Low-dose Doxepin Research Articles

Early objective adherence to hypoglossal nerve stimulation therapy.

To assess early adherence to therapy with hypoglossal nerve stimulation therapy. This is a prospective study of consecutive patients with moderate to severe obstructive sleep apnea who underwent implantation of hypoglossal nerve stimulation therapy within a single academic practice and attended a follow-up appointment after greater than 30 days of therapy use. Objective adherence data were extracted from an objective monitoring database and compared to patient characteristics. The study population was 79 participants who were 29.1% female with a mean age of 58.7 ± 12.8 years old, body mass index of 28.9 ± 3.4 kg/m2, and baseline apnea-hypopnea index of 33.8 ± 17.6 events/h. In the first 7 days after device activation, average use was 7.8 h/night, with 91.9% of nights with greater than 4 hours of therapy use and an average of 0.2 pauses in therapy per night. These figures remained stable after 30 days of use: 7.7 h/night, 91.0% of nights longer than 4 hours, and 0.3 pauses per night. Objective evidence of difficulty with acclimatization was associated with age less than 60 years (odds ratio 2.8, 95% confidence interval 1.1-7.1, P = .03) and a history of prior upper airway surgery (3.9, 1.2-11.9, P = .015). Insomnia was present in 31 patients and was not associated with objective evidence of difficulty tolerating therapy. Early adherence to hypoglossal nerve stimulation is excellent (92.4% >4 hours on >70% of nights), suggesting that the acclimatization period is straightforward in most. Younger age and a history of prior upper airway surgery appear to be associated with an increased risk of difficulty with acclimatization. Huyett P. Early objective adherence to hypoglossal nerve stimulation therapy. J Clin Sleep Med. 2022;18(2):631-636.

Comparative efficacy and safety of hypnotics for insomnia in older adults: a systematic review and network meta-analysis.

To compare the efficacy and safety of various hypnotics for identifying the best treatments for insomnia in older adults. We searched the EMBASE, PubMed, ClinicalTrials.gov, and ProQuest Dissertations and Theses A&I databases from the inception to September 12, 2020. Only randomized controlled trials comparing hypnotics with either another hypnotic or placebo for insomnia treatment in elderly people were included. Sleep outcomes, including total sleep time, sleep onset latency, wake after sleep onset, sleep efficiency, were derived from polysomnography, valid questionnaires, or sleep diaries. We identified 24 articles with 5917 older adults. Eszopiclone and low-dose doxepin were ranked the optimal therapy for prolonging objective and subjective total sleep time (26.69 and 28.19 min), respectively, compared to placebo. Zaleplon was the most effective therapy in reducing objective and subjective sleep onset latency (-21.63 and -15.86 min) compared with control. Temazepam was the best treatment for objective and subjective wake after sleep onset (-25.29 and -22.25 min) compared with control. Low-dose doxepin appeared to be the effective treatment for increasing objective sleep efficiency (6.08%) Triazolam showed the higher risk of overall adverse events (odds ratio, 1.96, 95% confidence interval 1.03-3.74) when compared to zaleplon. Considering study quality and the potential adverse effects of benzodiazepines and nonbenzodiazepines, low-dose doxepin seems to be the optimal pharmacotherapy for the improvements in total sleep time and sleep efficiency. Future RCTs investigating the treatment effects of hypnotics, particularly low-dose doxepin, on insomnia in older adults are warranted. PROSPERO Registration number: CRD42016046301.

Antidepressants and Their Impact on Sleep

Given the strong bidirectional relationship between sleep disruption and psychiatric conditions, particularly between depression and insomnia, it is important to understand the beneficial and potentially harmful effects of antidepressants on sleep. Antidepressants remain commonly used off-label for the treatment of chronic insomnia. SSRI, SNRI, and TCA drugs reduce REM sleep and increase REM latency. TCA drugs can be sedating or stimulating. Low-dose doxepin improves sleep continuity and is FDA approved for the treatment of chronic insomnia. Trazodone, the most commonly used antidepressant, reduces the number of awakenings. Preclinical studies have shown potential antidepressant effects of orexin antagonists, which are used to treat insomnia. Data on the usage of most antidepressants for insomnia remain limited. Low-dose doxepin is the only FDA-approved antidepressant for insomnia. Orexin antagonists may represent a future approach for treatment of both depression and insomnia.

