Mechanical Restraint in Inpatient Psychiatric Unit: Prevalence and Associated Clinical Variables.

Background and Objectives: mechanical restraint (MR) is a controversial issue in emergency psychiatry and should be better studied to implement other alternative therapeutic interventions. The aim of this study was to estimate the prevalence of MR in an Italian psychiatric unit and identify the sociodemographic and clinical characteristics as well as the pharmacological pattern associated with MR. Materials and Methods: all subjects (N = 799) consecutively admitted to an Italian psychiatric inpatient unit were recruited. Several sociodemographic and clinical characteristics were recorded. Results: The prevalence of MR was 14.1%. Males, a younger age, and a single and migrant status were associated with the MR phenomenon. MR was more prevalent in patients affected by other diagnoses and comorbid illicit substance use, in patients with aggressive behaviors, and those that were involuntary admitted, leading significantly to hospitalization over 21 days. Furthermore, the patients that underwent MR were taking a lower number of psychiatric medications. Conclusions: Unfortunately, MR is still used in emergency psychiatry. Future research should focus on the dynamics of MR development in psychiatry, specifically considering ward- and staff-related factors that could help identify a more precise prevention and alternative intervention strategies.

Eyes as gateways for environmental light to the substantia nigra: relevance in Parkinson's disease.

Recent data indicates that prolonged bright light exposure of rats induces production of neuromelanin and reduction of tyrosine hydroxylase positive neurons in the substantia nigra. This effect was the result of direct light reaching the substantia nigra and not due to alteration of circadian rhythms. Here, we measured the spectrum of light reaching the substantia nigra in rats and analysed the pathway that light may take to reach this deep brain structure in humans. Wavelength range and light intensity, emitted from a fluorescent tube, were measured, using a stereotaxically implanted optical fibre in the rat mesencephalon. The hypothetical path of environmental light from the eye to the substantia nigra in humans was investigated by computed tomography and magnetic resonance imaging. Light with wavelengths greater than 600 nm reached the rat substantia nigra, with a peak at 709 nm. Eyes appear to be the gateway for light to the mesencephalon since covering the eyes with aluminum foil reduced light intensity by half. Using computed tomography and magnetic resonance imaging of a human head, we identified the eye and the superior orbital fissure as possible gateways for environmental light to reach the mesencephalon.

Sociodemographic and Clinical Correlates Associated with the Frequent Service Users in an Italian Psychiatric Emergency Department.

BACKGROUND: The aim of the present study is to identify the main sociodemographic and clinical correlates associated with frequent service users (FSUs) in an Italian psychiatric emergency department. METHODS: This study is an observational and prospective clinical investigation. All subjects (N = 549) consecutively admitted to the Psychiatric Inpatient Unit of the IRCCS Ospedale Policlinico San Martino ((Genoa, Italy) were recruited over a period of 18 months. RESULTS: On average, FSUs were more likely to be single (75.0% vs. 64.0, p = 0.001), younger (38.79 years ± 14.68 vs. 45.94 years ± 16.94, p = 0.028), with an earlier onset (20.15 years ± 7.22 vs. 29.33 years ± 15.96, p < 0.001), and longer length of hospitalisation (13.65 days ± 12.40 vs. 9.89 ± 10.15, p = 0.006) compared to non-FSUs. While bipolar disorder was the most common primary diagnosis in both FSUs and non-FSUs, cluster B personality disorder was particularly elevated in FSUs (30.3% vs. 10.4%, p < 0.001). Furthermore, FSUs were more prone to substance use disorder (63.6% vs. 40.0%, p < 0.001), particularly cannabis (45.5% vs. 15.3%, p < 0.001), cocaine (33.3% vs. 10.4%, p < 0.001), and heroin (19.7% vs. 5.8%, p < 0.001), and were more likely to have non-suicidal self-injuries (21.2% vs. 6.8%, p < 0.001). FSUs were significantly more likely to be discharged against medical advice (18.2% vs. 5.6%, p < 0.001) or to have at least one escape attempt from the psychiatric ward (12.1% vs. 0.8%, p < 0.001). CONCLUSIONS: Specific clinical and social profiles of patients who repeatedly utilised the services of a psychiatric emergency department have been identified. Our findings can be used to develop suitable structures to support and reintegrate FSUs into society and work life.

