Probability Turns Material: The Boltzmann Equation.

We review, under a modern light, the conditions that render the Boltzmann equation applicable. These are conditions that permit probability to behave like mass, thereby possessing clear and concrete content, whereas generally, this is not the case. Because science and technology are increasingly interested in small systems that violate the conditions of the Boltzmann equation, probability appears to be the only mathematical tool suitable for treating them. Therefore, Boltzmann's teachings remain relevant, and the present analysis provides a critical perspective useful for accurately interpreting the results of current applications of statistical mechanics.

Falls at the interface between geriatric and psychiatric patients: a critical review from a psychopharmacological perspective.

Falls in the elderly represent one of the major clinical problems as they are serious events that often result in high residual disability and mortality rates. Knowledge on the subject derives mainly from geriatric and gerontopsychiatric research. However, gerontopsychiatric patients differ from geriatric patients not only for the psychiatric and neurological comorbidities, which are often not sufficiently taken into account in the scientific context, but also for the intake of psychotropic drugs, notoriously described as one of the main risk factors for falls. Such drugs are widely prescribed in this group of patients, often even off-label. Clinicians therefore should pay particular attention to falls, since various comorbidities and polypharmacy as a prescribing issue can have important consequences for clinical management. Falls have not been sufficiently investigated yet in a purely psychiatric context.

Wider and Stronger Inhibitory Ring of the Attentional Focus in Schizophrenia.

Anomalies of attentional selection have been repeatedly described in individuals with schizophrenia spectrum disorders. However, a precise analysis of their ability to inhibit irrelevant visual information during attentional selection is not documented. Recent behavioral as well as neurophysiological and computational evidence showed that attentional search among different competing stimuli elicits an area of suppression in the immediate surrounding of the attentional focus. In the present study, the strength and spatial extension of this surround suppression were tested in individuals with schizophrenia and neurotypical controls. Participants were asked to report the orientation of a visual "pop-out" target, which appeared in different positions within a peripheral array of non-target stimuli. In half of the trials, after the target appeared, a probe circle circumscribed a non-target stimulus at various target-to-probe distances; in this case, participants were asked to report the probe orientation instead. Results suggest that, as compared to neurotypical controls, individuals with schizophrenia showed stronger and spatially more extended filtering of visual information in the areas surrounding their attentional focus. This increased filtering of visual information outside the focus of attention might potentially hamper their ability to integrate different elements into coherent percepts and influence higher order behavioral, affective, and cognitive domains.

Systematic review and meta-analysis on the therapeutic reference range for escitalopram: Blood concentrations, clinical effects and serotonin transporter occupancy.

Introduction: A titration within a certain therapeutic reference range presupposes a relationship between the blood concentration and the therapeutic effect of a drug. However, this has not been systematically investigated for escitalopram. Furthermore, the recommended reference range disagrees with mean steady state concentrations (11-21 ng/ml) that are expected under the approved dose range (10-20 mg/day). This work systematically investigated the relationships between escitalopram dose, blood levels, clinical effects, and serotonin transporter occupancy. Methods: Following our previously published methodology, relevant articles were systematically searched and reviewed for escitalopram. Results: Of 1,032 articles screened, a total of 30 studies met the eligibility criteria. The included studies investigated escitalopram blood levels in relationship to clinical effects (9 studies) or moderating factors on escitalopram metabolism (12 studies) or serotonin transporter occupancy (9 studies). Overall, the evidence for an escitalopram concentration/effect relationship is low (level C). Conclusion: Based on our findings, we propose a target range of 20-40 ng/ml for antidepressant efficacy of escitalopram. In maintenance treatment, therapeutic response is expected, when titrating patients above the lower limit. The lower concentration threshold is strongly supported by findings from neuroimaging studies. The upper limit for escitalopram's reference range rather reflects a therapeutic maximum than a tolerability threshold, since the incidence of side effects in general is low. Concentrations above 40 ng/ml should not necessarily result in dose reductions in case of good clinical efficacy and tolerability. Dose-related escitalopram concentrations in different trials were more than twice the expected concentrations from guideline reports. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=215873], identifier [CRD42020215873].

