The Influence of Substance Use on Side Effects of Olanzapine, Quetiapine, Risperidone, and Ziprasidone in Psychosis.

BACKGROUND: Side effects restrict the optimal use of antipsychotics. Little is known about the influence of substance use on side effects. The aim of this study was to compare antipsychotic side effects in patients with psychosis with and without substance use, while also taking medication history and diagnosis into consideration. METHODS: All patients (n = 226, mean age 34, females 33%) diagnosed with schizophrenia spectrum disorders (SSD; F20-F29) or other psychosis (F30-F32; F10-F19), were treated with olanzapine, quetiapine, risperidone or ziprasidone, and were assessed at baseline, 4-weeks, 14-weeks, and 27-weeks. The UKU-Side Effects Self-Rating Scale version was used to evaluate the side effect profiles, and the information on substance use was based on the Clinician Drug Use Scale. RESULTS: At baseline, 30% of the patients used substances, 54% were diagnosed with SSD, and 47% were antipsychotic naïve. The occurrence of side effects in total was not different in patients with substance use compared to without after 4-weeks of treatment, nor in the follow-up period. At 4-weeks there were some group differences in relation to substance use, diagnosis, and medication history for single side effects. Patients with substance use showed more increased dream activity, less reduced salivation, and more gynecomastia. Patients with SSD showed less neurological side effects, orgasm dysfunction, and tension/inner unrest. The medication naïve patients showed increased hypokinesia/akinesia. CONCLUSION: Substance use alone does not influence the general magnitude of side effects of antipsychotic medication and does not indicate a different prescription practice in patients with psychosis and substance use.

The influence of substance use on the effectiveness of antipsychotic medication: a prospective, pragmatic study.

Background: Psychosis is associated with a high prevalence of substance use, leading to worsened prognosis. Less is known about how comorbid substance abuse may influence the effectiveness of antipsychotic medications. The aim of this study was to compare the effectiveness of second generation antipsychotics in patients with psychosis with and without substance use. Methods: All patients (n = 226) were aged >18 years old had symptom level scores of ≥4 on selected psychosis items on the Positive and Negative Syndrome Scale and met ICD-10 diagnostic criteria for psychosis. Information on substance use was collected based on the Clinician Drug Use Scale. Patients were grouped at baseline according to the presence of substance use, medication history and diagnosis group. Clinical symptoms at baseline and changes at follow-up were assessed with the PANSS. Results: At baseline about 30% of the patients used substances, most frequently cannabis followed by methamphetamine. About half (47%) of the patients had no prior exposure to antipsychotic medication at inclusion. Patients who had consumed substances showed no substantial differences in the PANSS score reduction as a result of antipsychotic medication compared to patients without substance. There were, however, some group differences in relation to pattern of change that were influenced by medication history. Substance use was found to be related to stronger reduction of positive symptoms from week 4 to week 27. Conclusion: Substance use alone did not influence antipsychotic effectiveness in this sample of patients with psychosis.

Predictors of treatment satisfaction in antipsychotic-naïve and previously medicated patients with acute-phase psychosis.

Background: Treatment satisfaction predicts treatment adherence and long-term outcome for patients with psychosis. It is therefore important to understand the underpinnings of patient satisfaction in psychosis treatment for optimal treatment delivery. Aims: To examine the associations between satisfaction and level and change in positive symptoms, insight, depression and side effects of antipsychotics in previously medicated and antipsychotic-naïve patients. Method: Data derive from a randomised trial, with 226 respondents at baseline and 104 at follow-up. The measures were the positive subscale and insight item from the Positive and Negative Syndrome Scale, Calgary Depression Scale, the UKU Consumer Satisfaction Rating Scale, and the UKU side effects scale. Structural equation modelling was used to test the model. The full information maximum likelihood estimator used all available data. Results: In the sample of 226 patients, 67.3% were male and 44.2% were antipsychotic-naïve. The mean age was 34.1 years. For previously medicated patients, satisfaction was predicted by level of insight (b = -2.21, ß = -0.42) and reduction in positive symptoms (b = -0.56, ß = -0.39). For antipsychotic-naïve patients, satisfaction was predicted by level and change of insight (b = -2.21, ß = -0.46), change in depression (b = -0.37, ß = -0.26) and side effects (b = -0.15, ß = -0.30). All predictors were significant at the 0.05 level. Conclusion: Reducing positive symptoms and side effects are important to enhance patient satisfaction. However, improving insight and reducing depression are more important in antipsychotic-naïve patients.

