Doxepin is more effective than zolpidem in improving executive function in patients with insomnia disorder.

BACKGROUND : Insomnia disorder is associated with an impairment in cognitive performance. Doxepin and zolpidem have been found to be effective in improving sleep. In this study, we aimed to compare the effects of doxepin and zolpidem on sleep structure and executive function in patients with insomnia disorder. METHODS: Patients with primary insomnia were randomly assigned to receive doxepin 6 mg/day orally or zolpidem 5-10 mg/day orally. Polysomnography (PSG) and the Pittsburgh Sleep Quality Index (PSQI) were used at baseline and after the 8-week treatment to compare clinical efficacy in the two groups. Safety was assessed using the Treatment Emergent Symptom Scale (TESS). Executive function was evaluated using the Wisconsin sorting card test (WSCT). RESULTS: Of 120 patients enrolled in the study, 60 participants were assigned to each group. A total of 109 participants (53 in the doxepin group and 56 in the zolpidem group) completed the study. After treatment, the wake after sleep onset (WASO) and total sleep time (TST) values in the doxepin group were 80.3 ± 21.4 min and 378.9 ± 21.9 min, respectively, which were significantly better than those in the zolpidem group (132.9 ± 26.5 min and 333.2 ± 24.2 min, respectively; (P < 0.05)). The sleep onset latency (SOL) value in the zolpidem group (20.3 ± 4.7 min) was significantly better than that in the doxepin group (28.2 ± 5.6 min; P < 0.05). The sleep efficiency (SE) in the doxepin group was 77.8 ± 4.2%, which was significantly better than that in the zolpidem group (68.6 ± 5.0%; P < 0.05). The PSQI score of the doxepin group was 6.1 ± 1.1, which was significantly lower than that in the zolpidem group (7.9 ± 1.9; P < 0.05). The treatment adverse events in the doxepin group was 23.3%, which was significantly higher than that in the zolpidem group (13.3%; P < 0.05). The WSCT showed a significant improvement in persistent errors (PE), random errors (RE), and categories in the two groups after 8-week treatment, and the improvement in RE and the categories was more obvious in the doxepin group (P < 0.05). CONCLUSIONS: Both doxepin and zolpidem were found to be effective in improving sleep quality, but the effects exhibited different patterns. Doxepin improved executive function more effectively than zolpidem in patients with insomnia disorder.

A novel chitosan-based doxepin nano-formulation for chemotherapy-induced oral mucositis: a randomized, double-blinded, placebo-controlled clinical trial.

OBJECTIVES: Considering the prevalence of oral mucositis, we aimed to use the analgesic effects of doxepin with chitosan's antimicrobial and bio-adhesive nature to fabricate a nano-formulation for treating chemotherapy-induced oral mucositis. MATERIALS AND METHODS: Nanogel was fabricated via ionic gelation and characterized. Sixty patients were randomly divided and received four different treatments for 14 days: diphenhydramine + aluminum-magnesium mouthwash (control), doxepin mouthwash (DOX MW), chitosan nanogel (CN), and doxepin/chitosan nanogel (CN + DOX). Lesions were assessed with four indices, National Cancer Institute (NCI), World Health Organization (WHO), World Conference on Clinical and Research in Nursing (WCCNR) and visual analog scale (VAS) before and 3, 7, and 14 days after interventions. Kruskal-Wallis test was used for pairwise comparison. RESULTS: CN had semisolid consistency, uniform spherical shape, an average size of 47.93 ± 21.69 nm, and a zeta potential of + 1.02 ± 0.16 mV. CN + DOX reduced WHO, WCCNR, and VAS scores significantly more than the control three days after the intervention. Seven days after the intervention, CN + DOX reduced NCI and WCCNR considerably more than the control; it reduced WCCNR significantly more than CN. Fourteen days after the intervention, CN + DOX decreased NCI markedly more than the control. CONCLUSION: Chitosan-based doxepin nano-formulation might be a promising alternative for routine treatments of oral mucositis.

Clinical efficacy and safety of low-dose doxepin in Chinese patients with generalized anxiety disorder: A before-after study.

