Clonidine for post-traumatic stress disorder: a systematic review of the current evidence

Background: Clonidine is a centrally acting anti-adrenergic agent that may have applications in post-traumatic stress disorder (PTSD), particularly for sleep.Objective: In this systematic review, we aimed to summarize the effect of clonidine on sleep quality and duration, nightmares, and PTSD symptom severity in adults with PTSD.Method: PubMed (Medline), Embase, PsycINFO, CINAHL, and clinicaltrials.gov were searched up to April 2023. Studies on clonidine use in adult PTSD patients reporting data on the effect on sleep, nightmares, and PTSD symptoms were included. A narrative summary and a meta-analysis of the study findings are presented.Results: Ten reports, accounting for N = 569 patients with PTSD (145 on clonidine and 436 controls), were included in the final selection. There were four case reports, four observational studies, one non-blind clinical trial, and one crossover randomized controlled trial (RCT). Median clonidine dose was 0.15 mg/day (range: 0.1-0.5 mg/day). Median follow-up time was 31 days (range: 3 days to 19 months). The quality of the evidence was rated from very low to low. There was marked between-study heterogeneity and low power in the individual studies, but many reported improved sleep quality, nightmare reduction, and improvement of PTSD symptoms for patients treated with clonidine. Meta-analysis was only possible for two studies reporting the effect of clonidine on nightmares, and showed no difference from the comparator (i.e. prazosin or terazosin) (odds ratio: 1.16; 95% confidence interval: 0.66 to 2.05), potentially pointing towards non-inferiority between these medications.Conclusions: Future research, such as well-powered RCTs, is needed to identify the efficacy in the lower dose range and the most suitable treatment group, and to obtain good evidence on the effects of clonidine in the treatment of sleep disorders related to PTSD.Post-traumatic stress disorder (PTSD) is associated with hyperarousal and sleep disorders, reflecting adrenergic nervous system involvement.The use of anti-adrenergic drugs to target the sympathetic activation in PTSD is rational. However, previous reports on prazosin, a peripherally acting agent, yielded weak evidence.Clonidine, a central adrenergic antagonist, shows promise in improving sleep, nightmares, and PTSD symptoms, but further research is needed because the quality of the current evidence is low.Antecedentes: La clonidina es un agente antiadren & eacute;rgico de acci & oacute;n central que podr & iacute;a tener aplicaciones en el trastorno de estr & eacute;s postraum & aacute;tico (TEPT), particularmente para el sue & ntilde;o.Objetivo: En esta revisi & oacute;n sistem & aacute;tica el objetivo fue resumir el efecto de la clonidina sobre la calidad y duraci & oacute;n del sue & ntilde;o, las pesadillas y la gravedad de los s & iacute;ntomas de TEPT en adultos con TEPT.M & eacute;todo: Se realizaron b & uacute;squedas en PubMed (Medline), Embase, PsycINFO, CINAHL y Clinicaltrials.gov hasta abril de 2023. Se incluyeron estudios sobre el uso de clonidina en pacientes adultos con TEPT informando datos sobre el efecto en el sue & ntilde;o, pesadillas y s & iacute;ntomas de TEPT. Se presenta un resumen narrativo y un metan & aacute;lisis de los hallazgos del estudio.Resultados: En la selecci & oacute;n final se incluyeron diez comunicaciones, que representaban N = 569 pacientes con TEPT (145 con clonidina y 436 controles). Hubo 4 informes de casos, 4 estudios observacionales, 1 ensayo cl & iacute;nico no ciego y 1 ensayo cl & iacute;nico aleatorizado (ECA) cruzado. La dosis mediana de clonidina fue de 0,15 mg/d & iacute;a (rango: 0,1-0,5 mg/d & iacute;a). La mediana del tiempo de seguimiento fue de 31 d & iacute;as (entre 3 d & iacute;as y 19 meses). La calidad de la evidencia se calific & oacute; de muy baja a baja. Hubo una marcada heterogeneidad entre los estudios y un poder estad & iacute;stico bajo en los estudios individuales, pero muchos informaron una mejor calidad del sue & ntilde;o, una reducci & oacute;n de las pesadillas y una mejor & iacute;a de los s & iacute;ntomas de TEPT en los pacientes tratados con clonidina. El metan & aacute;lisis solo fue posible para dos estudios que informaron el efecto de la clonidina sobre las pesadillas y no mostr & oacute; diferencias con el comparador (es decir, prazosina o terazosina) (OR: 1,16; IC del 95 %: 0,66; 2,05), potencialmente apuntando hacia una no inferioridad entre estos medicamentos.Conclusiones: Se necesitan investigaciones futuras, como ECA de suficiente poder, para identificar la eficacia en el rango de dosis m & aacute;s bajo, el grupo de tratamiento m & aacute;s adecuado y obtener buena evidencia de los efectos de la clonidina para el tratamiento de los trastornos del sue & ntilde;o relacionados con el TEPT

