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Arquivos de Neuro-psiquiatria May 2022Although, insomnia is one of the most common diseases that health professionals face in their practice, it receives little attention in medical training. Diagnosis is...
Although, insomnia is one of the most common diseases that health professionals face in their practice, it receives little attention in medical training. Diagnosis is based on a careful history taking, and physicians must be aware of the diagnostic criteria. Insomnia should not be considered a symptom, but a comorbid condition. Although cognitive behavioral therapy (CBT) has been the mainstay treatment for insomnia for many years, it is usually regarded as a novel therapeutic strategy, both because of scarcity of qualified psychologists and of limited knowledge about insomnia among physicians. GABA receptor acting drugs are being abandoned in the treatment of insomnia because of abuse and dependence potential and accident risk. Two main current therapeutic options with the best scientific evidence are the tricyclic antidepressant, doxepin, and a new melatoninergic receptor agonist, ramelteon. Newer drugs to treat insomnia are in the pipeline. Hypocretine blocking agents will be marketed in the near future.
Topics: Cognitive Behavioral Therapy; Humans; Sleep Initiation and Maintenance Disorders
PubMed: 35976314
DOI: 10.1590/0004-282X-ANP-2022-S124 -
Pharmaceutics Mar 2021Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in... (Review)
Review
Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in pain management methods made to date, peripheral neuropathic pain significantly impacts patients' quality of life, as pharmacological and non-pharmacological methods often fail or induce side effects. Topical treatments are gaining popularity in the management of peripheral neuropathic pain, due to excellent safety profiles and preferences. Moreover, topical treatments applied locally may target the underlying mechanisms of peripheral sensitization and pain. Recent studies showed that peripheral sensitization results from interactions between neuronal and non-neuronal cells, with numerous signaling molecules and molecular/cellular targets involved. This narrative review discusses the molecular/cellular mechanisms of drugs available in topical formulations utilized in clinical practice and their effectiveness in clinical studies in patients with peripheral neuropathic pain. We searched PubMed for papers published from 1 January 1995 to 30 November 2020. The key search phrases for identifying potentially relevant articles were "topical AND pain", "topical AND neuropathic", "topical AND treatment", "topical AND mechanism", "peripheral neuropathic", and "mechanism". The result of our search was 23 randomized controlled trials (RCT), 9 open-label studies, 16 retrospective studies, 20 case (series) reports, 8 systematic reviews, 66 narrative reviews, and 140 experimental studies. The data from preclinical studies revealed that active compounds of topical treatments exert multiple mechanisms of action, directly or indirectly modulating ion channels, receptors, proteins, and enzymes expressed by neuronal and non-neuronal cells, and thus contributing to antinociception. However, which mechanisms and the extent to which the mechanisms contribute to pain relief observed in humans remain unclear. The evidence from RCTs and reviews supports 5% lidocaine patches, 8% capsaicin patches, and botulinum toxin A injections as effective treatments in patients with peripheral neuropathic pain. In turn, single RCTs support evidence of doxepin, funapide, diclofenac, baclofen, clonidine, loperamide, and cannabidiol in neuropathic pain states. Topical administration of phenytoin, ambroxol, and prazosin is supported by observational clinical studies. For topical amitriptyline, menthol, and gabapentin, evidence comes from case reports and case series. For topical ketamine and baclofen, data supporting their effectiveness are provided by both single RCTs and case series. The discussed data from clinical studies and observations support the usefulness of topical treatments in neuropathic pain management. This review may help clinicians in making decisions regarding whether and which topical treatment may be a beneficial option, particularly in frail patients not tolerating systemic pharmacotherapy.
