Effects of vitamin B12 on bright light on cognitive and sleep-wake rhythm in Alzheimer-type dementia.

The present study investigated the effects of vitamin B12 (VB12) on circadian rhythm in Alzheimer-type dementia (ATD). Twenty-eight ATD patients were treated with bright light therapy (BLT) for 8 weeks. For the latter 4 weeks, half were treated with VB12 with BLT (BLT + VB12). We evaluated the cognitive state with Mini-Mental State Examination and the circadian rhythm with actigraphy after the fourth and eighth week. After the first 4 weeks BLT improved the circadian rhythm disturbances and cognitive state especially in the early stage of ATD. Although the latter 4 week-BLT caused no significant effects on the circadian rhythm; BLT + VB12 improved the vigilance level during the daytime. These results suggest that VB12 has some efficiency to enhance vigilance for ATD patients.

Open study of effects of alprazolam on seasonal affective disorder.

Seasonal affective disorder (SAD) differs from depression with melancholic features in atypical symptoms, such as hyperphagia, hypersomnia and weight gain. Moreover, SAD is confined to a certain season of the year. We examined the pharmacological efficacy of alprazolam for treatment of patients with SAD. Six patients with SAD were treated with alprazolam at doses of 1.2 mg/day or 1.2 mg/day first and then 2.4 mg/day for 2 weeks. The improvement was evaluated by the change of total score of the SIGH-SAD (with both 21 items HAMD and eight items atypical symptoms) and the clinical global impression (CGI). Although only two patients showed a remarkable improvement by SIGH-SAD, all patients showed a higher than moderate improvement with CGI. Our findings suggest that alprazolam might be efficacious for certain SAD patients.

Effects of bright light on cognitive and sleep-wake (circadian) rhythm disturbances in Alzheimer-type dementia.

Twenty-seven patients with Alzheimer-type dementia (ATD) were treated with bright light therapy in the morning for four consecutive weeks. The cognitive state of each patient was evaluated with the Mini-Mental-State Examination (MMSE) and circadian rhythm with actigram before and after therapy for all of the patients and those of two groups divided by the severity criteria of the Clinical Dementia Rating. The therapy improved the circadian rhythm disturbances. Although the therapy caused no remarkable effects on dementia severity, it improved the MMSE scores, especially in the early stages of ATD. These results suggest that bright light therapy improved the circadian rhythm disturbances and then bettered the cognitive state in early-stage ATD.

[Effects of bright light on cognitive disturbances in Alzheimer-type dementia].

We investigated the effectiveness of bright light therapy on cognitive disturbances and its effect on circadian (sleep-wake) rhythm in Alzheimer-type dementia (ATD). Twenty-seven patients with ATD were treated with bright light therapy in the morning for 4 consecutive weeks. We evaluated the cognitive functions and circadian rhythms of the patients as a whale, and as members of two groups (one: questionable and mild dementia: the other: moderate and severe dementia; both groups classified by the severity criteria of Clinical Dementia Rating). We assessed circadian rhythms by actigraphy and cognitive states by Mini-Mental-State Examination (MMSE) and Alzheimer's Disease Assessment Scale (ADAS) before and after light therapy. Bright light therapy improved circadian rhythm. Although bright light therapy had no Significant effect on the Severity of dementia, it improved the MMSE scores, cognitive functions of ADAS scores (memory > language) and non-cognitive functions of ADAS scores (behavior = mood), especially in the questionable and mild dementia group. These results suggest that bright light therapy improves cognitive functions with the modification of circadian rhythm, especially in the early stages of ATD.

Double-blind test on the efficacy of methylcobalamin on sleep-wake rhythm disorders.

The therapeutic effect of methylcobalamin (Met-12) on sleep-wake rhythm disorders was examined in a double-blind test. In the test group which was given a large dosage, a higher percentage of improvement was found compared to the control group with a small dosage, although the difference was not significant. The test group inconsistently showed significant improvement in both the sleep-wake cycle parameters and in clinical symptoms. The tendency was for the results to show a beneficial effect of Met-12 on rhythm disorders. However, because the percentage of improvement was low and significant improvement was inconsistent, Met-12 might be considered to have a low therapeutic potency and possible use as a booster for other treatment methods of the disorders.

