Proof-of-concept evidence for high-density EEG investigation of sleep slow wave traveling in First-Episode Psychosis.

Schizophrenia is thought to reflect aberrant connectivity within cortico-cortical and reentrant thalamo-cortical loops, which physiologically integrate and coordinate the function of multiple cortical and subcortical structures. Despite extensive research, reliable biomarkers of such "dys-connectivity" remain to be identified at the onset of psychosis, and before exposure to antipsychotic drugs. Because slow waves travel across the brain during sleep, they represent an ideal paradigm to study pathological conditions affecting brain connectivity. Here, we provide proof-of-concept evidence for a novel approach to investigate slow wave traveling properties in First-Episode Psychosis (FEP) with high-density electroencephalography (EEG). Whole-night sleep recordings of 5 drug-naïve FEP and 5 age- and gender-matched healthy control subjects were obtained with a 256-channel EEG system. One patient was re-recorded after 6 months and 3 years of continuous clozapine treatment. Slow wave detection and traveling properties were obtained with an open-source toolbox. Slow wave density and slow wave traveled distance (measured as the line of longest displacement) were significantly lower in patients (p < 0.05). In the patient who was tested longitudinally during effective clozapine treatment, slow wave density normalized, while traveling distance only partially recovered. These preliminary findings suggest that slow wave traveling could be employed in larger samples to detect cortical "dys-connectivity" at psychosis onset.

Tolerability of vortioxetine compared to selective serotonin reuptake inhibitors in older adults with major depressive disorder (VESPA): a randomised, assessor-blinded and statistician-blinded, multicentre, superiority trial.

Background: Major depressive disorder (MDD) is prevalent and disabling among older adults. Standing on its tolerability profile, vortioxetine might be a promising alternative to selective serotonin reuptake inhibitors (SSRIs) in such a vulnerable population. Methods: We conducted a randomised, assessor- and statistician-blinded, superiority trial including older adults with MDD. The study was conducted between 02/02/2019 and 02/22/2023 in 11 Italian Psychiatric Services. Participants were randomised to vortioxetine or one of the SSRIs, selected according to common practice. Treatment discontinuation due to adverse events after six months was the primary outcome, for which we aimed to detect a 12% difference in favour of vortioxetine. The study was registered in the online repository clinicaltrials.gov (NCT03779789). Findings: The intention-to-treat population included 179 individuals randomised to vortioxetine and 178 to SSRIs. Mean age was 73.7 years (standard deviation 6.1), and 264 participants (69%) were female. Of those on vortioxetine, 78 (44%) discontinued the treatment due to adverse events at six months, compared to 59 (33%) of those on SSRIs (odds ratio 1.56; 95% confidence interval 1.01-2.39). Adjusted and per-protocol analyses confirmed point estimates in favour of SSRIs, but without a significant difference. With the exception of the unadjusted survival analysis showing SSRIs to outperform vortioxetine, secondary outcomes provided results consistent with a lack of substantial safety and tolerability differences between the two arms. Overall, no significant differences emerged in terms of response rates, depressive symptoms and quality of life, while SSRIs outperformed vortioxetine in terms of cognitive performance. Interpretation: As opposed to what was previously hypothesised, vortioxetine did not show a better tolerability profile compared to SSRIs in older adults with MDD in this study. Additionally, hypothetical advantages of vortioxetine on depression-related cognitive symptoms might be questioned. The study's statistical power and highly pragmatic design allow for generalisability to real-world practice. Funding: The study was funded by the Italian Medicines Agency within the "2016 Call for Independent Drug Research".

Early identification of risk for eating disorders in Italian secondary school students: a cross-sectional study.

AIM: Eating disorders are major illnesses that primarily affect adolescents and young adults and seriously threaten public health. Early identification of at-risk individuals and timely initiation of treatment is crucial to improve outcomes. The Inside Out Institute Screener (IOI-S) is a rapid self-administration screening tool for high-risk and early-stage eating disorders. This study aimed to investigate the risk of having an eating disorder in a sample of Italian students by testing the Italian version of the IOI-S. METHODS: A multicentre cross-sectional study was conducted in a population of students aged 12-19 years; validity and reliability of the IOI-Sita were investigated. RESULTS: Four-hundred and ninety-one (81.97%) students were enrolled, 24.85% of whom were found to be at "very high risk" of an eating disorder, according to IOI-Sita. Younger (p<0.001) and female (p<0.001) students had higher risk scores. The EFA confirmed the original monodimensional structure of the tool, S-CVI=0.95%. The Content Validity Index of the scale (S-CVI) was 0.95, ω coefficient was 0.927. DISCUSSION AND CONCLUSIONS: This research confirms the need to screen for eating disorders in Italian youth adequately; the psychometric properties of the IOI-Sita confirm it as a valid and reliable tool for screening high-risk and early-stage eating disorders.