PubMed: 33810493
DOI: 10.3390/pharmaceutics13040450 -
Medicine Oct 2022Clinical and animal studies have reported that low-dose doxepin may have positive effects on generalized anxiety disorder (GAD); however, its effectiveness and clinical... (Randomized Controlled Trial)
Randomized Controlled Trial
Clinical and animal studies have reported that low-dose doxepin may have positive effects on generalized anxiety disorder (GAD); however, its effectiveness and clinical safety are less well understood. This study is a before-after study and aims to investigate the effectiveness and side effects of low-dose doxepin by evaluating Hamilton Anxiety Scale (HAMA) scores, hormones, blood glucose, serum lipids, body weight, and body mass index (BMI) in patients with GAD. Forty-nine patients (20 males and 29 females) with GAD were randomly assigned to receive low-dose doxepin (6.25 mg-12.5 mg per day) for 12 weeks between February 2015 and March 2016. HAMA scores, fasting blood glucose (FBG) body weight, BMI, and some serum biochemical indexes, such as adrenocorticotropic hormone (ACTH), free triiodothyronine (FT3), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDLC), and FBG, were assessed during pretreatment and post-treatment. Mean scores of HAMA decreased from 19.50 ± 1.22 to 8.50 ± 3.61 after low-dose doxepin treatment (P < .01). The serum levels of ACTH (4.33 ± 2.14 vs 6.12 ± 3.02 pmol/L), FT3 (4.78 ± 0.51 vs 5.15 ± 0.52 pg/mL), TC (4.55 ± 1.01 vs 5.93 ± 1.66 mmol/L), TG (1.69 ± 1.51 vs 3.39 ± 2.86 mmol/L), and LDLC (2.43 ± 0.88 vs 3.76 ± 1.25 mmol/L), and FBG (5.06 ± 0.43 vs 5.78 ± 0.81 mmol/L) were higher than that pretreatment with a significant difference (P < .01). Bodyweight (62.00 ± 7.45 vs 64.00 ± 6.44 kg, P = .23) and BMI (23.70 ± 2.35 vs 24.48 ± 2.11 kg/m2, P = .14) had no difference after treatment. These results suggest that low-dose doxepin has beneficial clinical efficacy and safety. Low-dose doxepin can ameliorate anxiety in GAD patients and has some effects on neuroendocrine systems and the metabolic activity of serum glucose and lipid.
Topics: Female; Male; Adrenocorticotropic Hormone; Anxiety Disorders; Blood Glucose; Body Weight; China; Cholesterol, LDL; Controlled Before-After Studies; Doxepin; Treatment Outcome; Triglycerides; Triiodothyronine; Humans
PubMed: 36281170
DOI: 10.1097/MD.0000000000031201 -
Brazilian Journal of Medical and... 2018The aim of this study was to investigate the efficacy, acceptability, and tolerability of antidepressants in treating post-stroke depression (PSD) by performing a... (Meta-Analysis)
Meta-Analysis Review
The aim of this study was to investigate the efficacy, acceptability, and tolerability of antidepressants in treating post-stroke depression (PSD) by performing a network meta-analysis of randomized controlled trials of the current literature. Eligible studies were retrieved from online databases, and relevant data were extracted. The primary outcome was efficacy as measured by the mean change in overall depressive symptoms. Secondary outcomes included discontinued treatment for any reason and specifically due to adverse events. Fourteen trials were eligible, which included 949 participants and 9 antidepressant treatments. Few significant differences were found for all outcomes. For the primary outcome, doxepin, paroxetine, and nortriptyline were significantly more effective than a placebo [standardized mean differences: -1.93 (95%CI=-3.56 to -0.29), -1.39 (95%CI=-2.59 to -0.21), and -1.25 (95%CI=-2.46 to -0.04), respectively]. Insufficient evidence exists to select a preferred antidepressant for treating patients with post-stroke depression, and our study provides little evidence that paroxetine may be the potential choice when starting treatment for PSD. Future studies with paroxetine and larger sample sizes, multiple medical centers, and sufficient intervention durations is needed for improving the current evidence.
Topics: Antidepressive Agents; Depressive Disorder; Female; Humans; Male; Network Meta-Analysis; Placebo Effect; Randomized Controlled Trials as Topic; Reproducibility of Results; Stroke; Time Factors; Treatment Outcome
PubMed: 29742266
DOI: 10.1590/1414-431x20187218 -
Cleveland Clinic Journal of Medicine 1992Urticaria and angioedema are commonly seen in the outpatient setting. Their pathogenesis involves complex cellular and humoral factors. Diagnosis depends on historical... (Review)
Review
Urticaria and angioedema are commonly seen in the outpatient setting. Their pathogenesis involves complex cellular and humoral factors. Diagnosis depends on historical information such as duration of symptoms, exacerbating factors, and atopy. While many etiologic factors have been implicated, in most chronic cases no specific etiology is found. This article reviews physical and hereditary syndromes and discusses therapeutic regimens based on the duration and severity of symptoms.
