How have the selective serotonin reuptake inhibitor antidepressants affected suicide mortality?

OBJECTIVE: We review evidence on two claims that have been made about the effects of selective serotonin reuptake inhibitor (SSRI) antidepressants; that they have: (i) decreased suicide rates in the population; and (ii) increased suicide rates in some individuals early in treatment. METHOD: We critically review evidence in the English-speaking peer-reviewed medical literature on: (i) meta-analyses of randomized controlled trials (RCTs) of SSRIs; (ii) observational studies of suicide risk in patients prescribed SSRIs and other antidepressants; and (iii) ecological studies of correlations between population use of SSRI use and population suicide rates. RESULTS: The largest and most recent meta-analyses of RCTs of SSRIs have found suggestive evidence that SSRIs increase suicidal ideation early in treatment compared with placebo. Observational studies have found an increased risk of self-harm within 9 days of an antidepressant drug being prescribed but the risk has been similar for the older tricyclic antidepressants and the SSRIs. Ecological studies in developed countries have found either that suicide rates have declined as SSRI use has increased, or have found no relationship between suicide rates and increased SSRI use. CONCLUSIONS: Meta-analyses of RCTs suggest that SSRIs increase suicide ideation compared with placebo but the observational studies suggest that SSRIs do not increase suicide risk more than older antidepressants. If SSRIs increase suicide risk in some patients, the number of additional deaths is very small because ecological studies have generally found that suicide mortality has declined (or at least not increased) as SSRI use has increased.     

Antidepressants and suicidal behaviour in unipolar depression

OBJECTIVE: To compare the rates of suicidal behaviour during vs. after discontinuation of treatment with antidepressants, and to determine the comparative rates of suicidal behaviour for patients maintained on tricyclic (TCA) vs. selective serotonin reuptake inhibitor (SSRI) antidepressants. METHOD: Charts were reviewed for 521 patients with major depressive disorder and/or dysthymic disorder. Periods of active treatment or discontinuation with SSRIs or TCAs were determined. Rates of completed suicide, suicide attempts, and hospitalization for suicidality were analyzed. RESULTS: There was greater than a five-fold increase in risk for suicidal behaviour after discontinuation of antidepressant treatment (P < 0.0001). The rates of suicidal behavior during treatment with SSRIs or TCAs were similar. CONCLUSION: Suicidal behaviour in unipolar depressed patients treated with antidepressants increases substantially after medication discontinuation. This effect occurred in both patients who were maintained on SSRIs and TCAs. The findings support a possible protective effect on suicidal behaviour for both SSRIs and TCAs.     

Suicide rates in clinical trials of SSRIs,other antidepressants,and placebo: analysis of FDA reports

OBJECTIVE: Previous reports suggesting that selective serotonin reuptake inhibitor (SSRI) use is associated with increased suicidal risk have not assessed completed suicides. The authors analyzed reports from randomized controlled trials to compare suicide rates among depressed patients assigned to an SSRI, other antidepressants, or placebo. METHOD: Food and Drug Administration (FDA) summary reports of the controlled clinical trials for nine modern FDA-approved antidepressants provided data for comparing rates of suicide. RESULTS: Of 48,277 depressed patients participating in the trials, 77 committed suicide. Based on patient exposure years, similar suicide rates were seen among those randomly assigned to an SSRI (0.59%, 95% confidence interval [CI]=0.31%-0.87%), a standard comparison antidepressant (0.76%, 95% CI=0.49%-1.03%), or placebo (0.45%, 95% CI=0.01%-0.89%). CONCLUSIONS: These findings fail to support either an overall difference in suicide risk between antidepressant- and placebo-treated depressed subjects in controlled trials or a difference between SSRIs and either other types of antidepressants or placebo.     

Antidepressant medication change in a clinical treatment setting: a comparison of the effectiveness of selective serotonin reuptake inhibitors.

