Difficulties during delivery, brain ventricle enlargement and cognitive impairment in first episode psychosis.

BACKGROUND: Patients with a first episode of psychosis (FEP) display clinical, cognitive, and structural brain abnormalities at illness onset. Ventricular enlargement has been identified in schizophrenia since the initial development of neuroimaging techniques. Obstetric abnormalities have been associated with an increased risk of developing psychosis but also with cognitive impairment and brain structure abnormalities. Difficulties during delivery are associated with a higher risk of birth asphyxia leading to brain structural abnormalities, such as ventriculomegaly, which has been related to cognitive disturbances. METHODS: We examined differences in ventricular size between 142 FEP patients and 123 healthy control participants using magnetic resonance imaging. Obstetric complications were evaluated using the Lewis-Murray scale. We examined the impact of obstetric difficulties during delivery on ventricle size as well as the possible relationship between ventricle size and cognitive impairment in both groups. RESULTS: FEP patients displayed significantly larger third ventricle size compared with healthy controls. Third ventricle enlargement was associated with diagnosis (higher volume in patients), with difficulties during delivery (higher volume in subjects with difficulties), and was highest in patients with difficulties during delivery. Verbal memory was significantly associated with third ventricle to brain ratio. CONCLUSIONS: Our results suggest that difficulties during delivery might be significant contributors to the ventricular enlargement historically described in schizophrenia. Thus, obstetric complications may contribute to the development of psychosis through changes in brain architecture.

Prodromal symptoms and the duration of untreated psychosis in first episode of psychosis patients: what differences are there between early vs. adult onset and between schizophrenia vs. bipolar disorder?

To assess the role of age (early onset psychosis-EOP < 18 years vs. adult onset psychosis-AOP) and diagnosis (schizophrenia spectrum disorders-SSD vs. bipolar disorders-BD) on the duration of untreated psychosis (DUP) and prodromal symptoms in a sample of patients with a first episode of psychosis. 331 patients with a first episode of psychosis (7-35 years old) were recruited and 174 (52.6%) diagnosed with SSD or BD at one-year follow-up through a multicenter longitudinal study. The Symptom Onset in Schizophrenia (SOS) inventory, the Positive and Negative Syndrome Scale and the structured clinical interviews for DSM-IV diagnoses were administered. Generalized linear models compared the main effects and group interaction. 273 AOP (25.2 ± 5.1 years; 66.5% male) and 58 EOP patients (15.5 ± 1.8 years; 70.7% male) were included. EOP patients had significantly more prodromal symptoms with a higher frequency of trouble with thinking, avolition and hallucinations than AOP patients, and significantly different median DUP (91 [33-177] vs. 58 [21-140] days; Z = - 2.006, p = 0.045). This was also significantly longer in SSD vs. BD patients (90 [31-155] vs. 30 [7-66] days; Z = - 2.916, p = 0.004) who, moreover had different profiles of prodromal symptoms. When assessing the interaction between age at onset (EOP/AOP) and type of diagnosis (SSD/BD), avolition was significantly higher (Wald statistic = 3.945; p = 0.047), in AOP patients with SSD compared to AOP BD patients (p = 0.004). Awareness of differences in length of DUP and prodromal symptoms in EOP vs. AOP and SSD vs. BD patients could help improve the early detection of psychosis among minors.

Obstetric complications and genetic risk for schizophrenia: Differential role of antenatal and perinatal events in first episode psychosis.

BACKGROUND: Obstetric complications (OCs) are key contributors to psychosis risk. However, it is unclear whether they increase psychosis vulnerability independently of genetic risk, in interaction with it, or are a manifestation of psychosis proneness. We examined the role of distinct types of OCs in terms of psychosis risk and tested whether they interact differently with genetic vulnerability, whilst accounting for other known environmental risk factors. STUDY DESIGN: 405 participants (219 first episode psychosis patients and 186 healthy volunteers) underwent a comprehensive assessment of OCs, measured using the Lewis-Murray scale and divided into complications of pregnancy, abnormalities of foetal growth and development, and complications of delivery. Participants were compared in terms of history of OCs, polygenic risk score for schizophrenia (PRS-SZ) and interactions between these. RESULTS: Both complications of pregnancy and abnormalities of foetal growth were significantly associated with case-control status (p = 0.02 and 0.03, respectively), whereas complications of delivery were not. PRS-SZ showed a significant association with psychosis (p = 0.04), but there were no significant interactions between genetic risk for schizophrenia and OCs, either when these were considered globally or separated based on their timeframe. CONCLUSIONS: We observed no significant interaction between genetic and obstetric vulnerability, yet distinct types of OCs may have a different impact on psychosis risk, based on their nature and timeframe. Examining their differential role might clarify their relative contributions to this risk.