[Long-term treatment of bipolar disorder: how should we use lithium salts?]. / Trattamento a lungo termine del disturbo bipolare: quale impiego dei sali di litio nella pratica clinica?

UNLABELLED: Despite the great quantity of evidence supporting the efficacy of lithium in the maintenance treatment of bipolar disorder (BD), its use has often been limited because of issues about the management of this compound. W aimed to evaluate the use of lithium in common clinical practice and to identify possible relationships between the trend over time of serum lithium levels and clinical course of the illness. METHODS: 98 patients with bipolar I and bipolar II disorder (DSM-IV-TR) on maintenance treatment with lithium salts were recruited and followed up in a naturalistic trial at the Day Hospital of Psychiatric Clinic of Pisa. Diagnosis was confirmed using a structured interview, the SCID-I. During symptom assessment, the Clinical Global Impression-Bipolar Version Scale (CGI-BP) was used. RESULTS: The sample is made up mainly of BI patients (87.8%) and lithium is used in association with anticonvulsants in 63%. Less than half of the sample (48%) presents average serum lithium levels in the therapeutic range (0.5-0.8 mEq/L); serum values of lithium within the range were seen more frequently in patients with manic/mixed episode, with manic/mixed polarity of onset, with a greater number of previous episodes, with a higher percentage of rapid cycling and in subjects treated with lithium associated with anticonvulsants. During the follow-up patients with average serum lithium levels within the therapeutic range obtained a clinical improvement in a significantly greater proportion compared to patients with average serum lithium levels lower than 0.50 mEq/L. DISCUSSION: In clinical practice, lithium is often used at doses determining serum levels at the lower limits of the therapeutic range. Preliminary data on the prospective course of the illness support the importance of maintaining serum values of lithium within the therapeutic range.

COVID-19 pandemic impact on the therapeutic setting in Mental Health Services.

BACKGROUND: The new 2019 coronavirus disease (COVID-19) outbreak forced mental health providers to overcome their general reluctance about telematic assistance, shifting from a face-to-face approach to online therapy to promote continuity of care for psychiatric patients. METHODS: An ad-hoc web-based survey questionnaire assessing the impact of the COVID-19 pandemic on therapeutic setting in Mental Health Services was sent via email from March 15, 2021 to June 15, 2021 to mental health providers in Genova, Italy. The survey was anonymous and a free Google Forms® software was used. RESULTS: Two hundred nineteen mental health providers completed the survey, and the overall response rate (ORR) was 65%. During the COVID-19 pandemic period, the continuity of care was mainly guaranteed using electronic devices. Psychologists reported a higher availability of video call assistance service to guarantee continuity of care for psychiatric patients compared to psychiatrists and psychotherapists (p<0,001). Psychiatrists reported the lowest degree of satisfaction about this new telematic approach (p<0,01), while psychologists and to a lesser extent psychotherapists speculated to use it even in non-pandemic times (p=0,02). CONCLUSIONS: COVID-19 pandemic creates an opportunity to overcome normative, technological and cultural barriers to the use of online psychotherapy, showing the importance of adapting the therapeutic setting to both collective and individual needs. Despite initial concerns about its effectiveness and efficacy, a general degree of satisfaction was expressed by the majority of the mental health providers. Further efforts will be needed to enhance this new way of working and to train therapists with particular regard to those employed in the public health system.

ß-Cells Different Vulnerability to the Parkinsonian Neurotoxins Rotenone, 1-Methyl-4-phenylpyridinium (MPP+) and 6-Hydroxydopamine (6-OHDA).

Neurotoxins such as rotenone, 1-methyl-4-phenylpyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) are well known for their high toxicity on dopaminergic neurons and are associated with Parkinson's disease (PD) in murine models and humans. In addition, PD patients often have glucose intolerance and may develop type 2 diabetes (T2D), whereas T2D patients have higher risk of PD compared to general population. Based on these premises, we evaluated the toxicity of these three toxins on pancreatic ß-cell lines (INS-1 832/13 and MIN6) and we showed that rotenone is the most potent for reducing ß-cells viability and altering mitochondrial structure and bioenergetics in the low nanomolar range, similar to that found in dopaminergic cell lines. MPP+ and 6-OHDA show similar effects but at higher concentration. Importantly, rotenone-induced toxicity was counteracted by α-tocopherol and partially by metformin, which are endowed with strong antioxidative and cytoprotective properties. These data show similarities between dopaminergic neurons and ß-cells in terms of vulnerability to toxins and pharmacological agents capable to protect both cell types.

