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Journal of Clinical Medicine Sep 2021The aim of this review was to assess the quality of international treatment guidelines for post-traumatic stress disorder (PTSD), and identify differences between... (Review)
Review
BACKGROUND
The aim of this review was to assess the quality of international treatment guidelines for post-traumatic stress disorder (PTSD), and identify differences between guideline recommendations, with a focus on the treatment of nightmares.
METHODS
Guidelines were identified through electronic searches of MEDLINE, CINAHL, PubMed, Embase and Science Direct, as well as web-based searches of international guideline repositories, websites of psychiatric organisations and targeted web-searches for guidelines from the three most populous English-speaking countries in each continent. Data in relation to recommendations were extracted and the AGREE II criteria were applied to assess for quality.
RESULTS
Fourteen guidelines, published between 2004-2020, were identified for inclusion in this review. Only five were less than 5 years old. Three guidelines scored highly across all AGREE II domains, while others varied between domains. Most guidelines consider both psychological and pharmacological therapies as first-line in PTSD. All but one guideline recommended cognitive behavioural therapy (CBT) as first-line psychological treatment, and selective serotonin reuptake inhibitors (SSRIs) as first-line pharmacological treatment. Most guidelines do not mention the targeted treatment of nightmares as a symptom of PTSD. Prazosin is discussed in several guidelines for the treatment of nightmares, but recommendations vary widely. Most PTSD guidelines were deemed to be of good quality; however, many could be considered out of date. Recommendations for core PTSD symptoms do not differ greatly between guidelines. However, despite the availability of targeted treatments for nightmares, most guidelines do not adequately address this.
CONCLUSIONS
Guidelines need to be kept current to maintain clinical utility. Improvements are most needed in the AGREE II key domains of 'applicability', 'rigour of development' and 'stakeholder involvement'. Due to the treatment-resistant nature of nightmares, guideline development groups should consider producing more detailed recommendations for their targeted treatment. More high-quality trials are also required to provide a solid foundation for making these clinical recommendations for the management of nightmares in PTSD.
PubMed: 34575284
DOI: 10.3390/jcm10184175 -
The New England Journal of Medicine Feb 2018In randomized trials, prazosin, an α-adrenoreceptor antagonist, has been effective in alleviating nightmares associated with post-traumatic stress disorder (PTSD) in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In randomized trials, prazosin, an α-adrenoreceptor antagonist, has been effective in alleviating nightmares associated with post-traumatic stress disorder (PTSD) in military veterans.
METHODS
We recruited veterans from 13 Department of Veterans Affairs medical centers who had chronic PTSD and reported frequent nightmares. Participants were randomly assigned to receive prazosin or placebo for 26 weeks; the drug or placebo was administered in escalating divided doses over the course of 5 weeks to a daily maximum of 20 mg in men and 12 mg in women. After week 10, participants continued to receive prazosin or placebo in a double-blind fashion for an additional 16 weeks. The three primary outcome measures were the change in score from baseline to 10 weeks on the Clinician-Administered PTSD Scale (CAPS) item B2 ("recurrent distressing dreams"; scores range from 0 to 8, with higher scores indicating more frequent and more distressing dreams); the change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index (PSQI; scores range from 0 to 21, with higher scores indicating worse sleep quality); and the Clinical Global Impression of Change (CGIC) score at 10 weeks (scores range from 1 to 7, with lower scores indicating greater improvement and a score of 4 indicating no change).
RESULTS
A total of 304 participants underwent randomization; 152 were assigned to prazosin, and 152 to placebo. At 10 weeks, there were no significant differences between the prazosin group and the placebo group in the mean change from baseline in the CAPS item B2 score (between-group difference, 0.2; 95% confidence interval [CI], -0.3 to 0.8; P=0.38), in the mean change in PSQI score (between-group difference, 0.1; 95% CI, -0.9 to 1.1; P=0.80), or in the CGIC score (between-group difference, 0; 95% CI, -0.3 to 0.3; P=0.96). There were no significant differences in these measures at 26 weeks (a secondary outcome) or in other secondary outcomes. At 10 weeks, the mean difference between the prazosin group and the placebo group in the change from baseline in supine systolic blood pressure was a decrease of 6.7 mm Hg. The adverse event of new or worsening suicidal ideation occurred in 8% of the participants assigned to prazosin versus 15% of those assigned to placebo.
