Is there an interrelationship between the effects of antipsychotics on psychopathology and on metabolism?

BACKGROUND: Increased body weight and hyperlipidemia caused by antipsychotics may be associated with improved antipsychotic efficacy in schizophrenia. If this association has a causal interrelationship via a genuine pathophysiological mechanism, then body weight loss in antipsychotic-treated patients would be accompanied by worsened psychopathology. This could have clinical implications. AIM: To explore whether the decreased body weight in these patients is associated with a worsened psychopathology. METHODS: In our previously published study, a 16 week treatment period with add-on orlistat (but not placebo) resulted in body weight loss in male (but not female) clozapine- or olanzapine-treated overweight or obese patients. In the current study, we investigated whether body weight loss in those male patients could worsen psychosis. Changes in the Positive and Negative Syndrome Scale (PANSS) scores within groups and body weight changes and lipid profiles over the treatment period were analysed by the paired samples t-test. Between-group comparisons were analysed by the independent samples t-test. RESULTS: Over the treatment period body weight decreased by 2.56 ± 3.25 kg from initial 106.02 ± 12.61 kg (p = 0.04) for the orlistat group, with no statistically significant changes for the placebo group. Lipid levels did not change in either group. The orlistat-induced weight decrease was not associated with worsening in the PANSS scores. CONCLUSIONS: Weight loss was not associated with a worsening of psychosis. The interrelationship between the antipsychotic-induced weigh gain and improved schizophrenia psychopathology observed in earlier studies appears to be indirect. Orlistat treatment in our study did not worsen psychopathology in this population.

Sleep architecture in homicidal women with antisocial personality disorder--a preliminary study.

The aim of the present study was to characterize sleep in severely violent women with antisocial personality disorder (ASP) as the primary diagnosis. Participants for this preliminary study were three drug-free female offenders ordered to undergo a forensic mental examination in a maximum security state mental hospital after committing homicide or attempted homicide. Ten healthy age- and gender-matched controls consisted of hospital staff with no history of physical violence. The most striking finding was the increased amount of slow wave sleep, particularly the deepest sleep stage, S4, in women with ASP. This finding is in agreement with previously reported results in habitually violent male criminals with ASP. Severe female aggression seems to be associated with profound changes in sleep architecture. Whether this reflects specific brain pathology, or a delay in the normal development of sleep patterns in the course of aging, needs to be clarified. From the perspective of sleep research, the biological correlates of severe impulsive violence seem to be similar in both sexes.

Topiramate add-on in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial.

OBJECTIVE: We tested the hypothesis that topiramate is more effective than placebo in reducing symptoms in patients with treatment-resistant schizophrenia when combined with ongoing antipsychotic medication. METHOD: Twenty-six hospitalized treatment-resistant patients with chronic DSM-IV-diagnosed schizophrenia participated in a randomized, double-blind, placebo-controlled trial in which 300 mg/day of topiramate was gradually added to their ongoing treatment (clozapine, olanzapine, risperidone, or quetiapine) over two 12-week crossover treatment periods. Data were collected from April 2003 to November 2003. RESULTS: In intention-to-treat analysis, topiramate was more effective than placebo in reducing Positive and Negative Syndrome Scale general psychopathologic symptoms (effect size = 0.7, p = .021), whereas no significant improvement was observed in positive or negative symptoms. CONCLUSION: Glutamate antagonist topiramate may be an effective adjuvant treatment in reducing general psychopathologic symptoms in patients with schizophrenia resistant to treatment with second-generation antipsychotics.

Increased deep sleep in a medication-free, detoxified female offender with schizophrenia, alcoholism and a history of attempted homicide: case report.

BACKGROUND: Psychiatric sleep research has attempted to identify diagnostically sensitive and specific sleep patterns associated with particular disorders. Both schizophrenia and alcoholism are typically characterized by a severe sleep disturbance associated with decreased amounts of slow wave sleep, the physiologically significant, refreshing part of the sleep. Antisocial behaviour with severe aggression, on the contrary, has been reported to associate with increased deep sleep reflecting either specific brain pathology or a delay in the normal development of sleep patterns. The authors are not aware of previous sleep studies in patients with both schizophrenia and antisocial personality disorder. CASE PRESENTATION: The aim of the present case-study was to characterize the sleep architecture of a violent, medication-free and detoxified female offender with schizophrenia, alcoholism and features of antisocial personality disorder using polysomnography. The controls consisted of three healthy, age-matched women with no history of physical violence. The offender's sleep architecture was otherwise very typical for patients with schizophrenia and/or alcoholism, but an extremely high amount of deep sleep was observed in her sleep recording. CONCLUSIONS: The finding strengthens the view that severe aggression is related to an abnormal sleep pattern with increased deep sleep. The authors were able to observe this phenomenon in an antisocially behaving, violent female offender with schizophrenia and alcohol dependence, the latter disorders previously reported to be associated with low levels of slow wave sleep. New studies are, however, needed to confirm and explain this preliminary finding.

In a randomized placebo-controlled add-on study orlistat significantly reduced clozapine-induced constipation.

Constipation is a common and potentially fatal side effect of clozapine treatment. Another important side effect of clozapine may also be significant weight gain. Orlistat is a weight-control medication that is known to induce loose stools as a common side effect. This study aimed to explore whether orlistat used to control clozapine-induced weight gain can simultaneously tackle clozapine-related constipation. In this 16-week randomized-controlled study, clozapine-treated patients received add-on orlistat (n=30) or add-on placebo (n=24). Colonic function was measured using the Bristol Stool Form Scale. There was a significant (P=0.039) difference in the prevalence of constipation in favor of orlistat over placebo in completers (n=40) at the endpoint. A decrease in the prevalence of constipation within the orlistat group (P=0.035) was observed (vs. no statistically significant changes in the placebo group). In clozapine-treated patients, orlistat may be beneficial not only for weight control but also as a laxative. As no established treatments for clozapine-induced constipation exist, orlistat can be considered for this population, although more studies are required.

