Adjunctive bright light treatment with gradual advance in unipolar major depressive disorder with evening chronotype - A randomized controlled trial.

BACKGROUND: Unipolar non-seasonal depressed patients with concomitant evening chronotype were associated with poor clinical outcomes and higher non-remission rate. This study aims to examine the efficacy of adjunctive bright light therapy with gradual timing advance in a randomized, assessor and prescriber-blinded controlled trial. METHOD: Participants were randomly allocated to receive 5 weeks of either bright white light therapy (BLT) or dim red light (DRL) with the same advancement protocol. Participants were followed up till 5 months after treatment. Primary outcomes included (i) remission rate and (ii) the severity of depression. The analysis was conducted using Kaplan-Meier survival analysis, Cox proportional hazard analysis and linear mixed models. RESULTS: A total of 93 participants (46.4 ± 11.7 years old, 80% female) were randomized. The cumulative remission rate for the BLT and the DRL groups was 67.4% and 46.7%, respectively. Time to remission was shorter for the BLT group relative to the DRL group (log-rank test p = 0.024). Cox proportional hazard survival analysis showed that patients in the BLT group had a higher probability of achieving remission relative to patients in the DRL group [hazard ratio = 1.9 (95% CI = 1.1- 3.4), p = 0.026]. Further sensitivity analysis demonstrated greater improvement in 17-Hamilton Depression Score (group × time interaction, p = 0.04) in the BLT group for those who were adherent to light therapy. CONCLUSIONS: The use of bright light therapy with gradual advance protocol is an effective adjunctive treatment resulting in quicker and a higher rate of remission of depression in patients with non-seasonal unipolar depression and evening-chronotype.

Caring burden of REM sleep behavior disorder - spouses' health and marital relationship.

OBJECTIVES: Idiopathic REM sleep behavior disorder (iRBD) is noxious due to the high prevalence of sleep-related injuries to patients and their bed-partners. In this study, we aimed to investigate the impact of patients' RBD symptoms on their spouses, in terms of the quality of sleep, and physical, mental and marital aspects. METHOD: A cross-sectional study comparing spouses of iRBD patients to the spouses of the age-and-sex-matched OSAS patients. RESULTS: 40 iRBD patients and their spouses (patients' age 66.6 ± 9.1, male 90%; spouses' age 62.9 ± 7.5), and 35 OSAS patients and their spouses (patients' age 67.8 ± 8.7 years old, male 80%; spouses' age 64.1 ± 9.1) were recruited. Almost all iRBD spouses (90%) reported disturbances by the nocturnal RBD behavioral symptoms of their bedpartners. About two-thirds (62.5%, N = 25) of the iRBD spouses reported a history of being injured during sleep. Spouses of both iRBD and OSAS patients reported a comparably high prevalence of insomnia, anxiety and depressive symptoms. Spouses of iRBD patients, however, reported more impaired quality of life and marital relationship. Nearly two-thirds of RBD couples continued co-sleeping, despite the risk of sleep-related injuries and nocturnal disturbances. CONCLUSIONS: Both iRBD and OSAS spouses exhibited a high prevalence of insomnia and mood problems. In particular, iRBD significantly and negatively affect the spouses' quality of life and the marital relationship. Optimization of iRBD treatment, proper diagnosis, and management of sleep and mental health aspects of spouses may help to lessen the caring burden.

Familial aggregation and heritability of insomnia in a community-based study.

BACKGROUND: Emerging data suggested a significant familial aggregation of insomnia. We aimed to clarify the familial aggregation and heritability of insomnia disorder by using structural clinical interviews for the ascertainment of insomnia and psychiatric disorders in a community-based sample. METHODS: Seventy-five adolescents with insomnia and their 180 first degree relatives, together with 141 age- and sex-matched non-insomnia controls and their 382 first degree relatives, were recruited. Each subject underwent a structured clinical interview and completed a series of psychometric inventories. The rates of insomnia disorder among the first degree relatives were employed to analyze familial aggregation. Heritability of insomnia was analyzed by SOLAR program as based on father-mother-offspring trios. RESULTS: Our study confirmed a significant familial aggregation of insomnia with a first degree relatives' recurrence risk of 2.33 for current insomnia and 2.82 for lifetime insomnia, respectively. The heritability±SE of current and lifetime insomnia disorder was 0.48±0.13 and 0.61±0.11 (p<0.001), respectively, which were higher than insomnia symptoms as estimated by the Insomnia Severity Inventory (h(2)±SE=0.27±0.09) and the Pittsburgh Sleep Quality Index (h(2)±SE=0.30±0.11). After exclusion of comorbid psychiatric disorders, the heritability for current and lifetime primary insomnia was 0.45±0.17 (p=0.007) and 0.58±0.21 (p=0.004), respectively. CONCLUSIONS: Our study demonstrates a significant familial aggregation with a high heritability of insomnia disorder. The strong heritability of insomnia persists despite the exclusion of psychiatric disorders. Further molecular genetic investigation of insomnia is indicated.

