Current Users Of Selective Serotonin Reuptake Inhibitors Research Articles

Selective Serotonin Reuptake Inhibitors and Risk of Noncardioembolic Ischemic Stroke: A Nested Case-Control Study.

Multiple studies have reported that the use of selective serotonin reuptake inhibitors (SSRIs) is associated with an increased risk of ischemic stroke; however, this finding may be the result of a confounding by indication. We examined the association using different approaches to minimize such potential bias. A nested case-control study was carried out in a Spanish primary health-care database over the study period 2001 to 2015. Cases were patients sustaining an ischemic stroke with no sign of cardioembolic or unusual cause. For each case, up to 5 matched controls (for exact age, sex, and index date) were randomly selected. Antidepressants were divided in 6 pharmacological subgroups according to their mechanism of action. The current use of SSRIs (use within a 30-day window before index date) was compared with nonuse, past use (beyond 365 days) and current use of other antidepressants through a conditional logistic regression model to obtain adjusted odds ratios and 95% CI. Only initiators of SSRIs and other antidepressants were considered. A total of 8296 cases and 37 272 matched controls were included. Of them, 255 (3.07%) were current users of SSRIs among cases and 834 (2.24%) among controls, yielding an adjusted odds ratio of 1.14 (95% CI, 0.97-1.34) as compared with nonusers, 0.94 (95% CI, 0.77-1.13) as compared with past-users and 0.74 (95% CI, 0.58-0.93) as compared with current users of other antidepressants. No relevant differences were found by duration (≤1, >1 year), sex, age (<70, ≥70 years old) and background vascular risk. The use of SSRIs was not associated with an increased risk of noncardioembolic ischemic stroke. On the contrary, as compared with other antidepressants, SSRIs appeared to be protective.

Antidepressants and the Risk of Cardiovascular Events in Elderly Affected by Cardiovascular Disease: A Real-Life Investigation From Italy.

The purpose of this study was to assess the possible relation between use of antidepressant (AD) drugs, that is, tricyclic ADs, selective serotonin reuptake inhibitors (SSRIs), and atypical ADs (AAs), and the risk of hospitalization for cardiovascular (CV) events among older patients with previous CV diseases. A nested case-control study was carried out among patients aged 65 years and older from 5 Italian health care territorial units who were discharged for CV disease during 2008 to 2010. The cohort was composed by 344,747 individuals, and of these, 97,739 (28%) experienced hospital admission for CV events (myocardial infarction, arrhythmia, stroke, heart failure) during follow-up (until 2014) and were included as cases. Up to 5 controls were randomly selected and matched to each. A conditional logistic regression was fitted to estimate the risk of CV events associated with ADs past or current use. A within-patient comparison was performed by the case-crossover design to account the effect of depression. Current users of SSRIs and AAs were at increased risk of CV events with odds ratios of 1.25 (95% confidence interval, 1.21-1.29) and 1.31 (1.25-1.37), respectively. An increased risk of arrhythmia and stroke was associated with current use of SSRIs and AAs, whereas an increased risk of heart failure was detected with current use of any ADs. The results were confirmed by the case-crossover approach. Evidence that AD use is associated with an increased risk of CV events in accordance with specific mechanisms of action among older people with CV disease was added by this study.

Use of Selective Serotonin Reuptake Inhibitors and Risk of Hip Fracture in the Elderly: A Case-Control Study in Taiwan

BackgroundThis population based study investigated the relationship between use of selective serotonin reuptake inhibitors (SSRIs) and hip fractures in the elderly in Taiwan. MethodsAnalysis of a random sample of 1 million insurance enrollees' data identified 4,891 patients with newly diagnosed hip fractures and 4,891 controls without hip fracture between 2000 and 2011. Both cases and controls were ≥65 years of age and were matched by sex, age, comorbidities, and index year of hip fracture diagnosis. Patients were considered current SSRI users if their last SSRI tablet was taken ≤7 days before the hip fracture diagnosis. Late use of SSRIs was defined as taking the last SSRI tablet ≥8 days before the hip fracture diagnosis. Non-SSRI users comprised individuals who never had an SSRI prescription. Odds ratios (ORs) and 95% confidence intervals (CIs) for hip fracture associated with SSRI use was estimated by multivariate unconditional logistic regression. ResultsAfter adjustment for covariants, multivariate regression analysis showed that the adjusted OR of hip fracture was 2.17 for current SSRI users (95% CI: 1.60–2.93) compared with those who never used SSRIs. The adjusted OR was 1.11 for individuals with late use of SSRIs (95% CI: 0.96–1.28) and was not significant. ConclusionsCurrent use of SSRIs was associated with a 2.17-fold increase in the odds of hip fracture in the elderly in Taiwan. Clinicians should consider the possibility of SSRI-associated hip fracture among old people currently taking SSRIs.

