Alcohol Use Disorder (AUD) is one of the most significant public health problems in Europe, being highly associated with several medical and psychiatric comorbidities. Sleep disturbances are in this interface and may include insomnia, alterations of sleep architecture and circadian rhythm abnormalities, breathing-related sleep disorders, and sleep-related movement disorders. Also, considering the three stages of the addiction cycle (binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation) and since these domains are reflected in key regions of the brain, it is possible to map these nearly ubiquitous sleep disturbances.

This review aims to summarize the current literature related to the association between sleep disorders and AUD, with a focus on its clinical aspects and neurobiology.

Non-systematic research was made recurring to the PubMed database, with the keywords “alcohol use disorder”, “sleep”, “sleep disorder”. The most relevant articles were selected, focusing on articles published in the last decade.

In patients with AUD, the prevalence of insomnia ranges from 36-91%. A possible mechanism underlies in a mismatch involving maintained activity in wake-promoting structures during non-rapid eye movement sleep (NREM) and a blunted homeostatic drive. On the other hand, alcohol consumption also affects the normal sleep-wake cycle, due to a disruption in the underlying circadian rhythms, a mechanism compassed by the suprachiasmatic nucleus and by photic and non-photic cues. Considering this, it seems highly likely that insomnia and circadian abnormalities may coexist in some individuals. Moreover, AUD is implicated in initiation or worsening of breathing-related events in sleep, especially when having a history of snoring or sleep apnoea syndrome and in period limb movement disorder.

Simultaneously, sleep disorders in AUD can be incorporated into the three-stage addiction cycle. In the binge/intoxication stage, excessive alcohol intake leads to a faster sleep onset but poor sleep quality, explained by the effects on GABAergic systems. During the withdrawal/negative affect stage, there is a decrease in slow-wave sleep and limited rapid eye movement (REM) sleep recovery, which can be explained by the alcohol-positive allosteric modulation of GABAA receptor and other mechanisms. Lastly, during the preoccupation/anticipation stage, the glutamatergic system dysregulation contributes to persistent sleep disturbances, including insomnia, decrease in slow-wave sleep, and an increase in REM sleep.

The knowledge of sleep disturbances associated with AUD has grown and has suggested a bidirectional process that appears to play an essential role in the addiction process. Further studies investigating this association are warranted.

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Psychiatry has been diagnosing its pathologies through the evaluation of the symptoms reported by patients, relying on a few complementary exams to exclude organic causes. Studies about transcranial magnetic stimulation and electroencephalography (TMS-EEG) are bringing, from a clinical point of view, crucial information to characterize the different pathophysiological biomarkers of the psychiatric diseases, leading not only to the evolution of diagnosis, but also to an improved, more individualized treatment.

Characterizing the state of the art of TMS-EEG and its use in psychiatric diagnosis and treatments of different diseases.

We undertook a narrative literature review by performing a search on PubMed for English-written articles from the last 10 years. The query used was “TMS-EEG”; “TMS-EEG” AND “Schizophrenia” OR “Major Depressive Disorder” OR “Bipolar Disorder”.

Transcranial magnetic stimulation (TMS) is a safe and reliable method of non-invasive brain stimulation that allows for the local activation of cortical areas through electromagnetic induction. When combining this method with electroencephalography (EEG), it enables the underlying mechanisms of brain diseases.

TMS is a powerful therapeutic technic in Major Depressive Disorder (MDD). The literature refers to an enhanced N45 and N100 amplitude, which indicates a baseline cortical inhibition that can indicate a depressed state, which can be used as a clinical biomarker to evaluate TMS treatments.

In Schizophrenia (SCZ), TMS-EEG reveals a decreased cortical inhibition and excitation. Indices of inhibition and excitation reductions were also related to cognitive deficits.

The current studies regarding Bipolar Disorder (BD) are not so consistent, revealing that there are shared neural pathways with MDD and SCZ. This is a pathology often misdiagnosed with MDD, so biomarkers would help to diagnose BD earlier and improve its prognostic.

TMS-EEG can be used to provide more accurate neural targets, leading to more powerful and personalized interventions in psychiatric disorders, as well as more accurate diagnoses.

As for future studies, it would be relevant to assess not only TMS treatment effects, but also pharmacological results in these different pathologies.