Sleep and sleep disorders during pregnancy and postpartum: The Life-ON study.

OBJECTIVE: to prospectively assess sleep and sleep disorders during pregnancy and postpartum in a large cohort of women. METHODS: multicenter prospective Life-ON study, recruiting consecutive pregnant women at a gestational age between 10 and 15 weeks, from the local gynecological departments. The study included home polysomnography performed between the 23rd and 25th week of pregnancy and sleep-related questionnaires at 9 points in time during pregnancy and 6 months postpartum. RESULTS: 439 pregnant women (mean age 33.7 ± 4.2 yrs) were enrolled. Poor quality of sleep was reported by 34% of women in the first trimester of pregnancy, by 46% of women in the third trimester, and by as many as 71% of women in the first month after delivery. A similar trend was seen for insomnia. Excessive daytime sleepiness peaked in the first trimester (30% of women), and decreased in the third trimester, to 22% of women. Prevalence of restless legs syndrome was 25%, with a peak in the third trimester of pregnancy. Polysomnographic data, available for 353 women, revealed that 24% of women slept less than 6 h, and 30.6% of women had a sleep efficiency below 80%. Sleep-disordered breathing (RDI≥5) had a prevalence of 4.2% and correlated positively with BMI. CONCLUSIONS: The Life-ON study provides the largest polysomnographic dataset coupled with longitudinal subjective assessments of sleep quality in pregnant women to date. Sleep disorders are highly frequent and distributed differently during pregnancy and postpartum. Routine assessment of sleep disturbances in the perinatal period is necessary to improve early detection and clinical management.

Optimal risk and diagnosis assessment strategies in perinatal depression: A machine learning approach from the life-ON study cohort.

This study aimed to assess the concordance of various psychometric scales in detecting Perinatal Depression (PND) risk and diagnosis. A cohort of 432 women was assessed at 10-15th and 23-25th gestational weeks, 33-40 days and 180-195 days after delivery using the Edinburgh Postnatal Depression Scale (EPDS), Visual Analogue Scale (VAS), Hamilton Depression Rating Scale (HDRS), Montgomery-Åsberg Depression Rating Scale (MADRS), and Mini International Neuropsychiatric Interview (MINI). Spearman's rank correlation coefficient was used to assess agreement across instruments, and multivariable classification models were developed to predict the values of a binary scale using the other scales. Moderate agreement was shown between the EPDS and VAS and between the HDRS and MADRS throughout the perinatal period. However, agreement between the EPDS and HDRS decreased postpartum. A well-performing model for the estimation of current depression risk (EPDS > 9) was obtained with the VAS and MADRS, and a less robust one for the estimation of current major depressive episode (MDE) diagnosis (MINI) with the VAS and HDRS. When the EPDS is not feasible, the VAS may be used for rapid and comprehensive postpartum screening with reliability. However, a thorough structured interview or clinical examination remains necessary to diagnose a MDE.

Evaluation of telepsychiatry during the COVID-19 pandemic across service users, carers and clinicians: an international mixed-methods study.