Topics: Acute Disease; Adrenal Cortex Hormones; Angioedema; Chronic Disease; Doxepin; Drug Therapy, Combination; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Urticaria
PubMed: 1361426
DOI: 10.3949/ccjm.59.5.529 -
The Cochrane Database of Systematic... Oct 2015Factors contributing to subjective fatigue in people with idiopathic Parkinson's disease (PD) are not well known. This makes it difficult to manage fatigue effectively... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Factors contributing to subjective fatigue in people with idiopathic Parkinson's disease (PD) are not well known. This makes it difficult to manage fatigue effectively in PD.
OBJECTIVES
To evaluate the effects of pharmacological and non-pharmacological interventions, compared to an inactive control intervention, on subjective fatigue in people with PD.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); MEDLINE (via PubMed); Ovid EMBASE; EBSCO CINAHL; Ovid PsycINFO; PEDro; and the WHO International Clinical Trials Registry Platform Search Portal up to April 2015. References of included studies and identified review articles were screened for additional studies. There were no restrictions based on language, date of publication or study setting.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that report on subjective fatigue in people with PD.
DATA COLLECTION AND ANALYSIS
Two review authors independently performed study selection, data collection and risk of bias assessments.
MAIN RESULTS
Eleven studies were eligible for this systematic review, with a total of 1817 people. Three studies included only people who experienced clinically relevant fatigue (Fatigue Severity Scale score ≥ 4 out of 7 or Multidimensional Fatigue Inventory total score > 48 out of 100), whereas all other studies did not select participants on the basis of experienced fatigue. Nine studies investigated the effects of medication (i.e. levodopa-carbidopa, memantine, rasagiline, caffeine, methylphenidate, modafinil or doxepin) on subjective fatigue. All studies were placebo controlled. There was insufficient evidence to determine the effect of doxepin on the impact of fatigue on activities in daily life (ADL) or fatigue severity (one study, N = 12, standardised mean difference (SMD) = -1.50, 95% confidence interval (CI) -2.84 to -0.15; low quality evidence). We found high quality evidence that rasagiline reduced or slowed down the progression of physical aspects of fatigue (one study, N = 1176, SMD = -0.27, 95% CI -0.39 to -0.16, I(2) = 0%). None of the other pharmacological interventions affected subjective fatigue in PD. With regard to adverse effects, only levodopa-carbidopa showed an increase for the risk of nausea (one study, N = 361, risk ratio (RR) = 1.85, 95% CI 1.05 to 3.27; high quality evidence). Two studies investigated the effect of exercise on fatigue compared with usual care. We found low quality evidence for the effect of exercise on reducing the impact of fatigue on ADL or fatigue severity (two studies, N = 57, SMD = -0.45, 95% CI -1.21 to 0.32, I(2) = 44%).
AUTHORS' CONCLUSIONS
Based on the current evidence, no clear recommendations for the treatment of subjective fatigue in PD can be provided. Doxepin may reduce the impact of fatigue on ADL and fatigue severity; however, this finding has to be confirmed in high quality studies. Rasagiline may be effective in reducing levels of physical fatigue in PD. No evidence was found for the effectiveness of levodopa-carbidopa, memantine, caffeine, methylphenidate, modafinil or exercise. Studies are needed to investigate the effect of exercise intensity on exercise capacity and subjective fatigue. Future studies should focus on interventions that address the maladaptive behavioural or cognitive aspects of fatigue in people with PD. Characteristics, such as severity and nature of perceived fatigue and underlying mood disorders should be considered to identify responders and non-responders when studying interventions for fatigue. The development of a core-set of self-report fatigue questionnaires with established responsiveness and known minimal important difference values will facilitate the interpretation of change in fatigue scores.
Topics: Central Nervous System Stimulants; Dopamine Agents; Exercise; Fatigue; Humans; Parkinson Disease; Randomized Controlled Trials as Topic
PubMed: 26447539
DOI: 10.1002/14651858.CD010925.pub2 -
Cureus Apr 2023Purpose At present, clinicians typically prescribe antidepressants based on the widely accepted "serotonin hypothesis." This study explores an alternative mechanism,...
