High-dose Olanzapine Research Articles

Management of high dose olanzapine poisoning in a young child under limited resource setting: a case report from Nepal

Introduction: Olanzapine, an atypical antipsychotic, is widely used for treating psychiatric conditions such as schizophrenia and bipolar disorder. Accidental overdose in children is rare but can lead to severe clinical effects. This case report discusses the management of a five-year-old male who accidently ingested 180 mg of olanzapine, the highest reported dose in a child under five years. Case Presentation: A five-year-old boy accidentally ingested 180 mg of Olanzapine, resulting in loss of consciousness and central nervous system depression. He exhibited hyperglycemia, elevated lactate, and prolonged prothrombin time, but no significant cardiovascular issues. Following intubation and supportive care, including intravenous medications and mechanical ventilation, the child gradually improved. He was discharged in stable condition with follow-up instructions. Discussion: Olanzapine toxicity in children presents with a variety of symptoms, including somnolence, hypotension, and neurological impairments, which are dose-dependent. Even in case of an exceptionally high overdose, the absence of cardiovascular toxicity supports safety profile of olanzapine. Common laboratory findings include hyperglycemia, elevated liver enzymes, and metabolic disturbances. Management involves airway protection, supportive care, and monitoring, as no specific antidote exists. Prompt and appropriate care, even in severe cases under limited resource settings, can lead to favorable outcomes. Conclusion: In cases of high dose accidental olanzapine poisoning in children, it is essential to begin quick intervention and comprehensive supportive care to achieve successful outcomes and can be managed even in limited resource settings. Preventive measures are crucial to avoid such incidents and careful monitoring is essential in managing pediatric olanzapine overdose.

Pneumonia Risk, Antipsychotic Dosing, and Anticholinergic Burden in Schizophrenia

Antipsychotic drugs (particularly clozapine) have been associated with pneumonia in observational studies. Despite studies of the associations between antipsychotic use and incident pneumonia, it remains unclear to what degree antipsychotic use is associated with increased risk of pneumonia, whether dose-response associations exist, and what agents are specifically associated with incident pneumonia. To estimate pneumonia risk associated with specific antipsychotics and examine whether polytherapy, dosing, and receptor binding properties are associated with pneumonia in patients with schizophrenia. This cohort study identified patients with schizophrenia or schizoaffective disorder (hereafter, schizophrenia) aged 16 years or older from nationwide Finnish registers from 1972 to 2014. Data on diagnoses, inpatient care, and specialized outpatient care were obtained from the Hospital Discharge Register. Information on outpatient medication dispensing was obtained from the Prescription Register. Study follow-up was from 1996 to 2017. Data were analyzed from November 4, 2022, to December 5, 2023. Use of specific antipsychotic monotherapies; antipsychotics modeled by dosage as low (<0.6 of the World Health Organization defined daily dose [DDD] per day), medium (0.6 to <1.1 DDDs per day), or high dose (≥1.1 DDDs per day); antipsychotic polypharmacy; and antipsychotics categorized according to their anticholinergic burden as low, medium, and high. The primary outcome was hospitalization for incident pneumonia. Pneumonia risk was analyzed using adjusted, within-individual Cox proportional hazards regression models, with no antipsychotic use as the reference. The study included 61 889 persons with schizophrenia (mean [SD] age, 46.2 [16.0] years; 31 104 men [50.3%]). During 22 years of follow-up, 8917 patients (14.4%) had 1 or more hospitalizations for pneumonia and 1137 (12.8%) died within 30 days of admission. Compared with no antipsychotic use, any antipsychotic use overall was not associated with pneumonia (adjusted hazard ratio [AHR], 1.12; 95% CI, 0.99-1.26). Monotherapy use was associated with increased pneumonia risk compared with no antipsychotic use (AHR, 1.15 [95% CI, 1.02-1.30]; P = .03) in a dose-dependent manner, but polytherapy use was not. When categorized by anticholinergic burden, only the use of antipsychotics with a high anticholinergic burden was associated with pneumonia (AHR, 1.26 [95% CI, 1.10-1.45]; P < .001). Of specific drugs, high-dose quetiapine (AHR, 1.78 [95% CI, 1.22-2.60]; P = .003), high- and medium-dose clozapine (AHR, 1.44 [95% CI, 1.22-1.71]; P < .001 and AHR, 1.43 [95% CI, 1.18-1.74]; P < .001, respectively), and high-dose olanzapine (AHR, 1.29 [95% CI, 1.05-1.58]; P = .02) were associated with increased pneumonia risk. Results of this cohort study suggest that in patients with schizophrenia, antipsychotic agents associated with pneumonia include not only clozapine (at dosages ≥180 mg/d) but also quetiapine (≥440 mg/d) and olanzapine (≥11 mg/d). Moreover, monotherapy antipsychotics and antipsychotics with high anticholinergic burden are associated with increased pneumonia risk in a dose-dependent manner. These findings call for prevention strategies aimed at patients with schizophrenia requiring high-risk antipsychotics.

