Cognitive effects of olanzapine treatment in schizophrenia

Improvement in some but not all domains of cognition during treatment with the atypical antipsychotic drugs clozapine, quetiapine, olanzapine, and risperidone has been reported in some but not all studies. It has been recently suggested that these reports are an artifact, related to lessening of the impairment due to typical neuroleptic drugs and anticholinergic agents. The purpose of this study was to further test the hypothesis that olanzapine, an atypical antipsychotic drug reported to have anticholinergic properties, improves cognition in patients with schizophrenia, including domains of cognition related closely to work and social function (ie, verbal learning and memory) and that this improvement is independent of improvement in psychopathology. Thirty-four patients with schizophrenia who were partial responders to typical antipsychotic drug treatment were evaluated with a comprehensive neurocognitive battery, including measures of executive functioning; verbal and visual learning and memory; working memory; immediate, selective, and sustained attention; perceptual/motor processing; and motor skills prior to and following treatment with olanzapine for 6 weeks. The Brief Psychiatric Rating Scale (BPRS) was used to assess psychopathology in patients treated with typical antipsychotic drugs. Subjects were switched to olanzapine (average dose 13.4 mg, range 5-20 mg) and reassessed following 6 weeks and 6 months of treatment. Significant improvement was noted in 9 of 19 cognitive tests, including measures of selective attention, verbal learning and memory, and verbal fluency. No cognitive test was worsened by olanzapine treatment. Improvements in the BPRS Total and Positive Symptom Subscale scores were noted. Improvements in verbal learning and memory, sustained attention, and psychomotor tracking were independent of improvement in psychopathology. These data suggest that olanzapine improved some but not all cognitive deficits in schizophrenia, including verbal memory, a cognitive domain impaired by anticholinergic drugs. The basis for the improvement in cognitive scores, which should lead to improvement in role functioning if real, is discussed.     

Metabolomic profiling to identify potential serum biomarkers for schizophrenia and risperidone action

Despite recent advances in understanding the pathophysiology of schizophrenia and the mechanisms of antipsychotic drug action, the development of biomarkers for diagnosis and therapeutic monitoring in schizophrenia remains challenging. Metabolomics provides a powerful approach to discover diagnostic and therapeutic biomarkers by analyzing global changes in an individual's metabolic profile in response to pathophysiological stimuli or drug intervention. In this study, we performed gas chromatography-mass spectrometry based metabolomic profiling in serum of unmedicated schizophrenic patients before and after an 8-week risperidone monotherapy, to detect potential biomarkers associated with schizophrenia and risperidone treatment. Twenty-two marker metabolites contributing to the complete separation of schizophrenic patients from matched healthy controls were identified, with citrate, palmitic acid, myo-inositol, and allantoin exhibiting the best combined classification performance. Twenty marker metabolites contributing to the complete separation between posttreatment and pretreatment patients were identified, with myo-inositol, uric acid, and tryptophan showing the maximum combined classification performance. Metabolic pathways including energy metabolism, antioxidant defense systems, neurotransmitter metabolism, fatty acid biosynthesis, and phospholipid metabolism were found to be disturbed in schizophrenic patients and partially normalized following risperidone therapy. Further study of these metabolites may facilitate the development of noninvasive biomarkers and more efficient therapeutic strategies for schizophrenia.     

Variations of rest-activity rhythm and sleep-wake in schizophrenic patients versus healthy subjects: An actigraphic comparative study

The objective of the present study was to compare the pattern of motor activity in unmedicated schizophrenia patients and healthy subjects, and to examine whether the pattern was affected by treatment with typical and atypical antipsychotics. Twenty unmedicated schizophrenic patients wore a wrist actigraph for five days. The actigraph recorded activity levels in one-minute epochs. Patients' pattern of activity was compared with that of healthy subjects. Patients were randomly assigned to treatment with low-dose haloperidol or risperidone. The impact of treatment on the pattern of activity was examined. Compared to controls, untreated patients showed a diminished mean activity count during morning, early and late night periods. Treatment with haloperidol or risperidone at effective doses showed a significant effect on activity level, being more prominent with haloperidol. The results suggest that unmedicated schizophrenic patients exhibit abnormally low levels of motor activity as measured with an objective activity meter. This persists after antipsychotic treatment even though symptoms improve. Future studies should clarify whether motor disturbances are a primary effect of the illness, or related to the illness-related lifestyle.     

