Treatment-emergent Weight Gain Research Articles

Weight gain and metabolic change as predictors of symptom improvement in first-episode schizophrenia spectrum disorder patients treated over 12 months

BackgroundTreatment-emergent weight gain is associated with antipsychotic efficacy in schizophrenia patients treated with clozapine and olanzapine. However, few studies have investigated this relationship in first-episode patients treated with other antipsychotics, in particular those with a lower obesogenic potential.AimTo investigate the relationships between weight gain and associated metabolic changes with psychopathology improvement in relation to age, sex, ethnicity, substance use, treatment duration and antipsychotic dose in first-episode schizophrenia spectrum disorder patients. MethodsThis single site cohort study included 106 minimally treated or antipsychotic-naive patients treated with flupenthixol decanoate over 12 months. Psychopathology was evaluated using the Positive and Negative Syndrome Scale (PANSS) and BMI, fasting blood lipids and glucose were assessed at regular intervals. Linear regression models were constructed to determine the effects of socio-demographic, clinical and metabolic factors as predictors of change in total PANSS score and factor-derived domains. ResultsBMI change scores were inversely correlated with change in PANSS total (R = −0.25; p = 0.011), positive (R = −0.23; p = 0.019), depressive anxiety (R = −0.21; p = 0.031) and disorganized symptoms (R = −0.32; p < 0.001). Linear regression analysis showed that increased BMI and treatment duration both predicted improvement in global psychopathology and disorganized symptoms independent of age, sex, ethnicity, substance use, co-medication with antidepressants and/or anticholinergics, as well as the dose and duration of antipsychotic exposure. ConclusionsOur findings suggest that the relationship between treatment-emergent weight gain and psychopathology improvement is not limited to patients treated with antipsychotics most associated with weight gain, and is not confounded by treatment duration and dose.

Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review.

Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed first. However, alongside with safety, efficacy should also be considered on a patient-tailored basis.

Increases in triglyceride levels are associated with clinical response to clozapine treatment

Increases in serum triglyceride (TG) levels are associated with clinical response to clozapine treatment. Clozapine is the most efficacious therapy for treatment of refractory schizophrenia, although its use is well recognised to be associated with substantial metabolic dysfunction. Interestingly, there is some evidence that the therapeutic benefit of clozapine is associated with treatment-emergent weight gain and dyslipidaemia, specifically hypertriglyceridaemia. In this prospective observational study, we examine associations between therapeutic response to clozapine in 49 patients with treatment-resistant schizophrenia and lipid dysregulation. An increase in TG levels was strongly predictive of clinical improvement (B=9.33, t =3.56, df=4, p<0.001) and of improvement in positive PANSS scores (B=2.85, t=3.61, df=4, p=0.001) as well as negative PANSS scores (B=1.93, t=2.36, df=4, p=0.02), when controlling for potential confounds of weight gain, change in waist circumference, baseline antipsychotic polypharmacy and serum clozapine levels. This finding suggests that clozapine's therapeutic efficacy is linked to serum lipid changes. Hypertriglyceridaemia as a predictor of clinical response in patients treated with clozapine merits further investigation in order to better elucidate its effect on the pharmacological activity of clozapine.

Body Weight and Metabolic Adverse Effects of Asenapine, Iloperidone, Lurasidone and Paliperidone in the Treatment of Schizophrenia and Bipolar Disorder

Background: The introduction of second-generation antipsychotics (SGAs) over the past 2 decades generated considerable optimism that better anti-psychotic treatments for schizophrenia and bipolar disorder were possible. SGAs offer several tolerability benefits over first-generation antipsychotics (FGAs), particularly with respect to extrapyramidal symptoms. However, SGAs can induce serious metabolic dysregulations, especially in drug-naive, first-episode, and child and adolescent populations, with olanzapine and clozapine having the highest propensity to cause these abnormalities. In this context, newer SGAs were developed to further improve the adverse effect burden of available agents. However, until now, the metabolic risk profile of the newly approved SGAs — asenapine, iloperidone, lurasidone and paliperidone (paliperidone extended release and paliperidone palmitate) — has not been compared.

