Eromona Whiskey

A systematic review and meta-analysis of Hypericum perforatum in depression: a comprehensive clinical review

The herbal remedy St Johns wort is widely used as an antidepressant but its efficacy has not been systematically investigated. Meta-analyses and systematic reviews of published trials strongly suggest St Johns wort is more effective than placebo although comparative efficacy to standard antidepressants is less clearly established. We updated and expanded previous meta-analyses of St Johns wort, scrutinised the validity of published reports and examined possible mechanisms of action. Twenty-two randomised controlled trials were identified. Meta-analysis showed St Johns wort to be significantly more effective than placebo (relative risk (RR) 1.98 (95% CI 1.49-2.62)) but not significantly different in efficacy from active antidepressants (RR 1.0 (0.90-1.11)). A sub-analysis of six placebo-controlled trials and four active comparator trials satisfying stricter methodological criteria also suggested that St Johns wort was more effective than placebo (RR 1.77 (1.16-2.70)) and of similar effectiveness to standard antidepressants (RR 1.04 (0.94-1.15)). There was no evidence of publication bias. Adverse effects occurred more frequently with standard antidepressants than with St Johns wort. The mechanism of action of St Johns wort remains unknown. Future research should include large scale, appropriately powered comparisons of St Johns wort and standard antidepressants.

Restarting clozapine after neutropenia: evaluating the possibilities and practicalities

Clozapine remains the antipsychotic of choice for refractory schizophrenia despite its propensity for serious blood disorders. When neutropenia or agranulocytosis occur in people taking clozapine, cessation of treatment is mandated and relapse often results. Because such patients are usually unresponsive to other antipsychotics, many clinicians consider restarting clozapine, despite the risks involved. However, the risks of clozapine rechallenge vary according to the cause and nature of the blood dyscrasia.Neutropenia can arise because of factors unrelated or indirectly related to clozapine treatment. These include benign ethnic neutropenia, concomitant drug therapy, co-existing medical conditions and drug interactions. In such cases, clozapine may be restarted if non-clozapine causes of neutropenia are identified and eliminated, although concurrent treatment with lithium (to induce leukocytosis) is sometimes necessary. Close monitoring of the patient is essential because it is rarely possible to completely rule out the contribution of clozapine to the blood dyscrasia and because lithium does not protect against clozapine-related agranulocytosis. In cases of clozapine-induced neutropenia (as distinct from agranulocytosis, which may have a different pathology) rechallenge may also be considered and, again, lithium co-therapy may be required.Where clozapine is clearly the cause of agranulocytosis, rechallenge should not be considered or undertaken unless there are very exceptional circumstances (severe and prolonged relapse following clozapine discontinuation). In these cases, re-exposure to clozapine may rarely be attempted where there are facilities for very close and frequent monitoring. Granulocyte colony-stimulating factor is likely to be required as co-therapy, given the very high likelihood of recurrence.Uncertainty over the likely cause of blood dyscrasia in people taking clozapine, coupled with uncertainty over the mechanism by which clozapine causes both neutropenia and agranulocytosis, makes any attempt to restart clozapine a high-risk venture requiring the utmost caution.

Reasons for discontinuing clozapine: matched, case–control comparison with risperidone long-acting injection

BACKGROUND Clozapine has a range of serious adverse effects that may give rise to an increased risk of death. AIMS To compare reasons for discontinuation of clozapine with reasons for discontinuation of risperidone long-acting injection in age-matched individuals treated in the same clinical environment. METHOD Comparison of patients receiving clozapine and an age-matched control group receiving risperidone injection. RESULTS We established outcome for 529 consecutive patients receiving clozapine and 250 receiving risperidone (161 discontinuers from each group were compared). Adverse effects (odds ratio OR=2.19, 95% CI 1.31-3.67) and death (OR=7.0, 95% CI 2.09-23.5) were more commonly observed as reasons for discontinuation of clozapine than of risperidone. Clozapine was less likely to be withdrawn because of ineffectiveness than was risperidone (OR=0.034, 95% CI 0.01-0.14). Standardised mortality ratio (SMR) was significantly raised for patients receiving clozapine (SMR=4.17, 95% CI 2.78-6.26). Pneumonia was the most common single cause of death. CONCLUSIONS Clozapine use in patients with severe mental illness was associated with a significantly increased risk of death compared with that for the general population. Causation could not be established. Adverse effects and death are common causes of clozapine discontinuation.