Obstetric complications and clinical presentation in first episode of psychosis.

OBJECTIVE: Psychotic disorders exhibit a complex aetiology that combines genetic and environmental factors. Among the latter, obstetric complications (OCs) have been widely studied as risk factors, but it is not yet well understood how OCs relate to the heterogeneous presentations of psychotic disorders. We assessed the clinical phenotypes of individuals with a first episode of psychosis (FEP) in relation to the presence of OCs. METHODS: Two-hundred seventy-seven patients with an FEP were assessed for OCs using the Lewis-Murray scale, with data stratified into three subscales depending on the timing and the characteristics of the obstetric event, namely: complications of pregnancy, abnormal foetal growth and development and difficulties in delivery. We also considered other two groups: any complications during the pregnancy period and all OCs taken altogether. Patients were clinically evaluated with the Positive and Negative Syndrome Scale for schizophrenia. RESULTS: Total OCs and difficulties in delivery were related to more severe psychopathology, and this remained significant after co-varying for age, sex, traumatic experiences, antipsychotic dosage and cannabis use. CONCLUSIONS: Our results highlight the relevance of OCs for the clinical presentation of psychosis. Describing the timing of the OCs is essential in understanding the heterogeneity of the clinical presentation.

Effects of psychosis-associated genetic markers on brain volumetry: a systematic review of replicated findings and an independent validation.

BACKGROUND: Given psychotic illnesses' high heritability and associations with brain structure, numerous neuroimaging-genetics findings have been reported in the last two decades. However, few findings have been replicated. In the present independent sample we aimed to replicate any psychosis-implicated SNPs (single nucleotide polymorphisms), which had previously shown at least two main effects on brain volume. METHODS: A systematic review for SNPs showing a replicated effect on brain volume yielded 25 studies implicating seven SNPs in five genes. Their effect was then tested in 113 subjects with either schizophrenia, bipolar disorder, 'at risk mental state' or healthy state, for whole-brain and region-of-interest (ROI) associations with grey and white matter volume changes, using voxel-based morphometry. RESULTS: We found FWER-corrected (Family-wise error rate) (i.e. statistically significant) associations of: (1) CACNA1C-rs769087-A with larger bilateral hippocampus and thalamus white matter, across the whole brain; and (2) CACNA1C-rs769087-A with larger superior frontal gyrus, as ROI. Higher replication concordance with existing literature was found, in decreasing order, for: (1) CACNA1C-rs769087-A, with larger dorsolateral-prefrontal/superior frontal gyrus and hippocampi (both with anatomical and directional concordance); (2) ZNF804A-rs11681373-A, with smaller angular gyrus grey matter and rectus gyri white matter (both with anatomical and directional concordance); and (3) BDNF-rs6265-T with superior frontal and middle cingulate gyri volume change (with anatomical and allelic concordance). CONCLUSIONS: Most literature findings were not herein replicated. Nevertheless, high degree/likelihood of replication was found for two genome-wide association studies- and one candidate-implicated SNPs, supporting their involvement in psychosis and brain structure.

Uncovering neurodevelopmental features in bipolar affective disorder.

Schizophrenia and bipolar disorder are genetically related and their clinical features overlap. Schizophrenia is conceptualised as a neurodevelopmental disorder but the evidence for bipolar disorder is less clear. Cluster-analytic approaches reveal different cognitive profiles within bipolar disorder, possibly reflective of differing neurodevelopmental loads, which are also suggested by recent genetic and neuroimaging studies. Such studies suggest the potential utility of further clinical subcategories in bipolar disorder based on neurodevelopmental load.Declaration of interestNone.

Altered Temporal Dynamics of Resting-State Functional Magnetic Resonance Imaging in Adolescent-Onset First-Episode Psychosis.

