The Role of Physicians in Expanded Access to Investigational Drugs: A Mixed-Methods Study of Physicians' Views and Experiences in The Netherlands.

Treating physicians have key roles to play in expanded access to investigational drugs, by identifying investigational treatment options, assessing the balance of risks and potential benefits, informing their patients, and applying to the regulatory authorities. This study is the first to explore physicians' experiences and moral views, with the aim of understanding the conditions under which doctors decide to pursue expanded access for their patients and the obstacles and facilitators they encounter in the Netherlands. In this mixed-methods study, semi-structured interviews (n = 14) and a questionnaire (n = 90) were conducted with medical specialists across the country and analysed thematically. Typically, our respondents pursue expanded access in "back against the wall" situations and broadly support its classic requirements. They indicate practical hurdles related to reimbursement, the amount of time and effort required for the application, and unfamiliarity with the regulatory process. Some physicians are morally opposed to expanded access, with an appeal to safety risks, lack of evidence, and "false hope." Some of these moral concerns and practical obstacles may be essential targets for change, if expanded access to unapproved drugs is to become available for wider groups of patients for whom standard treatment options are not-or no longer-available, on a more consistent and equal basis.

What do patients with unmet medical needs want? A qualitative study of patients' views and experiences with expanded access to unapproved, investigational treatments in the Netherlands.

BACKGROUND: Patients with unmet medical needs sometimes resort to non-standard treatment options, including the use of unapproved, investigational drugs in the context of clinical trials, compassionate use or named-patient programs. The views and experiences of patients with unmet medical needs regarding unapproved, investigational drugs have not yet been examined empirically. METHODS: In this qualitative study, exploratory interviews and focus groups were held with patients with chronic or life-threatening diseases (n = 39), about topics related to non-standard treatment options, such as the search for non-standard treatment options, patients' views of the moral obligations of doctors, and the conditions under which they would or would not wish to use non-standard treatment options, including expanded access to unapproved, investigational drugs. RESULTS: Respondents had very little knowledge about and/or experience with existing opportunities for expanded access to investigational drugs, although some respondents were actively looking for non-standard treatment options. They had high expectations of their treating physicians, assuming them to be aware of non-standard treatment options, including clinical trials elsewhere and expanded access programs, and assuming that they would inform their patients about such options. Respondents carefully weighed the risks and potential benefits of pursuing expanded access, citing concerns related to the scientific evidence of the safety and efficacy of the drug, side effects, drug-drug interactions, and the maintaining of good quality of life. Respondents stressed the importance of education and assertiveness to obtain access to good-quality health care, and were willing to pay out of pocket for investigational drugs. Patients expressed concerns about equal access to new and/or non-standard treatment options. CONCLUSION: When the end of a standard treatment trajectory comes into view, patients may prefer that treating physicians discuss non-standard treatment options with them, including opportunities for expanded access to unapproved, investigational drugs. Although our respondents had varying levels of understanding of expanded access programs, they seemed capable of making well-considered choices with regard to non-standard treatment options and had realistic expectations with regard to the safety and efficacy of such options. Dutch patients might be less likely to fall prey to false hope than often presumed.

Little to lose and no other options: Ethical issues in efforts to facilitate expanded access to investigational drugs.

BACKGROUND: Today, public and private bodies around the world are trying to facilitate and increase expanded access to unapproved, investigational drugs for patients with unmet medical needs. METHODS: This paper discusses three major shifts in the field of expanded access and presents an argumentative account of ethical issues connected with those shifts, based on a literature study and unstructured interviews with 35 stakeholders in the Netherlands. RESULTS AND DISCUSSION: Traditionally, expanded access has been based on three key principles: 1) it is exceptional, 2) it is done 'out of compassion', and 3) it has a therapeutic aim. Current efforts to facilitate expanded access affect these key principles, rendering expanded access a default option, allowing companies to charge for investigational drugs and gather data on its outcomes. These shifts may generate new ethical issues, including false hope, safety concerns and funding issues, which must be anticipated by physicians, pharmaceutical companies, payers and policymakers. CONCLUSION: Healthcare systems allow for the use of promising unapproved drugs in exceptional circumstances, but do not always assist patients with unmet medical needs in getting access. It is time to replace the current patchwork of practices with systems for expanded access in which criteria are clearly described, responsibilities are assigned and arrangements are made, so that patients will know what (not) to expect from expanded access.

