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".

Off-label long acting injectable antipsychotics in real-world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study.

INTRODUCTION: Information on the off-label use of Long-Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on- vs off-label LAIs and predictors of off-label First- or Second-Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. METHOD: In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off- or on-label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off-label group. RESULTS: SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on- and off-label use. Approximately 1 in 4 patients received an off-label prescription. In the off-label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. CONCLUSION: Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off-label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co-morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns.

Aggressiveness in the dreams of drug-naïve and clonazepam-treated patients with isolated REM sleep behavior disorder.

BACKGROUND: Although aggressive dream content is considered a distinctive feature of REM Sleep Behavior Disorder (RBD) and patients often report violent dreams during medical interviews, nonviolent behaviors (eating, drinking, urinating) and pleasant actions (e.g laughing, singing, dancing) or simply elemental, jerky limb movements are frequently observed during video-polysomnography. As a first-line pharmacological treatment, clonazepam has been shown to reduce motor symptoms during REM sleep, but its effect on dream content remains unclear. Here, we aimed to prospectively assess the dream content of individuals with drug-naïve isolated RBD (iRBD) and iRBD patients treated with clonazepam. METHODS: Thirteen (12 Male, 1 Female; age 65.38 ± 10.95) iRBD patients treated with clonazepam (iRBD-T), eleven (9 M, 2 F; age 68.90 ± 6.8) drug-naïve patients (iRBD-NT) and twelve (8 M, 1 F; age 63.33 ± 12.88) healthy control subjects of comparable age kept a dream diary over a 3-week period. Dream content analysis was conducted according to the Hall and Van de Castle method (HVdC). The Threat Simulation Scale (TSS) was employed to assess the frequency of threatening contents. RESULTS: A total of 214 dream reports were collected. No significant differences were found in the frequency of threatening dream contents between the iRBD subsamples and healthy control subjects (p = 0.732). The HVdC analysis detected higher levels of Friendliness in iRBD patients compared to the control group (p = 0.036). Increased levels of Aggressiveness were only observed when differentiating dreams in which dream enactment behaviors (DEB) were present compared to dreams without DEBs, both in the iRBD-T group (p = 0.007) and the iRBD-NT group (p = 0.012). CONCLUSION: Our study shows no difference in the frequency of violent or threatening dreams in drug-naïve iRBD patients, clonazepam-treated iRBD patients and healthy control individuals. Aggressiveness is more frequent when DEBs are reported, suggesting motor disinhibition could require sufficiently dramatic and emotionally intense dreams, independent of clonazepam treatment.

Tolerability and efficacy of vortioxetine versus SSRIs in elderly with major depression. Study protocol of the VESPA study: a pragmatic, multicentre, open-label, parallel-group, superiority, randomized trial.

INTRODUCTION: Depression is a highly prevalent condition in the elderly, with a vast impact on quality of life, life expectancy, and medical outcomes. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed agents in this condition and, although generally safe, tolerability issues cannot be overlooked. Vortioxetine is an antidepressant with a novel mechanism of action. Based on studies to date, it may have a promising tolerability profile in the elderly, as it does not adversely affect psychomotor or cognitive performance and does not alter cardiovascular and endocrine parameters. The present study aims to assess the tolerability profile of vortioxetine in comparison with the SSRIs considered as a single group in elderly participants with depression. The rate of participants withdrawing from treatment due to adverse events after 6 months of follow up will be the primary outcome. METHODS AND ANALYSIS: This is a pragmatic, multicentre, open-label, parallel-group, superiority, randomized trial funded by the Italian Medicines Agency (AIFA - Agenzia Italiana del Farmaco). Thirteen Italian Community Psychiatric Services will consecutively enrol elderly participants suffering from an episode of major depression over a period of 12 months. Participants will be assessed at baseline and after 1, 3 and 6 months of follow up. At each time point, the following validated rating scales will be administered: Montgomery-Åsberg Depression Rating Scale (MADRS), Antidepressant Side-Effect Checklist (ASEC), EuroQual 5 Dimensions (EQ-5D), Short Blessed Test (SBT), and Charlson Age-Comorbidity Index (CACI). Outcome assessors and the statistician will be masked to treatment allocation. A total of 358 participants (179 in each group) will be enrolled. ETHICS AND DISSEMINATION: This study will fully adhere to the ICH E6 Guideline for Good Clinical Practice. Participants' data will be managed and safeguarded according to the European Data Protection Regulation 2016/679. An external Ethical Advisory Board will help guarantee high ethical standards. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03779789 , Registered on 19 December 2018. Submitted on 19 December. EudraCT number: 2018-001444-66. TRIAL STATUS: Protocol version 1.5; 09/06/2018. Recruitment started In February 2019 and it is ongoing. It is expected to end approximately on 30 September 2021.