Olanzapine–fluoxetine combination for the treatment of bipolar depression

Introduction: Olanzapine–fluoxetine combination is one of only two products currently approved by the US FDA for the acute treatment of depressive episodes associated with bipolar disorder.Areas covered: This treatment evaluation reviews double-blind randomized controlled trials of olanzapine–fluoxetine combination for bipolar depression. A total of three primary study reports are found in the peer-reviewed literature. Additional data regarding the trials are obtained from study synopses disclosed on the internet by the manufacturer and from product labeling.Expert opinion: Number needed to treat for antidepressant response for olanzapine–fluoxetine combination versus placebo in the 8-week trials was 4 (95% CI 3 – 8), and that for remission was 5 (95% CI 3 – 8). Single-digit numbers needed to harm (NNH) values were observed for the treatment-emergent adverse events of weight gain (NNH 7, 95% CI 5 – 16) and diarrhea (NNH 9, 95% CI 5 – 30). NNH versus placebo for weight gain ≥ 7% from baseline was 6 (95% CI 4 – 10). When contrasted with lamotrigine, olanzapine–fluoxetine combination demonstrates statistically significantly greater improvement in depressive and manic symptoms but there is a higher incidence of treatment-emergent adverse events, weight gain and elevation in metabolic factors. Studies that directly compare quetiapine monotherapy with olanzapine–fluoxetine combination, the only two approved products for the treatment of bipolar depression, are not available. Nonetheless, indirect comparisons indicate similar efficacy outcomes but different tolerability profiles, with quetiapine principally being associated with sedation. Additional approved treatment options would be welcome.

Iloperidone, Asenapine, and Lurasidone: A Brief Overview of 3 New Second-Generation Antipsychotics

Three new second-generation antipsychotics were approved by the US Food and Drug Administration in 2009 and 2010: iloperidone, asenapine, and lurasidone. All 3 agents are approved for the treatment of acute schizophrenia in adults, and asenapine is also approved for the maintenance treatment of schizophrenia and as a monotherapy or as an adjunct to lithium or valproate for the treatment of bipolar manic or mixed episodes. The expectation is that these new agents will be less problematic regarding treatment-emergent weight gain and metabolic disturbances, which unfortunately can occur with several other second-generation antipsychotics. Asenapine is a sublingual preparation, in contrast to iloperidone and lurasidone, which are swallowed. Iloperidone and asenapine are dosed twice daily, in contrast to lurasidone, which is dosed once daily with food. Both asenapine and lurasidone can be initiated at a dose that is possibly therapeutic, but iloperidone requires 4 days of titration to reach its recommended target dose range. Although both asenapine and lurasidone can be associated with dose-related treatment-emergent akathisia, iloperidone is essentially free of extrapyramidal adverse effects or akathisia throughout its recommended dose range. Sedation and/or somnolence have been reported with each medication. They are the most common adverse events associated with asenapine treatment, and are clearly dose-related for lurasidone. In contrast, no therapeutic dose response for iloperidone, asenapine, or lurasidone is clearly evident from short-term clinical trials. Longer-term and naturalistic studies will be helpful in evaluating these agents and their role in the psychiatric armamentarium.

Tolerability of paliperidone: a meta-analysis of randomized, controlled trials

Balancing tolerability and efficacy of medications can be problematic for clinicians when assessing appropriate therapy for patients. For antipsychotic therapy, this can be especially challenging because of the hazardous movement and metabolic effects associated with them. Paliperidone is an atypical antipsychotic used for the treatment of schizophrenia and schizoaffective disorder. A systematic review of the literature for the tolerability of the drug, paliperidone, was performed. A total of 15 articles met the criteria for inclusion representing a total of 3779 patients. Data combination was conducted using the Mantel-Haenszel method, random effects model at 95% confidence. Adverse events with the greatest incidence in the paliperidone population were any treatment emergent adverse event (68%), extra-pyramidal symptoms (23%), headache (14%), insomnia (11%), somnolence (9%), tachycardia (9%) and weight gain (8%). Reported events most likely related to paliperidone [largest attributable risks (AR)] were extra-pyramidal symptoms (AR=10), reduction in acute psychosis (AR=8), any treatment emergent adverse event (AR=6), tachycardia (AR=4), and weight gain (AR=4). Events where incidence was entirely because of paliperidone (incidence equals AR) were hypersalivation (3), dysarthria (2), and sexual dysfunction (1). Reported events totally unrelated to paliperidone (AR=0) included anxiety, asthenia, constipation, depression, dyspepsia, glucose related events, and vomiting. Overall, a 50% reduction in treatment emergent psychosis was seen in schizophrenic patients treated with paliperidone, however the reduction of a psychotic event is about equal to the occurrence of an adverse event with paliperidone.