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 ±â€…1.22 to 8.50 ±â€…3.61 after low-dose doxepin treatment (P < .01). The serum levels of ACTH (4.33 ±â€…2.14 vs 6.12 ±â€…3.02 pmol/L), FT3 (4.78 ±â€…0.51 vs 5.15 ±â€…0.52 pg/mL), TC (4.55 ±â€…1.01 vs 5.93 ±â€…1.66 mmol/L), TG (1.69 ±â€…1.51 vs 3.39 ±â€…2.86 mmol/L), and LDLC (2.43 ±â€…0.88 vs 3.76 ±â€…1.25 mmol/L), and FBG (5.06 ±â€…0.43 vs 5.78 ±â€…0.81 mmol/L) were higher than that pretreatment with a significant difference (P < .01). Bodyweight (62.00 ±â€…7.45 vs 64.00 ±â€…6.44 kg, P = .23) and BMI (23.70 ±â€…2.35 vs 24.48 ±â€…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.

Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis.

BACKGROUND: Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder. METHODS: In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ. FINDINGS: We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36-0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27-0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52-0·99; moderate], 0·70 [0·51-0·95; moderate] and 0·71 [0·52-0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28-3·13; very low]; zolpidem: 1·79 [1·25-2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01-3·33; low]), daridorexant (3·45 [1·41-8·33; low), and suvorexant (3·13 [1·47-6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27-2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36-0·90; very low]; lemborexant: 0·41 [0·04-0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16-1·10; very low]) and zolpidem (0·60 [0·00-1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20-0·93; very low]; zolpidem: 0·43 [0·19-0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11-3·70; very low]). INTERPRETATION: Overall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice. FUNDING: UK National Institute for Health Research Oxford Health Biomedical Research Centre.

In-vitro antiviral activity of doxepin hydrochloride against group B coxsackievirus.

Group B coxsackievirus is an enterovirus that can cause a variety of diseases, including myocarditis, aseptic meningitis, and hand, foot, and mouth disease. Currently, there is no effective antiviral drug against this virus. In this study, we used a cytopathic effect-based viral inhibition assay to screen an FDA-approved drug library and found that doxepin hydrochloride had potential antiviral activity. Doxepin hydrochloride exhibited strong antiviral activity against coxsackievirus B types 1-3 with a 50% inhibitory concentration of 10.12 ± 0.85 µM. Moreover, doxepin hydrochloride did not exert antiviral activity against other enteroviruses, including enterovirus A71 (subtypes BrCr/C4) and coxsackievirus A (subtypes 6/10/16). Furthermore, doxepin hydrochloride inhibited virus replication in the early stage of the infection cycle rather than affecting the entry or assembly process. In addition, a few mechanism-related pharmacophores were discovered through gene association network analysis. These findings identify a possible lead compound for treating coxsackievirus B infection and simultaneously offer valuable clues for drug repositioning.

Optimizing doxepin therapy in dermatology: introducing blood level monitoring and genotype testing.

Doxepin, a tricyclic antidepressant, is the most efficacious antipruritic available to dermatologists; however its use is often suboptimal because of significant interindividual variability in doxepin plasma levels and clinical response between patients taking the same dose. As result, the Food and Drug Administration approves a maximum dose of 300 mg of doxepin per day and a 10 mg per cc liquid doxepin concentrate. These allow patients to significantly increase or decrease their dose, due to either a lack of clinical efficacy or side effects at typical dermatologic doses (often 10-25 mg per day). This review initially discusses the unique advantages of doxepin in dermatology. Then, it explores internal and external reasons why doxepin plasma levels and clinical response vary so significantly between patients, including genetic polymorphisms, drug interactions, comorbidities, sex, and ethnicity. Blood level monitoring is introduced, a tool dermatologists can use to optimize doxepin dosing in patients responding subtherapeutically to typical dermatologic doses. Without blood level monitoring, patients initially unresponsive to treatment could be labeled treatment failures when in fact they may be cases of inadequate dosing. Blood level monitoring allows for safe dose adjustments in these individuals to maximize patients' chances of achieving therapeutic success with this agent.

Comparison of gabapentin and doxepin in the management of uremic pruritus: A randomized crossover clinical trial.