Cannabinoid use and self-injurious behaviours: A systematic review and meta-analysis.

BACKGROUND: The increasing availability of high-potency cannabis-derived compounds and the use of synthetic cannabinoids may be responsible for severe side effects like cognitive impairment, psychosis or self-injurious behaviours (SIB). In particular, SIB like non-suicidal self-injury (NSSI) and deliberate self-harm (DSH) raise growing concern as a possible consequence of cannabis use. However, the research to date has not addressed the relationship between cannabinoid use and SIB systematically. METHODS: We conducted a systematic review on PubMed up to March 2020, using search terms related to cannabinoids and SIB. RESULTS: The search yielded a total of 440 abstracts. Of those, 37 studies published between 1995 and 2020 were eligible for inclusion. Cannabinoid use was significantly associated with SIB at the cross-sectional (OR=1.569, 95%CI [1.167-2.108]) and longitudinal (OR=2.569, 95%CI [2.207-3.256]) level. Chronic use, presence of mental disorders, depressive symptoms, emotional dysregulation and impulsive traits might further increase the likelihood of self-harm in cannabis users. Synthetic cannabinoids may trigger highly destructive SIB mainly through the psychotomimetic properties of these compounds. CONCLUSION: Cannabinoid use was associated with an increased prevalence of self-injury and may act as a causative factor with a duration-dependent manner. Emotional regulation and behavioural impulsivity functions might crucially moderate this association. Future studies should further investigate the mechanisms underlying this association, while exploring potential therapeutic applications of substances modulating the endocannabinoid system.

Long head of biceps in proximal fractures of the humerus: an underestimated problem?

BACKGROUND AND AIM OF THE WORK: The long head of biceps (LHB) is one of the tendons of the rotator cuff that runs strictly close to the humeral head. In case of pathology, it can be responsible for pain and shoulder impairment: in such cases, surgical options include tenotomy or tenodesis. The management of LHB along with surgery of the rotator cuff or during shoulder prosthetic replacement has been widely discussed in the literature. Conversely, the possibility of acute impingement and incarceration of LHB in proximal humerus fractures, as well as its role in shoulder pain in outcomes of these fractures, has been poorly considered. METHODS: The following aspects in the literature on LHB and proximal humerus fractures have been analysed: its management during fixation of fractures, the possibility of interference of the tendon with reduction of fractures or dislocations of the shoulder and its possible role in chronic pain after fixation of proximal humerus fractures. RESULTS: LHB can be an obstacle in the reduction of fractures, dislocations and fracture-dislocations. Only a few papers take into account acute surgery to LHB (tenotomy or tenodesis); most of the studies on fixation of proximal humerus fractures simply ignore the problem of LHB. The tendon can be a source of pain and a cause of disability in sequelae of these fractures. CONCLUSIONS: LHB should be taken into consideration both in the acute phase of fractures of the proximal humerus and in the outcomes. Other studies are needed to better understand its optimal management during fracture surgery.

Effects of water stress on spectral reflectance of bermudagrass.

In the south-central Italy, during summer rainfall does not supply a sufficient amount of water. Therefore, irrigation management during dry periods is important for maintaining turf quality. The hybrid bermudagrass (Cynodon dactylon (L.) Pers. × Cynodon transvaalensis Burtt-Davy) is known to represent the dominant warm-season turfgrass in warm to temperate climatic regions and its drought tolerance make bermudagrass a competitive turfgrass. A greenhouse experiment was conducted using uniform cores of hybrid bermudagrass, which were secured in a polyvinyl chloride cylinders and watered by constant sub-irrigation. The objectives of the present research were to measure the spectral reflectance with a new generation handheld spectroradiometer on hybrid bermudagrass and to explore various vegetation indices to be used as future detecting tool to study water stress in bermudagrass. Moreover, the potential uses of multivariate processing techniques for discriminating different water stress conditions in turfgrass has been investigated. Besides spectral indices, multivariate methods, although performed on a data set limited in terms of sample size, have shown a great potential for water stress monitoring in turfgrass and surely deserve further investigations. There are different indices that use distinct water absorption features independent of chlorophyll concentration, such as water index (WI = R900/R970) that has been reported to be a robust index of canopy water content and is used as an active indicator of changes in Leaf Relative Water Content (LRWC). Also, the ratio of WI with NDVI (WI/NDVI = (R900/R970)/((R800 - R680)/(R800 + R680)]) was found to be an effective indicator of water stress. Another vegetation index to detect water features is normalized difference water index (NDWI), designed to maximize reflectance of water by using green wavelengths. In our trial in bermudagrass the relationships studied, suggest that WI (900/970) and WI/NDVI, among the indices studied, are the more effective indicators of water stress. In fact, lower values of WI indicate higher water stress, while higher values of WI/NDVI indicate higher water stress levels.

