Candidate Gene-Based Association Study of Antipsychotic-Induced Movement Disorders in Long-Stay Psychiatric Patients: A Prospective Study

OBJECTIVE: Four types of antipsychotic-induced movement disorders: tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia, subtypes of TD (orofacial and limb truncal dyskinesia), subtypes of parkinsonism (rest tremor, rigidity, and bradykinesia), as well as a principal-factor of the movement disorders and their subtypes, were examined for association with variation in 10 candidate genes (PPP1R1B, BDNF, DRD3, DRD2, HTR2A, HTR2C, COMT, MnSOD, CYP1A2, and RGS2). METHODS: Naturalistic study of 168 white long-stay patients with chronic mental illness requiring long-term antipsychotic treatment, examined by the same rater at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. The authors genotyped 31 SNPs, associated with movement disorders or schizophrenia in previous studies. Genotype and allele frequency comparisons were performed with multiple regression methods for continuous movement disorders. RESULTS: VARIOUS SNPS REACHED NOMINAL SIGNIFICANCE: TD and orofacial dyskinesia with rs6265 and rs988748, limb truncal dyskinesia with rs6314, rest tremor with rs6275, rigidity with rs6265 and rs4680, bradykinesia with rs4795390, akathisia with rs4680, tardive dystonia with rs1799732, rs4880 and rs1152746. After controlling for multiple testing, no significant results remained. CONCLUSIONS: The findings suggest that selected SNPs are not associated with a susceptibility to movement disorders. However, as the sample size was small and previous studies show inconsistent results, definite conclusions cannot be made. Replication is needed in larger study samples, preferably in longitudinal studies which take the fluctuating course of movement disorders and gene-environment interactions into account

The association between alterations in motor and cognitive dimensions of schizophrenia-spectrum disorders: a systematic review

Motor and cognitive alterations in schizophrenia-spectrum disorders (SSD) share common neural underpinnings, highlighting the necessity for a thorough exploration of the connections between these areas. This relationship is crucial, as it holds potential significance in unraveling the underlying mechanisms of SSD pathophysiology, ultimately leading to advancements in clinical staging and treatment strategies. The purpose of this review was to characterize the relationship between different hyper and hypokinetic domains of motor alterations and cognition in SSD. We systematically searched the literature (PROSPERO protocol CRD42019145964) and selected 66 original scientific contributions for review, published between 1987 and 2022. A narrative synthesis of the results was conducted. Hyper and hypokinetic motor alterations showed weak to moderate negative correlations with cognitive function across different SSD stages, including before antipsychotic treatment. The literature to date shows a diverse set of methodologies and composite cognitive scores hampering a strong conclusion about which specific cognitive domains were more linked to each group of motor alterations. However, executive functions seemed the domain more consistently associated with parkinsonism with the results regarding dyskinesia being less clear. Akathisia and catatonia were scarcely discussed in the reviewed literature. The present review reinforces the intimate relationship between specific motor alterations and cognition. Identified gaps in the literature challenge the formulation of definitive conclusions. Nevertheless, a discussion of putative underlying mechanisms is included, prompting guidance for future research endeavors.info:eu-repo/semantics/publishedVersio

Clonidine augmentation in patients with schizophrenia:A double-blind, randomized placebo-controlled trial

Introduction: Noradrenergic imbalance in the brain of schizophrenia patients may underlie both symptomatology and deficits in basic information processing. The current study investigated whether augmentation with the noradrenergic α2-agonist clonidine might alleviate these symptoms. Methods: In a double-blind placebo-controlled randomized clinical trial, 32 chronic schizophrenia patients were randomly assigned to six-weeks augmentation with either 50 μg clonidine or placebo to their current medication. Effects on symptom severity and both sensory- and sensorimotor gating were assessed at baseline, 3- and 6-weeks. Results were compared with 21 age- and sex-matched healthy controls (HC) who received no treatment. Results: Only patients treated with clonidine showed significantly reduced PANSS negative, general and total scores at follow-up compared to baseline. On average, also patients treated with placebo showed minor (non-significant) reductions in these scores, likely indicating a placebo effect. Sensorimotor gating of patients was significantly lower at baseline compared to controls. It increased in patients treated with clonidine over the treatment period, whereas it decreased in both the HC and patients treated with placebo. However, neither treatment nor group effects were found in sensory gating. Clonidine treatment was very well tolerated. Conclusion: Only patients treated with clonidine showed a significant decrease on two out of the three PANSS subscales, while additionally retained their levels of sensorimotor gating. Given that there are only a few reports on effective treatment for negative symptoms in particular, our current results support augmentation of antipsychotics with clonidine as a promising, low-cost and safe treatment strategy for schizophrenia

