Second-generation Antipsychotics Olanzapine Research Articles

Second-generation antipsychotic olanzapine attenuates behavioral and prefrontal cortex synaptic plasticity deficits in a neurodevelopmental schizophrenia-related rat model

Second-generation antipsychotics are the drugs of choice for the treatment of neurodevelopmental-related mental diseases such as schizophrenia. Despite the effectiveness of these drugs to ameliorate some of the symptoms of schizophrenia, specifically the positive ones, the mechanisms beyond their antipsychotic effect are still poorly understood. Second-generation antipsychotics are reported to have anti-inflammatory, antioxidant and neuroplastic properties. Using the neonatal ventral hippocampus lesion (nVHL) in the rat, an accepted schizophrenia-related model, we evaluated the effect of the second-generation antipsychotic olanzapine (OLZ) in the behavioral, neuroplastic, and neuroinflammatory alterations exhibited in the nVHL animals. OLZ corrected the hyperlocomotion and impaired working memory of the nVHL rats but failed to enhance social behavior disturbances of these animals. In the prefrontal cortex (PFC), OLZ restored the pyramidal cell structural plasticity in the nVHL rats, enhancing the dendritic arbor length, the spinogenesis and the proportion of mature spines. Moreover, OLZ attenuated astrogliosis as well as some pro-inflammatory, oxidative stress, and apoptosis-related molecules in the PFC. These findings reinforce the evidence of anti-inflammatory, antioxidant, and neurotrophic mechanisms of second-generation antipsychotics in the nVHL schizophrenia-related model, which allows for the possibility of developing more specific drugs for this disorder and thus avoiding the side effects of current schizophrenia treatments.

Haloperidol, Olanzapin, Risperidon ve Klozapinin Organ Banyosu Sistemi Kullanılarak Fare Detrusor Kası Üzerine Etkileri

Objective: The bladder normally shows no contractility or activity during the filling phase. In the overactive urinary bladder, spontaneous contractions and detrusor instability are seen in the filling phase and urinary incontinence occurs. This study aims to demonstrate the effects of first-generation antipsychotic haloperidol and second-generation antipsychotics olanzapine, risperidone, and clozapine on mice isolated bladder using the organ bath system. Materials and Methods: 63 male inbred mice were divided as saline, haloperidol 0.125 mg/kg, haloperidol 0.25 mg/kg, olanzapine 1 mg/kg, olanzapine 2 mg/kg, risperidone 0.25 mg/kg, risperidone 0.5 mg/kg, clozapine 1.25 mg/kg and clozapine 2.5 mg/kg groups. Mice were treated with drugs for 21 days. Then, the effects of drugs were investigated on isoproterenol-induced relaxation responses of carbachol-induced contractions in isolated detrusor strips. Results: We showed that carbachol-induced contractions relaxed by isoproterenol and papaverine in mice detrusor strips obtained from olanzapine, risperidone, and clozapine treated groups. There were no significant differences in KCl-induced contractile responses among the groups.Conclusion: Olanzapine, risperidone, and clozapine increased the isoproterenol-induced relaxations of the detrusor muscle that increased the bladder capacity. These drugs might be clinically useful for the treatment of overactive urinary bladder in patients that should use antipsychotic drugs.

Recent Onset Cardiometabolic Effects amongst Patients Started on Psychotropics: A Cohort Study