BACKGROUND: Worldwide uptake of telepsychiatry accelerated during the COVID-19 pandemic. OBJECTIVE: To conduct an evaluation of the opinions, preferences and attitudes to telepsychiatry from service users, carers and clinicians in order to understand how telepsychiatry can be best used in the peri/post-COVID-19 era. METHODS: This mixed-methods, multicentre, international study of telepsychiatry was set in two sites in England and two in Italy. Survey questionnaires and focus group topic guides were co-produced for each participant group (service users, carers and clinicians). FINDINGS: In the UK, 906 service users, 117 carers and 483 clinicians, and in Italy, 164 service users, 56 carers and 72 clinicians completed the surveys. In all, 17 service users/carers and 14 clinicians participated in focus groups. Overall, telepsychiatry was seen as convenient in follow-ups with a specific purpose such as medication reviews; however, it was perceived as less effective for establishing a therapeutic relationship or for assessing acutely disturbed mental states. In contrast to clinicians, most service users and carers indicated that telepsychiatry had not improved during the COVID-19 pandemic. Most service users and carers reported that the choice of appointment modality was most often determined by the service or clinician. CONCLUSION AND RELEVANCE: There were circumstances in which telepsychiatry was seen as more suitable than others and clear differences in clinician, carer and service user perspectives on telepsychiatry. CLINICAL IMPLICATIONS: All stakeholders should be actively engaged in determining a hybrid model of care according to clinical features and service user and carer preferences. Clinicians should be engaged in training programmes on telepsychiatry.

Clinical trajectories of individuals with severe mental illness continuing and discontinuing long-acting antipsychotics: a one-year mirror-image analysis from the STAR Network Depot study.

Evidence on long-acting antipsychotics (LAIs) in unselected populations with severe mental illness is scant. In this mirror-image study, we compared multiple clinical outcomes 1 year before and after a first LAI prescription in adults with severe mental illness, describing clinical trajectories of LAI continuers and discontinuers. We compared LAI continuers and discontinuers through Mann-Whitney U test, Kaplan-Meier survival curves, regression for interval-censored data, and a maximum-likelihood mixed-model with individual random-effect and time as predictor. Of the 261 participants analyzed, 71.3% had schizophrenia-spectrum disorders, and 29.5% discontinued the LAI before 1 year. At baseline, LAI discontinuers had a shorter illness duration, lower attitude and adherence scores. The mirror-image analysis showed reduced hospital admissions only for LAI continuers. Over time, continuers spent less days hospitalized, but had more adverse events and more antipsychotics prescribed, with higher overall doses. In conclusion, this study shows that LAIs might be beneficial in unselected patient populations, provided that adherence is maintained. LAI continuers spent less time hospitalized, but received more antipsychotics and suffered from more cumulative adverse events over time. Therefore, the choice of initiating and maintaining a LAI should be carefully weighed on a case-by-case basis.

Shared and distinct abnormalities in sleep-wake patterns and their relationship with the negative symptoms of Schizophrenia Spectrum Disorder patients.

Sleep and rest-activity-rhythm (RAR) abnormalities are commonly reported in schizophrenia spectrum disorder (SSD) patients. However, an in-depth characterization of sleep/RAR alterations in SSD, including patients in different treatment settings, and the relationship between these alterations and SSD clinical features (e.g., negative symptoms) is lacking. SSD (N = 137 altogether, N = 79 residential and N = 58 outpatients) and healthy control (HC) subjects (N = 113) were recruited for the DiAPAson project. Participants wore an ActiGraph for seven consecutive days to monitor habitual sleep-RAR patterns. Sleep/rest duration, activity (i.e., M10, calculated on the 10 most active hours), rhythm fragmentation within days (i.e., intra-daily variability, IV; beta, steepness of rest-active changes), and rhythm regularity across days (i.e., inter-daily stability, IS) were computed in each study participant. Negative symptoms were assessed in SSD patients with the Brief Negative Symptom Scale (BNSS). Both SSD groups showed lower M10 and longer sleep/rest duration vs. HC, while only residential patients had more fragmented and irregular rhythms than HC. Compared to outpatients, residential patients had lower M10 and higher beta, IV and IS. Furthermore, residential patients had worse BNSS scores relative to outpatients, and higher IS contributed to between-group differences in BNSS score severity. Altogether, residentials and outpatients SSD had both shared and unique abnormalities in Sleep/RAR measures vs. HC and relative to one another, which also contributed to the patients' negative symptom severity. Future work will help establish whether improving some of these measures may ameliorate the quality of life and clinical symptoms of SSD patients.

Machine learning methods to predict outcomes of pharmacological treatment in psychosis.