None Declared

The Interpersonal Needs Questionnaire (INQ-15) and the Acquired Capability for Suicide Scale - Fearlessness About Death (ACSS-FAD) have been introduced to evaluate the theoretical constructs posit by Joiner’s Interpersonal Psychological Theory of Suicide (IPTS).

The present study aimed to evaluate the psychometric properties of the INQ-15 (which measures Thwarted Belongingness, TB, and Perceived Burdensomeness, PB) and the ACSS-FAD (measurement of Fearlessness About Death, FAD, dimension of the acquired capability) in a population of Italian university students.

Since there was no Italian version of the ACSS-FAD, we have translated it through an accurate multistage procedure. ACSS-FAD and INQ-15 have been administered to a sample of 1,665 Italian university students. We analyzed the factorial structure of the INQ-15 and the ACSS-FAD, their reliability, criterion, convergent and discriminant validity.

Principal Component Analysis confirmed a two-dimensional structure for INQ-15 and a one-factor structure for ACSS-FAD. Internal consistency reliability of the scales was good, respectively TB: α = .85; PB: α = .90; and FAD: α = .85. The INQ-15 demonstrated concurrent associations with suicidal ideation, while the ACSS-FAD with a history of suicidal planning/suicide attempt. Convergent and discriminant validity were also in line with previous studies.

Both INQ-15 and ACSS-FAD appropriately capture the respective constructs, proving to be valid measures for the assessment of suicide risk factors among Italian university students according to the IPTS. The valuable psychometric properties of the two scales established with this study in the Italian context encourages their use to advance the clinical understanding and prevention of suicide.

No significant relationships.

Since 2003 the national research program for solid organ transplantation in HIV patients is active at the Liver Transplantation Centre of Modena. HIV patients who enter this protocol are assessed by the CLP Service. The aim of the present study is to evaluate their psychiatric comorbidity.

An observational prospective study was conduced comparing ESLD patients with and without HIV. After the assessment, the psychiatrist compiled the TERS and the MADRS. Baseline (B) evaluation was made before the inclusion in the OLTx waiting list and the Follow-Up (FU) one was made 12 months later.

From January 2003 to December 2006 we assessed 553 patients: 39 (6%) with HIV and 361 (94%) without HIV. The two groups were homogeneous for gender (75% of male patients; p = ns) but not for age (46 ± 5 vs 56 ± 9; p = ns). Psychiatric anamnesis was negative in 176 (49%) patients without HIV and in 6 (15%) patients with HIV, p<0.001.

At baseline psychiatric comorbidity was present in 33 HIV patients (85%) and in 148 non HIV patients (41%), p<0.001.

At the follow-up MADRS highlights an improvement at all the items for HIV patients. In the non-HIV group score variation was: B = 7.10, FU = 8.15; in the HIV group: B = 10.20, FU = 4.09 (p<0.001).

The average score at TERS was higher in patients with HIV (43 ± 9 vs 35 ± 9, p = ns).

At B HIV patients with ESLD show a greater frailty to psychopathology but they quite improved during FU. The contrary happen in non-HIV group.

Clinical studies on cognitive effects of second generation antipsychotics produced disappointing findings probably due to the heterogeneity of the clinical populations under investigation, as well as to poor sensitivity of neurocognitive indices. Event-Related Potentials (ERPs) provide a functional measure of electrical brain activity time-locked to discrete stages of information processing. They have been widely used as putative biological markers of cognitive abnormalities in schizophrenia and represent useful indices in the investigation of the cognitive effects of psychotropic drugs.

The present study investigated the effect of risperidone, haloperidol and placebo on N1 and P3 in male healthy subjects.

ERPs were recorded during a three-tone oddball task in which target, standard and rare-nontarget tones were randomly presented. Subjects had to press a button when hearing a target tone. Amplitude and topography of the ERP component maps at peak latencies were compared across conditions. If a significant drug effect was obtained, changes in the cortical sources of the corresponding ERP component were analyzed using Low-Resolution Electromagnetic Tomography (LORETA).

The amplitude of N1 for attended stimuli and of P3 for rare-nontargets (P3a) was significantly increased only by risperidone. No significant change was observed in overall topographic features and in LORETA cortical sources of the same components. No significant drug effect was demonstrated for the latency of all the investigated components and for P3b amplitude.