Real-World Effectiveness of High-Dose Olanzapine and Clozapine for Treatment-Resistant Schizophrenia in Japan: A Retrospective Bidirectional Mirror-Image Study.

Clozapine is considered the gold standard medication for treatment-resistant schizophrenia (TRS). However, given that clozapine treatment is associated with the burden of regular blood monitoring and the risk of life-threatening adverse effects, high-dose olanzapine can serve as an alternative treatment. We conducted a bidirectional mirror-image study to evaluate the effectiveness of high-dose olanzapine compared with clozapine. We included patients with TRS who switched from olanzapine to clozapine or switched from clozapine to olanzapine, and received high-dose (>20 mg/d) olanzapine treatment for ≥4 weeks at Yamanashi Prefectural Kita Hospital. We obtained data on hospitalization, seclusion, and modified electroconvulsive therapy (mECT) during the clozapine phase and the olanzapine phase. A total of 44 patients were included. When patients switched from high-dose olanzapine to clozapine (n = 32), significant reductions were found in the total days of seclusion, the total number of mECT, and the number of patients who received mECT at least once. When patients switched from clozapine to high-dose olanzapine (n = 12), a significant reduction was found in the number of patients who received mECT at least once. When data from both directions of treatment were combined, significant reductions were found in the total days of seclusion, the total number of mECT, and the number of patients who received mECT at least once in favor of clozapine. Findings suggest that high-dose olanzapine may not be as effective as clozapine for patients with TRS in real-world practice. However, it should be noted that there are unique circumstances that restrict the use of clozapine in Japan.

Risk of congenital malformations associated with first-trimester exposure to antipsychotics: A propensity score-weighted population-based cohort study.

There is growing concern regarding teratogenic effect of antipsychotics. Previous research assessing association between antipsychotics and congenital malformations (CMs) yielded mixed results and were all derived from Western countries. We aimed to examine risk of major and organ/system-specific CMs associated with prenatal antipsychotic exposure in Hong Kong. This population-based study identified women aged 15-50 years who delivered their first/singleton child between 2003-2018 from public healthcare service database. Propensity score (PS)-weighted logistic-regression analyses were performed to examine risk of CMs following first-trimester exposure to antipsychotic classes (second- and first-generation antipsychotic; SGA and FGA) and six most frequently-prescribed individual antipsychotics. Of 465,069 women, 419 and 420 redeemed ≥1 prescription of SGA and FGA during first-trimester, respectively. Prevalence of any CMs was 4.9% (95%CI:4.9-5.0%) in unexposed-infants, 9.1% (6.7-12.3%) in SGA-exposed infants, and 6.2% (4.3-9.0%) in FGA-exposed infants. SGA exposure (adjusted-odds-ratio: 2.11 [95%CI:1.19-3.86]) was associated with increased risk of CMs. This finding was consistent with sensitivity analyses addressing exposure misclassification and confounding by treatment indication, but not with PS-matched sensitivity analysis. Elevated risk of CMs was observed in infants exposed to high-dose olanzapine (7.50 [1.65-36.13]) and high-dose quetiapine (15.03 [4.86-56.72]), but with wide-CIs. Organ/system-specific malformations were not associated with SGA, FGA or individual antipsychotics. We observed a small increased risk of major malformations associated with SGA, but was not consistently affirmed in sensitivity analyses, precluding firm conclusions. Research with large sample size clarifying comparative safety of individual antipsychotics on specific malformations is warranted.