Long-term outcomes and predictors of chronic insomnia: a prospective study in Hong Kong Chinese adults.

OBJECTIVES: We aimed to determine the longitudinal course and outcome of chronic insomnia in a five-year prospective study in Hong Kong Chinese adults. METHODS: Two thousand three hundred and sixteen middle-aged adults (53.3% females, 46.3 ± 5.1 years old at follow-up) were recruited at baseline and follow-up. Participants were divided into three groups: non-insomnia, insomnia symptoms, and insomnia syndrome (insomnia symptoms plus daytime symptoms). Upper airway inflammatory diseases, mental problems, and medical problems were additionally assessed at follow up. RESULTS: The incidence of insomnia (symptoms and syndrome) was 5.9%. The persistence rate of insomnia syndrome was 42.7% for insomnia syndrome and 28.2% for insomnia symptoms. New incidence of insomnia was associated with younger age, unemployment, and daytime symptoms, while persistence of insomnia was associated with female sex, lower education level, and daytime symptoms at the baseline (p<0.05). Baseline insomnia syndrome was significantly associated with upper airway inflammatory diseases (including asthma and laryngopharyngitis; adjusted OR=1.97-17.9), mental problems, and medical conditions (including arthritis, psychiatric disorders, chronic pain, and gastroesophageal reflux disease; AOR=2.29-3.77), whereas baseline insomnia symptoms were associated with poor mental health (AOR=2.43), psychiatric disorders (AOR=2.39), and chronic pain (AOR=2.95). CONCLUSIONS: Chronic insomnia is a common problem with considerable persistence and incidence rates among middle-aged Chinese adults. Insomnia syndrome has a higher persistence rate with more mental and medical comorbidities when compared with insomnia symptoms without daytime consequences.

Validation of a new REM sleep behavior disorder questionnaire (RBDQ-HK).

OBJECTIVES: There are limited screening instruments for diagnosis of REM sleep behavior disorder (RBD) and none for quantifying the severity of disease. We aimed to validate a 13-item self-reported RBD questionnaire (RBDQ-HK) for diagnostic and monitoring purposes. METHODS: Based on ICSD-II and our previous clinical and empirical work, the RBDQ-HK questionnaire was designed and administered in patients attending university-affiliated sleep clinic and psychiatric out-patient clinic, and subjects from the general population. ROC curve and exploratory factor analysis were employed to evaluate the scale, which had a score ranging from 0 to 100. RESULTS: One hundred and seven RBD patients [mean age 62.6 (15.5) years; male 70.1%] and 107 control subjects [mean age 55.3 (9.0) years, male 57.9%] completed the questionnaire. The diagnoses of all the study subjects were independently ascertained by clinical interview and PSG. RBD patients had a significantly higher total RBDQ-HK score [mean (s.d.): 32.1 (16.1), range 3-71] than the control group [9.5 (10.2), range 0-55] (p<0.005). The RBDQ-HK demonstrated robust psychometric properties with moderate sensitivity (82.2%), specificity (86.9%), positive predictive value (PPV; 86.3%), and negative predictive value (NPV; 83.0%), high internal consistency and test-retest reliability. Exploratory factor analysis revealed two components (dream-related and behavioral factors) that corresponded to the essential clinical features of RBD. The best cut-off for total score (range 0-100) was at 18/19 and the best cut-off for factor 2 (behavioral factors including sleep talking, shouting, limb movements and sleep-related injuries, range 0-70) was at 7/8. CONCLUSIONS: The RBDQ-HK has satisfactory validity and reliability as a measure of clinical RBD symptoms and severity. It may serve as an effective tool for diagnosis and evaluation of the disease course to facilitate future clinical and research studies.

Interrater and intrarater reliability in multiple sleep latency test.