Comparative Efficacy and Safety of Hypnotics for Insomnia in Older Adults: A Systematic Review and Network Meta-Analysis

Background: Hypnotics, such as benzodiazepines and nonbenzodiazepines, have been used to aid sleep and treat insomnia in older adults. However, there is limited information for the comparative efficacy and safety of different hypnotics for insomnia in older adults. Methods: EMBASE, PubMed, ClinicalTrials.gov, and ProQuest Dissertations and Theses A&I databases were searched. We included randomised controlled trials comparing hypnotics with either another hypnotic or placebo for insomnia treatment in elderly people. A multivariate random effect network meta-analysis in a frequentist framework was used for estimations of treatment effects and safety. Findings: Twenty-two articles with 5172 older adults were included. Eszopiclone was ranked as the best therapy for prolonging objective total sleep time (28·60 mins), and low-dose doxepin appeared to be the optimal treatment for increasing subjective total sleep time (28·19 mins) and objective sleep efficiency (6.8%) compared with control. Zaleplon was the most effective therapy in reducing objective and subjective sleep onset latency (-21·63 mins and -15·92 mins) compared with control. The risk of overall adverse events was highest with triazolam use (odd ratio, 1·89, 95% confidence interval 1·10 to 3·25) compared to placebo. Interpretation: Considering unclear risk of bias and the potential adverse effects of benzodiazepines and nonbenzodiazepines, we suggest that low-dose doxepin can be the optimal pharmacotherapy for the improvements of sleep duration and sleep efficiency. Future RCTs investigating the treatment effects of hypnotics, particularly low-dose doxepin, on insomnia in older adults are warranted. Funding Statement: HYC acknowledges the support of the Taiwan Ministry of Science and Technology (MOST 106-2314-B-038 -058 -MY3). YKT was supported by the Ministry of Science and Technology, Taiwan (MOST 106-2314-B-002 -098 -MY3). Declaration of Interests: All authors declared no conflicts of interest in this work. Ethics Approval Statement: The study is registered with PROSPERO, number CRD42016046301.

From Sleeplessness to Slumber: Person-Centered Approach to Insomnia

From Sleeplessness to Slumber: Person-Centered Approach to Insomnia

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.

小剂量多塞平治疗伴发焦虑症共病性失眠的临床疗效与安全性研究

小剂量多塞平治疗伴发焦虑症共病性失眠的临床疗效与安全性研究

Insomnia in Elderly Patients: Recommendations for Pharmacological Management.

