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A case of death due to combined use of multiple drugs is reported, and the pharmacokinetic interactions are discussed. A woman in her thirties was found dead in her home. A medico-legal autopsy found no findings suggestive of injury or natural disease. Toxicological analysis using liquid chromatography tandem mass spectrometry (LC-MS/MS) identified a toxic level of fluvoxamine (0.947 µg/mL), and concentrations greater than the therapeutic levels of levomepromazine (0.238 µg/mL) and trihexyphenidyl (0.225 µg/mL) were present, while bromazepam, haloperidol, sulpiride, and 7-aminoflunitrazepam were within or below their therapeutic ranges. Fluvoxamine is mainly metabolized by cytochrome P450 2D6 (CYP2D6), and levomepromazine is a potent CYP2D6 inhibitor. A high concentration of levomepromazine may increase the blood fluvoxamine level. Since the combined use of levomepromazine and fluvoxamine induces seizures, it may have been involved in causing the subject's death. In addition, combined use of trihexyphenidyl may potentiate anticholinergic effects of fluvoxamine overdose, including convulsions and coma. It was concluded that the cause of the subject's death was the interaction of multiple drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The clinical applications of antipsychotics for symptoms unrelated to schizophrenia, such as behavioral and psychological symptoms, in patients with Alzheimer's disease, and the likelihood of doctors prescribing antipsychotics for elderly people are increasing. In elderly people, drug-induced and aging-associated urinary disorders are likely to occur. The most significant factor causing drug-induced urinary disorders is a decrease in urinary bladder smooth muscle (UBSM) contraction induced by the anticholinergic action of therapeutics. However, the anticholinergic action-associated inhibitory effects of antipsychotics on UBSM contraction have not been sufficiently assessed. In this study, we examined 26 clinically available antipsychotics to determine the extent to which they inhibit acetylcholine (ACh)-induced contraction in rat UBSM to predict the drugs that should not be used by elderly people to avoid urinary disorders. Of the 26 antipsychotics, six (chlorpromazine, levomepromazine (phenothiazines), zotepine (a thiepine), olanzapine, quetiapine, clozapine (multi-acting receptor targeted antipsychotics (MARTAs))) competitively inhibited ACh-induced contractions at concentrations corresponding to clinically significant doses. Further, 11 antipsychotics (perphenazine, fluphenazine, prochlorperazine (phenothiazines), haloperidol, bromperidol, timiperone, spiperone (butyrophenones), pimozide (a diphenylbutylpiperidine), perospirone, blonanserin (serotonin-dopamine antagonists; SDAs), and asenapine (a MARTA)) significantly suppressed ACh-induced contraction; however, suppression occurred at concentrations substantially exceeding clinically achievable blood levels. The remaining nine antipsychotics (pipamperone (a butyrophenone), sulpiride, sultopride, tiapride, nemonapride (benzamides), risperidone, paliperidone (SDAs), aripiprazole, and brexpiprazole (dopamine partial agonists)) did not inhibit ACh-induced contractions at concentrations up to 10 -5  M. These findings suggest that chlorpromazine, levomepromazine, zotepine, olanzapine, quetiapine, and clozapine should be avoided by elderly people with urinary disorders.

We present here a fatal case of heatstroke, involving olanzapine and levomepromazine medications. A male in his sixties was found dead in his storage room in the middle of August, with a high rectal temperature. Autopsy revealed congestion of the lungs without any specific findings. Quantitative toxicological analysis demonstrated concentrations of olanzapine, levomepromazine, 7-aminonitrazepam, and 7-aminoflunitrazepam in a femoral blood sample of 0.433 µg/mL, 0.177 µg/mL, 0.604 µg/mL, and 0.041 µg/mL, respectively. The concentration of olanzapine exceeded toxic levels; however, levomepromazine level was within the therapeutic range. Due to the blocking mechanism of both olanzapine and levomepromazine against muscarinic receptors, they might depress sweating and impair heat dissipation. Based on autopsy findings, results of toxicological examination, and investigation by the authorities, we concluded that the cause of death was heatstroke under the influence of olanzapine and levomepromazine.

