RationaleThe last systematic analysis of suicidality in antidepressant clinical trials submitted for approval by the US Food and Drug Administration was in 2000. Given the attention to suicide and antidepressants in the early 2000s, the authors aimed to evaluate if there have been any changes in suicide rates in antidepressant clinical trials following 2000.Objective and MethodsThe Integrated Safety Summary data from approval packets for 14 investigational antidepressant programs (1991–2013, 40,857 patients, 10,890.5 exposure years) were used to calculate suicides and suicide attempts per 100,000 patient exposure years (standardized rates) for antidepressant and placebo treatment groups separately. Suicides/suicide attempt rates, mean age, and percent female were compared between 1991 and 1998 (pre-2000) and 2002–2013 (post-2000). Drug-placebo differences in suicide/suicide attempt rates were explored.ResultsAmong antidepressant-treated patients, the standardized suicide rate decreased significantly from pre- to post-2000 (643.6 to 25.8, p < 0.0001) as did the standardized suicide attempt rate (3975.7 to 645.4, p < 0.0001). For placebo-treated patients, the decrease was not significant for suicide rate (471.1 to 174.2, p = 0.66) but was significant for suicide attempt rate (from 3538.3 to 522.6, p < 0.001). Regression analysis showed a similar pattern with suicide/suicide attempt rates decreasing over time. None of the drug-placebo comparisons in suicide or suicide attempt rates were statistically significant. There was no change in percent female or mean age of patients in trials pre- and post-2000.ConclusionsDeaths by suicide and suicide attempts have decreased significantly in antidepressant clinical trials following 2000 compared to the decade before 2000. Basic demographic features of the patients have remained consistent and medication treatment effects on suicidality were not apparent. These findings may reflect enhanced screening procedures and effective exclusion of suicidal patients in clinical trials for depression.
Objectives: To evaluate the relationship between the mortality rates associated with psychiatric conditions like depression and schizophrenia compared with chronic medical conditions like hypertension and diabetes. Methods: Examined clinical trial safety data from New Drug Approval programmes reviewed by the US Food and Drug Administration and calculated all-cause and suicide/non-suicide mortality rates per 100,000 patient-exposure-years (PEY) for seven diabetes, 12 hypertension, 11 depression, and nine schizophrenia programmes (126,151 patients, 63,106.3 PEY). Results: Depression (894.8 ± 201.2) and schizophrenia (935.3 ± 214.6) had significantly higher all-cause mortality rates than diabetes (462.8 ± 70.8) and hypertension (448.4 ± 123.1). Psychiatric conditions had 1.9-2.1Â the medical conditions' mortality (p < 0.001). Non-suicide mortality rates for depression (506.2 ± 151.3), schizophrenia (550.9 ± 164.7), diabetes (457.2 ± 70.4) and hypertension (430.8 ± 120.6) were comparable. Only antidiabetics showed a signal for all-cause mortality (reduction of 37%, p ¼ 0.008). Conclusions: Depression and schizophrenia trial patients had comparable (if not higher) allcause mortality rates as older populations in diabetes and hypertension trials, even when excluding suicides. While generalizability of the rates themselves is limited, this study can adequately estimate the relational mortality among these conditions because of the high internal consistency of clinical trials. Potential signals for mortality reduction with active treatment should be considered for all investigational medications for chronic conditions with increased mortality, including psychotropics.
Background Agranulocytosis, defined as absolute neutrophil count (ANC) < 500/µL due to antithyroid drugs (ATDs), methimazole, carbimazole, and propylthiouracil (PTU), is a rare but serious complication with an occurrence of 0.1- 0.5%. ATDs induced agranulocytosis occurs abruptly, usually in the first three months of treatment but can occur any time after initiation of treatment, and although it is more common with a higher dose of methimazole > 30 mg/day, it can also occur with lower dosages. We present a rare case of agranulocytosis in a patient with Amiodarone-induced Thyrotoxicosis (AIT) with an ANC of 0/µL. Clinical Case A 68-year-old male with atrial fibrillation and heart failure was diagnosed with AIT when he presented to ED with thyrotoxicosis. Amiodarone was discontinued. Methimazole 40 mg daily with prednisone 20 mg daily was initiated. The ANC was 4360/µL. After nine weeks on methimazole, he presented with fever and tremors. The laboratory tests during this admission revealed WBC 1310/µL (4000-11000/µL) with granulocytes 0% (35%-80%), ANC 0/µL (1820-7420/µL), TSH < 0.01 (0.45-5.3mIU/mL), free T4 5.5 (0.58-1.64 ng/dL), free T3 4.4 (2.8-4.4 pg/dL). Methimazole was discontinued and antibiotics started. He received six doses of Granulocyte colony-stimulating factor (G-CSF) Filgrastim 480 mcg with an improvement of WBC to 6370/µL with a granulocyte count of 60% on the 6th day of admission. He eventually underwent thyroidectomy for treatment of the thyrotoxicosis. Discussion The proposed mechanism of agranulocytosis with ATDs is twofold. First, there is a direct toxic effect on mature circulating neutrophils and stem cells. The second is complement-mediated antibodies against granulocytes. Furthermore, AIT is associated with a higher risk for ATD induced agranulocytosis, although the mechanism remains elusive. The most common manifestations are fever and sore throat. The management includes discontinuation of ATD and starting antibiotics. G-CSF is used to treat agranulocytosis as it decreases the recovery time, the rate of infectious complications, and the mortality rate. Patients with ANC < 100/µL have a greater risk of infectious and fatal complications than patients with ANC > 100/µL. After resolution of agranulocytosis, methimazole or any other thionamides are generally not recommended due to concern for recurrence due to cross-reactivity among thionamides. Thyroidectomy or radioiodine therapy should be considered for definitive treatment of the hyperthyroidism in this circumstance. Conclusion Due to the low incidence and abruptness of agranulocytosis from ATDs, controversy exists over the value of routine monitoring of WBC count. This case emphasizes routine WBC monitoring could be considered in patients on higher doses of methimazole, especially in the first three months, due to the increased risk of agranulocytosis. Patient education on the life-threatening complication of ATD induced agranulocytosis is vital. It helps patients recognize early symptoms and seek medical care promptly, which aids in early intervention and reduces morbidity and mortality. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
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