Associations between C-reactive protein levels and cognition during the first 6 months after acute psychosis.

OBJECTIVE: Inverse relationships between the C-reactive protein (CRP) levels and cognitive performance in acute psychosis have been demonstrated. We aimed to investigate how the serum level and initial change of CRP in acutely admitted patients with psychosis was correlated with cognitive performance during a 6-months follow-up period. METHODS: The study is part of a pragmatic, randomised trial comparing four different second-generation antipsychotic drugs, and consists of 208 acute phase patients recruited at admittance for psychosis. This study reports data for all groups collectively, and does not compare treatment groups. Measurements of CRP and cognitive performance were conducted at baseline (T1) and after 4 weeks on average after inclusion (T2). Cognition was also assessed after 3 months (T3) and 6 months (T4) of follow-up. RESULTS: Global cognition improved during the follow-up period of 6 months, especially in the T1-T2 interval. The different cognitive subdomains showed different time-dependent profiles of improvement, with memory and attention improving significantly also in the later phases. Reduction of the CRP level during the initial follow-up interval (T1-T2) was associated with increased overall cognitive performance in the T2-T4 interval, but not in the T1-T2 interval. For the cognitive subdomains, we found an inverse association between change in CRP level and verbal abilities (T2-T4 interval), and attention (T2-T3 interval). CONCLUSION: These findings indicate that initial changes in the serum level of CRP in the acute phase of psychosis may predict cognitive function in later phases of the disease.

The serum level of C-reactive protein (CRP) is associated with cognitive performance in acute phase psychosis.

BACKGROUND: Inflammatory processes have been implicated in the etiology of schizophrenia and related psychoses, in which cognitive deficits represent core symptoms. The aim of the present study was to investigate possible associations between the level of the inflammation marker C-reactive protein (CRP) and cognitive performance in patients through the acute phase of psychosis. METHODS: A total of 124 patients were assessed at admittance to hospital and 62 patients were retested at discharge or after 6 weeks at the latest, with measurements of the CRP levels and alternative forms of the Repeatable Battery for the Assessment of Neuropsychological Status. RESULTS: There was an inverse relationship between overall cognitive performance and CRP level at admittance. The association increased in sub-analyses including only patients with schizophrenia. In cognitive subdomain analyses statistically significant inverse associations were found between the CRP level and Delayed memory and Attention, respectively. No associations were found between CRP level and other measures of psychopathology including psychosis symptoms, depression, or functioning. At follow-up the association between CRP level and cognition was no longer present. There was a significant increase in cognitive performance between baseline and follow-up. There was a stronger increase in overall cognition scores in patients with higher baseline CRP levels. CONCLUSIONS: The findings indicate that signs of inflammation may serve as a state-dependent marker of cognitive dysfunctions in acute psychosis. TRIAL REGISTRATION: ClinicalTrials.gov ID; NCT00932529 , registration date: 02.07.2009.

Patient satisfaction after acute admission for psychosis.

Background Measuring patient satisfaction in mental health care potentially provides valuable information, but studies in acutely admitted psychosis patients are scarce. Aims The aims were to assess satisfaction among patients acutely admitted with psychosis, to compare satisfaction in voluntarily versus involuntarily admitted patients, and to assess the influence of symptom load and insight. Methods The UKU Consumer Satisfaction Rating Scale (UKU-ConSat) was used. A total of 104 patients completed the UKU-ConSat at discharge/follow-up (between 6-11 weeks after admittance if not discharged earlier) (mean duration of stay 4 weeks), thus corresponding to the end of the acute treatment phase. Results A total of 88.4% had total scores above zero (satisfied). Only three of the eight single items were statistically significantly different among patients admitted voluntarily versus involuntarily, and only the information item score remained significantly different in adjusted analyses. Insight level at admittance, and an increasing level of insight during the acute phase were positively associated with patient satisfaction, whereas levels and changes in positive and negative psychosis symptoms were indirectly related to satisfaction via this process of insight. Conclusions The vast majority of the acutely admitted patients were satisfied with treatment. There were few differences between the involuntarily and voluntarily admitted patient groups, except that the involuntary care group was clearly less satisfied with the information provided. Poor insight had a major negative impact on treatment satisfaction in psychosis. The provision of sufficient and adequate information is an important target for mental health care service improvement.