Introduction: Mortality rates in schizophrenia patients due to cardiovascular events are reported to be more than the general population. Dyslipidaemia, obesity, diabetes, and hypertension are some of the common illnesses these patients are vulnerable to develop. The drugs which are used to treat schizophrenia and other related disorders i.e. antipsychotics causes increase in weight, dyslipidaemia and insulin resistance in some patients. Some agent’s i.e. Second Generation Antipsychotics (SGA) cause more of the above mentioned symptoms and than others agent’s i.e. First Generation Antipsychotics (FGA). The novelty of the study includes the emergence of Metabolic syndrome (MetS) in drug naïve or drug free patients who were prescribed trifluoperazine and olanzapine and comparative study of them. Aim: To assess the emergence of MetS in drug naïve patients of schizophrenia after the administration of trifluoperazine-FGA and olanzapine-SGA. Materials and Methods: A cohort study was conducted from May 2019 to March 2021, in the Department of Psychiatry, Shyam Shah Medical College, and Rewa, Madhya Pradesh, India. Study was started after the clearance from institutional ethical committee. The study included 41 drug naïve indoor and outdoor patients, diagnosed as schizophrenia according to International Classification of Diseases 10 Diagnostic Criteria for Research (ICD 10 DCR). The patients were divided into two groups, one group was prescribed FGA trifluoperazine and other was prescribed SGA olanzapine. Twenty patients were prescribed olanzapine and 21 patient’s trifluoperazine. Metabolic parameters were taken before onset of drug treatment therapy, after two and four months respectively. The patients were given medications for four months. The changes in metabolic parameters i.e., waist circumference, blood pressure, Fasting Blood Sugar (FBS), triglycerides, and Low HDL (High Density Lipoprotein) were compared using unpaired student’s t-test and repeated measure Analysis of Variance (ANOVA) with p-value <0.05 considered as significant. Results: It was found that out of total 41 patient, 4 patients (19.4%) and 12 patients (60%) patients prescribed trifluoperazine and olanzapine respectively developed Mets after four months of antipsychotic medication. Also, there was a significant change in various parameters of MetS in both groups as seen in repeated measure ANOVA. Conclusion: SGA cause significantly more changes in the metabolic parameters and compared to the FGA, increasing the likelihood of developing MetS and associated disorders like cerebrovascular accidents and diabetes mellitus type-II.

APA Releases Practice Guideline on Schizophrenia

APA Releases Practice Guideline on Schizophrenia

Off-Label Use of Second-Generation Antipsychotics in Borderline Personality Disorder: A Survey of Italian Psychiatrists.

The guidelines for borderline personality disorder (BPD) treatment suggest non-pharmacological treatment as the first option, but second-generation antipsychotics (SGAs) are among the overprescribed medications. This study aimed to explore Italian psychiatrists' attitudes toward off-label use of SGAs in BPD. A randomly selected sample of Italian psychiatrists completed a questionnaire regarding off-label prescription of SGAs. Most respondents reported the off-label use of SGAs. Among the reasons supporting the prescription of SGAs, the presence of strong published data was the most determining factor (51.5%). The SGA olanzapine is considered the most appropriate, followed by quetiapine and aripiprazole. Although off-label prescription of SGAs represents a common clinical practice in accordance with a worldwide trend, the use of long-acting injection formulations was considered inappropriate by 69% of psychiatrists in our sample. Our results reiterate the discrepancy between everyday clinical practice and international recommendations, and show how relevant the literature is in off-label drug prescription.

Effects of second-generation antipsychotics on human subcutaneous adipose tissue metabolism

ObjectiveMetabolic syndrome is prevalent in up to 50% of schizophrenia patients, which reduces their quality of life and their compliance with the treatment. It is unclear whether metabolic adverse effects of these agents are due to their direct effect on insulin-sensitive tissues or are secondary to increased adiposity. The study aimed to investigate the direct effects of the second-generation antipsychotics olanzapine and aripiprazole on human subcutaneous adipose tissue and isolated adipocyte metabolism. MethodsAbdominal subcutaneous adipose tissue needle biopsies were taken from 72 healthy subjects (49 F/23 M; age: 19–78 yr; BMI: 20.0–35.6 kg/m2). Isolated adipocytes or adipose tissue were respectively pre-incubated short- (30 min) and long-term (24 h, 72 h) with or without olanzapine (0.004 μM – 20 μM) and aripiprazole (0.002 μM – 100 μM). Pre-incubated adipose tissue was then snap-frozen for mRNA expression analysis of adipokines genes and genes involved in inflammation, adipogenesis, and mitochondrial function. Isolated adipocytes were used to measure basal and insulin-stimulated glucose uptake and lipolysis. ResultsAcute treatment with a therapeutic concentration of olanzapine decreases basal lipolysis in isolated adipocytes; this effect was not observed after long-term incubation with the drug. Supra-therapeutic concentration of aripiprazole reduced basal and insulin-stimulated glucose uptake after short- and long-term pre-incubation. Both drugs at supra-therapeutic concentrations downregulated the expression of the pro-inflammatory cytokines IL6 and IL1B genes after 72 h incubation. Similarly, supra-therapeutic concentrations of both drugs and therapeutic concentration of olanzapine, reduced the expression of PPARGC1A, PDK4, and CPT1B genes involved in the regulation of mitochondrial functions. Neither of the antipsychotics affected the expression of the main adipokines LEP and ADIPOQ, genes involved in the regulation of lipid metabolism, LPL and FASN, nor the master adipogenesis regulator, PPARG. ConclusionTherapheutic concentrations of olanzapine and aripiprazole have a moderate direct effect on adipocyte lipid and glucose metabolism, respectively. At supra-therapeutic concentrations, both of the antipsychotics seem to act as anti-inflammatory agents and mildly suppressed genes involved in the regulation of mitochondrial functions, which could potentially contribute to metabolic adverse effects. Alternatively, second-generation antipsychotics could induce metabolic side effects via acting on other insulin-sensitive tissues and central nervous system.

Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity

D-aspartate levels in the brain are regulated by the catabolic enzyme D-aspartate oxidase (DDO). D-aspartate activates NMDA receptors, and influences brain connectivity and behaviors relevant to schizophrenia in animal models. In addition, recent evidence reported a significant reduction of D-aspartate levels in the post-mortem brain of schizophrenia-affected patients, associated to higher DDO activity. In the present work, microdialysis experiments in freely moving mice revealed that exogenously administered D-aspartate efficiently cross the blood brain barrier and stimulates L-glutamate efflux in the prefrontal cortex (PFC). Consistently, D-aspartate was able to evoke L-glutamate release in a preparation of cortical synaptosomes through presynaptic stimulation of NMDA, mGlu5 and AMPA/kainate receptors. In support of a potential therapeutic relevance of D-aspartate metabolism in schizophrenia, in vitro enzymatic assays revealed that the second-generation antipsychotic olanzapine, differently to clozapine, chlorpromazine, haloperidol, bupropion, fluoxetine and amitriptyline, inhibits the human DDO activity. In line with in vitro evidence, chronic systemic administration of olanzapine induces a significant extracellular release of D-aspartate and L-glutamate in the PFC of freely moving mice, which is suppressed in Ddo knockout animals. These results suggest that the second-generation antipsychotic olanzapine, through the inhibition of DDO activity, increases L-glutamate release in the PFC of treated mice.

First and second generation antipsychotics differentially affect structural and functional properties of rat hippocampal neuron synapses

The therapy of patients suffering the psychiatric disorder schizophrenia requires the usage of antipsychotic drugs that are classified into two different groups, the first-generation (FGAs) and the second-generation antipsychotics (SGAs).This study compares the effects of the two FGAs haloperidol and flupentixol with those of the SGA olanzapine on synapse formation and synaptic activity of embryonic rat hippocampal neurons. To this end, the development of perineuronal nets (PNNs), the formation of synapses and the resulting spontaneous network activity under control and treatment conditions were studied using an indirect co-culture system of neurons and astrocytes in completely defined media.The number and extent of PNNs that consist of extracellular matrix superstructures surrounding synapses was not altered in hippocampal neurons by exposure to antipsychotic drugs. In contrast treatment of hippocampal neurons with haloperidol led to a slight decrease whereas olanzapine induced a significant increase of the number of structural synapses after 13days. This differential effect concerning synapse numbers was also reflected in the spontaneous activity of neuronal networks, as monitored on multielectrode arrays (MEAs). In that context, application of haloperidol reduced while olanzapine significantly enhanced network activity. Unexpectedly, flupentixol that is regarded as an FGA caused similar effects than the SGA olanzapine in that it augmented synapse number as well as network activity. Our pilot study provides a proof of concept that the neuron-astrocyte co-culture model can be used to investigate the impact of antipsychotics on pivotal parameters of neuronal cell biology. Thereby, it may support the comparative analysis of antipsychotics applied in the therapy of schizophrenia.

