Long‐term effectiveness of oral second‐generation antipsychotics in patients with schizophrenia and related disorders: a systematic review and meta‐analysis of direct head‐to‐head comparisons

Second‐generation antipsychotics (SGAs) are recommended for maintenance treatment in schizophrenia. However, comparative long‐term effectiveness among SGAs is unclear. Here we provide a systematic review and meta‐analysis of randomized trials lasting ≥?6 months comparing SGAs head‐to‐head in schizophrenia and related disorders. The primary outcome was all‐cause discontinuation. Secondary outcomes included efficacy and tolerability, i.e., psychopathology, inefficacy‐related and intolerability‐related discontinuation, relapse, hospitalization, remission, functioning, quality of life, and adverse events. Pooled risk ratio and standardized mean difference were calculated using random‐effects models. Across 59 studies (N=45,787), lasting 47.4±32.1 weeks (range 24‐186), no consistent superiority of any SGA emerged across efficacy and tolerability outcomes. Regarding all‐cause discontinuation, clozapine, olanzapine and risperidone were significantly (p<0.05) superior to several other SGAs, while quetiapine was inferior to several other SGAs. As to psychopathology, clozapine and olanzapine were superior to several other SGAs, while quetiapine and ziprasidone were inferior to several other SGAs. Data for other efficacy outcomes were sparse. Regarding intolerability‐related discontinuation, risperidone was superior and clozapine was inferior to several other SGAs. Concerning weight gain, olanzapine was worse than all other compared non‐clozapine SGAs, and risperidone was significantly worse than several other SGAs. As to prolactin increase, risperidone and amisulpride were significantly worse than several other SGAs. Regarding parkinsonism, olanzapine was superior to risperidone, without significant differences pertaining to akathisia. Concerning sedation and somnolence, clozapine and quetiapine were significantly worse than some other SGAs. In summary, different long‐term SGA efficacy and tolerability patterns emerged. The long‐term risk‐benefit profiles of specific SGAs need to be tailored to individual patients to optimize maintenance treatment outcomes.     

Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders,bipolar disorder and major depressive disorder: a systematic review and meta‐analysis

Metabolic syndrome (MetS) and its components are highly predictive of cardiovascular diseases. The primary aim of this systematic review and meta‐analysis was to assess the prevalence of MetS and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder, comparing subjects with different disorders and taking into account demographic variables and psychotropic medication use. The secondary aim was to compare the MetS prevalence in persons with any of the selected disorders versus matched general population controls. The pooled MetS prevalence in people with severe mental illness was 32.6% (95% CI: 30.8%‐34.4%; N = 198; n = 52,678). Relative risk meta‐analyses established that there was no significant difference in MetS prevalence in studies directly comparing schizophrenia versus bipolar disorder, and in those directly comparing bipolar disorder versus major depressive disorder. Only two studies directly compared people with schizophrenia and major depressive disorder, precluding meta‐analytic calculations. Older age and a higher body mass index were significant moderators in the final demographic regression model (z = ?3.6, p = 0.0003, r² = 0.19). People treated with all individual antipsychotic medications had a significantly (p<0.001) higher MetS risk compared to antipsychotic‐naïve participants. MetS risk was significantly higher with clozapine and olanzapine (except vs. clozapine) than other antipsychotics, and significantly lower with aripiprazole than other antipsychotics (except vs. amisulpride). Compared with matched general population controls, people with severe mental illness had a significantly increased risk for MetS (RR = 1.58; 95% CI: 1.35‐1.86; p<0.001) and all its components, except for hypertension (p = 0.07). These data suggest that the risk for MetS is similarly elevated in the diagnostic subgroups of severe mental illness. Routine screening and multidisciplinary management of medical and behavioral conditions is needed in these patients. Risks of individual antipsychotics should be considered when making treatment choices.     