Orlistat in clozapine- or olanzapine-treated patients with overweight or obesity: a 16-week open-label extension phase and both phases of a randomized controlled trial.

OBJECTIVE: To explore long-term effects of orlistat in adult clozapine- or olanzapine-treated patients with DSM-IV-diagnosed schizophrenia and overweight or obesity who tolerate orlistat. METHOD: Orlistat or placebo was added to clozapine or olanzapine in stable doses in a 16-week randomized controlled trial. Open-label orlistat was added to the antipsychotics during a 16-week extension phase for those completing the double-blind phase. No low-calorie diet or participation in behavioral programs was required. Body weight (primary outcome) and some metabolic parameters were measured prospectively. Analyses were performed for those completing both phases (ie, population differing from that reported earlier). The study was conducted from 2004 through 2005. RESULTS: During the open-label phase, the 44 patients experienced mean ± SD body weight loss of -1.29 ± 3.04 kg, P = .007. During both phases, men (but not women) showed a weight loss of -2.39 ± 5.45 kg, P = .023. Some subgroups showed desirable changes in several metabolic parameters. Prolonged (32 weeks) orlistat treatment yielded no additional benefits as compared to short (16 weeks) treatment. CONCLUSIONS: In clozapine- or olanzapine-treated overweight or obese patients able to take orlistat on a long-term basis, the drug, with no concomitant hypocaloric diet or behavioral interventions, caused moderate weight loss only in men. However, some metabolic benefits may be achieved independently of weight changes. In patients who do not respond to orlistat within the first 16 weeks, continuation treatment may provide no additional benefits. TRIAL REGISTRATION: controlled-trials.com Identifier: ISRCTN65731856.

Female impulsive aggression: a sleep research perspective.

The rate of violent crimes among girls and women appears to be increasing. One in every five female prisoners has been reported to have antisocial personality disorder. However, it has been quite unclear whether the impulsive, aggressive behaviour among women is affected by the same biological mechanisms as among men. Psychiatric sleep research has attempted to identify diagnostically sensitive and specific sleep patterns associated with particular disorders. Most psychiatric disorders are typically characterized by a severe sleep disturbance associated with decreased amounts of slow wave sleep (SWS), the physiologically significant, refreshing part of sleep. Among men with antisocial behaviour with severe aggression, on the contrary, increased SWS has been reported, reflecting either specific brain pathology or a delay in the normal development of human sleep patterns. In our preliminary study among medication-free, detoxified female homicidal offenders with antisocial personality disorder, the same profound abnormality in sleep architecture was found. From the perspective of sleep research, the biological correlates of severe impulsive aggression seem to share similar features in both sexes.

Orlistat in clozapine- or olanzapine-treated patients with overweight or obesity: a 16-week randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Undesirable metabolic effects of modern antipsychotics, especially clozapine and olanzapine, merit development of new weight-control strategies, including pharmacologic ones. We investigated the feasibility of treatment with orlistat, a weight-control drug with no central effects, for overweight/obesity in clozapine- or olanzapine-treated male and female patients. METHOD: Add-on orlistat was prescribed for 16 weeks in a randomized, double-blind, placebo-controlled clinical trial to patients who were receiving stable clozapine or olanzapine medication and were aged 18 to 65 years, with no compliance with nonpharmacologic programs or hypocaloric diet required. The primary efficacy variable was body weight change. The study was conducted from 2004 through 2005. RESULTS: Of 71 randomly assigned subjects, 63 were eligible for modified intent-to-treat analysis. While no statistically significant effect was observed in the whole population, male (but not female) patients benefited from treatment with orlistat (-2.36 kg vs. 0.62 kg on placebo, p = .011). There were 5 responders (16.1%) (those with >or= 5% weight loss) that received orlistat versus 2 responders (6.3%) that received placebo (number needed to treat = 11), but the difference was not statistically significant. CONCLUSIONS: Without a hypocaloric diet, the effect of orlistat in overweight/obese clozapine-or olanzapine-treated patients is modest and may only be seen in men. More studies should define the optimal length of treatment and feasibility of combination of orlistat with behavioral programs in this population.

Increased deep sleep in a medication-free, detoxified female offender with schizophrenia, alcoholism and a history of attempted homicide: effect of concomitant administration of quetiapine and citalopram.

BACKGROUND: An increased amount of deep sleep has been shown to be associated with antisocial personality disorder. This phenomenon has also been observed in a habitually violent female offender with schizophrenia and alcohol dependence. AIM: To evaluate sleep patterns in this patient and compare them with those of healthy, pro-social women of similar age, and in the same patient over time after treatment. METHOD: Multiple measures of sleep were taken over two consecutive nights with the presenting patient and with three age-matched healthy women. One year after the patient was established on atypical antipsychotic (quetiapine), and antidepressant (SSRI) medication (citalopram) her sleep evaluation was repeated. In each case only the second night's recordings were used in analyses. RESULTS: The patient differed significantly from the three healthy women on most sleep measures. After a year on the medication, the patient's sleep had improved and the non-REM sleep measures had come into the normal range. She had also shown a sustained clinical and behavioural improvement. DISCUSSION AND IMPLICATIONS: The literature suggests that both drugs had a part to play in the improvements in sleep, symptomatology and behaviour. The possibility that improvement in deep sleep is secondary to citalopram and that it is this that was specifically associated with violence reduction seems worthy of further study.