Borderline Personality Disorder and Posttraumatic Stress Disorder at Psychiatric Discharge Predict General Hospital Admission for Self-Harm.

We investigated whether posttraumatic stress disorder (PTSD) was predictor of suicidal behavior even when adjusting for comorbid borderline personality disorder (BPD) and other salient risk factors. To study this, we randomly selected 308 patients admitted to a psychiatric hospital because of suicide risk. Baseline interviews were performed within the first days of the stay. Information concerning the number of self-harm admissions to general hospitals over the subsequent 6 months was retrieved through linkage with the regional hospital registers. A censored regression analysis of hospital admissions for self-harm indicated significant associations with both PTSD (ß = .21, p < .001) and BPD (ß = .27, p < .001). A structural model comprising two latent BPD factors, dysregulation and relationship problems, as well as PTSD and several other variables, demonstrated that PTSD was an important predictor of the number of self-harm admissions to general hospitals(B = 1.52, p < .01). Dysregulation predicted self-harm directly (B = 0.28, p < .05), and also through PTSD [corrected]. These results suggested that PTSD and related dysregulation problems could be important treatment targets for a reduction in the risk of severe self-harm in high-risk psychiatric patients.

Auditory verbal hallucinations reflect stable auditory attention deficits: a prospective study.

INTRODUCTION: Previous studies have shown that auditory verbal hallucinations (AVHs) in psychosis are associated with reduced verbal auditory attention. Whether this is an effect of ongoing AVH or reflects a more stable cognitive vulnerability also present after treating the AVH is unknown. The aim of this study was to follow patients with acute psychosis with and without AVH, and to test their auditory attention in a more stabilised clinical phase. METHODS: Fifty patients (35 males and 15 females) were examined when admitted to an acute psychiatry ward and tested three months later with a dichotic listening test with attention instructions. The patients were divided into a frequent (n = 33) and non-frequent (n = 17) AVH group based on their score on the Positive and Negative Syndrome Scale item hallucinatory behaviour (≥4 and ≤3, respectively) at baseline. RESULTS: A significant interaction emerged between AVH group and attention instruction condition; the frequent AVH group failed to control their auditory attention as opposed to the non-frequent AVH group. CONCLUSIONS: Patients with frequent AVH in an acute psychotic state showed impaired auditory attention three months after their AVH had been treated, indicating a stable cognitive vulnerability factor for experiencing AVH.

Hallucinations in acutely admitted patients with psychosis, and effectiveness of risperidone, olanzapine, quetiapine, and ziprasidone: a pragmatic, randomized study.

BACKGROUND: Hallucinations are prevalent in schizophrenia and related psychotic disorders and may have severe consequences for the affected patients. Antipsychotic drug trials that specifically address the anti-hallucinatory effectiveness of the respective drugs in representative samples are rare. The aims of the present study were to investigate the rate and severity of hallucinations in acutely admitted psychotic patients at hospital admission and discharge or after 6 weeks at the latest, if not discharged earlier (discharge/6 weeks); and to compare the anti-hallucinatory effectiveness of risperidone, olanzapine, quetiapine, and ziprasidone with up to 2 years' follow-up. METHODS: Adult patients acutely admitted to an emergency ward for psychosis were consecutively randomized to risperidone, olanzapine, quetiapine, or ziprasidone and followed for up to 2 years in a pragmatic design. Participants were assessed repeatedly using the hallucinatory behavior item of the Positive and Negative Syndrome Scale (PANSS). RESULTS: A total of 226 patients, 30.5% of those assessed for eligibility, were randomized and 68% were hallucinating at baseline. This proportion was reduced to 33% at discharge/6 weeks. In the primary analyses based on intention to treat groups of patients experiencing frequent hallucinations, the quetiapine and ziprasidone groups both had faster decreases of the mean hallucination scores than the risperidone group. CONCLUSIONS: Hallucinations are fairly responsive to antipsychotic drug treatment and differential anti-hallucinatory effectiveness may be found among existing antipsychotic drugs. If replicated, this could pave the way for a more targeted pharmacotherapy based on individual symptom profiles, rather than on the diagnostic category. TRIAL REGISTRATION: ClinicalTrials.gov ID; NCT00932529.