Gabapentin and doxepin are well-known treatments of uremic pruritus in hemodialysis patients but no head-to-head studies were conducted to date. The aim of this trial is to compare the efficacy and the tolerability of gabapentin and doxepin in the treatment of uremic pruritus in hemodialysis patients. A single-blind crossover randomized trial was conducted that included hemodialysis patients with uremic pruritus. Patients were randomized to receive 10 mg doxepin daily or 100 mg gabapentin for 4 weeks and the two groups were treated conversely for another 4 weeks after a 4-week washout period. Eighty-five patients were screened for eligibility. Thirty-one met the inclusion criteria and four were excluded. Sixteen patients agreed and signed the consent and two withdrew from the study. VAS scores at baseline were 6.71 and 6.14, and dropped to 0.57 and 2.35 at week 4 in the gabapentin and doxepin groups, respectively. Mean scores of the 5-Domain Itch Scale (5-D) at baseline were 14.71 and 14.64, and dropped to 5.78 and 7.57 at week 4 in the gabapentin and doxepin groups, respectively. Mean scores of the Dermatology Life Quality Index (DLQI) at baseline were 9.6429 and 8.7857, and dropped to 0.71 and 3.35 at week 4 in the gabapentin and doxepin groups, respectively. Reductions in Visual Analog Scale (VAS), 5-D and DLQI were statistically significant (P < .05). No serious side effects were recorded. Limitations of this study include single-blind design, small number of included cases and lack of placebo control. Gabapentin was more effective than doxepin in decreasing uremic pruritus severity and improving quality of life of these patients.

Repurposing Doxepin to Ameliorate Steatosis and Hyperglycemia by Activating FAM3A Signaling Pathway.

Mitochondrial protein FAM3A suppresses hepatic gluconeogenesis and lipogenesis. This study aimed to screen drug(s) that activates FAM3A expression and evaluate its effect(s) on hyperglycemia and steatosis. Drug-repurposing methodology predicted that antidepressive drug doxepin was among the drugs that potentially activated FAM3A expression. Doxepin was further validated to stimulate the translocation of transcription factor HNF4α from the cytoplasm into the nucleus, where it promoted FAM3A transcription to enhance ATP synthesis, suppress gluconeogenesis, and reduce lipid deposition in hepatocytes. HNF4α antagonism or FAM3A deficiency blunted doxepin-induced suppression on gluconeogenesis and lipid deposition in hepatocytes. Doxepin administration attenuated hyperglycemia, steatosis, and obesity in obese diabetic mice with upregulated FAM3A expression in liver and brown adipose tissues (BAT). Notably, doxepin failed to correct dysregulated glucose and lipid metabolism in FAM3A-deficient mice fed on high-fat diet. Doxepin's effects on ATP production, Akt activation, gluconeogenesis, and lipogenesis repression were also blunted in FAM3A-deficient mouse livers. In conclusion, FAM3A is a therapeutic target for diabetes and steatosis. Antidepressive drug doxepin activates FAM3A signaling pathways in liver and BAT to improve hyperglycemia and steatosis of obese diabetic mice. Doxepin might be preferentially recommended as an antidepressive drug in potential treatment of patients with diabetes complicated with depression.

Doxepin in children and adolescents with symptoms of insomnia: a single-center experience.

STUDY OBJECTIVES: Pediatric insomnia is a widespread problem and especially difficult to manage in children with neurodevelopmental disorders. There are currently no US Food and Drug Administration-approved medications to use once first-line therapy fails. The objective of this study was to evaluate the efficacy and tolerability of doxepin in pediatric patients. METHODS: This is a retrospective single-center chart review of children and adolescents (2-17 years of age) whose sleep failed to improve with behavioral intervention and melatonin who were then trialed on doxepin. Treatment was initiated at a median starting dose of 2 mg and slowly escalated to a median maintenance dose of 10 mg. Improvement in sleep was recorded using a 4-point Likert scale reported by parents on follow-up visits. RESULTS: A total of 29 patients were included in the analysis. Mean follow-up duration was 6.5 ± 3.5 months. Of 29 patients, 4 (13.8%) patients discontinued doxepin because of lack of efficacy or side effects. Eight (27.6%) patients showed significant improvement of their insomnia, 8 (27.6%) showed moderate improvement, 10 (34.5%) showed mild improvement, and 3 (10.3%) showed minimal to no improvement on treatment with doxepin (P < .05) Only 2 patients (6.9%) experienced adverse effects in the form of behavioral side effects (aggression) and enuresis. CONCLUSIONS: Results of our studies suggest that low-dose doxepin is both effective and well tolerated in pediatric patients with insomnia.