The reMAP project: A retrospective, 15-year register study on inpatient care for youth with mental disorders.

AIM: We aimed to characterize youth hospitalization trends in a psychiatric inpatient unit from a large, public university hospital with a broad catchment area in Milan, Italy. METHODS: Hospitalization data of patients with an age at admission ≤ 35 were retrospectively retrieved over a time span of 15 years. The sample was comprised of 1982 admissions to a psychiatric ward, aggregated into ICD-10 diagnostic clusters and then analysed. We investigated the epidemiological trends with a focus on age at admission, gender, nationality and hospitalization rates, length of stay and "revolving door" readmissions within a year. RESULTS: Hospitalization rates increased for eating Disorders and decreased for non-affective psychotic disorders; median length of stay generally decreased; hospitalization rates for foreign youth increased, in particular for those diagnosed with non-affective psychotic disorders, personality disorders, and substance-related and addictive disorders. The revolving door phenomenon was also associated with non-affective psychoses and neurodevelopmental disorders, while found to increase for eating disorders. CONCLUSIONS: Hospitalization patterns reflect the general increase of foreign youth in the suburban tissue of a large metropolitan area like Milan. However, our data might underestimate the constant growth of mental health problems in foreign youth due to a generally lower access to services. Novel pharmacological treatments and early intervention programs might explain the decrease of hospitalization duration and hospitalization rate for youth with non-affective psychoses. The observed increase in hospitalization for young patients with eating disorders sustains the development of adequate policies tailored towards specialty wards.

Sleep endophenotypes of schizophrenia: slow waves and sleep spindles in unaffected first-degree relatives.

Sleep spindles and slow waves are the main brain oscillations occurring in non-REM sleep. Several lines of evidence suggest that spindles are initiated within the thalamus, whereas slow waves are generated and modulated in the cortex. A decrease in sleep spindle activity has been described in Schizophrenia (SCZ), including chronic, early course, and early onset patients. In contrast, slow waves have been inconsistently found to be reduced in SCZ, possibly due to confounds like duration of illness and antipsychotic medication exposure. Nontheless, the implication of sleep spindles and slow waves in the neurobiology of SCZ and related disorders, including their heritability, remains largely unknown. Unaffected first-degree relatives (FDRs) share a similar genetic background and several neurophysiological and cognitive deficits with SCZ patients, and allow testing whether some of these measures are candidate endophenotypes. In this study, we performed sleep high-density EEG recordings to characterise the spatiotemporal features of sleep spindles and slow waves in FDRs of SCZ probands and healthy subjects (HS) with no family history of SCZ. We found a significant reduction of integrated spindle activity (ISAs) in FDRs relative to HS, whereas spindle density and spindle duration were not different between groups. FDRs also had decreased slow wave amplitude and slopes. Altogether, our results suggest that ISAs deficits might represent a candidate endophenotype for SCZ. Furthermore, given the slow wave deficits observed in FDRs, we propose that disrupted cortical synchronisation increases the risk for SCZ, but thalamic dysfunction is necessary for the disorder to fully develop.

Dream content and intrusive thoughts in Obsessive-Compulsive Disorder.

Although central to any exhaustive theory of human subjectivity, the relationship between dream and waking consciousness remains uncertain. Some findings suggest that dream consciousness can be influenced by severe disorders of thought content. The suppression of unwanted thoughts has been shown to influence dream content in healthy individuals. In order to better define this phenomenon, we evaluated the persistence of obsessive/compulsive themes across the dream and waking cognition of OCD patients and in a control group of healthy subjects. Participants were administered a shortened version of the Thematic Apperception Test to produce a waking fantasy narration, and were trained to keep a dream diary. Dream and waking narrative contents were analyzed in order to recognize obsessive/compulsive themes, and to calculate Mean Dream Obsession/Compulsion (MDO, MDC) and Mean TAT Obsession/Compulsion (MTO, MTC) parameters. No differences were found between the two populations in terms of MDO, MDC, MTO, nor MTC. Density of obsessive and compulsive themes were significantly higher in dream reports than in waking narratives for both groups. No correlation was observed between MDO/MDC scores and Y-BOCS obsession/compulsion scores in the OCD group. These findings strengthen the discontinuity hypothesis, suggesting that ruminative aspects of cognition are somehow interrupted during dream activity.

