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Objective: Personalized dose optimization is desirable to improve subjective well-being and support rehabilitation. Therefore, N = 1 trials investigating tools to self-manage functional outcomes during dose optimization are necessary. The aim of this pilot study was to determine in two N = 1 trials whether an experience sampling method (ESM) smartphone app could be used to monitor and detect changes in subjective well-being and psychotic experiences during and after dose reduction., Method: Two participants with a psychotic disorder in remission underwent gradual dose reduction under a longitudinal self-monitoring paradigm, accompanied by regular clinical monitoring by the attending physician. Subjective well-being was monitored with an (ESM) app through momentary affective experience (positive and negative affect) and physical well-being (tiredness, feeling unwell, and pain). Momentary psychotic experiences were assessed with four items. Time-series linear regression models were used to detect changes in reduction phases compared to baseline., Results: Whereas significant improvements in subjective well-being and psychotic experiences during dose reduction were detected in one participant, the opposite was demonstrated for the other participant, showing worsened subjective well-being and increased psychotic experiences in the reduction phase compared to baseline., Conclusions and Implications for Practice: Self-monitoring with an ESM smartphone app offers a tool for detecting changes in subjective well-being and psychotic experiences during antipsychotic dose reduction. In this way, ESM may increase an individual's sense of control and empowerment. It may further facilitate dose optimization and shared decision-making at an individual level, which is required considering the high heterogeneity in psychotic disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Cognitive deficits may be characteristic for only a subgroup of first-episode psychosis (FEP) and the link with clinical and functional outcomes is less profound than previously thought. This study aimed to identify cognitive subgroups in a large sample of FEP using a clustering approach with healthy controls as a reference group, subsequently linking cognitive subgroups to clinical and functional outcomes., Methods: 204 FEP patients were included. Hierarchical cluster analysis was performed using baseline brief assessment of cognition in schizophrenia (BACS). Cognitive subgroups were compared to 40 controls and linked to longitudinal clinical and functional outcomes (PANSS, GAF, self-reported WHODAS 2.0) up to 12-month follow-up., Results: Three distinct cognitive clusters emerged: relative to controls, we found one cluster with preserved cognition ( n = 76), one moderately impaired cluster ( n = 74) and one severely impaired cluster ( n = 54). Patients with severely impaired cognition had more severe clinical symptoms at baseline, 6- and 12-month follow-up as compared to patients with preserved cognition. General functioning (GAF) in the severely impaired cluster was significantly lower than in those with preserved cognition at baseline and showed trend-level effects at 6- and 12-month follow-up. No significant differences in self-reported functional outcome (WHODAS 2.0) were present., Conclusions: Current results demonstrate the existence of three distinct cognitive subgroups, corresponding with clinical outcome at baseline, 6- and 12-month follow-up. Importantly, the cognitively preserved subgroup was larger than the severely impaired group. Early identification of discrete cognitive profiles can offer valuable information about the clinical outcome but may not be relevant in predicting self-reported functional outcomes.

Introduction: A strong link between voice-hearing experience and childhood trauma has been established. The aim of this study was to identify whether there were unique clusters of childhood trauma subtypes in a sample across the clinical spectrum of auditory verbal hallucinations (AVH) and to examine clinical and phenomenological features across these clusters. Methods: Combining two independent international datasets (the Netherlands and Australia), childhood trauma subtypes were examined using hierarchical cluster analysis. Clinical and phenomenological characteristics were compared across emerging clusters using MANOVA and chi-squared analyses. Results: The total sample ( n  = 413) included 166 clinical individuals with a psychotic disorder and AVH, 122 non-clinical individuals with AVH and 125 non-clinical individuals without AVH. Three clusters emerged: (1) low trauma ( n  = 299); (2) emotion-focused trauma ( n  = 71); (3) multi-trauma ( n  = 43). The three clusters differed significantly on their AVH ratings of amount of negative content, with trend-level effects for loudness, degree of negative content and degree of experienced distress. Furthermore, perceptions of voices being malevolent, benevolent and resistance towards voices differed significantly. Conclusion: The data revealed different types of childhood trauma had different relationships between clinical and phenomenological features of voice-hearing experiences. Thus, implicating different mechanistic pathways and a need for tailored treatment approaches.

