharmacy.

BACKGROUND: Prescribing errors put an enormous burden on health and the economy, claiming implementation of effective methods to prevent/reduce them. Polypharmacy regimens (five or more drugs) are highly prone to unacknowledged prescribing errors, since the complex network of drug-drug interactions, guidelines and contraindications is challenging to be adequately evaluated in the prescription phase, especially if different doctors are involved. Clinical decision support systems aimed at polypharmacy evaluation may be crucial to recognize and correct prescribing errors. METHODS: A commercial clinical decision support system (Drug-PIN®) was applied to estimate the frequency of unrecognized prescribing errors in a group of 307 consecutive patients accessing the hospital pre-admission service of the Sant'Andrea Hospital of Rome, Italy, in the period April-June 2023. Drug-PIN® is a two-step system, first scoring the risk (low, moderate or high) associated with a certain therapy-patient pair, then allowing therapy optimization by medications exchanges. We defined prescribing errors as cases where therapy optimization could achieve consistent reduction of the Drug-PIN® calculated risk. RESULTS: Polypharmacy was present in 205 patients, and moderate to high risk for medication harm was predicted by Drug-PIN® in 91 patients (29.6%). In 58 of them (63.7%), Drug-PIN® guided optimization of the therapy could be achieved, with a statistically significant reduction of the calculated therapy-associated risk score. Patients whose therapy cannot be improved have a statistically significant higher number of used drugs. Considering the overall study population, the rate of avoidable prescribing errors was 18.89%. CONCLUSIONS: Results suggest that computer-aided evaluation of medication-associated harm could be a valuable and actionable tool to identify and prevent prescribing errors in polypharmacy. We conducted the study in a Hospital pre-admission setting, which is not representative of the general population but represents a hotspot to intercept fragile population, where a consistent fraction of potentially harmful polypharmacy regimens could be promptly identified and corrected by systematic use of adequate clinical decision support tools.