The genetics of drug-related movement disorders, an umbrella review of meta-analyses

This umbrella review investigates which genetic factors are associated with drug-related movement disorders (DRMD), in an attempt to provide a synthesis of published evidence of candidate-gene studies. To identify all relevant meta-analyses, a literature search was performed. Titles and abstracts were screened by two authors and the methodological quality of included meta-analyses was assessed using 'the assessment of multiple systematic reviews' (AMSTAR) critical appraisal checklist. The search yielded 15 meta-analytic studies reporting on genetic variations in 10 genes. DRD3, DRD2, CYP2D6, HTR2A, COMT, HSPG2 and SOD2 genes have variants that may increase the odds of TD. However, these findings do not concur with early genome-wide association studies. Low-power samples are susceptible to 'winner's curse', which was supported by diminishing meta-analytic effects of several genetic variants over time. Furthermore, analyses pertaining to the same genetic variant were difficult to compare due to differences in patient populations, methods used and the choice of studies included in meta-analyses. In conclusion, DRMD is a complex phenotype with multiple genes that impact the probability of onset. More studies with larger samples using other methods than by candidate genes, are essential to developing methods that may predict the probability of DRMD. To achieve this, multiple research groups need to collaborate and a DRMD genetic database needs to be established in order to overcome winner's curse and publication bias, and to allow for stratification by patient characteristics. These endeavours may help the development of a test with clinical value in the prevention and treatment of DRMD

Antipsychotic-Induced Movement Disorders in Long-Stay Psychiatric Patients and 45 Tag SNPs in 7 Candidate Genes: A Prospective Study

Objective: Four types of antipsychotic-induced movement disorders: tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia, subtypes of TD (orofacial and limb truncal dyskinesia), subtypes of parkinsonism (rest tremor, rigidity, and bradykinesia), as well as a principal-factor of the movement disorders and their subtypes, were examined for association with variation in 7 candidate genes (GRIN2B, GRIN2A, HSPG2, DRD3, DRD4, HTR2C, and NQO1). Methods: Naturalistic study of 168 white long-stay patients with chronic mental illness requiring long-term antipsychotic treatment, examined by the same rater at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. The authors genotyped 45 tag SNPs in 7 candidate genes, associated with movement disorders or schizophrenia in previous studies. Genotype and allele frequency comparisons were performed with multiple regression methods for continuous movement disorders. Results: Various tag SNPs reached nominal significance; TD with rs1345423, rs7192557, r

Clonidine augmentation in patients with schizophrenia: A double-blind, randomized placebo-controlled trial

Introduction: Noradrenergic imbalance in the brain of schizophrenia patients may underlie both symptomatology and deficits in basic information processing. The current study investigated whether augmentation with the noradrenergic α2-agonist clonidine might alleviate these symptoms. Methods: In a double-blind placebo-controlled randomized clinical trial, 32 chronic schizophrenia patients were randomly assigned to six-weeks augmentation with either 50 μg clonidine or placebo to their current medication. Effects on symptom severity and both sensory- and sensorimotor gating were assessed at baseline, 3- and 6-weeks. Results were compared with 21 age- and sex-matched healthy controls (HC) who received no treatment. Results: Only patients treated with clonidine showed significantly reduced PANSS negative, general and total scores at follow-up compared to baseline. On average, also patients treated with placebo showed minor (non-significant) reductions in these scores, likely indicating a placebo effect. Sensorimotor gating of patients was significantly lower at baseline compared to controls. It increased in patients treated with clonidine over the treatment period, whereas it decreased in both the HC and patients treated with placebo. However, neither treatment nor group effects were found in sensory gating. Clonidine treatment was very well tolerated. Conclusion: Only patients treated with clonidine showed a significant decrease on two out of the three PANSS subscales, while additionally retained their levels of sensorimotor gating. Given that there are only a few reports on effective treatment for negative symptoms in particular, our current results support augmentation of antipsychotics with clonidine as a promising, low-cost and safe treatment strategy for schizophrenia