Preadmission use of selective serotonin reuptake inhibitors and short-term mortality in diabetic patients hospitalized due to stroke.

Patients with diabetes have an increased risk of stroke with a poor prognosis. Moreover, diabetic patients are at increased risk of depression and therefore likely to use selective serotonin reuptake inhibitors (SSRIs). We examined whether preadmission SSRI use was associated with increased mortality in diabetic patients hospitalized due to stroke. Population-based medical databases were used to identify all first-time stroke-related hospitalizations and subsequent mortality in diabetic patients in Denmark between 2004 and 2012 (n = 12 620). Based on redeemed prescriptions, SSRI use was categorized as current (new or long term), former or nonuse, and absolute 30-day mortality and mortality rate ratios (MRRs) were computed using Cox regression controlling for confounding factors. Amongst SSRI nonusers, 30-day stroke mortality was 15.8% (10.4% for ischaemic stroke, 41.8% for intracerebral haemorrhage and 27.3% for subarachnoid haemorrhage). Amongst current SSRI users, 30-day stroke mortality was 23.3% (17.1% for ischaemic stroke, 50.7% for intracerebral haemorrhage and 28.6% for subarachnoid haemorrhage). Current SSRI use was associated with increased 30-day stroke mortality compared with nonuse [adjusted MRR 1.3, 95% confidence interval (CI) 1.1-1.5], with the highest risk observed amongst new users (MRR 1.5, 95% CI 1.2-1.8). Overall stroke mortality was driven by increased mortality due to ischaemic stroke, with adjusted MRRs of 1.3 (95% CI 1.1-1.7) for current users and 1.7 (95% CI 1.2-2.4) for new users. Propensity score-matched results were similar and robust across subgroups. In patients with diabetes, preadmission SSRI use was associated with increased mortality following ischaemic stroke, compared with nonuse.

Risk of Seizures Associated with Antidepressant Use in Patients with Depressive Disorder: Follow-up Study with a Nested Case-Control Analysis Using the Clinical Practice Research Datalink.

Antidepressant use has been associated with an increased risk of seizures. Evidence on the association between antidepressant use at therapeutic doses and seizures mainly comes from clinical trials that were not designed to investigate this potential relationship. The objective of this study was to assess the risk of first-time seizures in association with exposure to antidepressants in patients with depressive disorders. We conducted a retrospective follow-up study with a nested case-control analysis between 1998 and 2012, using data from the UK-based Clinical Practice Research Datalink (CPRD). We estimated crude incidence rates with 95 % confidence intervals (CIs) of seizures in depressed patients who used selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), 'other antidepressants', no antidepressants, or who had used antidepressants in the past. To adjust for potential confounding, we estimated odds ratios of antidepressant drug use among cases with seizures and matched controls in a nested case-control analysis. Of 151,005 depressed patients, 619 had an incident seizure during follow-up. Incidence rates per 10,000 person-years were 12.44 (95 % CI 10.67-14.21) in SSRI users, 15.44 (95 % CI 8.99-21.89) in SNRI users, 8.33 (95 % CI 4.68-11.98) in TCA users, 9.33 (95 % CI 6.19-12.46) in non-users of antidepressants, and 5.05 (95 % CI 4.49-5.62) in past users of antidepressants. In the case-control analysis, relative risk estimates for seizures were increased in current users of SSRIs (adjusted odds ratio 1.98, 95 % CI 1.48-2.66) and SNRIs (adjusted odds ratio 1.99, 95 % CI 1.20-3.29), but not TCAs (adjusted odds ratio 0.99, 95 % CI 0.63-1.53), compared with non-users. Current use of SSRIs or SNRIs was associated with a twofold increased risk of first-time seizures compared with non-use, while current use of TCAs (mostly low dose) was not associated with seizures. Treatment initiation in SSRI and SNRI users was associated with a higher risk of seizures than longer-term treatment.