Comparison of olanzapine and risperidone in the EMBLEM Study: translation of randomized controlled trial findings into clinical practice

Data from the EMBLEM Study, a 2-year, prospective, observational study of health outcomes associated with acute treatment of patients experiencing a manic/mixed episode of bipolar disorder, was used to compare the effectiveness of olanzapine monotherapy versus risperidone monotherapy, and to investigate whether the treatment effects were similar to those reported in a 3-week, randomized controlled trial assessing the same treatments. Symptom severity measures included the Young Mania Rating Scale (YMRS), the 5-item Hamilton Depression Rating Scale, and the Clinical Global Impression-Bipolar Disorder Scale. A total of 245 EMBLEM inpatients were analyzed with YMRS >or=20: olanzapine (n=209), risperidone (n=36). Both the treatment groups had similar improvements in YMRS from baseline to 6 weeks, but there was a significantly greater improvement in 5-item Hamilton Depression Rating Scale in the olanzapine group. There was a similar improvement in Clinical Global Impression-Bipolar Disorder Scale in both the groups and the occurrence of treatment-emergent adverse events and weight gain did not differ between the treatment groups. The EMBLEM results partly support those of the randomized controlled trial, which suggests olanzapine and risperidone have similar improvements in mania but that olanzapine monotherapy may be more effective than risperidone monotherapy in the treatment of depressive symptoms associated with mania. Limitations include differences in study design, patient population, and length of follow-up.

Upstream genetic variant near INSIG2, influences response to carnitine supplementation in bipolar patients with valproate-induced weight gain.

The protein product of INSIG2 is involved in cholesterol and triglyceride metabolism and homeostasis. Variation at rs7566605 near the gene INSIG2 has been associated with increased BMI. To evaluate the effect of rs7566605/INSIG2 genotype on the ability of valproate-treated bipolar patients (BMI ≥ 25 kg/m2) to lose weight using carnitine supplementation during a 26-week lifestyle intervention study. Forty-eight bipolar patients with clinically significant treatment emergent weight gain were genotyped at the rs7566605 SNP. Participants were randomised to l-carnitine (15 mg/kg/day) or placebo for 26 weeks in conjunction with a moderately energy restricted, low-fat diet. Weight and body fat percent were measured fortnightly. Waist circumference measurements and dual-energy X-ray absorptiometry were used to assess changes in body composition. Obesity-related biomarkers were measured at baseline and 26 weeks. There was a significant interaction between rs7566605/INSIG2 genetic status and treatment with carnitine or placebo. Carnitine had no significant effect on body composition measures in G allele homozygous patients who lost between 0.97 and 2.23 kg of fat. However C allele carriers on average gained 2.28 kg when given a placebo. Carnitine supplementation in this group enabled average weight loss of 2.22 kg of fat (p = 0.01). Approximately half of this mass was in the vital truncal compartment (p = 0.002). Bioinformatic analysis detected that the SNP lies in a highly conserved 336 bp sequence which potentially affects INSIG2 gene expression. C-carriers at rs7566605, possibly regulating the homeostasis gene INSIG2, lost significantly less weight in this lifestyle intervention study. This effect was reversed by carnitine supplementation.

Massive weight gain of patients under neuroleptic treatment is due to increased adipose stem cell differentiation

Antipsychotic-induced weight gain is a key issue in the treatment of psychotic illnesses and affects 80% of individuals being treated with antipsychotic drugs. The atypical neuroleptics clozapine and olanzapine show the greatest weight-increasing potential but also the typical neuroleptic haloperidol and risperidone induce weight gain during therapy. This increase in weight is significantly correlated with clinical improvements, but the causes of treatment-emergent weight gain in schizophrenic patients are currently not yet understood.