OLANZAPİN VE L-KARNİTİNİN RAT TESTİS DOKUSU ÜZERİNDEKİ ETKİSİNİN ARAŞTIRILMASI

Objective&#x0D; Olanzapine has adverse effects on sexual dysfunction.&#x0D; There are a limited number of studies showing that it&#x0D; also causes structural changes in the reproductive&#x0D; system. This study aimed to examine the effects of&#x0D; L-Carnitine on testicular damage caused by Olanzapine&#x0D; in terms of histopathological, sperm parameters, and&#x0D; biochemical aspects.&#x0D; Material and Method&#x0D; A total of 48 adult Sprague-Dawley male rats were&#x0D; used in our study. Rats were divided into 6 groups,&#x0D; 8 rats in each group: the Control group (C), 200 mg/&#x0D; kg L-Carnitine administered group (LC), 2 mg/kg low&#x0D; dose Olanzapine administered group (LOZN), 2 mg/kg&#x0D; Olanzapine, and 200 mg/kg L-Carnitine administered&#x0D; group (LOZN+LC), 4 mg/kg Olanzapine administered&#x0D; group (HOZN), 4 mg/kg Olanzapine and 200 mg/&#x0D; kg L-Carnitine administered group (HOZN+LC).&#x0D; Testicular tissues were used for the determination of&#x0D; MDA, IL-1B, IL-6, TAS, TOS levels, and histological&#x0D; evaluation.&#x0D; Results&#x0D; In the groups receiving Olanzapine, a decrease in&#x0D; sperm count, an increase in MDA, IL-1β, TOS values,&#x0D; and dose-dependent histopathological changes in&#x0D; testicular tissue were observed. Histopathological&#x0D; changes were found at a lower rate in the Olanzapine&#x0D; and L-Carnitine administered groups compared to the&#x0D; Olanzapine-only groups.&#x0D; Conclusion&#x0D; It was concluded that the degenerative histological&#x0D; findings in the testicular structure observed in the&#x0D; high-dose Olanzapine administered groups might be&#x0D; caused by the oxidative stress induced by Olanzapine&#x0D; in the testicular tissue. L-Carnitine, on the other hand,&#x0D; was thought to be effective in reducing testicular&#x0D; degeneration by reducing oxidative damage.

Succesful Use of Lipid Emulsion Theraphy In a Case of Extremely High Dose Olanzapine Intoxication.

In olanzapine intoxication alterations in consciousness defined as "agitation despite sedation" as well as cardiovascular and extrapyramidal side effects due to anticholinergic effects can be seen. In this case report, we aimed to present a patient who received a very high dose of olanzapine for suicide purposes benefited from intravenous lipid emulsion treatment (LET). A 20-year-old male patient, who received 840 mg of olanzapine for suicide, was brought to the emergency room, when the Glasgow Coma Scale was 5, he was intubated and given a single dose of activated charcoal. Later, he was admitted to the intensive care unit (ICU) intubated. The olanzapine level was measured as 653 μg L-1. The patient was started on LET and woke up at the sixth hour. In addition to the lack of strong evidence regarding the use of LET in olanzapine intoxication, it is seen that lipid therapy has been used successfully in patients. Compared with the cases in the literature, LET was successfully applied in our case, where the blood olanzapine level was very high. Although there is no evidence-based treatment in olanzapine intoxication, we believe that LET has a positive effect on neurological recovery and survival.