BACKGROUND: This investigation focuses on the 3 most frequently used selective serotonin reuptake inhibitors (SSRIs) (paroxetine, fluoxetine, sertraline) and examines the rate of medication switches as a measure of effectiveness. We answer 2 questions: (1) What is the likelihood that a patient starting treatment with an SSRI will complete treatment with the same agent? and (2) Depending on the initial SSRI agent used, do patients switch at different frequencies? METHOD: A retrospective chart review was performed on 2779 patients treated in a university outpatient clinic from March 1995 to January 1997. Of these, 263 patients given antidepressants were randomly selected: 214 were prescribed SSRIs; 24, novel antidepressants; and 25, tricyclic antidepressants. RESULTS: There was no significant difference in rate of switching between the different classes of antidepressant (p = .1) nor between drugs within the SSRI class (p = .513). When medication change was the independent factor, significant differences between the groups were total time in treatment and number of visits (p < .001 and p = .011, respectively). Age, education, and Clinical Global Impressions-Severity of Illness scale scores (admission, discharge, and change) were not significantly different between the groups. CONCLUSION: Approximately 25% of patients started with an SSRI will switch to another antidepressant in the course of their treatment. The SSRIs appear to be equivalent in effectiveness. They are not interchangeable, because patients who discontinue one SSRI for lack of tolerability or response can generally be treated effectively with another.     

Adequacy of antidepressant treatment after discharge and the occurrence of suicidal acts in major depression: a prospective study

OBJECTIVE: Suicide attempts predict repeat attempts and suicide completion. Major depression requiring hospitalization is a risk factor for suicidal acts, particularly in the 2 years following discharge. The authors prospectively studied the adequacy of antidepressant treatment and its impact on suicidal acts in the 2 years after hospitalization for major depression. METHOD: Patients (N=136) with major depression were interviewed at 3 months, 1 year, and 2 years after admission. At each interview, the presence of major depression and suicidal acts and the adequacy of antidepressant treatment were assessed. Cox's proportional hazards analysis with time-varying covariates was used to model the risk of a suicide attempt during the follow-up period. RESULTS: Major depression in the follow-up period increased the risk of a suicide attempt sevenfold. For each suicide attempt in a subject's history, the risk for an attempt in the follow-up period increased by 30%. Antidepressant treatment during the follow-up period was mostly inadequate. Consequently, a relationship between adequacy of antidepressant treatment during follow-up and the risk of a suicide attempt could not be found. Furthermore, subjects with a history of a suicide attempt at baseline were not treated more vigorously than nonattempters. CONCLUSIONS: Antidepressant treatment of depressed patients is strikingly inadequate, even in suicide attempters, known to be at higher risk for suicidal acts. This deficiency undermines the ability to measure the antisuicidal effects of antidepressants in naturalistic studies. Controlled studies of antidepressants are needed to evaluate effects on suicidal acts.     

Antidepressant drug consumption and public health indicators in Italy, 1955 to 2000

OBJECTIVE: This study investigated the impact of the increasing consumption of selective serotonin reuptake inhibitors (SSRIs) and newer anti-depressants on the following public health indicators: (1) suicide rates, (2) proportion of completed suicides by poisoning with solid or liquid substances, and (3) hospital admissions for depression and proportion of admissions for depression that were first admissions. METHOD: Data collected by IMS Health on antidepressants dispensed in Italy from 1983 to 2000 were obtained from the Italian Ministry of Health, while data on suicide deaths from 1955 to 2000 were obtained from the Italian National Institute of Statistics. RESULTS: In Italy from 1983 to 2000, the use of tricyclic antidepressants remained substantially stable, and the use of SSRIs and newer agents dramatically increased. In contrast, suicide rates for males decreased from 1955 to 1974 and subsequently increased, reaching a peak in 1985 and then declining. In females, suicide rates remained substantially stable until 1978. A subsequent increase occurred up to 1985, followed by a steady decline. Suicide by poisoning using solids or liquids dropped by nearly 50% from 1986 to 2000. Admissions to the hospital for depression showed an erratic pattern; however, no decline was observed. No change was observed in the rate of first admissions for depression. CONCLUSION: Despite a reduction in suicides by poisoning using solids or liquids, the analysis of long-term trends in suicide did not suggest that increases in antidepressant prescribing lie behind recent reductions in population suicides. Furthermore, in Italy, newer antidepressants had no impact on the total number of admissions for depression or on the proportion of all admissions that were first admissions.     