Multiple sleep latency test (MSLT) remains the golden standard for the clinical diagnosis and management of excessive daytime sleepiness. However, there was limited data on the reliability measurement of MSLT. Forty-four (M/F ratio: 26/18, mean age of 43.4 +/- 13.9 years) subjects of an ongoing family study of narcolepsy underwent a standard polysomnogram and MSLT. Three trained staff of various level of experiences independently and blindly scored each nap (n = 219). To test for intrarater reliability, 100 naps (n = 20 subjects) were re-scored half a year later. The interrater reliability for the mean sleep latency of 5 naps, sleep latency, and rapid eye movement (REM) sleep latency of individual nap, presence and numbers of sleep onset REM periods varied from the range of 0.668 to 0.964. The mean interrater reliability for the clinical diagnosis of narcolepsy was 0.883 (range, 0.824-0.938), whereas it was 0.750 (range, 0.674-0.858) for the diagnosis of narcolepsy spectrum disorder (shortened mean sleep latency and/or the presence of sleep onset REM periods) and 0.796 (range, 0.697-0.846) for normal cases. The intrarater reliability for the sleep latency and sleep onset REM periods varied from the range of 0.625 to 0.991. Our study demonstrated excellent inter- and intrarater reliability in scoring the sleep latency and sleep onset REM periods of MSLT. They also had excellent agreement on the diagnosis of narcolepsy and an "excellent to good" agreement on the diagnosis of narcolepsy spectrum disorder and normal cases. Our study lent further support that MSLT was an objective measurement with high inter- and intrarater reliability across various sleep disorders and healthy controls among different sleep centers.

Delayed neuropsychiatric impairment after carbon monoxide poisoning from burning charcoal.

Poisoning by carbon monoxide from burning charcoal has become one of the popular and lethal ways of attempting suicide in Hong Kong. Survivors of the carbon monoxide poisoning often face acute and delayed adverse problems in both their physical and mental health. We report two cases of delayed onset neuropsychiatric complications caused by carbon monoxide poisoning from burning charcoal. These symptoms were characterised by a latent period, followed by an abrupt and profound deterioration in the neurocognitive function with a seemingly reversible course. The literature is reviewed regarding the aetiology, pathophysiology, and management of this condition. Regular monitoring of their neurocognitive function and forewarning of this potential complication to the survivors of carbon monoxide poisoning and their families should be essential.

Melkerrson-Rosenthal syndrome with cardiac involvement.

Melkerrson-Rosenthal syndrome (MRS) is a granulomatous disease usually restricted to the orofacial region. We report a case of MRS in a 37-year-old Malay patient who presented with complete heart block on a background of recurrent oro-facial swelling and facial diplegia. Lip biopsy showed lymphohistocytic granulomatous inflammation typical for MRS. Extensive work-up excluded other causes of the complete heart block. To our knowledge, this is the first reported case of MRS affecting cardiac connective tissues and the first report of MRS in an ethnic Malay. We postulate granulomatous infiltration of the conductive tissues as the basis for the heart block. Another unusual feature of the case was the presence of left eye abduction limitation.

Previously unrecognized obstructive sleep apnea in Chinese subjects with essential hypertension.

Obstructive sleep apnea (OSA) is found to affect 2-4% of the middle-aged population in several Caucasian studies, whereas the prevalence among other ethnic groups have not been clearly documented. It has been reported that OSA and systemic hypertension are highly associated; we therefore conducted a study on Chinese subjects who were receiving treatment for essential hypertension to assess the prevalence of OSA among this group. Ninety-two consecutive patients being followed up at a hypertension clinic were recruited for a questionnaire survey. The entire study group was aged 54.7 +/- 11.7 years, with 40 men. One male subject had a diagnosis of obstructive sleep apnea on nasal continuous positive airway pressure (nCPAP) treatment and 46 subjects agreed to an overnight sleep study. Those who underwent sleep study showed selection bias with a higher body mass index and more symptoms associated with OSA. Of the 46 who underwent sleep study, 16 (34.8%) had an obstructive apnea-hypopnea (AHI) score of >/=5 and excessive daytime sleepiness, with a median score of 26.2 (range, 8.3-64.9). Patients in the group with obstructive sleep apnea syndrome (OSAS) thus defined compared with those without OSAS had more men (64.7 vs 17.20%, p = 0.001) and an excess of smokers (31.5 vs 3.3%. p = 0.01) and had significantly more symptoms of excessive daytime sleepiness (p = 0.001), daytime fatigue (p = 0.007), and witnessed apneas (p = 0.008). Seven patients accepted treatment with nCPAP and reported improvement in symptoms, but there was no detectable change in clinic blood pressure measurements after 3 months of nCPAP treatment. This study demonstrated a high prevalence of previously unidentified OSAS among Chinese patients with essential hypertension. Increased awareness of both doctors and patients toward this potentially treatable problem is warranted.