High-dose olanzapine in treatment-resistant schizophrenia: a systematic review

Treatment-resistant schizophrenia (TRS) affects approximately 30% of people with schizophrenia. Clozapine is the gold standard treatment for TRS but is not always suitable, with a proportion of individuals intolerant of side effects or unable to engage in necessary blood monitoring. Given the profound impact TRS can have on those affected, alternative pharmacological approaches to care are needed. To review the literature on the efficacy and tolerability of high-dose olanzapine (>20 mg daily) in adults with TRS. This is a systematic review. We searched for eligible trials published prior to April 2022 in PubMed/MEDLINE, Scopus and Google Scholar. Ten studies met the inclusion criteria [five randomised controlled trials (RCTs), one randomised crossover trial and four open label studies]. Data were extracted for predefined primary outcomes (efficacy, tolerability). Compared with standard treatment, high-dose olanzapine was non-inferior in four RCTs, three of which used clozapine as the comparator. Clozapine was superior to high-dose olanzapine in a double-blind crossover trial. Open-label studies demonstrated tentative evidence in support of high-dose olanzapine use. It was better tolerated than clozapine and chlorpromazine in two respective RCTs, and was generally well tolerated in open-label studies. This evidence suggests high-dose olanzapine is superior for TRS when compared with other commonly used first- and second-generation antipsychotics, including haloperidol and risperidone. In comparison with clozapine, the data are encouraging for the use of high-dose olanzapine where clozapine use is problematic, but larger, better designed trials are needed to assess the comparative efficacy of both treatments. There is insufficient evidence to consider high-dose olanzapine equivalent to clozapine when clozapine is not contraindicated. Overall, high-dose olanzapine was well tolerated, with no serious side effects. This systematic review was preregistered with PROSPERO [CRD42022312817].

Toxicity manifestations and sex differences due to MARTA olanzapine.

Olanzapine is widely used as a treatment for schizophrenia and other psychiatric disorders. Its metabolic side effects, including weight gain and hyperglycemia, are a clinical problem; however, their full mechanism is not yet clearly understood. Recently, it was reported that the accumulation of oxidative stress in the hypothalamus may cause obesity and diabetes mellitus. Epidemiologically, metabolic side effects are known to be more likely to occur in women. In the present study, we investigated and tested the hypothesis that olanzapine induces oxidative stress in the hypothalamus and induces metabolic side effects. We also examined its association with sex differences. Olanzapine was administered intraperitoneally to male and female C57BL/6 mice, and the expression levels of oxidative stress-responsible genes in the hypothalamus and cerebral cortex were measured by qRT-PCR. In addition, olanzapine was administered intraperitoneally to C57BL/6 and Nrf2 KO mice, and the expression level of total glutathione was measured. Gene expressions induced by the Keap1-Nrf2-regulated system showed different responses to olanzapine for each gene. Under the conditions of this experiment, cystine-glutamate transporter was decreased although heme oxygenase-1 and γ-glutamylcysteine synthetase were increased. It was also clear that these responses were not hypothalamus-specific. Long-term feeding with olanzapine suppressed weight gain in males but not females. No glucose intolerance was observed at 13 weeks of administration. Furthermore, deaths occurred only in females. In conclusion, this study failed to provide evidence that olanzapine induces oxidative stress in a hypothalamic-specific manner. Instead, sex differences were observed in response to long-term and high-dose olanzapine administration, suggesting that individual susceptibility to olanzapine toxicity occurred in female mice.

Impact on hospital-wide antipsychotic prescribing practices through physician peer comparison letters.

Peer comparison is a behavioral strategy that provides feedback to individuals on how they compare with others. It is used to improve health care quality, reduce inappropriate prescribing, and improve physician performance. There is very little data on peer comparison and the impact on system-wide prescribing practices, particularly with antipsychotics. To that end, the Maryland statewide pharmacy and therapeutics committee reviews hospital-level antipsychotic data for 5 facilities on a quarterly basis, including high doses and polypharmacy. One facility, Springfield Hospital Center, consistently stood out in 2016 as having higher rates of high doses of haloperidol, olanzapine, and quetiapine as well as patients receiving 3 or more antipsychotics. The pharmacist began to send out individual letters to the psychiatrists detailing their prescribing habits in these areas compared with other psychiatrists and the other state facilities. Over the course of 4 years, the percentage of patients on high doses of 3 antipsychotics substantially decreased. The percentage of patients on polypharmacy in the facility decreased, but not at the same rate as the other hospitals, leaving the facility even higher than the state average at the end of the 4-year period. Pharmacist-initiated physician peer comparison letters were associated with a considerable decrease in the prevalence of high-dose olanzapine, haloperidol, and quetiapine but did not appear to impact antipsychotic polypharmacy. This type of communication may be beneficial for stimulating system-wide changes in prescribing practices for high doses of antipsychotics; however, more individualized interventions are likely needed to reduce antipsychotic polypharmacy.