BACKGROUND: Dynamic functional connectivity (dFC) alterations have been reported in patients with adult-onset and chronic psychosis. We sought to examine whether such abnormalities were also observed in patients with first episode, adolescent-onset psychosis (AOP), in order to rule out potential effects of chronicity and protracted antipsychotic treatment exposure. AOP has been suggested to have less diagnostic specificity compared to psychosis with onset in adulthood and occurs during a period of neurodevelopmental changes in brain functional connections. STUDY DESIGN: Seventy-nine patients with first episode, AOP (36 patients with schizophrenia-spectrum disorder, SSD; and 43 with affective psychotic disorder, AF) and 54 healthy controls (HC), aged 10 to 17 years were included. Participants underwent clinical and cognitive assessments and resting-state functional magnetic resonance imaging. Graph-based measures were used to analyze temporal trajectories of dFC, which were compared between patients with SSD, AF, and HC. Within patients, we also tested associations between dFC parameters and clinical variables. STUDY RESULTS: Patients with SSD temporally visited the different connectivity states in a less efficient way (reduced global efficiency), visiting fewer nodes (larger temporal modularity, and increased immobility), with a reduction in the metabolic expenditure (cost and leap size), relative to AF and HC (effect sizes: Cohen's D, ranging 0.54 to.91). In youth with AF, these parameters did not differ compared to HC. Connectivity measures were not associated with clinical severity, intelligence, cannabis use, or dose of antipsychotic medication. CONCLUSIONS: dFC measures hold potential towards the development of brain-based biomarkers characterizing adolescent-onset SSD.

Polygenic risk scores mediating functioning outcomes through cognitive and clinical features in youth at family risk and controls.

Schizophrenia and bipolar disorder exhibit substantial clinical overlap, particularly in individuals at familial high risk, who frequently present sub-threshold symptoms before the onset of illness. Severe mental disorders are highly polygenic traits, but their impact on the stages preceding the manifestation of mental disorders remains relatively unexplored. Our study aimed to examine the influence of polygenic risk scores (PRS) on sub-clinical outcomes over a 2-year period in youth at familial high risk for schizophrenia and bipolar disorder and controls. The sample included 222 children and adolescents, comprising offspring of parents with schizophrenia (n = 38), bipolar disorder (n = 80), and community controls (n = 104). We calculated PRS for psychiatric disorders, neuroticism and cognition using the PRS-CS method. Linear mixed-effects models were employed to investigate the association between PRS and cognition, symptom severity and functioning. Mediation analyses were conducted to explore whether clinical features acted as intermediaries in the impact of PRS on functioning outcomes. SZoff exhibited elevated PRS for schizophrenia. In the entire sample, PRS for depression, neuroticism, and cognitive traits showed associations with sub-clinical features. The effect of PRS for neuroticism and general intelligence on functioning outcomes were mediated by cognition and symptoms severity, respectively. This study delves into the interplay among genetics, the emergence of sub-clinical symptoms and functioning outcomes, providing novel evidence on mechanisms underpinning the continuum from sub-threshold features to the onset of mental disorders. The findings underscore the interplay of genetics, cognition, and clinical features, providing insights for personalized early interventions.

Epigenetic age deacceleration in youth at familial risk for schizophrenia and bipolar disorder.

Epigenetic modifications occur sequentially during the lifespan, but their pace can be altered by external stimuli. The onset of schizophrenia and bipolar disorder is critically modulated by stressors that may alter the epigenetic pattern, a putative signature marker of exposure to environmental risk factors. In this study, we estimated the age-related epigenetic modifications to assess the differences between young individuals at familial high risk (FHR) and controls and their association with environmental stressors. The sample included 117 individuals (6-17 years) at FHR (45%) and a control group (55%). Blood and saliva samples were used estimate the epigenetic age with six epigenetic clocks through methylation data. Environmental risk was measured with obstetric complications, socioeconomic statuses and recent stressful life events data. Epigenetic age was correlated with chronological age. FHR individuals showed epigenetic age deacceleration of Horvath and Hannum epigenetic clocks compared to controls. No effect of the environmental risk factors on the epigenetic age acceleration could be detected. Epigenetic age acceleration adjusted by cell counts showed that the FHR group was deaccelerated also with the PedBE epigenetic clock. Epigenetic age asynchronicities were found in the young at high risk, suggesting that offspring of affected parents follow a slower pace of biological aging than the control group. It still remains unclear which environmental stressors orchestrate the changes in the methylation pattern. Further studies are needed to better characterize the molecular impact of environmental stressors before illness onset, which could be critical in the development of tools for personalized psychiatry.