In recent years, machine learning (ML) has been a promising approach in the research of treatment outcome prediction in psychosis. In this study, we reviewed ML studies using different neuroimaging, neurophysiological, genetic, and clinical features to predict antipsychotic treatment outcomes in patients at different stages of schizophrenia. Literature available on PubMed until March 2022 was reviewed. Overall, 28 studies were included, among them 23 using a single-modality approach and 5 combining data from multiple modalities. The majority of included studies considered structural and functional neuroimaging biomarkers as predictive features used in ML models. Specifically, functional magnetic resonance imaging (fMRI) features contributed to antipsychotic treatment response prediction of psychosis with good accuracies. Additionally, several studies found that ML models based on clinical features might present adequate predictive ability. Importantly, by examining the additive effects of combining features, the predictive value might be improved by applying multimodal ML approaches. However, most of the included studies presented several limitations, such as small sample sizes and a lack of replication tests. Moreover, considerable clinical and analytical heterogeneity among included studies posed a challenge in synthesizing findings and generating robust overall conclusions. Despite the complexity and heterogeneity of methodology, prognostic features, clinical presentation, and treatment approaches, studies included in this review suggest that ML tools may have the potential to predict treatment outcomes of psychosis accurately. Future studies need to focus on refining feature characterization, validating prediction models, and evaluate their translation in real-world clinical practice.

Cortico-thalamic development and disease: From cells, to circuits, to schizophrenia.

The human brain is the most complex structure generated during development. Unveiling the ontogenesis and the intrinsic organization of specific neural networks may represent a key to understanding the physio-pathological aspects of different brain areas. The cortico-thalamic and thalamo-cortical (CT-TC) circuits process and modulate essential tasks such as wakefulness, sleep and memory, and their alterations may result in neurodevelopmental and psychiatric disorders. These pathologies are reported to affect specific neural populations but may also broadly alter physiological connections and thus dysregulate brain network generation, communication, and function. More specifically, the CT-TC system is reported to be severely affected in disorders impacting superior brain functions, such as schizophrenia (SCZ), bipolar disorder, autism spectrum disorders or epilepsy. In this review, the focus will be on CT development, and the models exploited to uncover and comprehend its molecular and cellular mechanisms. In parallel to animal models, still fundamental to unveil human neural network establishment, advanced in vitro platforms, such as brain organoids derived from human pluripotent stem cells, will be discussed. Indeed, organoids and assembloids represent unique tools to study and accelerate fundamental research in CT development and its dysfunctions. We will then discuss recent cutting-edge contributions, including in silico approaches, concerning ontogenesis, specification, and function of the CT-TC circuitry that generates connectivity maps in physiological and pathological conditions.

A machine learning approach on whole blood immunomarkers to identify an inflammation-associated psychosis onset subgroup.

Psychosis onset is a transdiagnostic event that leads to a range of psychiatric disorders, which are currently diagnosed through clinical observation. The integration of multimodal biological data could reveal different subtypes of psychosis onset to target for the personalization of care. In this study, we tested the existence of subgroups of patients affected by first-episode psychosis (FEP) with a possible immunopathogenic basis. To do this, we designed a data-driven unsupervised machine learning model to cluster a sample of 127 FEP patients and 117 healthy controls (HC), based on the peripheral blood expression levels of 12 psychosis-related immune gene transcripts. To validate the model, we applied a resampling strategy based on the half-splitting of the total sample with random allocation of the cases. Further, we performed a post-hoc univariate analysis to verify the clinical, cognitive, and structural brain correlates of the subgroups identified. The model identified and validated two distinct clusters: 1) a FEP cluster characterized by the high expression of inflammatory and immune-activating genes (IL1B, CCR7, IL12A and CXCR3); 2) a cluster consisting of an equal number of FEP and HC subjects, which did not show a relative over or under expression of any immune marker (balanced subgroup). None of the subgroups was related to specific symptoms dimensions or longitudinal diagnosis of affective vs non-affective psychosis. FEP patients included in the balanced immune subgroup showed a thinning of the left supramarginal and superiorfrontal cortex (FDR-adjusted p-values < 0.05). Our results demonstrated the existence of a FEP patients' subgroup identified by a multivariate pattern of immunomarkers involved in inflammatory activation. This evidence may pave the way to sample stratification in clinical studies aiming to develop diagnostic tools and therapies targeting specific immunopathogenic pathways of psychosis.

Effect of long-acting injectable antipsychotics on 1-year hospitalization in bipolar disorder: a mirror-image study.