Off-label indications for atypical antipsychotics: A systematic review

INTRODUCTION: With the introduction of newer atypical antipsychotic agents, a question emerged, concerning their use as complementary pharmacotherapy or even as monotherapy in mental disorders other than psychosis. MATERIAL AND METHOD: MEDLINE was searched with the combination of each one of the key words: risperidone, olanzapine and quetiapine with key words that refered to every DSM-IV diagnosis other than schizophrenia and other psychotic disorders, bipolar disorder and dementia and memory disorders. All papers were scored on the basis of the JADAD index. RESULTS: The search returned 483 papers. The selection process restricted the sample to 59 papers concerning Risperidone, 37 concerning Olanzapine and 4 concerning Quetiapine (100 in total). Ten papers (7 concerning Risperidone and 3 concerning Olanzapine) had JADAD index above 2. Data suggest that further research would be of value concerning the use of risperidone in the treatment of refractory OCD, Pervasive Developmental disorder, stuttering and Tourette's syndrome, and the use of olanzapine for the treatment of refractory depression and borderline personality disorder. DISCUSSION: Data on the off-label usefulness of newer atypical antipsychotics are limited, but positive cues suggest that further research may provide with sufficient hard data to warrant the use of these agents in a broad spectrum of psychiatric disorders, either as monotherapy, or as an augmentation strategy.     

Second generation antipsychotics and risk of diabetes type II--comparison between olanzapine and risperidone

Differences in the glucose metabolism were examined and analysed in this study between patients treated with olanzapine and risperidone in comparison with healthy volunteers. The aim of the study was to determine differences of the impaired glucose metabolism in the study groups as well as to point out to the possible mechanisms which bring to these differences. To the group of 15 schizophrenic patients treated with olanzapine, and group of 15 schizophrenic patients treated with risperidone and to 14 healthy volunteers oral glucose tolerancy test is applied in order to determine the level of the impaired glucose tolerance. In the group of the patients treated with olanzapine glucose tolerance was impaired in 33% of the patients, while in the group of the patients treated with risperidone in 20%. Impaired glucose tolerance mostly manifested as hyperinsulinemia. Authors discussed about possible mechanisms responsible for the impaired glucose tolerance in the patients treated with new antipsychotics. Authors conclude that insulin resistance is the main mechanism for development of the diabetes type II in the schizophrenic patients treated with antipsychotics. Insulin resistance is the result of the multiple effects of the antipsychotics, among which most common are: increased body mass and direct involvement of the antipsychotics in the glucose metabolism.     

The influence of risperidone on cognitive functions in schizophrenia

Introduction of the antipsychotics of the second generation (SGA) into the therapy of schizophrenia roused expectations that, finally, the cognitive dysfunction in schizophrenia could be eliminated by psychopharmacological therapy. The purpose of the study was to verify the effect of atypical antipsychotic risperidone on cognitive functions in schizophrenic patients. The study was carried out upon 48 male schizophrenic patients aged 21-47 years who were switched from the antipsychotics of the first generation (FGA) to the antipsychotic risperidone, due to intolerance, during the treatment. Intelligence, abstract and concrete thinking and mental speed, attention, and short-term non-verbal memory prior to the switch, one month after the switch, and three months after the switch to risperidone, were evaluated. One month after the switch the number of subjects with severe impairment of intellectual abilities decreased significantly from 62% to 15% and after three months the number was even lower-8%. The impairment of concrete and abstract thinking and mental speed also showed the same tendencies of decrease. The improvement of the cognitive functioning after the switch from the antipsychotics of the first generation to the antipsychotic risperidone is explained by removal of the antipsychotics of the first generation from the therapy and the consequential disinhibition of secondary cognitive impairments and by decreased average dose of anticholinergic and decreased number of patients who need anticholinergic therapy beside risperidone. The possibility of clear pro-cognitive effect of risperidone is suggested and its verification is proposed with strict control of other factors that improve cognitive functioning of schizophrenic patients during the treatment.     

Long-term efficacy of antipsychotic drugs in initially acutely ill adults with schizophrenia: systematic review and network meta-analysis

