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effects of doxepin 3 mg and 6 mg on wake after sleep onset (WASo). Data included in this Figure are derived from the ITT analysis set. < 0.0001 0.0009 < 0.0001 0.0248 P-value 3 mg 6 mg
Source publication
To evaluate the efficacy and safety of doxepin (DXP) 3 mg and 6 mg in adults diagnosed with primary insomnia.
The study was a randomized, double-blind, parallel-group, placebo-controlled trial. Patients meeting DSM-IV-TR criteria for primary insomnia were randomized to 35 days of nightly treatment with DXP 3 mg (n=75), DXP 6 mg (n=73), or placebo (...
Context in source publication
Context 1
... maintenance and duration: Unless otherwise noted, only significant results are presented. All of the fol- lowing comparisons were versus placebo unless otherwise noted. WASO was significantly improved on N1 (primary efficacy endpoint; P < 0.0001), N15 (P = 0.0053), and N29 (P = 0.0299; Figure 1) for DXP 3 mg, and on N1 (primary efficacy endpoint; P < 0.0001), N15 (P = 0.0023), and N29 (P = 0.0012) for DXP 6 mg. To determine if there were any effects based on ethnicity, summary statistics were further examined for WASO on N1 separately for African Americans and Caucasians, the 2 largest ethnic groups. Overall, the im- provement in WASO on N1 for DXP 3 mg and 6 mg treat- up to 4 weeks; results are provided for efficacy assessments on N1, N15, and ...
Citations
... Doxepin in small doses (3-6 mg/day) can improve the sleep status of adults and elderly patients with chronic insomnia due to its specific antihistamine mechanism of action. It is clinically well tolerated and does not cause withdrawal effects [15][16][17]. In 2010, the FDA approved the administration of doxepin in doses 3 mg and 6 mg for the treatment of insomnia characterized by difficulty in sleep maintenance [18]. ...
... Doxepin administered at low dose (6 mg/day) can improve the sleep status of adults and elderly patients with insomnia disorder because it functions through a specific antihistamine mechanism, exhibiting good clinical tolerance and no withdrawal effect [16,17,25]. In recent years, it has been one of the drugs recommended for insomnia treatment in several countries. ...
... In recent years, it has been one of the drugs recommended for insomnia treatment in several countries. Here, we conducted a clinical study of patients with insomnia disorder for 8 weeks, and the results showed that 6 mg/day doxepin could improve the sleep status of patients with insomnia disorder, a finding that was consistent with findings from previous studies [16]. The results of this study showed that the treatment of insomnia disorder with 6 mg/day doxepin improved sleep time and sleep efficiency. ...
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.
... Because it does not affect REM sleep or slow-wave sleep, it should have fewer adverse effects on memory and executive function. [73][74][75] Eszopiclone may help in sleep-onset and sleep-maintenance insomnia. Intermittent dosing is preferred, though some individuals may require long-term treatment. ...
Review article on sleep disturbance in older adults with comorbid substance use
... There was one study of doxepin available for analysis [80]. This was a randomized, double-blind, parallel-group, placebo-controlled trial in subjects meeting DSM-IV-TR criteria for primary insomnia who were randomized to 35 days of nightly treatment with doxepin 3 mg (n = 75), doxepin 6 mg (n = 73), or placebo (PBO; n = 73), followed by two nights of single-blind PBO to evaluate discontinuation effects. ...
... Withdrawal was assessed with the Benzodiazepine Withdrawal Symptom Questionnaire. Doxepin was associated with statistically improved sleep during a 2-day discontinuation period compared with baseline, and though mean sleep values were worse during discontinuation than during the end of double-blind treatment, this was not tested statistically [80]. ...
