Effect of a single-dose of olanzapine on sleep in healthy females and males.

The effect of a single dose of 10 mg olanzapine on healthy volunteers of both sexes was examined using polysomnography and power spectral analysis. The structure and continuity of sleep were unaffected by olanzapine in both sexes. The increase in both actual sleep time and slow wave sleep in females correlated with the increase in theta power, while delta power was not significantly elevated, suggesting that theta power may be a sensitive indicator of changes in sleep. The changes in sleep had the same tendency in men, but they were not significant. The difference between the sexes could not be explained by differences in body mass index. Olanzapine affects sleep probably through 5-HT(2C) receptors. The receptor gene is located on the X-chromosome, inducing an allelic difference between the females and males. This difference may contribute to the different effects of olanzapine on sleep. Olanzapine seems to preserve the normal structure of sleep and increase the amount of slow-wave sleep, which might be of additional benefit in treatment of schizophrenia. The effective clinical dose may be lower for females than males.

Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study.

BACKGROUND: Although case reports and open studies have reported augmentation with buspirone to be beneficial in the treatment of depression refractory to treatment with a selective serotonin reuptake inhibitor (SSRI), a recently published randomized, placebo-controlled, double-blind study failed to show superiority of buspirone over placebo in this respect. METHOD: One hundred two outpatients who fulfilled DSM-IV criteria for a major depressive episode and who had failed to respond to a minimum of 6 weeks of treatment with either fluoxetine or citalopram were included in this double-blind, randomized, placebo-controlled study. After a single-blind placebo wash-in period of 2 weeks while continuing their SSRI, the patients were randomly assigned to adjunctive treatment with either buspirone, 10 to 30 mg b.i.d., or placebo for 6 weeks. Patients were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impressions scale (CGI), and visual analogue scales. RESULTS: After the first week of double-blind treatment, there was a significantly greater reduction in MADRS score (p = .034) in the buspirone group as compared with placebo. At endpoint, there was no significant difference between treatment groups as a whole, although patients with initially high MADRS scores (> 30) showed a significantly greater reduction in MADRS score (p = .026) in the buspirone group as compared with placebo. CONCLUSION: Patients with severe depressive symptoms may benefit from augmentation with buspirone. It cannot be excluded that augmentation with buspirone may speed up the antidepressive response of patients refractory to treatment with fluoxetine or citalopram.

Marked clozapine-induced slowing of EEG background over frontal, central, and parietal scalp areas in schizophrenic patients.

The authors studied how clozapine treatment of patients with chronic schizophrenia affects the scalp topographic distribution of different frequency bands on EEG. Twenty-one patients treated with clozapine, in addition to zero to two typical neuroleptics (13 patients were treated with clozapine as the only neuroleptic), were compared with two control groups: one of healthy subjects and another of patients with schizophrenia receiving one to three typical neuroleptics and no clozapine. Significant differences in the EEG topography were seen between the groups: The theta and delta powers and were increased in the clozapine group compared with the two other groups (P < 0.001). Changes were observed over all electrodes, and were most prominent at the frontal, central, and parietal electrode locations. The nonclozapine-treated group of patients and the healthy control group did not differ significantly from each other. These results suggest that the topographic EEG features caused by clozapine are quite specific to it and can be differentiated from those of other neuroleptics.

Adjunctive nefazodone in neuroleptic-treated schizophrenic patients with predominantly negative symptoms: an open prospective pilot study.

A combination of nefazodone with a conventional neuroleptic would lead to a serotonin (5-HT)2 and D2 receptor blockade resembling that of an atypical neuroleptic, with an additional increase of 5-HT (and noradrenaline) turnover. This may be of benefit in some cases of schizophrenia. In this study, eight patients with schizophrenia with predominantly negative and/or depressive symptoms underwent an open prospective 26-week trial with nefazodone, added to conventional neuroleptics. The total Positive and Negative Syndrome Scale (PANSS) and the Montgomery-Asberg Depression Rating Scale (MADRS) scores (the last observations carried forward, LOCF) significantly (P < 0.05) decreased in these eight patients by a mean of 31% and 63%, respectively, mainly within the first 6 weeks. Positive symptoms, observed in three patients and panic attacks in two patients disappeared entirely. The doses of neuroleptics, stable during the first 6 weeks of the trial, subsequently were able to be decreased by 28%. Extrapyramidal symptoms noticeably improved during the phase of stable neuroleptic dose regimen. Of the three patients who discontinued the trial prematurely (after 14 weeks or more), only one evidenced a nefazodone-related adverse event. Adjunctive nefazodone may be a useful treatment option in this patient population, but additional studies are recommended.

