Major depressive disorder is a common psychiatric disorder associated with marked suffering, morbidity, mortality, and cost. The World Health Organization projects that by 2030, major depression will be the leading cause of disease burden worldwide. While numerous treatments for major depression exist, many patients do not respond adequately to traditional antidepressants. Thus, more effective treatments for major depression are needed, and targeting certain hormonal systems is a conceptually based approach that has shown promise in the treatment of this disorder. A number of hormones and hormone-manipulating compounds have been evaluated as monotherapies or adjunctive treatments for major depression, with therapeutic actions attributable not only to the modulation of endocrine systems in the periphery but also to the CNS effects of hormones on non-endocrine brain circuitry. The authors describe the physiology of the hypothalamic-pituitary-adrenal (HPA), hypothalamic-pituitary thyroid (HPT), and hypothalamic-pituitary-gonadal (HPG) axes and review the evidence for selected hormone-based interventions for the treatment of depression in order to provide an update on the state of this field for clinicians and researchers. The review focuses on the HPA axis-based interventions of corticotropin-releasing factor antagonists and the glucocorticoid receptor antagonist mifepristone, the HPT axis-based treatments of thyroid hormones (T3 and T4), and the HPG axis-based treatments of estrogen replacement therapy, the progesterone derivative allopregnanolone, and testosterone. While some treatments have largely failed to translate from preclinical studies, others have shown promising initial results and represent active fields of study in the search for novel effective treatments for major depression.

Hormonal Treatments for Major Depressive Disorder: State of the Art

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.

Insomnia in Elderly Patients: Recommendations for Pharmacological Management.

Off-label prescribing of psychiatric drugs is common, despite lacking strong scientific evidence of efficacy and potentially increasing risk for adverse events The goal of this study was to characterize prevalence of off-label prescriptions of psychiatric drugs and examine patient and clinician predictors of off-label use This manuscript presents a retrospective, cross-sectional study using data from the 2012 and 2013 National Ambulatory Medical Care Surveys (NAMCS) The study examined all adult outpatient visits to psychiatric practices for chronic care management with a single listed visit diagnosis in which at least one psychiatric drug was prescribed The main outcome measure was off-label prescribing of at least one psychiatric drug, defined as prescription for a condition for which it has not been approved for use by the FDA Among our sample representative of 185 billion outpatient visits, 185 million (13%) visits were to psychiatrists for chronic care management in which at least one psychiatric drug was prescribed Overall, the rate of off-label use was 129% (95% CI: 122-157) The most common off-label uses were for manic-depressive psychosis treated with citalopram and primary insomnia treated with trazodone Several patient and clinician characteristics were positively associated with off-label prescribing, including seeing a psychiatrist (OR: 106, 95% CI, 101-112; p = 003) instead of another type of clinician, the office visit taking place in the Western region of the country (OR: 109, 95% CI, 101-117; p = 002), and the patient having 3 or more chronic conditions (OR: 112, 95% CI, 102-114; p = 0003) In contrast, having Medicare coverage (OR: 093, 95% CI, 084-097; p = 004) and receiving payment assistance from a medical charity (OR: 091, 95% CI, 088-096; p = 003) instead of private insurance were negatively associated with off-label prescribing These results suggest that certain classes of psychiatric medications are being commonly prescribed to treat conditions for which they have not been determined by the FDA to be clinically efficacious and/or safe

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Patterns and predictors of off-label prescription of psychiatric drugs

Off-label uses of drugs for depression.

