Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers.

BACKGROUND: Melatonin is an important regulator of the sleep-wake cycle. A prolonged-release formulation of melatonin (PR-M) that essentially mimics the profile of the endogenous production of the hormone is effective in the treatment of insomnia in patients aged 55 years and older. Because hypnotics result in impairments of various cognitive skills, it is important to examine the cognitive effects associated with the use of PR-M. OBJECTIVES AND METHODS: The effects of therapeutic oral doses of PR-M (2 mg), zolpidem (10 mg) and their combination administered at bedtime on cognitive functions in healthy subjects aged 55 years and older (12 males + 4 females, age 59.4 +/- 3.2 years) were assessed in a randomized, double-blind, placebo-controlled, and four-way crossover study. Psychomotor functions, memory recall, and driving skills were assessed at 1 and 4 h following administration and the next morning. RESULTS: Compared to placebo, PR-M alone did not impaired performances on any cognitive tasks. Zolpidem significantly impaired psychomotor and driving performance 1 h and 4 h post-dosing, and early memory recall; these impairment were exacerbated with PR-M co-administration. No effects on next morning psychomotor or driving performance were observed except that the decline in memory recall after zolpidem was more pronounced in the next day. No pharmacokinetic interactions were found. CONCLUSIONS: This study extends previous researches showing impairment of cognitive functions by zolpidem within 5 h post-administration. Further, PR-M use was not found associated with impairment of psychomotor functions, memory recall, and driving skills, and point to a pharmacodynamic interaction between melatonin and GABA-A modulators.

Short-term treatment with gaboxadol improves sleep maintenance and enhances slow wave sleep in adult patients with primary insomnia.

RATIONALE: Gaboxadol is a selective extrasynaptic GABA(A) agonist, previously in development for the treatment of insomniac patients. OBJECTIVE: To evaluate the acute efficacy and safety of gaboxadol in primary insomnia (PI). METHODS: This was a randomised, double-blind, four-way crossover, polysomnograph study comparing gaboxadol 10 and 20 mg (GBX20) to placebo in 40 adults with the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for PI. Zolpidem 10 mg was used as an active reference. Treatment was administered on two consecutive nights in each treatment session. Next-day residual effects were evaluated 2 and 9 h after lights on. RESULTS: Efficacy analysis included the per-protocol population (n = 38) from night 2. GBX20 reduced wake after sleep onset (p < 0.01). Both doses of gaboxadol, but not zolpidem, reduced the number of night awakenings (p < 0.001). GBX20 and zolpidem increased total sleep time (p < 0.05). Neither dose of gaboxadol nor zolpidem significantly reduced sleep onset latency, although a trend was seen for zolpidem. Gaboxadol enhanced slow wave sleep (SWS) dose-dependently (gaboxadol 10 mg: p < 0.01, GBX20: p < 0.001). Patients reported improved sleep quality following GBX20 (p < 0.05). Both doses of gaboxadol were generally well tolerated with almost exclusively mild to moderately severe adverse events (AEs). More frequent and severe AEs followed GBX20. No serious AEs were reported. No drug treatment was associated with next-day residual effects. CONCLUSION: Acute administration of gaboxadol improves sleep maintenance and enhances SWS in a dose-dependent manner in adult patients with PI. Gaboxadol was not associated with next-day residual effects. Gaboxadol was generally well tolerated, although gaboxadol showed a dose-dependent increase in incidence and severity of AEs.

Sleep effects of a 24-h versus a 16-h nicotine patch: a polysomnographic study during smoking cessation.

BACKGROUND AND PURPOSE: Sleep disturbance is a common symptom of tobacco withdrawal and might contribute to early relapse vulnerability in abstinent smokers. This study was designed to compare the effects on sleep of nicotine patches applied either for 24 h (Nicopatch) or 16 h (Nicorette). PATIENTS AND METHODS: During a short smoking cessation period (48 h), this open-label, randomised, two-period crossover study compared the effects on sleep of the two nicotine patches in 20 heavy smokers (9 women, 11 men). During each period, polysomnographic recordings were performed from 12 pm to 7 am for two consecutive nights (baseline and treatment nights). Smoking cessation started from 8 pm the day of the baseline sleep recordings, and treatments were applied around 8 am the following morning. RESULTS: Compared to the 16-h nicotine patch, smokers who received the 24-h nicotine patch experienced significantly less microarousals, a greater proportion of slow wave sleep, a higher REM density and higher rapid eye movement (REM) beta activities. CONCLUSIONS: The results of this study suggest that a 24-h nicotine patch is more efficient than a 16-h nicotine patch to alleviate tobacco withdrawal-induced sleep disturbances.

