FFDOPA PET imaging has shown dopaminergic function indexed as K
differs between antipsychotic treatment responders and non-responders. However, the theragnostic potential of this biomarker to ...identify non-responders has yet to be evaluated. In view of this, we aimed to evaluate this as a theragnostic test using linear and non-linear machine-learning (i.e., Bernoulli, support vector, random forest and Gaussian processes) analyses and to develop and evaluate a simplified approach, standardised uptake value ratio (SUVRc). Both
FFDOPA PET approaches had good test-rest reproducibility across striatal regions (K
ICC: 0.68-0.94, SUVRc ICC: 0.76-0.91). Both our linear and non-linear classification models showed good predictive power to distinguish responders from non-responders (receiver operating curve area under the curve for region-of-interest approach: K
= 0.80, SUVRc = 0.79; for voxel-wise approach using a linear support vector machine: 0.88) and similar sensitivity for identifying treatment non-responders with 100% specificity (K
: ~50%, SUVRc: 40-60%). Although the findings were replicated in two independent datasets, given the total sample size (n = 84) and single setting, they warrant testing in other samples and settings. Preliminary economic analysis of
FFDOPA PET to fast-track treatment-resistant patients with schizophrenia to clozapine indicated a potential healthcare cost saving of ~£3400 (equivalent to $4232 USD) per patient. These findings indicate
FFDOPA PET dopamine imaging has potential as biomarker to guide treatment choice.
Recent work has suggested that disorganised speech might be a powerful predictor of later psychotic illness in clinical high risk subjects. To that end, several automated measures to quantify ...disorganisation of transcribed speech have been proposed. However, it remains unclear which measures are most strongly associated with psychosis, how different measures are related to each other and what the best strategies are to collect speech data from participants. Here, we assessed whether twelve automated Natural Language Processing markers could differentiate transcribed speech excerpts from subjects at clinical high risk for psychosis, first episode psychosis patients and healthy control subjects (total N = 54). In-line with previous work, several measures showed significant differences between groups, including semantic coherence, speech graph connectivity and a measure of whether speech was on-topic, the latter of which outperformed the related measure of tangentiality. Most NLP measures examined were only weakly related to each other, suggesting they provide complementary information. Finally, we compared the ability of transcribed speech generated using different tasks to differentiate the groups. Speech generated from picture descriptions of the Thematic Apperception Test and a story re-telling task outperformed free speech, suggesting that choice of speech generation method may be an important consideration. Overall, quantitative speech markers represent a promising direction for future clinical applications.
Background:
There is a pressing need for new classes of treatment for psychosis. A key therapeutic target for novel compounds is the NMDA receptor, which may be modulated by nitric oxide donors such ...as sodium nitroprusside (SNP). Recent studies of SNP in patients with psychosis have mixed results, and the drug has to be administered intravenously. Glyceryl trinitrate (GTN) is a well-established cardiovascular medicine that is also a nitric oxide donor, and can be given orally.
Aims:
We explored the safety and potential effects of GTN in unmedicated patients with a first episode of psychosis.
Methods:
This was a single-centre, randomised, double-blind, placebo-controlled trial from December 2016 to April 2019 (ClinicalTrials.gov identifier: NCT02906553). Patients received 3 × sprays of GTN or placebo for three consecutive days, and were re-assessed on Days 1, 2, 3 and 7. The primary outcome was cognition (Jumping to Conclusions task), secondary outcomes were symptoms (Positive and Negative Syndrome Scale (PANSS)), verbal memory (Hopkins Verbal Learning task), and mood (Bond–Lader Visual Analogue Scales).
Results:
Nineteen patients were randomised, and 13 participants were included in the analyses. Compared with placebo, GTN was well tolerated, but was not associated with significant effects on cognition, symptoms, or mood. Bayesian statistics indicate that our results were 2× more likely under the null hypothesis than the alternative hypothesis, providing anecdotal evidence that GTN does not improve psychotic symptoms.
Conclusions:
We found no indication of an effect of GTN on symptoms of psychosis or cognition.
Neuropsychological investigations can help untangle the aetiological and phenomenological heterogeneity of schizophrenia but have scarcely been employed in the context of treatment-resistant (TR) ...schizophrenia. No population-based study has examined neuropsychological function in the first-episode of TR psychosis.
We report baseline neuropsychological findings from a longitudinal, population-based study of first-episode psychosis, which followed up cases from index admission to 10 years. At the 10-year follow up patients were classified as treatment responsive or TR after reconstructing their entire case histories. Of 145 cases with neuropsychological data at baseline, 113 were classified as treatment responsive, and 32 as TR at the 10-year follow-up.
Compared with 257 community controls, both case groups showed baseline deficits in three composite neuropsychological scores, derived from principal component analysis: verbal intelligence and fluency, visuospatial ability and executive function, and verbal memory and learning (p values⩽0.001). Compared with treatment responders, TR cases showed deficits in verbal intelligence and fluency, both in the extended psychosis sample (t = -2.32; p = 0.022) and in the schizophrenia diagnostic subgroup (t = -2.49; p = 0.017). Similar relative deficits in the TR cases emerged in sub-/sensitivity analyses excluding patients with delayed-onset treatment resistance (p values<0.01-0.001) and those born outside the UK (p values<0.05).
Verbal intelligence and fluency are impaired in patients with TR psychosis compared with those who respond to treatment. This differential is already detectable - at a group level - at the first illness episode, supporting the conceptualisation of TR psychosis as a severe, pathogenically distinct variant, embedded in aberrant neurodevelopmental processes.