Use of Selective Serotonin Reuptake Inhibitors and Bone Mineral Density Change: A Population-Based Longitudinal Study in Middle-Aged and Elderly Individuals.

BACKGROUND: Longitudinal studies showed conflicting results regarding the association between use of selective serotonin reuptake inhibitors (SSRIs) and bone mineral density (BMD). Therefore, we investigate the association between-duration of-SSRI use and BMD, and change in BMD ([INCREMENT]BMD). METHODS: Data from the population-based Rotterdam Study cohort (1991-2008) were used. In total, 4915 men and 5831 postmenopausal women, aged 45 years and older, were included, having measurement visits at 4- to 5-year intervals. Multivariable linear mixed models were applied to examine the association between SSRI use, based on pharmacy records, duration of SSRI use, and repeated measures of BMD, and changes in BMD, compared with nonuse. Femoral neck BMD (grams per centimeters squared) was measured at 4 visits, comprising 19,861 BMD measurements. Three [INCREMENT]BMD periods were examined, comprising 7897 [INCREMENT]BMD values. Change in BMD was expressed in the annual percentage [INCREMENT]BMD between 2 consecutive visits. RESULTS: In men and women, we observed no association between SSRI and BMD when compared with nonuse (women: mean difference, 0.007 g/cm; 95% confidence interval, -0.002 to 0.017; P = 0.123). We did not find an association between duration of SSRI use and [INCREMENT]BMD (women: annual percentage change, -0.081; 95% confidence interval, -0.196 to 0.033; P = 0.164). CONCLUSIONS: In conclusion, use of SSRIs is not associated with BMD or [INCREMENT]BMD, after taking duration of treatment into account, in middle-aged and elderly individuals. Therefore, our results question previously raised concerns on the adverse effects of SSRIs on BMD.

The changing landscape of expanded access to investigational drugs for patients with unmet medical needs: ethical implications.

When patients are told that standard medical treatment options have been exhausted, their treating physicians may start looking for promising new drugs that are not yet approved, and still under investigation. Some patients can be included in clinical trials, but others cannot. It is not widely known that these patients might still be eligible for trying investigational drugs, in a therapeutic context. Worldwide, public and private parties are seeking to change this by informing patients and physicians about opportunities for expanded access and/or by facilitating its processes. When expanded access becomes available to larger groups of patients, ethical issues gain prominence, including informed consent, funding issues, disparities in access, and potential adverse effects on clinical drug development. Physicians, patients and policy-makers should not shift the responsibility to address these issues to pharmaceutical companies, but work together to resolve them.

Self-reported indications for antidepressant use in a population-based cohort of middle-aged and elderly.

Background Population-based studies investigating indications for antidepressant prescribing mostly rely on diagnoses from general practitioners. However, diagnostic codes might be incomplete and drugs may be prescribed 'off-label' for indications not investigated in clinical trials. Objective We aimed to study indications for antidepressant use based on self-report. Also, we studied the presence of depressive symptoms associated with the self-reported indications. Setting Our study population of antidepressant users was selected based on interview data between 1997 and 2013 from the prospective population-based Rotterdam Study cohort (age >45 years). Method Antidepressant use, self-reported indication for use, and presence of depressive symptoms (Center for Epidemiological Studies Depression Scale) were based on interview. Self-reported indications were categorized by the researchers into officially approved, clinically-accepted and commonly mentioned off-label indications. Main outcome measures A score of 16 and higher on the Center for Epidemiological Studies Depression Scale was considered as indicator for clinically-relevant depressive symptoms. Results The majority of 914 antidepressant users reported 'depression' (52.4 %) as indication for treatment. Furthermore, anxiety, stress and sleep disorders were reported in selective serotonin reuptake inhibitor and other antidepressant users (ranging from 5.9 to 13.3 %). The indication 'pain' was commonly mentioned by tricyclic antidepressant users (19.0 %). Indications were statistically significantly associated with higher depressive symptom scores when compared to non-users (n = 10,979). Conclusions Depression was the main indication for antidepressant treatment. However, our findings suggest that antidepressants are also used for off-label indications, subthreshold disorders and complex situations, which were all associated with clinically-relevant depressive symptoms in the middle-aged and elderly population.

