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.

Increased frequency of activated lymphocytes in the cerebrospinal fluid of patients with acute schizophrenia.

We compared the cerebrospinal fluid (CSF) cytology of 30 acutely psychotic patients at the initial phase of their hospital treatment with that of 46 control individuals with no psychiatric disorder or central nervous system (CNS) disease. The cytological profile of May-Grünwald-Giemsa stained CSF cell slides of the patients was significantly different from that of the control population. The most striking finding was a significantly increased frequency of lymphoid cells showing morphological features of activation/stimulation and a decreased proportion of normal small lymphocytes. Many of the cells with aberrant morphology displayed structural details similar to those of the 'P cells' previously described in the blood of schizophrenic patients. The patients' CSF also contained elevated proportions of monocytes/macrophages, some of which were found in 'rosettes' with activated lymphocytes indicating an increased intercellular adhesion. Possible pathogenic mechanisms behind lymphocyte activation and macrophage dominance in the CSF of acutely ill psychotic patients are discussed.

Risperidone versus clozapine in treatment-resistant schizophrenia: a randomized pilot study.

1. The atypical antipsychotic risperidone may constitute an alternative to clozapine, the current treatment of choice for refractory schizophrenia. The objectives of this study were to evaluate the effectiveness of risperidone in comparison to clozapine in everyday practice and to assess the feasibility of a pragmatic trial procedure. 2. Patients were randomly assigned to open-label clozapine or risperidone treatment for 10 weeks and treatment outcomes were assessed blindly. Twenty-one patients were recruited and nineteen entered the randomized phase. 3. Five of 10 participants allocated to clozapine and one of nine risperidone participants dropped out before study completion. Five clozapine patients and six risperidone patients achieved clinical improvement, defined as a 20% decrease in the Positive and Negative Symptom Scale (PANSS) total score. No significant differences between the groups were detected in baseline or endpoint positive or negative symptoms, disease severity, or global or social functioning scores. Patients' opinion on the drugs did not differ between groups. 4. The findings of the intention-to-treat analysis of this study corroborates previous findings that risperidone may be equally effective as clozapine, and supports the feasibility and need of a multicenter randomized pragmatic trial with sufficient power to detect differences between treatments.

Akathisia masked by hypokinesia.

Here, we will discuss the concept of subjective akathisia and present a patient case. Our patient was suffering from neuroleptic-induced hypokinesia and akathisia at the same time. The typical motor manifestations of akathisia were masked by hypokinesia, which made the diagnosis difficult. However, the subjective symptoms of akathisia were evident and distressing. Although not observable to bare eye, the pathognomonic pattern of motor activity detected in akathisia was demonstrated by actometric recording. Changing the conventional neuroleptic to an atypical one brought relief to the subjective symptoms of akathisia and hypokinesia, while the motor activity was clearly diminished in actometric recording. Actometric recording may be useful in diagnosing akathisia masked by hypokinesia, but the typical subjective symptoms of akathisia should not be ignored, even when actometry is not available to demonstrate the missing motor component of akathisia. Not only akathisia defined by DSM-IV but also subjective akathisia should be adequately treated to relieve the subjective distress, and to diminish the unfavorable effects on psychotic symptoms, behavior, and drug compliance.

Inverse correlation between hallucinations and serum prolactin in patients with non-affective psychoses.

Serum prolactin (PRL) was correlated with clinical symptomatology in 17 drug-free patients suffering from non-affective psychoses. A clear-cut negative correlation was found between the Comprehensive Psychiatric Rating Scale (CPRS) items assessing hallucinations and serum PRL levels (r=-6.14, P=0.009). No correlation was observed between clinical measures (total CPRS score, schizophrenia subscale score or depression and anxiety subscale score) and serum PRL.

Positive treatment effect of estradiol in postpartum psychosis: a pilot study.

BACKGROUND: Postpartum illnesses with psychiatric symptoms and serious adverse sequelae are highly prevalent during the childbearing years. Despite multiple medical contacts, these illnesses often remain unidentified and untreated. To study the association between estradiol and puerperal psychosis, we measured serum concentration of estradiol and performed an open-label trial of physiologic 17beta-estradiol in women with this disorder. METHOD: Ten women with ICD-10 psychosis with postpartum onset consecutively recruited from a psychiatric duty unit were studied. Serum estradiol concentration was measured at baseline and weekly during sublingual 17beta-estradiol treatment for 6 weeks. The treatment effect was evaluated by a clinician-rated psychiatric symptom scale (the Brief Psychiatric Rating Scale [BPRS]). RESULTS: The baseline serum estradiol levels (mean = 49.5 pmol/L; range, 13-90 pmol/L) were even lower than the threshold value of gonadal failure, and the patients exhibited high scores on the psychiatric symptom scale (mean BPRS total score = 78.3; range, 65-87). During the first week of 17beta-estradiol treatment, psychiatric symptoms diminished significantly (BPRS score decreased to a mean of 18.8, p < .001). Until the end of the second week of treatment, serum estradiol concentrations rose to near the values normally found during the follicular phase, and the patients became almost free of psychiatric symptoms. CONCLUSION: The reversal of psychiatric symptoms in all patients by treating documented estradiol deficiency suggests that estradiol plays a role in the pathophysiology and may have a role in the treatment of this condition. There was a rebound of psychotic symptoms in the 1 patient who discontinued estradiol treatment. Given the small number of patients, this area deserves further study.