Genetic and Structural Brain Correlates of Cognitive Subtypes Across Youth at Family Risk for Schizophrenia and Bipolar Disorder.

OBJECTIVE: Cognitive impairment is an important feature of schizophrenia (SZ) and bipolar disorder (BP) with severity across the two disorders characterized by significant heterogeneity. Youth at family risk for SZ and BP were clustered based on cognitive function and examined in terms of the clinical, genetic, and brain imaging correlates of cluster membership. METHOD: One hundred sixty participants, 32 offspring of patients with SZ, 59 offspring of patients with BP and 69 offspring of healthy control parents underwent clinical and cognitive assessments, genotyping and structural MRI. K-means clustering was used to group family risk participants based on cognitive measures. Clusters were compared in terms of cortical and subcortical brain measures as well as polygenic risk scores. RESULTS: Participants were grouped in 3 clusters with intact, intermediate, and impaired cognitive performance. The intermediate and impaired clusters had lower total brain surface area compared with the intact cluster, with prominent localization in frontal and temporal cortices. No between-cluster differences were identified in cortical thickness and subcortical brain volumes. The impaired cluster also had poorer psychosocial functioning and worse PRS-COG compared with the other 2 clusters and with offspring of healthy control parents, while there was no significant between-cluster difference in terms of PRS-SZ and PRS-BP. PRS-COG predicted psychosocial functioning, yet this effect did not appear to be mediated by an effect of PRS-COG on brain area. CONCLUSION: Stratification based on cognition may help to elucidate the biological underpinnings of cognitive heterogeneity across SZ and BP risk.

Altered White Matter Integrity at Illness Onset in Adolescents With a First Episode of Psychosis.

Background: Disruption in white matter integrity has been consistently observed in individuals with psychosis. However, whether such abnormalities are already present at illness onset or are related to downstream processes remains elusive. The study of adolescents with a recent onset of psychosis provides the opportunity to evaluate white matter integrity proximally to disease onset. Methods: Twenty-six adolescents (aged 15.9 ± 1.3 years) with a first episode of psychosis (FEP) (less than 6 months duration) were compared with 26 age and sex-matched healthy controls (HC) (16.8 ± 2 years). In participants with a FEP, clinical diagnoses were confirmed after a minimum of 1 year follow-up (main categories: schizophrenia, bipolar disorder, or schizoaffective disorder). Anatomical images and diffusion tensor sequences were acquired using a 1.5T scanner. Whole brain, voxel-wise group differences in fractional anisotropy (FA) were investigated between participants with a FEP and controls. Results: Relative to HC, FEP participants displayed decreased FA in the right posterior cingulate gyrus, encompassing the right superior and posterior corona radiata, and the right parahippocampal gyrus, including the cingulum and fornix. FEP patients showed no areas of increased FA relative to HC. The results remained significant after controlling for medication, cannabis use and intelligence. Conclusion: Our findings indicate that adolescents with recent onset of psychotic disorders show decreased white matter integrity in circuits implicated in cognitive functions and emotion regulation.

Prediction of transition to psychosis from an at-risk mental state using structural neuroimaging, genetic, and environmental data.

Introduction: Psychosis is usually preceded by a prodromal phase in which patients are clinically identified as being at in an "At Risk Mental State" (ARMS). A few studies have demonstrated the feasibility of predicting psychosis transition from an ARMS using structural magnetic resonance imaging (sMRI) data and machine learning (ML) methods. However, the reliability of these findings is unclear due to possible sampling bias. Moreover, the value of genetic and environmental data in predicting transition to psychosis from an ARMS is yet to be explored. Methods: In this study we aimed to predict transition to psychosis from an ARMS using a combination of ML, sMRI, genome-wide genotypes, and environmental risk factors as predictors, in a sample drawn from a pool of 246 ARMS subjects (60 of whom later transitioned to psychosis). First, the modality-specific values in predicting transition to psychosis were evaluated using several: (a) feature types; (b) feature manipulation strategies; (c) ML algorithms; (d) cross-validation strategies, as well as sample balancing and bootstrapping. Subsequently, the modalities whose at least 60% of the classification models showed an balanced accuracy (BAC) statistically better than chance level were included in a multimodal classification model. Results and discussion: Results showed that none of the modalities alone, i.e., neuroimaging, genetic or environmental data, could predict psychosis from an ARMS statistically better than chance and, as such, no multimodal classification model was trained/tested. These results suggest that the value of structural MRI data and genome-wide genotypes in predicting psychosis from an ARMS, which has been fostered by previous evidence, should be reconsidered.