Introduction: Cognitive deficits are present in some, but not all patients with schizophrenia-spectrum disorders (SSD). We and others have demonstrated three cognitive clusters: cognitively intact patients, patients with deficits in a few domains and those with global cognitive deficits. This study aimed to identify cognitive subtypes of early-phase SSD with matched controls as a reference group, and evaluated cognitive subgroups regarding clinical and brain volumetric measures., Methods: Eighty-six early-phase SSD patients were included. Hierarchical cluster analysis was conducted using global performance on the Brief Assessment of Cognition in Schizophrenia (BACS). Cognitive subgroups were subsequently related to clinical and brain volumetric measures (cortical, subcortical and cortical thickness) using ANCOVA., Results: Three distinct cognitive clusters emerged: relative to controls we found one cluster of patients with preserved cognition (n = 25), one moderately impaired cluster (n = 38) and one severely impaired cluster (n = 23). Cognitive subgroups were characterized by differences in volume of the left postcentral gyrus, left middle caudal frontal gyrus and left insula, while differences in cortical thickness were predominantly found in fronto-parietal regions. No differences were demonstrated in subcortical brain volume., Discussion: Current results replicate the existence of three distinct cognitive subgroups including one relatively large group with preserved cognitive function. Cognitive subgroups were characterized by differences in cortical regional brain volume and cortical thickness, suggesting associations with cortical, but not subcortical development and cognitive functioning such as attention, executive functions and speed of processing., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Schizophrenia-spectrum disorders (SSD) are highly heterogeneous in risk factors, symptom characteristics, and disease course outcome. Although speech anomalies have long been recognized as a core symptom of SSD, speech markers are an unexplored source of symptom heterogeneity that may be informative in recognizing relevant subtypes. This study investigated speech heterogeneity and its relation to clinical characteristics in a large sample of patients with SSD and healthy controls. Speech samples were obtained from 142 patients with SSD and 147 healthy controls by means of open-ended interviews. Speech was analyzed using standardized open-source acoustic speech software. Hierarchical clustering was conducted using acoustic speech markers. Symptom severity was rated with the Positive and Negative Syndrome Scale, and cognition was assessed with the Brief Assessment of Cognition for Schizophrenia. Three speech clusters could be distinguished in the patient group that differed regarding speech properties, independent of medication use. One cluster was characterized by mild speech disturbances, while two severely impaired clusters were recognized (fragmented speakers and prolonged pausers). Both clusters with severely impaired speech had more severe cognitive dysfunction than the mildly impaired speakers. Prolonged pausers specifically had difficulties with memory-related tasks. Prolonged pausing, as opposed to fragmented speaking, related to chronic active psychosis and refractory psychotic symptoms. Based on speech clustering, subtypes of patients emerged with distinct disease trajectories, symptomatology, and cognitive functioning. The identification of clinically relevant subgroups within SSD may help to characterize distinct profiles and benefit the tailoring of early intervention and improvement of long-term functional outcome. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background: The symptom severity of a substantial group of schizophrenia patients (30-40%) does not improve through pharmacotherapy with antipsychotic medication, indicating a clear need for new treatment options to improve schizophrenia outcome. Meta-analyses, genetic studies, randomized controlled trials, and post-mortem studies suggest that immune dysregulation plays a role in the pathophysiology of schizophrenia. Some anti-inflammatory drugs have shown beneficial effects on the symptom severity of schizophrenia patients. Corticosteroids are effective in various chronic inflammatory and autoimmune disorders. Prednisolone, a potent glucocorticosteroid, has minor mineral-corticosteroid potencies and can adequately pass the blood-brain barrier and its side effects and safety profile are well known. Therefore, the effect of prednisolone can be studied as a proof of concept for immune modulation as a treatment for schizophrenia., Methods/design: In total, 90 subjects aged 18-70 years and diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder (Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) 295.x) or psychosis not otherwise specified (NOS; 298.9) will be included. The time interval between the onset of psychosis and study entry should not exceed 7 years. Patients will be randomized 1:1 to either prednisolone or placebo daily for a period of 6 weeks in addition to a stable dose of antipsychotic medication. Study medication will be initiated at 40 mg for 3 days, after which it will be tapered down within 6 weeks after initiation, following inflammatory bowel diseases treatment guidelines. Primary outcome is change in symptom severity, expressed as change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of treatment. Cognitive functioning (measured through the Brief Assessment of Cognition in Schizophrenia (BACS)) and change in Global Assessment Functioning (GAF) and depressive symptoms as measured with the Calgary Depression Scale for Schizophrenia (CDS) will be assessed, in addition to various immunological biomarkers. Secondary outcomes are a 4- and 6-month follow-up assessment of PANSS, BACS, and GAF scores and immunological biomarkers. Additionally, a subgroup of patients will be included in the magnetic resonance imaging (MRI) part of the study where MR spectroscopy and structural, functional, and diffusion MRI will be conducted., Discussion: It is expected that prednisolone addition to current antipsychotic medication use will reduce symptom severity and will improve cognition when compared to placebo., Trial Registration: ClinicalTrials.gov, NCT02949232 and NCT03340909. Registered 31 October 2016 and 14 November 2017. EudraCT-number 2014-000520-14 and 2017-000163-32.

