Sodium valproate and clozapine induced neutropenia: A case control study using register data.

BACKGROUND: The use of clozapine is limited due to the occurrence of neutropenia, and the rare but life threatening adverse event of agranulocytosis. There is little epidemiological research into clinical factors that may impact on this risk. We conducted a case control study examining the clinical risk factors for neutropenia patients treated with clozapine. METHOD: A case-control study was conducted within a database of anonymised electronic clinical records. All patients who discontinued clozapine due to a neutropenic event were included as cases. Matched controls were selected from patients with a documented clozapine exposure at the time of the clozapine neutropenic event of the case patient, matched by duration of clozapine treatment. RESULTS: 136 cases and 136 controls were included. In multivariable analysis, the concurrent use of sodium valproate was associated with neutropenia (Odds Raito (OR) 2.28, 95%CI: 1.27-4.11, p=0.006). There was a dose-response effect, with greater associations for higher doses. Patients who discontinued clozapine due to neutropenia were more likely to be of black ethnicity (OR 2.99, p<0.001), were younger (t=5.86, df=267, p<0.001), and received lower doses of clozapine (t=-2.587, p=0.01) than those who did not develop neutropenia. CONCLUSION: We identified an association between the concurrent use of sodium valproate and an increased risk of clozapine associated neutropenia. These results, taken in combination with the results from previous case series, suggest that the risk of clozapine associated neutropenia could be reduced by avoiding concurrent valproate treatment.

The Use of Granulocyte Colony-Stimulating Factor in Clozapine Rechallenge: A Systematic Review.

PURPOSE/BACKGROUND: Clozapine is associated with hematological abnormalities, with neutropenia and agranulocytosis of most concern. Granulocyte colony-stimulating factor (G-CSF) has been used to support clozapine rechallenge after neutropenia with the aim of maintaining the neutrophil count. This study aims to explore the practice, use, safety, and efficacy of G-CSF in this context. METHODS/PROCEDURES: We conducted a systematic review to identify all studies investigating or describing G-CSF as a prophylaxis to enable continued clozapine treatment during a rechallenge. FINDINGS/RESULTS: We identified 32 reports of patients who received G-CSF either regularly (n = 23) or as required (n = 9) to support clozapine rechallenge after an episode of neutropenia necessitating discontinuation of clozapine. Seventy-five percent (n = 24) of published cases remained on clozapine with the use of continual prophylactic G-CSF or after single G-CSF administrations (n = 8). Seventy percent (n = 16) of patients in receipt of continual prophylactic G-CSF were successfully maintained on clozapine. However, 1 of the 3 episodes of rechallenge in those with a history of severe agranulocytosis (absolute neutrophil count <0.1 × 10/L) had a recurrence of agranulocytosis at week 9. IMPLICATIONS/CONCLUSIONS: Our findings suggest that G-CSF can sometimes be safely used to support the maintenance of normal neutrophil counts and clozapine use after neutropenia. Publication bias is an important limitation, however. Also, few reports clearly documented the presence or absence of an independent nonclozapine cause of the index neutropenia, which may have increased success rates. Furthermore, adverse events were not systematically recorded. Prospective studies are needed to determine safety because if agranulocytosis occurs on clozapine while supported by G-CSF, there is no obvious alternate rescue therapy to promote granulopoiesis. From the available data, it is not possible to recommend this course of action for someone with a true clozapine agranulocytosis.

Autoantibodies against voltage-gated potassium channel and glutamic acid decarboxylase in psychosis: A systematic review, meta-analysis, and case series.

Antibodies to the voltage-gated potassium channel (VGKC) complex and glutamic acid decarboxylase (GAD) have been reported in some cases of psychosis. We conducted the first systematic review and meta-analysis to investigate their prevalence in people with psychosis and report a case series of VGKC-complex antibodies in refractory psychosis. Only five studies presenting prevalence rates of VGKC seropositivity in psychosis were identified, in addition to our case series, with an overall prevalence of 1.5% (25/1720) compared to 0.7% in healthy controls (12/1753). Meta-analysis established that the pooled prevalence of GAD65 autoantibodies was 5.8% (95% confidence interval [CI]: 2.0-15.6%; I2 = 91%; nine studies) in psychotic disorders, with a prevalence of 4.6% (95%CI: 1.2-15.9%; nine studies; I2 = 89%) and 6.2% (95%CI: 1.2-27.0%; two studies; I2 = 69%) in schizophrenia and bipolar disorder, respectively. People with psychosis were more likely to have GAD65 antibodies than controls (odds ratio [OR], 2.24; 95%CI: 1.28-3.92%; P = 0.005; eight studies; I2 = 0%). Among 21 participants with treatment-resistant psychosis, none had VGKC antibodies. The prevalence of VGKC antibodies is low in psychosis. Our preliminary meta-analysis suggests that GAD autoantibodies are more common in people with psychosis than in controls, although few studies accounted for the possibility of co-existing type 1 diabetes mellitus and the clinical significance of reported GAD titers remains unclear. The paucity of studies reporting thresholds for defining GAD abnormality and rates of comorbid type 1 diabetes mellitus precludes interpretations regarding the influence of GAD antibodies on the development of psychotic disorders and may have led to an overestimate of the prevalence of GAD. Our case series fails to support the hypothesis that VGKC antibodies are linked to treatment resistance in psychosis, but the literature to date is remarkably sparse.

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 × 10 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.