A review of the adverse effects and safety of noradrenergic antidepressants

There are a variety of noradrenergic antidepressants available, most of which act by inhibiting neuronal noradrenaline re-uptake, although few drugs are specific for this action. Where drugs have numerous actions the adverse effects of noradrenaline reuptake may be difficult to isolate, although in this respect the adverse effects of reboxetine, a specific noradrenaline re-uptake inhibitor, are illuminating. Noradrenergic antidepressants typically cause minor changes in blood and heart rate, sweating and insomnia. Other pharmacological actions shown by non-specific antidepressants may act to worsen or mitigate these adverse effects. Noradrenergic drugs are less likely than selective serotonin reuptake inhibitors (SSRIs) to cause sexual dysfunction but more likely to cause urinary hesitancy. Doubts remain over the relative propensity for antidepressants with different modes of action to cause diabetes and hyponatraemia. Noradrenergic actions do not seem to confer a risk of death in overdose.

The importance of the recognition of benign ethnic neutropenia in black patients during treatment with clozapine: case reports and database study

Clozapine is the treatment of choice in refractory schizophrenia. Its more extensive use is limited by adverse effects and the need for regular blood monitoring. However, black patients are disadvantaged with respect to clozapine usage. Lower baseline Absolute Neutrophil Count compared with Whites leads to a greater frequency of blood testing, treatment interruptions and discontinuation. This may in part be explained by Benign Ethnic Neutropenia, but too few black patients are thus registered. The four cases described in this report underline some of the difficulties if this problem is under-recognized. Moreover, in our sample of 191 clozapine recipients in an inner London hospital, black patients account for approximately half, but only a small proportion, 8/95 (8.4%) are registered as having Benign Ethnic Neutropenia. None of the Benign Ethnic Neutropenia-registered patients discontinued treatment for haematological reasons. To optimize clozapine treatment and improve long-term outcomes, a significantly greater proportion of Black patients should be registered as having Benign Ethnic Neutropenia.

Optimizing outcomes in clozapine rechallenge following neutropenia: a cohort analysis

OBJECTIVE Certain patients with treatment-refractory schizophrenia may be rechallenged with clozapine following previous neutropenia. Evidence guiding patient selection and the effectiveness of lithium and granulocyte-colony stimulating factor (G-CSF) in rechallenge is limited, and factors associated with successful outcomes are unclear. METHOD Outcomes were studied in patients rechallenged with clozapine at a tertiary referral center between January 2007 and December 2013, following 1 or more previous trials terminated due to neutropenia, defined as an absolute neutrophil count (ANC) < 1.5 × 10(9)/L. Demographic characteristics, details of each clozapine trial including ANC, and coprescribed medication were extracted, and factors associated with rechallenge outcomes were examined. RESULTS Nineteen patients underwent clozapine rechallenge following previous neutropenia; 4 (21%) experienced further neutropenia, 2 of which developed agranulocytosis. Compared to successfully rechallenged patients, unsuccessfully rechallenged patients were significantly older (t = 2.10, P = .05), experienced onset of neutropenia sooner (W = 10.0, P = .03), and were more commonly coprescribed valproate. In addition to 5 patients with benign ethnic neutropenia (BEN), 8 patients not of an ethnicity associated with BEN also had idiopathic low neutrophil counts at baseline; lithium and G-CSF coprescription facilitated successful rechallenge in these patients. CONCLUSIONS In this selected population, the initial neutropenia was unlikely to be related to clozapine in a substantial proportion of cases. This group was successfully rechallenged following careful consideration of the risks and benefits, and lithium and G-CSF contributed to allowing continued clozapine therapy. In addition to black patients, other ethnic groups can have persistently low ANC unrelated to clozapine.