Parkinson's disease and light: The bright and the Dark sides.

Light exerts a major influence on human behaviour and health, mainly owing to the importance of sight in our lives, but also due to its entrainment of daily rhythms via the suprachiasmatic nucleus, the master pacemaker. Light may also be a useful clinical medium, as in lumino-therapy for the improvement of depressed mood. Further, as discussed herein, local application of near infrared light to the substantia nigra exerts neuroprotective properties in models of Parkinson's disease. However, light also has a darker side. In general, as regards the growing problem to human health - and the natural world - of excess exposure to artificial light: both urban glow and ubiquitous screens. Moreover, over-exposure to light, in particular fluorescent light, disrupts circadian rhythms and sleep, and may damage dopaminergic neurons. Is it, then, a neglected risk factor for Parkinson's disease? The present article discusses epidemiological and experimental evidence supporting beneficial and potentially deleterious impact of light on dopaminergic neurons and highlights the mechanisms whereby light might influence neuronal tissue.

Apomorphine offers new insight into dopaminergic neuron vulnerability in mesencephalic cultures.

The mechanism by which the dopamine neurons of the substantia nigra pars compacta degenerate in Parkinson's disease, is partly unknown. Dopamine could be implicated in this phenomenon, and in order to explain its toxicity several hypotheses have been suggested. The similarity between apomorphine and dopamine as regards their chemical, pharmacological and toxicological properties provided a basis for investigating the nature of the toxicity of the former agent. In this study we describe some effects of apomorphine on mouse mesencephalic cell cultures at relatively low concentrations (from 0.5 to 2.5microM), apomorphine produced a neurotrophic effect, consisting of a 60% increase in dopaminergic neuron survival as measured by [(3)H] dopamine uptake. At high concentrations (over 20microM), however, apomorphine induced an increasing cytotoxic effect, as measured by the marked decrease in [(3)H] dopamine uptake, and by the direct observation of the dopaminergic neurons after TH immunostaining. This study may offer a new strategy for investigating the mechanisms underlying DA neuron vulnerability.

Characterization of the Engrailed mutant mice as experimental models for Parkinson's disease.

Engrailed genes are homeodomain-containing transcription factors necessary for the development and maintenance of mesencephalic dopaminergic neurons. Deletion in the Engrailed genes has been shown to affect the survival of mesencephalic dopaminergic neurons both during development and in the adult. Here we describe for the first time a significant reduction in striatal dopamine levels in En1+/-;En2+/- mice compared with their En2+/- littermates, accompanied by a modest reduction in the number of nigral DA neurons. Our results strengthen previous evidence indicating Engrailed genes as survival factors for mature dopaminergic neurons. Furthermore, our data suggest a role for these transcription factors in the maintenance of synaptic dopaminergic neurotransmission in adult neurons.

Partial agonist actions at dopamine D2L receptors are modified by co-transfection of D3 receptors: potential role of heterodimer formation.

The effects of aripiprazole, S33592, bifeprunox, N-desmethylclozapine and preclamol acting as partial agonists on recombinant D(2L) and D(3) receptors expressed both separately and concomitantly in COS-7 cells are evaluated here. Aripiprazole, S33592, bifeprunox, N-desmethylclozapine and preclamol behave as partial agonists on D(2L) receptors coupled with adenylyl cyclase, but they behave as antagonists on co-expression of D(3) with D(2L) receptors. These data raise the intriguing hypothesis that antipsychotic actions of "partial agonists" such as aripiprazole may not reflect inefficient stimulation of D(2) and/or D(3) receptors but, by analogy with other antipsychotics, may instead represent a blockade of D(2)/D(3) heterodimers (and/or D(3) receptors) that are "weakly" coupled to transduction mechanisms postsynaptically of the dopaminergic pathway.