Metabolic Impairments Precede Changes in Hunger and Food Intake Following Short-Term Administration of Second-Generation Antipsychotics

The second-generation antipsychotics (SGAs) are associated with weight gain and an increased incidence of metabolic diseases. The metabolic impairments are assumed a consequence of increased body adiposity secondary to central nervous system-associated increases in food intake. We have previously reported that, independent of weight gain, 9 days of olanzapine administration to control subjects is associated with insulin resistance and increases in postprandial levels of insulin and glucagon-like peptide 1 to a mixed meal challenge. This current report describes previously unpublished data on the effects of the SGAs olanzapine and aripiprazole compared with placebo on detailed hunger and satiety responses over the 12-day inpatient evaluation as well as postprandial ghrelin and leptin responses prior to and following administration of the 2 SGAs. We found no changes in hunger, fullness, or in the orexigenic hormone ghrelin or satiety hormone leptin, consistent with our previous report indicating no change in weight during this study. The results indicate that the SGAs are associated with metabolic changes prior to changes in hunger, satiety, and food intake, and this temporal separation suggests that there are differential mechanisms mediating SGA-associated changes in metabolism and food intake.

Weight gain and obesity in schizophrenia: epidemiology, pathobiology, and management.

To review recent advances in the epidemiology, pathobiology, and management of weight gain and obesity in patients with schizophrenia and to evaluate the extent to which they should influence guidelines for clinical practice. A Medline literature search was performed to identify clinical and experimental studies published in 2005-2014 decade. Weight gain and obesity increase the risk of adult-onset diabetes mellitus and cardiovascular disorders, non-adherence with pharmacological interventions, quality of life, and psychiatric readmissions. The etiology includes adverse effects of antipsychotics, pretreatment/premorbid genetic vulnerabilities, psychosocial and socioeconomic risk factors, and unhealthy lifestyle. Patients with schizophrenia have higher intake of calories in the form of high-density food and lower energy expenditure. The inverse relationship between baseline body mass index and antipsychotic-induced weight gain is probably due to previous antipsychotic exposure. In experimental models, the second-generation antipsychotic olanzapine increased the orexigenic stimulation of hypothalamic structures responsible for energy homeostasis. The management of weight gain and obesity in patients with schizophrenia centers on behavioural interventions using caloric intake reduction, dietary restructuring, and moderate-intensity physical activity. The decision to switch antipsychotics to lower-liability medications should be individualized, and metformin may be considered for adjunctive therapy, given its favorable risk-benefit profile.

Electrophysiological Neuroimaging using sLORETA Comparing 22 Age Matched Male and Female Schizophrenia Patients.

The purpose of this electrophysiological neuroimaging study was to provide a deeper mechanistic understanding of both olanzapine and risperidone pharmacodynamics relative to gender. In doing so, we age-matched 22 men and women and evaluated their resting-state EEG recordings and later used standard low resolution brain Electrotomography to visualize the differences in brain activity amongst the two patient groups. In this investigation, electroencephalogram (EEG) data were analyzed from male and female schizophrenia patients treated with either olanzapine or risperidone, both atypical antipsychotics, during their in-patient stay at the Department of Psychiatry. Twenty-two males and females were age-matched and EEG recordings were analyzed from 19 Ag/AgCl electrodes. Thirty-seconds of resting EEG were spectrally transformed in standardized low resolution electromagnetic tomography (sLORETA). 3D statistical non-paramentric maps for the sLORETA Global Field Power within each band were finally computed. The results indicated that, relative to males patients, females schizophrenia patients had increased neuronal synchronization in delta frequency, slow-wave, EEG band located in the dorsolateral prefrontal cortex, within the middle frontal gyrus (t= -2.881, p < 0.03580). These findings suggest that females experience greater dopamine (D2) receptor and serotonin (5-HT2) receptor neuronal blockade relative to age-matched males. Further, our finding provided insight to the pharmacodynamics of second-generation antipsychotics olanzapine and risperidone. When compared to male patients, female patients, suffering from schizophrenia, have D2 and 5-HT2 receptors that are blocked more readily than age-matched male schizophrenia patients. Clinically, this may translate into a quicker time to treatment-response in females as compared to male patients.

The antipsychotic olanzapine interacts with the gut microbiome to cause weight gain in mouse.

The second-generation antipsychotic olanzapine is effective in reducing psychotic symptoms but can cause extreme weight gain in human patients. We investigated the role of the gut microbiota in this adverse drug effect using a mouse model. First, we used germ-free C57BL/6J mice to demonstrate that gut bacteria are necessary and sufficient for weight gain caused by oral delivery of olanzapine. Second, we surveyed fecal microbiota before, during, and after treatment and found that olanzapine potentiated a shift towards an “obesogenic” bacterial profile. Finally, we demonstrated that olanzapine has antimicrobial activity in vitro against resident enteric bacterial strains. These results collectively provide strong evidence for a mechanism underlying olanzapine-induced weight gain in mouse and a hypothesis for clinical translation in human patients.