Most acute phase antipsychotic drug trials in schizophrenia last only a few weeks, but patients must usually take these drugs much longer. We examined the long-term efficacy of antipsychotic drugs in acutely ill patients using network meta-analysis. We searched the Cochrane Schizophrenia Group register up to March 6, 2022 for randomized, blinded trials of at least 6-month duration on all second-generation and 18 first-generation antipsychotics. The primary outcome was change in overall symptoms of schizophrenia; secondary outcomes were all-cause discontinuation; change in positive, negative and depressive symptoms; quality of life, social functioning, weight gain, antiparkinson medication use, akathisia, serum prolactin level, QTc prolongation, and sedation. Confidence in the results was assessed by the CINeMA (Confidence in Network Meta-Analysis) framework. We included 45 studies with 11,238 participants. In terms of overall symptoms, olanzapine was on average more efficacious than ziprasidone (standardized mean difference, SMD=0.37, 95% CI: 0.26-0.49), asenapine (SMD=0.33, 95% CI: 0.21-0.45), iloperidone (SMD=0.32, 95% CI: 0.15-0.49), paliperidone (SMD=0.28, 95% CI: 0.11-0.44), haloperidol (SMD=0.27, 95% CI: 0.14-0.39), quetiapine (SMD=0.25, 95% CI: 0.12-0.38), aripiprazole (SMD=0.16, 95% CI: 0.04-0.28) and risperidone (SMD=0.12, 95% CI: 0.03-0.21). The 95% CIs for olanzapine versus aripiprazole and risperidone included the possibility of trivial effects. The differences between olanzapine and lurasidone, amisulpride, perphenazine, clozapine and zotepine were either small or uncertain. These results were robust in sensitivity analyses and in line with other efficacy outcomes and all-cause discontinuation. Concerning weight gain, the impact of olanzapine was higher than all other antipsychotics, with a mean difference ranging from –4.58 kg (95% CI: –5.33 to –3.83) compared to ziprasidone to –2.30 kg (95% CI: –3.35 to –1.25) compared to amisulpride. Our data suggest that olanzapine is more efficacious than a number of other antipsychotic drugs in the longer term, but its efficacy must be weighed against its side effect profile.     

A comparison of olanzapine and risperidone on the risk of psychiatric hospitalization in the naturalistic treatment of patients with schizophrenia

BACKGROUND: Decreasing hospital admissions is important for improving outcomes for people with schizophrenia and for reducing cost of hospitalization, the largest expenditure in treating this persistent and severe mental illness. This prospective observational study compared olanzapine and risperidone on one-year psychiatric hospitalization rate, duration, and time to hospitalization in the treatment of patients with schizophrenia in usual care. METHODS: We examined data of patients newly initiated on olanzapine (N = 159) or risperidone (N = 112) who continued on the index antipsychotic for at least one year following initiation. Patients were participants in a 3-year prospective, observational study of schizophrenia patients in the US. Outcome measures were percent of hospitalized patients, total days hospitalized per patient, and time to first hospitalization during the one-year post initiation. Analyses employed a generalized linear model with adjustments for demographic and clinical variables. A two-part model was used to confirm the findings. Time to hospitalization was measured by the Kaplan-Meier survival formula. RESULTS: Compared to risperidone, olanzapine-treated patients had significantly lower hospitalization rates, (24.1% vs. 14.4%, respectively, p = 0.040) and significantly fewer hospitalization days (14.5 days vs. 9.9 days, respectively, p = 0.035). The mean difference of 4.6 days translated to $2,502 in annual psychiatric hospitalization cost savings per olanzapine-treated patient, on average. CONCLUSIONS: Consistent with prior clinical trial research, treatment-adherent schizophrenia patients who were treated in usual care with olanzapine had a lower risk of psychiatric hospitalization than risperidone-treated patients. Lower hospitalization costs appear to more than offset the higher medication acquisition cost of olanzapine.     

Publication Bias in Antipsychotic Trials: An Analysis of Efficacy Comparing the Published Literature to the US Food and Drug Administration Database

Background

Publication bias compromises the validity of evidence-based medicine, yet a growing body of research shows that this problem is widespread. Efficacy data from drug regulatory agencies, e.g., the US Food and Drug Administration (FDA), can serve as a benchmark or control against which data in journal articles can be checked. Thus one may determine whether publication bias is present and quantify the extent to which it inflates apparent drug efficacy.

Methods and Findings

FDA Drug Approval Packages for eight second-generation antipsychotics—aripiprazole, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, risperidone long-acting injection (risperidone LAI), and ziprasidone—were used to identify a cohort of 24 FDA-registered premarketing trials. The results of these trials according to the FDA were compared with the results conveyed in corresponding journal articles. The relationship between study outcome and publication status was examined, and effect sizes derived from the two data sources were compared. Among the 24 FDA-registered trials, four (17%) were unpublished. Of these, three failed to show that the study drug had a statistical advantage over placebo, and one showed the study drug was statistically inferior to the active comparator. Among the 20 published trials, the five that were not positive, according to the FDA, showed some evidence of outcome reporting bias. However, the association between trial outcome and publication status did not reach statistical significance. Further, the apparent increase in the effect size point estimate due to publication bias was modest (8%) and not statistically significant. On the other hand, the effect size for unpublished trials (0.23, 95% confidence interval 0.07 to 0.39) was less than half that for the published trials (0.47, 95% confidence interval 0.40 to 0.54), a difference that was significant.