Objectives: Methotrimeprazine is commonly used for the management of nausea but never tested formally against other drugs used in this setting. The aim was to demonstrate superior antiemetic efficacy., Design: Double-blind, randomised, controlled trial of methotrimeprazine versus haloperidol., Setting: 11 palliative care sites in Australia., Participants: Participants were >18 years, had cancer, an average nausea score of ≥3/10 and able to tolerate oral medications. Ineligible patients had acute nausea related to treatment, nausea for which a specific antiemetic was indicated, were about to undergo a procedure or had received either of the study drugs or a change in glucocorticoid dose within the previous 48 hours., Interventions: Based on previous studies, haloperidol was used as the control. Participants were randomised to encapsulated methotrimeprazine 6·25 mg or haloperidol 1·5 mg one time or two times per day and assessed every 24 hours for 72 hours., Main Outcome Measures: A ≥two-point reduction in nausea score at 72 hours from baseline. Secondary outcome measures were as follows: complete response at 72 hours (end nausea score less than 3), response at 24 and 48 hours, vomiting episodes, use of rescue antiemetics, harms and global impression of change., Results: Response to treatment at 72 hours was 75% (44/59) in the haloperidol (H) arm and 63% (36/57) in the methotrimeprazine (M) arm with no difference between groups (intention-to-treat analysis). Complete response rates were 56% (H) and 51% (M). In the per protocol analysis, there was no difference in response rates: (85% (44/52) (H) and 74% (36/49) (M). Complete per protocol response rates were 64% (H) and 59% (M). Toxicity worse than baseline was minimal with a trend towards greater sedation in the methotrimeprazine arm., Conclusion: This study did not demonstrate any difference in response rate between methotrimeprazine and haloperidol in the control of nausea., Trial Registration Number: ACTRN 12615000177550., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Early clinical response predicts symptomatic remission and recovery in the maintenance treatment phase of first-episode schizophrenia (FES). However, little is known about predictors of symptomatic remission during acute treatment of severely ill patients with FES. Here, we conducted a secondary analysis of our retrospective observational study, which examined response, remission and treatment-resistance rates in seriously ill patients with FES spectrum disorders involuntarily hospitalized and treated with algorithm-based pharmacotherapy., Methods: We performed a retrospective chart review of 131 involuntarily admitted patients with schizophrenia or schizoaffective disorder. Our algorithm aimed to delay olanzapine treatment, standardize medications and suggest initiation of clozapine after failure of third-line antipsychotic treatment. The duration of each adequate antipsychotic treatment at an optimal dosage was 4 weeks or more. Remission was defined using the symptom-severity component of consensus remission criteria. A logistic regression model was applied to identify significant predictors of remission at discharge., Results: Overall, 74 patients (56%) were in remission at discharge. Non-remitters were hampered from becoming remitters mainly by the presence of negative symptoms. There were no differences in first-line antipsychotics, dosage of antipsychotics at time of response and adherence rates to algorithm-based pharmacotherapy between remitters and non-remitters. Shorter duration of untreated psychosis, favourable early response and less negative symptoms at baseline were identified as independent predictors of remission at discharge., Conclusions: The importance of early intervention and specific and adequate treatments of negative symptoms is highlighted., (© 2017 John Wiley & Sons Australia, Ltd.)

Background: This is an updated version of the original Cochrane Review published in Issue 4, 2013, on Levomepromazine for nausea and vomiting in palliative care.Nausea and vomiting are common, distressing symptoms for patients receiving palliative care. There are several drugs which can be used to treat these symptoms, known as antiemetics. Levomepromazine is an antipsychotic drug is commonly used as an antiemetic to alleviate nausea and vomiting in palliative care settings., Objectives: To evaluate the efficacy of, and adverse events associated with, levomepromazine for the treatment of nausea and vomiting in palliative care patients., Search Methods: For this update we searched electronic databases, including those of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, up to February 2015. We searched clinical trial registers on 7 October 2015 for ongoing trials., Selection Criteria: Randomised controlled trials of levomepromazine for the treatment of nausea or vomiting, or both, in adults receiving palliative care. We excluded studies in which symptoms were thought to be due to pregnancy or surgery., Data Collection and Analysis: We assessed the potential relevance of studies based on titles and abstracts. We obtained copies of any study reports that appeared to meet the inclusion criteria for further assessment. At least two review authors read each paper to determine suitability for inclusion and discussed discrepancies in order to achieve a consensus., Main Results: In the original review, we identified 421 abstracts using the search strategy. We considered eight studies for inclusion but ultimately excluded them all from the review. We updated the search in February 2015 and identified 35 abstracts, but again none met the inclusion criteria. We identified two trials from clinical trial registers, one of which is ongoing and one of which was closed due to poor recruitment., Authors' Conclusions: As in the initial review, we identified no published randomised controlled trials examining the use of levomepromazine for the management of nausea and vomiting in adults receiving palliative care, and our conclusion (that further studies of levomepromazine and other antiemetic agents are needed to provide better evidence for their use in this setting) remains unchanged. We did, however, identify one ongoing study that we hope will contribute to the evidence base for this intervention in future updates of this review.

Objective: This study was a comparative investigation of the clinical efficacy and safety of intramuscular (IM) olanzapine, IM haloperidol, and IM levomepromazine in acute agitated patients with schizophrenia., Methods: The subjects were 122 inpatients. Their clinical symptoms were assessed using Positive and Negative Syndrome Scale Excited Component (PANSS-EC), PANSS, and Agitation-Calmness Evaluation Scale, and their safety were assessed using the Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale (BARS), and Drug-induced Extrapyramidal Symptoms Scale (DIEPSS)., Results: The mean changes from baseline on the PANSS-EC, Agitation-Calmness Evaluation Scale, Abnormal Involuntary Movement Scale, BARS, and DIEPSS scores were significantly better in both IM olanzapine and IM levomepromazine than in IM haloperidol. Of these, the mean changes from baseline on the BARS and DIEPSS scores were significantly better in IM olanzapine than in IM levomepromazine. The mean change from baseline on the PANSS positive score was significantly better in both IM olanzapine and IM haloperidol than in IM levomepromazine., Conclusions: The results of this study suggest the possibility that the anti-agitation effects of IM olanzapine and IM levomepromazine are more rapid than those of IM haloperidol. No worsening of EPS was observed. Our results also suggest that compared with IM levomepromazine, IM olanzapine is safer and affords greater improvement in symptoms., (Copyright © 2014 John Wiley & Sons, Ltd.)