Clonidine for post-traumatic stress disorder: a systematic review of the current evidence

Background: Clonidine is a centrally acting anti-adrenergic agent that may have applications in post-traumatic stress disorder (PTSD), particularly for sleep.Objective: In this systematic review, we aimed to summarize the effect of clonidine on sleep quality and duration, nightmares, and PTSD symptom severity in adults with PTSD.Method: PubMed (Medline), Embase, PsycINFO, CINAHL, and clinicaltrials.gov were searched up to April 2023. Studies on clonidine use in adult PTSD patients reporting data on the effect on sleep, nightmares, and PTSD symptoms were included. A narrative summary and a meta-analysis of the study findings are presented.Results: Ten reports, accounting for N = 569 patients with PTSD (145 on clonidine and 436 controls), were included in the final selection. There were four case reports, four observational studies, one non-blind clinical trial, and one crossover randomized controlled trial (RCT). Median clonidine dose was 0.15 mg/day (range: 0.1-0.5 mg/day). Median follow-up time was 31 days (range: 3 days to 19 months). The quality of the evidence was rated from very low to low. There was marked between-study heterogeneity and low power in the individual studies, but many reported improved sleep quality, nightmare reduction, and improvement of PTSD symptoms for patients treated with clonidine. Meta-analysis was only possible for two studies reporting the effect of clonidine on nightmares, and showed no difference from the comparator (i.e. prazosin or terazosin) (odds ratio: 1.16; 95% confidence interval: 0.66 to 2.05), potentially pointing towards non-inferiority between these medications.Conclusions: Future research, such as well-powered RCTs, is needed to identify the efficacy in the lower dose range and the most suitable treatment group, and to obtain good evidence on the effects of clonidine in the treatment of sleep disorders related to PTSD

The Measurement of Language Lateralization with Functional Transcranial Doppler and Functional MRI: A Critical Evaluation

Cerebral language lateralization can be assessed in several ways. In healthy subjects, functional MRI (fMRI) during performance of a language task has evolved to be the most frequently applied method. Functional transcranial Doppler (fTCD) may provide a valid alternative, but has been used rarely. Both techniques have their own strengths and weaknesses and as a result may be applied in different fields of research. Until now, only one relatively small study (n = 13) investigated the correlation between lateralization indices (LIs) measured by fTCD and fMRI and showed a remarkably high correlation. To further evaluate the correlation between LIs measured with fTCD and fMRI, we compared LIs of 22 healthy subjects (12 left- and 10 right-handed) using the same word generation paradigm for the fTCD as for the fMRI experiment. LIs measured with fTCD were highly but imperfectly correlated with LIs measured with fMRI (Spearman's rho = 0.75, p < 0.001). The imperfectness of the correlation can partially be explained by methodological restrictions of fMRI as well as fTCD. Our results suggest that fTCD can be a valid alternative for fMRI to measure lateralization, particularly when costs or mobility are important factors in the study design

Negative parenting, epigenetic age, and psychological problems: prospective associations from adolescence to young adulthood

Background: Epigenetic clocks are based on DNA methylation levels of several genomic loci and have been developed as indices of biological aging. Studies examining the effects of stressful environmental exposures have shown that stress is associated with differences between epigenetic age and chronological age (i.e., Epigenetic Age acceleration, EA). This pre-registered longitudinal study examined the long-term effects of negative parenting and psychological problems throughout adolescence (ages 13–17 years) on EA in late adolescence (age 17 years) and EA changes from late adolescence to young adulthood (age 25 years). Further, it examined how (change in) EA is related to changes in psychological problems from adolescence to young adulthood. Methods: We used data from a sample of 434 participants followed from age 13 to age 25, with saliva collected at ages 17 and 25. We estimated EA using four commonly used epigenetic clocks and analyzed the data using Structural Equation Modeling. Results: While negative parenting was not related to EA nor change in EA, (change in) EA was related to developmental indices such as externalizing problems and self-concept clarity. Conclusions: Declining psychological well-being during young adulthood was preceded by EA

Negative parenting, epigenetic age, and psychological problems: prospective associations from adolescence to young adulthood

