Glucagon-like peptide-1 analogs against antipsychotic-induced weight gain: potential physiological benefits.

BACKGROUND: Antipsychotic-induced weight gain constitutes a major unresolved clinical problem which may ultimately be associated with reducing life expectancy by 25 years. Overweight is associated with brain deterioration, cognitive decline and poor quality of life, factors which are already compromised in normal weight patients with schizophrenia.Here we outline the current strategies against antipsychotic-induced weight gain, and we describe peripheral and cerebral effects of the gut hormone glucagon-like peptide-1 (GLP-1). Moreover, we account for similarities in brain changes between schizophrenia and overweight patients. DISCUSSION: Current interventions against antipsychotic-induced weight gain do not facilitate a substantial and lasting weight loss. GLP-1 analogs used in the treatment of type 2 diabetes are associated with significant and sustained weight loss in overweight patients. Potential effects of treating schizophrenia patients with antipsychotic-induced weight gain with GLP-1 analogs are discussed. CONCLUSIONS: We propose that adjunctive treatment with GLP-1 analogs may constitute a new avenue to treat and prevent metabolic and cerebral deficiencies in schizophrenia patients with antipsychotic-induced weight gain. Clinical research to support this idea is highly warranted.

Augmenting clozapine with sertindole: a double-blind, randomized, placebo-controlled study.

Clozapine augmentation with antipsychotic drugs is widely used despite sparse evidence supporting this strategy. Sertindole is a nonsedating atypical antipsychotic drug with low affinity for cholinergic receptors, which makes it potentially suitable for augmentation of clozapine. The study design was a 12-week, double-blind, randomized, placebo-controlled study including patients with International Statistical Classification of Diseases, 10th Revision schizophrenia (F20.0-F20.3) and treated with clozapine for at least 6 months who had not achieved sufficient response. Patients were randomized 1:1 to either sertindole 16 mg or placebo, and assessment was done at baseline and after 6 and 12 weeks. Assessment included the Positive and Negative Syndrome Scale, Clinical Global Impression, Udvalg for Kliniske Undersøgelser, World Health Organization Quality of Life Brief, Drug Attitude Inventory, fasting glucose, lipids, and electrocardiogram. Clozapine augmentation with sertindole was not superior to placebo regarding total score or subscale score of the Positive and Negative Syndrome Scale, Clinical Global Impression, World Health Organization Quality of Life Brief, or Drug Attitude Inventory. No increased adverse effects compared with placebo were found. Four patients randomized to sertindole experienced a significant worsening of psychosis, and 2 of them required psychiatric admission. Metabolic parameters were unchanged during the study, but augmentation of clozapine with sertindole was associated with a 12-millisecond (SD, 20-millisecond) QTc prolongation compared with 0 millisecond (SD, 20 milliseconds) in the placebo group (P < 0.03). Augmentation with sertindole showed no benefits compared with placebo. Psychiatrists should be aware that augmentation might not add any benefits for the patients and in some cases worsen psychosis.

Progressive striatal and hippocampal volume loss in initially antipsychotic-naive, first-episode schizophrenia patients treated with quetiapine: relationship to dose and symptoms.

First-generation antipsychotics have been associated with striatal volume increases. The effects of second-generation antipsychotics (SGAs) on the striatum are unclear. Moreover, SGAs may have neuroprotective effects on the hippocampus. Dose-dependent volumetric effects of individual SGAs have scarcely been investigated. Here we investigated structural brain changes in antipsychotic-naive, first-episode schizophrenia patients after 6 months treatment with the SGA, quetiapine. We have recently reported on baseline volume reductions in the caudate nucleus and hippocampus. Baseline and follow-up T1-weighted images (3 T) from 22 patients and 28 matched healthy controls were analysed using tensor-based morphometry. Non-parametric voxel-wise group comparisons were performed. Small volume correction was employed for striatum, hippocampus and ventricles. Dose-dependent medication effects and associations with psychopathology were assessed. Patients had significant bilateral striatal and hippocampal loss over the 6-month treatment period. When compared to controls the striatal volume loss was most pronounced with low quetiapine doses and less apparent with high doses. Post-hoc analyses revealed that the striatal volume loss was most pronounced in the caudate and putamen, but not in accumbens. Conversely, hippocampal volume loss appeared more pronounced with high quetiapine doses than with low doses. Clinically, higher baseline positive symptoms were associated with more striatal and hippocampal loss over time. Although patients' ventricles did not change significantly, ventricular increases correlated with less improvement of negative symptoms. Progressive regional volume loss in quetiapine-treated, first-episode schizophrenia patients may be dose-dependent and clinically relevant. The mechanisms underlying progressive brain changes, specific antipsychotic compounds and clinical symptoms warrant further research.

Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial - the SMART trial protocol.

BACKGROUND: Treatment of schizophrenia frequently includes prolonged benzodiazepine administration despite a lack of evidence of its use. It is often difficult to discontinue benzodiazepines because of the development of dependence. We aim to assess if melatonin can facilitate the withdrawal of prolonged benzodiazepine administration in patients with schizophrenia. Furthermore, we aim to investigate the association of benzodiazepine dose reduction with the following clinically important variables: sleep, psychophysiology, cognition, social function, and quality of life. METHODS/DESIGN: Randomized, blinded, two-armed, parallel superiority trial. We plan to include 80 consenting outpatients diagnosed with schizophrenia or schizoaffective disorder, 18-55 years of age, treated with antipsychotic drug(s) and at least one benzodiazepine derivative for the last three months before inclusion. EXCLUSION CRITERIA: currently under treatment for alcohol or drug abuse, aggressive or violent behavior, known mental retardation, pervasive developmental disorder, dementia, epilepsy, terminal illness, severe co morbidity, inability to understand Danish, allergy to melatonin, lactose, starch, gelatin, or talc, hepatic impairment, pregnancy or nursing, or lack of informed consent. After being randomized to prolonged-release melatonin (Circadin®) 2 mg daily or matching placebo, participants are required to slowly taper off their benzodiazepine dose. The primary outcome measure is benzodiazepine dose at 6 months follow-up. Secondary outcome measures include sleep, psychophysiological, and neurocognitive measures. Data are collected at baseline and at 6 months follow-up regarding medical treatment, cognition, psychophysiology, sleep, laboratory tests, adverse events, psychopathology, social function, and quality of life. Data on medical treatment, cognition, psychophysiology, adverse events, social function, and quality of life are also collected at 2 and 4 months follow-up. DISCUSSION: The results from this trial will examine whether melatonin has a role in withdrawing long-term benzodiazepine administration in schizophrenia patients. This group of patients is difficult to treat and therefore often subject to polypharmacy which may play a role in the reduced life expectancy of patients compared to the background population. The results will also provide new information on the association of chronic benzodiazepine treatment with sleep, psychophysiology, cognition, social function, and quality of life. Knowledge of these important clinical aspects is lacking in this group of patients. TRIAL REGISTRATION: ClinicalTrials NCT01431092.

Sensorimotor gating and habituation in antipsychotic-naive, first-episode schizophrenia patients before and after 6 months' treatment with quetiapine.

Impaired prepulse inhibition of the startle reflex (PPI) in schizophrenia has been replicated in many studies. However, previous results may have been influenced by course of illness, and antipsychotic medication. Studies on antipsychotic-naive, first-episode schizophrenia patients are lacking, since these patients are so difficult to recruit. Furthermore, longitudinal studies are few, and their results are inconsistent: some results indicating a reduction of PPI deficits by treatment with atypical antipsychotics, while others do not. This study reports on PPI, habituation and sensitization of the human startle reflex in a large group of antipsychotic-naive, first-episode schizophrenia patients, and the effect of subsequent treatment with quetiapine. Thirty-four antipsychotic-naive, first-episode schizophrenia patients (24 males, 10 females), and age- and gender-matched healthy controls were tested in a psychophysiological test battery at baseline and again after 6 months. During this period, the patients were treated with quetiapine, while the controls received no treatment. Sixteen patients completed the study. At baseline, male patients showed significantly lower PPI than controls. Treatment with quetiapine for 6 months increased male PPI to a level where it was no longer statistically different from the controls. The much smaller group of females did not show PPI deficits at baseline. In addition, compared to controls, patients appeared highly aroused and showed a strong yet non-significant trend for reduced sensitization at baseline, but not at follow-up. Patients and controls showed similar levels of habituation, both at baseline, and at follow-up. These findings indicate that PPI deficits are already present from the earliest stage of clinical onset of schizophrenia, before the patients have received any antipsychotic treatment. In addition, following 6 months' treatment with quetiapine these PPI deficits were normalized. Furthermore, the results suggest that schizophrenia patients in the antipsychotic-naive state show reduced levels of sensitization, yet normal levels of habituation.