Objective: This retrospective chart review assessed the efficacy, dose, and safety of methotrimeprazine in palliating end-of-life symptoms in children and infants., Methods: A retrospective chart review was conducted of 18 hospitalized pediatric patients who were treated with methotrimeprazine in their last two weeks of life. Data collected included age, diagnosis, symptoms, methotrimeprazine dose, route, efficacy, and any documented adverse effects., Results: Patients' ages ranged from 16 days to 17 years. Underlying conditions included malignancies, trauma, and various neurodegenerative and congenital diseases. All patients (n = 18) were treated for symptoms of agitation, delirium, or restlessness. Most patients also experienced respiratory secretions/congestion (n = 15), pain (n = 13), and/ or dyspnea (n = 9). Less common symptoms included nausea/emesis (n = 5) and spasticity (n = 1). Methotrimeprazine dosages ranged from 0.02 mg/kg/dose to 0.5 mg/kg/dose. Routes of administration included intravenous (n = 13), oral/gastrostomy tube (n = 6), or subcutaneous (n = 4). Sedation (n = 6) was the only documented adverse effect, although when agitation was present, this was potentially an intended and perceived-to-be-beneficial effect., Conclusion: Methotrimeprazine, an old drug with diverse receptor activity and multiple routes of administration, appears to be an effective tool in treating complicated end-of-life symptoms in children and infants. This study provides a foundation for analysis with prospective and comparative trials, which may further quantify its benefit.

Background: Nausea and vomiting are common, distressing symptoms for patients receiving palliative care. There are several agents which can be used to treat these symptoms. Levomepromazine is an antipsychotic drug which is commonly used to alleviate nausea and vomiting in palliative care settings., Objectives: To evaluate the efficacy of and adverse events (both minor and serious) associated with the use of levomepromazine for the treatment of nausea and vomiting in palliative care patients., Search Methods: We searched the electronic databases including CENTRAL, MEDLINE, and EMBASE using relevant search terms and synonyms in March 2013., Selection Criteria: Randomised controlled trials of levomepromazine for the treatment of nausea or vomiting, or both, for adults receiving palliative care. Studies where symptoms were thought to be due to pregnancy or surgery were excluded., Data Collection and Analysis: The potential relevance of studies was assessed based on titles and abstracts. Any study reports which appeared to meet the inclusion criteria were obtained for further assessment. All three authors read these papers to determine their suitability for inclusion and discussed discrepancies to achieve a consensus., Main Results: The search strategy identified 421 abstracts from which eight studies were considered but all were excluded from the review., Authors' Conclusions: No randomised controlled trials were identified examining the use of levomepromazine for nausea and vomiting in palliative care. Further studies of levomepromazine and other antiemetic agents are needed to provide better evidence for their use in this setting.

Two schizophrenic patients who had been taking medication for a long period presented with visual disturbance of 6-month duration. Slit-lamp examination revealed fine, discrete, and brownish deposits on the posterior cornea. In addition, bilateral star-shaped anterior subcapsular lens opacities, which were dense, dust-like granular deposits, were noted. Although we strongly suspected that the patient might have taken one of the drugs of the phenothiazine family, we were unable to obtain a history of medications other than haloperidol and risperidone, which were taken for 3 yr. We performed a drug profiling test using urine samples and detected methotrimeprazine. The patient underwent surgery for anterior subcapsular lens opacities. Visual acuity improved in both eyes, but the corneal deposits remained. We report an unusual case of methotrimeprazine-induced corneal deposits and cataract in a patient with psychosis, identified by using the urine drug profiling test.

Background: Levomepromazine is an 'older' typical antipsychotic medication licensed for use in schizophrenia but sparingly prescribed in the United Kingdom., Objectives: To determine the clinical effects and safety of levomepromazine compared with placebo or antipsychotic medications for schizophrenia and schizophreniform psychoses., Search Strategy: We searched the Cochrane Schizophrenia Group's Register (December 2008) which is based on regular searches of, amongst others, BIOSIS, CENTRAL CINAHL, EMBASE, MEDLINE and PsycINFO. References of all identified studies were inspected for further trials. We also contacted relevant pharmaceutical companies for additional information., Selection Criteria: All randomised trials comparing levomepromazine with placebo or other antipsychotics for schizophrenia and schizophreniform psychoses were included., Data Collection and Analysis: Data were extracted independently. For dichotomous outcomes, we calculated relative risk (RR) (random-effects model), 95% confidence intervals (CI) and, where appropriate, number needed to treat (NNT) was calculated. We avoided the use of number needed to harm (NNH), as an alternative we used number needed to treat for an additional beneficial outcome (NNTB) and number needed to treat for an additional harmful outcome (NNTH) to indicate the direction of effect. For continuous outcomes, we calculated weighted mean differences (WMD)., Main Results: The review currently includes 4 RCTs with 192 participants. For our primary outcome of leaving the study early, levomepromazine was not significantly different compared with other antipsychotics. The levomepromazine arm was significantly better on CGI severity compared with chlorpromazine (n=38, 1 RCT, WMD -0.80 CI -1.51 to -0.09). Risperidone was better for CGI endpoint scores (n=42, 1 RCT, RR 2.33 CI 1.11 to 4.89, NNT 3 CI 2 to 10) compared with levomepromazine. Recipients given levomepromazine had a better BPRS endpoint score (n=38, 1 RCT, WMD -9.00, CI -17.46 to -0.54) and PANSS total score (n=38, 1 RCT, WMD -15.90, CI -30.30 to -1.50) than chlorpromazine. Risperidone recipients noticed a significant difference for the outcome 'at least 20% reduction' on BPRS endpoint score (n=42, 1 RCT, RR 3.33 CI 1.07 to 10.42, NNT 3 CI 2 to 14) compared with levomepromazine. Levomepromazine caused less tremor (n=41, 1 RCT RR 0.12 CI 0.02 to 0.87 NNTB 3 CI 2 to 8), less antiparkinsonian medication administration (n=79, 2 RCTs, RR 0.39 CI 0.17 to 0.90, NNTB 5, CI 2 to 21) compared with haloperidol. Levomepromazine caused less akathisia compared with chlorpromazine, but more hypotension compared with risperidone (n=42, 1 RCT, RR 2.50 CI 1.21 to 5.18, NNTH 3, CI 2 to 7). Dizziness was common with levomepromazine compared with other antipsychotic medications., Authors' Conclusions: Available data does not enable us to confidently comment on the effectiveness of levomepromazine for schizophrenia. Larger, more robust, studies comparing levomepromazine with other antipsychotics including clozapine are much needed.