Asenapine in the Treatment of Acute Mania: A Real-World Observational Study With 6 Months Follow-Up.

Asenapine is a second-generation antipsychotic with a unique pharmacological profile that was recently approved for the treatment of moderate/severe manic episodes. Real-world data on rapidity of action in inpatient settings are lacking.The aims of the current real-world observational study were to evaluate: (i) short-term efficacy of asenapine after 7 days (T0-T1) in patients hospitalized for a manic episode in the course of bipolar I disorder or schizoaffective disorder (group A), (ii) differences in length of stay (LoS), and (iii) rehospitalization compared to a control population (group B) with a 6-month follow-up.Twenty patients were included in each group. The mean total Young Mania Rating Scale score decreased by 12.6 (SD ±10.3; t(17) = 5.2, P < 0.005), implying a mean 37.8% improvement. A statistically significant reduction was observed for all Young Mania Rating Scale items, except for "sexual interest." The mean total BPRS score decreased by 17.2 (SD ±14.9; t(17) = 4.9, P < 0.005). A statistically significant reduction was observed for several items, including "conceptual disorganization," "grandiosity," "unusual thought content," and "excitement". Length of stay was 17.9 (SD ±9.0) days for group A and 14.7 (SD ±12.7) days for group B; the result of the Kruskal-Wallis test showed no significant differences (χ = 2.199, P = 0.138). Despite a high discontinuation rate, only 17.7% of patients in group A were rehospitalized in the following 6 months compared to 41.2% of those in group B (relative risk = 0.43, 95% confidence interval, 0.13-1.39).Findings from this small, preliminary study at least partially support the results of previous trials, confirming effectiveness and tolerability in the context of comorbidity and polypsychopharmacology.

Post-bereavement hallucinatory experiences: A critical overview of population and clinical studies.

BACKGROUND: Removal of the "bereavement exclusion" criterion for major depression and proposed research criteria for persistent complex bereavement disorder in DSM-V pose new compelling issues regarding the adequacy of current nosographical boundaries. Post-bereavement hallucinatory experiences (PBHE) are abnormal sensory experiences that are frequently reported by bereaved individuals without a history of mental disorder. Given current uncertainty over the continuum of psychotic experiences in the general population, whether or not they should be considered pathological remains unclear. METHODS: In order to systemize available knowledge, we reviewed the literature describing general population and clinical studies on PBHEs. Given the relatively low number of articles, all peer-reviewed, published studies in English were included. No study characteristics or publication date restrictions were imposed. RESULTS: Overall, evidence suggests a strikingly high prevalence of PBHEs - ranging from 30% to 60% - among widowed subjects, giving consistence and legitimacy to these phenomena. LIMITATIONS: Whereas general population studies had adequate sample size numbers, all studies in the bereaved population had a very small number of subjects. No consensus for method of evaluation exists in the literature, with some studies using a free interview method and others using semi-structured interviews. CONCLUSIONS: The available literature appears to support an elevated frequency of PBHEs in bereaved individuals, but further research is needed to increase the reliability of these findings and refine the boundaries between physiological and pathological experiences.

Right hemisphere neural activations in the recall of waking fantasies and of dreams.