Selective Serotonin Reuptake Inhibitors Decrease Pancreatic Insulin Secretion in Older Adults and Increase the Risk of Insulin Dependence in Type 2 Diabetes Patients.

OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) may decrease insulin secretion, but evidence from population studies is scarce. We investigated the association between SSRIs and markers for glucose-insulin homeostasis in a nondiabetic older population. Furthermore, we studied the association between SSRI use and insulin dependence in a diabetic population of older adults. METHODS: This study was embedded in the prospective population-based Rotterdam Study cohort (1991-2012). In nondiabetic participants, fasting glucose and insulin levels and the homeostasis model assessment for insulin sensitivity and secretion were compared between participants using SSRIs and participants using no antidepressant. In diabetic patients using oral glucose-lowering agents, the risk of insulin dependence, defined as the start of insulin treatment, was compared between participants using SSRIs and participants using no antidepressant. RESULTS: In nondiabetic participants, SSRI users (n = 87) had, compared with participants using no antidepressants (n = 5,505), a significantly (P < .05) lower level of insulin (8.8 mU/L and 9.9 mU/L, respectively), a lower degree of insulin resistance (2.2% and 2.4%, respectively), and less insulin secretion (89.1% and 100.4%, respectively), but a similar glucose level. Furthermore, > 90 days of consecutive use of SSRIs in diabetic patients was associated with a 2.17 times higher risk (95% confidence interval, 1.02-4.60) of starting insulin treatment than that of participants using no antidepressants. CONCLUSIONS: Use of SSRIs was associated with lower insulin secretion in nondiabetic participants and an increased risk of insulin dependence in type 2 diabetics in older adults. However, additional studies are required to confirm our results.

Use of Selective Serotonin Reuptake Inhibitors and Sleep Quality: A Population-Based Study.

STUDY OBJECTIVES: Poor sleep is a risk factor for the development and recurrence of depression. Selective serotonin reuptake inhibitor (SSRI) use is consistently associated with good subjective sleep in clinically depressed patient populations. However, studies in the general population are lacking. Our objective was to investigate the association between SSRIs and subjective sleep in a middle-aged and elderly population in a daily practice setting. METHODS: We included participants from the prospective Rotterdam Study cohort. Participants had up to two subjective sleep measurements assessed with Pittsburgh Sleep Quality Index ([PSQI], number of measurements = 14,770). SSRI use was based on pharmacy records. We assessed the association between SSRIs and PSQI score and its sub-components, with nonusers of any antidepressant as reference. Analyses were, among others, adjusted for presence of depressive symptoms and concurrent psycholeptic drug use. RESULTS: We included 9,267 participants, average baseline age 66.3 y (standard deviation 10.6), and 57.6% women. SSRI use was significantly associated with a 0.78-point lower PSQI score (95% confidence interval [CI] -1.11; -0.44) which reflects better sleep, compared with non-use. The association was more prominent in continuous SSRI users (-0.71 points, 95% CI -1.18; -0.24). Of the sub-components, SSRIs were associated with 0.70-h longer sleep duration (95% CI 0.56; 0.85), higher sleep quality, higher sleep efficiency, and in contrast more daytime dysfunction. CONCLUSIONS: SSRI use was associated with better subjective sleep, after adjustment for depressive symptoms and concurrent psycholeptic drug use. This suggests that, in clinical practice in the middle-aged and elderly population, the sleep quality of some persons may benefit from, continued, SSRI use.