Long-acting injectable (LAI) antipsychotics are often used for the long-term management also of bipolar disorder (BD). Nonetheless, evidence on their effect on pragmatic outcomes such as hospitalization risk in BD is inconsistent. We carried out a mirror-image study comparing rates and number of days of hospitalization, one year before and after the initiation of LAI treatment, in a sample of subjects with BD. Participants were selected from the STAR Network Depot Study, a pragmatic, observational, multicenter research involving a cohort of inpatients and outpatients consecutively started on LAI treatment. Variations in rates and in total number of days of hospitalization between the 12 months before and those after treatment initiation were analyzed. Among 461 individuals screened for eligibility, we included 71 adults with BD, initiated either on first- (FGA) or second-generation (SGA) LAIs. We found a significant decrease in terms of 12-month hospitalization rates (p < 0.001) and number of days (p < 0.001) after LAI initiation, without any effect by age, gender, alcohol/substance use disorders, and symptom severity. Subgroup analyses based on antipsychotic class, history of LAI treatment, and concomitant oral medications, confirmed the decreasing trend on both hospitalization rates and number of days. However, these reductions were not significant among participants who continued this treatment for less than 6 months. Comprehensively, this study supports the role of LAIs as effective maintenance treatment options for BD. Further research is needed to identify clinical characteristics of people with BD who would most benefit from long-acting formulations of antipsychotics.

Two-Injection Start Regimen of Long-Acting Aripiprazole in 133 Patients With Schizophrenia.

PURPOSE/BACKGROUND: Based on a population-pharmacokinetic model, the European Medicines Agency has recently approved a simplified starting strategy of aripiprazole once a month (AOM), injectable and long-acting antipsychotic, with two 400 mg injections and a single oral 20 mg dose of aripiprazole, administered on the same day, instead of 1 injection and 14 daily administrations of concurrent oral aripiprazole. However, to our knowledge, no previous study has reported the safety and tolerability of this regimen in real-world patients. METHODS/PROCEDURES: We retrospectively reviewed medical records of 133 patients who received the newly approved 2-injection start regimen as part of their standard care in 10 Italian clinical centers. FINDINGS/RESULTS: Adverse effects were mild or moderate, with no clinically evident difference from the adverse effects observed in previous trials where AOM was started with a single injection followed by 14 days of orally administered aripiprazole. None of the patients who started AOM after the 2-injection start regimen experienced severe adverse effects or severe adverse effects. IMPLICATIONS/CONCLUSIONS: The coadministration of 2 injections of 400 mg aripiprazole and 20 mg oral aripiprazole was not associated with safety concerns beyond those reported after a single injection followed by 14 days of orally administered aripiprazole. Our results should be interpreted with caution, due to the limited sample size and to the retrospective design of the study.

Perinatal mental health and COVID-19: Navigating a way forward.

The COVID-19 pandemic and its aftermath have increased pre-existing inequalities and risk factors for mental disorders in general, but perinatal mental disorders are of particular concern. They are already underdiagnosed and undertreated, and this has been magnified by the pandemic. Access to services (both psychiatric and obstetric) has been reduced, and in-person contact has been restricted because of the increased risks. Rates of perinatal anxiety and depressive symptoms have increased. In the face of these challenges, clear guidance in perinatal mental health is needed for patients and clinicians. However, a systematic search of the available resources showed only a small amount of guidance from a few countries, with a focus on the acute phase of the pandemic rather than the challenges of new variants and variable rates of infection. Telepsychiatry offers advantages during times of restricted social contact and also as an additional route for accessing a wide range of digital technologies. While there is a strong evidence base for general telepsychiatry, the particular issues in perinatal mental health need further examination. Clinicians will need expertise and training to navigate a hybrid model, flexibly combining in person and remote assessments according to risk, clinical need and individual patient preferences. There are also wider issues of care planning in the context of varying infection rates, restrictions and vaccination access in different countries. Clinicians will need to focus on prevention, treatment, risk assessment and symptom monitoring, but there will also need to be an urgent and coordinated focus on guidance and planning across all organisations involved in perinatal mental health care.

Poor sleep quality may contribute to dysfunctional illness perception, physical and emotional distress in hospitalised patients: results of a national survey of the Italian Society of Consultation-Liaison Psychiatry.