Despite considerable psychotherapeutic advancement since the discovery of chlorpromazine, almost one third of patients with schizophrenia remain resistant to dopamine-blocking antipsychotics, and ...continue to be exposed to unwanted and often disabling side effects, but little if any clinical benefit. Even clozapine, the superior antipsychotic treatment, is ineffective in approximately half of these patients. Thus treatment resistant schizophrenia (TRS), continues to present a major therapeutic challenge to psychiatry. The main impediment to finding novel treatments is the lack of understanding of precise molecular mechanisms leading to TRS. Not only has the neurobiology been enigmatic for decades, but accurate and early detection of patients who are at risk of not responding to dopaminergic blockade remains elusive. Fortunately, recent work has started to unravel some of the neurobiological mechanisms underlying treatment resistance, providing long awaited answers, at least to some extent. Here we focus on the scientific advances in the field, from the clinical course of TRS to neurobiology and available treatment options. We specifically emphasize emerging evidence from TRS imaging and genetic literature that implicates dysregulation in several neurotransmitters, particularly dopamine and glutamate, and in addition genetic and neural alterations that concertedly may lead to the formation of TRS. Finally, we integrate available findings into a putative model of TRS, which may provide a platform for future studies in a bid to open the avenues for subsequent development of effective therapeutics.Despite considerable psychotherapeutic advancement since the discovery of chlorpromazine, almost one third of patients with schizophrenia remain resistant to dopamine-blocking antipsychotics, and continue to be exposed to unwanted and often disabling side effects, but little if any clinical benefit. Even clozapine, the superior antipsychotic treatment, is ineffective in approximately half of these patients. Thus treatment resistant schizophrenia (TRS), continues to present a major therapeutic challenge to psychiatry. The main impediment to finding novel treatments is the lack of understanding of precise molecular mechanisms leading to TRS. Not only has the neurobiology been enigmatic for decades, but accurate and early detection of patients who are at risk of not responding to dopaminergic blockade remains elusive. Fortunately, recent work has started to unravel some of the neurobiological mechanisms underlying treatment resistance, providing long awaited answers, at least to some extent. Here we focus on the scientific advances in the field, from the clinical course of TRS to neurobiology and available treatment options. We specifically emphasize emerging evidence from TRS imaging and genetic literature that implicates dysregulation in several neurotransmitters, particularly dopamine and glutamate, and in addition genetic and neural alterations that concertedly may lead to the formation of TRS. Finally, we integrate available findings into a putative model of TRS, which may provide a platform for future studies in a bid to open the avenues for subsequent development of effective therapeutics.
Brain presynaptic dopaminergic function can be assessed using 18F-DOPA positron emission tomography (PET). Regional 18F-DOPA utilization may be used to index dopaminergic abnormalities over time or ...dopaminergic response to treatment in clinical populations. Such studies require prior knowledge of the stability of the 18F-DOPA signal in the brain regions of interest. Test–retest reliability was examined in eight healthy volunteers who each received two 18F-DOPA PET scans, approximately 2 years apart. 18F-DOPA utilization (kicer) was determined using graphical analysis relative to a reference tissue input (Patlak and Blasberg, 1985). Reproducibility (measured as the within-subjects variation) and reliability (measured as intraclass correlation coefficients, ICCs) of 18F-DOPA kicer were assessed in the structural and functional subdivisions of the striatum and select extrastriatal brain regions. Voxel-based median ICC maps were used to visualize the distribution of 18F-DOPA kicer reliability across the brain. The caudate and putamen, and associative and sensorimotor, striatal subdivisions showed good reliability across the two scan sessions with bilateral ICCs ranging from 0.681 to 0.944. Reliability was generally lower in extrastriatal regions, with bilateral ICCs ranging from 0.235 in the amygdala to 0.894 in the thalamus. These data confirm the utility of 18F-DOPA PET in assessing dopaminergic function in the striatum and select extrastriatal areas but highlight the limitations in using this approach to measure dopaminergic function in low uptake extrastriatal brain areas. This information can be used to optimize the experimental design of future studies investigating changes in brain dopaminergic function with 18F-DOPA.
Negative psychotic symptoms are among the most disabling features of schizophrenia, and are strongly associated with relatively poor clinical and functional outcomes. However, there are no effective ...treatments for negative symptoms, and this represents a major unmet clinical need. Recent research has shown that negative symptoms are already present in many patients at illness onset. There is evidence that cariprazine may improve negative symptoms in patients with chronic schizophrenia. However, its utility in treating negative symptoms in the early stage of the disorder is unclear. Here, we report six cases of patients with first-episode psychosis who were treated with cariprazine.
Self-harm in first-episode psychosis Harvey, Samuel B; Dean, Kimberlie; Morgan, Craig ...
British journal of psychiatry
192, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Little is known about self-harm occurring during the period of untreated first-episode psychosis.
To establish the prevalence, nature, motivation and risk factors for self-harm occurring during the ...untreated phase of first-episode psychosis.
As part of the AESOP (Aetiology and Ethnicity in Schizophrenia and Other Psychoses) study, episodes of self-harm were identified among all incident cases of psychosis presenting to services in south-east London and Nottingham over a 2-year period.
Of the 496 participants, 56 (11.3%) had engaged in self-harm between the onset of psychotic symptoms and first presentation to services. The independent correlates of self-harm were: male gender, belonging to social class I/II, depression and a prolonged period of untreated psychosis. Increased insight was also associated with risk of self-harm.
Self-harm is common during the pre-treatment phase of first-episode psychosis. A unique set of fixed and malleable risk factors appear to operate in those with first-episode psychosis. Reducing treatment delay and modifying disease attitudes may be key targets for suicide prevention.
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