Chinese demented inpatients admitted following a suicide attempt: a case series

OBJECTIVE: Suicide attempt is rarely reported in dementia. This study explores the clinical and phenomenological aspects as well as the treatment of Chinese demented patients who have attempted suicide. METHODS: During a 1-year period, demented patients admitted to a geropsychiatric unit as a result of suicide attempt were investigated for factors related to suicide attempt, such as motives and method. RESULTS: In this 1-year survey, seven demented patients (11.7% of all demented patients) were admitted immediately following a suicide attempt. All seven patients had mild or moderate dementia. Three had significant clinical depression symptoms on admission. In all patients, delusions were the primary cause of suicide attempt. Their suicidal ideations were improved with antipsychotic and antidepressant treatment. CONCLUSION: These cases, taken together, suggest that suicide attempt can occur in patients with dementia. It is important for clinicians to be aware of the risk of suicide in patients with dementia, especially those associated with delusions, even if they have no major depression or suicide attempt history. Antidepressants and antipsychotics may play a critical role in the treatment of suicide attempt in dementia.     

Response and remission rates in different subpopulations with major depressive disorder administered venlafaxine, selective serotonin reuptake inhibitors, or placebo.

BACKGROUND: Most examinations of the clinical efficacy of drugs used to treat depression pool subjects across gender and age groups. This investigation compared these patient subpopulations on the basis of remission and response rates associated with venlafaxine and selective serotonin reuptake inhibitor (SSRI) treatment. METHOD: A meta-analysis of original data from 8 comparable double-blind, active-controlled, randomized clinical trials (4 also placebo-controlled) was conducted. Antidepressant efficacy was assessed for patients (N = 2,045) aged 18 to 83 years (subgroups: < or = 40, 41-54, 55-64, and > or = 65 years) who met DSM-III-R criteria for major depression or DSM-IV criteria for major depressive disorder and were randomly assigned to receive venlafaxine (immediate release, N = 474; extended release, N = 377), one of several SSRIs (N = 748), or placebo (N = 446) for up to 8 weeks. Symptoms of depression were assessed using the Hamilton Rating Scale for Depression (HAM-D). Remission was defined as a HAM-D-17 score < or = 7, response was defined as > or = 50% decrease in HAM-D-21 score, and absence of depressed mood was defined as a HAM-D depressed mood item score of 0. RESULTS: We detected no significant age-by-treatment, gender-by-treatment, or age-by-gender-by-treatment interactions; men and women of different ages within a given antidepressant treatment group exhibited similar rates of remission, response, and absence of depressed mood. Regardless of age or gender, remission rates during venlafaxine therapy were significantly higher than during SSRI therapy (remission rates at week 8: venlafaxine, 40%-55% vs. SSRI, 31%-37%; p < .05). Regardless of patient age or gender, onset of remission was more rapid with venlafaxine than with SSRI treatment. By contrast, rates of absence of depressed mood with venlafaxine (34%-42%) and SSRIs (31%-37%) did not differ significantly and tended to be similar for all patient subgroups. CONCLUSION: These data suggest that men and women have comparable responses to SSRIs and venlafaxine across various age groups. Moreover, patients exhibited a more rapid onset and a greater likelihood of remission with venlafaxine therapy than with SSRI therapy regardless of age or gender.     

One-year costs of second-line therapies for depression

BACKGROUND: We compared patterns of medical resource utilization and costs among patients receiving a serotonin-norepinephrine reuptake inhibitor (venlafaxine), one of the selective serotonin reuptake inhibitors (SSRIs), one of the tricyclic agents (TCAs), or 1 of 3 other second-line therapies for depression. METHOD: Using claims data from a national managed care organization, we identified patients diagnosed with depression (ICD-9-CM criteria) who received second-line antidepressant therapy between 1993 and 1997. Second-line therapy was defined as a switch from the first class of antidepressant therapy observed in the data set within 1 year of a diagnosis of depression to a different class of antidepressant therapy. Patients with psychiatric comorbidities were excluded. RESULTS: Of 981 patients included in the study, 21% (N = 208) received venlafaxine, 34% (N = 332) received an SSRI, 19% (N = 191) received a TCA, and 25% (N = 250) received other second-line antidepressant therapy. Mean age was 43 years, and 72% of patients were women. Age, prescriber of second-line therapy, and prior 6-month expenditures all differed significantly among the 4 therapy groups. Total, depression-coded, and non-depression-coded 1-year expenditures were, respectively, $6945, $2064, and $4881 for venlafaxine; $7237, $1682, and $5555 for SSRIs; $7925, $1335, and $6590 for TCAs; and $7371, $2222, and $5149 for other antidepressants. In bivariate analyses, compared with TCA-treated patients, venlafaxine- and SSRI-treated patients had significantly higher depression-coded but significantly lower non-depression-coded expenditures. Venlafaxine was associated with significantly higher depression-coded expenditures than SSRIs. However, after adjustment for potential confounding covariables in multivariate analyses, only the difference in depression-coded expenditures between SSRI and TCA therapy remained significant. CONCLUSION: After adjustment for confounding patient characteristics, 1-year medical expenditures were generally similar among patients receiving venlafaxine, SSRIs, TCAs, and other second-line therapies for depression. Observed differences in patient characteristics and unadjusted expenditures raise questions as to how different types of patients are selected to receive alternative second-line therapies for depression.     