Purpose: Long-term persistence of use, lack of co-prescribed anticholinergic antiparkinson drugs and low mortality may indicate effectiveness and safety of antipsychotic drugs. We aimed to assess 3-year prescription persistence, concomitant use of anticholinergics and mortality related to the use of all antipsychotic agents available in Norway., Methods: Data were drawn from the Norwegian Prescription Database on the sales of antipsychotic and anticholinergic antiparkinson agents in 2004 to a total of 52,427 patients. The primary study group was a subgroup of 34,494 patients who were prescribed only one antipsychotic agent in 2004. The patients were re-investigated in 2007. For each of the 13 antipsychotic agents studied, assumed prescription persistence was assessed in light of use of anticholinergic antiparkinson agents in 2004, and casualty rates were noted., Results: The highest persistence was demonstrated for zuclopenthixol (69.8%) and clozapine (88.4%). Zuclopenthixol was often co-prescribed with anticholinergics (22.2%), in contrast to clozapine (3.6%). Ziprasidone was associated with a low mortality (OR = 0.08), while chlorprotixene and haloperidol were associated with a high mortality (OR = 1.34 and 3.97, respectively) compared to levomepromazine., Conclusions: Clozapine demonstrated a high degree of continuity of prescription and a low level of concomitant use of anticholinergics. Zuclopenthixol also demonstrated a high degree of continuity of prescription, despite a considerable degree of co-prescribed anticholinergics. We did not find that any antipsychotic other than ziprasidone was associated with a low mortality. The use of haloperidol seemed to confer a mortality risk three times that of any of the other antipsychotic agents included.

Objective: To investigate the etiologic diagnoses of parkinsonism, underlining aspects of each form and comparing our findings with those published in a similar setting, 10 years before., Methods: A large cohort of 1528 patients with parkinsonism was analyzed, gathering data on demography, motor and non-motor characteristics, as well as the final etiologic diagnoses based on established criteria., Results: Parkinson's disease (PD) was the most common diagnosis representing 74.7%, followed by drug-induced parkinsonism (DIP) in 7.9%, vascular parkinsonism (VP) in 3.9%, other neurodegenerative disorders in 10%, and rare sporadic causes, divided as genetic, infectious and others, that summed 3.5%. Comparative analysis of these groups showed that each has particularities that extend beyond their diagnostic criteria., Conclusions: The main conclusions are that the most important causes of parkinsonism in this setting are typical, with PD been the most common diagnosis, although other causes were frequent, encompassing one fourth of all cases. Although DIP was identified in a particularly large part of this cohort, this proportion is smaller than demonstrated previously in a Brazilian study conducted in the 90s. This decrease probably reflects higher awareness regarding the risk of this motor complication and the more widely used newer antipsychotics., (Copyright 2010 Elsevier B.V. All rights reserved.)

Neuroleptics are a suspected cause of sudden death in psychiatric patients, especially in those with pre-existing cardiac lesions. As these lesions were previously shown to be associated with selenium (Se) deficiency, the aim of the present study was to evidence the possible protective effect of Se supplementation against cardiac lesions induced by the combination of the neuroleptic drugs levomepromazine and risperidone in the rabbit. Two groups of 6 rabbits were treated with 3 mg/kg of levomepromazine daily intramuscularly combined with 1 mg/kg of risperidone intramuscularly every other week for 3 consecutive months, and one group additionally received a solution of sodium selenite (2 microg/kg/day) intramuscularly during the whole treatment period. Furthermore, one group of six untreated animals was given the Se supplementation and another group of six control animals received saline daily. Blood samples were drawn before and at the end of the treatment period for the measurement of serum Se levels. At the end of the study, all animals were sacrificed and their hearts were removed for the measurement of tissue Se concentrations. In addition, the hearts were prepared for histopathological examination. A variety of cardiac lesions was found in the neuroleptics-treated animals without supplementation and to a lesser extent in the control and Se-supplemented untreated animals. Importantly, only rare cardiac lesions were observed in neuroleptics-Se-treated animals. The most striking differences in Se concentrations were noted in the myocardium: as compared to controls, there was a 43% reduction in neuroleptics-treated, but non-Se-supplemented animals (p < .01), at the end of the treatment period, whereas only a 14% reduction (p < .05) was noted in the neuroleptics-Se-treated animals. These results confirm that neuroleptics induce cardiac lesions associated with Se deficiency. Selenium supplementation markedly decreased the incidence and severity of neuroleptics-induced cardiac lesions and these findings may serve as a basis for further evaluation of the protective role of Se supplementation in neuroleptics-treated patients. However, Se supplementation in normal animals without Se deficiency was also shown to be cardiotoxic.