Olanzapine Versus Placebo in the Treatment of Adolescents With Bipolar Mania

The purpose of this study was to evaluate the efficacy and safety of olanzapine for the treatment of acute manic or mixed episodes associated with bipolar disorder in adolescents. A 3-week multicenter, parallel, double-blind, randomized placebo-controlled trial was conducted at 24 sites in the United States and two sites in Puerto Rico. The participants were outpatient and inpatient male and female adolescents 13-17 years of age with an acute manic or mixed episode. Subjects received either olanzapine (2.5-20 mg/day [N=107]) or placebo (N=54). The mean change from baseline to endpoint in the Young Mania Rating Scale total score was the primary outcome measure. The mean baseline-to-endpoint change in the Young Mania Rating Scale total score was significantly greater for patients receiving olanzapine relative to patients receiving placebo, and a greater proportion of olanzapine-treated patients met response and remission criteria (44.8% versus 18.5% and 35.2% versus 11.1%, respectively). The mean baseline-to-endpoint weight change was significantly greater for patients receiving olanzapine relative to patients receiving placebo (3.7 kg versus 0.3 kg), and the incidence of treatment-emergent weight gain > or =7% of baseline was higher for olanzapine-treated patients (41.9% versus 1.9%). The mean baseline-to-endpoint changes in prolactin, fasting glucose, fasting total cholesterol, uric acid, and the hepatic enzymes aspartate transaminase and alanine transaminase were significantly greater in patients treated with olanzapine relative to patients receiving placebo. Olanzapine was effective in the treatment of bipolar mania in adolescent patients. Patients treated with olanzapine, however, had significantly greater weight gain and increases in the levels of hepatic enzymes, prolactin, fasting glucose, fasting total cholesterol, and uric acid.

Olanzapine versus placebo in adolescent mania

Objective: This study evaluated the efficacy and safety of olanzapine(OLA)for the treatment of acute mania in adolescents with bipolar disorder. Methods: In this 3-week randomized, double-blind trial, pats. 13–17 years of age with a manic or mixed episode received either OLA (2.5–20mg/day; N=107) or placebo (N=54). The primary efficacy analysis was mean change from baseline-to-endpoint in Young Mania Rating Scale (YMRS) total score. Results: Signif. greater reductions in YMRS total score were observed for OLA vs. plac. (-17.7 vs. -10.0, p<.001; ES, 0.84). OLA treatment was associated with higher rates of response and remission (44.8% vs. 18.5%; p=.002, and 35.2% vs. 11.1%; p=.001) and shorter times to reach those criteria (p=.003 and p=.002) vs. plac. Somnolence, sedation, increased appetite, weight gain were treatment-emergent adverse events reported signif. more frequently among the OLA treatment group. The incidence of treatment-emergent weight gain ≥7% (41.9% vs. 1.9%; p<.001), and hyperprolactinemia were signif. greater for OLA relative to placebo. The incidence of treatment-emergent abnormal levels of glucose, cholesterol, triglycerides, or uric acid did not differ signif. between treatment groups. Other safety information including lab values and vital signs will be presented. Conclusions: Olanzapine was effective in the treatment of adolescents with bipolar mania. The types of adverse events appeared to be similar to those in adults, but may have differed in magnitude.

Weight Changes During Treatment With Olanzapine in Older Adult Patients With Dementia and Behavioral Disturbances

Treatment-emergent weight gain has been reported in younger patients receiving atypical antipsychotics, but less is known about weight gain in adults aged 65 years and older. This was a post hoc analysis of 1267 patients with dementia and behavioral disturbances treated with olanzapine (1 to 20 mg/d) in clinical trials, most of whom were underweight (body mass index <18.5 kg/m2) or of normal weight (body mass index, 18.5-24.9 kg/m2) at baseline. Weight changes over the first 20 weeks of treatment in olanzapine-treated patients, as estimated by a repeated measures analysis model, were significantly greater in the combined categories of underweight and normal weight (1.22 kg and 1.29 kg, respectively) versus overweight and obese (0.56 kg and 0.53 kg, respectively; P = .006). The estimated probability of gaining more than 7% of initial body weight was significantly greater in patients treated with olanzapine versus active comparator (P < .001) or placebo (P < .001). Weight gain in olanzapine-treated older patients with dementia and behavioral disturbances was significantly greater in individuals with a baseline body mass index of less than 25 kg/m2.