Effects of trazodone on polysomnography, blood concentration and core body temperature in healthy volunteers.

Polysomnography, blood concentration and core body temperature recordings were performed on 12 healthy volunteers with administration of trazodone and placebo. Trazodone increased slow wave sleep (SWS), and decreased the average, the highest and lowest core body temperature significantly compared to placebo. The blood concentration of trazodone correlated positively with amplitude (the difference between the highest and lowest temperature) and %SWS during the first period of a sleep phase divided into three periods, and negatively with the lowest temperature. The appearance time of the lowest temperature correlated negatively with %SWS.

Association between delta waves during sleep and negative symptoms in schizophrenia. Pharmaco-eeg studies by using structurally different hypnotics.

We examined the effects of benzodiazepine (BZD) hypnotics and zopiclone (ZPC), a nonbenzodiazepine hypnotic, on sleep and psychiatric symptoms in schizophrenia, as well as the clinical correlates of these variables. Seven male schizophrenic patients chronically taking neuroleptics together with BZD were studied. We replaced BZD with ZPC and performed polysomnography (PSG) and Brief Psychiatric Rating Scale (BRPS) scoring before and after an 8-week ZPC treatment. The replacement of BZD with ZPC increased the mean amplitude of high-amplitude low-frequency delta waves on the frontal derivation recognized by period-amplitude analysis, and it decreased the BPRS negative-symptom score. Under the BZD treatment, the negative-symptom score correlated inversely with the mean amplitude of high-amplitude low-frequency delta waves. This correlation was weak and not significant under the ZPC treatment. Therefore, delta waves during sleep have a close correlation to negative symptoms in schizophrenia, and such a correlation could be influenced by hypnotics. Although these are preliminary findings, it was suggested that, compared with BZD, ZPC might be a beneficial hypnotic in regard to both sleep and negative symptoms of chronic schizophrenic patients.

Effects of trazodone hydrochloride and imipramine on polysomnography in healthy subjects.

Polysomnography was performed on eight healthy men with trazodone hydrochloride, imipramine and placebo. Trazodone hydrochloride increased slow wave sleep significantly. Imipramine prolonged rapid eye movement (REM) latency and decreased the percentage of REM sleep significantly. Trazodone decreased stages 1 and 2 sleep, while imipramine increased it. These findings suggest that the antidepressive effect of trazodone might be different from that of imipramine with the suppression of REM sleep.

A study of ring 20 chromosome karyotype with epilepsy.

We reported a 24-year-old woman with moderate mental retardation and partial epilepsy. She developed complex partial seizures at 3 years of age and generalized tonic convulsions at 9 years. Chromosome analysis revealed that she had mosaicism (87%) of 46, XX, and r(20) (p13,q13.3). Her electroencephalogram showed bilateral 2-3 Hz sharp and wave complex over the bilateral frontopolar, and centro-parieto-occipital areas. Computed tomographic and magnetic resonance image examinations were normal. Twenty-five cases of ring 20 chromosome karyotypes (including this case) have been reported in the literature; 19 showed epilepsy, and 18 showed moderate mental retardation. Many of the patients showed growth retardation and minor malformations. The ring 20 syndrome is associated with a high incidence of epilepsy, particularly partial epilepsy. Our findings indicate that the main features of the ring 20 syndrome are partial epilepsy and mental retardation.

[Recent progress in development of hypnotic drugs].

The patient of insomnia in the advanced countries come up to 25 approximately 33% in populations. The pharmaco-therapy, especially hypnotic drug is useful treatment in insomnia. I reviewed the developing hypnotic drugs in Japan. One benzodiazepine and 2 non-benzodiazepines. These hypnotics have selective affinity to benzodiazepine receptor omega 1 subtype. The half-life-time of the developing benzodiazepine hypnotic drug is long, therefore the rebound insomnia can not be recognized. Those of non-benzodiazepine hypnotics are short, namely 1-3 hours. The former drug has finished the clinical studies and waiting the permission for marketing from the government. The latter have still been under the clinical studies. We can expect these hypnotics will bring a certain advantages for our insomnia treatment in future.