Prospective and concurrent correlates of emotion perception in psychotic disorders: a naturalistic, longitudinal study of neurocognition, affective blunting and avolition.

This naturalistic study investigated longitudinal and cross-sectional symptomatic and neurocognitive correlates of social cognition indexed by emotion perception. Participants were 31 persons admitted to a psychiatric emergency ward due to acute psychosis. Positive and negative (i.e., affective blunting and avolition) symptoms were assessed at baseline and 12-month follow-up using the Positive and Negative Syndrome Scale. Participants completed neuropsychological assessments with alternative versions of the Repeatable Battery for the Assessment of Neuropsychological Status at baseline and at 12-month follow-up. Emotion perception was measured using the Face/Voice Emotion Test at 12-month follow-up. Correlational analyses (Spearman's rho) revealed strong and statistically significant associations between neurocognition and emotion perception (baseline r = 0.58, follow-up r = 0.43). Associations between positive symptoms and emotion perception were weak or non-existent (baseline r = 0.13, follow-up r  =  -0.01). Emotion perception was moderately, but not significantly, associated with affective blunting at follow-up (r = 0.33), but not at baseline (r = 0.21). The association with avolition was non-existent (baseline r  =  -0.05, follow-up r = 0.01). This study supports the notion that emotion perception has neurocognitive correlates. The cross-sectional trend level association with affective blunting suggests that the ability to perceive emotions might be related to, but dissociable from the ability to express emotions.

The influence of glutamatergic antagonism on motor variability, and comparison to findings in schizophrenia patients.

OBJECTIVE: The primary aim of this explorative study was to investigate the influence of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine on motor activity in healthy subjects. Secondarily, we wanted to compare these data to findings in a sample of schizophrenia patients. METHODS: The healthy subjects acted as their own controls in an open-within-subject design. Motor activity was recorded with an actigraph worn for 24 h in the drug-free, and steady-state memantine conditions, respectively. Motor activity levels for 1-min intervals were analysed by means of both linear and nonlinear methods. The schizophrenia patients were monitored only once, without memantine manipulation. RESULTS: The root mean square successive differences (RMSSD) and the RMSSD/SD ratio were increased by memantine, and memantine was also associated with lower autocorrelation (lag 1) but in recordings from the right arm only. These movement patterns partly corresponded to those found in a sample of drug-treated schizophrenia patients. Total activity level, standard deviation (SD) and sample entropy were not significantly different in the memantine versus drug-free condition. CONCLUSION: The findings suggest a role for the NMDA receptor in the regulation of motor activity in healthy individuals as memantine increased the variability in the motor recordings and the alterations between adjacent motor recordings. It is suggested that the findings may be relevant to the role played by glutamate and the NMDA receptor functioning to the motor disturbances in schizophrenia.

Admissions to a Norwegian emergency psychiatric ward: patient characteristics and referring agents. A prospective study.

BACKGROUND: In Norway, general practitioners serve as gatekeepers for specialist psychiatric care. Out-of-hours primary healthcare (i.e. casualty clinics) is responsible for the major part of acute psychiatric referrals. There are concerns regarding regular general practitioners' (rGPs') role in emergency psychiatric care of their enlisted patients. Also, the quality of casualty clinics' care and their gatekeeper function are questioned. AIMS: To investigate differences between acute admissions to a psychiatric hospital from casualty clinics, rGPs, specialist psychiatric services and other specialist services regarding characteristics of patients and circumstances of the referrals. METHODS: A prospective observational study. In the period of 1 May 2005 to 30 April 2008, anonymous information was recorded for all consecutive admissions (n = 5317) to the psychiatric acute unit (PAU) at a psychiatric hospital serving 400,000 inhabitants. The recorded information was: referring agent, circumstances of the referral, patient characteristics, and assessments by the receiving psychiatric resident and the therapist in charge of treatment at the PAU. RESULTS: There were only small differences between patients referred to PAU from casualty clinics, rGPs, specialist psychiatric services and other specialist services. The referrals from the different referring agents seemed equally well founded. However, the casualty clinics used more police assistance and coercion, and legal basis for admissions was more frequently converted than for other referring agents. CONCLUSION: Casualty clinics seem to function adequately as gatekeepers. The high proportion of casualty clinic referrals with converted legal basis might indicate unnecessary use of coercion.

