Benefit-Risk Assessment of Psychotropic Drugs in Older Patients with Chronic Obstructive Pulmonary Disease.

Depression, anxiety, and other mental health disorders, including bipolar disorder and schizophrenia, occur commonly in older adults with chronic obstructive pulmonary disease (COPD), and they are often inadequately treated. We review the available evidence for benefits and risks of pharmacologic treatments (e.g. selective serotonin reuptake inhibitors [SSRIs], serotonin-noradrenaline reuptake inhibitors [SNRIs], tricyclic antidepressants [TCAs], antipsychotic drugs, and benzodiazepines) for common mental illnesses in older persons with COPD. Evidence to use both SSRIs/SNRIs and TCAs from randomized controlled trials is uncertain for treating major depression in patients with COPD. However, population-based findings indicate that they are widely used, and this valuable intervention (preferably SSRIs/SNRIs) should not be denied for selected patients after evaluating potential risks and benefits, especially patients presenting with major depression and suicidal ideation, when a collaborative-care approach is being used. Although there is some evidence for the short-term use of benzodiazepines for treating insomnia, breathlessness, and anxiety in patients with COPD, their long-term use should be closely monitored or avoided to reduce the increased rate of major adverse events. Currently, there are only limited data on the use of antipsychotic drugs for managing schizophrenia or bipolar disorder in older patients with COPD. Hence, clinicians should use extra caution when prescribing antipsychotic agents and be vigilant for symptoms of acute respiratory failure and other adverse effects. Psychotropic medications are clearly beneficial for younger, healthy persons with depression and anxiety; however, the risk-benefit calculation is not so clear for treating psychological problems, schizophrenia, and bipolar disorder in older adults with COPD, given older-adult sensitivity to medications and the mixed findings of relatively few controlled trials.

Use of tricyclic antidepressants and other anticholinergic medicines by older Aboriginal Australians: association with negative health outcomes.

BACKGROUND: Aboriginal and Torres Strait Islander Australians have a relatively high prevalence of multimorbidity requiring treatment with medications. This study examines medication use and anticholinergic burden (ACB) among a cohort of older Aboriginal and Torres Strait Island people. METHOD: This cross-sectional study involving five Aboriginal communities (two in metropolitan Sydney and three on the mid-north coast of New South Wales) used a structured interview process to assess cognition, depression, and activities of daily living for a cohort of older adults (aged 60 years and over). Participants also reported on their health status, medical history, and prescription medications during the interview. ACB was calculated, and its association with adverse health outcomes including cognitive impairment, falls, hospitalization, and depressive symptoms were examined. RESULTS: Most participants (95%) were taking at least one regular medication with polypharmacy (≥5 medications) observed in 43% of participants; 12.2% had a significant ACB (≥3) with antidepressants being a major contributor. Anticholinergic medication use was associated with cognitive impairment, recent hospitalization (past 12 months), and depressive symptoms. After controlling for age, sex, and comorbidity, only the presence of depressive symptoms remained significantly associated with the use of anticholinergic medication (odds ratio 2.86; 95% confidence interval 1.48-5.51). CONCLUSIONS: Clinically significant ACB was common in older Aboriginal Australians and was largely attributable to inappropriate use of tricyclic antidepressants. Greater awareness of medication-related risk factors among both health care professionals and Aboriginal communities can play an important role in improving health and quality of life outcomes.

Estimating the Use of Potentially Inappropriate Medications Among Older Adults in the United States.

OBJECTIVES: Inappropriate prescribing of medications is common in health care, and is an important safety concern, especially for older adults, who have a high burden of comorbidity and are at greater risk for medication-related adverse events. This study aims to estimate the extent and cost of potentially inappropriate prescribing of medications to older adults in the United States. DESIGN: A cross-sectional study. SETTING: Medicare Part D Prescription Drug Program data set (2014-2018). PARTICIPANTS: Older adults who were enrolled in Medicare Part D Prescription Drug Program between 2014 and 2018. MEASUREMENTS: Potentially inappropriate medications were identified using the 2019 American Geriatrics Society Beers Criteria®. RESULTS: In 2018, 7.3 billion doses of potentially inappropriate medications were dispensed. The most common medications by number of doses dispensed were proton pump inhibitors, benzodiazepines, and tricyclic antidepressants, and the top five unique medications by reported spending were dexlansoprazole, esomeprazole, omeprazole, dronedarone, and conjugated estrogens. From 2014 to 2018, 43 billion doses of potentially inappropriate medications were dispensed, with a reported spending of $25.2 billion. CONCLUSION: Potentially inappropriate medication use among older adults is both common and costly. Careful attention to potentially inappropriate medication use and deprescribing when clinically appropriate could reduce costs and potentially improve outcomes among older adults.