Antipsychotic medication is often prescribed to persons with dementia exhibiting behavioural and psychological symptoms (BPSD). Use of atypical antipsychotics in elderly persons with dementia is associated with an increased risk of serious cerebrovascular adverse events and increased mortality. Based on a review of available literature, we conclude that atypical antipsychotics have a modest effect on BPSD and potentially serious side effects and that conventional antipsychotics appear to have even less favourable effects and adverse event profiles. Antipsychotic medication in patients with dementia exhibiting BPSD should only be prescribed for short-term treatment of severe symptoms associated with considerable distress or serious risk. Non-pharmacological interventions should be the first-line treatment approach in most cases.

We present a case of medication-induced akathisia in a 47-year-old woman with metastatic carcinoma of the ovary. Severe pacing and restlessness started after commencing a subcutaneous infusion with cyclizine 150 mg, haloperidol 2.5 mg and oxycodone 20 mg. She was also taking levomepromazine and fluoxetine orally at the time. By making changes to her medication, her symptoms resolved gradually. During the time of convalescence, she gained great symptomatic relief from using exercise pedals and it allowed her to go about usual everyday activities, such as eating and reading, while continuously treading the pedals.

Purpose: To evaluate the parameters of dogs anesthetized by different dissociative drugs protocols through continuous intravenous infusion., Methods: Thirty healthy dogs of both sexes were assigned randomly to three groups (G1, G2, and G3). G1 was administered with methotrimeprazine as a pre-anesthetic medication, intravenously midazolam-ketamine as bolus for induction and midazolam-ketamine by continuous intravenous infusion for a 60 minute-period of maintenance. G2: the same as for G1. plus an increase in the midazolam dose during maintenance. G3: the same treatment as for G2, plus the addition of xylazine during maintenance. Immediately after induction the anesthetic maintenance started, and measures were taken 15 minutes after pre-medication, at 10 minutes intervals, during maintenance (M0 to M7)., Results: Bradycardia, atrioventricular blockage, bradypnea and hypoxemia were shown in G3. G1 and G2 showed a slight hypotension only., Conclusion: There were some advantages by using the continuous intravenous via: no parameters oscillation and reduction in the anesthetic recovery period. The increase in midazolam dose brought about little parametric variations which were greater when xylazine was used, with a consequent hypoxemia, bradyarrhytmia, and decrease in respiratory frequency and minute volume.

Objective: We compared the effect of levomepromazine (LMP) with chlorpromazine (CPZ) in treatment-resistant schizophrenia (TRS)., Methods: We carried out a double-blind, parallel group study (n = 19/arm) with balanced randomization in blocks of 4 and stratification by sex. Subjects entered a 30-week trial, of which phases I-III were open: phase I (wk 0-6) baseline; phase II (wk 7-9) stepwise transition to haloperidol (HAL), 30 mg/d, plus benztropine (BT), 4 mg/d; phase III (wk 10-15) HAL, 40-60 mg/d, plus BT, 4-6 mg/d; phase IV (wk 16-20) stepwise transition to LMP or CPZ (500 mg/d) following randomization; phase V (wk 21-28) stepwise increase of LMP or CPZ (600-1000 mg/d, dose reduction permitted) to establish optimum dose; and phase VI (wk 29-30) optimized dose maintained. Criteria for TRS were based on those established by Kane et al in 1988. The criterion for a response to treatment was a reduction of 25% or more in total Brief Psychiatric Rating Scale score., Results: Both LMP (p = 0.007) and CPZ (p = 0.030) improved TRS relative to baseline. Although there was no significant difference between the 2 groups in treatment response at study end point, hierarchical linear modelling of longitudinal outcome revealed a significant (p = 0.006) advantage of LMP over CPZ for the BPRS total score. Ten of 19 participants on LMP and 8 of 19 on CPZ met the criterion for treatment response, and 9 of the 18 responders did so on 200-700 mg/d phenothiazine. The mean dose of responders was 710 (standard deviation [SD] 265) mg/d (LMP) and 722 (SD 272) mg/d (CPZ). Akathisia was associated with a nonresponse to phenothiazines (p = 0.010). BPRS scores increased significantly on HAL (p = 0.006). Two of 19 participants on LMP and 5 of 19 on CPZ withdrew early from the study., Conclusion: LMP and CPZ may be useful in the management of TRS. A modest advantage of LMP compared with CPZ was seen in longitudinal analysis. High doses of neuroleptics may contribute to TRS; reduction of neuroleptics to modest or moderate doses should be considered before categorizing a patient as treatment resistant.

Introduction: Nausea and vomiting are distressing symptoms affecting between 20% and 70% of patients with advanced cancer. Methotrimeprazine is a phenothiazine antipsychotic used in palliative care for the management of terminal agitation and nausea/vomiting but there is only anecdotal evidence to support its use in palliative care., Aim: To establish whether nausea/vomiting in palliative care patients is improved by the administration of low-dose methotrimeprazine., Methods: Patients with advanced malignancy were entered at different treatment levels according to symptom severity. The dose was altered according to response (minimum dose 6.25 mg daily po, maximum 25 mg by 24-h subcutaneous infusion). Symptoms and side effects were recorded daily from 0 (baseline) to day 5 using a four-point scale. Any improvement in nausea/vomiting score was taken as a response., Results: Sixty-five patients were entered. The cause of nausea and vomiting was multifactorial in the majority of patients, 35/65 (54%). As expected in a study of patients with poor performance status, the attrition rate was high. Of 53 patients evaluable for response at day 2, 33 (62%) showed some improvement in nausea or vomiting. At day 5, improvement was seen in 20/34 (58%). There was no significant change in "side effects" from baseline with time., Conclusion: These results suggest that methotrimeprazine has antiemetic activity.