Lack of association between HLA-DR antigens and sleep-onset REM periods in major depression.

Narcolepsy is the disease disclosing the strongest association with the HLA system. Almost 100% of cases are associated with HLA-DR2 antigen. Moreover, narcolepsy is often characterized by the occurrence of sleep-onset REM (SOREM) periods. SOREM has also been demonstrated in major depression. To further investigate the relationship between SOREM and HLA-DR2, HLA-DR and HLA-DQ antigens were assessed in 50 research diagnostic criteria (RDC) major depressed patients. Depressed patients were elected for HLA typing on the basis of the presence of at least one SOREM period (n = 29) or three REM latencies above 50 min (n = 21) during three consecutives EEG nights recording. No significant differences were observed in the frequency of HLA-DR or HLA-DQ antigens between patients and controls. These results demonstrate a lack of association between SOREM and HLA-DR2 in major depression, and also do not confirm the presence of an association between antigens encoded by the HLA region of the chromosome 6 and major depressive illness.

Changes in EEG power density during sleep laboratory adaptation in depressed inpatients.

BACKGROUND: The aim of the present study was to evaluate the first-night effect in depressed inpatients, using standard sleep measures as well as all-night spectral analysis of the sleep electroencephalogram (EEG). METHODS: Eighteen drug-free, depressed inpatients were studied for 3 consecutive nights in the hospital sleep laboratory. RESULTS: Visual sleep scoring results showed a slight but measurable first-night effect, characterized by a reduction of rapid eye movement (REM) sleep amount and increased wakefulness. Sleep EEG spectral analysis showed significantly reduced delta (p <.01) and theta (p <.05) power density in non-REM (NREM) sleep of the first night compared with that of the second and third nights. These differences were limited to the early part of the sleep period, a time during the night that is particularly vulnerable to the effects of depressive disorder. In contrast to the NREM sleep findings, spectral REM variables studied did not significantly vary across the three nights. CONCLUSIONS: The results obtained suggest that first-night data should not be simply discarded but could be used in subsequent analyses and could be considered useful in the evaluation of the sleep of depressed patients.

Neuroendocrine and clinical characteristics of major depressed patients exhibiting sleep-onset REM.

BACKGROUND: Previous reports suggest an association between sleep-onset REM (SOREM) and some clinical characteristics in depressive illness such as age, psychosis, and depression severity. The present study is aimed at further investigating clinical and neuroendocrine correlates of SOREM, controlling for the age-related variability in clinical data. METHODS: Thyroid-stimulating hormone response to thyrotropin-releasing hormone, postdexamethasone cortisol levels, and clinical characteristics of 25 major depressive (MD) patients exhibiting SOREM in at least one of three consecutive recording nights were compared to those of 25 age- and sex-matched MD patients with three REM latencies above 50 min. RESULTS: SOREM patients experienced more affective episodes leading to hospitalization and a shorter duration of current episode than patients with three REM latencies above 50 min. No association between psychosis and SOREM could be demonstrated, and hypothalamic-pituitary-adrenal or -thyroid axis disturbances were not more prevalent in SOREM patients. CONCLUSIONS: Our results suggest that clinical history rather than cross-sectional clinical characteristics relates to the occurrence of SOREM in major depressed patients.

Shortened REM latency as a psychobiological marker for psychotic depression? An age-, gender-, and polarity-controlled study.