Determining the most effective insomnia medication for patients may require therapeutic trials of different medications. In addition, medication side effects, interactions with co-administered medications, and declining therapeutic efficacy can necessitate switching between different insomnia medications or deprescribing altogether. Currently, little guidance exists regarding the safest and most effective way to transition from one medication to another. Thus, we developed evidence-based guidelines to inform clinicians regarding best practices when deprescribing or transitioning between insomnia medications. Five U.S.-based sleep experts reviewed the literature involving insomnia medication deprescribing, tapering, and switching and rated the quality of evidence. They used this evidence to generate recommendations through discussion and consensus. When switching or discontinuing insomnia medications, we recommend benzodiazepine hypnotic drugs be tapered while additional CBT-I is provided. For Z-drugs zolpidem and eszopiclone (and not zaleplon), especially when prescribed at supratherapeutic doses, tapering is recommended with a 1–2-day delay in administration of the next insomnia therapy when applicable. There is no need to taper DORAs, doxepin, and ramelteon. Lastly, off-label antidepressants and antipsychotics used to treat insomnia should be gradually reduced when discontinuing. In general, offering individuals a rationale for deprescribing or switching and involving them in the decision-making process can facilitate the change and enhance treatment success.
... However, at low doses, doxepin has been reported as a weight-neutral agent. 190,191 While studies on tricyclic antidepressants have shown an increased risk of developing diabetes, 192 this effect is seen largely with prolonged use and in moderate to high doses, which one study defined as >30 mg for doxepin. 192 Interestingly, a study in mice found that 4 weeks of doxepin in diet-induced obese mice and in db/db diabetic mice improved hyperglycemia, hepatic steatosis, and obesity, likely through the activation of a mitochondrial protein (FAM3A) that suppresses hepatic gluconeogenesis and lipogenesis. ...
The global epidemic of obesity and type 2 diabetes parallels the rampant state of sleep deprivation in our society. Epidemiological studies consistently show an association between insufficient sleep and metabolic dysfunction. Mechanistically, sleep and circadian rhythm exert considerable influences on hormones involved in appetite regulation and energy metabolism. As such, data from experimental sleep deprivation in humans demonstrate that insufficient sleep induces a positive energy balance with resultant weight gain, due to increased energy intake that far exceeds the additional energy expenditure of nocturnal wakefulness, and adversely impacts glucose metabolism. Conversely, animal models have found that sleep loss–induced energy expenditure exceeds caloric intake resulting in net weight loss. However, animal models have significant limitations, which may diminish the clinical relevance of their metabolic findings. Clinically, insomnia disorder and insomnia symptoms are associated with adverse glucose outcomes, though it remains challenging to isolate the effects of insomnia on metabolic outcomes independent of comorbidities and insufficient sleep durations. Furthermore, both pharmacological and behavioral interventions for insomnia may have direct metabolic effects. The goal of this review is to establish an updated framework for the causal links between insufficient sleep and insomnia and risks for type 2 diabetes and obesity.
... which is the only antidepressant licensed for the treatment of sleep maintenance problems in the USA.[25][26][27] In two placebo controlled industry funded trials on doxepin for elderly insomnia patient with sleep maintenance problems a Patient Global Impression scale (PGI)28 assessing 'Increased sleep duration' was reported. ...
Purpose: Low dose amitriptyline is prescribed off-label to improve sleep maintenance in patients with insomnia disorder. Data on treatment outcomes are limited. We aimed to assess patient-reported treatment effect and side effects of low dose amitriptyline for insomnia in routine care data.
Methods: Cross-sectional study. 752 consecutive patients with insomnia disorder having sleep maintenance problems were treated in an outpatient Sleep Clinic with low dose amitriptyline (10-20 mg based on self-titration). Treatment was intended to improve sleep maintenance. Before the planned follow-up consultation (approximately 6 weeks after start treatment) patients completed an online treatment evaluation questionnaire. Treatment (dose, adherence), sleep, fatigue, satisfaction and side effects were assessed by multiple-choice questions with room for free-text elaboration.