Cerebrospinal fluid angiotensin-converting enzyme (ACE) correlates with length of illness in schizophrenia.

The aim of the study was to evaluate a possible progression with time of cerebrospinal fluid (CSF) angiotensin-converting enzyme (ACE) levels in treated schizophrenia patients. CSF ACE was determined in duplicate by a sensitive inhibitor-binding assay (IBA) from morning CSF samples of 56 acute and chronic in-patients with schizophrenic psychoses diagnosed according to DSM-IV. CSF ACE correlated significantly with length of schizophrenic psychosis (r=0.39, p=0.003). There was also a positive significant correlation between CSF ACE and duration of current psychotic episode (r=0.39, p=0.003) as well as duration of current hospitalization (r=0.66, p<0.001). These significances were maintained even when patients who were not treated with antipsychotics at the time of sampling were excluded. The correlations also remained significant when controlling for current neuroleptic dose in chlorpromazine equivalents. Serum ACE did not correlate with any clinical variable. No significant correlations between serum or CSF ACE and age, diagnostic subgroup, gender, serum ACE, CSF to serum albumin ratios, or neuroleptic dose in chlorpromazine equivalents were detected. The elevation of CSF ACE seemed to be confined to a subgroup of chronic patients with few positive symptoms. Elevated CSF ACE may reflect an increased solubilization of ACE from cell membranes in the central nervous system or constitute an increased expression of the ACE gene in response to some stimuli. This may be a function of treatment or a result of the deteriorating schizophrenic process.

Current antipsychotic dose correlates to mononuclear cell counts in the cerebrospinal fluid of psychotic patients.

Elevated cerebrospinal fluid (CSF) angiotensin I-converting enzyme (ACE) levels have been evidenced in patients with schizophrenia who have been treated with antipsychotics. In order to explore a possible mononuclear cell origin of CSF ACE, the authors determined CSF ACE and CSF mononuclear cell counts from 25 acutely psychotic patients, who had been drug-free for at least 4 months but started on conventional antipsychotic medication within a few days before sampling. No correlations were found between CSF to serum ACE ratio and CSF mononuclear cell counts. However, CSF total mononuclear cell count, CSF lymphocyte count, and CSF mononuclear phagocyte count evidenced significant positive correlations with current dose of antipsychotic medication expressed as chlorpromazine equivalents. The authors conclude that no indication of a relationship between mononuclear cells and CSF ACE activity was found. Surprisingly, a relationship between chlorpromazine dose and CSF mononuclear cell counts was found, which may indicate drug-related changes in cell-mediated immunity. This finding needs replication and further corroboration in well-designed studies.

Measuring neuroleptic-induced akathisia by three-channel actometry.

Three-channel actometry was used to study neuroleptic-induced akathisia (NIA), a common and often serious disorder in association of traditional neuroleptic therapy. The aim was to explore the diagnostic possibilities of actometry in NIA and to examine in detail the motor phenomenology of the disorder in detail. The actometers were attached to the ankles and waists of ten patients, suffering from NIA, and to ten matched healthy controls. Five of the patients were changed to olanzapine treatment, and these patients were re-examined during the no-NIA condition. NIA was associated with manyfold movement activity during controlled rest (sitting) but not with increased daily overall motor activity. Movement frequencies in NIA seemed to be pathognomonic. Actometry is promising for investigation and clinical assessment of NIA. Olanzapine proved to be an adequate treatment choice for NIA patients.

Accumulation of macrophages in the CSF of schizophrenic patients during acute psychotic episodes.

OBJECTIVE: There have been numerous reports of organic or structural abnormalities in the central nervous system (CNS) of patients with schizophrenia. Given that pathological conditions in the CNS are frequently reflected in the cell profiles of CSF, the authors compared the cytology of CSF from schizophrenic patients with that from a reference population in order to find out trails of elementary pathogenetic events in this serious psychiatric disease. METHOD: CSF samples from 35 patients with acute schizophrenia and 46 comparison subjects were prepared by Millipore filtration. The total and differential counts of CSF mononuclear cells were performed by light microscopy. RESULTS: At the beginning of treatment, the proportion of mononuclear phagocytes/macrophages in the patients' CSF was significantly higher than that in the comparison subjects. During treatment with conventional neuroleptic medication, the cytology returned to normal in several patients. CONCLUSIONS: The high proportion of macrophages in schizophrenia without a significantly higher total cell count may reflect neurodevelopmental disorder, a neurodegenerative process, or subtle CNS immunoactivation with mobilization of microglia.

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.