Chronic insomnia affects 57% of the elderly in the United States, with impairment of quality of life, function, and health. Chronic insomnia burdens society with billions of dollars in direct and indirect costs of care. The main modalities in the treatment of insomnia in the elderly are psychological/behavioral therapies, pharmacological treatment, or a combination of both. Various specialty societies view psychological/behavioral therapies as the initial treatment intervention. Pharmacotherapy plays an adjunctive role when insomnia symptoms persist or when patients are unable to pursue cognitive behavioral therapies. Current drugs for insomnia fall into different classes: orexin agonists, histamine receptor antagonists, non-benzodiazepine gamma aminobutyric acid receptor agonists, and benzodiazepines. This review focuses on Food and Drug Administration (FDA)-approved drugs for insomnia, including suvorexant, low-dose doxepin, Z-drugs (eszopiclone, zolpidem, zaleplon), benzodiazepines (triazolam, temazepam), and ramelteon. We review the indications, dosing, efficacy, benefits, and harms of these drugs in the elderly, and discuss data on drugs that are commonly used off-label to treat insomnia, and those that are in clinical development. The choice of a hypnotic agent in the elderly is symptom-based. Ramelteon or short-acting Z-drugs can treat sleep-onset insomnia. Suvorexant or low-dose doxepin can improve sleep maintenance. Eszopiclone or zolpidem extended release can be utilized for both sleep onset and sleep maintenance. Low-dose zolpidem sublingual tablets or zaleplon can alleviate middle-of-the-night awakenings. Benzodiazepines should not be used routinely. Trazodone, a commonly used off-label drug for insomnia, improves sleep quality and sleep continuity but carries significant risks. Tiagabine, sometimes used off-label for insomnia, is not effective and should not be utilized. Non-FDA-approved hypnotic agents that are commonly used include melatonin, diphenhydramine, tryptophan, and valerian, despite limited data on benefits and harms. Melatonin slightly improves sleep onset and sleep duration, but product quality and efficacy may vary. Tryptophan decreases sleep onset in adults, but data in the elderly are not available. Valerian is relatively safe but has equivocal benefits on sleep quality. Phase II studies of dual orexin receptor antagonists (almorexant, lemborexant, and filorexant) have shown some improvement in sleep maintenance and sleep continuity. Piromelatine may improve sleep maintenance. Histamine receptor inverse agonists (APD-125, eplivanserin, and LY2624803) improve slow-wave sleep but, for various reasons, the drug companies withdrew their products.

Antidepressants for insomnia in adults.

Insomnia disorder is a subjective condition of unsatisfactory sleep (e.g. sleep onset, maintenance, early waking, impairment of daytime functioning). Insomnia disorder impairs quality of life and is associated with an increased risk of physical and mental health problems including anxiety, depression, drug and alcohol abuse, and increased health service use. hypnotic medications (e.g. benzodiazepines and 'Z' drugs) are licensed for sleep promotion, but can induce tolerance and dependence, although many people remain on long-term treatment. Antidepressant use for insomnia is widespread, but none is licensed for insomnia and the evidence for their efficacy is unclear. This use of unlicensed medications may be driven by concern over longer-term use of hypnotics and the limited availability of psychological treatments. To assess the effectiveness, safety and tolerability of antidepressants for insomnia in adults. This review incorporated the results of searches to July 2015 conducted on electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 6), MEDLINE (1950 to 2015), Embase (1980 to 2015) and PsycINFO (1806 to 2015). We updated the searches to December 2017, but these results have not yet been incorporated into the review. Randomised controlled trials (RCTs) of adults (aged 18 years or older) with a primary diagnosis of insomnia and all participant types including people with comorbidities. Any antidepressant as monotherapy at any dose whether compared with placebo, other medications for insomnia (e.g. benzodiazepines and 'Z' drugs), a different antidepressant, waiting list control or treatment as usual. Two review authors independently assessed trials for eligibility and extracted data using a data extraction form. A third review author resolved disagreements on inclusion or data extraction. The search identified 23 RCTs (2806 participants).Selective serotonin reuptake inhibitors (SSRIs) compared with placebo: three studies (135 participants) compared SSRIs with placebo. Combining results was not possible. Two paroxetine studies showed significant improvements in subjective sleep measures at six (60 participants, P = 0.03) and 12 weeks (27 participants, P < 0.001). There was no difference in the fluoxetine study (low quality evidence).There were either no adverse events or they were not reported (very low quality evidence).Tricyclic antidepressants (TCA) compared with placebo: six studies (812 participants) compared TCA with placebo; five used doxepin and one used trimipramine. We found no studies of amitriptyline. Four studies (518 participants) could be pooled, showing a moderate improvement in subjective sleep quality over placebo (standardised mean difference (SMD) -0.39, 95% confidence interval (CI) -0.56 to -0.21) (moderate quality evidence). Moderate quality evidence suggested that TCAs possibly improved sleep efficiency (mean difference (MD) 6.29 percentage points, 95% CI 3.17 to 9.41; 4 studies; 510 participants) and increased sleep time (MD 22.88 minutes, 95% CI 13.17 to 32.59; 4 studies; 510 participants). There may have been little or no impact on sleep latency (MD -4.27 minutes, 95% CI -9.01 to 0.48; 4 studies; 510 participants).There may have been little or no difference in adverse events between TCAs and placebo (risk ratio (RR) 1.02, 95% CI 0.86 to 1.21; 6 studies; 812 participants) (low quality evidence).'Other' antidepressants with placebo: eight studies compared other antidepressants with placebo (one used mianserin and seven used trazodone). Three studies (370 participants) of trazodone could be pooled, indicating a moderate improvement in subjective sleep outcomes over placebo (SMD -0.34, 95% CI -0.66 to -0.02). Two studies of trazodone measured polysomnography and found little or no difference in sleep efficiency (MD 1.38 percentage points, 95% CI -2.87 to 5.63; 169 participants) (low quality evidence).There was low quality evidence from two studies of more adverse effects with trazodone than placebo (i.e. morning grogginess, increased dry mouth and thirst). We identified relatively few, mostly small studies with short-term follow-up and design limitations. The effects of SSRIs compared with placebo are uncertain with too few studies to draw clear conclusions. There may be a small improvement in sleep quality with short-term use of low-dose doxepin and trazodone compared with placebo. The tolerability and safety of antidepressants for insomnia is uncertain due to limited reporting of adverse events. There was no evidence for amitriptyline (despite common use in clinical practice) or for long-term antidepressant use for insomnia. High-quality trials of antidepressants for insomnia are needed.

Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery.

Although the GABAergic benzodiazepines (BZDs) and Z-drugs (zolpidem, zopiclone, and zaleplon) are FDA-approved for insomnia disorders with a strong evidence base, they have many side effects, including cognitive impairment, tolerance, rebound insomnia upon discontinuation, car accidents/falls, abuse, and dependence liability. Consequently, the clinical use of off-label drugs and novel drugs that do not target the GABAergic system is increasing. The purpose of this review is to analyze the neurobiological and clinical evidence of pharmacological treatments of insomnia, excluding the BZDs and Z-drugs. We analyzed the melatonergic agonist drugs, agomelatine, prolonged-release melatonin, ramelteon, and tasimelteon; the dual orexin receptor antagonist suvorexant; the modulators of the α2δ subunit of voltage-sensitive calcium channels, gabapentin and pregabalin; the H1 antagonist, low-dose doxepin; and the histamine and serotonin receptor antagonists, amitriptyline, mirtazapine, trazodone, olanzapine, and quetiapine. The pharmacology and mechanism of action of these treatments and the evidence-base for the use of these drugs in clinical practice is outlined along with novel pipelines. There is evidence to recommend suvorexant and low-dose doxepin for sleep maintenance insomnia; there is also sufficient evidence to recommend ramelteon for sleep onset insomnia. Although there is limited evidence for the use of the quetiapine, trazodone, mirtazapine, amitriptyline, pregabalin, gabapentin, agomelatine, and olanzapine as treatments for insomnia disorder, these drugs may improve sleep while successfully treating comorbid disorders, with a different side effect profile than the BZDs and Z-drugs. The unique mechanism of action of each drug allows for a more personalized and targeted medical management of insomnia.

Clinical Practice Guideline on Management of Sleep Disorders in the Elderly.

Clinical Practice Guideline on Management of Sleep Disorders in the Elderly.