Anti-depressant therapy and cancer risk: A nested case-control study

Previous studies demonstrated a possible association between anti-depressant therapy with selective serotonin reuptake inhibitors (SSRI) and tricyclic anti-depressants (TCA), several genetic and hormonal pathways and cancer risk, with inconsistent results. Exposure to serotonin-norepinephrine reuptake inhibitors (SNRI) was not studied extensively. We sought to evaluate the association between exposure to SSRIs, TCAs and SNRIs and the five most common solid tumors. We conducted nested case-control studies using a large UK population-representative database. Cases were those with any medical code for the specific malignancy. For every case, four controls matched on age, sex, practice site, and duration of follow-up before index date were selected using incidence-density sampling. Exposure of interest was SSRI, SNRI or TCA therapy before index date. Odds ratios (ORs) and 95% CIs were estimated for each anti-depressant class using conditional logistic-regression analysis, adjusted for potential confounders, such as obesity, smoking history and alcohol consumption. Results109,096 cancer patients and 426,402 matched controls were included. Current SSRI users with treatment initiation>one year before index date had modestly higher risk for lung and breast cancers with ORs of 1.27 (95% CI 1.16–1.38) and 1.12 (95% CI 1.06–1.18), respectively. Among current TCA users, there was a higher risk only for lung cancers with OR of 1.45 (95% CI 1.31–1.6). There was no statistically significant association between current SNRI therapy and cancer risk. DiscussionTreatment with SSRI and TCA might be associated with increased lung cancer risk. SSRI therapy might be associated with modest increase in breast cancer risk.

Antidepressants and Suicide Attempts in Children

Recent data showing possible increased risk for suicidal behavior among children and adolescents treated with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) antidepressants have created significant concern among patients, families, and providers, including concerns about the risk of individual antidepressants. This study was designed to compare the risk for medically treated suicide attempts among new users of sertraline, paroxetine, citalopram, escitalopram, and venlafaxine to risk for new users of fluoxetine. A retrospective cohort study included 36,842 children aged 6 to 18 years enrolled in Tennessee Medicaid between 1995 and 2006 who were new users of 1 of the antidepressant medications of interest (defined as filling no prescriptions for antidepressants in the preceding 365 days). Medically treated suicide attempts were identified from Medicaid files and vital records and confirmed with medical record review. Four hundred nineteen cohort members had a medically treated suicide attempt with explicit or inferred attempt to die confirmed through medical record review, including 4 who completed suicide. The rate of confirmed suicide attempts for the study drugs ranged from 24.0 per 1000 person-years to 29.1 per 1000 person-years. The adjusted rate of suicide attempts did not differ significantly among current users of SSRI and SNRI antidepressants compared with current users of fluoxetine. Users of multiple antidepressants concomitantly had increased risk for suicide attempt. In this population-based study of children recently initiating an antidepressant, there was no evidence that risk of suicide attempts differed for commonly prescribed SSRI and SNRI antidepressants.

Use of selective serotonin reuptake inhibitors and lifestyle among women of childbearing age: a Danish cross-sectional survey

ObjectiveTo examine the use of selective serotonin reuptake inhibitors (SSRIs) among Danish women of childbearing age according to lifestyle factors.DesignCross-sectional survey.SettingThe Central Denmark Region.Participants4234 women (71.5% of the invited women)...

Selective Serotonin Reuptake Inhibitors and the Risk of Cataracts: A Nested Case-Control Study