Pharmacogenomics: An evolving clinical tool for precision medicine.

Pharmacogenomics, ie, the study of how an individual's genomic profile influences his or her response to drugs, has emerged as a clinical tool to optimize drug therapy. Certain variants in some genes increase the risk of severe, life-threatening adverse effects from certain drugs. Integrating pharmacogenomics into clinical practice to assist in drug selection and dosing has the potential to improve the outcomes of treatment, reduce the risk of drug-induced morbidity and death, and be cost-effective.

Pitfalls of using the risk ratio in meta-analysis.

For meta-analysis of studies that report outcomes as binomial proportions, the most popular measure of effect is the odds ratio (OR), usually analyzed as log(OR). Many meta-analyses use the risk ratio (RR) and its logarithm because of its simpler interpretation. Although log(OR) and log(RR) are both unbounded, use of log(RR) must ensure that estimates are compatible with study-level event rates in the interval (0, 1). These complications pose a particular challenge for random-effects models, both in applications and in generating data for simulations. As background, we review the conventional random-effects model and then binomial generalized linear mixed models (GLMMs) with the logit link function, which do not have these complications. We then focus on log-binomial models and explore implications of using them; theoretical calculations and simulation show evidence of biases. The main competitors to the binomial GLMMs use the beta-binomial (BB) distribution, either in BB regression or by maximizing a BB likelihood; a simulation produces mixed results. Two examples and an examination of Cochrane meta-analyses that used RR suggest bias in the results from the conventional inverse-variance-weighted approach. Finally, we comment on other measures of effect that have range restrictions, including risk difference, and outline further research.

Assessment of adverse events in clinical drug trials: Identifying amitriptyline's placebo- and baseline-controlled side effects.

Adverse events in clinical drug trials are often poorly assessed and reported. The absence of baseline assessment and structured symptom lists, as well as the fact that most drug trials are industry-sponsored are common sources of bias. In addition, adverse events are usually assessed in patient samples, which can bias results because of the misattribution of symptoms that are part of the illness to medication intake. We aimed to identify amitriptyline's placebo- and baseline-controlled side effects by examining a sample of healthy adults, using structured assessments via a symptom list. Forty healthy individuals were randomized equally to either a group taking 50 mg amitriptyline on four consecutive days or to a placebo control group. Complaints were assessed via the Generic Assessment of Side Effects Scale prior to and after four days of medication intake. Frequency of complaints and their intensity were compared after medication intake between the two groups while controlling for complaints at baseline. The amitriptyline group's participants reported having suffered from "dry mouth," "dizziness," "subjective blood circulation-associated problems," and "constipation" significantly more often. When taking into account the complaint's intensity, the amitriptyline group also reported higher intensities for "dry mouth," "dizziness," and "subjective blood circulation-associated problems." Our results emphasize the importance of a structured and well-controlled harm assessment. Future drug trials should report the placebo- and baseline-controlled side effects with a clear causal relationship to the intake of the drug under investigation, in addition to the frequency of complaints and their odds ratios. (PsycINFO Database Record

Prevalence and predictors of tricyclic antidepressant use among elderly Koreans in primary-care and specialty clinics.