Studies on the relationship between in vitro metabolism and certain physicochemical characteristics of some 9-alkyl-/9-aralkyl adenines.

Previous studies demonstrated that biological N1-oxidation occurred for some 9-alkyl-/9-aralkyladenines, but not for others, when mammalian hepatic microsomal incubates were used as enzyme source. In order to understand the mechanisms controlling the metabolic fate of these compounds, the relationship between N1-oxidation and certain physicochemical characteristics of these substrates was studied. It was found that there was no marked link between N1-oxidation and the computer predicted pKa values of the substances studied. However, a computer predicted LogP value in the range 1.3-4 seems to be the most favourable for N1-oxidation. The 1H-NMR and 13C-NMR spectroscopic characteristics of the substrates, which reflect certain electronic characteristics of the purine moiety, also showed a correlation with their N1-oxidation. The electronic effects of the substrates in relation to their metabolism was investigated using computer modelling techniques; the results showed that different substituents at the 9-position of adenine may modify the electronic characteristics of the purine moiety thus affecting their metabolism. The conformation of the substrates may also be an important controlling factor for their N1-oxidative metabolism.

Mutagenicity testing of 9-N-substituted adenines and their N-oxidation products.

Adenine together with certain 9-N-substituted derivatives such as 9-methyl, 9-benzyl, 9-benzhydryl, and 9-trityl were tested against Salmonella typhimurium strains TA97, TA98, and TA100 in the absence and presence of rat hepatic S9 prepared from Aroclor 1254 pretreated rats. All compounds were positive toward TA98 in the presence of the metabolic activating system, whereas they all lacked mutagenic activity in the absence of S9, and toward TA97 and TA100 with or without S9 when tested at 100 ng/plate. A similar pattern was observed for the corresponding 1-N-oxides. 6-Hydroxylaminopurine was not mutagenic toward TA100 at 100 ng/plate, whereas it was toxic toward TA97 and TA98 at this level. When tested at 1 ng/plate, hydroxylaminopurine was still toxic to TA98 but produced twice the spontaneous reversion rate to TA97 without metabolic activation. Surprisingly, 9-methyl-6-hydroxylaminopurine was only active toward TA98 in the presence of S9, whereas 9-benzyl-6-hydroxylaminopurine was highly active toward TA97 and TA100 in the absence of S9 and even more active in the presence of S9. This compound was inactive toward TA98 in the absence of S9. The results generally support the concept that nuclear N-oxidation of aminoazaheterocycles is a detoxication process, whereas N-hydroxylation of the exo amino group is a toxication reaction.

Conformational analysis of 9-substituted adenines in relation to their microsomal N1-oxidation.

Metabolic N-oxidation of adenine, 9-methyladenine, 9-benzyladenine, 9-benzhydryladenine and 9-trityladenine has been investigated using hepatic microsomes from hamster, guinea-pig, rabbit, mouse, rat, and dog. N1-Oxide formation occurs with 9-benzyladenine and 9-benzhydryladenine using liver preparations of all species examined, although to different extents. The N-oxidase activity was found, amongst rodents, in the order hamster greater than mouse greater than rabbit greater than rat greater than guinea-pig. Microsomal preparations from dog liver contained a small quantity of P-450 and yet produced a relatively large amount of the N-oxides, possibly indicating that other cytochromes in addition to P-450 may be involved in the N-oxidation of these compounds. The most favourable conformations of these 9-substituted analogues have been established using computer graphics modelling and 1H NMR techniques. Results obtained confirmed the importance of the stereochemical properties of these compounds in relation to N1-oxidation. These observations substantiate and extend our previous findings on the electronic, lipophilic, and stereochemical factors affecting the N-oxidation of adenine derivatives.

Biological N-oxidation of adenine and 9-alkyl derivatives.

In vitro metabolism of adenine, 9-methyladenine, and 9-benzyladenine using hepatic microsomes of hamster, mouse and rat was investigated. The results indicated that adenine was apparently not susceptible to microsomal N-oxidation. N-oxidation of 9-methyladenine was also not detected, whereas N-demethylation was observed with hepatic microsomes derived from hamster and rat but not from mouse. With 9-benzyladenine, both 1-N-oxide formation and N-debenzylation occurred with microsomes of all species in various amounts. N-Hydroxylation of the 6-amino group was not observed with any substrate in any species. Metabolic results are discussed in relation to chemical structure, electronic, lipophilic and steric factors.