BACKGROUND: Previous reports suggest that the clinical dichotomy separating psychotic and nonpsychotic depression corresponds to different neurobiological profiles. The aim of the present study is to further investigate the psychobiological correlates of these two particular depressive subtypes. METHODS: Thyroid-stimulating hormone response to thyrotropin-releasing hormone postdexamethasone cortisol levels, and electroencephalgraphic sleep characteristics of 44 psychotic major depressive patients were compared to those of 44 nonpsychotic depressives matched for age, gender, and polarity. RESULTS: Some biological disturbances usually associated with depression (increased wakefulness, diminished rapid eye movement latency, hypercortisolism, blunted thyroid-stimulating hormone response to thyrotropin-releasing hormone stimulation) seemed to be significantly more pronounced in the psychotic depressed group as a reflection of greater illness severity; however, shortened REM latency was not influenced by severity and seemed to be more specifically related to the co-occurrence of psychotic and depressive symptoms. CONCLUSIONS: Our data provide further support for the validity of the clinical dichotomy separating psychotic and nonpsychotic major depression independently of severity.

The dexamethasone suppression test and sleep electroencephalogram in nonbipolar major depressed inpatients: a multivariate analysis.

BACKGROUND: The present study further examined relationships between postdexamethasone cortisol plasma values and sleep electroencephalogram (EEG) parameters. METHODS: The dexamethasone suppression test (DST) and polysomnographic recordings were performed in a sample of 300 inpatients with primary major depressive disorder (MDD) (102 men and 198 women, mean age 44 +/- 12 years, range 20-74 years) consecutively admitted to Erasme Hospital (Brussels, Belgium) between 1981 and 1992. RESULTS: The DST was abnormal in 40% of the sample. Postdexamethasone cortisol plasma values at 4:00 PM were significantly influenced by age, but not by gender. They were also significantly and positively correlated with weight loss, total scores on the Hamilton Depression Rating Scale, total scores on the Newcastle Scale, percentage of awakenings during sleep, and percent of stage 1. They were significantly and negatively correlated with percent of stage 2, slow-wave sleep, and REM sleep. Multiple regression analyses were conducted in two successive steps. First among clinical variables, only age and depressive symptom severity remained correlated with postdexamethasone plasma cortisol values. In the second step, with age and severity held constant, postdexamethasone plasma cortisol values were positively associated with amount of wake time and stage 1, and negatively with amount of slow-wave sleep. CONCLUSIONS: These findings provide further indirect support for an overarousal state in MDD with sympathoadrenal system hyperactivity and impaired sleep continuity. They also underline the importance of taking into account various clinical confounding factors in the interpretation of both DST and sleep EEG results.

Nonlinkage of bipolar illness to tyrosine hydroxylase, tyrosinase, and D2 and D4 dopamine receptor genes on chromosome 11.

OBJECTIVE: Previous linkage and allelic association studies using DNA polymorphisms, cosegregation of cytogenetic abnormalities with psychiatric illness, and assignment of genes involved in neutotransmitter metabolism suggested that chromosome 11 may harbor a gene predisposing to bipolar illness. The authors examined linkage in the families of 14 probands with bipolar illness, with the candidate genes tyrosine hydroxylase (TH), D4 dopamine receptor (DRD4) at 11p15, tyrosinase (TYR) at 11q14-q21, and D2 dopamine receptor (DRD2) at 11q22-q23, as well as with the c-Harvey-ras oncogene (HRAS) and insulin gene (INS), both located at 11p15, a region that previously showed linkage to bipolar illness. METHOD: The genetic data were analyzed with both lod score analysis (parametric) and affected-sib-pair analysis (nonparametric); both narrow and broad definitions of the clinical phenotype were used. Further influences of diagnostic uncertainties were accounted for by using diagnostic probability classes weighing the stability of each phenotype. RESULTS: Two-point linkage results excluded close linkage of bipolar illness to each candidate gene; negative results were also obtained when the narrow definition of the clinical phenotype was used. Moreover, multipoint linkage analysis of HRAS and INS excluded the 11p15 region encompassing both DRD4 and TH. In agreement with the negative linkage results, affected-sib-pair analysis did not show preferential sharing of marker alleles at any of the candidate genes. CONCLUSIONS: The negative results obtained under different genetic models exclude a frequent role for DRD4, TH, TYR, and DRD2 in the pathogenesis of bipolar illness.