Shaped before birth: Obstetric complications identify a more severe clinical phenotype among patients presenting a first affective or non-affective episode of psychosis.

Obstetric complications (OCs) may contribute to the heterogeneity that characterizes psychiatric illness, particularly the phenotypic presentation of first episode psychoses (FEP). Our aim was to examine the relationship between OCs and socio-demographic, clinical, functioning and neuropsychological characteristics in affective and non-affective FEP. We performed a cross-sectional,study where we recruited participants with FEP between 2011 and 2021, and retrospectively assessed OCs using the Lewis-Murray scale. OCs were used as a dichotomous variable and further stratified into three subtypes: complications of pregnancy, abnormal fetal growth and development, and difficulties in delivery. We performed a logistic stepwise forward regression analysis to examine variables associated with the presence of OCs. Of the 104 participants (67 affective FEP and 37 non-affective FEP), 31.7% (n = 33) had experienced OCs. Subjects with OCs showed a more gradual emergence of prodromal symptoms as well as higher negative and total Positive and Negative Syndrome Scale (PANSS) scores. In the multivariate analysis, the presence of OCs was independently associated with a younger age at first episode of any type (OR = 0.904, p = 0.003) and slower emergence of prodromal symptoms (OR = 0.274, p = 0.011). When considering specific types of OCs, those related with fetal growth were associated with worse neuropsychological performance, while OCs at delivery were related to earlier onset of illness and more severe symptoms. In conclusion, OCs signaled a specific FEP phenotype characterized by earlier and more protracted onset of illness as well as more burdensome symptoms, independently of FEP type (i.e., affective vs non-affective). These results indicate a potential target of early intervention in FEP.

Theory of mind performance and prefrontal connectivity in adolescents at clinical high risk for psychosis.

Theory of mind(ToM) impairment is a key feature of psychotic disorders and has been documented in individuals at clinical high-risk for psychosis (CHR), suggesting that it may predate illness onset. However, no study to date has examined brain functional correlates of ToM in individuals at CHR during adolescence. The "Reading-the-Mind-in-the-Eyes" test was used to measure ToM performance in 50 CHR youth, 15 of whom transitioned to psychosis (CHR-t) at follow-up (12 ± 6 months) and 36 healthy volunteers. Resting-state functional MRI was acquired to evaluate functional connectivity within the default mode network. Group by age interaction revealed an age-positive association in ToM performance in healthy volunteers, which was not present in adolescents at CHR-t. Intrinsic functional connectivity in the medial prefrontal cortex was reduced in adolescents at CHR-t relative to those who did not transition and to healthy volunteers. Survival analyses revealed that participants at CHR with lower medial prefrontal cortex connectivity were at greatest risk of developing psychosis at follow-up. We demonstrate that lack of age-related maturation of ToM and reduced medial prefrontal cortex connectivity both precede the onset of psychosis during adolescence. Medial prefrontal cortex connectivity holds potential as a brain-based marker for the early identification of transition to psychosis.

Cognitive heterogeneity in the offspring of patients with schizophrenia or bipolar disorder: a cluster analysis across family risk.

BACKGROUND: Neurocognitive impairment is considered to lie on a continuum of severity across schizophrenia (SZ) and bipolar disorder (BP), possibly reflecting a gradient of neurodevelopmental load. Cluster analyses have identified different levels of impairment across the two disorders, from none to widespread and severe. We for the first time used this approach to examine cognitive function pooling together children and adolescents at familial risk of SZ or BP. METHODS: 220 participants, 49 offspring of individuals with schizophrenia (SZO), 90 offspring of individuals with bipolar disorder (BPO) and 81 offspring of healthy control parents (HC), aged 6 to 17 years, underwent a comprehensive clinical and cognitive assessment. Cognitive measures were used to group SZO and BPO using K-means clustering. Cognitive performance within each of the clusters was compared to that of HC and clinical variables were compared between clusters. RESULTS: We identified three cognitive subgroups: a moderate impairment group, a mild impairment group, and a cognitively intact group. Both SZO and BPO were represented in each of the clusters, yet not evenly, with a larger proportion of the SZO in the moderately impaired cluster, but also a subgroup of BPO showing moderate cognitive dysfunction. LIMITATIONS: Participants have yet to reach the age of onset for the examined disorders. CONCLUSIONS: The findings point to a range of neurodevelopmental loadings across youth at familial risk of both SZ and BP. They have therefore important implications for the stratification of cognitive functioning and the possibility to tailor interventions to individual levels of impairment.