A 1H-MR spectroscopy study of changes in glutamate and glutamine (Glx) concentrations in frontal spectra after administration of memantine.

Glutamate is the major excitatory neurotransmitter in the brain and therefore important for cognitive functions. The aim of the study was to investigate if administration of the N-methyl-D-aspartate receptor antagonist memantine to healthy individuals would affect brain activation when performing an auditory attention task. The task was a variant of a dichotic listening task with different instructions that tap demands for attention and cognitive control. We asked the question if memantine administration would lead to reduction in glutamatergic neurotransmission in areas related to attention and cognitive control. Left and right frontal glutamate and glutamine (Glx) concentrations were measured, using (1)H-MR spectroscopy. Twenty-five healthy adults were scanned twice in a counterbalanced design, either drug naive or after administration of memantine for 21 days. The results showed that memantine significantly reduced Glx concentrations, and this reduction was associated with a reduction in brain activation in prefrontal cortex, which could have implications for understanding the neuronal mechanisms underlying higher cognitive functions such as cognitive control.

Anti-depressive effectiveness of olanzapine, quetiapine, risperidone and ziprasidone: a pragmatic, randomized trial.

BACKGROUND: Efficacy studies indicate anti-depressive effects of at least some second generation antipsychotics (SGAs). The Bergen Psychosis Project (BPP) is a 24-month, pragmatic, industry-independent, randomized, head-to-head comparison of olanzapine, quetiapine, risperidone and ziprasidone in patients acutely admitted with psychosis. The aim of the study is to investigate whether differential anti-depressive effectiveness exists among SGAs in a clinically relevant sample of patients acutely admitted with psychosis. METHODS: Adult patients acutely admitted to an emergency ward for psychosis were randomized to olanzapine, quetiapine, risperidone or ziprasidone and followed for up to 2 years. Participants were assessed repeatedly using the Positive and Negative Syndrome Scale-Depression factor (PANSS-D) and the Calgary Depression Scale for Schizophrenia (CDSS). RESULTS: A total of 226 patients were included. A significant time-effect showing a steady decline in depressive symptoms in all medication groups was demonstrated. There were no substantial differences among the SGAs in reducing the PANSS-D score or the CDSS sum score. Separate analyses of groups with CDSS sum scores > 6 or ≤6, respectively, reflecting degree of depressive morbidity, revealed essentially identical results to the primary analyses. There was a high correlation between the PANSS-D and the CDSS sum score (r = 0.77; p < 0.01). CONCLUSIONS: There was no substantial difference in anti-depressive effectiveness among olanzapine, quetiapine, risperidone or ziprasidone in this clinically relevant sample of patients acutely admitted to hospital for symptoms of psychosis. Based on our findings we can make no recommendations concerning choice of any particular SGA for targeting symptoms of depression in a patient acutely admitted with psychosis. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: http://www.clinicaltrials.gov/: NCT00932529.

Cardiovascular risk in patients admitted for psychosis compared with findings from a population-based study.

BACKGROUND: Schizophrenia and related psychoses are associated with excess morbidity and mortality from cardiovascular disease (CVD). Single-site studies on CVD-related risk factors in representative samples of acutely admitted inpatients are scarce. AIMS: To assess the levels of risk factors related to CVD in patients acutely admitted to hospital for symptoms of psychosis. METHODS: Eligible patients aged 18-65 years were included consecutively in the Bergen Psychosis Project (BPP). CVD-related risk factors were recorded at admittance and at discharge or after 6 weeks at the latest. The recordings of 218 patients with psychosis (BPP) were compared with the findings of 50,219 subjects from the population-based Nord-Trøndelag Health Study 1995-97 (HUNT2) survey. RESULTS: Diastolic blood pressures were higher for BPP women and men, whereas body mass indexes (BMIs) and total cholesterol levels were higher in HUNT2 women and men. On categorical measures, smoking was more prevalent in the patients compared with the HUNT2 subjects. Metabolic syndrome was present in 11.8% and 21.9% of BPP women and men, respectively. At discharge or 6 weeks from admission, 3.2% and 18.6% of BPP women and men, respectively, had metabolic syndrome. BMIs and total cholesterol levels had worsened during the inpatient treatment period. Only one patient had a diagnosis corresponding to the CVD risk found, and only four patients received antidiabetics, antihypertensives or lipid-lowering drugs. CONCLUSIONS: Some CVD-related risk factors were high in the patients at admission, some worsened and CVD risk factors seem to be suboptimally addressed, which should warrant increased awareness on the topic in clinical practice.