Risk Factors for Tremor in a Population of Patients with Severe Mental Illness:An 18-year Prospective Study in a Geographically Representative Sample (The Curacao Extrapyramidal Syndromes Study XI)

BACKGROUND: The aim was to assess incidence, prevalence and risk factors of medication-induced tremor in African-Caribbean patients with severe mental illness (SMI).METHOD: A prospective study of SMI patients receiving care from the only mental health service of the previous Dutch Antilles. Eight clinical assessments, over 18 years, focused on movement disorders, medication use, and resting tremor (RT) and (postural) action tremor (AT). Risk factors were modeled with logistic regression for both current (having) tremor and for tremor at the next time point (developing). The latter used a time-lagged design to assess medication changes prior to a change in tremor state.RESULTS: Yearly tremor incidence rate was 2.9% and mean tremor point prevalence was 18.4%. Over a third of patients displayed tremor during the study. Of the patients, 5.2% had AT with 25% of cases persisting to the next time point, while 17.1% of patients had RT of which 65.3% persisted. When tremor data were examined in individual patients, they often had periods of tremor interspersed with periods of no tremor. Having RT was associated with age (OR=1.07 per year; 95% confidence interval 1.03-1.11), sex (OR=0.17 for males; 0.05-0.78), cocaine use (OR=10.53; 2.22-49.94), dyskinesia (OR=0.90; 0.83-0.97), and bradykinesia (OR=1.16; 1.09-1.22). Developing RT was strongly associated with previous measurement RT (OR=9.86; 3.80-25.63), with previous RT severity (OR=1.22; 1.05-1.41), and higher anticholinergic load (OR= 1.24; 1.08-1.43). Having AT was associated with tremor-inducing medication (OR= 4.54; 1.90-10.86), cocaine use (OR=14.04; 2.38-82.96), and bradykinesia (OR=1.07; 1.01-1.15). Developing AT was associated with, previous AT severity (OR=2.62 per unit; 1.64-4.18) and tremor reducing medication (OR=0.08; 0.01-0.55).CONCLUSIONS: Long-stay SMI patients are prone to developing tremors, which show a relapsing-remitting course. Differentiation between RT and AT is important as risk factors differ and they require different prevention and treatment strategies.</p

Capillary refill time response to a fluid challenge or a vasopressor test:an observational, proof-of-concept study

Background: Several studies have validated capillary refill time (CRT) as a marker of tissue hypoperfusion, and recent guidelines recommend CRT monitoring during septic shock resuscitation. Therefore, it is relevant to further explore its kinetics of response to short-term hemodynamic interventions with fluids or vasopressors. A couple of previous studies explored the impact of a fluid bolus on CRT, but little is known about the impact of norepinephrine on CRT when aiming at a higher mean arterial pressure (MAP) target in septic shock. We designed this observational study to further evaluate the effect of a fluid challenge (FC) and a vasopressor test (VPT) on CRT in septic shock patients with abnormal CRT after initial resuscitation. Our purpose was to determine the effects of a FC in fluid-responsive patients, and of a VPT aimed at a higher MAP target in chronically hypertensive fluid-unresponsive patients on the direction and magnitude of CRT response. Methods: Thirty-four septic shock patients were included. Fluid responsiveness was assessed at baseline, and a FC (500 ml/30 mins) was administered in 9 fluid-responsive patients. A VPT was performed in 25 patients by increasing norepinephrine dose to reach a MAP to 80–85 mmHg for 30 min. Patients shared a multimodal perfusion and hemodynamic monitoring protocol with assessments at at least two time-points (baseline, and at the end of interventions).Results: CRT decreased significantly with both tests (from 5 [3.5–7.6] to 4 [2.4–5.1] sec, p = 0.008 after the FC; and from 4.0 [3.3–5.6] to 3 [2.6 -5] sec, p = 0.03 after the VPT. A CRT-response was observed in 7/9 patients after the FC, and in 14/25 pts after tobjehe VPT, but CRT deteriorated in 4 patients on this latter group, all of them receiving a concomitant low-dose vasopressin. Conclusions: Our findings support that fluid boluses may improve CRT or produce neutral effects in fluid-responsive septic shock patients with persistent hypoperfusion. Conversely, raising NE doses to target a higher MAP in previously hypertensive patients elicits a more heterogeneous response, improving CRT in the majority, but deteriorating skin perfusion in some patients, a fact that deserves further research.</p