[The interesting anti-H1 effects in maintenance insomnia: A reflection on the comparative advantages of doxylamine and doxepin]. / Les effets anti-H1 intéressants dans les insomnies de maintien : réflexion sur les intérêts comparés de la doxylamine et de la doxépine.

Doxylamine (Donormyl®, Lidene®, Generics) is commonly proposed by pharmacists as a sleeping pill which does not require a prescription. In France, today it is only prescribed for occasional insomnia in adults. In light of knowledge about the role of the histamine H1 inverse agonist drugs in the treatment of insomnia, and specifically the low dose doxepin (3 mg and 6 mg) marketed in the US and Canada (Silenor®), we suggest that the use of doxylamine may be appropriate for treating insomnia in the last third of the night. Better information to the pharmacist on the prescription of this anti-H1 hypnotic would be beneficial to the patient.

Nortriptyline serum concentration as a predictor for cardiac risk in amitriptyline-treated patients.

PURPOSE: Tricyclic antidepressants have been shown to affect electrocardiogram (ECG) parameters, but there is limited evidence in relation to the serum concentrations. Therefore, we aimed to evaluate a prediction of cardiac risk in amitriptyline- and doxepin-treated patients by serum concentrations. PATIENTS AND METHODS: The association between serum concentrations of amitriptyline (n = 100) and doxepin (n = 71) and ECG parameters was retrospectively examined using linear regression analysis. Mann-Whitney U tests were applied to evaluate differences in QTc intervals in patients with serum concentrations above and below the upper limit of the therapeutic reference range, as well as the alert level of each target drug. RESULTS: The sum serum concentration of amitriptyline and the nortriptyline serum concentration were significantly associated with an increased PQ interval (p = 0.020, p = 0.007), as well as with increased QTcB (p = 0.012, p < 0.001) and QTcF intervals (p = 0.025, p < 0.001). The nortriptyline concentration was significantly associated with the QRS interval (p = 0.003). In patients with active moiety concentrations above the alert level (300 ng/ml) and nortriptyline concentrations above the reference range (170 ng/ml), the QTcB interval was significantly prolonged (p = 0.032, p = 0.007). No significant association with any ECG parameter was detected for doxepin serum concentrations. CONCLUSION: The effect of amitriptyline on ECG parameters may be explained by nortriptyline alone. Accordingly, with increasing nortriptyline concentrations, the potential risk for an atrioventricular block, a bundle branch block, and prolongation of QTc interval may increase significantly.

Doxepin cream is not effective in reducing itch in burn scar patients: A multicenter triple-blind randomized clinical crossover trial.

OBJECTIVE: To evaluate the effect of doxepin hydrochloride 5% cream on reducing pruritus in burn scar patients compared to a placebo cream. METHOD: We conducted a multicenter triple-blind randomized clinical placebo-controlled crossover trial in which burn patients ≥18 years with an itch intensity ≥3 on a Visual Analogue Scale (VAS) were randomized between a doxepin-placebo or placebo-doxepin treatment protocol. Patients used each cream during two weeks with a wash-out period of one week in between. Primary outcome was change in itch intensity in two weeks' time using the VAS. Secondary outcome included the impact of itch (Burn Itch Questionnaire). Other parameters were the use of hydrating cream, silicon treatment, pressure garments, and other antipruritic medication. RESULTS: Twenty-seven patients were included. The change in itch intensity (VAS) was not different during the doxepin and placebo period (p=0.994); neither the doxepin cream nor placebo cream reduced itch intensity. However, based on the Burn Itch Questionnaire, we observed a statistically significant decrease in itch intensity and improvement in impact scores in both treatment groups, but no difference in the degree of reduction between the groups. CONCLUSION: Doxepin cream was not effective in reducing pruritus in our burn patient study population.