Purpose At present, clinicians typically prescribe antidepressants based on the widely accepted "serotonin hypothesis." This study explores an alternative mechanism, the stress mechanism, for selecting antidepressants based on patients' medical history. Methods This study investigated clinicians' prescribing patterns for the 15 most common antidepressants, including amitriptyline, bupropion, citalopram, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, mirtazapine, nortriptyline, paroxetine, ropinirole, sertraline, trazodone, and Venlafaxine. The least absolute shrinkage and selection operator (LASSO) logistic regression was used to identify factors that affect the remission of depression symptoms after receiving an antidepressant. Results The study found that a wide range of factors influenced the propensity of clinicians to prescribe antidepressants, with the number of predictors ranging from 51 to 206 variables. The prevalence of prescribing an antidepressant ranged from 0.5% for doxepin to 24% for the combination of more than one antidepressant. The area under the receiver operating curves (AROC) ranged from 77.2% for venlafaxine to 90.5% for ropinirole, with an average AROC of 82% for predicting the propensity of medications. A variety of diagnoses and prior medications affected remission, in agreement that the central mechanism for the impact of medications on the brain is through stress reduction. For example, psychotherapy, whether done individually or in a group, whether done for a short or long time, and whether done with evaluation/assessment or not, had an impact on remission. Specifically, teenagers and octogenarians were less likely to benefit from bupropion, citalopram, escitalopram, fluoxetine, and sertraline compared to patients between 40 and 65 years old. The findings of this study suggest that considering a patient's medical history and individual characteristics is crucial for selecting the most effective antidepressant treatment. Conclusions Many studies have raised doubt about the serotonin hypothesis as the central mechanism for depression treatment. The identification of a wide range of predictors for prescribing antidepressants highlights the complexity of depression treatment and the need for individualized approaches that consider patients' comorbidities and previous treatments. The significant impact of comorbidities on the response to treatment makes it improbable that the mechanism of action of antidepressants is solely based on the serotonin hypothesis. It is hard to explain how comorbidities lead to the depletion of serotonin. These findings open up a variety of courses of action for the clinical treatment of depression, each addressing a different source of chronic stress in the brain. Overall, this study contributes to a better understanding of depression treatment and provides valuable insights for clinicians in selecting antidepressants based on patients' medical history.
PubMed: 37168173
DOI: 10.7759/cureus.37117 -
The Cochrane Database of Systematic... Jul 2008Clozapine is widely used for people with schizophrenia. Although agranulocytosis, weight gain, and cardiac problems are serious problems associated with its use,... (Review)
Review
BACKGROUND
Clozapine is widely used for people with schizophrenia. Although agranulocytosis, weight gain, and cardiac problems are serious problems associated with its use, hypersalivation, sometimes of a gross and socially unacceptable quantity, is also common (30-80%).
OBJECTIVES
To determine the clinical effects of pharmacological interventions for clozapine-induced hypersalivation.
SEARCH STRATEGY
We searched the Cochrane Schizophrenia Group Trials Register (March 2007), inspected references of all identified studies for further trials, contacted relevant pharmaceutical companies, drug approval agencies and authors of trials.
SELECTION CRITERIA
We included randomised controlled trials comparing pharmacological interventions, at any dose and by any route of administration, for clozapine-induced hypersalivation.
DATA COLLECTION AND ANALYSIS
We extracted data independently. For dichotomous data (homogenous) we calculated relative risk (RR) with 95% confidence intervals (CI) and numbers needed to treat (NNT) on an intention-to-treat basis. We calculated weighted mean difference (WMD) for continuous data.
MAIN RESULTS
Of the 15 trials identified, 14 were conducted in China and 14 in hospitals. The quality of reporting was poor with no studies clearly describing allocation concealment and much data were missing or unusable. All results are vulnerable to considerable bias. Most frequently the primary outcome was the diameter of the wet patch on the pillow. Antimuscarinics (astemizole, diphenhydramine, propantheline, doxepin) were the most commonly evaluated drugs. For the outcome of 'no clinically important improvement' astemizole and diphenhydramine were more effective than placebo (astemizole: n=97, 2 RCTs, RR 0.61 CI 0.47 to 0.81 NNT 3 CI 2 to 5; diphenhydramine: n=131, 2 RCTs, RR 0.43 CI 0.31 to 0.58, NNT 2 CI 1.5 to 2.5), but the doses of astemizole used were those that can cause toxicity. Data involving propantheline were heterogeneous (I2= 86.6%), but both studies showed benefit over placebo. Adverse effects were poorly recorded. Of the other interventions, oryzanol (rice bran oil and rice embryo oil extract) showed benefit over the antimuscarinic doxepin in terms of 'no clinically important change' (n=104, 1 RCT, RR 0.45 CI 0.27 to 0.75, NNT 4 CI 2 to 7). The Chinese medicine suo quo wan (comprises spicebush root, Chinese yam and bitter cardamom) showed benefit over doxepin (n=70, 1 RCT, RR 'no clinically important change' 0.31 CI 0.16 to 0.59, NNT 3 CI 1.5 to 3.7).