OBJECTIVES: Tricyclic antidepressants (TCAs) are prescribed with caution in the elderly due to diverse side effects. We analyzed the patterns of TCA use in elderly patients in primary-care and specialty clinics and investigated factors influencing TCA prescriptions. MATERIALS AND METHODS: Elderly patients (≥ 65 years old) prescribed antidepressants in primary-care clinics in 2013 were included from the Health Insurance Review and Assessment Service-Aged Patient Sample (HIRA-APS). Prevalence of TCA prescriptions was assessed by insurance coverage status, clinical specialty, and region. Multiple logistic regression analysis was performed to compute odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with TCA prescriptions. RESULTS: TCAs and selective serotonin reuptake inhibitors (SSRIs) comprised 45.2% and 15.0% of all antidepressant prescriptions, respectively. TCAs comprised 61.5% and 20.7% of antidepressant prescriptions for pain and depression, respectively. Patients aged ≥ 85 years were less likely to be treated with TCAs (OR 0.81, 95% CI 0.79 - 0.84) than those aged 65 - 69 years. The odds for being prescribed TCAs were higher for patients residing in cities (OR 1.20, 95% CI 1.18 - 1.23), treated in nonpsychiatric clinics (OR 5.64, 95% CI 5.53 - 5.76), and those covered by Veteran's Health (OR 1.62, 95% CI 1.37 - 1.90) when compared to patients residing in the Seoul metropolitan area, treated in psychiatric clinics, or covered by National Health Insurance, respectively. The prescriptions of TCAs with pain diagnoses were much higher than prescriptions for depression (OR 1.87, 95% CI 1.82 - 1.93). CONCLUSIONS: Compared with a 2005 report, the prevalence of TCA prescriptions in elderly patients in Korea has decreased substantially, but remains high. Various efforts should be considered to reduce TCA prescriptions in the elderly.
.

Association of Antidepressant Medications With Incident Type 2 Diabetes Among Medicaid-Insured Youths.

Importance: Antidepressants are one of the most commonly prescribed classes of psychotropic medications among US youths. For adults, there is emerging evidence on the increased risk of type 2 diabetes in association with antidepressant use. However, little is known about the antidepressant treatment-emergent risk of type 2 diabetes among youths. Objective: To assess the association between antidepressant use and the risk of incident type 2 diabetes in youths by antidepressant subclass and according to duration of use, cumulative dose, and average daily dose. Design, Setting, and Participants: A retrospective cohort study was conducted using Medicaid claims data from 4 geographically diverse, large states of youths 5 to 20 years of age who initiated antidepressant treatment from January 1, 2005, to December 31, 2009. Exposures: Antidepressant use (selective serotonin reuptake inhibitors [SSRIs] or serotonin-norepinephrine reuptake inhibitors [SNRIs], tricyclic or other cyclic antidepressants, and other antidepressants) was assessed using the following 4 time-varying measures: current or former use, duration of use, cumulative dose, and average daily dose. Main Outcomes and Measures: Incident type 2 diabetes was assessed using discrete-time failure models, adjusting for disease risk score estimated using more than 125 baseline and time-dependent covariates. Results: In this cohort of 119 608 youths aged 5 to 20 years who initiated antidepressant treatment (59 087 female youths and 60 521 male youths; 54.7% between 5 and 14 years of age) with a mean follow-up of 22.8 months, 79 285 [66.3%] had SSRI or SNRI exposure. The risk of type 2 diabetes was significantly greater during current use than former use of SSRIs or SNRIs (absolute risk, 1.29 per 10 000 person-months vs 0.64 per 10 000 person-months; adjusted relative risk [RR], 1.88; 95% CI, 1.34-2.64) and tricyclic or other cyclic antidepressants (absolute risk, 0.89 per 10 000 person-months vs 0.48 per 10 000 person-months; RR, 2.15; 95% CI, 1.06-4.36), but not of other antidepressants (absolute risk, 1.15 per 10 000 person-months vs 1.12 per 10 000 person-months; RR, 0.99; 95% CI, 0.66-1.50). Furthermore, for youths currently using SSRIs or SNRIs, the risk of type 2 diabetes increased with the duration of use (RR, 2.66; 95% CI, 1.45-4.88 for >210 days and RR, 2.56; 95% CI, 1.29-5.08 for 151-210 days compared with 1-90 days) and with the cumulative dose (RR, 2.44; 95% CI, 1.35-4.43 for >4500 mg and RR, 2.17; 95% CI, 1.07-4.40 for 3001-4500 mg compared with 1-1500 mg in fluoxetine hydrochloride dose equivalents). By contrast, neither the duration nor the cumulative dose of other antidepressants was associated with an increased risk of type 2 diabetes. The risk of type 2 diabetes increased significantly with the average daily dose among youths with more than 150 days of SSRI or SNRI use (RR, 2.39; 95% CI, 1.04-5.52 for >15.0 vs ≤15.0 mg/d) but not among youths with 1 to 150 days of SSRI or SNRI use. Conclusions and Relevance: In a large cohort of youths insured by Medicaid, the use of SSRIs or SNRIs-the most commonly used antidepressant subclass-was associated with an increased risk of type 2 diabetes that intensified with increasing duration of use, cumulative dose, and average daily dose.