Clozapine enhances differentiation of adipocyte progenitor cells

A common side effect of antipsychotic treatment with atypical neuroleptics is a significant weight gain. This stabilizes in the short to medium term but with clozapine often continues beyond the first year leading to weight gains of up to 20–30 kg.1 This increase in weight is significantly correlated with clinical improvements, but the causes of treatment-emergent weight gain in schizophrenic patients are currently unknown. It is assumed that the perception of satiety is impaired, as patients experience a lower suppression of appetite after meals when consuming atypical neuroleptics.1 Supporting this hypothesis, clozapine has been found to increase serum leptin levels within days after starting treatment.2 Unfortunately, strict food reduction shows little success indicating that central pathways rather than peripheral actions of atypical neuroleptics or their mediators are involved in weight gain. Evaluation of the body composition revealed an increase in body fat under antipsychotic treatment with atypical antipsychotic drugs,3 and blockade of serotonin and histamine receptors by these drugs was previously shown to be associated with weight gain.4 In addition to enhanced lipid accumulation in adipocytes, enhanced differentiation of preadipocytes can increase body fat. Our study addresses the question of whether clozapine-induced weight gain is based on neo-formation of adipose tissue from precursor cells. All experiments had been approved by the Ethical Committee of the Aachen University of Technology.

Is Hunger a Driver of the Cognitive Development?

In their recent paper, Elman et al, 2006 nicely summarized the possible associations between food intake and reward mechanisms in patients with schizophrenia. They hypothesized that schizophrenic patients may have a predilection for excessive consumption of fast food-type nutrition owing to functionally impaired neural substrate comprising homeostatic and reward mechanisms. In our view, recent neuroendocrine findings in basic research can also help us to understand these complex mechanisms better. Diano et al, 2006 have found evidence that a hormone produced in the stomach directly stimulates the higher brain functions of spatial learning and memory development. The study showed that the hormone ghrelin, previously associated with growth hormone release and appetite, has a direct, rapid, and powerful influence on the hippocampus, a higher brain region critical for learning and memory: peripheral ghrelin can enter the hippocampus and bind to local neurons promoting alterations in connections between nerve cells in mice and rats. Ghrelin is synthesized principally in the stomachFthe first hormone found to stimulate appetite and food intake in humans, a peptide that has a role in the regulation of feeding behavior. Ghrelin also provides a peripheral signal to the hypothalamus to stimulate food intake and adiposity. This important finding can have a large impact on how we see the development of cognitive processes, especially in the light of the treatment efforts of such disabling conditions like schizophrenia. Atypical antipsychotics are widely used in the treatment of schizophrenia (Lieberman et al, 2005). Considerable evidence suggests that atypical antipsychoticassociated weight gain seems positively correlated with clinical and cognitive improvement of schizophrenic patients (Ascher-Svanum et al, 2005). During treatment with olanzapine, weight gain may be observed, frequently with an increase in appetite, but it is not clear whether or not this increase fully explains the weight gain. Antipsychoticrelated weight gain is consistent across geographies, although the extent is variable (Sussman, 2001). On the other hand, some studies found correlation between ghrelin levels and atypical antipsychotic treatment: for example, the concentration of circulating ghrelin is significantly increased during olanzapine treatment (Murashita et al, 2005). Assessment of the relationship between atypical antipsychotic use, weight gain, and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Can it be possible that the positive correlation between treatment-related weight gain and cognitive improvement is a result of the increased ghrelin production? It is possible that those antipsychotics, where treatment-emergent weight gain is observed, may have more impact on cognitive improvements of the patients as well. Polimeni and Reiss (2003) and Karagianis (2003) have commented about how schizophrenia fits with the theory of evolution. Natural selection suggests that traits are preserved and perpetuated if they offer some survival advantage. The paranoia associated with schizophrenia can actually be seen as an advantage in a hostile environment. If this weight gain–cognition relationship hypothesis is valid, it can also be explained by the evolution theory of natural selection. Simply put, those individuals who had enough food around did not need to be clever enough to seek more nutritive territories. Those who were hungry and were clever enough to survive despite this might pass on their cognitive advantages to their descendents. Furthermore, those who had to fight for food everyday had probably less effective sleep at night, which is also linked to higher ghrelin levels (Copinschi, 2005). In this aspect, besides driving other advantages, hunger was probably a driver of the evolution of the cognitive processes, and ghrelin may have been the mediator. Of course, we do not state here that overweight people are somehow smarter, because it is not the case and it is easy to explain: hunger is just increasing ghrelin level, which may boost the brain power, and the urge to find food also creates more competitive skills. However, obesity is controlled by many other factors, for example, physical activity level, Online publication: 31 May 2006 at http://www.acnp.org/citations/ Npp053106060193/default.pdf Received 23 March 2006; revised 9 May 2006; accepted 25 May 2006 *Correspondence: Dr T Treuer, Neuroscience Research, Lilly Hungaria, H-1075 Budapest, Hungary, Tel: + 36304752080, E-mail: treuert@lilly.com Neuropsychopharmacology (2006) 31, 2326–2327 & 2006 Nature Publishing Group All rights reserved 0893-133X/06 $30.00