Acute, subchronic and withdrawal sleep EEG changes during treatment with paroxetine and amitriptyline: a double-blind randomized trial in major depression.

Paroxetine (30 mg), a selective serotonin (5-HT) reuptake inhibitor, was compared in a double-blind trial to amitriptyline (150 mg) in a sample of 40 inpatients aged 18-65 years who fulfilled Research Diagnostic Criteria for major depression. Patients were studied after a placebo drug washout period of 10 days and after an active 4-week treatment period. Sleep EEG recordings were performed before and at the end of the study as well as during acute treatment (first 2 days) and following withdrawal of active medication. Paroxetine shows an antidepressant effect similar to amitriptyline with a different side-effect profile typical of 5-HT reuptake inhibition. Paroxetine and amitriptyline decreased the amount of REM sleep, a well-known effect of classical antidepressants. Paroxetine also shared with other 5-HT reuptake inhibitors an alerting effect on sleep that was not shown to be detrimental on subjective sleep quality.

Association between novelty-seeking and the dopamine D3 receptor gene in bipolar patients: a preliminary report.

Recent studies in healthy controls suggest an association between novelty-seeking (NS) and the dopamine D4 receptor (DRD4) gene. In this study, we further investigated the relationship between genes implicated in dopamine as well as serotonin neurotransmission and personality traits in bipolar (BP) disorder. Scores on the Tridimensional Personality Questionnaire were examined in 37 recovered Research Diagnostic Criteria-diagnosed BP patients genotyped for DRD3, DRD4, and serotonin 2A receptor (5HTR2a) polymorphisms. Carriers of DRD3 allele 1 showed significantly lower NS values compared to patients without this allele. Scores on NS and on harm-avoidance were not related to DRD4 or 5HTR2a polymorphisms. These preliminary results suggest a role for D3 receptor in NS expression in BP patients.

5-HT2a receptor polymorphism gene in bipolar disorder and harm avoidance personality trait.

The purpose [corrected] of this study was to investigate the relationship between bipolar disorder and the harm avoidance personality trait (HA), and the genetic contribution of the polymorphic DNA variation T102C in exon 1 of 5-HTR2a (chromosome 13q14-21) in bipolar disorder and HA personality trait. Forty bipolar patients and 89 normal subjects completed the TPQ questionnaire and were genotyped for 5-HT2a. Bipolar patients scored higher than normal subjects on the HA dimension. However, no contribution of the 5-HTR2a polymorphism on the bipolar disorder or on the HA personality trait emerged. Despite the limited sample size, these results exclude a major effect of the 5-HTR2a polymorphism on bipolar disorder and HA personality trait but not a minor effect.

Linkage analysis of bipolar illness with X-chromosome DNA markers: a susceptibility gene in Xq27-q28 cannot be excluded.

Transmission studies have supported the presence of a susceptibility gene for bipolar (BP) illness on the X-chromosome. Initial linkage studies with color blindness (CB), glucose-6-phosphate dehydrogenase (G6PD) deficiency, and the blood coagulation factor IX (F9) have suggested that a gene for BP illness is located in the Xq27-q28 region. We tested linkage with several DNA markers located in Xq27-q28 in 2 families, MAD3 and MAD4, that previously were linked to F9 and 7 newly ascertained families of BP probands. Linkage was also examined with the gene encoding the alpha 3 subunit of the gamma-amino butyric acid receptor (GABRA3), a candidate gene for BP illness located in this region. The genetic data were analyzed with the LOD score method using age-dependent penetrance of an autosomal dominant disease gene and narrow and broad clinical models. In MAD3 and MAD4 the multipoint LOD score data suggested a localization of a BPI gene again near F9. In the 7 new families the overall linkage data excluded the Xq27-q28 region. However, if the families were grouped according to their proband's phenotype BPI or BPII, a susceptibility gene for BPI disorder at the DXS52-F8 cluster could not be excluded.

A European multicenter association study of HTR2A receptor polymorphism in bipolar affective disorder.