Correction to: Clinical Pharmacokinetics of Atypical Antipsychotics: An Update.

The pharmacokinetics of CRP was tested in small short-term studies in both healthy volunteers and in subjects with schizophrenia, with similar results [242].

Hallucinatory disorder, an original clinical picture? Clinical and imaging data.

OBJECTIVE: The aim of this study was to verify the existence of areas of clinical and neurofunctional homogeneity in a group of patients with auditory verbal hallucinations (AVHs) as an isolated symptom, attributable to what we have called "Hallucinatory Disorder" (HD) in an attempt to propose a clinical picture that is distinct from Schizophrenia. METHOD: Nine patients clinically characterised by chronic AVHs were compared with nine schizophrenic patients using the Structured Clinical Interview for DSM-III-R, BPRS, PANSS, SAPS, SANS, HRS-A, HRS-D, CDSS, MMSE, CGI and PSYRATS. Both groups of patients and nine healthy subjects underwent EEG and SPECT examinations. RESULTS: Considering the psychopathological dimensions of Schizophrenia, in the HD patients clinical evaluations revealed a mono-dimensional clinical profile, whereas all these dimensions contributed to the clinical picture of the schizophrenic patients. The SPECT data showed that the schizophrenic patients had a reduced rCBF in some areas of the right frontal lobe, while the HD patients did not show any area of hypoperfusion. The SPECT hyperperfusion data showed an activation pattern in the HD patients that was characterised by the involvement of various cortical and subcortical cerebral areas, similar to those found in studies of inner speech and auditory verbal imagery. CONCLUSIONS: The two groups of patients present significant differences that seem capable of supporting the proposed hypothesis that HD may be an independent nosographical entity.

Verbal learning and hippocampal dysfunction in schizophrenia: A meta-analysis.

This meta-analysis summarizes research examining whether deficits in verbal learning are related to bilateral hippocampal volume reductions in patients with or at risk for schizophrenia and in healthy controls. 17 studies with 755 patients with schizophrenia (SCZ), 232 Genetic High Risk (GHR) subjects and 914 healthy controls (HC) were included. Pooled correlation coefficients were calculated between hemisphere (left, right or total) and type of recall (immediate or delayed) for each diagnostic group individually (SCZ, GHR and HC). In SCZ, left and right hippocampal volume positively correlated with immediate (r=0.256, 0.230) and delayed (r=0.132, 0.231) verbal recall. There was also a correlation between total hippocampal volume and delayed recall (r=0.233). None of these correlations were significant in healthy controls. There was however, a positive correlation between left hippocampal volume and immediate recall in the GHR group (r=0.356). The results suggest that hippocampal volume affects immediate and delayed verbal learning capacity in schizophrenia and provides further evidence of hippocampal dysfunction in the pathophysiology of schizophrenia.

Clinical Pharmacokinetics of Atypical Antipsychotics: An Update.

Therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding side effects by maintaining long-term exposure to minimally effective blood concentrations. The rationale for using therapeutic drug monitoring in relation to second-generation antipsychotics is still being discussed at least with regard to the real clinical utility, but there is evidence that it can improve efficacy, especially when patients do not respond or develop side effects using therapeutic doses. Furthermore, drug plasma concentration determinations can be of some utility in medico-legal problems. This review concentrates on the clinical pharmacokinetic data related to clozapine, risperidone, paliperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole, sertindole, asenapine, iloperidone, lurasidone, brexpiprazole and cariprazine and briefly considers the main aspects of their pharmacodynamics. Optimal plasma concentration ranges are proposed for clozapine, risperidone, paliperidone and olanzapine because the studies of quetiapine, amisulpride, asenapine, iloperidone and lurasidone provide only limited information and there is no direct evidence concerning ziprasidone, aripiprazole, sertindole, brexpiprazole and cariprazine: the few reported investigations need to be confirmed and extended.