Sense of body ownership and body agency in schizophrenia.

Recent research suggests that embodiment sensations (sense of body ownership and sense of body agency) are altered in schizophrenia. Using a mirror box illusion setup, we tested if the anomalous embodiment experience depends on deficient processing of visuomotor synchrony, disrupted processing of movement mode, or both. The task required participants to press a lever with their index while looking at the image of the experimenter's hand moving on a similar lever. The illusion of embodiment could arise because looking toward the direction of their own hand the participant saw the reflection of the experimenter's hand visually superimposed to his own one through a mirror. During the illusion induction, we systematically varied visuomotor asynchrony (4 delays were imposed on the movement of the experimenter's hand) and the mode of movement (the participant could perform active vs. passive movements). The strength of the illusion of embodiment of the external hand was assessed with explicit judgments of ownership and agency. Patients' data showed an anomalous modulation of ownership with respect to visuomotor synchrony manipulation and an altered modulation of agency with respect to both visuomotor synchrony and movement mode manipulations. Results from the present study suggest that impairments affecting both the processing of temporal aspects of visuomotor signals and the processing of type of movement underlie anomalous embodiment sensations in schizophrenia. Hypotheses about potential deficits accounting for our results are proposed.

Therapeutic Reference Range for Aripiprazole in Schizophrenia Revised: a Systematic Review and Metaanalysis.

RATIONALE: While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges. OBJECTIVES: Here, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders. METHODS: The relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed (N = 3,373) and pharmacokinetic influences investigated. RESULTS: Fifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120-270 ng/ml and 180-380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders. CONCLUSIONS: High interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers.

Therapeutic Drug Monitoring of Antidepressants: An Underused but Potentially Valuable Tool in Primary Care.

Depressive disorders are among the most burdensome diseases globally in terms of prevalence, as well as in terms of quality of life, morbidity, and mortality. Hence, it is becoming increasingly common for primary care physicians to administer and monitor the treatment of individuals affected by depressive disorders. In this framework, Therapeutic Drug Monitoring (TDM) comes to the forefront. TDM is the measurement of specific drugs in the blood or plasma/serum, and its usefulness lies in the fact that it allows physicians to assess drug levels to personalize and optimize treatments. TDM has been used for decades to measure several classes of psychotropic drugs, such as antiepileptics and antipsychotics, but the use of this tool is still in its infancy in regard to antidepressants. In the context of primary care, TDM of antidepressant drug treatment shows promise, as it can enable primary care physicians to monitor the safety and efficacy of the treatment, leaving to secondary care, i.e., psychiatrists, the management of the more complex clinical cases.

Venlafaxine and O-desmethylvenlafaxine serum levels are positively associated with antidepressant response in elder depressed out-patients.

BACKGROUND: Therapeutic Drug Monitoring (TDM) represents one of the most promising tools in clinical practice to optimise antidepressant treatment. Nevertheless, little is still known regarding the relationship between clinical efficacy and serum concentration of venlafaxine (VEN). The aim of our study was to investigate the association between serum concentration of venlafaxine + O-desmethylvenlafaxine (SCVO) and antidepressant response (AR). METHODS: 52 depressed outpatients treated with VEN were recruited and followed in a naturalistic setting for three months. Hamilton Depression Rating Scale-21 was administered at baseline, at month 1 and at month 3 to assess AR. SCVO was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCVO and AR. RESULTS: Our results showed an association between AR and SCVO that follows a bell-shaped quadratic function with a progressive increase of AR within the therapeutic reference range of SCVO (i.e. 100-400 ng/mL) and a subsequent decrease of AR at higher serum levels. DISCUSSION: This study strongly suggests that TDM could represent a more appropriate tool than the oral dosage to optimise the treatment with VEN. Specifically, highest efficacy might be achieved by titrating patients at SCVO levels around 400 ng/mL.

Antidepressant efficacy is correlated with plasma levels: mega-analysis and further evidence.