CONCLUSIONS
In this trial involving military veterans who had chronic PTSD, prazosin did not alleviate distressing dreams or improve sleep quality. (Funded by the Department of Veterans Affairs Cooperative Studies Program; PACT ClinicalTrials.gov number, NCT00532493 .).
Topics: Adrenergic alpha-1 Receptor Antagonists; Adult; Combined Modality Therapy; Dose-Response Relationship, Drug; Double-Blind Method; Dreams; Female; Hospitals, Veterans; Humans; Male; Middle Aged; Prazosin; Psychiatric Status Rating Scales; Psychotherapy; Sleep; Sleep Wake Disorders; Stress Disorders, Post-Traumatic; Suicidal Ideation; Treatment Failure; United States; Veterans
PubMed: 29414272
DOI: 10.1056/NEJMoa1507598 -
Journal of the American Veterinary... May 2022To determine if prazosin administration decreased the rate of recurrent urethral obstruction (rUO) before hospital discharge and within 14 days.
OBJECTIVE
To determine if prazosin administration decreased the rate of recurrent urethral obstruction (rUO) before hospital discharge and within 14 days.
ANIMALS
388 cats with urethral obstruction.
PROCEDURES
Veterinarians who either always or never prescribed prazosin (generally, 0.5 to 1 mg, PO, q 12 h for 14 days) were recruited to complete observational surveys. Patient data and characteristics of relieving the obstruction, including perception of a gritty feel within urethra or difficulty unobstructing the cat, were recorded. The rate of development of rUO before hospital discharge and by day 14 was compared between cats that received or did not receive prazosin with the Fisher exact test. Other variables were similarly compared between cats with and without rUO.
RESULTS
302 (78%) cats received prazosin, while 86 (22%) did not. There was no association between prazosin administration and risk of rUO prior to discharge, with 34 of 302 (11.3%) cats receiving prazosin and 5 or 86 (5.8%) not receiving prazosin developing rUO. Within 14 days, a significantly higher proportion of prazosin-treated cats (73/302 [24%]) developed an rUO, compared with the proportion of non-prazosin-treated cats (and 11/86 [13%]). The perception of a "gritty feeling urethra" or difficulty of performing the catheterization was associated with increased risk of rUO.
CLINICAL RELEVANCE
Prazosin administration increased the likelihood of rUO by 14 days; ongoing investigation of other therapies to decrease rUO in cats is warranted. Without specific indications, the use of prazosin for the prevention of rUO should be discouraged.
Topics: Animals; Cat Diseases; Cats; Prazosin; Urethra; Urethral Obstruction
PubMed: 35290210
DOI: 10.2460/javma.21.10.0469 -
Human Psychopharmacology Mar 2016Symptoms of sleep disturbance, particularly nightmares and insomnia, are a central feature of post-traumatic stress disorder (PTSD). Emerging evidence suggests that...
Symptoms of sleep disturbance, particularly nightmares and insomnia, are a central feature of post-traumatic stress disorder (PTSD). Emerging evidence suggests that specific treatment of PTSD-related sleep disturbance improves other symptoms of the disorder, which in turn suggests that such disturbance may be fundamental to development and maintenance of the disorder. This mini-review focuses on pharmacological treatment of sleep disturbance in adult PTSD (specifically, studies testing the efficacy of antidepressants, adrenergic inhibiting agents, antipsychotics and benzodiazepine and non-benzodiazepine hypnotics). We conclude that only prazosin, an adrenergic inhibiting agent, has had its efficacy established by multiple randomised controlled trials. There is also high-level evidence supporting use of eszopiclone, as well as risperidone and olanzapine as adjunct therapy. Antidepressants such as sertraline, venlafaxine and mirtazapine, benzodiazepines such as alprazolam and clonazepam and non-benzodiazepine hypnotics such as zolpidem appear ineffective in treating PTSD-related sleep disturbance. Most studies that report reduced frequency of nightmares and insomnia also report decreases in overall symptom severity. Such findings suggest that (i) sleep disruption is central to PTSD; (ii) treating sleep disruption may be an effective way to address other symptoms of the disorder and (iii) PTSD symptoms tend to cluster together in predictable ways.