Atypical antipsychotics induce both proinflammatory and adipogenic gene expression in human adipocytes in vitro

Schizophrenia requires lifelong treatment, potentially causing systemic changes in metabolic homeostasis. In the clinical setting, antipsychotic treatment may differentially lead to weight gain among individual patients, although the molecular determinants of such adverse effects are currently unknown. In this study, we investigated changes in the expression levels of critical regulatory genes of adipogenesis, lipid metabolism and proinflammatory genes during the differentiation of primary human adipose-derived stem cells (ADSCs). These cells were isolated from patients with body mass indices <25 and treated with the second-generation antipsychotics olanzapine, ziprasidone, clozapine, quetiapine, aripiprazole and risperidone and the first-generation antipsychotic haloperidol. We found that antipsychotics exhibited a marked effect on key genes involved in the regulation of cell cycle, signal transduction, transcription factors, nuclear receptors, differentiation markers and metabolic enzymes. In particular, we observed an induction of the transcription factor NF-KB1 and NF-KB1 target genes in adipocytes in response to these drugs, including the proinflammatory cytokines TNF-α, IL-1β, IL-8 and MCP-1. In addition, enhanced secretion of both IL8 and MCP-1 was observed in the supernatant of these cell cultures.In addition to their remarkable stimulatory effects on proinflammatory gene transcription, three of the most frequently prescribed antipsychotic drugs, clozapine, quetiapine and aripiprazole, also induced the expression of essential adipocyte differentiation genes and the adipocyte hormones leptin and adiponectin, suggesting that both glucose and fat metabolism may be affected by these drugs. These data further suggest that antipsychotic treatments in patients alter the gene expression patterns in adipocytes in a coordinated fashion and priming them for a low-level inflammatory state.

The prevalence of antipsychotic polypharmacy in schizophrenic patients discharged from psychiatric units in Poland

BackgroundThe term antipsychotic polypharmacy (APP) refers to the concurrent use of two or more antipsychotic drugs in schizophrenia. The aim of this study was to investigate the range of APP in schizophrenic patients discharged from psychiatric units in Poland, and to determine its demographical and clinical correlates. MethodsData on the pharmacological treatment of 207 patients with a diagnosis of schizophrenia, discharged from six psychiatric hospitals from September–December 2011 were recorded by experienced psychiatrists. Clinical and demographical information was obtained on each patient. The severity of symptoms at admission, and their improvement during hospitalization were assessed using the Clinical Global Impression Scale. ResultsAt discharge, 52.7% of the patients were prescribed one, 42.5% two and 4.8% three antipsychotic drugs (AP). When two AP were applied, it was usually a combination of two second generation antipsychotics (SGA) (46%), or of both first generation antipsychotics (FGA) and SGA (48%). The SGA's olanzapine and risperidone were those most commonly prescribed. Patients treated with two or more AP had a higher number of previous hospitalizations than patients receiving antipsychotic monotherapy. Mood stabilizers were prescribed for nearly one third of the patients, while antidepressants and benzodiazepines were prescribed for fewer than 10%. ConclusionsThe prevalence of polypharmacy in Poland is similar to that reported in other countries. This may suggest that, in a substantial proportion of schizophrenic patients clinical response to the antipsychotic monotherapy is unsatisfactory. Further studies focusing on the efficacy and safety of strategies in the treatment of patients with schizophrenia not responding to antipsychotic monotherapy are necessary.

Olanzapine and sibutramine have opposing effects on the motivation for palatable food

Both olanzapine and sibutramine target serotonergic and noradrenergic neurotransmission and influence body weight, but in opposite ways. The second-generation antipsychotic olanzapine, an antagonist at serotonergic and noradrenergic receptors, frequently induces weight gain as a side-effect, whereas sibutramine, a noradrenaline/serotonin reuptake inhibitor, is known as a weight-reducing agent. To investigate whether altered motivation for palatable food influences the effect of these drugs on body weight, we determined their effects on responding for sucrose pellets under a progressive ratio schedule of reinforcement in rats. We found that a low dose of olanzapine selectively increased responding to sucrose, without affecting free-feeding intake of sucrose. In contrast, sibutramine dose-dependently reduced responding to sucrose and similarly reduced free-feeding intake. Furthermore, coadministration of a dose of sibutramine that failed to affect responding to sucrose when administered alone prevented the increase in motivation by the effective dose of olanzapine. These data show that increased motivation for palatable food is likely to be a significant contributor to olanzapine-induced weight gain. Moreover, the ability of sibutramine to reduce this motivation for palatable food may play an important role in the efficacy of sibutramine as an add-on treatment to counteract olanzapine-induced weight gain.