Use of antidepressants and the risk of myocardial infarction in middle-aged and older adults: a matched case-control study.

PURPOSE: Antidepressants, specifically selective serotonin reuptake-inhibiting antidepressants (SSRIs), decrease platelet activation and aggregation in in vitro experiments and could therefore decrease the risk of myocardial infarction (MI). However, prior studies addressing this hypothesis showed contradictory results. Our purpose was to investigate the association between the use of any antidepressant drug and incident MI among middle-aged and older adults. METHODS: We embedded a case-control study in the prospective Rotterdam Study (1991-2011). Controls were matched to MI cases based on sex and age at the same calendar date, and confounding factors were taken into account as time-varying covariates. The relative risk of MI during current and past use of an antidepressant was analyzed with conditional logistic regression with never use of antidepressant drugs as the reference category. RESULTS: A total of 744 out of a cohort of 9499 study participants developed MI during follow-up. After statistical adjustment for traditional cardiovascular risk factors and depression, current use of any antidepressant was associated with a lower risk of MI (odds ratio (OR), 0.71; 95 % confidence interval (CI), 0.51-0.98) compared with never use of any antidepressant. SSRI use showed the lowest relative risk (OR, 0.65; 95 % CI, 0.41-1.02), albeit marginally not statistically significant. Past use of any of the antidepressant classes was not associated with a lower risk of MI. CONCLUSIONS: Current use of antidepressants was associated with a lower risk of MI. Of the different classes, the use of SSRIs showed the lowest risk of MI, and therefore confirming the research hypothesis.

Antidepressant Use Is Associated With an Increased Risk of Developing Microbleeds.

BACKGROUND AND PURPOSE: Serotonin-specific antidepressants may increase the risk of adverse bleeding events. In a previous cross-sectional study, we did not observe an association between antidepressant use and presence of subclinical cerebral bleedings. In this study, we investigated longitudinally whether antidepressant use is associated with an increased risk of new subclinical cerebral microbleeds. METHODS: In total, 2559 participants aged ≥45 years of the population-based Rotterdam Study, all without microbleeds at baseline, underwent baseline and repeat brain magnetic resonance imaging between 2005 and 2013 (mean time interval, 3.9 years; SD, 0.5) to determine the incidence of microbleeds. Antidepressant use (yes versus no) was assessed between baseline and follow-up scan. In additional analyses, antidepressants were classified as low, intermediate, or high affinity for the serotonin transporter, and alternatively as selective serotonin reuptake inhibitors or non-selective serotonin reuptake inhibitors. We used multivariable logistic regression models to investigate the association of antidepressants with incident microbleeds. RESULTS: Antidepressant use was associated with a higher cerebral microbleed incidence (odds ratio, 2.22; 95% confidence interval, 1.31-3.76) than nonuse. When stratified by affinity for the serotonin transporter, intermediate serotonin affinity antidepressant use was associated with an increased risk of developing microbleeds (odds ratio, 3.07; 95% confidence interval, 1.53-6.17). Finally, selective serotonin reuptake inhibitor and non-selective serotonin reuptake inhibitor use were both associated with increased microbleed incidence. CONCLUSIONS: Antidepressant use was associated with an increased risk of developing microbleeds. Our results may support findings from previous clinical studies about increased intracranial and extracranial bleeding risk in antidepressant users.

Antidepressants with a high serotonin reuptake transporter affinity and serum lipid levels in a population-based study in older adults.