Selective Serotonin 5-HT2A Receptor Antagonists and Inverse Agonists Specifically Promote Slow Wave Sleep (Stage N3) in Man

Several drug classes are widely prescribed when difficulties with sleep induction or sleep maintenance occur, as is the case in patients with an insomnia disorder. These include the benzodiazepine and non-benzodiazepine receptor allosteric modulators, the melanin receptor agonist ramelteon, low-dose doxepin, and the orexin receptor antagonist suvorexant. Benzodiazepines are often less than satisfactory, since they are known to produce reductions in both N3 sleep and rapid-eye movement (REM) sleep. Similarly, low-dose doxepin has been associated with a reduction in REM sleep. Initially, it was shown that the non-selective serotonin 5-HT2A/2C receptor antagonists’ ritanserin, ketanserin, seganserin, and ICI-169,369 increase N3 sleep in subjects with normal sleep. Ritanserin produced also an increase of N3 sleep in poor sleepers, patients with a chronic insomnia disorder, and psychiatric patients with a generalized anxiety disorder or a mood disorder. More recent evidence indicates that the selective 5-HT2A receptor antagonist volinanserin and the 5-HT2A receptor inverse agonists’ nelotanserin and pimavanserin significantly increase N3 sleep in subjects with normal sleep. Nelotanserin was also shown to augment N3 sleep in patients with a chronic insomnia disorder. N2 sleep tended to decrease in most of these studies, while REM sleep showed no significant changes. The present review which summarizes these findings is the basis for a proposal for a new therapeutic strategy. It is proposed that the co-administration of a selective 5-HT2A receptor antagonist or inverse agonist along with a hypnotic drug could be a valid clinical strategy for normalizing sleep induction and maintenance and for promoting N3 sleep in patients with an insomnia disorder.

Therapy Update for Insomnia in the Elderly.

To offer an update on insomnia in older adults and treatment options. A search of PubMed using the terms "insomnia" and "older adults" was performed. Current guidelines, review articles, and drug database and manufacturer package inserts were utilized to provide relevant information. All English-language articles from 2012 to February 2017 and their bibliographies were reviewed for relevance. Current guidelines from the American College of Physicians, the American Academy of Sleep Medicine, and the American Geriatrics Society's Beers criteria were reviewed. Insomnia is a frequent complaint in the elderly. Treatment guidelines for this specific population are lacking. Anticholinergics, doxepin > 6 mg, benzodiazepines (BZDs), and non BZD receptor agonists (BzDRAs) are potentially inappropriate drugs for older adults. For adults with chronic insomnia, sleep hygiene practices and cognitive behavioral therapy should be considered as the initial treatments. If drug therapy is required or desired, the guidelines recommend short-term uses of BZDs (triazolam or temazepam), BzDRAs, low-dose doxepin (≤ 6 mg), ramelteon, or suvorexant. Risks and benefits of pharmacotherapy should be discussed with patients and caregivers prior to treatment initiation. Frequent and regular monitoring for adverse events is warranted to prevent detrimental outcomes. Nonpharmacologic interventions are the first-line therapy for adults with chronic insomnia. Short-term drug therapy may be considered as an alternative or add-on treatment. Hypnotic use is associated with harm and requires close monitoring, especially in older adults.

Arousability and Fall Risk During Forced Awakenings From Nocturnal Sleep Among Healthy Males Following Administration of Zolpidem 10 mg and Doxepin 6 mg: A Randomized, Placebo-Controlled, Four-Way Crossover Trial.

To examine and compare the arousability threshold and fall risk upon awakening of doxepin (6 mg) versus zolpidem (10 mg). A total of 52 healthy adult males were included in a double-blind, placebo-controlled, four-way crossover study. The experimental procedure included four nights with polysomnography in the lab (zolpidem, doxepin, and their respective placebo conditions). Arousability was measured using an auditory awakening threshold delivered at the peak-plasma concentration for the active hypnotics and at matched times for the respective placebo conditions. Fall risk during the night was measured following awakening using the Berg Balance Scale and the Tandem Walk Task. Both arousability and fall risk were lower in the doxepin condition compared to the zolpidem condition. Furthermore, arousability and fall risk for doxepin did not differ significantly from the placebo conditions. A significantly greater proportion of participants in the zolpidem condition (63.5%) did not wake until receiving the loudest tone (110 dB) as compared to the doxepin (17.6%) and placebo conditions (17.3%, 5.8%). Results suggest that zolpidem has greater risks for balance and awakening threshold compared with low-dose doxepin. Future prospective studies should extend results to clinical samples with population-level risk of injury and arousability.