Plasma interleukin-1 beta and sleep architecture in schizophrenia and other nonaffective psychoses.

OBJECTIVE: It has been reported that sleep deprivation may enhance interleukin (IL)-1 beta production of healthy subjects. Furthermore, patients with acute psychoses have been reported to exhibit higher levels of IL-1 beta than healthy controls. The present study examined polysomnographic sleep and morning IL-1 beta plasma values in 20 drug-free patients with acute nonaffective psychoses. METHODS: Ten patients with DSM-III diagnosis of schizophrenia, five with delusional disorder, and five with atypical psychosis underwent polysomnographic sleep registrations and their morning blood levels of IL-1 beta were measured. RESULTS: IL-1 beta values correlated negatively with the length of the sleep period (p = 0.010) and the relative time of rapid eye movement (REM) sleep (p = 0.038), and positively with REM latency (p = 0.043). CONCLUSIONS: It is concluded that reduced sleep, possibly especially reduced REM sleep, may be a reason for increased morning IL-1 beta values in these patients. Additional studies on IL-1 beta in psychiatric patients should consider the possibility of sleep disturbances as a possible explanation for deviations in IL-1 beta levels.

No differences in phospholipase-A2 activity between acute psychiatric patients and controls.

The phospholipase-A2 activity in plasma from 62 psychiatric patients admitted in an acute state to psychiatric hospital was determined by a fluorometric assay and compared to that of age- and sex-matched controls. Contrary to earlier findings, no significant differences were found between patients and controls.

Clozapine response in early treatment-resistant schizophrenia.

Eleven consecutive schizophrenic patients with a mean duration of illness of 2.2 (range 0.9-3.8) years and early signs of resistance to conventional neuroleptics were studied prospectively in a 26-week open trial with clozapine (mean dose 192.5 mg at week 8 and 225.0 mg at end-point). Of the ten patients who completed the study, nine improved by 20% or more on total Brief Psychiatric Rating Scale (BPRS) scores; six (good responders) showed more than 30%, and four (fair responders) 21-26% improvement on total Positive and Negative Syndrome Scale (PANSS) scores. The improvement was observed mainly within the first 8 weeks. Duration of illness correlated negatively (P=0.047) with the decrease of positive PANSS scores. The duration of illness of the fair responders was more than twice that of the good responders. Clozapine appears to be a safe and effective treatment alternative for early treatment-resistant schizophrenic patients. These patients seem to respond to relatively low clozapine doses. Early rather than late transfer to clozapine in this population may be of benefit for later clinical outcome.

The effect of fluoxetine on sleep: a longitudinal, double-blind polysomnographic study of healthy volunteers.

Fluoxetine, a selective inhibitor of serotonin (5-HT) uptake, was compared with placebo in a randomized double-blind longitudinal trial in 12 healthy volunteers. Sleep polygraphic recordings were performed at home twice before and once after 6 days of medication. After 6 days fluoxetine significantly decreased the amount of rapid eye movement (REM) sleep. The sleep-onset latency and REM latency were increased, but there was no significant increase in the amount of awakenings during night. The relative proportion of stages 2 and 3 increased after fluoxetine administration, although there was no significant change with regard to total amount of slow-wave sleep. Fluoxetine did not induce prominent eye movements during non-rapid eye movement (NREM) sleep in this study. Results of the subjective assessment revealed tendencies of improved sleep and well-being in the fluoxetine group. It is concluded that a comparatively small dose of fluoxetine (20 mg/day) causes the same type of changes in REM sleep which are characteristic of most antidepressive drugs.

Antidepressant efficacy and quality of life in depression: a double-blind study with moclobemide and fluoxetine.