PCSK9 mediates dyslipidemia induced by olanzapine treatment in schizophrenia patients.

It is controversial whether dyslipidemia induced by antipsychotics in schizophrenia patients is due to weight gain or direct effects of drug treatment. However, recent evidence showed that olanzapine can cause acute dyslipidemia independent of weight change, and the underlying mechanism remains unclear. To study the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in olanzapine-induced dyslipidemia, we analyzed in schizophrenic patients and in experimental models involving mice and cells to understand the mechanism. Disturbances in lipid homeostasis caused by 8-week olanzapine treatment were prospectively evaluated in first-episode schizophrenic patients. Additionally, mice were administered olanzapine for 5 or 8 weeks to delineate liver actions for PCSK9 contributing to olanzapine-induced dyslipidemia. Olanzapine directly affected lipid metabolism, suggesting dyslipidemia is independent of weight gain in schizophrenia patients. Olanzapine administration significantly increased plasma PCSK9, which was positively correlated with the increment in low-density lipoprotein cholesterol (LDL-C) (r=0.77, p<0.001). Increased expression of PCSK9 in liver tissue of olanzapine-treated mice occurred prior to olanzapine-induced LDL-C abnormality. Hepatic sterol regulatory element binding protein-2 (SREBP-2) protein levels increased in mice treated with olanzapine but largely declined in olanzapine (10μM) treated HepG2 cells, which suggested high concentration of olanzapine-induced PCSK9 increase was not SREBP-2-dependent. However, expressions of sterol regulatory element binding protein-1c (SREBP-1c) significantly increased in the higher dose treated groups, which was consistent with PCSK9 increases. Activation of SREBP-1c after high-dose olanzapine treatment promotes PSCK9 expression, and consequently the degradation of low-density lipoprotein receptors results in LDL-C increase. Lipid disturbances caused by olanzapine are independent of weight gain. The study explored the relationship between SREBP-1c and PCSK9 in regulating lipoprotein metabolism after olanzapine treatment in vitro and in vivo. Further exploration of olanzapine-induced PCSK9 regulatory mechanisms may help identify control points for inhibition of olanzapine-mediated dyslipidemia.

Olanzapine Reduction From High Dose to Standard Dose: A Retrospective Chart Review.

Although high-dose olanzapine might be a treatment option in patients with treatment-resistant schizophrenia, it can be reduced to the standard dose after symptoms are stabilized. We examined the rate of olanzapine reduction from high to standard dose and whether this change was successful. We included patients who received high-dose olanzapine (>20 mg/d) for 4 weeks or longer at our hospital. First, we retrospectively followed the patients for 6 years and estimated the percentage of those whose olanzapine was reduced from high to standard dose. Second, we followed patients who received olanzapine reduction for 1 year and estimated the rate of success based on the study-defined criteria for unsuccessful reduction. We also explored factors associated with the dose reduction and successful results. Among 110 patients who received high-dose olanzapine treatment, 72 had their olanzapine dose reduced to the standard dose for 6 years; the duration of high-dose olanzapine treatment was significantly and negatively associated with a reduction in olanzapine (hazard ratio, 0.98; 95% confidence interval, 0.98-0.99). Among the patients whose olanzapine was reduced, 50 achieved successful reduction for 1 year. Among the reasons for the reduction, an unknown reason was significantly associated with successful reduction (hazard ratio, 4.93; 95% confidence interval, 1.55-22.8). The findings suggest that high-dose olanzapine can be reduced to the standard dose after stabilization of symptoms in most patients with schizophrenia.