Doxepin in difficult-to-treat chronic urticaria: A retrospective, cross-sectional study from Turkey.

Doxepin is an old tricyclic antidepressant, whose efficacy in chronic urticaria had been well documented until 1990. However, over the past three decades, there has been limited data on its use. We aimed to assess the efficacy and safety of doxepin in the treatment of patients with chronic urticaria who were poorly responsive to antihistamines. In this retrospective, cross-sectional, single-center study from Turkey, data were examined from patients with chronic urticaria who had poor antihistamine responses and received doxepin therapy from 1998 to 2017. Patient data were analyzed with regard to the duration of the disease, age, sex, treatment outcomes using a weekly urticaria activity score (UAS7), and adverse effects of doxepin therapy. A reduction of ≥90% in UAS7 was defined as "complete response," 30-89% as "partial response" and <30% as "no significant response." Thirty-six patients were included in this study. Doxepin was effective in a majority (n = 27, 75%) of the patients with a short onset time. Sixteen patients (44.4%) showed a complete response. Mild sedative and anticholinergic side effects were well tolerated. Doxepin seems to be a reasonable, efficient, and affordable alternative for the treatment of chronic urticaria in patients who respond poorly to antihistamine therapy.

Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain: The Alliance A221304 Randomized Clinical Trial.

Importance: Oral mucositis causes substantial morbidity during head and neck radiotherapy. In a randomized study, doxepin mouthwash was shown to reduce oral mucositis-related pain. A common mouthwash comprising diphenhydramine-lidocaine-antacid is also widely used. Objective: To evaluate the effect of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash for the treatment of oral mucositis-related pain. Design, Setting, and Participants: A phase 3 randomized trial was conducted from November 1, 2014, to May 16, 2016, at 30 US institutions and included 275 patients who underwent definitive head and neck radiotherapy, had an oral mucositis pain score of 4 points or greater (scale, 0-10), and were followed up for a maximum of 28 days. Interventions: Ninety-two patients were randomized to doxepin mouthwash (25 mg/5 mL water); 91 patients to diphenhydramine-lidocaine-antacid; and 92 patients to placebo. Main Outcome and Measures: The primary end point was total oral mucositis pain reduction (defined by the area under the curve and adjusted for baseline pain score) during the 4 hours after a single dose of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with a single dose of placebo. The minimal clinically important difference was a 3.5-point change. The secondary end points included drowsiness, unpleasant taste, and stinging or burning. All scales ranged from 0 (best) to 10 (worst). Results: Among the 275 patients randomized (median age, 61 years; 58 [21%] women), 227 (83%) completed treatment per protocol. Mucositis pain during the first 4 hours decreased by 11.6 points in the doxepin mouthwash group, by 11.7 points in the diphenhydramine-lidocaine-antacid mouthwash group, and by 8.7 points in the placebo group. The between-group difference was 2.9 points (95% CI, 0.2-6.0; P = .02) for doxepin mouthwash vs placebo and 3.0 points (95% CI, 0.1-5.9; P = .004) for diphenhydramine-lidocaine-antacid mouthwash vs placebo. More drowsiness was reported with doxepin mouthwash vs placebo (by 1.5 points [95% CI, 0-4.0]; P = .03), unpleasant taste (by 1.5 points [95% CI, 0-3.0]; P = .002), and stinging or burning (by 4.0 points [95% CI, 2.5-5.0]; P < .001). Maximum grade 3 adverse events for the doxepin mouthwash occurred in 3 patients (4%); diphenhydramine-lidocaine-antacid mouthwash, 3 (4%); and placebo, 2 (2%). Fatigue was reported by 5 patients (6%) in the doxepin mouthwash group and no patients in the diphenhydramine-lidocaine-antacid mouthwash group. Conclusions and Relevance: Among patients undergoing head and neck radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash vs placebo significantly reduced oral mucositis pain during the first 4 hours after administration; however, the effect size was less than the minimal clinically important difference. Further research is needed to assess longer-term efficacy and safety for both mouthwashes. Trial Registration: ClinicalTrials.gov Identifier: NCT02229539.