The debate around optimal target dose for first-line antidepressants (ADs) is still ongoing. Along this line, therapeutic drug monitoring (TDM) represents one of the most promising tools to improve clinical outcome. Nevertheless, a few data exist regarding the concentration-effect relationship of first-line ADs which limits TDM implementation in routine clinical practice. We conducted the first patient-level concentration-response mega-analysis including data acquired by us previously and explored the concentration dependency of first-line AD (206 subjects). Further, new data on mirtazapine are reported (18 subjects). Hamilton Depression Rating Scale-21 administered at baseline, at month 1 and month 3 was used as the measure of efficacy to assess antidepressant response (AR). When pooling all four first-line ADs together, normalized plasma levels and AR significantly fit a bell-shaped quadratic function with a progressive increase of AR up to around the upper normalized limit of the therapeutic reference range with a decrease of AR at higher serum levels. Our results complement the available evidence on the issue and the recent insights gained from dose-response studies. A concentration-dependent clinical efficacy, such as previously demonstrated for tricyclic compounds, also emerge for first-line ADs. Our study supports a role for TDM as a tool to optimize AD treatment to obtain maximum benefit.

Adult ADHD: a study on evaluation and treatment pathways in Italian Mental Health Services.

Attention Deficit and Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that often persists into adulthood. The Italian situation regarding the clinical management of childhood ADHD shows some criticalities, despite the high prevalence rate: diagnostic assessments are often inaccurate, protocols for transition from childcare services are almost non-existent and the Italian National Registry for ADHD in childhood was drawn up only in 2007, hence the first specialized services were created later than the rest of Europe. On the basis of these issues, we investigated the Italian situation with regard to disorders in adulthood, comparing the different European operational models, assuming that these critical issues are reflected in the clinical management of the disorder in adulthood. In fact, unlike other European countries, there are no official guidelines governing the clinical management of the disorder in adulthood and evidence-based pharmacotherapies, available in most European countries, are off-label or not allowed in Italy. The aim of the study is to evaluate the current state of knowledge and working method in relation to adult ADHD in the Italian background and to identify the main evaluation and treatment pathways in Italian Mental Health Services. The study is also an attempt to clarify which services are operational on the Italian territory, with the aim of improving the quality of interventions for the clinical population. Three hundred thirty-eight services have been identified in all Italian Regions and Autonomous Provinces, including Mental Health Centres (CSM), Pathological Addition Services (SERD), Psychiatric Diagnosis and Treatment Services (SPDC). An ad-hoc survey with closed-ended questions was administered by telephone to each selected centre and the results were compared with the European literature.

Survey on centres and procedures for the diagnosis and treatment of adult ADHD in public services in Italy.

Attention deficit/hyperactivity disorder (ADHD) often persists into adulthood. Although its persistence and relative high prevalence, ADHD in adults is often underdiagnosed and undertreated in Italy, leading to poor clinical and functional outcomes, and higher costs of illness. The aims of the study were to identify the Italian mental health services for ADHD in adults, describe the diagnostic and treatment procedures they follow, and compare this offer with the recommendations of the German and English guidelines. The centres, that adopt a clinical and assessment protocol for adult ADHD diagnosis (carried out by specifically trained personnel) and prescribe pharmacological treatment for adult ADHD, were selected from the list of accredited services provided by the Appendix B.2 of the ISTISAN 16/37 Reports of the ISS. An ad-hoc survey including open-ended and close-ended questions was sent to each selected centre in February 2020. The overall picture resulting from the data analysis was compared with the recommendations of the German and English guidelines. The present survey shows that only a few centres are specialised in the diagnosis and treatment of ADHD in adults in Italy. Furthermore, there are no national guidelines for adult ADHD in Italy. The collected data also suggest that there is no a unified practice shared by the Centres both for the patient's transition from child and adolescent to adult mental health services and for the diagnostic-therapeutic process. It is therefore crucial to create specific protocols and develop national guidelines to better identify and diagnose ADHD in adults and provide targeted and more efficient multimodal treatments.

Defective Embodiment of Alien Hand Uncovers Altered Sensorimotor Integration in Schizophrenia.