Role of CYP2E1 in the mouse model of MPTP toxicity.

It has been shown that diethyldithiocarbamate (DDC) potentiates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice as a result of increased levels of 1-methyl-4-phenylpyridinium ion (MPP(+)) in the striatum. Brain CYP2E1 inhibition by DDC in C57Bl mice was responsible for increased toxicity and striatal MPP(+) accumulation. However, CYP2E1-null mice did not show any enhanced sensitivity to MPTP or any MPP(+) accumulation. This unexpected finding suggested that the CYP2E1-null mice compensate with other isozymes as already described for acetaminophen-induced liver damage. MPP(+) intoxication of mesencephalic cell cultures from CYP2E1-null mice indicated a reduced sensitivity of dopaminergic (DA) neurons from knockout animals. Surprisingly, MPP(+) cell distribution under these conditions indicated that the toxin accumulates more intracellularly in knockout cultures, suggesting further that CYP2E1 has a role in MPP(+) storage and efflux.

Tabagism and its management in Italian Psychiatric Intensive Care General Hospital Units / La gestione del tabagismo nei Servizi Psichiatrici di Diagnosi e Cura.

Aim: The aim of this paper was to survey the current management of the problem of smoking in our Mental Health Units, the structural characteristics of the units and how a total smoking ban would be perceived by doctors and nurses. Method: An 18 items survey about smoking habits of inpatients and department inner regulations was sent to the Head Physician and the Charge Nurse of all the Intensive Psychiatric Care General Hospital Units in Italy (228 units), in order to increase the answer rate and to investigate if the perception of the problem is eventually different between the two groups. Results: We collected 65 answers from Head Physician and 79 from Nurses. Both groups think that the smoking rates for inpatients are between 50-100%. Most of the units is locked, with or without an external space, so that a total smoking ban is considered difficult to achieve by both groups. A very high rate of units has no specific rooms for smokers. In most cases the issue management is solved by a self-regulation, based on collecting cigarettes and lighters and granting a limited number of cigarettes per day. Anyway, an institutional intervention would be appreciated especially by nurses, who seem to be even more involved in the issue management and both of groups seem to badly judge the lack of sources to face the eventual ban: particularly the possibility to offer nicotine replacement therapy, a cognitive-behavioural support and providing more staff education would all be considered useful to implement the success rate of the ban. By the way, both of groups seem skeptical about the possibility of a total smoking-free policy in Acute Psychiatric Hospital Units. Though, a difference in the problem's perception between the two groups has been noticed. Discussion: Smoking cessation remains a neglected area in psychiatry, in part due to misconceptions about smoking in the mentally ill, i.e. the idea that smoking cessation will exacerbate mental illness, aggression and suicide risk, even though these believes are not supported by evidence; in part due to the lack of institutional intervention and the structural deficiencies of the units.

Molecular targets of atypical antipsychotics: From mechanism of action to clinical differences.

The introduction of atypical antipsychotics (AAPs) since the discovery of its prototypical drug clozapine has been a revolutionary pharmacological step for treating psychotic patients as these allow a significant recovery not only in terms of hospitalization and reduction in symptoms severity, but also in terms of safety, socialization and better rehabilitation in the society. Regarding the mechanism of action, AAPs are weak D2 receptor antagonists and they act beyond D2 antagonism, involving other receptor targets which regulate dopamine and other neurotransmitters. Consequently, AAPs present a significant reduction of deleterious side effects like parkinsonism, hyperprolactinemia, apathy and anhedonia, which are all linked to the strong blockade of D2 receptors. This review revisits previous and current findings within the class of AAPs and highlights the differences in terms of receptor properties and clinical activities among them. Furthermore, we propose a continuum spectrum of "atypia" that begins with risperidone (the least atypical) to clozapine (the most atypical), while all the other AAPs fall within the extremes of this spectrum. Clozapine is still considered the gold standard in refractory schizophrenia and in psychoses present in Parkinson's disease, though it has been associated with adverse effects like agranulocytosis (0.7%) and weight gain, pushing the scientific community to find new drugs as effective as clozapine, but devoid of its side effects. To achieve this, it is therefore imperative to characterize and compare in depth the very complex molecular profile of AAPs. We also introduce relatively new concepts like biased agonism, receptor dimerization and neurogenesis to identify better the old and new hallmarks of "atypia". Finally, a detailed confrontation of clinical differences among the AAPs is presented, especially in relation to their molecular targets, and new means like therapeutic drug monitoring are also proposed to improve the effectiveness of AAPs in clinical practice.