Distress associated with physical illness is a well-known risk factor for adverse illness course in general hospitals. Understanding the factors contributing to it should be a priority and among them dysfunctional illness perception and poor sleep quality may contribute to it. As poor sleep quality is recognised as a major risk factor for health problems, we aimed to study its association with illness perception and levels of distress during hospitalisation. This cross-sectional study included a consecutive series of 409 individuals who were hospitalised in medical and surgical units of different hospitals located throughout the Italian national territory and required an assessment for psychopathological conditions. Sleep quality was assessed with the Pittsburgh (Sleep Quality Index), emotional and physical distress with the Edmonton Symptom Assessment System (ESAS), and illness perception with the Brief Illness Perception Questionnaire (BIPQ). Differences between groups, correlations and mediations analyses were computed. Patients with poor sleep quality were more frequently females, with psychiatric comorbidity, with higher scores in the ESAS and BIPQ. Poor sleep quality was related to dysfunctional illness perception, and to both emotional and physical distress. In particular, by affecting cognitive components of illness perception, poor sleep quality may, directly and indirectly, predict high levels of distress during hospitalisation. Poor sleep quality may affect >70% of hospitalised patients and may favour dysfunctional illness perception and emotional/physical distress.Assessing and treating sleep problems in hospitalised patients should be included in the routine of hospitalised patients.

State of Mind Assessment in Relation to Adult Attachment and Text Analysis of Adult Attachment Interviews in a Sample of Patients with Anorexia Nervosa.

BACKGROUND: Attachment theory represents one of the most important references for the study of the development of an individual throughout their life cycle and provides the clinician with a profound key for the purposes of understanding the suffering that underlies severe psychopathologies such as eating disorders. As such, we conducted a cross-sectional study with a mixed-methods analysis on a sample of 32 young women with anorexia nervosa (AN); this study was embedded in the utilized theoretical framework with the following aims: 1. to evaluate the state of mind (SoM) in relation to adult attachment, assuming a prevalence of the dismissing (DS) SoM and 2. to analyze the linguistic attachment profile emerging from the transcripts of the AAIs. METHODS: Interviews were transcribed verbatim, coded, and analyzed using the linguistic inquiry and word count (LIWC) method. RESULTS: The results were observed to be consistent with the referenced literature. The prevalence of a DS SoM (68.75%) is observed in the study sample, whereas the results of the lexical analysis of the stories deviate from expectations. Notably, the lexical results indicate the coexistence of the dismissing and entangled aspects at the representational level. CONCLUSIONS: The study results suggest a high level of specificity in the emotional functioning of patients with AN, with a focusing on a pervasive control of emotions that is well illustrated by the avoidant/ambivalent (A/C) strategy described in Crittenden's dynamic-maturational model. These findings and considerations have important implications for clinical work and treatment, which we believe must be structured on the basis of starting from a reappraisal of emotional content.

Changes of consultation-liaison psychiatry practice in Italian general hospitals: A comparative 20-year multicenter study.

Introduction: Conducted under the auspices of the Italian Society of Consultation Liaison Psychiatry (SIPC) the aim of this study was to describe the characteristics of Consultation Liaison Psychiatry (CLP) activity in Italy (SIPC-2-2018) over the past 20 years by comparing with data from the first Italian nation-wide study (SIPC-1-1998). Methods: We collected data on CLP visits of 3,943 patients from 10 Italian hospitals over a period of 1 year. Data were compared with those from the SIPC-1 1998 study (4,183 participants). Patients were assessed with the same ad hoc 60-item Patient Registration Form recording information from five different areas: Sociodemographic, hospitalization-related, consultation-related, interventions and outcome. Results: Compared with participants from the previous study, SIPC-2-2018 participants were significantly older (d = 0.54) and hospitalized for a longer duration (d = 0.20). The current study detected an increase in the proportion of referrals from surgical wards and for individuals affected by onco-hematologic diseases. Depressive disorders still represented the most frequent psychiatric diagnosis, followed by adjustment and stress disorders and delirium/dementia. Also, CLP psychiatrists prescribed more often antidepressants (Φ = 0.13), antipsychotics (Φ = 0.09), mood stabilizers (Φ = 0.24), and less often benzodiazepines (Φ = 0.07). Conclusion: CLP workload has increased considerably in the past 20 years in Italy, with changes in patient demographic and clinical characteristics. A trend toward increase in medication-based patient management was observed. These findings suggest that the psychiatric needs of patients admitted to the general hospital are more frequently addressed by referring physicians, although Italian CLP services still deserve better organization and autonomy.