Hippocampal and caudate volume reductions in antipsychotic-naive first-episode schizophrenia.

BACKGROUND: Enlarged ventricles and reduced hippocampal volume are consistently found in patients with first-episode schizophrenia. Studies investigating brain structure in antipsychotic-naive patients have generally focused on the striatum. In this study, we examined whether ventricular enlargement and hippocampal and caudate volume reductions are morphological traits of antipsychotic-naive first-episode schizophrenia. METHODS: We obtained high-resolution 3-dimensional T1-weighted magnetic resonance imaging scans for 38 antipsychotic-naive first-episode schizophrenia patients and 43 matched healthy controls by use of a 3-T scanner. We warped the brain images to each other by use of a high-dimensional intersubject registration algorithm. We performed voxel-wise group comparisons with permutation tests. We performed small volume correction for the hippocampus, caudate and ventricles by use of a false discovery rate correction (p < 0.05) to control for multiple comparisons. We derived and analyzed estimates of brain structure volumes. We grouped patients as those with (n = 9) or without (n = 29) any lifetime substance abuse to examine the possible effects of substance abuse. RESULTS: We found that hippocampal and caudate volumes were decreased in patients with first-episode schizophrenia. We found no ventricular enlargement, differences in global volume or significant associations between tissue volume and duration of untreated illness or psychopathology. The hippocampal volume reductions appeared to be influenced by a history of substance abuse. Exploratory analyses indicated reduced volume of the nucleus accumbens in patients with first-episode schizophrenia. LIMITATIONS: This study was not a priori designed to test for differences between schizophrenia patients with or without lifetime substance abuse, and this subgroup was small. CONCLUSION: Reductions in hippocampal and caudate volume may constitute morphological traits in antipsychotic-naive first-episode schizophrenia patients. However, the clinical implications of these findings are unclear. Moreover, past substance abuse may accentuate hippocampal volume reduction. Magnetic resonance imaging studies addressing the potential effects of substance abuse in antipsychotic-naive first-episode schizophrenia patients are warranted.

Effects of donepezil adjunctive treatment to ziprasidone on cognitive deficits in schizophrenia: a double-blind, placebo-controlled study.

The objective of this study was to examine the effects of adjunctive treatment with the acetylcholinesterase inhibitor, donepezil, on cognitive deficits and psychopathology in schizophrenic patients treated with the antipsychotic, ziprasidone. The design of the study was double blind, placebo controlled, and longitudinal. Patients were treated with ziprasidone for 8 weeks, thereafter randomized to 4 months of double-blind adjunctive treatment with either donepezil (dose, 5-10 mg) or placebo. The severity of psychopathology (PANSS) and the cognitive deficits were examined at baseline and after 4 months. A total of 21 schizophrenic patients were enrolled, of whom 11 patients completed the trial (donepezil, n = 7; placebo, n = 4). There were no within- or between-group differences in changes on the Positive and Negative Syndrome Scale scores or a global cognitive score. Within-group improvements (all at trend level P = 0.07) were seen in the placebo group on Trail-Making Test B, immediate verbal recall, and set-shifting errors. The donepezil group showed a significant deterioration on planning efficiency (P = 0.04). Between-group differences were found between the lack of improvement in immediate verbal recall in the donepezil group and the improvement in the placebo group (P = 0.02), and between the deterioration of planning efficiency in the donepezil group and the stability in the placebo group (trend level, P = 0.07). Linear regression analyses showed that neither baseline psychopathology scores, baseline levels of cognitive deficits, nor psychopathology changes over time accounted for these changes in cognitive scores. The study found no evidence of improved cognition after treatment with donepezil, although the conclusions that can be drawn are limited by the small sample size.