Higher cerebrospinal fluid angiotensin-converting enzyme levels in neuroleptic-treated than in drug-free patients with schizophrenia.

The aim of this study was to replicate our earlier finding of elevated angiotensin-converting enzyme (ACE) in cerebrospinal fluid (CSF) in schizophrenia and to elucidate the role of neuroleptic treatment in this phenomenon. Drug-free and medicated patients with acute schizophrenic psychoses, as well as healthy controls were recruited. Levels of ACE were measured in CSF and serum from 7 drug-free patients, 36 neuroleptic-treated patients, and 19 healthy control subjects. Although ACE levels in CSF did not differ between patients and controls, the drug-free patients showed significantly lower levels than the neuroleptic-treated patients. Serum ACE did not differ between groups. The elevation of CSF ACE may be more prominent in patients with deficit symptoms than in those with mainly psychotic symptoms. The possible enhancement of CSF ACE production or solubility by neuroleptic treatment is discussed. Elevated ACE levels in CSF may, together with other possible factors, cause polydipsia, stimulate secretion of arginine vasopressin, and even affect neuron growth and differentiation in schizophrenic psychoses.

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.

A longitudinal study of cerebrospinal fluid angiotensin-converting enzyme in neuroleptic-treated schizophrenia.

1. The aim of the study was to replicate our earlier finding of elevated cerebrospinal fluid (CSF) angiotensin-converting enzyme (ACE) in neuroleptic-treated schizophrenia and to elucidate the correlations between CSF ACE, neuroleptic treatment, and psychotic symptoms in a longitudinal study. 2. Levels of ACE were measured in CSF and serum from 9 acutely psychotic schizophrenic patients at two separate points of time; within a few days of admission and at follow-up after 3-4 weeks. CSF ACE was also determined from 9 healthy controls. 3. The schizophrenic patients showed non-significantly higher levels of CSF ACE than the controls. Although a significant clinical improvement was observed and the neuroleptic medication was reduced during the follow-up period, there were no significant differences in serum or CSF ACE between the two observation points in the schizophrenia group.

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.

Long-term efficacy and safety of milnacipran compared to clomipramine in patients with major depression.

Milnacipran is a new antidepressive drug, a combined noradrenaline/serotonin (NA/5-HT) reuptake inhibitor, which has been suggested to be as effective as and better tolerated than tricyclic antidepressants. Since long-term studies are lacking, we compared the efficacy, safety and tolerability of milnacipran and clomipramine in a double-blind, randomized, parallel-group study setting during 26 weeks of treatment in patients with major depression. A total of 107 patients were treated with either milnacipran (n=52) or clomipramine (n=55). Due to active treatment of duration less than 12 days in four patients and protocol deviation in one patient, in total 47 milnacipran-treated patients were eligible for efficacy analysis. Nine patients in the clomipramine group continued on active treatment for less than 12 days. Thus 46 clomipramine-treated patients were finally included in the efficacy analysis. After 1 week of dose escalation, there was a fixed dosage regimen of either milnacipran (200 mg daily) or clomipramine (150 mg daily) during weeks 2 to 10, followed by flexible dosing of milnacipran (100, 150 or 200 mg daily) or clomipramine (75, 100 or 150 mg daily) during weeks 11 to 26. A total of 53 patients (49%) completed the 26-week study period; 21% (11/52) of the patients in the milnacipran group and 38% (21/55) of the patients in the clomipramine group discontinued their medication prematurely due to adverse events, whereas 19% (10/52) of those on milnacipran and 7% (4/55) of those on clomipramine treatment withdrew due to either lack of efficacy or clinical deterioration. The mean change (+/-SD) in the Hamilton Depression Rating Scale (HAMD) score between the baseline and the last rating ranged from 23.7+/-3.1 to 12.0+/-9.5 in the milnacipran-treated patients and from 23.1+/-3.5 to 8.0+/-8.5 in the clomipramine-treated patients, revealing a significant difference in favour of clomipramine. In total 58% of the milnacipran-treated patients vs. 72% of the clomipramine-treated patients showed a > or = 50% reduction in their baseline HAMD scores and 45% vs. 63% had an HAMD score of < or = 7 at the last rating, respectively. Moreover, the time to the onset of the antidepressant action (defined as > or = 50% reduction of the baseline HAMD score) showed a significant difference in favour of clomipramine. In addition, clomipramine was significantly more efficacious in patients with a baseline HAMD score of > or = 24 as evidenced by the analysis of the HAMD score at week 6 and at the last rating. The Montgomery Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) scale did not show significant differences between the treatment groups. The safety analysis did not reveal any differences of clinical significance in cardiovascular variables between the study drugs. Dry mouth was significantly less frequently reported by the milnacipran-treated patients during the early and later phases (weeks 6 to 26) of the study, while insomnia was more common in the milnacipran group during weeks 1 to 6. In conclusion, milnacipran appeared to be less effective than clomipramine in the long-term treatment of depression. The side-effects of the drugs differed to a certain extent, and milnacipran tended to be somewhat better tolerated than clomipramine.