High-dose olanzapine in treatment resistant schizophrenia. A case report and literature review

ObjectiveWe report a case of a 58-year-old gentleman who was hospitalised intermittently for one year due to treatment resistant schizophrenia. Prior to hospitalisation he had been prescribed standard antipsychotics for decades without full resolution of positive psychotic symptoms. During his final admission lasting six months he was guarded, suspicious, irritable, constantly paced the corridor and displayed thought block and paranoid persecutory delusions. He would not enter the assessment room or allow any blood or ECG monitoring, however, he was compliant with oral medication. He was successfully treated with high dose olanzapine (40mg/day) and was discharged to the community. The aim of this study is to bring awareness and add to the body of evidence for the use of high-dose olanzapine in patients with treatment resistant schizophrenia in whom a trial of clozapine is not possible.Case reportThe patient gave written consent for this case report to be written and presented. An extensive literature review was performed and key papers were identified. Discussion focuses on the key areas in the literature.DiscussionThis case demonstrates that high-dose olanzapine can be used effectively as an alternative to clozapine in treatment resistant schizophrenia.ConclusionThis case highlights the need for further evaluation of high-dose olanzapine as an alternative to clozapine in patients with treatment-resistant schizophrenia.

High dose olanzapine versus clozapine: risks and benefits in adolescents with psychosis

High dose olanzapine versus clozapine: risks and benefits in adolescents with psychosis

Systemic review: High dose olanzapine treatment for treatment resistant schizophrenia

ObjectivesSchizophrenia is a major mental illness with a progressive course. Thirty percent of cases of patients with schizophrenia do not respond to adequate trials of at least 2 different groups of antipsychotics,are currently classified as having treatment resistant schizophrenia (TRS). Clozapine remains the gold standard, treatment of choice for TRS. However, clozapine does not come without its own challenges. Its risk profile, particularly agranulocytosis, reported in 1% of cases, has led to the necessity of weekly blood counts within the first 18 weeks of treatment and subsequently every month with slow dose titration. Clinically, sedation, weight gain and hypersalivation may further hamper the compliance of patients. Non-compliance has been reported to cause rebound psychosis. Recent studies have raised questions as to which antipsychotic is most efficacious for TRS. Thus, we conducted a systematic review of high dose olanzapine treatment for people with TRS.MethodA systematic review of prospective studies found through search of PubMed, Scopus and hand-searched key papers which included randomized controlled trials and open-label studies which looked at high dose of olanzapine treatment response for TRS.ResultsThe study is currently ongoing and preliminary results will be presented at the conference in April 2017.ConclusionsThe gravity of burden TRS brings to patients extends itself to their families, carers and clinicians. Further evidence on which antipsychotic is more efficacious for patients with TRS would have huge implications in terms of health benefits for the patients, better informed clinical decisions and also health economics in general.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Systemic review: High dose olanzapine treatment for treatment resistant schizophrenia

ObjectivesSchizophrenia is a major mental illness with a progressive course. Thirty percent of cases of patients with schizophrenia do not respond to adequate trials of at least 2 different groups of antipsychotics are currently classified as having treatment resistant schizophrenia (TRS). Clozapine remains the gold standard, treatment of choice for TRS. However, clozapine does not come without its own challenges. Its risk profile, particularly agranulocytosis, reported in 1% of cases, has led to the necessity of weekly blood counts within the first 18 weeks of treatment and subsequently every month with slow dose titration. Clinically, sedation, weight gain and hypersalivation may further hamper the compliance of patients. Non-compliance has been reported to cause rebound psychosis. Recent studies have raised questions as to which antipsychotic is most efficacious for TRS. Thus, we conducted a systematic review of high dose olanzapine treatment for people with TRS.MethodA systematic review of prospective studies found through search of PubMed, Scopus and hand-searched key papers which included randomized controlled trials and open-label studies which looked at high dose of olanzapine treatment response for TRS.ResultsThe study is currently ongoing and preliminary results will be presented at the conference in April 2017.ConclusionsThe gravity of burden TRS brings to patients extends itself to their families, carers and clinicians. Further evidence on which antipsychotic is more efficacious for patients with TRS would have huge implications in terms of health benefits for the patients, better informed clinical decisions and also health economics in general.Disclosure of interestThe authors have not supplied their declaration of competing interest.

High-dose olanzapine for bipolar depression: proceed with caution.