Disproportionality Analysis for the Assessment of Abuse and Dependence Potential of Pregabalin in the French Pharmacovigilance Database.

BACKGROUND AND OBJECTIVE: Pregabalin abuse and dependence has been increasingly described; however, it is not described in France. Our study aimed to investigate the abuse and dependence potential of pregabalin by a disproportionality analysis, in the French Pharmacovigilance Database (FPVD), in comparison with amitriptyline and clonazepam. METHODS: We performed a case/noncase study in the FPVD. Between January, 1 2010 and December, 31 2015, we identified cases of abuse and or dependence (excluding isolated withdrawal syndromes) using MedDRA (Medical Dictionary for Regular Activities) terms. Exposure to pregabalin was defined as the mention of pregabalin in the report. Clonazepam was used as positive control and amitriptyline as negative control. RESULTS: Among the 184,310 reports in the database, 521 were abuse or dependence cases. Exposure to pregabalin was found in eight (1.5 %) of them. We did not find any significant association between exposure to pregabalin and drug abuse or dependence: reporting odds ratio (ROR) = 1.1 95 % confidence interval (CI) (0.6-2.3). ROR for clonazepam was 5.7 95 % CI (3.5-9.2). No case of an amitriptyline-related abuse or dependence was recorded in the FPVD. CONCLUSIONS: The first cases of pregabalin-related abuse or dependence reported in France occurred later than in other European countries, since none had been described before 2010. This analysis in the FPVD did not find a higher proportion of abuse/dependence with pregabalin in comparison with other drugs. Considering evidence of pregabalin abuse worldwide, this analysis underlines the limitations of spontaneous reporting system in the field of addictovigilance.

Clinical management following self-harm in a UK-wide primary care cohort.

BACKGROUND: Little is known about the clinical management of patients in primary care following self-harm. METHODS: A descriptive cohort study using data from 684 UK general practices that contributed to the Clinical Practice Research Datalink (CPRD) during 2001-2013. We identified 49,970 patients with a self-harm episode, 41,500 of whom had one complete year of follow-up. RESULTS: Among those with complete follow-up, 26,065 (62.8%, 62.3-63.3) were prescribed psychotropic medication and 6318 (15.2%, 14.9-15.6) were referred to mental health services; 4105 (9.9%, CI 9.6-10.2) were medicated without an antecedent psychiatric diagnosis or referral, and 4,506 (10.9%, CI 10.6-11.2) had a diagnosis but were not subsequently medicated or referred. Patients registered at practices in the most deprived localities were 27.1% (CI 21.5-32.2) less likely to be referred than those in the least deprived. Despite a specifically flagged NICE 'Do not do' recommendation in 2011 against prescribing tricyclic antidepressants following self-harm because of their potentially lethal toxicity in overdose, 8.8% (CI 7.8-9.8) of individuals were issued a prescription in the subsequent year. The percentage prescribed Citalopram, an SSRI antidepressant with higher toxicity in overdose, fell sharply during 2012/2013 in the aftermath of a Medicines and Healthcare products Regulatory Agency (MHRA) safety alert issued in 2011. CONCLUSIONS: A relatively small percentage of these vulnerable patients are referred to mental health services, and reduced likelihood of referral in more deprived localities reflects a marked health inequality. National clinical guidelines have not yet been effective in reducing rates of tricyclic antidepressant prescribing for this high-risk group.

A change in the trend in dosulepin usage following the introduction of a prescribing indicator but not after two national safety warnings.