Pharmacoepidemiological study of antipsychotics in the psychiatry unit of a tertiary care hospital: A retrospective descriptive analysis

Aims: Pharmacoepidemiology is an interface discipline that studies the interactions between drugs and populations. Pharmacoepidemiological studies reveal the differences that exist between the conditions of premarketing trials (done on a limited sample population) and those of actual practice. Antipsychotic prescribing patterns have changed globally over the last few years. Hence, we wanted to observe the prescribing pattern of antipsychotics in our hospital and assess the rationality of the prescriptions and the prevalence of antipsychotic usage in the community. Materials and Methods: This was a retrospective observational analysis of case records of patients receiving antipsychotic prescriptions in the psychiatry outpatient clinic of a tertiary care hospital during the period 1 st January 2006 to 31 st December 2006. We studied the following parameters: Antipsychotic drugs prescribed, completeness and rationality of prescriptions, WHO prescribing indicators, defined daily dose (DDD)/1000/day (DID), prescribed daily dose (PDD), and the PDD to DDD ratio. Results: Antipsychotics were prescribed in 32.88% patients (olanzapine: 65.66%, risperidone: 19.19%, aripiprazole: 7.07%, others: 8.08%). The average number of drugs/prescription: 2.19, prescribing by generic names: 63.64%, prescribing from WHO essential medicines list (EML) and injections: 3.03%. There were no prescriptions for fixed-dose combinations (FDC). DID of antipsychotics: 0.0008 mg. PDD to DDD ratios Conclusion: The second-generation antipsychotics olanzapine, risperidone, and aripiprazole were the most commonly prescribed antipsychotics. Prescriptions were complete and without polypharmacy. Favorable and unfavorable outcomes were seen for two and three WHO prescribing indicators, respectively. Antipsychotic consumption in the community was low. Adequate dosing was seen for all antipsychotics, except quetiapine and haloperidol (where there was underdosing). Choosing drugs from the EML-based hospital formulary will decrease cost of therapy and promote rational use of medicines.

Comparative efficacy study of haloperidol, olanzapine and risperidone in delirium

Objective The objective of the study was to assess the efficacy and safety of second-generation antipsychotics olanzapine and risperidone vs. haloperidol in patients of delirium admitted to medical and surgical wards. Methods Prospective follow-up single-blind randomized controlled trials were performed. Consecutive patients with delirium referred to the consultation–liaison psychiatry team were eligible for the study. The study sample comprised 64 patients, with 20 subjects in the haloperidol group, 21 subjects in the risperidone group and 23 subjects in the olanzapine group. A flexible dose regimen (haloperidol −0.25 to 10 mg; risperidone −0.25 to 4 mg; olanzapine −1.25 to 20 mg) was used. Delirium Rating Scale-Revised-98 (DRS-R98) was used as the primary efficacy measure, and mini mental status examination (MMSE) was used as a secondary efficacy measure. Results There was no significant difference in mean baseline DRS-R98 severity scores and MMSE scores between the three groups. However, there were a significant reduction in DRS-R98 severity scores and a significant improvement in MMSE scores over the period of 6 days, but there was no difference between the three groups. Four patients in the haloperidol group, six subjects in the risperidone group and two subjects in the olanzapine group experienced some side effects. Conclusions Risperidone and olanzapine are as efficacious as haloperidol in the treatment of delirium.