A multicentre, randomized, naturalistic, open-label study between aripiprazole and standard of care in the management of community-treated schizophrenic patients Schizophrenia Trial of Aripiprazole: (STAR) study.

BACKGROUND: Naturalistic effectiveness trials of atypical antipsychotics are needed to provide broader information on efficacy, safety, and tolerability in patients with schizophrenia treated in a community practice setting. METHOD: In this 26-week, open-label, multicentre study, patients with schizophrenia requiring a switch in antipsychotic medication because current medication was not well tolerated and/or clinical symptoms were not well controlled were randomized to receive aripiprazole or an atypical antipsychotic standard of care (SOC) treatment (i.e., olanzapine, quetiapine, or risperidone based on the investigator's judgment of the optimal treatment for the individual patient and the patient's prior response to antipsychotic medication). The primary objective was to compare the effectiveness of a 26-week treatment of aripiprazole versus SOC, as measured by the Investigator Assessment Questionnaire (IAQ) total score at Week 26 last observation carried forward (LOCF) (primary endpoint), a validated measure that monitors relief or worsening of 10 key symptoms associated with the psychopathology of schizophrenia and side effects of antipsychotic treatment. Secondary objectives were to further assess effectiveness using the Clinical Global Impression - Global Improvement (CGI-I) and Clinical Global Impression - Severity of Illness scale, to assess time to treatment discontinuation, patient preference of medication, quality of life, and the tolerability of aripiprazole compared with SOC. RESULTS: Aripiprazole treatment (n=268) resulted in significantly better effectiveness than SOC treatment (n=254; P<0.001; Week 26 LOCF) as evidenced by the IAQ total score beginning at Week 4 (the first assessment point) and sustained through Week 26. A similar relationship was demonstrated among patients who completed the study (observed cases analysis); aripiprazole was associated with significantly better effectiveness at all time points with a greater differential effect from SOC over time. Patients treated with aripiprazole also demonstrated significantly greater improvements on the CGI-I scale (responder rate, P=0.009 at Week 26 LOCF), as well as on quality of life (Quality of Life scale total score; P<0.001 at Week 26). Furthermore, a significantly higher proportion of patients receiving aripiprazole rated their study medication as "much better" on the Preference of Medication Questionnaire (POM) scale than their pre-study medication compared with SOC patients (P<0.001; Week 26). Time to treatment discontinuation and rates of discontinuation due to adverse events were similar in both treatment groups. The incidence of patients with one or more extrapyramidal symptom (e.g., akathisia, dystonia, parkinsonian events, and residual events) was higher in patients receiving aripiprazole compared with patients treated with SOC (13.5% vs. 5.6%); however, a higher proportion of patients in the SOC-treated group had clinically significant weight gain (21.2% vs. 7.3% for aripiprazole) and potentially clinically relevant elevated fasting levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and serum prolactin compared with patients receiving aripiprazole. CONCLUSIONS: Aripiprazole is an effective atypical antipsychotic for the treatment of schizophrenia, demonstrating better effectiveness than SOC agents used in this study in patients for whom a switch in antipsychotic medication was warranted.

Association between the CCR5 32-bp deletion allele and late onset of schizophrenia.

OBJECTIVE: The 32-bp deletion allele in chemokine receptor CCR5 has been associated with several immune-mediated diseases and might be implicated in schizophrenia as well. METHOD: The authors genotyped DNA samples from 268 schizophrenia patients and 323 healthy subjects. Age at first admission to a psychiatric hospital department served as a measure of disease onset. RESULTS: Patients and comparison subjects differed marginally in their genotype distribution, with a slightly higher frequency of the deletion allele seen in the patients. The authors found the deletion allele to be associated with higher age at first admission. After age at first admission was analyzed as a continuous variable, it was dichotomized using 40 years as the cutoff. With this approach the authors found that genotype distributions of patients with age at first admission above the cutoff (possible cases of late-onset schizophrenia) and healthy subjects differed significantly. This was reflected in an increased frequency of the deletion allele in the patient subgroup. Patients with ages at first admission below and above 40 years significantly differed in distribution of genotypes and alleles, with an overrepresentation of the deletion allele in the latter subgroup of patients. CONCLUSIONS: These findings suggest that the CCR5 32-bp deletion allele is a susceptibility factor for schizophrenia with late onset. Alternatively, the CCR5 32-bp deletion allele may act as a modifier by delaying the onset of schizophrenia without affecting the disease susceptibility.