Granulocyte colony stimulating factor (G-CSF) can allow treatment with clozapine in a patient with severe benign ethnic neutropaenia (BEN): a case report.

Clozapine is the treatment of choice for treatment-resistant schizophrenia, but it is associated with a risk of neutropaenia and agranulocytosis. Clozapine use is regulated by mandatory blood monitoring in the UK, requiring cessation of treatment should the absolute neutrophil count (ANC) drop below specified values. Benign reductions in the ANC in non-white populations are common, and this can preclude a patient from receiving treatment with clozapine. A diagnosis of benign ethnic neutropaenia can reduce these treatment restrictions (UK specific), but the degree of neutropaenia can be significant enough to still prevent treatment. In this report, we show that response to granulocyte colony stimulating factor (G-CSF) may be quite variable and difficult to predict, but with careful monitoring it can be used to increase the ANC count and allow continued treatment with clozapine.

Evaluation of an antipsychotic information sheet for patients.

Introduction. The objective of this study was to develop a decision aid that patients and clinicians might use to help the patient in the process of selecting an antipsychotic medication. In addition, we aimed to determine the antipsychotic that patients would choose given the information contained in the leaflet. Method. We designed a questionnaire for patients to appraise the contents of the leaflet, their understanding of the leaflet and the potential impact of the leaflet on compliance and therapeutic relationship between patient and doctor. Results. We recruited 30 stable patients with a diagnosis of a psychotic illness to evaluate the leaflet and to determine patient choice. Over 90% of patients felt that the leaflet improved their knowledge of antipsychotic medication. Seventy-six percent of patients agreed that the leaflet contained the right type and amount of information. Seventy percent of respondents believed the leaflet would improve the trust between them and their doctors, and almost half (47%) stated they were more likely to take their medicine after reading the leaflet. Forty percent of patients would prefer to switch antipsychotic medication, with quetiapine being the most frequently preferred option. Conclusion. The results indicate that, for patients in the stable phase of their illness, the leaflet is a useful tool in selecting an antipsychotic medication and may represent a way forward in improving outcomes in patients with psychotic disorders. A larger study examining outcomes using this tool would establish its clinical utility.

Clozapine-Associated Agranulocytosis Treatment With Granulocyte Colony-Stimulating Factor/Granulocyte-Macrophage Colony-Stimulating Factor: A Systematic Review

Purpose/Background Clozapine is associated with hematological abnormalities, notably neutropenia, which may progress to agranulocytosis. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used to reduce the frequency and duration of clozapine-associated neutropenia. This review aims to explore the use, efficacy, and tolerability of these cytokines in the treatment of clozapine-associated agranulocytosis. Methods/Procedures We conducted a systematic review of published interventional and observational studies, case series, and case reports where G-CSF/GM-CSF was used to treat clozapine-associated agranulocytosis. Findings/Results We identified 29 reports (40 patients). The median duration of neutrophil recovery time after stopping clozapine and starting cytokine treatment was 7 days (range, 2–13 days) for those with agranulocytosis (absolute neutrophil count < 0.5 × 109 cells/L). Ninety-four percent (n = 29) had no serious adverse reactions, and no deaths occurred. Implications/Conclusions Our findings indicate that G-CSF/GM-CSF use is well tolerated and suggest that G-CSF can sometimes be safely used to reduce the duration of neutropenia associated with clozapine use. However, the interpretation of this outcome is difficult, given the likely publication bias for positive outcomes in case reports.

Melperone in treatment-refractory schizophrenia: a case series

Objective: Clozapine is the treatment of choice in refractory schizophrenia, but a substantial proportion of patients experience inadequate response or tolerate the drug poorly. Melperone has been suggested as a possible alternative in such patients. This case series examines the efficacy of melperone in refractory schizophrenia. Method: All patients prescribed melperone at the South London and Maudsley NHS Foundation Trust were identified using a pharmacy database. The main outcome was to determine the proportion of patients discharged on melperone. Results: Three of 21 patients were discharged on melperone. The primary reason for discontinuation was lack of efficacy. Conclusion: Melperone may be an option in a very few patients with refractory schizophrenia, but it should not be considered as an alternative to clozapine.