Older-generation antidepressants have been associated with increasing the risk of cataracts. Although animal studies have alluded to a potential link between selective serotonin reuptake inhibitors (SSRIs) and the development of cataracts, no large population based-study has addressed this potential association. This study sought to quantify the risk of cataracts with SSRIs by conducting a pharmacoepidemiologic study using the linked administrative databases in the province of Quebec, Canada. Nested case-control study. A cohort of subjects who had received a coronary revascularization procedure from 1995 through 2004 in the province of Quebec, Canada. Using an administrative data set, a case-control study was conducted within a cohort of Quebec residents who had received a coronary revascularization procedure from 1995 through 2004. Cases were defined as those with the first diagnosis of a cataract diagnosed by an ophthalmologist. For each case, 10 controls were selected and matched to the cases by index date, age, and cohort entry. Crude and adjusted rate ratios (RRs) and corresponding confidence intervals (CIs) were computed for current use of SSRIs. Rate ratios were adjusted for gender, corticosteroid use, statins, high blood pressure, antihypertensives, and antidiabetics. First International Classification for Disease (Ninth Revision) code for a cataract diagnosed by an ophthalmologist. Eighteen thousand seven hundred eighty-four cases and 187 840 controls met our study inclusion criteria. The adjusted RR for cataracts among current users of SSRIs was 1.15 (95% CI, 1.08-1.23). The risk of cataracts was highest with fluvoxamine (RR, 1.39; 95% CI, 1.07-1.80), followed by venlafaxine (RR, 1.33; 95% CI, 1.14-1.55) and paroxetine for cataract surgery (RR, 1.23; 95% CI, 1.05-1.45). The average time to diagnosis of cataracts while on SSRI therapy was 656 days. A possible association was found between current exposure to SSRIs, especially fluvoxamine and venlafaxine, and a future diagnosis of cataracts. The possibility that this observation may be the result of the effect of smoking, which could not be controlled for in the study, cannot be excluded. Future studies are needed to confirm this association in other populations.

Preadmission use of SSRIs alone or in combination with NSAIDs and 30-day mortality after peptic ulcer bleeding

Objective. Use of selective serotonin reuptake inhibitors (SSRIs) increases the risk of upper gastrointestinal bleeding and this risk is amplified by concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs). The aim of the study was to examine the impact of SSRI use alone or in combination with NSAIDs on 30-day mortality after peptic ulcer bleeding (PUB). Material and methods. A population-based cohort study of patients with a first hospitalization with PUB in three Danish counties was carried out between 1991 and 2005 using medical databases. We calculated 30-day mortality rate ratios (MRRs) associated with the use of SSRIs, alone or in combination with NSAIDs, adjusted for important covariates. Results. Of 7415 patients admitted with PUB, 5.9% used SSRIs only, and 3.8% used SSRIs in combination with NSAIDs, with a 30-day mortality of 11.8% and 11.3%, respectively. Compared with patients who used neither SSRIs nor NSAIDs, the adjusted 30-day MRR was 1.02 (95% CI: 0.76–1.36) for current users of SSRIs and 0.89 (0.62–1.28) for the combined use of SSRIs with NSAIDs. There was a 2.11-fold (95% CI 1.35–3.30) increased risk of death associated with SSRI use starting within 60 days of admission; for those younger than 80 years, the adjusted MRR was 1.54 (0.72–3.29), and 2.57 (1.47–4.49) for those older than 80 years. Conclusions. Use of SSRIs, alone or in combination with NSAIDs, was not associated with increased 30-day mortality following PUB. However, increased mortality was found in patients who started SSRI therapy, particularly among those older than 80 years. We can only speculate on whether this finding is due to pharmacological action or confounding factors.

An Association Between Selective Serotonin Reuptake Inhibitor Use and Serious Upper Gastrointestinal Bleeding

In vitro studies have shown that selective serotonin reuptake inhibitors (SSRIs) inhibit platelet aggregation. It is controversial whether use of SSRIs is a cause of clinically important bleeding; results from observational studies have been equivocal. A population-based case-control study was conducted in Denmark. The 3652 cases all had a first discharge diagnosis of serious upper gastrointestinal bleeding (UGB) from 1995 to 2006. Controls (n = 36,502), matched for age and sex, were selected by risk-set sampling. Data on drug exposure and medical history were retrieved from a prescription database and the county's patient register. Confounders were controlled for by conditional logistic regression and the case-crossover design. The adjusted odds ratio (OR) of UGB among current, recent, and past users of SSRIs was 1.67 (95% confidence interval [CI], 1.46-1.92), 1.88 (95% CI, 1.42-2.5), and 1.22 (95% CI, 1.07-1.39). The adjusted OR for concurrent use of SSRI and nonsteroidal anti-inflammatory drugs (NSAIDs) was 8.0 (95% CI, 4.8-13). The adjusted OR for the concurrent use of NSAID, aspirin, and SSRI was 28 (95% CI, 7.6-103). Of the UGB cases, 377 were current users of SSRI; the adjusted OR for UGB in the case crossover analysis was 2.8 (95% CI, 2.2-3.6). The adjusted OR among users of proton pump inhibitors was 0.96 (95% CI, 0.50-1.82). Use of SSRI was associated with UGB, consistent with its antiplatelet effects. SSRIs should be prescribed with caution for patients at high risk for UGB.