The CATIE and CUtLASS Studies in Schizophrenia

Numerous double-blind studies have compared second-generation antipsychotics (SGAs) with first-generation antipsychotics (FGAs), with most finding better efficacy and tolerability for SGAs. However, these 'efficacy trials' were generally short term and included only highly selected patients. Mostly because of weight gain and other metabolic effects of the SGAs, as well as their high acquisition price, the debate on the (cost) effectiveness of the SGAs led to two pragmatic clinical trials with no sponsorship by industry. Both trials had broad inclusion criteria and long follow-up, and tried to mimic clinical routine: CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) and CUtLASS (Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study). 1493 patients participated in CATIE, an 18-month, double-blind trial comparing the SGAs olanzapine, quetiapine, risperidone and ziprasidone with the FGA perphenazine. If efficacy or tolerability was insufficient, patients were re-randomized to a medication other than the one they previously received. Improvement of psychopathology and of quality of life was only moderate. Overall, 74% of patients discontinued study medication before 18 months, and the median time to discontinuation was 4.6 months. Aside from olanzapine (time to discontinuation 9.2 months), the other SGAs did not differ from each other or from perphenazine. Except for adverse effects as a reason for discontinuation, differences between the SGAs and the FGA were minimal. In CUtLASS, a 12-month open-label trial, 277 patients were randomized to receive an FGA or a SGA. Again, efficacy was rather similar between the two groups, with only limited improvement of psychopathology and quality of life. The authors of both trials concluded that SGAs do not markedly differ from FGAs regarding compliance, quality of life and effectiveness. The methodological problems of both trials have been discussed extensively. Patients had psychotic symptoms that were moderate in severity and were at least partially treatment resistant. The marginal improvement observed indicated that this population might not be appropriate to detect differences between FGAs and SGAs. Specific issues of CATIE include the exclusion of patients with tardive dyskinesia in the perphenazine arm and the high discontinuation rate. In CUtLASS, the concept of including 13 different FGAs and four SGAs in the respective classes was problematic. It is of interest that the most widely prescribed drug was sulpiride--of the FGAs, this is probably the 'most atypical' drug. Aside from the finding that the advantages of the SGAs are not as strong as early trials and marketing suggested or promised, the trials do not provide much helpful information regarding everyday practice. For tardive dyskinesia, no conclusions at all can be drawn. Similarly, methodological problems inhibited the detection of the other major advantage of the SGAs, i.e. the improved subjective well-being/quality of life while receiving these agents. It is well known that patients' and doctors' perspectives differ markedly, and the Quality of Life Scale (QLS), an expert-rated scale used in both trials, might not be sensitive enough to detect the subjective advantages reported by the majority of patients in other trials. CATIE and CUtLASS suggest that SGAs do not live up to all the previous expectations. However, even if most of these advantages are debatable, the lower risk of tardive dyskinesia and the better subjective effects should be strong enough reasons to favour these drugs. There is no single antipsychotic that is best for every schizophrenia patient, as individual responses differ markedly. For successfully individualized treatment, a multitude of antipsychotic options are needed.

Letter

Back to table of contents Previous article Next article LetterFull AccessLetterJohn M. Davis M.D.Stefan Leucht M.D.Ira D. Glick M.D.John M. Davis M.D.Search for more papers by this authorStefan Leucht M.D.Search for more papers by this authorIra D. Glick M.D.Search for more papers by this authorPublished Online:13 Jan 2015https://doi.org/10.1176/ps.2009.60.1.125aAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail CATIE Findings RevisitedTo the Editor: We applaud the special section in the May 2008 issue with commentaries interpreting findings from the landmark Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study ( 1 , 2 ). The introduction stated that "the literature suggests little evidence that, with the exception of clozapine, second-generation antipsychotics confer superior efficacy in ameliorating positive and negative symptoms and improving cognition or that they are more tolerable." Our meta-analysis ( 3 ) is one of ten published reports cited at the end of this statement. For the record, like the animals in Animal Farm, some second-generation antipsychotics—olanzapine, risperidone, and amisulpride—were shown in our analysis to be superior to first-generation antipsychotics. In addition, the report by Lieberman and colleagues ( 4 ) of results from phase I of CATIE showed that olanzapine was superior in efficacy to the first-generation antipsychotic perphenazine. We agree that clozapine is more effective than first-generation antipsychotics and that given the data currently available, the other second-generation antipsychotics—quetiapine, ziprasidone, and aripiprazole—have not been shown to have better efficacy than first-generation agents.

Antipsychotics May Influence Patients' Risk for Heart Disease

Antipsychotics May Influence Patients' Risk for Heart Disease