Background Insomnia is the most commonly reported sleep problem in industrialized countries worldwide being present in about 368% of the general population In Italy, such a percentage seems to be even higher Although insomnia can be an independent disorder, it is most frequently observed as a comorbid condition and may precipitate, exacerbate, or prolong a broad range of comorbid conditions including physical and mental illnesses Evaluating and targeting insomnia in the Italian clinical practice should be a priority Methods The present expert options and recommendations development process was based on the RAND/UCLA Appropriateness Method for conceptualizing, designing, and carrying out the appropriateness of procedures for the diagnosis and treatment Only available options in Italy were taken into considerations Results We evaluated 12 international guidelines and 12 most recent systematic reviews for insomnia evaluation and treatment produced in the last 10 years Conclusions Our findings suggested that symptoms of insomnia must always be assessed in the Italian clinical practice by evaluating nocturnal and daytime symptoms, comorbid conditions and lifestyle In a patient with chronic insomnia with and without comorbidity, insomnia treatment should be always initiated CBT-Insomnia therapy should be the first option accordingly to availability The choice of the drug should be based on different factors such as type of insomnia, age, comorbidities, and potential side effects Melatonin 2 mg prolonged release should be the first choice in subjects >55 years If the choice would be a Z-drug or a short-acting benzodiazepine (in subjects <65 years old) or a sedating antidepressant, the use should be in the short term (≤4 weeks) and then proceeds to tapering under clinical monitoring

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Expert Opinions and Consensus Recommendations for the Evaluation and Management of Insomnia in Clinical Practice: Joint Statements of Five Italian Scientific Societies.

We conducted a systematic review of the published literature relating to the assessment and measurement of wellness in order to answer the following questions: 1) What is the working definition of wellness? 2) What wellness assessment instruments have been evaluated or applied in medical settings? 3) How valid, reliable, and accessible are these wellness assessment tools? The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for this systematic review. Studies published from1990 to 2016 on wellness assessment were identified through Medline and PsycINFO using the following keywords: "assessment" OR "evaluation" OR "measurement" AND "wellness" OR "wellbeing." Two authors independently conducted a focused analysis then reached a consensus on 23 studies that met the specific selection criteria. This review revealed that there is a lack of uniform definition of wellness. The studies utilizing wellness assessment tools demonstrate strongest reliability values for the following instruments: Wellness Evaluation of Lifestyle, Five-factor Wellness Evaluation of Lifestyle, Perceived Wellness Survey, the Optimal Living Profile, and the Body-Mind-Spirit Wellness Behavior and Characteristic Inventory. However, there is insufficient evidence to support the clinical utility of a single particular wellness instrument. Properly defining wellness might help drive the development and validation of more precise assessment and measurement methods. This could reinforce interventions that promote wellness.

The Assessment and Measurement of Wellness in the Clinical Medical Setting: A Systematic Review

OBJECTIVE: While trazodone is approved for the treatment of depression, the off-label use of this medication for insomnia has surpassed its usage as an antidepressant. In this systematic review, we examined the evidence for the efficacy and safety of trazodone for insomnia. METHODS: A literature search was conducted using MEDLINE/PubMed databases from the past 33 years (1983-2016) and the keywords insomnia, trazodone, sedative, treatment, and hypnotics. The results were restricted to English language and human subjects. All randomized clinical trials, meta-analyses, observational studies, and placebo-controlled trials regarding trazodone for the treatment of primary or secondary insomnia were reported, per PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The study selection process yielded a total of 45 studies. RESULTS: Evidence for the efficacy of trazodone has been repeatedly demonstrated for primary insomnia, as well as secondary insomnia, including for symptoms that are a result of depression, dementia, and being a healthy man. Earlier studies (1980-2000) focused on utilizing trazodone at high doses (≥100mg/d) for the treatment of insomnia among the depressed population; however, since the 2000s, the utility of trazodone has been expanded to treat secondary insomnia among the non-depressed population as well. The side effects are dose-dependent, and the most common is drowsiness. CONCLUSION: A review of the literature suggests that there are adequate data supporting the efficacy and general safety of the low-dose use of trazodone for the treatment of insomnia.

Marina Abdelmesseh

Papers

The Assessment and Measurement of Wellness in the Clinical Medical Setting: A Systematic Review

Trazodone for Insomnia: A Systematic Review.