Background: Sleep apnea syndrome occurs when, during sleep, breathing stops for 10 seconds or longer, with an index of 5 times or more an hour. It is clinically characterized by loud snoring at night, continuous or interrupted by pauses followed by loud breathing. Sleep is fitful, broken by arousals, and yields little rest. There is daytime excessive sleepiness with repeated involuntary falling asleep, often unknown by the subject., Clinical Description: In this article, we describe an observation of central sleep apnea syndrome in a female patient receiving an opiate replacement therapy., Method: An analysis of the before and after methadone withdrawal polysomnograhic tracing was done for this patient., Results: This diagnosis etiology and physiopathology are critically approached. Clinicians should be careful in treating induced sleep disorders in such patients., Conclusion: Prescribing benzodiazepines during an opiate withdrawal of the methadone type is not recommended when central apnea occurs.

Background: Delayed chemotherapy-induced emesis (DCIE) has significant patient and health economic impact. Up to 50% of patients on chemotherapy may develop DCIE. There is no accepted standard of care for DCIE., Patients and Methods: A prospective observational study of patients with high grade DCIE needing admission to hospital over a 2-year period. Single cycle delayed anti-emetic failure (DAF) per patient is reported. Twenty-five mg/24 hours subcutaneous levomepromazine rescue (SLR) was used. Control of nausea and vomiting was recorded in 2 time-periods: 0 to 24 hours and 24 to 48 hours., Results: Thirty-two patients (12 male, 20 female) required SLR. Median age 58 years (r. 35-76). Grade 0 nausea and vomiting (N and V) was attained within 24 hours in 75% and 81% of patients, respectively, and in 94% of patients for both by 48 hours. Side-effects of sedation and hypotension were mild., Conclusion: Levomepromazine has efficacious anti-emetic qualities in the rescue of patients with high grade DCIE needing hospital admission.

Background: The use of sedation at the end of life has aroused ethical controversy, attracting accusations of hastening death by gradually increasing sedative doses. The doctrine of double effect has been introduced as an ethical defense. This study aimed to determine how sedative doses change at the end of life and how often the doctrine of double effect might be relevant., Methods: Case note review was performed of 237 consecutive patients who died in a specialist palliative care unit. Sedative dose changes during the last week of life were noted and survival from admission was compared between groups of patients receiving no sedation, sedation for 7 days, or a commencement of sedation in the last 48 hours of life. There was detailed review of notes from patients who received a marked increase in sedative dose to explore the applicability of the doctrine of double effect., Results: Sedation was given to 48% of patients. Of these, 13% received sedatives for 7 days or more, while 56% commenced sedative use only in the last 48 hours of life. The groups receiving no sedation or sedation for less than 48 hours had the shortest survival from admission (mean, 14.3 and 14.2 days), whereas the 7-day sedation group survived for a mean of 36.6 days (P<.001). Sedative use and dose increased toward the end of life, but the detailed case note review disclosed only 2 cases where the doctrine of double effect may have been implicated., Conclusion: Sedative dose increases in the last hours of life were not associated with shortened survival overall, suggesting that the doctrine of double effect rarely has to be invoked to excuse sedative prescribing in end-stage care.

A number of psychotropic drugs, including tricyclic antidepressants, phenothiazine and lithium, have a well demonstrated risk of cardiotoxicity. Each individual therapeutic class has potentially deleterious effects on electrophysiology and myocardial function. The authors report a case showing how serious side effects may result from the association of these different classes in the presence of a coexistent heart disease, even when the underlying disease is mild.

Clozapine is an atypical antipsychotic known for its efficacy in refractory schizophrenia. However, according to different epidemiological studies clozapine can induce neutropenia in less than 3% of patients and may represent a major problem for the management of treatment-resistant patients not responding to conventional or other atypical antipsychotics. Recently, a few case of neutropenia have been reported following the addition of other medications to clozapine, notably paroxetine, risperidone, trimethoprim-sulfamethoxazole and erythromycin. In our report we present the case of Mr A., a 40-year-old Caucasian patient with a 20-year history of paranoid schizophrenia. After numerous trials with conventional antipsychotics, partial remission of psychotic symptoms was obtained with clozapine. Over the past eight years during his treatment with clozapine, the patient presented 2 episodes of neutropenia. The first episode came five years after starting clozapine and was attributed to the addition 6 weeks earlier of haloperidol (2 mg/day) to clozapine (250 mg/day) and divalproex (1,500 mg/day). Recently, one week after the addition of risperidone (2 mg/day) to clozapine (550 mg/day), leukocytes count dropped from 12 100/mm(3) to 5 700/mm(3) and neutrophils from 7 400/mm(3) to 900/mm(3). The patient was also taking haloperidol (4 mg/day), methotrimeprazine (35 mg/day), procyclidine (5 mg/day) and valproic acid (1,500 mg/day). Twelve days after discontinuation of risperidone, leukocytes and neutrophils count increased to 11,100/mm(3) and 6,300/mm(3) respectively while the treatment with clozapine was continued. The first eighteen weeks of treatment represent the period where the risk of neutropenia is the highest. In our patient neutropenia occurred 5 and 7 years after starting clozapine. It is proposed that the two neutropenic episode were precipitated by adding respectively haloperidol and risperidone to clozapine. Also, divalproex can potentially cause a decrease in white blood cell count and may have contributed to the two neutropenic episode. It is suggested that drug interactions may be responsible for neutropenia in clozapine treated patients and that clozapine should not necessarily be discontinued in the presence of neutropenia. Also we propose that hematological surveillance should be done on a weekly basis for 4 to 6 weeks following the addition of psychotropic drugs known for their potential to cause neutropenia when associated with clozapine. Therefore polypharmacy may contribute to cause neutropenia in clozapine treated patients and that discontinuation of an antipsychotic should be done before introducing another one.