AUTHORS' CONCLUSIONS
There are currently insufficient data to confidently inform clinical practice. The limitations of these studies are plentiful and the risk of bias is high. These trials, however, are invaluable guides for current and future study design. Well conducted randomised trials are possible. Some may be underway. Current practice outside of well designed randomised trials should be clearly justified.
Topics: Antipsychotic Agents; Clozapine; Drugs, Chinese Herbal; Muscarinic Antagonists; Phenylpropionates; Randomized Controlled Trials as Topic; Sialorrhea
PubMed: 18646130
DOI: 10.1002/14651858.CD005579.pub2 -
American Journal of Physiology. Cell... Jun 2017Platelet adhesion, activation, and aggregation are essential for primary hemostasis, but are also critically involved in the development of acute arterial thrombotic...
Platelet adhesion, activation, and aggregation are essential for primary hemostasis, but are also critically involved in the development of acute arterial thrombotic occlusion. Stimulation of the collagen receptor glycoprotein VI (GPVI) leads to phospholipase Cγ2-dependent inositol triphosphate (IP) production with subsequent platelet activation, due to increased intracellular Ca concentration ([Ca]). Although tricyclic antidepressants have been shown to potentially impair platelet activation, nothing is hitherto known about potential effects of the tricyclic antidepressant doxepin on platelet Ca signaling and thrombus formation. As shown in the present study, doxepin significantly diminished the stimulatory effect of GPVI agonist collagen-related peptide (CRP) on intracellular Ca release as well as subsequent extracellular Ca influx. Doxepin was partially effective by impairment of CRP-dependent IP production. Moreover, doxepin abrogated CRP-induced platelet degranulation and integrin αβ activation and aggregation. Finally, doxepin markedly blunted in vitro platelet adhesion to collagen and thrombus formation under high arterial shear rates (1,700). In conclusion, doxepin is a powerful inhibitor of GPVI-dependent platelet Ca signaling, platelet activation, and thrombus formation.
Topics: Animals; Antidepressive Agents, Tricyclic; Blood Platelets; Calcium; Calcium Signaling; Carrier Proteins; Cell Degranulation; Cells, Cultured; Doxepin; Female; Gene Expression Regulation; Inositol 1,4,5-Trisphosphate; Ion Transport; Male; Mice; Mice, Inbred C57BL; Peptides; Phospholipase C gamma; Platelet Activation; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Platelet Membrane Glycoproteins; Stress, Mechanical; Thrombosis
PubMed: 28404545
DOI: 10.1152/ajpcell.00262.2016 -
Current Neuropharmacology 2022In contrast to that of other monoamine neurotransmitters, the association of the histaminergic system with neuropsychiatric disorders is not well documented. In the last... (Review)
Review
In contrast to that of other monoamine neurotransmitters, the association of the histaminergic system with neuropsychiatric disorders is not well documented. In the last two decades, several clinical studies involved in the development of drugs targeting the histaminergic system have been reported. These include the H3R-antagonist/inverse agonist, pitolisant, used for the treatment of excessive sleepiness in narcolepsy, and the H1R antagonist, doxepin, used to alleviate symptoms of insomnia. The current review summarizes reports from animal models, including genetic and neuroimaging studies, as well as human brain samples and cerebrospinal fluid measurements from clinical trials, on the possible role of the histaminergic system in neuropsychiatric disorders. These studies will potentially pave the way for novel histamine-related therapeutic strategies.
Topics: Animals; Brain; Histamine; Piperidines; Receptors, Histamine
PubMed: 34521328
DOI: 10.2174/1570159X19666210909144930