Background: Epigenetic clocks are based on DNA methylation levels of several genomic loci and have been developed as indices of biological aging. Studies examining the effects of stressful environmental exposures have shown that stress is associated with differences between epigenetic age and chronological age (i.e., Epigenetic Age acceleration, EA). This pre-registered longitudinal study examined the long-term effects of negative parenting and psychological problems throughout adolescence (ages 13–17 years) on EA in late adolescence (age 17 years) and EA changes from late adolescence to young adulthood (age 25 years). Further, it examined how (change in) EA is related to changes in psychological problems from adolescence to young adulthood. Methods: We used data from a sample of 434 participants followed from age 13 to age 25, with saliva collected at ages 17 and 25. We estimated EA using four commonly used epigenetic clocks and analyzed the data using Structural Equation Modeling. Results: While negative parenting was not related to EA nor change in EA, (change in) EA was related to developmental indices such as externalizing problems and self-concept clarity. Conclusions: Declining psychological well-being during young adulthood was preceded by EA

Delayed school progression and mental health problems in adolescence:A population-based study in 10,803 adolescents

Background Accumulating evidence suggests that several adult mental disorders, particularly psychoses, are preceded by impairments in cognitive function, reflected in scholastic underachievement. This study investigates the association between scholastic underachievement and general mental health problems in adolescence, using delay in school progression as a marker of poor scholastic performance.MethodCross-sectional secondary school survey comprising 10,803 adolescents. Participants completed the Strengths and Difficulties Questionnaire (SDQ) to assess mental health problems. The association of delayed school progression with the SDQ was investigated using logistic regression with SDQ as outcome and delayed school progression as primary exposure of interest while adjusting for socio-demographic characteristics, adverse life events, school-related factors, risk taking behaviour, healthy lifestyle and physical health.ResultsUnadjusted analysis showed an association between delayed school progression and total mental health problems (OR 1.83, 95% CI 1.27 - 2.63) in adolescents. After adjusting for other risk factors (socio-demographic factors and life events) in a logistic regression model the association between delayed school progression en mental health problems was attenuated (OR 1.33, 95% CI 0.86 - 2.05).ConclusionDelayed school progression is associated with general mental health problems in adolescence, but this relationship is heavily confounded by other factors. A causal relationship between impaired cognitive function such as poor scholastic performance and general mental health at adolescence is less likely and delayed school progression may merely be considered an indicator of risk for mental health problems.</p

Shape and volume changes of the superior lateral ventricle after electroconvulsive therapy measured with ultra-high field MRI

The subventricular zone (SVZ) of the lateral ventricles harbors neuronal stem cells in adult mammals. Rodent studies report neurogenic effects in the SVZ of electroconvulsive stimulation. We hypothesize that if this finding translates to depressed patients undergoing electroconvulsive therapy (ECT), this would be reflected in shape changes at the SVZ. Using T1-weighted MR images acquired at ultra-high field strength (7T), the shape and volume of the ventricles were compared from pre to post ECT after 10 ECT sessions (in patients twice weekly) or 5 weeks apart (controls) using linear mixed models with age and gender as covariates. Ventricle shape significantly changed and volume significantly decreased over time in patients for the left ventricle, but not in controls. The decrease in volume of the ventricles was associated to a decrease in depression scores, and an increase in the left dentate gyrus, However, the shape changes of the ventricles were not restricted to the neurogenic niche in the lateral walls of the ventricles, providing no clear evidence for neurogenesis as sole explanation of volume changes in the ventricles after ECT

Accelerated brain aging as a biomarker for staging in bipolar disorder:An exploratory study

Background:Two established staging models outline the longitudinal progression in bipolar disorder (BD) based on episode recurrence or inter-episodic functioning. However, underlying neurobiological mechanisms and corresponding biomarkers remain unexplored. This study aimed to investigate if global and (sub)cortical brain structures, along with brain-predicted age difference (brain-PAD) reflect illness progression as conceptualized in these staging models, potentially identifying brain-PAD as a biomarker for BD staging. Methods:In total, 199 subjects with bipolar-I-disorder and 226 control subjects from the Dutch Bipolar Cohort with a high-quality T1-weighted magnetic resonance imaging scan were analyzed. Global and (sub)cortical brain measures and brain-PAD (the difference between biological and chronological age) were estimated. Associations between individual brain measures and the stages of both staging models were explored. Results:A higher brain-PAD (higher biological age than chronological age) correlated with an increased likelihood of being in a higher stage of the inter-episodic functioning model, but not in the model based on number of mood episodes. However, after correcting for the confounding factors lithium-use and comorbid anxiety, the association lost significance. Global and (sub)cortical brain measures showed no significant association with the stages. Conclusions:These results suggest that brain-PAD may be associated with illness progression as defined by impaired inter-episodic functioning. Nevertheless, the significance of this association changed after considering lithium-use and comorbid anxiety disorders. Further research is required to disentangle the intricate relationship between brain-PAD, illness stages, and lithium intake or anxiety disorders. This study provides a foundation for potentially using brain-PAD as a biomarker for illness progression.</p