Topics: Humans; Hypnotics and Sedatives; Sleep Wake Disorders; Stress Disorders, Post-Traumatic
PubMed: 26856810
DOI: 10.1002/hup.2522 -
Journal of Psychopharmacology (Oxford,... May 2018Behavioural and psychological symptoms of dementia (BPSD) include agitation and aggression in people with dementia. BPSD is common on inpatient psychogeriatric units and...
INTRODUCTION
Behavioural and psychological symptoms of dementia (BPSD) include agitation and aggression in people with dementia. BPSD is common on inpatient psychogeriatric units and may prevent individuals from living at home or in residential/nursing home settings. Several drugs and non-pharmacological treatments have been shown to be effective in reducing behavioural and psychological symptoms of dementia. Algorithmic treatment may address the challenge of synthesizing this evidence-based knowledge.
METHODS
A multidisciplinary team created evidence-based algorithms for the treatment of behavioural and psychological symptoms of dementia. We present drug treatment algorithms for agitation and aggression associated with Alzheimer's and mixed Alzheimer's/vascular dementia. Drugs were appraised by psychiatrists based on strength of evidence of efficacy, time to onset of clinical effect, tolerability, ease of use, and efficacy for indications other than behavioural and psychological symptoms of dementia.
RESULTS
After baseline assessment and discontinuation of potentially exacerbating medications, sequential trials are recommended with risperidone, aripiprazole or quetiapine, carbamazepine, citalopram, gabapentin, and prazosin. Titration schedules are proposed, with adjustments for frailty. Additional guidance is given on use of electroconvulsive therapy, optimization of existing cholinesterase inhibitors/memantine, and use of pro re nata medications.
CONCLUSION
This algorithm-based approach for drug treatment of agitation/aggression in Alzheimer's/mixed dementia has been implemented in several Canadian Hospital Inpatient Units. Impact should be assessed in future research.
Topics: Aggression; Algorithms; Alzheimer Disease; Dementia; Drug Administration Schedule; Guidelines as Topic; Humans; Psychomotor Agitation; Psychotropic Drugs
PubMed: 29338602
DOI: 10.1177/0269881117744996 -
Lancet (London, England) Nov 2015Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by... (Comparative Study)
Comparative Study Randomized Controlled Trial
Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.
BACKGROUND
Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure.
METHODS
In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18-79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25-50 mg), bisoprolol (5-10 mg), doxazosin modified release (4-8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and ClinicalTrials.gov number, NCT02369081.
FINDINGS
Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (-8·70 mm Hg [95% CI -9·72 to -7·69]; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; -4·26 [-5·13 to -3·38]; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (-4·03 [-5·04 to -3·02]; p<0·0001) and versus bisoprolol (-4·48 [-5·50 to -3·46]; p<0·0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion.
INTERPRETATION
Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition.
FUNDING
The British Heart Foundation and National Institute for Health Research.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic beta-1 Receptor Antagonists; Aged; Bisoprolol; Cross-Over Studies; Double-Blind Method; Doxazosin; Female; Humans; Hypertension; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Spironolactone; Treatment Outcome
PubMed: 26414968
DOI: 10.1016/S0140-6736(15)00257-3 -
The Journal of Clinical Investigation Oct 2019Parkinson's disease (PD) is a common neurodegenerative disease that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP...
Parkinson's disease (PD) is a common neurodegenerative disease that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP levels are common features of PD. Previous studies revealed that terazosin (TZ) enhances the activity of phosphoglycerate kinase 1 (PGK1), thereby stimulating glycolysis and increasing cellular ATP levels. Therefore, we asked whether enhancement of PGK1 activity would change the course of PD. In toxin-induced and genetic PD models in mice, rats, flies, and induced pluripotent stem cells, TZ increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function. Because TZ is prescribed clinically, we also interrogated 2 distinct human databases. We found slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs. These findings suggest that enhancing PGK1 activity and increasing glycolysis may slow neurodegeneration in PD.