The efficacy of moclobemide (300-450 mg/day) was compared with fluoxetine (20-40 mg/day) in a double-blind, multicentre study in 209 patients with new episodes of depression selected from 612 consecutive depressed patients representative of those consulting psychiatric services in Finland. Antidepressant efficacy was assessed with the Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Depression Rating Scale and Clinical Global Impression (CGI). The Medical Outcome Study Short-form General Health Survey (SF-20) and 15D Measure of Quality of Life were used to measure effectiveness in terms of health-related quality of life. Efficacy was evident with both drug treatments, with 67% in the moclobemide group and 57% in the fluoxetine group having a reduction in HDRS of more than 50%. Similarly, 77% of the patients in the moclobemide group and 67% in the fluoxetine group were assessed on the CGI as much better or very much better after 6 weeks of treatment. The most commonly reported adverse events were nausea, other gastrointestinal symptoms, nervousness, dizziness and sleep disorders. Nausea was significantly more common in the fluoxetine group and was found especially in women. Premature terminations of treatment were 18% in the moclobemide and 21% in the fluoxetine group. A significant change for the better in quality of life was found in both treatment groups, even at week 2 but especially after 6 weeks of treatment. Improvement was not only seen in dimensions measuring depression or mental health but also in other dimensions.

Plasma levels of interleukin-1 beta and interleukin-6 in schizophrenia, other psychoses, and affective disorders.

Plasma levels of interleukin (IL)-1 beta and IL-6 were measured in 60 acutely hospitalized psychiatric patients and in 60 healthy controls by enzyme-linked immunosorbent assay (ELISA). Almost no IL-6 was detected in the plasma of the patients or controls. The mean level of IL-1 beta was found to be significantly higher in schizophrenic patients than in their corresponding controls (P = 0.03). The acute schizophrenics, but not the group of chronic schizophrenics, contributed to this increase. No correlation with age, duration of illness or overt psychopathology was found. The neuroleptic medication did not prove to have a significant effect on the plasma IL-1 beta levels. There was no difference between non-psychotic affective disorder patients (N = 17) and the controls.

Plasma and cerebrospinal fluid interleukin-1 beta and interleukin-6 in hospitalized schizophrenic patients.

Interleukin (IL)-1 beta and IL-6 levels in plasma and cerebrospinal fluid (CSF) of 14 medicated schizophrenic patients and 9 controls were measured by enzyme-linked immunosorbent assay. Almost no detectable levels of IL-6 in plasma or CSF from patients or controls were found. With regard to mean plasma or CSF levels of IL-1 beta there were no statistically significant differences between the two groups investigated. The dose of neuroleptic medication the patients used did not correlate with the IL-1 beta plasma levels. For the whole series of subjects (n = 23) or for the schizophrenic patients (n = 14) no correlation between the plasma and CSF levels of IL-1 beta was found.

Is there a seasonal variation in the interferon-producing capacity of healthy subjects?

Induced production of interferon-alpha (IFN-alpha) and IFN-gamma was studied in 101 blood samples from 49 healthy subjects during 1 year. The results indicate a seasonal variation of the IFN-producing capacity, with a decrease in summertime, in Finland.

Effects of light treatment on sleep structure in seasonal affective disorder.

Twelve outpatients with seasonal affective disorder (depression, winter type) were treated by 1 h of bright light exposure for five mornings. The intervention produced a significant reduction in depression scores, but no change was seen in the sleep electroencephalographic variables recorded after light treatment. Significant changes were seen, however, in ratings of subjective sleepiness. The acrophase of the circadian sleepiness rhythm was phase advanced, the mean level of the sleepiness rhythm was diminished, and the mean values of sleepiness scores were reduced at 8 and 10 a.m. This minimal influence of bright light on sleep structure is unlikely to explain the well-documented antidepressant effect.

Interferon-alpha as adjuvant treatment in chronic schizophrenia.

The therapeutic use of interferon (IFN)-alpha administered as adjuvant medication in chronic schizophrenia was investigated. Natural leukocyte IFN-alpha was given to 9 long-term hospitalized chronic schizophrenic patients daily as subcutaneous injection of 3 million units 5 times a week. The trial followed a placebo-controlled double-blind crossover design. Each treatment period lasted for 8 weeks with a 2-week washout period in between. IFN-alpha did not prove to be beneficial for the total group of patients. Yet, 3 patients improved during the IFN-alpha drug period. The clinical improvement was seen as better social competence and less affective tension in the ward surroundings.

Plasma concentrations of remoxipride and haloperidol in relation to prolactin and short-term therapeutic outcome in schizophrenic patients.