Genetics of Antipsychotic Treatment Emergent Weight Gain in Schizophrenia

Classic and modern antipsychotics can induce substantial weight gain causing diabetes, lipid abnormalities and psychological distress. Treatment emergent weight gain varies within the broad class of antipsychotics; however, an individual's propensity to develop weight gain largely depends on genetic factors. The first part of this review highlights current ideas and concepts related to antipsychotic-induced weight gain, including principles on energy homeostasis. The second part summarizes genetic findings emphasizing studies published after 2003 as prior studies have been reviewed in detail elsewhere. Candidate gene studies have produced significant findings in the 5-hydroxytryptamin 2C (5HT2C) and adrenergic alpha2a (ADRalpha2a) receptor genes, as well as in the leptin, guanine nucleotide binding protein (GNB3) and synaptomal-associated protein 25kDa (SNAP25) genes. Results from genome-wide association and linkage studies point to several chromosomal regions (e.g., 12q24) and some specific genes (e.g., promelanin concentrating hormone [PMCH], polycyctic kidney and hepatic disease 1 [PKHD1], peptidylglycine alpha-amidating monooxygenase [PAM]). However, more efforts are needed before risk prediction and personalized medicine can be made available for antipsychotic-induced weight gain.

Weight Management Program for Treatment-Emergent Weight Gain in Olanzapine-Treated Patients With Schizophrenia or Schizoaffective Disorder

The main objective was to assess the efficacy of a weight management program designed for outpatients taking olanzapine for schizophrenia or schizoaffective disorder and to compare these patients with a randomized control group. The effects of the weight management program were also assessed with regard to safety and quality of life. Forty-eight patients were enrolled in a 12-week, randomized, multicenter weight management study. Thirty-three patients were randomly allocated to an intervention group in which they received olanzapine within a weight management program. Fifteen patients were allocated to a control group in which they were given olanzapine treatment as usual outpatients. Weight, body mass index (BMI), and measurements of safety and quality of life were evaluated. The study was conducted from January 7, 2003, to September 16, 2003. Thirty-six patients (75%) completed this study. We found significant differences in weight (-3.94 +/- 3.63 kg vs. -1.48 +/- 1.88 kg, p = .006) and BMI (-1.50 +/- 1.34 vs. -0.59 +/- 0.73, p = .007) change from baseline to endpoint between the intervention and control groups, respectively. Significant differences in weight reduction were initially observed at week 8 (p = .040). No significant differences were found with regard to the safety outcomes. When the ratio of low-density lipoproteins to high-density lipoproteins was calculated, change from baseline was greater in the intervention group than the control group (-0.19 vs. -0.04), but the difference was not statistically significant (p = .556). After the completion of the weight management program, there was a trend toward statistical difference in the physical health score changes between the weight management and control groups (1.12 in the intervention group vs. -0.93 in the control group, p = .067). The weight management program was effective in terms of weight reduction in patients with schizophrenia or schizoaffective disorder taking olanzapine and was also found to be safe in terms of psychiatric symptoms, vital signs, and laboratory data. In addition, such a weight management program might improve quality of life in patients with schizophrenia or schizoaffective disorder with respect to their physical well-being.