Effectiveness of second-generation antipsychotics: a naturalistic, randomized comparison of olanzapine, quetiapine, risperidone, and ziprasidone.

BACKGROUND: No clear recommendations exist regarding which antipsychotic drug should be prescribed first for a patient suffering from psychosis. The primary aims of this naturalistic study were to assess the head-to-head effectiveness of first-line second-generation antipsychotics with regards to time until drug discontinuation, duration of index admission, time until readmission, change of psychopathology scores and tolerability outcomes. METHODS: Patients >or= 18 years of age admitted to the emergency ward for symptoms of psychosis were consecutively randomized to risperidone (n = 53), olanzapine (n = 52), quetiapine (n = 50), or ziprasidone (n = 58), and followed for up to 2 years. RESULTS: A total of 213 patients were included, of which 68% were males. The sample represented a diverse population suffering from psychosis. At admittance the mean Positive and Negative Syndrome Scale (PANSS) total score was 74 points and 44% were antipsychotic drug naïve. The primary intention-to-treat analyses revealed no substantial differences between the drugs regarding the times until discontinuation of initial drug, until discharge from index admission, or until readmission. Quetiapine was superior to risperidone and olanzapine in reducing the PANSS total score and the positive subscore. Quetiapine was superior to the other drugs in decreasing the PANSS general psychopathology subscore; in decreasing the Clinical Global Impression - Severity of Illness scale score (CGI-S); and in increasing the Global Assessment of Functioning - Split version, Functions scale score (GAF-F). Ziprasidone was superior to risperidone in decreasing the PANSS positive symptoms subscore and the CGI-S score, and in increasing the GAF-F score. The drugs performed equally with regards to most tolerability outcomes except a higher increase of hip-circumference per day for olanzapine compared to risperidone, and more galactorrhoea for risperidone compared to the other groups. CONCLUSIONS: Quetiapine appears to be a good starting drug candidate in this sample of patients admitted to hospital for symptoms of psychosis. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: http://www.clinicaltrials.gov/: NCT00932529.

The effects of the glutamate antagonist memantine on brain activation to an auditory perception task.

Glutamate is critically involved in the regulation of cognitive functions in humans. There is, however, sparse evidence regarding how blocking glutamate action at the receptor site during a cognitive task affects brain activation. In the current study, the effects of the glutamate antagonist memantine were examined with functional magnetic resonance imaging (fMRI). Thirty-one healthy adults were scanned twice in a counter-balanced design, either in a no-drug session or after administration of memantine for 21 days. The subjects performed a simple auditory perception task with consonant-vowel stimuli. Group-level spatial independent component analysis (ICA) was used to decompose the data and to extract task-related activations. The focus was on four task-related ICA components with frontotemporal localization. The results showed that glutamate-blockage resulted in a significant enhancement in one component, with no significant effect in the other three components. The enhanced effect of memantine was in the middle temporal gyrus, superior frontal gyrus, and middle frontal gyrus. It is suggested that the results reflect effects of glutamatergic processes primarily through non-N-methyl-D-aspartate (NMDA) receptor pathways. Moreover, the results demonstrate that memantine can be used as a probe which allows for studying the effect of excitatory neurotransmission on neuronal activation.

Acute clozapine exposure in vivo induces lipid accumulation and marked sequential changes in the expression of SREBP, PPAR, and LXR target genes in rat liver.