A patient with chronic renal failure (CRF) developed neuroleptic malignant syndrome (NMS) after administration of risperidone and levomepromazine. In addition to the typical symptoms of NMS, massive intestinal bleeding was observed during the episode. This report suggests that NMS in a patient with CRF may be complicated by intestinal bleeding and needs special caution for this complication.

Objective: To date only five reports of neuroleptic malignant syndrome (NMS) related to olanzapine exist. The first case report was published in November 1998., Method: We report the case of a 78-year-old woman suffering from chronic schizophrenia who developed a NMS while being treated with olanzapine and levomepromazine. Before this her medication had been unchanged for more than 2 years., Results: When treated with olanzapine and levomepromazine, the patient had a fulminant NMS which was complicated with pneumonia. When the neuroleptic drug treatment was discontinued, the patient recovered. However, when this combination was restarted later due to severe agitation and hallucinations, the symptoms of NMS reappeared., Conclusion: This case report shows that the neuroleptic malignant syndrome can occur during olanzapine treatment as well as during treatment with conventional neuroleptics. This syndrome may develop even after a long and stable neuroleptic treatment.

The cytochrome enzyme P450 2D6 (CYP2D6) is thought to play a role in the human metabolism of fluvoxamine. Levomepromazine is a potent inhibitor of CYP2D6. We coadministered a low dosage of levomepromazine and fluvoxamine in 15 patients and found that the low dosage of levomepromazine was effective in counteracting the fluvoxamine-induced insomnia and did not increase plasma fluvoxamine levels. These results suggest that the inhibition of CYP2D6 by levomepromazine has little effect on fluvoxamine metabolism. Therefore, a low dosage of levomepromazine, used as a hypnotic agent, appears to be effective and safe when coadministered with fluvoxamine. Since this was a pilot study without a placebo control, a double-blind placebo-controlled study is needed to confirm our preliminary findings.

Levomepromazine (previously known as methotrimeprazine), despite virtually no high quality scientific data to support its use, has become a very popular antiemetic for use in patients with advanced cancer. This article considers the reasons for this.

Arrhythmogenic effects of phenothiazines appear to be associated with sudden death, whereas respiratory complications have received little attention. In this report we describe 5 cases with accompanying obstruction of the airways after intramuscular injections of levomepromazine (LPZ), a potent sedative phenothiazine, in combination with intravenous injections of benzodiazepine (BZ) during a 3-month period in a psychiatric intensive care unit. Two out of 5 cases were unpredictable because obstruction of the airways occurred 2 hours or more after the last injection. As compared with patients who received parenteral (intravenous or intramuscular) injections during the same period, the dose of intramuscular LPZ was significantly large in the 5 cases with obstruction of the airways. All 5 of these cases received intramuscular LPZ 0.52 mg/kg or more. In contrast, there was no patient with obstruction of the airways who received only intramuscular LPZ, the combination of LPZ and HDL, or BZ and HDL. The occurrence of obstruction of the airways among patients who received both intramuscular LPZ and intravenous BZ was significantly higher than among patients who received other drug regimes. These preliminary results suggest that the intramuscular use of LPZ with intravenous BZ may be a risk for obstruction of the airways.