Our findings suggest that risperidone has a favorable effect on early attention processes and automatic attention allocation.

To evaluate long-term treatment with ziprasidone versus haloperidol (up to 196 weeks), as assessed by PANSS negative score and and its association with quality-of-life (QLS).

The study included two treatment periods: (i) a 40-week, randomized, double-blind phase comparing ziprasidone (ZIP 80-160 mg/d given BID, N=227; ZIP 80-120 mg/d given QD, N=221) versus haloperidol (HAL 5-20 mg/d, N=151), followed by (ii) a 3-year, double-blind extension phase on the same double-blind medications (ZIP BID N=72, ZIP QD N=67, and HAL N=47, respectively). We adapted the Andreasen et al. approach to define negative symptom remission based on attainment of a score ≤3 (mild or less) for at least 6 months on all 7 PANSS negative symptom items. MMRM and GEE models were applied to analyze mean changes in PANSS negative, negative symptom remission rate, and QLS scores over time.

In the 40-week core study, ziprasidone was associated with greater improvement in efficacy and QLS outcomes than haloperidol, but the differences were not statistically significant (p>0.05). However, MMRM analysis of PANSS negative and QLS scores over 196 weeks demonstrated differential treatment effects favoring ziprasidone (80-160 mg/d BID vs. haloperidol) (all p<0.05). Ziprasidone-treated subjects (given BID) were significantly more likely to achieve negative symptom remission (46%) than haloperidol-treated (32%) subjects (p<0.05) during the continuation phase; while ziprasidone given QD (46%) showed a trend to enhanced remission (p<0.08).

These findings support the potential for enhanced social and functional outcomes during long-term treatment with an atypical antipsychotic agent.

Recent research indicates intramuscular ziprasidone produces a significant, early (within 24 hours) improvement in psychotic symptoms. In this analysis, we evaluated the potential for an early antipsychotic response to oral ziprasidone in subjects with acute bipolar mania.

We conducted a pooled analysis of two 3-week, randomized, double-blind, placebo-controlled trials of ziprasidone (40-160 mg/d) in hospitalized patients (N=415) with bipolar I disorder, and a current manic (N=257) or mixed episode (N=158), with (N=151) or without (N=245) psychotic features. Efficacy assessments included the Mania Rating Scale (MRS, derived from the SADS-C). Remission was defined as achieving a MRS score <= 12. Improvement in psychosis was evaluated by a sum of the three SADS-C psychosis items (delusions, hallucinations, and suspiciousness). MMRM and logistic regression analyses were applied to estimate the time course of response.

Significantly greater response rate (>50% decrease from baseline) and improvement in the SADS-C psychosis score were observed in the ziprasidone group (versus placebo) as early as Day 4 (p<0.01), and the magnitude of improvement increased with time (p<0.003). At Day 21, remission rate with ziprasidone monotherapy was 49% versus 36% in the placebo group (p=0.02). Early antipsychotic response at Day 4 was an accurate predictor of remission at Day 21 (p<0.01, ROC=0.76).

Ziprasidone was associated with a rapid onset of response in psychotic symptoms in patients with acute bipolar mania. This early reduction in psychotic symptoms was found to mediate overall improvement in manic symptoms and predict remission at endpoint.

Several factor analytic studies have shown than anhedonia and avolition are included in the same factor, suggesting that motivational deficits in schizophrenia are related to a reduced experience of pleasure; however other studies have not confirmed this hypothesis. More recently, it has been hypothesized that avolition is related to a difficulty in anticipating reward value and\or regulating behavior on the basis of the associations between value and action.

This study is aimed to verify an impairment of reward anticipation in patients with deficit schizophrenia (DS), but not in those with non-deficit schizophrenia (NDS) and its association with primary negative symptoms, using event-related potentials (ERPs).

ERPs were recorded in 11 patients with DS, 23 patients with NDS and 23 healthy controls (HC), during anticipation of five different outcomes, small (SR) or large (LR) reward, small (SP) or large (LP) punishment or no-outcome (NO), and during feedback processing.

Patients did not differ from HC on indices of anticipatory or consummatory anhedonia, but they showed reduced motivation. During reward anticipation, only patients with primary and persistent avolition showed ERPs abnormalities, with respect to HC, in the early processing stages and a reduced activity of cortical generators in the cingulate, in the temporal-occipital and fronto-parietal regions, that are involved in the attention modulation and visual perceptual processing.