Striatal Dopamine Transporter Modulation After Rotigotine: Results From a Pilot Single-Photon Emission Computed Tomography Study in a Group of Early Stage Parkinson Disease Patients.

INTRODUCTION: Several in vitro data have reported negative interference by dopamine-agonists on the expression of dopamine transporter (DAT), whereas the majority of imaging studies have shown that neither L-dopa nor dopamine-agonists interfere with DAT availability. As yet, there are no in vivo studies on DAT expression after treatment with rotigotine. METHODS: We evaluated presynaptic nigrostriatal function in 8 patients with de novo Parkinson disease (age, 59 ± 6.2 years; male/female sex, 5/3) using 123-I- N-ω-fluoropropyl-2-ß-carbomethoxy-3-ß-(4-iodophenyl)nortropane (FP-CIT) single-photon emission computed tomography before and after 3 months of treatment with rotigotine (mean dose, 7.75 ± 1.98 mg). For data analysis, specific (left and right caudate, left and right putamen) to nonspecific (occipital cortex) binding ratios, putamen-to-caudate ratios, and asymmetry indices were calculated. RESULTS: After rotigotine, motor symptoms improved in all patients (Unified Parkinson Disease Rating Scale III mean score, 11.88 ± 2.59 vs 7.63 ± 1.92 on therapy; P = 0.0022). Striatal FP-CIT levels showed a significant improvement in every patient at the follow-up scan. Comparisons between before and after treatment in the whole group revealed a significant improvement in FP-CIT uptake in both caudate and putamen (P < 0.001 in each nucleus). Putamen-to-caudate ratio and asymmetry indices did not show any significant difference before and after treatment. DISCUSSION: Although the study population was small, we found DAT overexpression after chronic treatment with rotigotine, presumably related to its pharmacological profile. The DAT upregulation by rotigotine in an opposite direction with respect to early Parkinson disease compensatory mechanisms might reduce the risk of dyskinesia, but it could imply less motor benefit because of less stimulation by the dopamine itself on dopaminergic receptors.

Clozapine as the most efficacious antipsychotic for activating ERK 1/2 kinases: Role of 5-HT2A receptor agonism.

Antipsychotics (APDs) are divided into first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) based on the concept that SGAs have reduced motor side effects. With this premise, this study examined in HeLa and other cell lines the effects of different APDs on the activation of ERK1/2 (Extracellular signal-regulated kinases) and AKT (Protein Kinase B) kinases, which may be affected in schizophrenia and bipolar disorder. Among the SGAs, Clozapine clearly resulted as the most effective drug inducing ERK1/2 phosphorylation with potency in the low micromolar range. Quetiapine and Olanzapine showed a maximal response of about 50% compared to Clozapine, while FGAs such as Haloperidol and Sulpiride did not have any relevant effect. Among FGAs, Chlorpromazine was able to partially activate ERK1/2 at 30% compared to Clozapine. Referring to AKT activation, Clozapine, Quetiapine and Olanzapine demonstrated a similar efficacy, while FGAs, besides Chlorpromazine, were incapable to obtain any particular biological response. In relation to ERK1/2 activation, we found that 5-HT2A serotonin receptor antagonists Ketanserin and M100907, both partially reduced Clozapine effect. In addition, we also observed an increase of potency of Clozapine effect in HeLa transfected cells with recombinant 5-HT2A receptor and in rat glioma C6 cells that express a higher amount of this receptor. This indicates that ERK1/2 stimulation induced by Clozapine could, to some extent, be mediated by 5-HT2A receptor, through a novel mechanism that is called "biased agonism", even though other cellular targets are involved. This evidence may be relevant to explain the superiority of Clozapine among the APDs.