Nonadherence to antipsychotic treatment in patients with schizophrenic disorders

Adherence to treatment is a general indicator of quality and success of communication between the physician and the patient. It means the extent to which patient behaviour, in terms of taking medications, following diets, or executing life-style changes, coincides with medical or health advice. Nonadherence to antipsychotic therapy in patients with schizophrenia is far more widespread than clinicians assume. Lower nonadherence in therapy based on antipsychotics of the second generation compared with conventional medications has already been indicated by early reports. The consequences of nonadherence include exacerbation of symptoms, an increased relapse rate, psychiatric hospitalization hospitalisation, and less favourable patient prognosis. There are several factors that cause treatment nonadherence in schizophrenia: causes derived from the schizophrenic disorder itself, patient characteristics, causes associated associated with the health-care system, and the antipsychotic treatment itself.     

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.     

Dopamine D3 receptors as a novel target for improving the treatment of schizophrenia

Schizophrenia is a complex and serious disorder which affects some 0.5-1.0% of the population. The disease generally begins in adolescence. This early onset, together with the progressive and often irreversible nature of schizophrenia, account for its high social cost. Positive symptoms, such as hallucinations, are generally well-controlled by antipsychotics, whereas cognitive and deficit symptoms are poorly-treated. All antipsychotic agents, irrespective of their overall receptor-binding profiles, interact with dopaminergic mechanisms that are known to be perturbed in schizophrenic patients. Dopamine exerts its actions via five classes of receptor, offering a broad palette of targets for the conception of novel antipsychotic agents. The present article focuses on the relevance of dopamine D3 receptors to the aetiology and treatment of schizophrenia. Experimental studies suggest that, as compared to other drugs, antipsychotic agents which preferentially block D3 receptors may possess therapeutic advantages, notably in the control of cognitive symptoms. The first clinical studies for the evaluation of this hypothesis have recently got underway.     

Correlation of cognitive functions with some aspects of illness, treatment and social functioning in recurrently hospitalized schizophrenic patients

Cognitive deficits are found to be contributors to poorer psychosocial functioning, rehabilitation outcome and lack of treatment success in schizophrenia. Aim of the study was to examine correlation of cognitive functions with some aspects of illness, treatment and social functioning in a group of recurrently hospitalized schizophrenic patients (N=60). Deficient results on psychomotor processing speed, verbal fluency and verbal learning correlated with the longer duration of illness, higher number of hospitalizations and shorter duration of regular antipsychotic treatment. Deficient results on verbal fluency correlated with the younger age of onset, poor functional autonomy and organizational skills, whereas deficient results on psychomotor processing and verbal learning correlated with poor organizational skills alone. Score on verbal fluency was predictive of social skills impairment, whereas score on psychomotor processing was predictive of functional autonomy and organizational skills impairment. Functioning of different cognitive domains could be predictive of functioning in different social domains. Interplay of specific cognitive deficit and social functioning could be responsible for recurrent hospitalizations and unfavorable treatment choices.     

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.     

Glutamate and Schizophrenia: Beyond the Dopamine Hypothesis

1. After 50 years of antipsychotic drug development focused on the dopamine D2 receptor, schizophrenia remains a chronic, disabling disorder for most affected individuals.2. Studies over the last decade demonstrate that administration of low doses of NMDA receptor antagonists can cause in normal subjects the negative symptoms, cognitive impairments and physiologic disturbances observed in schizophrenia.3. Furthermore, a number of recently identified risk genes for schizophrenia affect NMDA receptor function or glutamatergic neurotransmission.4. Placebo-controlled trials with agents that directly or indirectly activate the glycine modulatory site on the NMDA receptor have shown reduction in negative symptoms, improvement in cognition and in some cases reduction in positive symptoms in schizophrenic patients receiving concurrent antipsychotic medications.5. Thus, hypofunction of the NMDA receptor, possibly on critical GABAergic inter-neurons, may contribute to the pathophysiology of schizophrenia.     

Pharmacotherapy of schizophrenic patients: preponderance of off-label drug use

Multiple drug class combinations are often prescribed for the treatment of schizophrenia, although antipsychotic monotherapy reflects FDA labeling and scientific justification for combinations is highly variable. This study was performed to gain current data regarding drug treatment of schizophrenia as practiced in the community and to assess the frequencies of off-label drug class combinations. 200 DSM IV-diagnosed schizophrenic patients recruited from community treatment sources participated in this cross-sectional study of community based schizophrenic patients. Drug class categories include First and Second Generation Antipsychotic drugs (FGA and SGA, respectively), mood stabilizers, antidepressants and anti-anxiety drugs. 25.5% of patients received antipsychotic monotherapy; 70% of patients received an antipsychotic and another drug class. A total of 42.5% of patients received more than one antipsychotic drug. The most common drug class combination was antipsychotic and a mood stabilizer. Stepwise linear discriminant function analysis identified the diagnosis of schizoaffective schizophrenia, history of having physically hurt someone and high scores on the General Portion of the PANSS rating scale predicted the combined use of an antipsychotic drug and a mood stabilizer. "Real world" pharmacotherapy of schizophrenia has developed its own established practice that is predominantly off-label and may have outstripped current data support. The economic implications for public sector payers are substantial as well as for the revenue of the pharmaceutical industry, whose promotion of off-label drug use is an increasingly problematic. These data are consistent with the recognition of the therapeutic limitations of both first and second generation antipsychotic drugs.     