WHAT IS KNOWN AND OBJECTIVE: The tricyclic antidepressant dosulepin has been associated with an increased risk of toxicity in overdose compared with other antidepressants. In the UK, the MHRA and NICE have issued advice on the prescribing of dosulepin, and a National Prescribing Indicator (NPI) to monitor usage was introduced in Wales in 2011. The aim of this study was to assess whether trends in dosulepin usage in Wales and NE England changed following the two pieces of safety guidance and the introduction of the National Prescribing Indicator in Wales. METHODS: Primary care dosulepin usage in the 12 months prior to and following MHRA safety advice (in 2007), NICE guideline CG90 (in 2009) and the introduction of the NPI (in 2011) was obtained. Usage was measured using defined daily doses (DDDs) per 1000 prescribing units (PUs). The trends in the 12 months prior to and following the introduction of prescribing advice and the NPI were compared using an autoregressive integrated moving average (ARIMA) model. RESULTS AND DISCUSSION: In Wales, the trend in dosulepin usage did not change significantly prior to and following the MHRA advice: -0·18 and -0·43 DDDs/1000PUs per month, respectively (P = 0·07), or prior to and following NICE CG90: -0·30 and -0·49 DDDs/1000PUs per month, respectively (P = 0·35). In the 12 months prior to and following the introduction of the NPI, the trend was -0·45 and -0·98 DDDs/1000PUs per month, respectively (P = 0·001). In NE England, the trend did not alter significantly following the NICE advice or the introduction of the NPI in Wales. WHAT IS NEW AND CONCLUSION: The trend in dosulepin usage in Wales altered significantly following the introduction of the NPI, but not after the other prescribing advice. This association, coupled with the absence of a significant change in NE England over the same period, provided some evidence of the effectiveness of the NPI in prompting a change in prescribing behaviour in Wales.

Orthostatic hypotension and drug therapy in patients at an outpatient comprehensive geriatric assessment unit.

OBJECTIVE: To assess the rate of orthostatic hypotension and factors associated with it among elderly patients who underwent a comprehensive, ambulatory geriatric assessment. METHODS: The study included patients 65 years and older who were assessed in the outpatient comprehensive geriatric assessment unit. Data were collected from the computerized medical record including sociodemographic data, lifestyle, falls, blood pressure, BMI, functional and cognitive status, medications, and comorbidity. RESULTS: The study population consisted of 571 patients who underwent assessment over a nine-year period. The mean age was 83.7 ±â€Š6.1, 35.9% were men, and 183 (32.1%) were diagnosed with orthostatic hypotension. Multiple drugs, in general, and multiple drugs with the potential to cause orthostatic hypotension in particular increased the risk for orthostatic hypotension after adjustment for age, sex, chronic comorbidity, and supine systolic blood pressure ≥150 mmHg [odds ratio (OR) = 1.09, 95% confidence interval (CI): 1.03-1.14 and OR = 1.22, 95% CI: 1.08-1.37, respectively]. In addition, α-blockers and calcium channel blockers increased the risk for orthostatic hypotension after similar adjustments (OR = 1.82, 95% CI: 1.01-3.16 and OR = 1.66, 95% CI: 1.11-2.48, respectively). Similarly, two additional drug types increased the risk for orthostatic hypotension: selective serotonin reuptake inhibitors (OR = 2.09, 95% CI: 1.33-3.19) and tricyclic antidepressants (OR = 4.36, 95% CI: 1.85-10.06). There were no specific associations between age, cognitive and functional state, morbidity (as measured by the Charlson Comorbidity Index), and specific diseases, and orthostatic hypotension. CONCLUSION: The results of the present study reinforce evidence of an association between drug therapy and orthostatic hypotension.

Pharmacokinetic and bioequivalence assessment of two formulations of tianeptine sodium in healthy male volunteers.

BACKGROUND: Tianeptine is widely used for controlling depressive symptoms. OBJECTIVE: The aim of this study was to evaluate the bioequivalence between the generic (test) formulation containing tianeptine sodium 12.5 mg and the branded (reference) formulation Stablon® with regard to their pharmacokinetic profiles. METHODS: A randomized, two-sequence, two-treatment crossover study was conducted in healthy male Korean volunteers. All of the enrolled subjects were allocated to one of two sequence groups. They were administered a tablet of the test or reference formulation and then administered the alternative formulation after a 7-day washout period. The blood samples were taken before dosing and at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, and 10 hours after dosing. The plasma concentrations of tianeptine were analyzed using high-performance liquid chromatography with tandem mass spectrometer. Tolerability was assessed throughout the study. RESULTS: The pharmacokinetic parameters were assessed in the 40 subjects who completed the study. The tianeptine C(max) for the test formulation was 283.13 ± 57.58 ng/mL (mean ± SD) and that for the reference formulation was 272.50 ± 59.00 ng/mL. The AUC(last) of tianeptine was 803.24 ± 180.94 ng×h/mL for the test formulation and 792.27 ± 180.93 ng×h/mL for the reference formulation. The geometric mean ratio (%) of the test to reference formulation was 104.04 (90% CI, 99.66 - 108.61) for C(max) and 101.30 (98.01 - 104.71) for AUC(last). Clinically significant adverse events were not reported during the study. CONCLUSION: The test and reference formulations of tianeptine were bioequivalent with regard to the pharmacokinetic parameters of Cmax and AUC(last). Both formulations were tolerated by all of the participants.