The Effects of Benzodiazepine and Nonbenzodiazepine Agents, Ramelteon, Low-dose Doxepin, Suvorexant, and Selective Serotonin 5-HT2A Receptor Antagonists and Inverse Agonists on Sleep and Wakefulness

Several agents are known to improve sleep induction and/or maintenance in patients with insomnia disorder. These include the benzodiazepine (BZD) and non-BZD receptor allosteric modulators, the melatonin receptor agonist ramelteon, low-dose doxepin, and suvorexant. One of the drawbacks of the BZDs is their known reduction in both N3 sleep [also known as slow wave sleep or delta sleep and characterized by the occurrence of slow high amplitude delta (0.5–2 Hz) waves] and rapid eye movement (REM) sleep. Low-dose doxepin has shown similar association with decrease in REM sleep. By contrast, suvorexant increases REM sleep. The available evidence tends to indicate that irrespective of their mechanisms of action, the selective serotonin 5-HT2A receptor antagonists and inverse agonists, including volinanserin, pruvanserin, and nelotanserin, when given in isolated administration, increases slow wave sleep in laboratory animals. Wakefulness and REM sleep were decreased in some studies. Moreover, subjects with normal sleep showed significant increase in N3 sleep following the administration of eplivanserin, nelotanerin, and pimavanserin. Nelotanserin has also been shown to augment N3 sleep in patients with chronic insomnia disorder. N2 sleep tended to decrease in most of these studies, while REM sleep showed no significant changes. Taken together, these evidences suggest that the coadministration of a selective 5-HT2A receptor antagonist or inverse agonist with a hypnotic drug could be a valid clinical strategy for normalizing sleep induction and maintenance and for promoting N3 sleep in patients with insomnia disorder. Additionally, the 5-HT2A receptor agents may have a potential value for improving the cognition and memory deficits in patients with a chronic insomnia disorder as well as elderly patients who show reductions in N3 sleep.

Efficacy and safety evaluation of citalopram and doxepin on sleep quality in comorbid insomnia and anxiety disorders.

Anxiety disorders are frequently comorbid with insomnia, and sleep disturbance in patients with anxiety disorders is the most common complaint. Antidepressants can affect sleep quality; however, their effect in patients with comorbid insomnia and anxiety disorders is unclear. The aim of the present study was to comprehensively evaluate the dose, treatment duration, treatment efficacy and safety of clinical citalopram and doxepin application in patients with comorbid insomnia and anxiety disorders. It was found that both citalopram (20 mg/day) and low-dose doxepin (12.5 mg/day) significantly improved sleep latency, duration and disturbances, as well as daytime dysfunction and the global Pittsburgh Sleep Quality Index during the 12-week treatment period. Notably, low-dose doxepin significantly improved sleep latency in patients after treatment for 8 and 12 weeks as compared with citalopram. It was further observed that both citalopram and low-dose doxepin improved anxiety. A significant and positive correlation was found between the improvement in the sleep quality and anxiety in the two treatment groups. Citalopram and low-dose doxepin both showed good efficacy and a low adverse reaction rate in the treated patients. These data support a potential application of citalopram and low-dose doxepin in the treatment of patients with comorbid insomnia and anxiety disorders.

Drug treatment of primary insomnia: a meta-analysis of polysomnographic randomized controlled trials.