Results: 53.7% of the patients reported to use amitriptyline up to 10 mg/day, 42.9% used a self-increased dose of mostly 20 mg/day, while 3.5% had discontinued treatment. 73.9 % of the total study population reported improvement of sleep maintenance, 31.3% improved sleep onset, 35.2% improved daytime fatigue, and 45.8% reported to be (very) satisfied with treatment results. 66.1% reported at least one side effect. The reported side effects were generally the already known side-effects of amitriptyline.
Conclusion: These patient-reported outcomes support the clinical observations that low dose amitriptyline improves sleep maintenance on the short term and that it is generally well tolerated. This further justifies randomized controlled trials in patients with insomnia disorder and sleep maintenance problems to assess the effectiveness and safety of low dose amitriptyline on the short and long term. This article is protected by copyright. All rights reserved.
... [18] In this study, we also found that the incidence of adverse reactions was very low (8.3%), including constipation, facial flushing, and daytime sleepiness using low-dose doxepin treatment, suggesting that low-dose doxepin treatment has good clinical safety, which is consistent with other studies. [9,32] On the other hand, intake high-dose doxepin (average 75-300 mg/day) was prone to having more adverse effects. [33] Based on the data on high-dose doxepin treatment, there might be an excess of admissions and poisons for the patients with anxiety or depression, so a low dose of doxepin may be necessary to reduce drug toxicity in clinical practice. ...
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.
... Its high affinity for histamine H1-receptor allows it to exert sedation at a low dose by selectively blocking the receptor [144]. Even doxepin at a daily dose of 6 mg is the safest and well-suited sleep medication for elderly patients [145,146]. Although this drug has minimal risk of dependence, the recommendation is to avoid taking it within 3 h of the meal due to its delayed initiation of action and subsequent next-day somnolence [29]. ...
This review is intended to provide an updated summary of, but not limited to, classification, etiopathogenesis, diagnosis, and treatment strategies for insomnia disorder. The severity of insomnia symptoms irrespective of co-existing primary medical condition/s in the studied patients classified insomnia as ‘insomnia disorder’ to prioritize the clinical attention on insomnia (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition). The frequency and duration of symptoms further divided insomnia into chronic, short-term, and other insomnia disorder (International Classification of Sleep Disorders, Third Edition). This disorder is a phenomenal state of hyperarousal developed and perpetuated by environmental, behavioral, cognitive, genetic, socioeconomic, preexisting medical factors. Overarching physiological, cortical, behavioral, and cognition changes in hyperarousal manifest insomnia disorder. It, sometimes, leads to the co-occurrence of other chronic medical condition/s. The contemporary diagnosis of insomnia disorder needs to consider modified diagnostic criteria, growing evidence on insomnia disorder symptoms, associated factors, co-existing medical condition/s (if any) to identify the subjective severity of insomnia disorder and design a treatment plan. The recommended treatment strategies include cognitive-behavioral therapy for insomnia (CBTI) and pharmacotherapy. However, CBTI lacks accessibility, qualified facilitators, and pharmacotherapy has limitations like side effects, physiological tolerance/dependence. The investigation of phytocompounds subdued these drawbacks of existing treatments as some compounds showed anti-insomniac potential. Furthermore, complementary alternative medicines (CAMs) like mindfulness-based practices, acupuncture, listening to music, Yogasanas, Pranayama, digital cognitive behavioral therapy for insomnia (dCBTI) during bedtime proved supportive in insomnia disorder treatment.
... However, there are reports of weight gain in this Esmirtazapine study. 40,41 Zopiclone and Eszopiclone are cyclopyrrolone drugs whose mechanism of action differs from Zolpidem by acting on the a1 and a2 subunits of the GABA-A receptor. This drug has shown efficacy in treating early chronic insomnia or sleep maintenance and is well tolerated by the elderly. ...