Background: Antipsychotic medication is effective for symptomatic treatment in schizophrenia-spectrum disorders. After symptom remission, continuation of antipsychotic treatment is associated with lower relapse rates and lower symptom severity compared to dose reduction/discontinuation. Therefore, most guidelines recommend continuation of treatment with antipsychotic medication for at least 1 year. Recently, however, these guidelines have been questioned as one study has shown that more patients achieved long-term functional remission in an early discontinuation condition-a finding that was not replicated in another recently published long-term study., Methods/design: The HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment) study is a multicenter pragmatic single-blind randomized controlled trial in two parallel conditions (1:1) investigating the effects of continuation versus dose-reduction/discontinuation of antipsychotic medication after remission of a first episode of psychosis (FEP) on personal and social functioning, psychotic symptom severity, and health-related quality of life. In total 512 participants will be included, aged between 16 and 60 years, in symptomatic remission from a FEP for 3-6 months, and for whom psychosis was not associated with severe or life-threatening self-harm or violence. Recruitment will take place at 24 Dutch sites. Patients are randomized (1:1) to: continuation of antipsychotic medication until at least 1 year after remission (original dose allowing a maximum reduction of 25%, or another antipsychotic drug in similar dose range); or gradual dose reduction till eventual discontinuation of antipsychotics according to a tapering schedule. If signs of relapse occur in this arm, medication dose can be increased again. Measurements are conducted at baseline, at 3, and 6 months post-baseline, and yearly during a follow-up period of 4 years., Discussion: The HAMLETT study will offer evidence to guide patients and clinicians regarding questions concerning optimal treatment duration and when to taper off medication after remission of a FEP. Moreover, it may provide patient characteristics associated with safe dose reduction with a minimal risk of relapse., Trial Status: Protocol version 1.3, October 2018. The study is active and currently recruiting patients (since September 2017), with the first 200 participants by the end of 2019. We anticipate completing recruitment in 2022 and final assessments (including follow-up 3.5 years after phase one) in 2026., Trial Registration: European Clinical Trials Database, EudraCT number 2017-002406-12. Registered 7 June 2017.