The observation that people with schizophrenia misattribute the source of their own actions has led to the hypothesis that they suffer from altered sensorimotor processes underlying sense of agency. Furthermore, rubber hand studies suggest an abnormal experience of embodiment in schizophrenia. However, this latter finding is based on a procedure that elicits ownership sensations for a fake hand by visuo-tactile stimulation, leaving the agency subcomponent of embodiment relatively untouched. By using a visuo-motor version of the embodiment illusion able to actively elicit also sense of agency for an alien hand, we tested whether the putative sensorimotor deficits are also involved in altering embodiment sensations in schizophrenia. Subjective (questionnaire) and perceptual (forearm bisection performance) indexes of the embodiment illusion were collected. Differently from controls, both the explicit agency component and the implicit body metrics update were not modulated by the extent of visuo-motor congruency in participants with schizophrenia. We conclude that motor prediction and/or temporal binding window impairments may alter the feeling of embodiment and body representation in schizophrenia.

Duloxetine plasma level and antidepressant response.

BACKGROUND: Major Depressive Disorder (MDD) is associated with a high rate of inadequate treatment response, which is mainly due to the large inter-individual genetic variability in pharmacokinetic and pharmacodynamic targets of antidepressant drugs. Little is still known about the exact association between plasma level of first-line antidepressants and clinical response. This is particularly true for duloxetine, a dual serotonin and norepinephrine reuptake inhibitor recommended as first-line treatment for MDD. The aim of this study was to investigate the association between serum concentration of duloxetine (SCD) and antidepressant response (AR). METHODS: 66 MDD patients treated with duloxetine 60 mg/day monotherapy were recruited in an outpatient setting and followed for three months. Hamilton Depression Rating Scale - 21 (HAMD-21) was administrated at baseline, at month 1, and at month 3 to assess AR. SCD was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCD and AR. RESULTS: SCD showed a high inter-individual variability in our sample, despite the duloxetine fixed oral dosage. We found a strong association between SCD and AR following a bell-shaped function at month 1 and at month 3. Nonetheless, within the recommended SCD range of 30-120 ng/mL a more linear correlation between SCD and AR was observed. DISCUSSION: Our results suggest that for duloxetine the association between SCD and AR likely follows a bell-shaped quadratic function with poor AR at subtherapeutic SCD and progressive decrease of AR at higher SCD. The maximum antidepressant efficacy seems to require SCD values next to the highest recommended SCD (30-120 ng/mL), probably because of the optimal saturation of both serotonin and norepinephrine transporters. Thus, taking into account the observed high interindividual variability of SCD, our findings suggest that for MDD patients treated with duloxetine, SCD could be a useful tool to guide the treatment by optimizing the oral dosage in order to increase the AR rate.

Escitalopram plasma levels and antidepressant response.

Major Depression Disorder (MDD) has a highly variable treatment response due to the large inter-individual variation in the pharmacokinetics and pharmacodynamics of drug treatments. In detail the correlation between plasma level and efficacy has been much debated. Among first-line drugs for MDD, one of the most used is escitalopram. In the present study we investigated the association between serum concentration of escitalopram (SCE) and antidepressant response (AR). 70 MDD patients treated with escitalopram monotherapy were recruited and followed for three months. Hamilton Depression Rating Scale - 21 (HAMD-21) was administrated at baseline, month 1, and month 3 to assess AR. SCE was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCE and AR. We found an association between SCE and AR both at month 1 (p<0.001) and month 3 (p=0.0003), which persists also excluding 3 patients with SCE equal to 0. Interestingly, by excluding patients with SCE < 20ng/mL, i.e. with a SCE lower than the putative therapeutic threshold, these associations disappeared. The curvilinear function AR = a + (SCE-SCE2) explained a higher proportion of variance compared to the linear other models (p<0.001). Our results suggest that for escitalopram the association between SCE and AR likely follows a nearly-asymptotic function, with poor AR at sub-therapeutic SCE and stable AR response at therapeutic SCE. Thus, when a patient reaches the therapeutic SCE range, further increase of escitalopram dosage seems to be useless, although further studies are needed to confirm our findings.

Differential impairment of interhemispheric transmission in bipolar disease.