Serum IL-1beta,sIL-2R,IL-6, IL-8 and TNF-alpha in schizophrenic patients,relation with symptomatology and responsiveness to risperidone treatment.

Activation of the inflammatory response system and varied levels of cytokines in acute schizophrenia have been suggested by recent studies. Psychopharmacologic agents can differentially effect cytokine production, which suggests that therapeutic function of neuroleptics may involve immunomodulation. The present study was carried out to examine: (i) serum concentrations of interleukin (IL)-1beta, soluble interleukin-2 receptor (sIL-2R), IL-6, IL-8 and tumour necrosis factor (TNF)-alpha in schizophrenic patients; (ii) their relation with psychopathological assessment; and (iii) the relation of the initial cytokine levels with responsiveness to risperidone therapy. Thirty-four drug-free schizophrenic patients with acute exacerbation and 23 age- and gender-matched healthy controls were recruited for this study. Psychopathological assessments at admission and throughout risperidone treatment for 60 days were recorded. Serum cytokine concentrations were determined with chemilumunescence assays. According to our results, serum IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha concentrations adjusted for age, gender, body mass index and smoking were no different in patients with schizophrenia and controls and among subtypes of schizophrenia. However, the initial TNF-alpha concentrations had a significant effect on Brief Psychiatric Rating Scale and Scale Assessment of Positive Symptoms scores. The initial cytokine concentrations of the patients responsive to risperidone were not significantly different from those of non-responsive patients. The present study demonstrates that plasma levels of IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha adjusted for confounding factors are not altered in drug-free schizophrenic patients at acute exacerbation. We suggest that, if cytokine production is altered in schizophrenia, these alterations may not be detectable in systemic circulation. According to our results, the therapeutic effect of risperidone is not related to basal levels of the aforementioned cytokines. However, serum TNF-alpha may contribute to symptomatology in schizophrenia     

Alterations in Brain Extracellular Dopamine and Glycine Levels Following Combined Administration of the Glycine Transporter Type-1 Inhibitor Org-24461 and Risperidone

The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D₂ dopamine receptors. N-methyl-d-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D₂ dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced dopaminergic side effects characteristic for antipsychotic medication.     

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.     

利培酮联合氯氮平在长住院精神分裂症的随机对照研究

目的:探讨利培酮联合氯氮平治疗精神分裂症的疗效和安全性。方法:200例长住院符合国际疾病分类第10版(ICD-10)诊断标准的精神分裂症患者随机分为利培酮联合氯氮平组(简称联合组,N=90)和单用利培酮组(简称单用组,N=110),采用简明精神病量表(The brief psychiatric rating scale,BPRS)及阳性和阴性症状量表(the Positive and Negative Syndrome Scale,PANSS)评定疗效,采用治疗中需处理的不良反应症状量表(Treatment Emergent Symptoms Scale,TESS)评定安全性。结果:联合组的显效率高于单用组(84.44%vs.64.54%,P<0.05);两组治疗后BPRS、PANSS评分均低于治疗前[如,联合组BPRS评分(23.02±6.26)vs.(45.01±5.78),PANSS评分(54.42±10.11)vs.(84.71±10.31),P<0.05;单用组BPRS评分(25.86±6.59)vs.(44.78±5.47),PANSS评分(57.70±10.15)vs.(85.96±10.13),P<0.05];治疗后,联合组BPRS、PANSS评分低于单用组[如,BPRS评分联合组(23.02±6.26)vs.单用组(25.86±6.59),PANSS评分联合组(55.42±10.11)vs.单用组(57.70±10.15),P<0.05]。两组TESS评分在治疗后差异无统计学意义(P>0.05)。结论:利培酮联合氯氮平治疗精神分裂症可提高疗效,安全性较高,是一种值得借鉴的策略。     

Changes in calcineurin expression induced in the rat brain by the administration of antipsychotics