Selective Serotonin Reuptake Inhibiting Antidepressants Are Associated With an Increased Risk of Nonvertebral Fractures

Fractures related to osteoporosis and falling constitute a major health problem in the elderly population. Exposure to antidepressants is associated with an increased risk of falls and fractures, but most previous studies incriminate tricyclic antidepressants (TCAs) rather than selective serotonin reuptake inhibitors (SSRIs). To examine the association between antidepressants, including TCAs, SSRIs, and other antidepressants and the risk of nonvertebral fractures in elderly. Prospective population-based cohort study. The Rotterdam Study, consisting of 7983 individuals aged 55 years and older. All persons from the Rotterdam Study. One thousand two hundred nineteen persons experienced a nonvertebral fracture, 25 during TCA use and 18 during SSRI use. After adjustment for age, sex, lower-limb disability, and depression, the risk of nonvertebral fracture was 2.35 (95% confidence interval, 1.32-4.18) for current users of SSRIs compared with nonusers of antidepressants. Multiple adjusting for many possible risk factors did not affect the association. To deal with potential confounding by indication, we subsequently restricted the analysis to antidepressant users (n = 1217). Compared with past users of TCAs or SSRIs, current users of SSRIs had a 2.07-fold (95% confidence interval, 1.23-3.50) increased risk of fracture, which further increased with prolonged use. In this analysis, depressive state at baseline and during follow-up did not play a role, suggesting absence of confounding by indication. The use of TCAs was associated with an increased fracture risk that decreased with prolonged use. Not only users of TCAs but also of SSRIs have a significantly increased risk of nonvertebral fractures, in SSRI users especially after prolonged use. Despite fewer early adverse effects of SSRIs, physicians treating elderly depressive patients should be aware of the unfavorable long-term consequence of SSRIs on fracture risk.

Clinical impact of selective serotonin reuptake inhibitors therapy with bleeding risks

The selective serotonin reuptake inhibitors (SSRIs) are extensively used for the treatment of multiple psychiatric conditions. In vitro and ex vivo data with these agents indicate they may have varying degrees of antiplatelet activity via multiple receptors. Reports of bleeding in patients receiving SSRIs appeared soon after their introduction. A review of the literature suggests SSRI therapy may increase the risk of bleeding especially with concomitant aspirin or nonsteroidal anti-inflammatory agents. Clinicians should exercise caution when prescribing these agents in high risk patients and maintain awareness of the potential contribution of SSRIs to unexplained bleeding episodes.

Effect of Selective Serotonin Reuptake Inhibitors on Requirement for Allogeneic Red Blood Cell Transfusion Following Coronary Artery Bypass Surgery

Selective serotonin reuptake inhibitors (SSRIs) inhibit platelet function, and use of these drugs has been associated with bleeding events. The objective of this study was to examine whether the requirement for red blood cell transfusion was increased following preoperative use of SSRIs among patients undergoing coronary artery bypass grafting (CABG). A population-based cohort study of transfusion requirements (red blood cells, fresh frozen plasma, and/or platelets) was conducted among patients undergoing CABG at either Aalborg or Skejby Hospitals between 1 January 1998 and 31 December 2003. All prescriptions for antidepressants, including SSRIs, filled before the date of admission for CABG were identified using prescription databases. Patients were categorized according to use of antidepressants (never users, current users [<90 days before admission for CABG], and former users). Antidepressants were classified according to their action on serotonin and norepinephrine reuptake mechanisms. Relative risk (RR) for transfusion were adjusted for: age; sex; preoperative use of platelet inhibitors (low-dose aspirin [acetylsalicylic acid], clopidogrel, and dipyridamole), NSAIDs and oral anticoagulants; place of surgery; extracorporeal circulation; concomitant valve surgery; and Charlson comorbidity index score. There were 124 (3.5%) current users of SSRIs among 3454 patients. Adjusted RRs for transfusion among current users of SSRIs, users of nonselective serotonin reuptake inhibitor antidepressants, and users of other antidepressants were 1.1 (95% CI 0.9, 1.3), 0.9 (95% CI 0.6, 1.3), and 1.0 (95% CI 0.7, 1.5), respectively, when compared with never users of any type of antidepressant. The adjusted RR among former SSRI users was 1.0 (95% CI 0.7, 1.4). Risk of re-exploration for bleeding and mortality within 30 days did not differ according to the examined drug-exposure categories. Preoperative use of SSRIs was not associated with any substantially increased requirement for allogeneic red blood cell transfusion among patients undergoing CABG. The main strengths of this study are its relatively large size, the use of prospectively collected data obtained from population-based databases with complete follow-up, and the ability to examine specific types of antidepressants. The limitations include a lack of detailed clinical data regarding other factors that may influence transfusion requirements.