Current therapy issues and unmet clinical needs in the treatment of schizophrenia: a review of the new generation antipsychotics.

This review discusses the atypical antipsychotics, focusing on the possibility of symptom reduction with a minimum of side-effects. A selective review of clinically relevant reports, studies and meta-analyses is presented. The results from clinical trials suggest that atypical agents improve negative and affective symptoms, and cognitive functioning more than typical antipsychotics, but that the pattern of effects on these domains, as well as on suicidality, appears to differ. In clinical trials, the newer drugs generally have less extrapyramidal side-effects (EPS) than typical antipsychotics. However, amisulpride, risperidone, olanzapine and ziprasidone still show evidence of a dose-related increase in EPS, whereas clozapine, quetiapine, sertindole and aripiprazole do not. Weight gain, increased blood lipids/cholesterol, and insulin resistance/type 2 diabetes are emerging as significant treatment-associated concerns, particularly for clozapine and olanzapine. Sedation has been reported for all the newer compounds except sertindole. The considerable variation in benefit/risk profiles of the atypical compounds can help the clinician to select the most appropriate treatment for individual patients.

Postprandial prolactin suppression appears absent in antipsychotic-treated male patients.

INTRODUCTION: Hyperprolactinemia is a common side-effect of antipsychotic treatment. Antipsychotics and hyperprolactinemia are both considered risk factors of metabolic disturbances and diabetes. Investigations on prolactin response to meal ingestion in antipsychotic-treated patients are missing. MATERIAL AND METHODS: In a case-control design, 49 antipsychotic-treated, clinically stable, non-diabetic, schizophrenia spectrum male patients were compared with 93 healthy male controls by age (33.1, SD 7.4 vs. 32.9, SD 6.6 years), body mass index (26.2, SD 4.6 vs. 26.1, SD 3.9 kg/m(2)) and waist circumference (96.4, SD 13.0 vs. 96.7, SD 11.9 cm). Serum-prolactin was measured in the morning and 90 min after ingestion of a standardized liquid meal (2268 kJ). RESULTS: Fasting prolactin levels varied considerably, and mean fasting prolactin levels did not significantly differ between patients and controls (12.33, SD 11.58 vs. 10.06, SD 8.67 ng/ml, p = 0.623). In the controls, postprandial serum prolactin was significantly reduced (Δ -2.53, SD 9.75 ng/ml, p = 0.016). In antipsychotic-treated patients postprandial serum prolactin tended to increase (Δ 2.62, SD 10.96 ng/ml, p = 0.081). Analyses of subgroups based on the prolactinogenic liability of their antipsychotic treatment indicated 22 to 65% higher postprandial prolactin levels with high and intermediate prolactinogenic antipsychotics. DISCUSSION: A physiological postprandial suppression of serum prolactin appears absent in antipsychotic-treated males. Marked variability in fasting prolactin levels may reflect individual variations in the diurnal cycle. Uniform acquisition procedures accounting for diurnal variation and food intake may enhance reliability of prolactin levels in antipsychotic-treated male patients.

[Why is QT interval interesting?]. / Hvorfor skal vi interessere os for QT-intervallet?