Plasma concentrations of remoxipride and haloperidol as well as prolactin (PRL) were determined in 20 patients with acute symptoms of schizophrenia. Ten patients received remoxipride and ten patients haloperidol for a period of 6 weeks. A significant linear correlation was found between the plasma level of remoxipride and the dosage applied (P less than 0.02) as well as between the corresponding haloperidol dosage and plasma concentration (P less than 0.05). In both patient groups a significant reduction in psychopathology was observed during the trial period (P less than 0.001). In the haloperidol group this was associated with a clearcut elevation of plasma PRL, whereas in the remoxipride group after an initial rise for 4 weeks, the mean PRL level returned to baseline at the end of the study.

Prolactin response to submaximal stimulation by TRH in nonaffective psychoses.

Nonaffective psychotic symptoms are heterogeneous and probably caused by mixed biopathology. A preliminary investigative tool to study pituitary dopamine activity, the prolactin response to submaximal stimulation by thyrotropin-releasing hormone (TRH) (mini-TRH test) was correlated in 20 subjects with nonaffective psychoses to positive psychotic symptoms as assessed by the Comprehensive Psychiatric Rating Scale psychosis subscale. A significant positive correlation was observed between the response and ratings of nonparanoid symptoms, especially nonparanoid delusions and disrupted thoughts. Because, in addition to pituitary dopamine activity, there is evidence to suggest that the response reflects extrapituitary dopamine activity as well, the results extend the evidence that nonparanoid acute productive psychotic symptoms may be associated with hypoactivity rather than with hyperactivity of brain dopaminergic systems.

Remoxipride and haloperidol in schizophrenia: a double-blind multicentre study.

Ninety-two patients with schizophrenia were included in a double-blind multicentre parallel-group trial comparing remoxipride and haloperidol. The mean daily dose during the last week of treatment was 316 mg (range, 150-600 mg) in the remoxipride group and 8.7 mg (range, 5-20 mg) in the haloperidol group. The study period was six weeks with at least one day of washout. Both Clinical Global Impression (CGI) rating, and Brief Psychiatric Rating Scale (BPRS) total scores declined at the end of the trial compared with pretreatment values in both groups. No significant differences were found between the remoxipride and haloperidol groups with regard to the treatment outcome. Treatment-emergent extrapyramidal symptoms were statistically more frequent and more severe during haloperidol than during remoxipride treatment. Haloperidol-treated patients reported also significantly more concentration difficulties. Severe extrapyramidal side effects in the haloperidol group and clinical ineffectiveness in the remoxipride group were the most frequent reasons for premature discontinuation of treatment.

Fusimotor reflexes in triceps surae muscle elicited by stretch of muscles in the contralateral hind limb of the cat.

Experiments were performed on twenty-one cats anaesthetized with alpha-chloralose. The aim of this study was to investigate the reflex effects on triceps surae and plantaris fusimotor neurones elicited by tonic stretch of the contralateral posterior biceps and semitendinosus (p.b.s.t.) and the contralateral triceps surae and plantaris muscles, to compare these effects with the effects evoked by flexion or extension of the intact contralateral hind limb (Appelberg, Hulliger, Johansson & Sojka, 1984) and to clarify the interactions between the reflexes from contralateral and ipsilateral muscles. Activity in fusimotor neurones was studied indirectly by recording from primary muscle spindle afferents of the triceps surae and plantaris muscle. The mean rate of firing and the modulation of the afferent response to sinusoidal extension of the triceps surae and plantaris muscles was determined. Control measurements were made with the ipsilateral p.b.s.t., the contralateral p.b.s.t. and the contralateral triceps and plantaris muscles relaxed. Tests were made with tonic stretch of one of these muscles alone or with two of them simultaneously. With stretch of the contralateral p.b.s.t. ten out of eighty-four primary afferents (11.9%) showed predominantly dynamic reflexes (six out of forty-one in spinalized preparations: 14.6%), twenty-two (26.2%) showed mixed or predominantly static effects (one spinalized: 2.4%) and fifty-two units (61.9%) showed no effect (thirty-four spinalized: 83.0%). The reflex effects could be reproduced by electrical stimulation of the cut contralateral p.b.s.t. nerve either at group II or at group III strength. With stretch of the contralateral triceps and plantaris muscles seventy out of seventy-six (92.1%) primary muscle spindle afferents showed no effect and six (7.9%) mixed or predominantly static reflex effects. In general, the reflex effects were not accompanied by detectable electromyographic (e.m.g.) activity in the ipsilateral triceps and plantaris (recorded with surface or needle electrodes), indicating that the reflexes mainly involved gamma-motoneurones. The difference in efficacy between contralateral flexor (p.b.s.t.) and extensor (triceps and plantaris) muscles seems to be in accordance with the response pattern found with extension or flexion of the intact contralateral hind limb (Appelberg et al. 1984).(ABSTRACT TRUNCATED AT 400 WORDS)

Fusimotor reflexes in triceps surae muscle elicited by extension of the contralateral hind limb in the cat.