Selective serotonin reuptake inhibitors and the risk of stroke: a population-based case-control study.

Selective serotonin reuptake inhibitors (SSRIs) have been associated with increased risk of bleeding complications, possibly as a result of inhibition of platelet aggregation. Little is known about the risk of intracerebral hemorrhage in users of SSRIs and whether the effect on platelet aggregation reduces the risk of ischemic stroke. We used population-based data to estimate the risk of hemorrhagic and ischemic stroke in users of SSRIs. We performed a nested case-control study in Funen County (465 000 inhabitants), Denmark. All patients with a first-ever stroke discharge diagnosis in the period of 1994 to 1999 were identified, and a validated diagnosis of stroke was reached in 4765 cases. In all, 40 000 controls were randomly selected from the background population. Information on drug use for cases and controls was retrieved from a prescription registry with full coverage of the county. Odds ratios were adjusted for age, sex, calendar year, and use of other medication. To evaluate the effect of various potential confounders not recorded in the register data, we performed separate analyses on data from 2 large population-based surveys with more detailed information on risk factors. Of 659 patients with hemorrhagic stroke, 21 were current users of SSRIs. The adjusted odds ratio of hemorrhagic stroke in current SSRI users compared with never users was 1.0 [95% confidence interval (CI), 0.6 to 1.6]. Of 2717 patients with ischemic stroke, 100 were current users of SSRIs, and the adjusted odds ratio of ischemic stroke in cases compared with controls was 1.1 (95% CI, 0.9 to 1.4). The survey data indicated that additional confounder control would not have led to an increase in the relative risk estimates. Current exposure to SSRIs is not associated with increased risk of intracerebral hemorrhage and is probably not associated with a decreased risk of ischemic stroke.

Selective serotonin reuptake inhibitors and myocardial infarction.

Depression is an independent risk factor for myocardial infarction (MI). Selective serotonin reuptake inhibitors (SSRIs) may reduce this risk through attenuation of serotonin-mediated platelet activation in addition to treatment of depression itself. case-control study of first MI in smokers 30 to 65 years of age was conducted among all 68 hospitals in an 8-county area during a 28-month period. Cases were patients hospitalized with a first MI. Approximately 4 community control subjects per case were randomly selected from the same geographic area using random digit dialing. Detailed information regarding use of antidepressant medication as well as other clinical and demographic data were obtained by telephone interview. A total of 653 cases of first MI and 2990 control subjects participated. After adjustment, using multivariable logistic regression, for age, sex, race, education, exercise, quantity smoked per day, body mass index, aspirin use, family history of MI, number of physician encounters, and history of coronary disease, diabetes, hypertension, or hypercholesterolemia, the odds ratio for MI among current SSRI users compared with nonusers was 0.35 (95% CI 0.18, 0.68; P<0.01). Non-SSRI antidepressant users had a nonsignificant reduction in MI risk with wide confidence intervals (adjusted odds ratio 0.48, CI 0.17, 1.32; P=0.15). However, analysis of this group was limited by the small number of exposed subjects. The use of SSRIs may confer a protective effect against MI. This could be attributable to the inhibitory effect SSRIs have on serotonin-mediated platelet activation or possibly amelioration of other factors associated with increased risk for MI in depression.