Recently, with the increase in elderly population, we have had more opportunities to administer neuroleptics to elderly patients for hallucinatory delusional state, delirium, psychomotor excitement, wandering etc. However, little is known about the characteristics of the neuroleptic malignant syndrome (NMS) in elderly patients, which is the most serious side effect of neuroleptics. In this paper, we present the clinical course of five NMS patients in the presenium and senium. Case 1 was 72-year-old male who was diagnosed as having dementia of Alzheimer's type (with late onset). He showed nocturnal wandering, insomnia, and irritability. Tiapride 60 mg per day had been administered previously. Just after the addition of oxypertine 10 mg per day, NMS occurred, and he died of pneumonia a week later. Case 2 was 75-year-old male who was diagnosed as having vascular dementia. He showed insomnia, hyperactivity and wandering. He had been given levomepromazine (LPZ) 10 mg per day over a long period of time. At first, he had daily episodic fever, however, serum CPK levels did not increase at that time. A month later, all the symptoms of NMS appeared and then the patient's condition suddenly deteriorated and he died three days later. Case 3 was a 64-year-old male who was diagnosed as having dementia of Alzheimer's type (with early onset). He showed insomnia, irritability and violence. Tiapride 50-125 mg per day was administered along with oxypertine 50-115 mg per day. Almost two months later, NMS occurred. He had daily episodic fever at first, extrapyramidal symptoms and autonomic instabilities gradually increased. Soon after symptoms of NMS were completed. In this case, NMS seemed to be induced by bacterial pneumonia after long term administration of LPZ 5 mg per day. Case 4 was a 75-year-old female who was diagnosed as having dementia of Alzheimer's type (with late onset). She showed hallucinatory delusional state. Although she had autonomic instabilities just after adminstration of haloperidol 1-2 mg per day, NMS itself occurred after discontinuing the neuroleptic. Case 5 was a 61-year-old female who was diagnosed as having schizophrenia at the age of forty. She was given various neuroleptics over a period of time. The neuroimaging in SPECT showed her cerebral cortex was generally hypoactive. She had a tendency to have autonomic instabilities after the administration of relatively high potential neuroleptics. Risperidone 3-6 mg per day was administered, and almost a month later, autonomic instabilities increased and she was diagnosed as having NMS. All the patients would be able to have brain dysfunction, which suggested that such patients may be liable to NMS. In our patients, NMS occurred after the additional administration of oxypertine 10 mg per day or after long time administration of LPZ 5 mg per day. It was suggested that NMS could occur after the administration of low dose and relatively low potential neuroleptics in elderly patients. Our 3 of 5 patients showed the delayed type of NMS, which might be relatively more frequent in senior and presenior patients than in younger patients. In case 3, NMS was induced by the somatic disease (bacterial pneumonia), however in other cases, NMS was not always induced by somatic disease. Our 4 of 5 patients experienced some of the symptoms of NMS--episodic fever, extrapyramidal symptoms and autonomic instabilities--before the onset of NMS. Such symptoms may be "pre-steps" to NMS. Once NMS occurred, the patient's systemic condition tended to deteriorate acutely. Due to the fact that our 2 of 5 patients died, it was suggested that the prognosis of the NMS patients in presenium and senium tends to be much worse. It is important to find the "pre-steps" to NMS and treat them as soon as possible for better prognosis.

Emigration is often followed by psychic disorders. The special issue of Germans from the GUS-States immigrating to Germany is presented. The modus of paranoid reaction is discussed along the biography and the criteria of ICD 10. The acute paranoid psychosis was complicated by a neuroleptic malignant syndrome.

To date, no universally applicable recommendations are available for the treatment of patients with postherpetic neuralgia. A mixture of clinical anecdotes, experimental findings and observations from clinical trials form the basis of the medical arsenal for this condition. Tricyclic antidepressants are commonly used, and clinical experience and several investigations have documented their effectiveness. Today, single entity antidepressants, which can be combined with neuroleptics to increase analgesia, are generally recommended for the treatment of postherpetic neuralgia. Some authors also recommend the additional administration of an opioid if analgesia is inadequate. Just over a decade ago, opioids were considered ineffective for the treatment of neuropathic pain; however, more recent investigations relating to the use of opioids, primarily in the treatment of nontumour-related chronic pain, have led to a revision of their use in neuropathic pain. Nevertheless, the use of opioid therapy for neurogenic pain remains controversial. Tramadol is a synthetic, centrally acting analgesic with both opioid and nonopioid analgesic activity. The nonopioid component is related to the inhibition of noradrenaline (norepinephrine) reuptake and stimulation of serotonin (5-hydroxytryptamine; 5-HT) release at the spinal level. In this regard, there are parallels with antidepressants, which are believed to potentiate the effect of biogenic amines in endogenous pain-relieving systems. There is evidence that, in tramadol, both mechanisms act synergistically with respect to analgesia. The aim of this pilot study was to investigate, for the first time, the analgesic efficacy and tolerability of tramadol, compared with the antidepressant clomipramine, in the treatment of postherpetic neuralgia. If necessary, clomipramine was used in combination with the neuroleptic levomepromazine. The study allowed individualised dosages at predetermined intervals up to a maximum daily dose of tramadol 600mg and clomipramine 100mg, or clomipramine 100mg with or without levomepromazine 100mg. 21 (60%) of 35 randomised patients (> or = 65 years) received the study medication over the 6-week period [tramadol n = 10; clomipramine with or without levomepromazine) n = 11]. After 3 weeks' treatment the dosage in both groups remained almost constant for the rest of the 6-week treatment phase (mean daily dose: tramadol 250 to 290mg; clomipramine 59.1 to 63.6mg). Only 3 patients required the combination of clomipramine and levomepromazine. At the outset, both groups recorded an average pain level of 'moderate' to 'very severe'. In correlation with increasing the study medication, this had decreased to 'slight' by the end of the treatment, when 9 of 10 patients in the tramadol group and of 6 of 11 patients in the clomipramine group retrospectively rated their analgesia as excellent, good or satisfactory. The psychological/physical condition of the patients did not change significantly during tramadol treatment. Sensitivity and depression parameters decreased in the clomipramine group. The incidence of adverse events for all patients was similar in both groups (tramadol 76.5%; clomipramine with or without levomepromazine 83.3%). In conclusion, tramadol would appear to be an interesting therapeutic alternative for pain relief in postherpetic neuralgia, particularly in patients who are not depressed. In clinical practice, tramadol and clomipramine can best be used differentially. For example, tramadol could be the drug of first choice in patients with obvious cardiovascular disease (not an uncommon problem in the > or = 65 year age group) in whom antidepressants are contraindicated, and similarly in patients in whom an antidepressant effect is not required. (ABSTRACT TRUNCATED)