OBJECTIVE: We aimed to investigate the association between antidepressants and serum lipid levels in a population-based study in older adults. METHODS: We included participants from the prospective Rotterdam Study with data on lipid levels (total, low-density lipoprotein (LDL) and high-density lipoprotein cholesterol, and triglycerides). We classified antidepressants based on binding affinity to the serotonin transporter (low/intermediate- and high-affinity antidepressants). We compared lipid levels in users of these groups of antidepressants with lipid levels in non-users. Furthermore, we studied effect modification by the 102 C>T polymorphism (HTR2A gene), which is associated with antidepressant drug response and metabolic outcomes. RESULTS: Compared with non-users (N = 6438), LDL cholesterol level was higher (2.9 versus 3.1 mmol/L, respectively; p = 0.05) in users of high-affinity antidepressants (N = 89). Similar levels of the other lipids were observed between the groups for the other lipids. The mean difference in serum LDL cholesterol level between non-users and users of high-affinity antidepressants was largest in participants with the CC genotype compared with the other genotypes (notably 0.47 mmol/L), indicative of effect modification (p-value for interaction = 0.03). CONCLUSION: Antidepressants with a high serotonin reuptake transporter affinity were associated with higher LDL cholesterol levels, which were modified by a common genetic variation in the HTR2A gene.

Sex-specific association between antidepressant use and body weight in a population-based study in older adults.

OBJECTIVE: To investigate the association between antidepressant use and body weight in a population-based study in older adults. METHOD: All participant records (N = 7,269) from the prospective Rotterdam Study with data on anthropometrics and current depressive symptoms were studied post hoc (data were collected between September 1993 and December 2011). The association between antidepressant use, derived from pharmacy records, and change in body mass index (BMI) between repeated examination rounds was analyzed. Current depressive symptoms (assessed by questionnaire) and baseline BMI (for the change in BMI analysis only) were deemed important covariates. Additional analyses were stratified by sex and restricted to long-term use (≥ 90 days) and by level of binding affinity to the serotonin reuptake transporter (denoted as hSERT antidepressants). RESULTS: Participants who used selective serotonin reuptake inhibitors (SSRIs, n = 198) had a larger increase in BMI compared to nonusers (+0.74 and +0.23 kg/m(2), respectively, P < .001) between repeated examination rounds. No change in BMI was observed for users of tricyclic antidepressants (n = 146) and other antidepressants (n = 57) compared to nonusers. Weight gain was observed only in women who were treated for ≥ 90 days with hSERT antidepressants or SSRIs, and not in men (P value for interaction = .002). CONCLUSIONS: Within our study of older adults, hSERT antidepressants were associated with an increased body weight in women, which is supported by the biological function of serotonin in weight control and the differences in serotonergic signaling between males and females.

Use of selective serotonin re-uptake inhibitors and the heart rate corrected QT interval in a real-life setting: the population-based Rotterdam Study.

AIMS: Selective serotonin re-uptake inhibitors (SSRIs), specifically citalopram and escitalopram, are thought to cause QTc prolongation, although studies have shown contradictory results. Nevertheless, a maximum citalopram dosage of 20 mg in high risk patients (e.g. >60 years of age) is recommended. We aimed to investigate the association between use of (individual) SSRIs and QTc in a population-based study in older adults. METHODS: This study, which was part of the prospective Rotterdam Study (period 1991-2012), included participants with up to five electrocardiograms (ECGs). We used linear mixed models to compare QTc F (QT corrected according to Fridericia) measured during use of individual SSRIs with QTc F measured during non-use of any antidepressant. For citalopram, analyses were additionally restricted to a maximum dosage of 20 mg in participants aged 60 years and older. RESULTS: We included 12 589 participants with a total of 26 620 ECGs of which 436 ECGs were made during SSRI use. The mean QTc F was similar during use of any drugs from the SSRI class and during non-use. After stratifying to individual SSRIs, ECGs recorded during use of citalopram had the longest QTc compared with ECGs recorded during non-use (+12.8 ms, 90% CI 7.5, 18.2). This result remained similar in the analysis comprising participants aged 60 years and older with a maximum prescribed daily dosage of 20 mg citalopram. CONCLUSIONS: Although no SSRI class effect was observed, use of citalopram was associated with a longer QTc F, even after considering the recommended restrictions. Other SSRIs may not give a clinically relevant QTc F prolongation.