Although insomnia is a frequent health complaint that is often treated with drugs, little is known about differences in treatment efficacy of various drug classes on objective versus subjective outcome measures. Our aim was to compare treatment efficacy of classical benzodiazepines, benzodiazepine receptor agonists (zopiclone, zolpidem and zaleplon), antidepressants (including low-dose doxepin), neuropeptides, progesterone receptor antagonists, hormones, melatonin receptor agonists, antihistamines, antiepileptics, and narcotics addressing primary insomnia. We conducted a comprehensive literature search (up to 5 April 2013) using PubMed, Cochrane Clinical Trials, PQDT OPEN, OpenGREY, ISI Web of Knowledge, PsycINFO, PSYNDEX, and the WHO International Clinical Trials Registry Platform. Only polysomnographic, parallel-group, randomized controlled drug trials were included; eligibility was determined by two independent authors. We used a random effects model, based on 31 studies reporting 80 treatment conditions, covering 3,820 participants. Effect size estimates for the total sample of pooled drug classes suggest that there is a small-to-moderate, significant, and robust effect for objective outcomes (sleep onset latency g = -0.36, total sleep time g = 0.27) and subjective outcomes (sleep onset latency g = -0.24, total sleep time g = 0.21). Results indicate higher effect sizes for benzodiazepine receptor agonists and classical benzodiazepines compared with antidepressants (including low-dose doxepin) and for classical benzodiazepines compared with benzodiazepine receptor agonists. Benzodiazepine receptor agonists demonstrated higher effect sizes for objective outcomes. Data on drug safety were not analyzed. Future studies should use objective and subjective assessment. Focusing on efficacy, clinicians should favor benzodiazepine receptor agonists and classical benzodiazepines over antidepressants (including low-dose doxepin) for primary insomnia treatment, but the additional consideration of different side effect profiles can lead to alternative treatment decisions.

Efficacy and safety of low-dose doxepin in depressed patients suffering from insomnia: a retrospective, naturalistic case series analysis.

Low-dose doxepin has produced favorable results in healthy adults and elderly persons with chronic or transient insomnia, while exhibiting an amenable adverse event profile. The aim of this article is to investigate the efficacy and safety of low-dose doxepin for insomnia in depressed patients. In this retrospective case series analysis, the files of 17 inpatients diagnosed with major depressive disorder (MDD) and comorbid insomnia between January 1, 2011, and October 1, 2012 who had received a course of off-label doxepin (< 25 mg/d) were analyzed with regard to dose, efficacy, and safety for up to 4 weeks of treatment. Hamilton Depression Rating Scale (HDRS) sleep item scores were used to estimate efficacy. Our results showed no improvement in sleep onset and sleep maintenance insomnia in patients with MDD during the 4 weeks of treatment. We found a significant improvement in insomnia between baseline and week 3 when considering all 3 HDRS sleep items (P = .058). Contrasting previous results in healthy subjects, low-dose doxepin does not seem to improve sleep onset or maintenance in patients with MDD. Further research, preferably placebo-controlled, double-blind sleep laboratory trials, is necessary to determine whether low-dose doxepin may be beneficial in this important patient subgroup.

Novel Developments in the Pharmacological Management of Insomnia

Advances in the basic science of sleep/wake neurophysiology are driving the exploration of new pharmacologic approaches with continued improvement in efficacy and safety.

Therapeutic rationale for low dose doxepin in insomnia patients

Histamine is an excitatory neurotransmitter in central nervous system. It plays an important role in the regulation of the sleep-wake cycle. Antidepressant with sleep-promoting effects, for example, doxepin, promotes sleep not through a sedative action but through resynchronisation of circadian cycle. The stimulation of the H1 receptor is thought to play an important role in mediating arousal. Doxepin has a high affinity for the H1 receptor, making it a selective H1 antagonist at low dose and it has been shown to display sedating properties. Compared to other sedative antidepressant, low dose doxepin is the only tricyclic drug which has been evaluated by well-designed, randomised, double blind, placebo controlled studies in both adult and elderly patients. Doxepin is not designated as controlled substance/unscheduled drugs and thus may be of special advantage to use in patients with a history of substance abuse. Hence, well-documented therapeutic efficacy, tolerability and lack of important adverse effects make the low dose doxepin as a unique, rational drug for the treatment of insomnia in adult and elderly patients.