[Study of diazepam with quantitative EEGs taken with eyes opened and topography].

Diazepam is a representative drug of benzodiazepines. The subjects were 9 right-handed healthy male volunteers 21 25 years of age. Double blind crossover trials with placebo control were conducted in a random sequence at an interval of 1 week. Diazepam 10 mg and placebo were administered as single oral doses. Three-minute EEGs were recorded with subjects' eyes opened before and 2 h after drug administration. One-minute out of the 3-minute EEGs was analyzed with FFT, and the absolute amplitude power (microV) was calculated. These results were subjected to Student's t-test (double difference) and displayed with topographic maps (t statistic significance probability mapping). Diazepam decreased the delta absolute amplitude power over left-parietal dominance, theta absolute amplitude power diffusely and alpha absolute amplitude power over parietal region dominance. It also increased the beta absolute amplitude power over left-antero-temporal region dominance. The EEG profiles taken with subjects' eyes open were different from those of diazepam with eyes-closed vigilance controlled concerning the degree of decrease of delta and beta activities and region of the effect on alpha activity.

[The efficiency of alprazolam for seasonal affective disorder (SAD, autumn/winter type)].

We experienced a 49 years old female SAD patient who showed a good response the next day after alprazolam 1.2 mg administration. The back ground EEG of the patient showed a abnormal EEG with slow waves. The personality was colored with historical features. The nadir of body core temperature from rectum slightly delayed in remission phase compared with depressive phase. The patient became hypomania and calmed down gradually. Alprazolam treatment is seemed to be available for SAD patients.

Relationship between the effects of a hypnotic drug, zopiclone, on polysomnography and on daytime EEGs.

The correlation between the effects of zopiclone (ZPC), a nonbenzodiazepine hypnotic drug, on sleep polysomnograms and on daytime EEGs was examined in 12 healthy adult male volunteers. Sleep polysomnograms were recorded after a single oral administration of ZPC 10 mg or placebo according to the double-blind crossover method. Daytime EEGs were recorded after the administration of ZPC, 7.5 mg, or placebo in the same manner, and recorded for 3 min with closed eyes at rest. Then, square roots of the absolute power (amplitude) of the delta-, theta-, alpha-, and beta-activities were calculated from the power spectrum obtained by the fast Fourier transform method. As a result, ZPC decreased the percentage of stage 1 sleep in total sleep time, while it increased the percentage of stage 2, total sleep time, and time of slow wave sleep in the first and second sleep cycles (SWS 1 and 2). Changes in SWS 1 and 2 correlated positively with the amplitude changes in daytime resting delta-activity. This indicates that the increase of SWS due to ZPC could be related to the change of delta-activity in the daytime resting EEG.

Zopiclone versus diazepam effects on EEG power maps in healthy volunteers.

EEG effects of zopiclone (7.5 mg), a cyclopyrrolone derivative with hypnotic action, were compared with effects of diazepam (10 mg). Multichannel EEG recordings, double-blind crossover trials with placebo, and oral single doses were used in healthy volunteers. Vigilance-controlled EEG before and after zopiclone (and placebo), and before and after diazepam (and placebo) were analyzed into FFT power spectra. Effects were assessed as placebo-referred pre-post-medication power differences in four frequency bands. Overall statistics showed significant (P < 0.007) global differences between medication effects in the delta frequency band (0.5-3.5 Hz). After zopiclone, fronto-central delta increased bilaterally, whereas after diazepam delta decreased over centro-parietal to right temporo-occipital regions. These spatially different brain electric effects show that different neuronal populations must have become active in response to zopiclone and diazepam.

Zopiclone pharmacodynamics: by monitoring event-related potentials and psychometric scores.