Antidepressant polypharmacy and the potential of pharmacokinetic interactions: Doxepin but not mirtazapine causes clinically relevant changes in venlafaxine metabolism.

BACKGROUND: To uncover pharmacokinetic interactions between venlafaxine and doxepin or mirtazapine in a naturalistic sample. METHODS: A therapeutic drug monitoring database containing plasma concentrations of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN) was analyzed. We included 1067 of 1594 patients in the analysis. Three study groups were considered; a group of patients under venlafaxine without confounding medications, V0 (n = 905), a group of patients co-medicated with doxepin, VDOX (n = 25) and a second group, co-medicated with mirtazapine, VMIR, n = 137. Plasma concentrations of VEN, ODVEN and the clinically relevant active moiety, sum of venlafaxine and O-desmethylvenlafaxine (ODVEN) (AM), as well as dose-adjusted plasma concentrations (C/D) were compared. RESULTS: Median concentrations in the doxepin group showed 57.7% and 194.4% higher values for AM and VEN respectively; these differences were statistically significant (p < 0.001 for AM and p = 0.002 for VEN). Similar differences were detected for C/D concentrations of active moiety and VEN (p < 0.001 and p = 0.001) with higher values also in the doxepin group. The ratios ODVEN/VEN were lower in the doxepin group (p < 0.001). A co-medication with mirtazapine did not cause any changes in venlafaxine metabolism. CONCLUSIONS: Higher concentrations for VEN and AM imply an inhibiting effect of doxepin on the metabolism of venlafaxine, although the huge variability of concentrations has to be taken into account. It is recommended to monitor plasma concentrations in combination treatment to avoid problems in safety and efficacy. LIMITATIONS: Despite the large size of our study sample, the naturalistic nature of this data may arise some concerns of information bias potentially resulting from non-standardized data recording.

Comparative efficacy and acceptability of antidepressant treatment in poststroke depression: a multiple-treatments meta-analysis.

OBJECTIVE: The aim of this study is to create a rank order of the comparative efficacy and acceptability (risk of all-cause discontinuation) of antidepressant treatment in poststroke depression (PSD) by integrating direct and indirect evidence. DESIGN: Multiple-treatments meta-analysis of randomised controlled trials. PARTICIPANTS: Patients with depression following stroke. INTERVENTIONS: 10 antidepressants and placebo in the acute treatment of PSD. OUTCOME MEASURES: The primary outcomes were the overall efficacy, defined as the mean change of the total depression score. The secondary outcome was the acceptability, defined as risk of all-cause discontinuation. These estimates as standardised mean differences or ORs with 95% CIs. RESULTS: We identified 12 suitable trials, with data from 707 participants. All drugs were significantly more effective than placebo apart from sertraline, nefiracetam and fluoxetine. Most of the comparisons for acceptability revealed no significant differences except that paroxetine had significantly lower all-cause discontinuation than doxepin, citalopram and fluoxetine. Standardised mean differences compared with placebo for efficacy varied from -6.54 for the best drug (reboxetine) to 0.51 for the worst drug (nefiracetam). ORs compared with placebo for acceptability ranged from 0.09 for the best drug (paroxetine) to 3.42 for the worst drug (citalopram). For the efficacy rank, reboxetine, paroxetine, doxepin and duloxetine were among the most efficacious treatments, the cumulative probabilities of which were 100%, 85.7%, 83.2%, 62.4%, respectively. With respect to the acceptability rank, paroxetine, placebo, sertraline and nortriptyline were among the most acceptable treatments, the cumulative probabilities of which were 92.4%, 63.5%, 57.3%, 56.3%. CONCLUSION: After weighing the efficacy and acceptability, we conclude that paroxetine might be the best choice when starting acute treatment for PSD, and fluoxetine might be the worst choice. TRIAL REGISTRATION NUMBER: This systematic review has been registered in the Prospective Register of Systematic Review Protocols (PROSPERO) public database (CRD42017054741; http://www.crd.york.ac.uk/PROSPERO).

Doxepin Mitigates Noise-induced Neuronal Damage in Primary Auditory Cortex of Mice via Suppression of Acid Sphingomyelinase/Ceramide Pathway.