To the Editor: High-dose olanzapine has gained momentum as an effective pharmacotherapy in individuals diagnosed with treatment-resistant schizophrenia, yet there is little evidence regarding its safety.1–4 Olanzapine is also indicated for the treatment of bipolar disorder; however, few guidelines are available regarding dosing of olanzapine for individuals with treatment-resistant bipolar disorder. The following case report highlights the need for increased guidance in the management of treatment-resistant bipolar disorder. Case report. Mr A is a white man with a long history of psychiatric disorders, specifically bipolar I disorder (DSM-IV-TR criteria). He also has a diagnosis of posttraumatic stress disorder and a history of alcohol dependence and cannabis use (DSM-IV-TR criteria); however, he is reported to have not used cannabis for over 2 years. Mr A complained of severe mood swings including daily anxiety and panic attacks several times weekly and paranoia. After failing treatment with several other mood stabilizers and antipsychotic medications and declining treatment with clozapine, olanzapine was prescribed by his primary care provider. Olanzapine was increased over the course of 4 weeks to 80 mg/d (40 mg oral twice a day) to control his symptoms. Mr A reported that the anxiety and panic attacks did not occur as frequently; however, he was now experiencing erectile dysfunction, which was believed to be due to high-dose olanzapine. Despite the erectile dysfunction, Mr A asked to maintain high-dose olanzapine, as he felt the benefits outweighed the risks. Over the following 2 weeks, his depressive symptoms fluctuated, and Mr A reported that he was still struggling with posttraumatic stress disorder but managing better with other symptoms. At the time of his presentation to the inpatient psychiatry ward, 5 weeks after the prescription of high-dose olanzapine, Mr A reported increasing anxiety, depression, paranoid delusions, guilt, and suicidal ideation. He also described symptoms similar to hyperreligiosity. Mr A denied use of any illicit drugs or alcohol prior to arriving at the hospital. The olanzapine dose was reduced to 40 mg/d (20 mg oral twice a day). Following this reduction, he showed immediate improvement in symptoms and felt significantly better. Mr A was provided with education regarding the benefits and risks of high-dose olanzapine and reported that this was “new information,” and he had not been adequately told of the dangers. At discharge, Mr A was stable on 40 mg/d of olanzapine. Although some studies have indicated the benefits of high-dose olanzapine, the dose is typically in the range of 20–60 mg/d rather than 80-mg/d, as was prescribed to Mr A.1,2 Greater guidance is needed to clarify procedures involved in dose escalation of olanzapine and monitoring of side effects. Further clinical trials highlighting the benefits and risks of high-dose olanzapine with a foundation on understanding mechanisms of treatment resistance should be a priority.

Use of very-high-dose olanzapine in treatment-resistant schizophrenia

Schizophrenia is a chronic illness with a progressive course that can be marked by resistance to antipsychotic treatment. This can make therapeutic support challenging for the practitioner, with results that are partial and unsatisfactory. In the literature, treatment with high-dose olanzapine (>20mg/day) appears to be a good alternative to clozapine, the gold standard for treatment-resistant schizophrenia. In the present observational prospective study, we studied the clinical and biological profiles of patients treated with olanzapine doses up to 100mg/day. In total, 50 patients were clinically and biologically assessed. We found a linear relationship between oral dose and serum concentration (Pearson's r=0.83, p<0.001) with effects of tobacco (p<0.05) and of coffee and tea consumption (p<0.01). Tolerance seemed to be good regardless of dose. No link was found between concentration and efficiency. Despite a nonexhaustive assessment of pharmacokinetic parameters, not least pharmacogenetic data (e.g., genotyping of cytochrome P450-1A2 or glycoprotein P Abcb1a), pharmacokinetic aspects alone cannot account for why the disease may sometimes be resistant to 20mg of olanzapine but respond to higher doses. A nuclear imaging study exploring brain occupancy by high-dose olanzapine, coupled with the abovementioned pharmacokinetic assessment, may prove a relevant experimental paradigm for studying the pathophysiological mechanisms of resistant schizophrenia.