Antipsychotics and the risk of diabetes: A general data review

Recently, attention has focused on a potential link between schizophrenia and diabetes, with speculation that this potential associationis stronger in patients who are prescribed atypical antipsychotics. Pharmacoepidemiological studies can help to evaluate this potential association. Source data on the incidence of diabetes in patients treated with antipsychotics is available in the FDA MedWatch database, prescription claims databases and other patient registries. These data indicate that antipsychotic drugs may increase the risk of developing diabetes and that there may be an interaction with age. However, current data are insufficient to accurately assess potential differences in the risk of diabetes between users of individual antipsychotic medications. In addition, antipsychotic treatment-emergent diabetes has several distinct features, notably relating to age of onset, gender ratio, rate of deterioration of glycaemic control, and independence from initial treatment emergent weight gain. Nonetheless, guidelines for the control of risk factors for diabetes developed for the general population appear to be applicable to patients with schizophrenia.

Weight gain as a prognostic indicator of therapeutic improvement during acute treatment of schizophrenia with placebo or active antipsychotic

Treatment-emergent weight gain may be a general marker of therapeutic improvement, even when improvements occur in the absence of active antipsychotic treatment. To investigate the association between treatment-emergent weight gain and therapeutic improvement across placebo and active treatments, and to examine the association between reported treatment-emergent weight changes and the treatments' reported efficacy. Data from a randomized, double-blind trial comparing treatment of schizophrenia with placebo and olanzapine were used to correlate weight change and change in psychopathology. Additionally, we correlated effect sizes of the efficacy of clozapine, olanzapine, risperidone, haloperidol and placebo (reported in meta-analytical reviews), with their reported weight changes. Weight gain significantly correlated with clinical improvements for placebo and olanzapine. The correlation between treatments' efficacy and corresponding weight changes was high (r 0.88, p 0.05). Treatment-emergent weight gain appears to be an important marker of symptom reduction, and may not be exclusively attributable to pharmacological perturbations.

Acute weight gain, gender, and therapeutic response to antipsychotics in the treatment of patients with schizophrenia

BackgroundPrevious research indicated that women are more vulnerable than men to adverse psychological consequences of weight gain. Other research has suggested that weight gain experienced during antipsychotic therapy may also psychologically impact women more negatively. This study assessed the impact of acute treatment-emergent weight gain on clinical and functional outcomes of patients with schizophrenia by patient gender and antipsychotic treatment (olanzapine or haloperidol).MethodsData were drawn from the acute phase (first 6-weeks) of a double-blind randomized clinical trial of olanzapine versus haloperidol in the treatment of 1296 men and 700 women with schizophrenia-spectrum disorders. The associations between weight change and change in core schizophrenia symptoms, depressive symptoms, and functional status were examined post-hoc for men and women and for each medication group. Core schizophrenia symptoms (positive and negative) were measured with the Brief Psychiatric Rating Scale (BPRS), depressive symptoms with the BPRS Anxiety/Depression Scale and the Montgomery-Asberg Depression Rating Scale, and functional status with the mental and physical component scores on the Medical Outcome Survey-Short Form 36. Statistical analysis included methods that controlled for treatment duration.ResultsWeight gain during 6-week treatment with olanzapine and haloperidol was significantly associated with improvements in core schizophrenia symptoms, depressive symptoms, mental functioning, and physical functioning for men and women alike. The conditional probability of clinical response (20% reduction in core schizophrenia symptom), given a clinically significant weight gain (at least 7% of baseline weight), showed that about half of the patients who lost weight responded to treatment, whereas three-quarters of the patients who had a clinically significant weight gain responded to treatment. The positive associations between therapeutic response and weight gain were similar for the olanzapine and haloperidol treatment groups. Improved outcomes were, however, more pronounced for the olanzapine-treated patients, and more olanzapine-treated patients gained weight.ConclusionsThe findings of significant relationships between treatment-emergent weight gain and improvements in clinical and functional status at 6-weeks suggest that patients who have greater treatment-emergent weight gain are more likely to benefit from treatment with olanzapine or haloperidol regardless of gender.