Purpose of Review: To provide an update of recent studies relevant for maintenance treatment with antipsychotic medication after a first psychotic episode (FEP)., Recent Findings: Despite controversy derived from a follow-up analysis from an earlier study showing that attempted early discontinuation after remission was associated with improved long-term functioning, most other studies support better long-term outcome with continuous maintenance treatment after the first episode. However, the main question is not whether, but for how long maintenance treatment after FEP should be offered. Consistent evidence shows that withdrawal from antipsychotics increases the risk for a relapse or re-hospitalization. On the other hand, maintenance treatment is associated with the risk to develop burdensome antipsychotic-induced side-effects and one should keep in mind that around 20% of FEP will not have a second episode. In this regard, the decision for maintenance treatment for periods above some months must be the result of a comprehensive risk-benefit evaluation during a shared decision-making process., Summary: There is no replicated evidence that prognosis can be improved by discontinuing antipsychotic medication after a FEP. There is a clear need for additional studies to develop single-subject outcome predictors and to identify long-term efficacy of maintenance treatment beyond relapse (e.g. recovery).

Cannabis remains the most frequently used illicit drug worldwide. It produces a broad range of acute effects, such as euphoria, increased heart rate and perceptual alterations. Over the last few decades, a substantial number of experiments have been conducted to provide insight into the acute effects of cannabis on cognition. Here, we systematically review studies that investigated the impact of administration of cannabis or [INCREMENT]-tetrahydrocannabinol, the main psychoactive constituent of cannabis, on human executive function, in particular, on the three principal domains of inhibition, working memory and reasoning/association. Our findings suggest that cannabis use results in acute impairment of inhibition, with the strongest effects after pulmonary administration of higher doses of [INCREMENT]-tetrahydrocannabinol. Results from neuroimaging studies indicate that these effects are predominantly modulated through neural processes in the inferior frontal gyrus. Working memory and reasoning/association are less clearly affected by cannabis administration, possibly because of compensational neural mechanisms to overcome the effects of cannabis intoxication on performance accuracy. Factors that may account for the variation in results are the extent to which a paradigm involves attentional processes, differences between studies in administration methods and variation in the patients' history of cannabis use.

When differential diagnosis of dementia includes both Alzheimer's disease (AD) and the behavioural variant of frontotemporal dementia (bvFTD), distribution of cerebral glucose metabolism as measured using [ 18 F]‑2‑fluoro‑2‑deoxy‑d‑glucose positron emission tomography ([ 18 F]FDG-PET) may be helpful. One important clue for differentiation is the presence of hypometabolism in the posterior cingulate cortex (PCC), usually associated with AD. PCC hypometabolism however, could also be present in bvFTD. Therefore, the specificity of PCC hypometabolism was examined. Based on visual reading PCC hypometabolism was present in 69-73/81 probable AD patients, in 10-16/33 probable bvFTD patients, and in 0-1/22 cognitive normal (CN) subjects. Findings were validated using a PCC to reference tissue [ 18 F]FDG standard uptake value ratio (SUVr) cut-off, which was derived from the receiver operating characteristic (ROC) separating probable AD from CN, resulting in 9-14/33 bvFTD patients having PCC hypometabolism, depending on the reference tissue used. In conclusion, PCC hypometabolism is not restricted to AD.

The recently discovered fur gene encodes a membrane-associated protein with a recognition function. To further characterize the gene, we studied its expression by Northern blot analysis using poly(A)-selected RNA from a variety of organs of African green monkey and rat. The fur gene appeared to be differentially expressed, relatively high levels of fur mRNA being present in specimens of liver and kidney, low levels in brain, spleen, and thymus, and very low levels in heart muscle, lung, and testis. mRNA levels in specimens of human lung tissue without neoplastic lesions were also very low. Similar analyses of primary human lung carcinomas of different histopathological types revealed a highly selective and strong elevation of fur expression in nonsmall cell lung carcinomas, but not in small cell lung carcinomas. These results indicate that fur expression can be used to discriminate between these two types of human lung cancer.