Assessing Prolongation of the Heart Rate Corrected QT Interval in Users of Tricyclic Antidepressants: Advice to Use Fridericia Rather Than Bazett's Correction.

A prolonged heart rate corrected QT interval (QTc) increases the risk of sudden cardiac death. Some methods of heart rate correction (notably Bazett) overestimate QTc in people with high heart rates. Studies suggest that tricyclic antidepressants (TCAs) can prolong the QTc and increase heart rate. Therefore, we aimed to study whether TCA-induced QTc prolongation is a false-positive observation due to overestimation at high heart rates. For this, we included 12,734 participants from the prospective population-based Rotterdam Study, with a total of 27,068 electrocardiograms (ECGs), of which, 331 during TCA use. Associations between use of TCAs, QTc, and heart rate were studied with linear repeated measurement analyses. QT was corrected for heart rate according to Bazett (QTcBazett), Fridericia (QTcFridericia), or a correction based on regression coefficients obtained from the Rotterdam Study data (QTcStatistical). On ECGs recorded during TCA use, QTcBazett was 6.5 milliseconds (95% confidence interval, 4.0-9.0) longer, and heart rate was 5.8 beats per minute (95% confidence interval, 4.7-6.9) faster than during nonuse. QTcFridericia and QTcStatistical were not statistically significantly longer during TCA use than during nonuse. Furthermore, QTcBazett was similar for ECGs recorded during TCA use and nonuse after statistical adjustment for heart rate. According to our results, TCA use does not seem to be associated with QTc prolongation. Therefore, the current advice of regulatory authorities to restrict the use of these drugs and to do regular checkups of the QTc may need to be revised. Other formulas, like Fridericia's, might be preferred.

Identifying genetic loci associated with antidepressant drug response with drug-gene interaction models in a population-based study.

It has been difficult to identify genes affecting drug response to Selective Serotonin Reuptake Inhibitors (SSRIs). We used multiple cross-sectional assessments of depressive symptoms in a population-based study to identify potential genetic interactions with SSRIs as a model to study genetic variants associated with SSRI response. This study, embedded in the prospective Rotterdam Study, included all successfully genotyped participants with data on depressive symptoms (CES-D scores). We used repeated measurement models to test multiplicative interaction between genetic variants and use of SSRIs on repeated CESD scores. Besides a genome-wide analysis, we also performed an analysis which was restricted to genes related to the serotonergic signaling pathway. A total of 273 out of 14,937 assessments of depressive symptoms in 6443 participants, use of an SSRI was recorded. After correction for multiple testing, no plausible loci were identified in the genome-wide analysis. However, among the top 10 independent loci with the lowest p-values, findings within two genes (FSHR and HMGB4) might be of interest. Among 26 genes related to the serotonergic signaling pathway, the rs6108160 polymorphism in the PLCB1 gene reached statistical significance after Bonferroni correction (p-value = 8.1e-5). Also, the widely replicated 102C > T polymorphism in the HTR2A gene showed a statistically significant drug-gene interaction with SSRI use. Therefore, the present study suggests that drug-gene interaction models on (repeated) cross-sectional assessments of depressive symptoms in a population-based study can identify potential loci that may influence SSRI response.

Prescription and indication trends of antidepressant drugs in the Netherlands between 1996 and 2012: a dynamic population-based study.

PURPOSE: Antidepressant drug use increases worldwide. It is pivotal to closely monitor the use of antidepressants and to determine in what subpopulations the rise is most substantial. In a Dutch primary care database, we aimed to investigate the (sex- and age-specific) prevalence and incidence of antidepressant prescription and to monitor the indication of incident prescriptions over a 17-year period (1996-2012). METHODS: This study, embedded in the Integrated Primary Care Information database, included all patients aged 10 years or older. Per calendar year, prevalence and incidence of antidepressant drug prescription were calculated by drug class (tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and others), sex, and age. The indication of incident prescriptions (e.g., depression, anxiety, sleep disorders, and neuropathic pain) was determined based on the International Classification of Primary Care codes. RESULTS: In total, 1.49 million patients were included. For all antidepressants together, the prevalence increased over time. However, incident prescription of specific SSRIs decreased from 2000 onward. During the study period, incidence and prevalence were higher in older and female patients. The increase in prevalence and the decrease in incidence were more pronounced in females than that in males. Furthermore, antidepressants were increasingly prescribed for indications such as neuropathic pain and sleep disorders. CONCLUSIONS: In Dutch primary care, prevalent prescription of antidepressants continued to increase, but incident prescription of particular SSRIs decreased from 2000 onward. In later years, antidepressants were less frequently prescribed for depression-related indications in incident users.