Conclusions

The magnitude of publication bias found for antipsychotics was less than that found previously for antidepressants, possibly because antipsychotics demonstrate superiority to placebo more consistently. Without increased access to regulatory agency data, publication bias will continue to blur distinctions between effective and ineffective drugs. Please see later in the article for the Editors'' Summary     

三种非典型抗精神病药对儿童青少年精神分裂症患者血脂、肝功能和认知功能的影响

摘要 目的：探讨利培酮、阿立哌唑、奥氮平分别对儿童青少年精神分裂症患者肝功能、血脂和认知功能的影响。方法：选取2015年1月至2019年12月我院收治的84例儿童青少年精神分裂症患者,采用乱数表法随机分为阿立哌唑组（n=28,阿立哌唑治疗）、利培酮组（n=28,利培酮治疗）、奥氮平组（n=28,奥氮平治疗）,均治疗8周,对比三组患者症状评分、血脂、肝功能、认知功能以及不良反应。结果：三组治疗8周后阳性与阴性症状量表（PANSS）评分整体比较无差异（P>0.05）,三组治疗8周后PANSS评分均较治疗前降低（P<0.05）。奥氮平组、利培酮组治疗8周后三酰甘油(TG)、总胆固醇(TC)、低密度脂蛋白(LDL-C)高于阿立哌唑组,且奥氮平组高于利培酮组（P<0.05）;奥氮平组、利培酮组治疗8周后高密度脂蛋白(HDL-C)低于阿立哌唑组,且奥氮平组低于利培酮组（P<0.05）。三组不良反应发生率整体比较无差异（P>0.05）。阿立哌唑组治疗8周后延迟回忆数、即刻回忆数、回忆总数、再认数评分均高于利培酮组、奥氮平组（P<0.05）。利培酮组治疗8周后ALT、AST、TBIL高于治疗前（P<0.05）,利培酮组治疗8周后ALT、AST、TBIL高于阿立哌唑组、奥氮平组（P<0.05）。结论：利培酮、阿立哌唑、奥氮平应用于儿童青少年精神分裂症中,可获得相当的治疗效果,其中利培酮对肝功能影响较大,奥氮平对人体血脂影响较大,阿立哌唑对血脂、肝功能影响轻,改善认知功能效果优于利培酮、奥氮平。     

Maintenance treatment of bipolar disorders

Conventional antipsychotic drugs, although efficacious in the treatment of mania, have not demonstrated a significant usefulness in the maintenance treatment of bipolar disorder. This has primarily been due to a tendency to induce depressive symptoms and depressive recurrences in this group of patients in the course of long-term administration. However, the picture has changed following the introduction of second-generation antipsychotics. These drugs have pro-depressant properties (if any) that are much weaker than conventional antipsychotics. Furthermore, their tolerability, especially in long-term treatment, is more favorable compared to classical antipsychotics. Clinical observations of the action profile of second-generation antipsychotic drugs in the treatment of schizophrenia have pointed to a possibility of these agents possessing mood-stabilizing properties. The first such suggestion was made by Zarate (1995) in connection with clozapine. The prevention of manic and depressive recurrences in bipolar disorder is a hallmark of the definition of mood-stabilizers.     