Calcineurin (CN) was recently identified as a susceptibility gene for schizophrenia as well as showing altered RNA expression levels in the post-mortem brains of individuals with schizophrenia. CN knockout mice show a number of behaviours associated with schizophrenia, including deficits in sensorimotor gating, suggesting a link between CN and psychosis. Concurrently, we found, using genome screening techniques, that antipsychotics alter CN expression levels. Therefore, western blotting, in situ hybridization, immunocytochemistry and phosphatase assays were employed to determine what effect antipsychotics have on CN. The results indicate that clozapine, risperidone and haloperidol cause substantial reductions in the A subunit of CN but not CN B at both the RNA and protein levels in the striatum and prefrontal cortex. The changes could only be observed after repeated treatment with antipsychotics but not after acute administration. The alterations in CN protein levels were specific to antipsychotics and mediated by D2 dopamine receptor antagonism. However, despite reductions in CN protein levels, the phosphatase activity of CN was significantly elevated after treatment with antipsychotics. Collectively the results suggest that CN may be a common target for antipsychotics and that antipsychotic-induced alterations in CN may represent one of the mechanisms by which antipsychotics alleviate psychosis.     

Structural contributions of antipsychotic drugs to their therapeutic profiles and metabolic side effects

Antipsychotic drugs have various neuropharmacological properties as a result of their structural diversity. Despite their therapeutic benefits, most of the prescribed atypical antipsychotics can induce severe side effects, including weight gain, type II diabetes mellitus, and cardiovascular diseases. Among the developed atypical antipsychotic agents, tetracyclic dibenzodiazepine and thienobenzodiazepine compounds, particularly clozapine and olanzapine, are associated with the greatest weight gain and metabolic disturbances. However, the unique chemical structure of these compounds causes the low risk of side effects reported for typical antipsychotics (e.g. extrapyramidal symptoms and tardive dyskinesia). This report reviews the recent discovery of the potential role of the chemical structure of antipsychotics in their therapeutic properties and metabolic disturbances. By developing structure-activity relationship studies for atypical antipsychotics, we will improve our understanding of the structural modifications of these chemical classes that lead to reduced weight gain, which will be an invaluable step toward the discovery of the next generation of atypical antipsychotics. In this review, we suggest that a novel dibenzodiazepine or thienobenzodiazepine antipsychotic drug with lower affinity for H(1) receptors may significantly advance schizophrenia therapy.     

Quality of life in the long-term treatment and the role of second-generation antipsychotics

Health-related quality of life (QoL) represents important measure of treatment outcome in mental disorders. Numerous studies indicate that QoL of people with schizophrenia and bipolar disorder is similar to that of patients with chronic physical conditions. It has been shown that schizophrenia patients can themselves reliably assess their QoL; in addition to the objective scales various self-reporting instruments are used. Patients with bipolar disorder have QoL consistently higher than patients with schizophrenia and similar to that found in people with unipolar depression. Quality of life can be negatively affected by drug-induced side-effects and subjective treatment response. The second-generation antipsychotics (SGA) have superior efficacy on QoL over classical antipsychotics in approximately half of the studies with schizophrenia; in the other half those groups are comparable. However, in none of the trials novel antipsychotics were inferior. All SGA (clozapine, olanzapine, risperidone, amisulpride, quetiapine, ziprasidone, or remoxipride) have been found to be beneficial for patients well-being. The most investigated drugs that convincingly improve QoL in schizophrenia are olanzapine and risperidone (including depot form). Results of several studies indicate that individual antipsychotics may differ in their effects on QoL, with suggested superiority of olanzapine. In bipolar disorder, SGA consistently showed their superiority over placebo in effects on QoL. The most studied SGA in bipolar disorder is olanzapine. More long-term controlled double-blind trials are needed to definitively uphold superiority and different effects of individual SGA on QoL of patients with schizophrenia and bipolar disorder.     

The binding of [3H]AF-DX 384 is reduced in the caudate-putamen of subjects with schizophrenia.

Clinical studies of cholinergic pharmacotherapy, together with the putative role of the muscarinic receptor system in the neurophysiology of human behavior, support a possible muscarinic cholinergic involvement in schizophrenia. The present study has measured the density of [3H]AF-DX 384 labelled receptors (muscarinic M2 and M4) in the caudate-putamen, obtained at autopsy, from 19 subjects who had schizophrenia, and 20 subjects who did not have schizophrenia. [3H]AF-DX 384 binding was reduced in caudate-putamen from schizophrenic subjects (104 +/- 10.3 vs 145 +/- 901 fmol mg(-1) TE; mean +/- s.e.; p = 0.007). Preliminary analysis of patient drug data as well as rat studies suggest that the reduced [3H]AF-DX 384 binding in caudate-putamen of schizophrenic subjects is not wholly due to antipsychotic drug treatment, or anticholinergic medication for the treatment of extrapyramidal effects. These data suggest that the muscarinic cholinergic system may be involved in the pathology of schizophrenia.