Our data suggest that anhedonia and avolition are partially independent constructs and that avolition is related to the inability to modulate attention and amplify visual perceptual processing of reward stimuli.

Previous studies have reported that patient with schizophrenia have preserved hedonic capacity, but impaired ability to anticipate future reward (anticipatory anhedonia) that, according to some authors, may underlie other aspects of negative symptoms, such as avolition.

The aim of our study was to demonstrate an impairment of reward anticipation in patients with deficit schizophrenia (DS), characterized by primary and persistent negative symptoms, but not in those with non-deficit schizophrenia (NDS) with respect to healthy controls (HC), by means of functional magnetic resonance imaging (fMRI).

fMRI was recorded during the execution of the ’Monetary Incentive Delay’ task in 11 patients with DS, 23 patients with NDS and 23 HC, during the anticipation of five different outcomes, small (SR) or large (LR) reward, small (SP) or large (LP) punishment or no-outcome (NO).

The ventral striatum response to reward anticipation was preserved in subjects with schizophrenia. Only patients with DS, compared with HC, showed a significant reduction in the left caudate during the anticipation of reward. The reduced activity of the caudate correlated with the scores for avolition but not for anhedonia.

Our preliminary data suggest an involvement of the caudate in the abnormal processing of reward stimuli in patients with DS and show that avolition and anhedonia are subtended by different functional abnormalities.

The Mismatch Negativity (MMN) is an event-related potential (ERP) sensitive to early auditory deviance detection and has been shown to be reduced in patients with schizophrenia. Moreover, MMN amplitude reduction to duration deviant tones was found to be related to functional outcomes particularly, to social cognition and real-life functioning.

In the context of a multicentre study of the Italian Network for Research on Psychoses, our study focused on the investigation of early auditory discrimination components in relation to functioning in real-life in patients with schizophrenia.

ERPs were recorded in 64 chronic, stabilized patients with schizophrenia during the presentation of standard, duration deviants and frequency deviants tones while watching a cartoon. The Specific Level of Functioning (SLOF) scale was used to measure real-life functioning. Psychopathology, neurocognition and social cognition were measured by state of art instruments. Regression analyses were carried out using SLOF domains as dependent variables and MMN, psychopathology, neurocognition, extrapyramidal symptoms and social cognition as independent predictors.

Latency of MMN entered the regression equation only for the SLOF domain of common activities explaining less variance than social cognition and positive symptoms.

In stabilized patients with schizophrenia pre-attentive deficits, as indexed by MMN and P3a amplitude reduction, do not show any association with psychopathology or functioning. Latency of MMN was an independent predictor of some aspects of functioning with a smaller effect than social cognition and psychopathology domains.

Patients with schizophrenia often show a reduced ability to experience pleasure, but previous studies demonstrated that they are more characterized by “anticipatory anhedonia”, rather than a deficit in experiencing pleasure itself (“consummatory anhedonia”). However, the brain circuits related to anticipation of pleasure and processing of reward signals in schizophrenia are yet unclear.

We aimed to examine reward anticipation and feedback processing using event-related potentials (ERPs) in 24 stabilized patients with schizophrenia and 14 healthy controls.

ERPs were recorded during a Monetary Incentive Delay task during anticipation of five different outcomes, small (SR) or large (LR) reward, small (SP) or large (LP) punishment or no-outcome (NO), and during feedback processing.

Patients had lower scores on TEPS anticipatory pleasure and BIS/BAS fun-seeking scales and higher scores for anhedonia and punishment sensitivity, than controls. The anticipation-related negativity was reduced in patients. Controls, but not patients, showed a larger amplitude for LP versus NO and LR. Fronto-central amplitude in patients was inversely correlated with TEPS anticipatory pleasure. The feedback-related negativity had a lower amplitude for LR than for all other conditions in controls, but not in patients. Only in controls, FRN was inversely correlated with TEPS consummatory pleasure.

The frontal negativity during outcome anticipation discriminate punishment from other outcomes only in controls. The lower the amplitude of this component, the greater the deficit in anticipatory pleasure. As to FRN, only controls modulate the frontal negativity during processing of outcome and this modulation is associated with consummatory pleasure.