Antidepressant use and the risk of suicide: a population-based cohort study.

BACKGROUND: The existing literature provides contradictory evidence on antidepressant use and risk of suicide. Some studies have shown that the use of Selective Serotonin Reuptake Inhibitors (SSRIs) is associated with an increased risk of suicide, especially during the first months of treatment, whereas other studies did not confirm this association. For this reason, our objective was to investigate the association between antidepressant use and risk of suicide in incident antidepressant users in relation to time since starting therapy. METHODS: We conducted a population-based cohort study within the Dutch Integrated Primary Care Information (IPCI) database, in incident users of antidepressant therapy between 1994 and 2012 (n=27,712). Cox proportional hazard models were used to study the association between current use of SSRIs, tricyclic antidepressants (TCA) and other antidepressants and risk of suicide or attempted suicide. RESULTS: During follow-up, a total of 280 incident antidepressant users attempted or committed suicide. Current use of SSRIs (hazard ratio (HR): 0.78, 95% CI: 0.57-1.07), TCAs (HR: 0.82, 95% CI: 0.48-1.42) or other antidepressants (HR: 0.75, 95% CI: 0.47-1.18) was not statistically significantly associated with suicide compared to past use of any of the antidepressants. LIMITATIONS: Although a large healthcare database was used, the number of reported cases of suicide (attempt) was low. CONCLUSIONS: This study did not indicate an increase in risk of suicide after starting treatment with SSRIs, TCAs or other antidepressants compared with past antidepressant use.

Inhibition of serotonin reuptake by antidepressants and cerebral microbleeds in the general population.

BACKGROUND AND PURPOSE: Serotonin reuptake inhibiting antidepressants decrease platelet aggregation. This may cause an increased risk of intracerebral hemorrhage. However, the risk of subclinical microbleeds, which are highly prevalent in middle-aged and elderly people, is unknown. We studied whether serotonin reuptake inhibiting antidepressants increase the frequency of cerebral microbleeds and secondarily whether they lower the presence of ischemic vascular damage. METHODS: Within the population-based Rotterdam Study, information on antidepressant use was obtained from continuously monitored pharmacy records. Brain MRI was available in 4945 participants (55% women, mean age 64 years) between 2005 and 2011. We categorized antidepressants based on affinity for the serotonin transporter: high, intermediate, or low. Microbleeds (presence and location) and ischemic lesions (lacunes, white matter lesions) were rated on MRI. Logistic and linear regression, adjusted for age, sex, depressive symptoms, and cardiovascular risk were used to study the association of antidepressants with microbleeds and ischemic vascular lesions. RESULTS: Antidepressant use with strong serotonin reuptake inhibition was not associated with microbleed presence (odds ratio compared with nonuse, 1.03; confidence interval, 0.75-1.39) irrespective of microbleed location in the brain. Exclusion of antithrombotic users or persons with cortical infarcts did not change our results. Furthermore, serotonin reuptake inhibition was not related to ischemic vascular brain damage. CONCLUSIONS: In the general population, use of serotonin reuptake inhibiting antidepressants is not related to presence of cerebral microbleeds. This strengthens the idea that the platelet inhibitor effects of antidepressant drugs with affinity for serotonin are minimal and further supports the safety of selective serotonin reuptake inhibitors for nongastrointestinal bleedings.