Experiments were performed in thirty-two cats anaesthetized with chloralose. The aim of the study was to investigate the reflex effects of flexion or extension of the contralateral hind limb on ipsilateral fusimotor neurones, to compare these effects with the effects elicited by stretch of the ipsilateral posterior biceps and semitendinosus (p.b.s.t.) muscles (Appelberg, Hulliger, Johansson & Sojka, 1982) and to clarify the interactions between the reflexes elicited from the ipsilateral and the contralateral side. Activity in fusimotor neurones was studied indirectly by recording from primary and secondary muscle spindle afferents of the triceps surae muscle. The mean rate of firing and the modulation of the afferent response to sinusoidal extension of the triceps surae was determined. Control measurements were made with the ipsilateral p.b.s.t. muscles relaxed and the contralateral hind limb in resting position. Tests were made with stretch of the ipsilateral p.b.s.t. and/or extension/flexion of the contralateral hind limb. With extension of the contralateral hind limb 64 out of 210 primary afferents (30.5%) showed predominantly dynamic reflexes (41 out of 134 in spinalized preparations: 30.6%), 25 (11.9%) showed mixed or predominantly static effects (1 spinalized: 0.7%), 121 (57.6%) showed no effect (92 spinalized: 68.7%). Flexion of the limb gave, with only two exceptions, no observable effect. Thirty-three secondary afferents were investigated. Five responded to extension of the contralateral hind limb with excitatory reflex effects. Flexion did not influence the secondary afferents. Mostly the reflex effects were not accompanied by detectable electromyogram (e.m.g.) activity in the ipsilateral triceps (surface recordings), indicating that the reflexes mainly involved gamma-motoneurones. A comparison was made between the reflexes elicited by stretch of the ipsilateral p.b.s.t. and extension of the contralateral hind limb. The percentage of responsive units was higher for the contralateral stimulus. Spinalization almost abolished the statis reflex responses to both ipsi- and contralateral stimulation, and it increased the number of dynamic responses to ipsilateral stimulation. The ipsilaterally elicited reflexes also seemed more dependent upon background activity. Ipsilateral stimulus could facilitate or reduce a contralaterally evoked response, even when the ipsilateral stimulus alone gave no effect. The reflexes could also summate. Quite often combined stimuli changed the character of the reflex from dynamic to static or vice versa.(ABSTRACT TRUNCATED AT 400 WORDS)

Actions on gamma-motoneurones elicited by electrical stimulation of group I muscle afferent fibres in the hind limb of the cat.

The reflex actions, elicited by graded electrical stimulation of hind-limb muscle, skin and joint nerves were studied in an extended series of experiments in extra-and intracellular recordings from 120 lumbar gamma-motoneurones of cats anaesthetized with chloralose. The present report deals with the action of group I muscle afferent fibres, which was examined in ninety-five gamma-cells. Of the gamma-cells 83% were classified as either static or dynamic by stimulation in the mesencephalic area for dynamic control. The general responsiveness (i.e. number of input nerves with effect/number of input nerves tested) of the cells was very high (89.9%). The responsiveness to stimulation of group I muscle afferent fibres was extremely low, both in flexor and extensor gamma-motoneurones and irrespective of whether they were static or dynamic. There was no difference, as regards the low incidence of group I muscle reflex action, between stimulation of autogenetic and heteronymous nerves. Among the rare reflex effects elicited from group I muscle fibres inhibition was four times as frequent as excitation. Inhibitory effects could be provoked from the autogenetic as well as from the heteronymous nerves. In contrast, excitatory effects were almost always autogenetic. The scarcity of group I muscle action on gamma-motoneurones is in striking contrast to the well known and powerful reflex actions of Ia and Ib fibres on alpha-motoneurones. These findings are discussed in relation to the concept of alpha-gamma linkage, and it is concluded that skeletomotor and fusimotor activity cannot be rigidly linked under all conditions.