The available data on the role of 5-HT in a variety of behaviors support the hypothesis that a dysfunction in brain serotoninergic system activity contributes to vulnerability to major depression. The diversity in the electrophysiological actions of 5-HT in the central nervous system can now be categorized according to receptor subtypes and their respective effector mechanisms. In particular, the implication of central postsynaptic 5-HT2A receptor in affective disorders has been supported by findings consistent with the hypothesis of 5-HT2A receptor up-regulation in depression. For these reasons, the 5-HT2A receptor (HTR2A) gene can be considered as a candidate gene in bipolar affective disorder (BPAD). We tested the possible genetic contribution of the polymorphic DNA variation T102C in exon 1 of HTR2A (chromosome 13q14-21) gene in a large European multicentric case-control sample. Allele and genotype frequencies, as well as homo-heterozygote distributions were compared between the two groups of 309 bipolar affective disorder patients and 309 matched controls. No significant differences were observed in the allelic and genotypic (also for homo-heterozygote) distribution between BPAD and controls. These results indicate that, in our sample, the 5-HT2A receptor polymorphism studied is unlikely to play a major role in the genetic susceptibility to BPAD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:136-140, 2000.

Mild to moderate sleep respiratory events: one negative night may not be enough.

STUDY OBJECTIVES: Reports on the reproducibility of apnea-hypopnea indexes (AHIs) across sequential polysomnography (PSG) sessions are conflicting, leading to a lack of clear recommendations on the optimal use of this technique: is one night of monitoring sufficient or is a second night required in order to safely reject the diagnosis? DESIGN: Retrospective comparison of two consecutive nights. SETTING: Sleep unit of a tertiary-care facility. PATIENTS: Two hundred forty-three subjects with suspected sleep apneas. INTERVENTIONS: Two sequential PSG sessions in a sleep unit. MEASUREMENTS AND RESULTS: Using analysis of covariance for repeated measures, with age and body mass index as covariates and gender as a cofactor, a classic first-night effect was found for sleep variables. In addition, a night effect was demonstrated for sleep respiratory variables. Moreover, the high variability of AHIs showed that many patients had their condition diagnosed on only one of the two nights, and more often on the second night than on the first. The gain in detection by adding a second night when the results of testing on the first were negative was between 15% and 25%, according to the AHI obtained on night 1. CONCLUSIONS: Considering the disability associated with sleep apnea/hypopnea syndrome, as well as its global cost for society, the present study shows that it is worth performing two consecutive PSG sessions or at least a second one when the result of the first one is negative in all patients admitted for apnea detection.

Correlations using the NREM-REM sleep cycle frequency support distinct regulation mechanisms for REM and NREM sleep.

Polysomnograms of most homeothermic species distinguish two states, rapid eye movement (REM) and non-REM (NREM) sleep. These alternate several times during the night for reasons and following rules that remain poorly understood. It is unknown whether each state has its own function and regulation or whether they represent two facets of the same process. The present study compared the mean REM/NREM sleep ratio and the mean number of NREM-REM sleep cycles across 3 consecutive nights. The rationale was that, if REM and NREM sleep are tightly associated, their ratio should be comparable whatever the cycle frequency in the night. Twenty-six healthy subjects of both sexes were recorded at their home for 4 consecutive nights. The correlation between the REM/NREM sleep ratio and the number of cycles was highly significant. Of the two sleep components, REM sleep was associated to the number of cycles, whereas NREM sleep was not. This suggests that the relationship between REM sleep and NREM sleep is rather weak within cycles, does not support the concept of NREM-REM sleep cycles as miniature units of the sleep process, and favors the concept of distinct mechanisms of regulation for the two components.

Critical analysis of the theories advanced to explain short REM sleep latencies and other sleep anomalies in several psychiatric conditions.

One of the most consistent and most studied sleep modifications in several psychiatric conditions is the shortening of the rapid eye movement (REM) sleep latency. While its clinical usefulness is still to be proven and its meaning relatively obscure, the appearance of a short REM latency continues to be a daily fact in sleep laboratories. Many theories compete to explain what is observed, the most important being the circadian rhythm hypotheses, the homeostatic model and the reciprocal interaction model. These three are summarised and their pros and cons are exposed in a systematic manner. Points of conflict, possible convergences and limitations are discussed in the light of recent developments on the general theories of sleep regulation.