BACKGROUND: Several antipsychotic drugs (APDs) have high propensity to induce weight gain and dyslipidemia in patients, with clozapine and olanzapine as the most potent drugs. These lipid-related effects have been attributed to drug-mediated blockade or antagonism of histamine H1 and serotonin 5-HT2 receptors as well as activation of hypothalamic AMP-activated protein kinase. We recently showed that APDs activate lipid biosynthesis in cultured liver cells through stimulation of the sterol regulatory element-binding protein (SREBP) transcription factors. OBJECTIVE: The objective of the study was to search for clozapine-related lipogenic effects in peripheral tissues in vivo using rat liver as target organ. MATERIALS AND METHODS: Adult female Sprague-Dawley rats were administered single intraperitoneal injections of clozapine (25 and 50 mg/kg). Hepatic lipid levels were measured during a 48-h time course. Real-time quantitative PCR was used to analyze expression of genes involved in lipid biosynthesis, oxidation, efflux, and lipolysis. RESULTS: We identified an initial up-regulation of central lipogenic SREBP target genes, followed by a marked and sustained down-regulation. We also observed a sequential transcriptional response for fatty acid beta-oxidation and cholesterol efflux genes, normally controlled by the peroxisome proliferator activated receptor alpha and liver X receptor alpha transcription factors, and also down-regulation of genes encoding major lipases. The transcriptional responses were associated with a significant accumulation of triacylglycerol, phospholipids, and cholesterol in the liver. CONCLUSION: These results demonstrate that acute clozapine exposure affects SREBP-regulated lipid biosynthesis as well as other lipid homeostasis pathways. We suggest that such drug-induced effects on lipid metabolism in peripheral tissues are relevant for the metabolic adverse effects associated with clozapine and possibly other APDs.

Treatment of schizophrenia with antipsychotics in Norwegian emergency wards, a cross-sectional national study.

BACKGROUND: Surveys on prescription patterns for antipsychotics in the Scandinavian public health system are scarce despite the prevalent use of these drugs. The clinical differences between antipsychotic drugs are mainly in the areas of safety and tolerability, and international guidelines for the treatment of schizophrenia offer rational strategies to minimize the burden of side effects related to antipsychotic treatment. The implementation of treatment guidelines in clinical practice have proven difficult to achieve, as reflected by major variations in the prescription patterns of antipsychotics between different comparable regions and countries. The objective of this study was to evaluate the practice of treatment of schizophrenic patients with antipsychotics at discharge from acute inpatient settings at a national level. METHODS: Data from 486 discharges of patients from emergency inpatient treatment of schizophrenia were collected during a three-month period in 2005; the data were collected in a large national study that covered 75% of Norwegian hospitals receiving inpatients for acute treatment. Antipsychotic treatment, demographic variables, scores from the Global Assessment of Functioning and Health of the Nation Outcome Scales and information about comorbid conditions and prior treatment were analyzed to seek predictors for nonadherence to guidelines. RESULTS: In 7.6% of the discharges no antipsychotic treatment was given; of the remaining discharges, 35.6% were prescribed antipsychotic polypharmacy and 41.9% were prescribed at least one first-generation antipsychotic (FGA). The mean chlorpromazine equivalent dose was 450 (SD 347, range 25-2800). In the multivariate regression analyses, younger age, previous inpatient treatment in the previous 12 months before index hospitalization, and a comorbid diagnosis of personality disorder or mental retardation predicted antipsychotic polypharmacy, while previous inpatient treatment in the previous 12 months also predicted prescription of at least one FGA. CONCLUSION: Our national survey of antipsychotic treatment at discharge from emergency inpatient treatment revealed antipsychotic drug regimens that are to some degree at odds with current guidelines, with increased risk of side effects. Patients with high relapse rates, comorbid conditions, and previous inpatient treatment are especially prone to be prescribed antipsychotic drug regimens not supported by international guidelines.

Antipsychotic-induced hyperprolactinemia: a cross-sectional survey.

OBJECTIVE: To investigate the prevalence of hyperprolactinemia and common hyperprolactinemia-related symptoms and explore the association between them in patients using a modern antipsychotic drug regimen and, in addition, investigate the prevalence of the inert fraction of prolactin called macroprolactin, which, to our knowledge, has not been investigated systematically in this population before. Macroprolactin may cause misdiagnosis of hyperprolactinemia. METHOD: A cross-sectional design was applied, and 106 patients who were using antipsychotics for symptoms of psychosis were included. RESULTS: Hyperprolactinemia was found in 39% of the patients. Women were overrepresented in the group with the highest prolactin levels. Macroprolactin was not detected in any cases. Several of the second-generation antipsychotics were associated with hyperprolactinemia. Pearson correlation between prolactin level and symptoms revealed no association, and some patients did not report any symptoms despite grossly elevated levels of biologically active prolactin. CONCLUSIONS: The results suggest that hyperprolactinemia is still an important and prevalent side effect. In patients using antipsychotics with prolactin-elevating potential, prolactin levels should be routinely measured to prevent potential long-term complications of "silent" hyperprolactinemia, although we are still in the early stages of knowing what to do with the information.