Capillary refill time response to a fluid challenge or a vasopressor test:an observational, proof-of-concept study

Background: Several studies have validated capillary refill time (CRT) as a marker of tissue hypoperfusion, and recent guidelines recommend CRT monitoring during septic shock resuscitation. Therefore, it is relevant to further explore its kinetics of response to short-term hemodynamic interventions with fluids or vasopressors. A couple of previous studies explored the impact of a fluid bolus on CRT, but little is known about the impact of norepinephrine on CRT when aiming at a higher mean arterial pressure (MAP) target in septic shock. We designed this observational study to further evaluate the effect of a fluid challenge (FC) and a vasopressor test (VPT) on CRT in septic shock patients with abnormal CRT after initial resuscitation. Our purpose was to determine the effects of a FC in fluid-responsive patients, and of a VPT aimed at a higher MAP target in chronically hypertensive fluid-unresponsive patients on the direction and magnitude of CRT response. Methods: Thirty-four septic shock patients were included. Fluid responsiveness was assessed at baseline, and a FC (500 ml/30 mins) was administered in 9 fluid-responsive patients. A VPT was performed in 25 patients by increasing norepinephrine dose to reach a MAP to 80–85 mmHg for 30 min. Patients shared a multimodal perfusion and hemodynamic monitoring protocol with assessments at at least two time-points (baseline, and at the end of interventions).Results: CRT decreased significantly with both tests (from 5 [3.5–7.6] to 4 [2.4–5.1] sec, p = 0.008 after the FC; and from 4.0 [3.3–5.6] to 3 [2.6 -5] sec, p = 0.03 after the VPT. A CRT-response was observed in 7/9 patients after the FC, and in 14/25 pts after tobjehe VPT, but CRT deteriorated in 4 patients on this latter group, all of them receiving a concomitant low-dose vasopressin. Conclusions: Our findings support that fluid boluses may improve CRT or produce neutral effects in fluid-responsive septic shock patients with persistent hypoperfusion. Conversely, raising NE doses to target a higher MAP in previously hypertensive patients elicits a more heterogeneous response, improving CRT in the majority, but deteriorating skin perfusion in some patients, a fact that deserves further research.</p

FPGA-based Fused Smart Sensor for Real-Time Plant-Transpiration Dynamic Estimation

Plant transpiration is considered one of the most important physiological functions because it constitutes the plants evolving adaptation to exchange moisture with a dry atmosphere which can dehydrate or eventually kill the plant. Due to the importance of transpiration, accurate measurement methods are required; therefore, a smart sensor that fuses five primary sensors is proposed which can measure air temperature, leaf temperature, air relative humidity, plant out relative humidity and ambient light. A field programmable gate array based unit is used to perform signal processing algorithms as average decimation and infinite impulse response filters to the primary sensor readings in order to reduce the signal noise and improve its quality. Once the primary sensor readings are filtered, transpiration dynamics such as: transpiration, stomatal conductance, leaf-air-temperature-difference and vapor pressure deficit are calculated in real time by the smart sensor. This permits the user to observe different primary and calculated measurements at the same time and the relationship between these which is very useful in precision agriculture in the detection of abnormal conditions. Finally, transpiration related stress conditions can be detected in real time because of the use of online processing and embedded communications capabilities