There is abundant evidence that the cerebral white matter and in particular the corpus callosum show several structural abnormalities in both schizophrenia (SCZ) and bipolar disease (BD). However, which cognitive functions are impaired as a result of these anomalies is still unclear. Previous behavioural tests of interhemispheric crosstalk have shown a differential impairment in SCZ with interhemispheric transmission time, as tested with the Poffenberger paradigm, essentially normal but with an abnormally enhanced interhemispheric summation effect, as tested with the redundant signal effect. The present study was inspired by this discrepancy and by the more general question of a possible overlap between the pathophysiology of SCZ and BD. We tested both SCZ and BD patients in the Poffenberger paradigm and redundant signal effect and found a similar dissociation, namely a normal interhemispheric transfer time and an abnormal redundant signal effect. The only difference between the two groups was a selective slowing of speed of response of the dominant right hand in the SCZ group suggesting an impairment of left hemisphere functions. These results cast further light on the question of common and differential impairments of basic psychological functions in the two diseases.

ErbB3 mRNA leukocyte levels as a biomarker for major depressive disorder.

BACKGROUND: In recent years, the identification of peripheral biomarkers that are associated with psychiatric diseases, such as Major Depressive Disorder (MDD), has become relevant because these biomarkers may improve the efficiency of the differential diagnosis process and indicate targets for new antidepressant drugs. Two recent candidate genes, ErbB3 and Fgfr1, are growth factors whose mRNA levels have been found to be altered in the leukocytes of patients that are affected by bipolar disorder in a depressive state. On this basis, the aim of the study was to determine if ErbB3 and Fgfr1 mRNA levels could be a biomarkers of MDD. METHODS: We measured by Real Time PCR ErbB3 and Fgfr1 mRNA expression levels in leukocytes of MDD patients compared with controls. Successively, to assess whether ErbB3 mRNA levels were influenced by previous antidepressant treatment we stratified our patients sample in two cohorts, comparing drug-naive versus drug-free patients. Moreover, we evaluated the levels of the transcript in MDD patients after 12 weeks of antidepressant treatment, and in prefrontal cortex of rats stressed and treated with an antidepressant drug of the same class. RESULTS: These results showed that ErbB3 but not Fgfr1 mRNA levels were reduced in leukocytes of MDD patients compared to healthy subjects. Furthermore, ErbB3 levels were not affected by antidepressant treatment in either human or animal models CONCLUSIONS: Our data suggest that ErbB3 might be considered as a biomarker for MDD and that its deficit may underlie the pathophysiology of the disease and is not a consequence of treatment. Moreover the study supports the usefulness of leukocytes as a peripheral system for identifying biomarkers in psychiatric diseases.

Enhanced redundancy gain in schizophrenics: a correlate of callosal dysfunction?

An abnormal pattern of hemispheric asymmetry, possibly as a result of disturbed interhemispheric communication, is widely, albeit by no means unanimously, held as a major cause of schizophrenia. To behaviourally test interhemispheric communication in schizophrenia we used a task that has been shown to be a reliable indicator of callosal functioning, namely, the redundant signals effect (RSE). It consists of the speeding of simple reaction time when responding to double as opposed to single visual stimuli. When the stimuli in a pair are presented to different hemispheres patients who underwent total commissurotomy or suffer from callosal agenesis show a paradoxically enhanced RSE with respect to healthy controls. Therefore, if schizophrenia patients have a callosal abnormality they ought to show a similar effect. In three experiments we tested a total of 55 patients with a diagnosis of schizophrenia and 51 healthy controls. In Experiment 1 we presented unilateral single stimuli and bilateral simultaneous double stimuli. The RSE was reliably larger in schizophrenics than in controls. In Experiment 2 the temporal interval between the two stimuli in a pair was varied. We found that while in controls the RSE disappeared with interstimulus intervals longer than 17ms, in schizophrenia patients there was a RSE only for simultaneous double stimuli. Finally, in Experiment 3 we found that there was no enhanced redundancy gain in schizophrenics when the double stimuli were presented to one and the same hemisphere, and therefore, with no need for callosal transmission. All in all, the present results provide evidence of a callosal dysfunction in schizophrenia that impairs interhemispheric integration.