A six month randomized controlled trial of long acting injectable risperidone 50 and 100 mg in treatment resistant schizophrenia

It has been suggested that atypical antipsychotic drugs (A-APDs) other than clozapine may be effective to improve positive symptoms in some patients with treatment resistant schizophrenia (TRS), if both the dose is higher, and the duration of the trial longer, than those which have been ineffective in non-TRS (NTRS) patients. This hypothesis was tested with long acting injectable risperidone (Risperdal Consta®, RLAI). One hundred sixty TRS patients selected for persistent moderate–severe delusions or hallucinations, or both, were randomized to RLAI, 50 or 100mg biweekly, in a six month, outpatient, double-blind, multicenter trial. We hypothesized that RLAI, 100mg, would be more effective than RLAI, 50mg. However, both doses produced clinically significant and equivalent improvement in PANSS Total, Positive, and Negative subscale scores, as well as key cognitive, global and functional measures, with increasing response during the course of the study, confirming the value of longer clinical trial duration for patients with TRS, but not superiority of the higher dose. The overall response rate was comparable to that previously reported for clozapine and high dose olanzapine, another A-APD, in TRS. Both doses of RLAI were equally well tolerated, producing minimal extrapyramidal side effects and few drop outs. Plasma levels of the active moiety, risperidone+9-hydroxyrisperidone, during treatment with RLAI 100mg, were comparable to those for 6–8mg/day oral risperidone, which have not been effective in TRS. Further study of RLAI, ≥50–100mg biweekly, should compare it with clozapine and oral risperidone in TRS, with duration of treatment ≥six months.

Adverse effects associated with high-dose olanzapine therapy in patients admitted to inpatient psychiatric care

Context. In 2012, Danish psychiatrist raised concerns regarding the use of high-dose olanzapine in the treatment of patients. The present study was part of an audit carried out by the Mental Health Services of the Capitol Region of Denmark regarding this topic. Objective. To assess the potential risks associated with high-dose olanzapine treatment (> 40 mg daily) in inpatient psychiatric units. Methods. The study was an observational case series based on review of patient charts. The main inclusion criterion was treatment with at least one daily dose > 40 mg olanzapine during the index admission in the period between 1st of January and 15th of March 2012. Six additional criteria were applied in order to target the subgroup of patients most likely to have experienced an adverse event due to treatment with olanzapine. The physician order entry system and the central patient register containing patient specific information about diagnoses and treatments were used for identification of study population. Results. The 91 patients included in the study received maximum daily doses of olanzapine ranging from 45 to 160 mg and in 25% of patients, the total antipsychotic load exceeded 2000 mg of chlorpromazine equivalents. Extrapyramidal symptoms and sedation were the most frequent adverse events with frequencies of 27% and 25%, respectively. Furthermore, other well-known adverse events such as weight gain (14%), hypotension (2%), neuroleptic malignant syndrome (2%) and corrected QT-interval (QTc) prolongation (1%) were also observed in some patients. Five patients died and in two of these cases, olanzapine was concluded to be a possible contributing cause of death. Conclusion. Increased frequency of extrapyramidal symptoms and sedation as well as severe toxicity was observed in patients treated with up to 160 mg olanzapine per day. In order to prevent harmful outcomes, the clinicians should be ready to act appropriately if toxic effects of olanzapine occur. Treatment cessation should be immediate if serious adverse events such as neuroleptic malignant syndrome arise.

The possibility that requiring high-dose olanzapine cannot be explained by pharmacokinetics in the treatment of acute-phase schizophrenia

We examined clinical characteristics including serum olanzapine concentrations for acute schizophrenia patients who required above conventional doses. We performed a rater-blinded, randomized clinical trial in 12 psychiatric emergency sites. Eligible patients were 18–64 years old and met diagnostic criteria for schizophrenia, acute schizophrenia-like psychotic disorder, or schizoaffective disorder. A total of 42 patients were randomly assigned by means of sealed envelopes to receive risperidone (3–12mg/day; n=20) and olanzapine (10–40mg/day; n=22), with follow-up at 8 weeks. The Negative score of the Positive and Negative Syndrome Scale was significantly higher in patients who required high doses than in patients who responded to conventional doses. Serum olanzapine concentrations at the time of oral 20mg/day could be obtained from 5 out of 7 patients who subsequently required high-dose olanzapine. All values were more than 30ng/mL after 11–16h from dosing to sample collection, and the mean value was 47.876 (S.D. 21.546) ng/mL. Such concentrations are appropriate with respect to a therapeutic range of 20–50ng/mL. The present study has shown evidence that the reason for requiring high-dose olanzapine cannot be explained by pharmacokinetics in the treatment of acute-phase schizophrenia.