A prolonged Q-T interval is generally associated with increased risk of ventricular arrhythmias, like torsade de pointes, and death. It has recently become apparent that not only antiarrhythmic drugs such as sotalol and Kinidin, but also a variety of nonantiarrhythmic drugs, like certain antihistamines, antimicrobial drugs, psychiatric drugs, and cisapride, may induce prolongation of the Q-T interval and torsade de pointes. Special concern should be drawn to the co-administration of drugs that interfere with the metabolism and elimination of these drugs, such as ketoconazole. Patients with congenital long Q-T syndrome, patients with heart disease, with hypokalaemia or hypomagnesaemia, and women have an increased risk. Every sign on dizziness or syncope should be regarded as a warning sign of possible arrhythmia in patients treated with drugs that potentially prolong the Q-T interval. Measurement of the Q-T interval before and during treatment is generally recommended in high-risk patients.

[Diagnosis and treatment of depression in general practice. A questionnaire study]. / Diagnostik og behandling af depression i almen praksis. En spørgeskemaundersøgelse.

INTRODUCTION: The purpose of this questionnaire study was to assess the knowledge and attitude of general practitioners (GPs) towards the use of diagnostic criteria in clinical practice, and the extent to which diagnostic tools are used as a prerequisite for the treatment of depressive patients in general practice. MATERIAL AND METHODS: A total of 758 out of 1,700 randomly selected GPs responded to the questionnaire. The GPs' demographic data (age, sex, number of years in practice, supplementary education), diagnostic practice (knowledge of depressive core symptoms and diagnostic tools and scales), and clinical practice (assessment of the effectiveness of treatment, duration of treatment, aim of treatment, and use of psychotherapy) were registered. RESULTS: The study showed that GPs, who had taken part in supplementary training in psychiatric issues within the preceding year, to a higher extent than the rest of the GPs used diagnostic tools for all or most patients. This group of GPs also had a significantly greater knowledge of the depressive core symptoms as described in the ICD-10. When compared with the other group of GPs, they also felt themselves more confident of the diagnosis of depression before prescribing antidepressive medication. The vast majority of both groups felt that many depressive patients remained undiagnosed, because they simply do not consult their GPs. They also found that it was often questionable whether the symptoms were caused by life crisis or depression--and whether or not the depressive symptoms of these patients required drug treatment. DISCUSSION: The questionnaire study shows that the GPs' level of knowledge of diagnostics of depression is insufficient. There is an obvious need for supplementary training in general practice, thereby increasing the knowledge and the use of diagnostic criteria in order to make diagnoses of depression more correct and to improve treatment.

Glucometabolic hormones and cardiovascular risk markers in antipsychotic-treated patients.

OBJECTIVE: Treatment with antipsychotic drugs is widely associated with metabolic side effects such as weight gain and disturbed glucose metabolism, but the pathophysiologic mechanisms are unclear. METHOD: Fifty nondiabetic (fasting plasma glucose ≤ 7.0 mmol/L), antipsychotic-treated male patients (ICD-10 diagnosis code F20, F21, F22, F25, F28, or F60; mean ± SD age = 33.0 ± 6.7 years; body mass index [BMI; kg/m²] = 26.0 ± 4.7; waist circumference = 95.9 ± 13.3 cm; glycated hemoglobin A1c [HbA1c] = 5.7% ± 0.3%) and 93 age- and waist circumference-matched healthy male controls (age = 33 ± 7.3 years; BMI = 26.1 ± 3.9; waist circumference = 94.6 ± 11.9 cm; HbA1c = 5.7% ± 0.3%) participated in this cross-sectional study. Blood was sampled in the fasting state and 90 minutes after ingestion of a standardized liquid meal (2,268 kJ). The primary outcomes were glucometabolic hormones and cardiovascular risk markers. Data were collected between March 2008 and February 2010. RESULTS: Compared to healthy controls, patients were characterized by elevated fasting levels of proinsulin, C-peptide, and glucose-dependent insulinotropic polypeptide (GIP) (P < .05) and higher postprandial levels of insulin, proinsulin, C-peptide, and GIP (P ≤ .02). Also, patients exhibited elevated plasma levels of C-reactive protein and signs of dyslipidemia. Fasting plasma levels of insulin, glucagon, glucagon-like peptide-1 (GLP-1), ghrelin, leptin, adiponectin, tumor necrosis factor-α, plasminogen activator inhibitor-1, and interleukin-6 and postprandial levels of glucagon, GLP-1, ghrelin, leptin, and adiponectin did not differ between groups. CONCLUSIONS: Presenting with an insulin resistant-like pattern, including beta cell hypersecretion and elevated GIP levels, nondiabetic antipsychotic-treated patients display emerging signs of dysmetabolism and a compromised cardiovascular risk profile. The appetite-regulating hormones GLP-1 and ghrelin appear not to be influenced by antipsychotic treatment. Our findings provide new clinical insight into the pathophysiology associated with metabolic side effects of antipsychotic treatment and put emphasis on the importance of implementing metabolic screening into psychiatric practice. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00627757.