Antipsychotic drugs differentially modulate apolipoprotein D in rat brain

Apolipoprotein-D (apoD), a member of the lipocalin family of proteins, binds to arachidonic acid and cholesterol among other hydrophobic molecules. Recently, elevated apoD levels have been reported in the post-mortem brains, as well as plasma, of schizophrenic patients and in rodent brains after chronic treatment with clozapine (CLOZ). These findings and the evidence for altered membrane lipid metabolism in schizophrenia suggest that apoD may have a role in the pathophysiology of illness, and also in the differential clinical outcome following treatment with typical and atypical antipsychotic drugs. Here, we compared the effects of these antipsychotics on the expression of apoD in rat brain. Chronic treatment with typical antipsychotic, haloperidol (HAL) reduced apoD expression in hippocampus, piriform cortex and caudate-putamen (p = 0.027-0.002), whereas atypical antipsychotics, risperidone (RISP) and olanzapine (OLZ) increased (p = 0.051 to < 0.001 and p = 0.048 to < 0.001, respectively) apoD expression. In hippocampus, HAL-induced changes were present in CA1, CA3 and dentate gyrus, however, apoD levels in motor cortex were unchanged. There were also very dramatic effects of HAL on the neuronal morphology, particularly, cellular shrinkage and disorganization with the loss of neuropil. Post-treatment, either with RISP or OLZ, was very effective in restoring the HAL-induced reduction of apoD, as well as cellular morphology. Similarly, pre-treatments were also effective, but slightly less than post-treatment, in preventing HAL-induced reduction of apoD. The increased expression of apoD by atypical antipsychotics may reflect a novel molecular mechanism underlying their favorable effects compared with HAL on cognition, negative symptoms and extra-pyramidal symptoms in schizophrenia.     

Long-term pharmacological treatment of bipolar disorders

Several lines of clinical, genetic, and pharmacological evidence point to an association between bipolar and psychotic disorders. The goals of maintenance and prophylactic treatment of bipolar disorder include the prevention of new episodes and the improvement of social, family, and occupational functioning. This goal can be mainly achieved by using long-term adequate pharmacological treatment that is tolerable to patients. Among mood-stabilizers, the main drugs used for such treatment, the role of atypical antipsychotics has greatly increased in recent years. Lithium still remains the drug that has produced the most convincing evidence of prophylactic action and has undergone the longest periods of observation. There has also been good confirmation for the maintenance efficacy of such anticonvulsant drugs as carbamazepine, valproate, and lamotrigine, the last having the strongest properties for prophylaxis of depressive episodes. The case for the usefulness of second-generation antipsychotic drugs in the long-term treatment of bipolar disorder has been rapidly accumulating. Based on controlled trials, the best evidence for maintenance efficacy exists for olanzapine. The vast majority of patients with bipolar illness experience inadequate response to monotherapy with mood-stabilizing drugs during long-term treatment. Some issues connected with polypharmacy targeting optimal maintenance results are discussed. In addition, the long-term management and the role of antidepressants in treatment of non-bipolar I illness is also briefly described.     

Safety of 80 antidepressants,antipsychotics, anti‐attention‐deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta‐review of 78 adverse effects

Mental disorders frequently begin in childhood or adolescence. Psychotropic medications have various indications for the treatment of mental dis­orders in this age group and are used not infrequently off‐label. However, the adverse effects of these medications require special attention during developmentally sensitive periods of life. For this meta‐review, we systematically searched network meta‐analyses and meta‐analyses of randomized controlled trials (RCTs), individual RCTs, and cohort studies reporting on 78 a priori selected adverse events across 19 categories of 80 psychotropic medications – including antidepressants, antipsychotics, anti‐attention‐deficit/hyperactivity disorder (ADHD) medications and mood stabilizers – in children and adolescents with mental disorders. We included data from nine network meta‐analyses, 39 meta‐analyses, 90 individual RCTs, and eight cohort studies, including 337,686 children and adolescents. Data on ≥20% of the 78 adverse events were available for six antidepressants (sertraline, escitalopram, paroxetine, fluoxetine, venlafaxine and vilazodone), eight antipsychotics (risperidone, quetiapine, aripiprazole, lurasidone, paliperidone, ziprasidone, olanzapine and asenapine), three anti‐ADHD medications (methylphenidate, atomoxetine and guanfacine), and two mood stabilizers (valproate and lithium). Among these medications with data on ≥20% of the 78 adverse events, a safer profile emerged for escitalopram and fluoxetine among antidepressants, lurasidone for antipsychotics, methylphenidate among anti‐ADHD medications, and lithium among mood stabilizers. The available literature raised most concerns about the safety of venlafaxine, olanzapine, atomoxetine, guanfacine and valproate. Nausea/vomiting and discontinuation due to adverse event were most frequently associated with antidepressants; sedation, extrapyramidal side effects, and weight gain with antipsychotics; anorexia and insomnia with anti‐ADHD medications; sedation and weight gain with mood stabilizers. The results of this comprehensive and updated quantitative systematic meta‐review of top‐tier evidence regarding the safety of antidepressants, antipsychotics, anti‐ADHD medications and mood stabilizers in children and adolescents can inform clinical practice, research and treatment guidelines.     