Antidepressant use and risk for preeclampsia.

BACKGROUND: Prior studies suggest that women who use antidepressants during pregnancy have an increased risk for preeclampsia, yet the comparative safety of specific antidepressants remains unclear. US nationwide Medicaid Analytic eXtract (MAX) data have not been used to study medication safety during pregnancy. METHODS: We identified 100,942 pregnant women with depression from 2000 to 2007 MAX data. We used pharmacy dispensing records to ascertain exposure to selective serotonin reuptake inhibitor (SSRI), serotonin-norepenephrine reuptake inhibitor (SNRI), tricyclic, bupropion, other antidepressant monotherapy or polytherapy, and specific antidepressants, during the second trimester and first half of the third trimester. Relative risks (RRs) and 95% confidence intervals (CIs) were adjusted for delivery year, preeclampsia risk factors, depression severity proxies, other antidepressant indications, other medications, and healthcare utilization. RESULTS: The risk of preeclampsia was 5.4% among women with depression and no antidepressant exposure. Compared with these women, the risk for preeclampsia was higher among those receiving SNRI (RR: 1.52, 95% CI = 1.26-1.83) and tricyclic monotherapy (RR: 1.62, 95% CI = 1.23-2.12), but not SSRI monotherapy (RR: 1.00, 95% CI = 0.93-1.07) or other antidepressants. Compared with women receiving SSRI monotherapy, preeclampsia risk was higher among women with SNRI (RR: 1.54, 95% CI = 1.28-1.86) and tricyclic (RR: 1.64, 95% CI = 1.25-2.16) monotherapy. None of the specific SSRIs was associated with preeclampsia. The RR with venlafaxine was 1.57 (95% CI = 1.29-1.91) and with amitriptyline 1.72 (95% CI = 1.24-2.40). CONCLUSIONS: In this population, SNRIs and tricyclics were associated with a higher risk of preeclampsia than SSRIs.

An update on the drug treatment of neuropathic pain. Part 1: antidepressants.

Neuropathic pain refers to pain that arises as a direct consequence of a lesion or disease affecting the somatosensory nervous system.(1) Many cases of neuropathic pain run a chronic course, and treatment may be difficult because commonly used analgesics, including NSAIDs and to some extent opioids, are often ineffective. In addition, the use of other pharmacological treatments can be limited by unwanted effects. Management requires a multidisciplinary approach and may involve the use of drug therapy (including antidepressants, anticonvulsants and opioids) with non-pharmacological interventions (including psychological therapies, transcutaneous electrical nerve stimulation and interventional procedures). This month and next month we review the drug treatment of neuropathic pain. In this first part we discuss neuropathic pain and the use of antidepressants.

Assessment of abuse of tianeptine from a reimbursement database using 'doctor-shopping' as an indicator.

Doctor-shopping is a patient behaviour characterized by simultaneous consultations of several physicians during the same period. Some case reports have described an abuse of tianeptine, an atypical antidepressant. Our objective was to assess the extent of abuse of this drug with a method quantifying doctor-shopping in comparison with other antidepressants and benzodiazepines (BZD). All dispensations of antidepressants and BZD during the year 2005 in a French area of 4.5 million inhabitants were extracted from a reimbursement database. For each patient, two quantities were computed: quantity dispensed and obtained by doctor-shopping. Tianeptine and other drugs were compared using their doctor-shopping indicator (DSI), defined as the percentage of drug obtained by doctor-shopping among dispensed quantity; 410 525 patients received at least one antidepressant dispensation during the year 2005. Tianeptine was the sixth most dispensed antidepressant. The DSI of tianeptine was 2.0%, ranking it first among antidepressant (the second being mianserine with a DSI of 1%). Flunitrazepam has the highest DSI (30.2%), the DSI of the five following BZD (clonazepam, zolpidem, oxazepam, diazepam, bromazepam) range from 3.0% to 2.0%. Tianeptine is associated with higher DSI, compared with other antidepressants, suggesting that it may be subject to abuse in the population. Moreover, its DSI as a measure of diversion is similar to the DSI of diazepam or bromazepam.