National Patterns of Medication Treatment for Depression, 1987 to 2001

BACKGROUND: We investigated trends in antidepressant use, as well as broader changes in depression treatment, following the availability of selective serotonin reuptake inhibitors (SSRIs). METHOD: Using data from the National Disease and Therapeutic Index, a nationally representative survey of U.S. office-based physicians conducted by IMS HEALTH, we analyzed trends in antidepressant prescribing patterns from 1987 through the third quarter of 2001. Annual sample sizes of physician visits by patients reported to have depression ranged from 3901 visits in 1987 to 6639 in 1998. Outcomes examined included the frequency of depression visits, the likelihood of antidepressant therapy, and the use of specific medications. RESULTS: The estimated national number of physician visits by patients with depression increased from 14.4 million visits in 1987 to 24.5 million in 2001 (annualized). The rate of antidepressant medication treatment in these patients also increased from 70% in 1987 to 89% in 2001. In 1987, tricyclic antidepressants were prescribed to 47% of patients with depression. The most common individual antidepressants were amitriptyline (14%), trazodone (12%), doxepin (8%), and desipramine (6%). In 1989, a year after its introduction, fluoxetine was prescribed to 21% of patients with depression. The introduction of other SSRIs led aggregate SSRI use to grow to 38% in 1992, 60% in 1996, and 69% in 2000. In 2001, sertraline (18%), paroxetine (16%), fluoxetine (14%), citalopram (13%), and bupropion (9%) were the leading antidepressants, while tricyclics were used in only 2% of patients. The use of benzodiazepines in depression declined from 21% of patients in 1987 to 8% in 2001. CONCLUSION: The increasing therapeutic dominance of SSRIs may have contributed to other changes in depression treatment, including declining benzodiazepine use, increased aggregate antidepressant treatment rates, and increased reporting of depression.     

Antidepressant drug therapy and suicide in severely depressed children and adults: A case-control study

CONTEXT: The Food and Drug Administration has issued a boxed warning concerning increased suicidal ideation and behavior associated with antidepressant drug treatment in children and adolescents. It is unknown whether antidepressant agents increase the risk of suicide death in children or adults. OBJECTIVE: To estimate the relative risk of suicide attempt and suicide death in severely depressed children and adults treated with antidepressant drugs vs those not treated with antidepressant drugs. DESIGN: Matched case-control study. SETTING: Outpatient treatment settings in the United States. PARTICIPANTS: Medicaid beneficiaries from all 50 states who received inpatient treatment for depression, excluding patients treated for pregnancy, bipolar disorder, schizophrenia or other psychoses, mental retardation, dementia, or delirium. Controls were matched to cases for age, sex, race or ethnicity, state of residence, substance use disorder, recent suicide attempt, number of days since hospital discharge, and recent treatment with antipsychotic, anxiolytic/hypnotic, mood stabilizer, and stimulant medications. MAIN OUTCOME MEASURES: Suicide attempts and suicide deaths. RESULTS: In adults (aged 19-64 years), antidepressant drug treatment was not significantly associated with suicide attempts (odds ratio [OR], 1.10; 95% confidence interval [CI], 0.86-1.39 [521 cases and 2394 controls]) or suicide deaths (OR, 0.90; 95% CI, 0.52-1.55 [86 cases and 396 controls]). However, in children and adolescents (aged 6-18 years), antidepressant drug treatment was significantly associated with suicide attempts (OR, 1.52; 95% CI, 1.12-2.07 [263 cases and 1241 controls]) and suicide deaths (OR, 15.62; 95% CI, 1.65-infinity [8 cases and 39 controls]). CONCLUSIONS: In these high-risk patients, antidepressant drug treatment does not seem to be related to suicide attempts and death in adults but might be related in children and adolescents. These findings support careful clinical monitoring during antidepressant drug treatment of severely depressed young people.