To investigate the pharmacological effects of zopiclone in the central nervous system, we monitored event-related potentials (ERPs, N100 and P300), the reaction time and the scores for subjective mental and emotional state (by using the Polarity Profile Questionnaire, PPQ) on 10 healthy right-handed male volunteers between 21 and 32 years old. Subjects were randomly allocated to receive a single oral administration of zopiclone 7.5 mg or placebo at the first-session, and the drug was crossed over at the second session 1 week later. ERPs, the reaction time and the psychometric scores were monitored at pre-drug, and 1, 3 and 5 hours after drug administration. In the zopiclone group, the reaction time was prolonged significantly at 1 hour after drug administration, the amplitudes of the ERPs significantly decreased at 1 and 3 hours after, and the PPQ scores showed significant changes. Maximum effects on the psychometric scores appeared later than those on ERPs and reaction time. Zopiclone decreased the arousal level and sensory sensitivity, and induced sedation through changes in subjective mental and emotional states.

A multicenter study of sleep-wake rhythm disorders: clinical features of sleep-wake rhythm disorders.

A multicenter study of sleep-wake rhythm disorders (i.e. non-24 hour sleep-wake syndrome; non-24), delayed sleep phase syndrome (DSPS), irregular sleep-wake pattern (irregular sleepers), and long sleepers, was conducted with the co-operation of 25 institutions. One hundred and twenty-one primary sleep-wake rhythm disorders were diagnosed and were classified as 13 non-24, 90 DSPS, 12 irregular and six long sleepers. The mean onset age was about 20 years old and psycho-social factors associating the onset of the disorder were identified in 36% of these patients. The major factors of sleep-wake disorders were personal relationships, advancing to a higher level education, gaining employment, and changes in environment. Most patients were 'night active' prior to appearance of their symptoms. Increase in night activities of modern society seem to result in the occurrence of such sleep-wake rhythm disorders.

A multicenter study of sleep-wake rhythm disorders: therapeutic effects of vitamin B12, bright light therapy, chronotherapy and hypnotics.

One hundred and six subjects with primary sleep-wake rhythm disorders [13 non-24 hour sleep-wake syndrome (non-24), 76 delayed sleep phase syndrome (DSPS), 11 irregular sleep-wake pattern (irregular) and six long sleepers] were treated with vitamin B12, bright light, chronotherapy and/or hypnotics. These therapies caused moderate or remarkable improvement in 32% of the non-24, 42% of DSPS, 45% of irregular and 67% of long sleepers. A lack of adequate sleep, unpleasant feelings at waking and daytime drowsiness were also improved in DSPS.

Effects of a small dose of triazolam on P300 and resting EEG.

The aim of the present study was to clarify whether cognitive impairments caused by benzodiazepines (BDZs) are a consequence of their specific direct effects on cognitive function or whether they are explained as secondary effects of increased sleepiness. Ten healthy men (mean age, 33.9 years) participated in two experimental sessions in a randomized cross-over, double-blind study: in one session subjects were given a placebo and in the other they were given 0.125 mg triazolam (TRZ). Each experimental session was conducted on 1 day. After a pre-drug EEG recording and an event-related potential (ERP) recording, under an oddball paradigm, subjects took the TRZ or placebo orally at 1000 hours. Thereafter, EEG and ERP recording sessions, following the same procedure as the pre-drug sessions, were conducted at 1, 2, 4, 6 and 8 h after drug administration. The EEG and ERP recordings from Cz and Pz referred to the bilaterally linked ear electrodes were used. We found that P300 latency was significantly prolonged in TRZ condition at 2 h (Pz) and 4 h (Cz and Pz) after TRZ, and that the P300 amplitude was significantly reduced at 2 h (Cz and Pz) and 4 h (Pz) after TRZ, compared to the same times after placebo. The absolute power values for the theta (4-7 Hz), alpha 1 (8-9 Hz), and alpha 2 (10-12 Hz) bands did not differ at any measurement time between the treatments. Only the beta band (13-19 Hz) power value was significantly elevated after the TRZ administration (versus placebo). No significant sedative effects were detected in subjective measurements. These results indicate that a single oral dose of 0.125 mg TRZ caused cortical changes without distinct general sedation or subjective sleepiness.