Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Adjunctive low-dose docosahexaenoic acid (DHA) for major depression: An open-label pilot trial.

OVERVIEW: Whilst the majority of evidence supports the adjunctive use of eicosapentaenoic acid (EPA) in improving mood, to date no study exists using low-dose docosahexaenoic acid (DHA) alone as an adjunctive treatment in patients with mild to moderate major depressive disorder (MDD). METHODS: A naturalistic 8-week open-label pilot trial of low-dose DHA, (260 mg or 520 mg/day) in 28 patients with MDD who were non-responsive to medication or psychotherapy, with a Hamilton Depression Rating Scale (HAM-D) score of greater than 17, was conducted. Primary outcomes of depression, clinical severity, and daytime sleepiness were measured. RESULTS: After 8 weeks, 54% of patients had a ≥50% reduction on the HAM-D, and 45% were in remission (HAM-D ≤ 7). The eta-squared statistic (0.59) indicated a large effect size for the reduction of depression (equivalent to Cohen's d of 2.4). However confidence in this effect size is tempered due to the lack of a placebo. The mean score for the Clinical Global Impression Severity Scale was significantly improved by 1.28 points (P < 0.05). Despite a significant reduction in the HAM-D score for middle insomnia (P = 0.02), the reduction in excessive daytime somnolence on the total Epworth Sleepiness Scale (ESS) did not reach significance. No significant adverse reactions to DHA were found. CONCLUSION: Within the major limits of this open-label pilot study, the results suggest that DHA may provide additional adjunctive benefits in patients with mild- to -moderate depression.

Common questions about the diagnosis and management of fibromyalgia.

Fibromyalgia has a distinct pathophysiology involving central amplification of peripheral sensory signals. Core symptoms are chronic widespread pain, fatigue, and sleep disturbance. Most patients with fibromyalgia have muscle pain and tenderness, forgetfulness or problems concentrating, and significant functional limitations. Fibromyalgia is diagnosed using an updated set of clinical criteria that no longer depend on tender point examination; laboratory testing may rule out other disorders that commonly present with fatigue, such as anemia and thyroid disease. Patients with fibromyalgia should be evaluated for comorbid functional pain syndromes and mood disorders. Management of fibromyalgia should include patient education, symptom relief, and regular aerobic physical activity. Serotoninnorepinephrine reuptake inhibitors, tricyclic antidepressants, antiepileptics, and muscle relaxants have the strongest evidence of benefit for improving pain, fatigue, sleep symptoms, and quality of life. Multiple complementary and alternative medicine therapies have been used but have limited evidence of effectiveness. Opioids should be used to relieve pain in carefully selected patients only if alternative therapies are ineffective.

Complementary home mechanical ventilation techniques. SEPAR Year 2014.

This is a review of the different complementary techniques that are useful for optimizing home mechanical ventilation (HMV). Airway clearance is very important in patients with HMV and many patients, particularly those with reduced peak cough flow, require airway clearance (manual or assisted) or assisted cough techniques (manual or mechanical) and suctioning procedures, in addition to ventilation. In the case of invasive HMV, good tracheostomy cannula management is essential for success. HMV patients may have sleep disturbances that must be taken into account. Sleep studies including complete polysomnography or respiratory polygraphy are helpful for identifying patient-ventilator asynchrony. Other techniques, such as bronchoscopy or nutritional support, may be required in patients on HMV, particularly if percutaneous gastrostomy is required. Information on treatment efficacy can be obtained from HMV monitoring, using methods such as pulse oximetry, capnography or the internal programs of the ventilators themselves. Finally, the importance of the patient's subjective perception is reviewed, as this may potentially affect the success of the HMV.

A yoga program for the symptoms of post-traumatic stress disorder in veterans.

The purpose of this pilot study was to evaluate the feasibility and effectiveness of a yoga program as an adjunctive therapy for improving post-traumatic stress disorder (PTSD) symptoms in Veterans with military-related PTSD. Veterans (n = 12) participated in a 6 week yoga intervention held twice a week. There was significant improvement in PTSD hyperarousal symptoms and overall sleep quality as well as daytime dysfunction related to sleep. There were no significant improvements in the total PTSD, anger, or quality of life outcome scores. These results suggest that this yoga program may be an effective adjunctive therapy for improving hyperarousal symptoms of PTSD including sleep quality. This study demonstrates that the yoga program is acceptable, feasible, and that there is good adherence in a Veteran population.

[Using a laser based program in patients diagnosed with fibromyalgia]. / Utilización de un programa con láser en pacientes diagnosticados de fibromialgia.