Disturbances in hypothalamo pituitary adrenal and thyroid axis identify different sleep EEG patterns in major depressed patients.

This study was aimed at investigating the relationships between sleep EEG abnormalities and hypothalamo pituitary adrenal (HPA) and hypothalamo pituitary thyroid (HPT) disturbances in major depressive disorder. Post dexamethasone (DXM) cortisol levels and the dual TSH response to 08:00 h and 23:00 h TRH administration were determined after a 2 weeks wash-out period in a group of 113 DSM-IV major depressed patients (72 females aged 44.3+/-13.0 and 41 males aged 45.7+/-11) who were consecutively admitted to undergo sleep EEG recordings. Post-DXM cortisolemia, 08:00 and 23:00 post-TRH TSH values, time spent in rapid eye movement sleep (REMS), in slow wave sleep (SWS), and in stage 2 as well as time awake after sleep onset were introduced in a principal component (PC) analysis. The four 3 PC scores explaining up to 74% of the data set were further calculated for each patients and used in a cluster analysis. A three-cluster solution was retained. Controlling for the effects of age and gender, patients belonging to these three clusters could clearly be differentiated on the basis of their neuroendocrine responses and on their sleep EEG profiles. Compared to the two other clusters, cluster I (n=26) patients showed the most severe sleep continuity disturbances. Post-DXM cortisol escape and sleep architecture disturbances (consisting of a shortening of REMS latency and a decreased SWS) identified patients belonging to cluster II (n=39). Patients in cluster III (n=48) had the lowest TSH response to TRH and the less marked sleep EEG alteration. Clinical or demographic variables were unable to differentiate the three clusters. Our results suggest that different biological dysfunctions could each underlie particular neuroendocrine and sleep EEG disturbances in major depression.

The first-night effect may last more than one night.

The first-night effect in sleep polysomnographic studies is usually considered to last for one night. However, a few observations have indicated that variables associated to rapid eye movement sleep take longer to stabilize. Notwithstanding, current opinion holds that second nights of recording can be used without restriction for research and clinical purposes. The goal of this study was to describe the dynamics of habituation to polysomnography in optimal conditions. Twenty-six young, carefully screened, healthy subjects were recorded in their home for four consecutive full polysomnographies. Repeated measures ANOVA were applied. Between the two first nights, while there were no differences in sleep duration in non-rapid eye movement sleep, marked modifications in corresponding spectral power were observed. The dynamics of adaptation of rapid eye movement sleep appeared to be a process extending up to the fourth night. Similar dynamics in NREMS and REMS homeostasis have been observed in sleep deprivation studies, and it appears that the same mechanisms may be responsible for the FNE. The longer habituation process of REMS in particular has important implications for sleep research in psychiatry.

Biological markers as classifiers for depression: a multivariate study.

1. Delta TSH, REM latency, 4 pm and 11 pm post-dexamethasone cortisol values were determined after a wash-out period in a group of 74 non-selected depressed patients who were diagnosed (according to RDC with the SADS) as follows: 46 definite and 10 probable MD, 4 minor and 14 intermittent depression. 2. These biological variables, as well as gender, age and basal TSH were introduced in a principal component analysis. The four first PC scores explaining up to 77% of the data set were further calculated for each patients and used in a cluster analysis. A three clusters solution was retained. 3. DST escape and increased TSH response to TRH each identified subgroups of depressed patients. Conversely, blunted TSH response or REM latency were inefficient to classify patients. 4. Thus, HPA hyperactivity characterized CL-I patients (n = 29). These were more severely depressed, displayed more endogenous features and were reported as being more anxious. 5. Increased TSH response to TRH identified CL-III, exclusively composed of female patients (n = 10) that displayed more apparent sadness and tended to be older. 6. In CL-II, the usual sex-ratio for depressive illness was reversed and patients (n = 35) exhibited the least HPA axis disturbances and the same rate of blunted TSH response than in CL-I. They were also less severely depressed, displayed less endogenous characteristics and were rated as more mood reactive. 7. These results suggest heterogeneity in biological disturbances in depression and further stress the importance for controlling age, gender and severity of illness in studies investigating biological markers in depression.