Neuronal damage in primary auditory cortex (A1) underlies complex manifestations of noise exposure, prevention of which is critical for health maintenance. Acid sphingomyelinase (ASM) catalyzes generation of ceramide (Cer) which if over-activated mediates neuronal disorders in various diseases. Tricyclic antidepressants (TCAs), by restraining ASM/Cer, benefits multiple neuronal anomalies, so we aimed to elucidate the effect of TCA on noise induced hearing loss and auditory cortex derangement, unraveling mechanism involved. The mice were exposed to noise with frequencies of 20-20 KHz and intensity of 95 dB. Doxepin hydrochloride (DOX), a kind of TCAs, was given intragastrically by 5 mg kg-1  days-1 . Morphology of neurons was examined using hematoxylin-eosin (HE) and Nissl staining. Apoptosis was assayed through transferase-mediated dUTP nick end labeling (TUNEL). The content of ASM, Cer or acid ceramidase (AC) was detected by western blot and immunohistochemistry analysis. We demonstrated intense, broad band noise caused upward shift of auditory brainstem response (ABR) threshold to sound over frequencies 4-32 KHz, with prominent morphologic changes and enhanced apoptosis in neurons of primary auditory cortex (A1) (P < 0.05). DOX partly restored noise-caused hearing loss alleviating morphologic changes or apoptosis remarkably (P < 0.05). Both ASM and Cer abundance were elevated significantly by noise which was reversed upon DOX treatment (P < 0.05), but neither noise nor DOX altered AC content. DOX had no influence on hearing, neuronal morphology or ASM/Cer in control mice. Our result suggests DOX palliates noise induced hearing loss and neuronal damage in auditory cortex by correcting over-activation of ASM/Cer without hampering intrinsic behavior of it. Anat Rec, 300:2220-2232, 2017. © 2017 Wiley Periodicals, Inc.

Insomnia: Pharmacologic Therapy.

Insomnia accounts for more than 5.5 million visits to family physicians each year. Although behavioral interventions are the mainstay of treatment, pharmacologic therapy may be necessary for some patients. Understanding the risks and benefits of insomnia medications is critical. Controlled-release melatonin and doxepin are recommended as first-line agents in older adults; the so-called z-drugs (zolpidem, eszopiclone, and zaleplon) should be reserved for use if the first-line agents are ineffective. For the general population with difficulty falling asleep, controlled-release melatonin and the z-drugs can be considered. For those who have difficulty staying asleep, low-dose doxepin and the z-drugs should be considered. Benzodiazepines are not recommended because of their high abuse potential and the availability of better alternatives. Although the orexin receptor antagonist suvorexant appears to be relatively effective, it is no more effective than the z-drugs and much more expensive. Sedating antihistamines, antiepileptics, and atypical antipsychotics are not recommended unless they are used primarily to treat another condition. Persons with sleep apnea or chronic lung disease with nocturnal hypoxia should be evaluated by a sleep specialist before sedating medications are prescribed.

Impact of drug therapy on brachioradial pruritus.

Few studies have described therapeutic options in brachioradial pruritus. We describe a cross-sectional study of brachioradial pruritus patients treated in an outpatient unit. We reviewed medical records and interviewed brachioradial pruritus patients without indication for decompressive surgery, in order to access the perceptions of intensity of pruritus prior to treatment and response to therapy. We found that antidepressants and anticonvulsants were the most frequently prescribed drugs. Best reductions in pruritus were associated with its highest intensities prior to treatment, and with longer periods of therapy.

A Review of Suvorexant, Doxepin, Ramelteon, and Tasimelteon for the Treatment of Insomnia in Geriatric Patients.

Geriatric patients often experience insomnia because of physiological and neurological changes that occur during the aging process. Use of benzodiazepines, nonbenzodiazepine hypnotics, and diphenhydramine for the treatment of insomnia pose an increased risk of cognitive impairment, falls, and fractures in this patient population. Therapeutic alternatives approved by the Food and Drug Administration include suvorexant, doxepin, ramelteon, and tasimelteon, which have shown efficacy and safety in various studies. This paper explores and outlines the available safety and efficacy data associated with these medications and reviews their potential place in therapy in treating insomnia in the geriatric population.