In this study, the benefits of a program of treatment by laser were evaluated on the improvement of symptoms associated with fibromyalgia. A total of 31 participants took part in the study, all of them women, randomized into two groups: intervention with laser and placebo. The intervention with girlase E11010 consisted of the individual application of six frequencies on seven anatomical zones of the body. The results were statistically significant differences for "weariness" and "difficulty sleeping" variables. In the rest of the variables, we did not find any statistical significance. One of the conclusions from the present study is the need for development of new research to verify the influence of girlase E1.1010 in the improvement of symptoms associated with fibromyalgia.

Relationship between gastro-oesophageal reflux and airway diseases: the airway reflux paradigm.

Our understanding of the relationship between gastro-oesophageal reflux and respiratory disease has recently undergone important changes. The previous paradigm of airway reflux as synonymous with the classic gastro-oesophageal reflux disease (GORD) causing heartburn has been overturned. Numerous epidemiological studies have shown a highly significant association of the acid, liquid, and gaseous reflux of GORD with conditions such as laryngeal diseases, chronic rhinosinusitis, treatment resistant asthma, COPD and even idiopathic pulmonary fibrosis. However, it has become clear from studies on cough hypersensitivity syndrome that much reflux of importance in the airways has been missed, since it is either non- or weakly acid and gaseous in composition. The evidence for such a relationship relies on the clinical history pointing to symptom associations with known precipitants of reflux. The tools for the diagnosis of extra-oesophageal reflux, in contrast to the oesophageal reflux of GORD, lack sensitivity and reproducibility. Unfortunately, methodology for detecting such reflux is only just becoming available and much additional work is required to properly delineate its role.

[Effects of aerobic exercise program and relaxation techniques on anxiety, quality of sleep, depression, and quality of life in patients with fibromyalgia: a randomized controlled trial]. / Efectos de un programa de ejercicios aeróbicos y técnicas de relajación sobre el estado de ansiedad, calidad del sueño, depresión y calidad de vida en pacientes con fibromialgia: ensayo clínico aleatorizado.

BACKGROUND AND OBJECTIVE: Fibromyalgia is considered as a combination of physical, psychological and social disabilities. The purpose of the present study was to determine the benefits of aerobic exercise program and progressive relaxation techniques on anxiety, quality of sleep, depression and quality of life in patients with fibromyalgia. PATIENTS AND METHOD: An experimental study was performed with a placebo control group. Fifty-six fibromyalgia patients were randomly assigned to intervention (aerobic exercises+progressive relaxation techniques) and placebo (sham treatment with disconnected magnet therapy device) groups. Outcome measures were anxiety (STAI- State Trait Anxiety Inventory), quality of sleep (Pittsburgh sleep quality index), depression (Beck depression inventory) and quality of life (questionnaire SF-36). Measures were performed at baseline and after 10-weeks treatment. RESULTS: After 10 weeks of treatment, the intervention group showed significant reduction (p<0.05) in sleep duration, trait anxiety and quality of life. CONCLUSIONS: The combination of aerobic exercise program and progressive relaxation techniques contribute to improve night rest, trait anxiety and quality of life in patients with fibromyalgia.

[Tinnitus]. / Tinnitus.

Tinnitus is a symptom caused by the dysfunction of the auditory system associated with hyperactive networks of the central auditory tract. Intimate relationship of the auditory tract with the limbic system may lead to a stress reaction with subsequent sleep disturbances, distress and depression. The target of tinnitus treatment shoud be the annoyance caused by tinnitus, not the sensation itself. Optimally, all tinnitus patients should be treated according to the TRT-principles including careful diagnostics, informational counceling and sound-based therapies. Some patients need sleep therapy as well as anti-depressive therapy.

Case report: Treatment of mild traumatic brain injury with hyperbaric oxygen.

Two United States Air Force Airmen were injured in a roadside improvised explosive device (IED) blast in Iraq in January 2008. Both airmen suffered concussive injuries and developed irritability, sleep disturbances, headaches, memory difficulties and cognitive difficulties as symptoms of mild traumatic brain injury (mTBI). Six months after injury, repeat Automated Neuropsychological Assessment Metrics (ANAM) testing showed deterioration, when compared to pre-injury baseline ANAM assessment, in all measured areas (simple reaction time, procedural reaction time, code substitution learning, code substitution delayed, mathematical processing, and matching to sample). The airmen were treated with hyperbaric oxygen in treatments of 100% oxygen for one hour at 1.5 atmospheres absolute, resulting in rapid improvement of headaches and sleep disturbances, improvement in all symptoms and resolution of most symptoms. Repeat ANAM testing after completion of the hyperbaric treatments - nine months after initial injury - showed improvement in all areas, with most measures improving to pre-injury baseline levels. The airmen received no other treatment besides medical monitoring. Repeat neuropsychologic testing confirmed the improvement. We conclude that the improvement in symptoms and ANAM performance is most likely attributable to HBO treatment.

The syndrome of optic nerve hypoplasia.