Coronavirus disease-19 (COVID-19) is a systemic viral infection. COVID-19 patients show diverse clinical presentations ranging from asymptomatic, mild symptoms to severe symptoms characterized by severe respiratory distress. Sleep disorders or insomnia is one of the psychiatric problems that arise during the COVID-19 pandemic. The term used to define this particular insomnia is coronasomnia or COVID-19 insomnia. Data show that the prevalence of this problem is increasing, especially in the confirmed COVID-19 patient group. Anti-insomnia drugs such as hypnotics, sedatives, and anxiolytics are the easiest option. As with drugs generally, anti-insomnia drugs are associated with various safety issues, especially in people with COVID-19. Therefore, their use may be hazardous. The literature review aims to make health practitioners aware of the anti-insomnia drugs that have the best efficacy and safety issues that are clinically relevant from the use of anti-insomnia drugs and the interactions of anti-insomnia drugs with various drugs used in the treatment of COVID-19. The articles were explored on PubMed and Cochrane Library, whereas the drug–drug interactions between the anti-insomnia and COVID-19 drugs were searched on Drugs.com Interaction Checker and Lexiomp-interact. Overall anti-insomnia drugs have efficacy in improving sleep parameters. Orexin receptor antagonist drugs have good efficacy in increasing WASO, LPS, and SE with an acceptable safety profile. Meanwhile, the combination of zolpidem, lorazepam, and diphenhydramine improved TST parameters better than other drugs. Side effects such as drowsiness and dizziness were among the most commonly reported effects. Therefore, attention and monitoring of the use of anti-insomnia drugs in COVID-19 patients need to be carried out by considering the side effects and interactions that are very risky.
... Consistent with this preclinical finding, a randomized, placebo-controlled trial in patients with chronic primary insomnia showed that doxepin prevented early morning awakenings as well as improved sleep in the latter part of the night [60]. Several other studies showed similar improvement in sleep maintenance and sleep duration with doxepin compared to placebo [61][62][63][64][65]. The U.S. food and drug administration (FDA) has approved doxepin for the clinical treatment of insomnia [66]. ...
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.
... The side effects-including tiredness, headache, palpitation, perspiration, constipation, as well as sleep-and micturition-related problems [20,21]-of tricyclic antidepressants may reduce patient compliance and thus increase health care costs and exacerbate the physical and financial burdens on patients themselves and their caregivers [8,9]. However, in comparison with different antipsychotics (e.g., clozapine, risperidone, olanzapine, and haloperidol), doxepin treatment is less likely to alter the patient's physical parameters (e.g., body weight and lipid profile) in the long term [22][23][24]. Moreover, in mice, long-term doxepin administration was noted to reduce body and white adipose tissue (WAT) weights-an observation inconsistent with the findings of most human studies [25]. ...
Doxepin is commonly prescribed for depression and anxiety treatment. Doxepin-related disruptions to metabolism and renal/hepatic adverse effects remain unclear; thus, the underlying mechanism of action warrants further research. Here, we investigated how doxepin affects lipid change, glucose homeostasis, chromium (Cr) distribution, renal impairment, liver damage, and fatty liver scores in C57BL6/J mice subjected to a high-fat diet and 5 mg/kg/day doxepin treatment for eight weeks. We noted that the treated mice had higher body, kidney, liver, retroperitoneal, and epididymal white adipose tissue weights; serum and liver triglyceride, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine levels; daily food efficiency; and liver lipid regulation marker expression. They also demonstrated exacerbated insulin resistance and glucose intolerance with lower Akt phosphorylation, GLUT4 expression, and renal damage as well as higher reactive oxygen species and interleukin 1 and lower catalase, superoxide dismutase, and glutathione peroxidase levels. The treated mice had a net-negative Cr balance due to increased urinary excretion, leading to Cr mobilization, delaying hyperglycemia recovery. Furthermore, they had considerably increased fatty liver scores, paralleling increases in adiponectin, FASN, PNPLA3, FABP4 mRNA, and SREBP1 mRNA levels. In conclusion, doxepin administration potentially worsens renal injury, nonalcoholic fatty liver disease, and diabetes.