The story-like organization of dreams is characterized by a pervasive bizarreness of events and actions that resembles psychotic thought, and largely exceeds that observed in normal waking fantasies. Little is known about the neural correlates of the confabulatory narrative construction of dreams. In this study, dreams, fantasies elicited by ambiguous pictorial stimuli, and non-imaginative first- and third-person narratives from healthy participants were recorded, and were then studied for brain blood oxygen level-dependent functional magnetic resonance imaging on a 3.0-Tesla scanner while listening to their own narrative reports and attempting a retrieval of the corresponding experience. In respect to non-bizarre reports of daytime activities, the script-driven recall of dreams and fantasies differentially activated a right hemisphere network including areas in the inferior frontal gyrus, and superior and middle temporal gyrus. Neural responses were significantly greater for fantasies than for dreams in all regions, and inversely proportional to the degree of bizarreness observed in narrative reports. The inferior frontal gyrus, superior and middle temporal gyrus have been implicated in the semantic activation, integration and selection needed to build a coherent story representation and to resolve semantic ambiguities; in deductive and inferential reasoning; in self- and other-perspective taking, theory of mind, moral and autobiographical reasoning. Their degree of activation could parallel the level of logical robustness or inconsistency experienced when integrating information and mental representations in the process of building fantasy and dream narratives.

Stability of cognition across wakefulness and dreams in psychotic major depression.

Cognitive bizarreness has been shown to be equally elevated in the dream and waking mentation of acutely symptomatic inpatients diagnosed with affective and non-affective psychoses. Although some studies have reported on dream content in non-psychotic depression, no study has previously measured this formal aspect of cognition in patients hospitalized for Psychotic Major Depression (PMD). Sixty-five dreams and 154 waking fantasy reports were collected from 11 PMD inpatients and 11 age- and sex-matched healthy controls. All narrative reports were scored by judges blind to diagnosis in terms of formal aspects of cognition (Bizarreness). Dream content was also scored (Hall/Van de Castle scoring system). Unlike controls, PMD patients had similar levels of cognitive bizarreness in their dream and waking mentation. Dreams of PMD patients also differed from those of controls in terms of content variables. In particular, Happiness, Apprehension and Dynamism were found to differ between the two groups. Whereas dream content reflects a sharp discontinuity with the depressive state, cognitive bizarreness adequately measures the stability of cognition across dreams and wakefulness in PMD inpatients.

Are delusional contents replayed during dreams?

The relationship between dream content and waking life experiences remains difficult to decipher. However, some neurobiological findings suggest that dreaming can, at least in part, be considered epiphenomenal to ongoing memory consolidation processes in sleep. Both abnormalities in sleep architecture and impairment in memory consolidation mechanisms are thought to be involved in the development of psychosis. The objective of this study was to assess the continuity between delusional contents and dreams in acutely psychotic patients. Ten patients with a single fixed and recurring delusional content were asked to report their dreams during an acute psychotic break. Sixteen judges with four different levels of acquaintance to the specific content of the patients' delusions were asked to group the dreams, expecting that fragments of the delusional thought would guide the task. A mathematical index (f,t) was developed in order to compare correct groupings between the four groups of judges. Most judges grouped the dreams slightly above chance level and no relevant differences could be found between the four groups [F(3,12)=1.297; p=n.s.]. Scoring of dreams for specific delusional themes suggested a continuity in terms of dream and waking mentation for two contents (Grandiosity and Religion). These findings seem to suggest that at least some delusional contents recur within patients' dreams. Future studies will need to determine whether such continuity reflects ongoing consolidation processes that are relevant to current theories of delusion formation and stabilization.

Challenging the myth of REM sleep behavior disorder: no evidence of heightened aggressiveness in dreams.

OBJECTIVES: Dreams are commonly described as violent, threatening, and aggressive in patients with REM behavior disorder (RBD), but very few studies have directly investigated dream content in this population. We systematically assessed dreams in subjects with a confirmed diagnosis of idiopathic RBD (iRBD) and explored psychological traits within the group with specific focus on aggressiveness. METHODS: A total of 129 dream reports was collected, of which 77 belonged to 12 iRBD patients and 52 belonged to 12 control subjects. Transcripts were analyzed with measures of both form and content. The Thematic Apperception Test was used to assess patients' personality traits and to yield information on formal aspects of waking thought processes. RESULTS: No statistically significant differences were found between the dreams of iRBD patients and those of normal controls in any of the applied measures. In wakefulness, passivity was found to differ between the two populations and was being higher in the iRBD group (F(9,14)=4.84, p<0.05). CONCLUSIONS: Our results do not support the anecdotal view that dreams of RBD patients contain more aggressive elements than those of the general population. However, over 80% of the patients were on treatment at the time of data collection. The "mild" waking temperament could be interpreted as an early subtle sign of the apathy that is commonly described in the context of neurodegenerative disorders.