Topics: Adenosine Triphosphate; Aged; Aged, 80 and over; Animals; Brain; Disease Progression; Dopamine; Drosophila melanogaster; Female; Glycolysis; Humans; Induced Pluripotent Stem Cells; Male; Mice; Mice, Inbred C57BL; Nerve Degeneration; Parkinson Disease; Parkinsonian Disorders; Phosphoglycerate Kinase; Prazosin; Rats
PubMed: 31524631
DOI: 10.1172/JCI129987 -
International Journal of Environmental... Dec 2022Nightmares are highly prevalent and distressing for the sufferer, which underlines the need for well-documented treatments. A comprehensive literature review and... (Meta-Analysis)
Meta-Analysis Review
Nightmares are highly prevalent and distressing for the sufferer, which underlines the need for well-documented treatments. A comprehensive literature review and meta-analysis of the effects of different pharmacological placebo-controlled randomized clinical trials, covering the period up to 1 December 2022, was performed. Searches were conducted in PubMed, Embase, Web of Science, PsychInfo, Cinahl, and Google Scholar, resulting in the identification of 1762 articles, of which 14 met the inclusion criteria: pharmacological intervention of nightmares, based on a placebo-controlled randomized trial published in a European language, reporting outcomes either/or in terms of nightmare frequency, nightmare distress, or nightmare intensity, and reporting sufficient information enabling calculation of effect sizes. Most studies involved the effect of the α-adrenergic antagonist prazosin in samples of veterans or soldiers suffering from posttraumatic stress disorder. Other medications used were hydroxyzine, clonazepam, cyproheptadine, nabilone, and doxazosin. The vast majority of studies were conducted in the USA. The studies comprised a total of 830 participants. The Clinician-Administered PTSD Scale was the most frequently used outcome measure. The results showed an overall effect size of Hedges' = 0.50 (0.42 after adjustment for publication bias). The synthetic cannabinoid nabilone (one study) showed the highest effect size ( = 1.86), followed by the histamine H-antagonist hydroxyzine (one study), and prazosin (10 studies), with effect sizes of = 1.17 and = 0.54, respectively. Findings and limitations are discussed, and recommendations for future studies are provided.
Topics: Humans; Dreams; Randomized Controlled Trials as Topic; Prazosin; Adrenergic alpha-1 Receptor Antagonists; Stress Disorders, Post-Traumatic; Hydroxyzine
PubMed: 36613097
DOI: 10.3390/ijerph20010777 -
Drug Design, Development and Therapy 2021To investigate the effect of doxazosin on autophagy and the activation of hepatic stellate cells (HSCs) in vivo and in vitro and determine the underlying mechanism.
PURPOSE
To investigate the effect of doxazosin on autophagy and the activation of hepatic stellate cells (HSCs) in vivo and in vitro and determine the underlying mechanism.
METHODS
In vivo, a mouse liver fibrosis model was induced by the intraperitoneal injection of carbon tetrachloride (CCl). Doxazosin was administered at doses of 2.5, 5 and 10 mg/(kg*day) by gavage. After 20 weeks, blood and liver tissues were collected for serological and histological analysis, respectively. Blood analysis, hematoxylin and eosin (HE) staining, Masson's trichrome staining, immunohistochemistry and immunofluorescence staining were used to measure the extent of liver fibrosis in model and control mice. In vitro, the human HSC cell line LX-2 was cultured and treated with different doses of doxazosin for the indicated times. The effects of doxazosin on LX-2 cell proliferation and migration were examined by Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. The number of autophagosomes in LX-2 cells was observed by transmission electron microscopy (TEM). Infection with green fluorescent protein (GFP)-LC3B adenovirus, GFP-red fluorescent protein (RFP)-LC3B adenovirus and mCherry-EGFP-LC3 adeno-associated virus was performed to examine changes in autophagic flux in vitro and in vivo. Cell apoptosis was measured by flow cytometry in vitro and by TUNEL assays both in vitro and in vivo. Immunoblotting was performed to evaluate the expression levels of proteins related to fibrosis, autophagy, apoptosis, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR).
RESULTS
Doxazosin inhibited HSC proliferation and migration. HSC activation was attenuated by doxazosin in a concentration-dependent manner in vivo and in vitro. Doxazosin also blocked autophagic flux and induced apoptosis in HSCs. In addition, the PI3K/Akt/mTOR pathway was activated by doxazosin and regulated fibrosis, autophagy and apoptosis in HSCs.
CONCLUSION
The study confirmed that doxazosin could inhibit autophagy by activating the PI3K/Akt/mTOR signaling pathway and attenuate liver fibrosis.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Apoptosis; Autophagy; Carbon Tetrachloride; Cell Line; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Doxazosin; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 34456560
DOI: 10.2147/DDDT.S317701