Impaired mitophagosome–lysosome fusion mediates olanzapine-induced aging

The lifespan of schizophrenia patients is significantly shorter than the general population. Olanzapine is one of the most commonly used antipsychotic drugs (APDs) for treating patients with psychosis, including schizophrenia and bipolar disorder. Despite their effectiveness in treating positive and negative symptoms, prolonged exposure to APDs may lead to accelerated aging and cognitive decline, among other side effects. Here we report that dysfunctional mitophagy is a fundamental mechanism underlying accelerated aging induced by olanzapine, using in vitro and in vivo (Caenorhabditis elegans) models. We showed that the aberrant mitophagy caused by olanzapine was via blocking mitophagosome–lysosome fusion. Furthermore, olanzapine can induce mitochondrial damage and hyperfragmentation of the mitochondrial network. The mitophagosome–lysosome fusion in olanzapine-induced aging models can be restored by a mitophagy inducer, urolithin A, which alleviates defective mitophagy, mitochondrial damage, and fragmentation of the mitochondrial network. Moreover, the mitophagy inducer ameliorated behavioral changes induced by olanzapine, including shortened lifespan, and impaired health span, learning, and memory. These data indicate that olanzapine impairs mitophagy, leading to the shortened lifespan, impaired health span, and cognitive deficits. Furthermore, this study suggests the potential application of mitophagy inducers as therapeutic strategies to reverse APD-induced adverse effects associated with accelerated aging.     

The effects of atypical antipsychotics on visceral fat distribution in first episode, drug-naive patients with schizophrenia

The aim of this study was to determine the location of antipsychotic-induced weight gain in drug na?ve, first episode patients with schizophrenia. Various fatness and fat distribution parameters (by Computerized Tomography scanning and anthropometry) and 1600 hr plasma cortisol were measured in 19 (15 men and 4 women) subjects with schizophrenia (mean age = 31.0 years; mean body mass index [BMI] = 24.6 kg/m2) and an equal number of age- and sex- matched controls (mean age = 32.6 yr; mean BMI = 23.0 kg/m2). Patients were then given either olanzapine or risperidone. Sixteen patients were re-tested following a treatment period lasting approximately 6 months. Patients with schizophrenia, had significantly more intra-abdominal fat [IAF] (116.8 +/- 20.2 cm2 vs. 38.0 +/- 4.8 cm2, respectively; t = 3.80, df = 18, p < 0.0001) and had higher levels of plasma cortisol (360.2 +/- 49.6 nmol/L vs. 192.7 +/- 19.7 nmol/L, respectively; t = 3.13, df = 18, p < 0.003) than appropriately matched control subjects. Treatment with atypical antipsychotics did not result in a significant increase in IAF (116.8 +/- 20.2 cm2 vs. 131.7 +/- 20.9 cm2; p = NS) though visceral fat stores still remained significantly higher than those seen in controls (38.0 +/- 4.8 cm2) (F = 9.34; df = 2, 51; p < 0.0003). However, plasma levels of cortisol did significantly decrease (360.2 +/- 49.6 nmol/L +/- vs. 316.2 +/- 48.4 nmol/L; p < 0.05). Pre-treatment levels of IAF did not differ between those who received risperidone and those who were given olanzapine (123.0 +/- 35.9 cm2 vs. 113.1 +/- 15.7 cm2, respectively; t = 0.20, df = 16, p < 0.84). The increase in IAF did not differ between those given risperidone and those who received olanzapine (26.9 +/- 12.1 cm2 vs. 18.24 +/- 11.44 cm2, respectively; t = 0.50, df = 16, p < 0.63). Patients with drug na?ve, first episode, schizophrenia have higher levels of visceral fats stores as compared to matched control subjects. Treatment with atypical antipsychotics does not result in a significant increase in IAF distribution.     

Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial

Schizophrenia is a chronic, complex and heterogeneous mental disorder, with pathological features of disrupted neuronal excitability and plasticity within limbic structures of the brain. These pathological features manifest behaviorally as positive symptoms (including hallucinations, delusions and thought disorder), negative symptoms (such as social withdrawal, apathy and emotional blunting) and other psychopathological symptoms (such as psychomotor retardation, lack of insight, poor attention and impulse control). Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P < 0.001 at week 4). Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia.     

Determination of olanzapine in serum by high-performance liquid chromatography using ultraviolet detection considering the easy oxidability of the compound and the presence of other psychotropic drugs

A method for determination of the atypical neuroleptic drug olanzapine in serum was developed. After a single-step liquid–liquid extraction, the compound was separated from other constituents on a normal-phase silica gel column using a buffer–methanol mobile phase and measured by UV absorption at 270 nm. Addition of 0.25% ascorbic acid to serum protects olanzapine against oxidation during extraction and stabilizes the easily oxidised compound during storage. Inter-day variation was <8% at serum levels found in olanzapine treated patients. Analytical interference from coadministered psychoactive drugs and their metabolites were studied. Only risperidone, also a relatively newly developed antipsychotic drug, interfered, but the most commonly used antidepressants and traditional antipsychotics and their metabolites did not interfere.     

Serum hepcidin / ferroportin levels in bipolar disorder and schizophrenia

BackgroundDespite several alternatives for cellular iron influx, the only mechanism for cellular iron efflux is ferroportin mediated active transport. In cases of ferroportin dysfunction, iron accumulates in the cell and causes ferroptosis. Hepcidin suppresses ferroportin levels and inflammatory activation increases hepcidin production. Mild inflammation in schizophrenia and bipolar disorder may alter hepcidin and ferroportin.MethodsThe study included a total of 137 patients aged 18–65 years, 57 diagnosed with schizophrenia and 80 with bipolar disorder, according to the DSM-IV diagnostic criteria, and a control group (HC) of 42 healthy individuals. Biochemical analyses, thyroid function tests, hemogram, serum iron level, iron-binding capacity, and ferritin levels were examined. Serum levels of hepcidin and ferroportin were measured with enzyme-linked immunosorbent assay (ELISA) method.ResultsA statistically significant difference was determined between the groups in terms of the serum ferroportin levels (F = 15.69, p < 0.001). Post-hoc analyses showed that the schizophrenia group had higher ferroportin levels than in the bipolar group (p < 0.001) and HCs (p < 0.001). Hepcidin levels did not differ between the groups. Chlorpromazine equivalent doses of antipsychotics correlated with ferroportin levels (p = 0.024).ConclusionFerroportin levels were increased in the schizophrenia group, although iron and hepcidin levels were within normal ranges. Antipsychotics may alter the mechanisms which control ferroportin levels. Further studies are needed to examine the relationships between antipsychotics and iron metabolism for determination of causal relationship.     

Prescribing trends in bipolar disorder: cohort study in the United Kingdom THIN primary care database 1995-2009

Objectives

To determine changes in prescribing patterns in primary care of antipsychotic and mood stabiliser medication in a representative sample of patients with bipolar disorder in the United Kingdom over a fifteen year period and association with socio-demographic factors.

Methods

We identified 4700 patients in the Health Improvement Network (THIN) primary care database, who had received treatment for bipolar disorder between 1995 and 2009. The proportion of time for which each individual was prescribed a particular medication was studied, along with variation by sex, age and social depravation status (quintiles of Townsend scores). The number of drugs an individual was taking within a particular year was also examined.

Results

In 1995, 40.6% of patients with bipolar disorder were prescribed a psychotropic medication at least twice. By 2009 this had increased to 78.5% of patients. Valproate registered with the greatest increase in use (22.7%) followed by olanzapine (15.7%) and quetiapine (9.9%). There were differences by age and sex; with young (18–30 year old) women having the biggest increase in proportion of time on medication. There were no differences by social deprivation status. By 2009, 34.2% of women of childbearing age were treated with valproate.

Conclusions

Lithium use overall remained relatively constant, whilst second generation antipsychotic and valproate use increased dramatically. Changes in prescribing practice preceded published trial evidence, especially with the use of second generation antipsychotics, perhaps with inferences being made from treatment of schizophrenia and use of first generation antipsychotics. Women of childbearing age were prescribed valproate frequently, against best advice.