[Problems when switching antipsychotics]. / Problemer ved skift af antipsykotika.

Most patients with schizophrenia switch antipsychotics (APs) either due to lack of efficacy or due to side effects. Changing AP, especially switching from clozapine, may lead to deterioration in the patient's condition because of pharmacodynamic differences between the existing and the new AP. A meta-analysis including four studies found no differences between switch strategies while three recent studies each found a positive short term effect of a crossover strategy compared to an abrupt switch. Based on the lack of evidence we recommend a slow withdrawal with a crossover strategy when switching AP.

Association of antipsychotic polypharmacy with health service cost: a register-based cost analysis.

OBJECTIVE: To investigate the association of antipsychotic polypharmacy in schizophrenia with cost of primary and secondary health service use. METHOD: Comparative analysis of health service cost for patients prescribed antipsychotic polypharmacy versus antipsychotic monotherapy. Resource utilisation and costs were described using central Danish registers for a 2 year period (2007-2008). We included patients attached to one of two Danish psychiatric referral centres in 1 January 2008 and/or 1 January 2009. Their prescribed treatment with either antipsychotic polypharmacy or monotherapy at the two cross-sectional dates was recorded and used as proxy of polypharmacy exposure during the preceding year. A multivariate generalised linear model was fitted with total costs of primary and secondary health service use as dependent variable, and antipsychotic polypharmacy, diagnosis, age, gender, disease duration, psychiatric inpatient admissions, and treatment site as covariates. RESULTS: The sample consisted of 736 outpatients with a diagnosis in the schizophrenia spectrum. Antipsychotic polypharmacy was associated with significantly higher total health service costs compared with monotherapy (2007: 25% higher costs; 2008: 17% higher costs) when adjusting for potential confounders and risk factors. A subgroup analysis suggested that the excessive costs associated with antipsychotic polypharmacy were partly accounted for by the functional level of the patients. CONCLUSION: The results demonstrate that antipsychotic co-prescribing is associated with increased use of health care services, even though no causal relations can be inferred from an observational study.

Alterations of the brain reward system in antipsychotic naïve schizophrenia patients.

BACKGROUND: Various schizophrenic symptoms are suggested to be linked to a dysfunction of the brain reward system. Several studies have found alterations in the reward processing in patients with schizophrenia; however, most previous findings might be confounded by medication effects. METHODS: Thirty-one antipsychotic-naïve schizophrenia patients and 31 age- and gender-matched healthy control subjects were examined with functional magnetic resonance imaging while playing a variant of the monetary incentive delay task. The task variant made it possible to separate overall salience (defined as arousing events) into behavioral salience (events where a predicted reward requires performance) and valence anticipation (the anticipation of a monetarily significant outcome). Furthermore, the evaluation of monetary gain and loss was assessed. RESULTS: During reward anticipation, patients had a significant attenuation of the activation in ventral tegmentum, ventral striatum, and anterior cingulate cortex during presentation of salient cues. This signal attenuation in ventral striatum was correlated with the degree of positive symptoms. Signal attenuation was most pronounced for behavioral salience and nonsignificant for value anticipation. Furthermore, patients showed a changed activation pattern during outcome evaluation in right prefrontal cortex. CONCLUSION: Our results suggest that changes during reward anticipation in schizophrenia are present from the beginning of the disease. This supports a possible involvement of reward disturbances in the pathophysiology of schizophrenia. The most pronounced changes were seen in relation to overall salience. In ventral striatum these changes were associated with the degree of positive symptoms.