Treatment with duloxetine in adults and the incidence of cardiovascular events.

BACKGROUND: Cardiovascular events are inconclusively associated with duloxetine use in clinical trials and spontaneous reports. This analysis of cardiovascular events in relation to duloxetine use within a large health insurance database provides further data on the association. METHODS: This cohort study was conducted within a population with commercial health insurance. Adults with depression who initiated duloxetine were matched to separate cohorts of initiators of venlafaxine, selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants (TCAs), along with untreated patients with depression, and enrollees without depression. The cohorts were followed for cardiovascular events (acute myocardial infarction, sudden death, hypertensive crisis, arrhythmia, and coronary revascularization), which were identified through health insurance claims and confirmed upon review of underlying medical records. Proportional hazards and Poisson regression models were used for comparisons. RESULTS: There were approximately 64,000 person-years of follow-up among all cohorts (including 17,386 person-years among 21,457 duloxetine initiators), yielding 279 cardiovascular events. Relative to duloxetine initiators, those without depression had lower rates of combined events (incidence rate ratio [IRR], 0.51; 95% confidence interval [CI], 0.32-0.81) and coronary revascularizations (IRR, 0.51; 95% CI 0.29-0.89). The IR of each of the cardiovascular outcomes did not differ across the other cohorts, even accounting for time since last duloxetine dispensing. CONCLUSION: The incidence of cardiovascular events did not differ among duloxetine initiators relative to other antidepressant comparators or those with untreated depression but was higher than those without depression, suggesting that depression itself (or associated morbidities) may affect the risk of cardiovascular events.

Use of antidepressant agents and the risk of type 2 diabetes.

PURPOSE: To determine whether there is an association between antidepressant use and the risk of developing type 2 diabetes. METHODS: This study was a retrospective cohort analysis using the Texas Medicaid prescription claims database. Data were extracted for new users of either antidepressant agents (exposed) or benzodiazepines (unexposed) from January 1, 2002 through December 31, 2009. Patients aged 18-64 years without a prior history of diabetes were included. Cox proportional hazards regression was used to examine the association between diabetes incidence among exposed and unexposed groups, while controlling for demographic and clinical covariates. RESULTS: Among the total study population (N = 44,715), the majority were in the exposed (N = 35,552) versus the unexposed (N = 9,163) group. A total of 2,943 patients (6.6%) developed type 2 diabetes during the follow-up period. Antidepressant use was associated with an increase in the risk of diabetes when compared to benzodiazepine use (adjusted hazard ratio [HR] 1.558, 95% confidence interval [CI] 1.401-1.734). The association was observed with tricyclic antidepressants (TCAs; HR 1.759, 95% CI 1.517-2.040), serotonin-norepinephrine reuptake inhibitors (SNRIs; HR 1.566. 95% CI 1.351-1.816), selective serotonin reuptake inhibitors (SSRIs; HR 1.481, 95% CI 1.318-1.665), and "other" antidepressants (HR 1.376; 95% CI 1.198-1.581). CONCLUSIONS: The results of this study suggest that antidepressant use is associated with an increased risk of diabetes. This association was observed with use of TCAs, SNRIs, SSRIs, and "other" antidepressants.

Antidepressants and fracture risk in older adults: a comparative safety analysis.

We examined variations in fracture rates among patients initiated on antidepressant drug treatment as identified from Medicare data in two US states and assessed whether the observed variation could be explained by affinity for serotonin transport receptors. We used Cox proportional hazards models to compare fracture rates of the hip, humerus, pelvis, wrist, and a composite of these, among propensity score-matched cohorts of users of secondary amine tricyclics, tertiary amine tricyclics, selective serotonin reuptake inhibitors (SSRIs), and atypical antidepressants. As compared with secondary amine tricyclics, SSRIs showed the highest association with composite fracture rate (hazard ratio 1.30; 95% confidence interval (CI) 1.12-1.52), followed by atypical antidepressants (hazard ratio 1.12; 95% CI 0.96-1.31) and tertiary amine tricyclics (hazard ratio 1.01; 95% CI 0.87-1.18). The results were robust to sensitivity analyses. Although SSRI use was associated with the highest rate of fractures, variation in fracture risk across specific antidepressant medications did not depend on affinity for serotonin transport receptors.