The congenital malformation known as optic nerve hypoplasia (ONH) has been recognized in the past 30 years as an epidemic cause of congenital blindness. It was believed to occur either as an isolated anomaly or as a component of the syndrome of septo-optic dysplasia, which has evolved to include midline brain malformations and hypopituitarism. Evidence now suggests that ONH infrequently occurs in isolation. Most afflicted children will have hypothalamic dysfunction and/or neurodevelopmental impairment, regardless of MRI findings or severity of ONH. Adverse outcomes can often be ameliorated with early intervention. Thus, the syndrome of ONH should be suspected in all infants with signs of hypothalamic dysfunction or vision impairment.

The two faces of Eve: dopamine's modulation of wakefulness and sleep.

In Parkinson's disease (PD), waking is frequently punctuated by sleep episodes, including rapid eye movement (REM) (i.e., dream) sleep, and sleep is interrupted by motor activities such as periodic limb movements and REM sleep behavior disorder. Because these pathologic behaviors are unaccounted for by contemporary models, this review summarizes the complex effects of dopamine (DA) on normal and pathological waking-sleeping. Maintenance of wakefulness is probably promoted by mesocorticolimbic DA circuits, and suppression of nocturnal movement appears to be influenced by indirect pathways linking midbrain DA neurons with pre-motor structures in the mesopontine tegmentum and ventromedial medulla. A diencephalospinal DA system may have an additional important role in mediating state-specific sensorimotor activity that is relevant to periodic limb movements and restless legs syndrome.

Hallucinations and sleep disturbances in Parkinson's disease.

Visual hallucinations (VHs) occur frequently in Parkinson's disease (PD). VHs occur more frequently in elderly patients with longer duration of illness, cognitive impairment, and sleep disturbances. The relationship between the use of antiparkinsonian drugs and VHs is complicated, but most drugs used to treat parkinsonian motor symptoms induce VHs and psychosis in some PD patients. The "continuum hypothesis" proposing that medication-induced psychiatric symptoms in PD begin with drug-induced sleep disturbances, followed by vivid dreams, with progression to hallucinatory and delusional experiences has been challenged. In some patients, VHs may represent intrusion of REM sleep-related imagery into wakefulness. Improving REM sleep abnormalities in PD (e.g., stimulants, anticholinesterase inhibitors) is one strategy now being tested to improve VHs in PD.

Melatonin acutely improves the neuroendocrine architecture of sleep in blind individuals.

In blind individuals, the absence of light cues results in disturbances of sleep and sleep-related neuroendocrine patterns. The Zeitgeber influence of light on the timing of sleep is assumed to be mediated by melatonin, a hormone of the pineal gland, whose secretion is inhibited by light and enhanced during darkness. Here, we investigated whether a single administration of melatonin improves sleep and associated neuroendocrine patterns in blind individuals. In a double-blind crossover study, 12 totally blind subjects received 5 mg melatonin and placebo orally 1 h before bedtime starting at 2300 h. The dose used enhanced blood melatonin concentrations to clearly supraphysiological levels. Melatonin increased total sleep time and sleep efficiency (P < 0.05, respectively) and reduced time awake (P < 0.05). The increment in total sleep time was primarily due to an increase in stage 2 sleep (P < 0.01) and a slight increase in rapid eye movement sleep (P < 0.06). Most important, melatonin normalized in parallel the temporal pattern of ACTH and cortisol plasma concentration. While after placebo, ACTH and cortisol levels did not differ between early and late sleep, melatonin induced the typical suppression of pituitary-adrenal activity during early sleep and a distinct rise during late sleep (P < 0.01, respectively). Cortisol nadir values were also decreased after melatonin (P < 0.05). We conclude from these data that in totally blind individuals the single administration of a clearly pharmacological dose of melatonin can improve sleep function by synchronizing in time the inhibition of pituitary-adrenal activity with central nervous sleep processes.

Kava and valerian in the treatment of stress-induced insomnia.

Kava and valerian are herbal remedies, claimed to have anxiolytic and sedative properties respectively, without dependence potential or any appreciable side-effects. In this pilot study, 24 patients suffering from stress-induced insomnia were treated for 6 weeks with kava 120 mg daily. This was followed by 2 weeks off treatment and then, 5 having dropped out, 19 received valerian 600 mg daily for another 6 weeks. Stress was measured in three areas: social, personal and life-events; insomnia in three areas also: time to fall asleep, hours slept and waking mood. Total stress severity was significantly relieved by both compounds (p < 0.01) with no significant differences between them; as was also insomnia (p < 0.01). The proportion of patients with no side-effects was 58% with each drug respectively and the 'commonest' effect was vivid dreams with valerian (16%), followed by dizziness with kava (12% ). These compounds may be useful in the treatment of stress and insomnia but further studies are required to determine their relative roles for such indications.