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.     

Antidepressant drug use & the risk of suicide

There have been longstanding concerns about the propensity of antidepressants to precipitate suicidality in vulnerable individuals. To investigate this further, first we have analyzed all clinical trials, and in particular trials submitted to regulators for evidence on the relative risk of antidepressants versus placebo for this hazard. Second, we have compiled current epidemiological evidence germane to the issue. Third, we have constructed a model (Investigative Medication Routine; IMR) to shed light on the interactions between drug uptake, patient numbers on treatment and suicidal events. The clinical trial data gives rise to a relative risk of suicide on antidepressants over placebo of the order of a 2.0-2.5 times greater risk with treatment. These figures are supported by epidemiological findings. Investigative Medication Routine translates such findings into estimates of likely adverse outcomes, and explains why apparently increasing consumption of antidepressants would not be expected to lead to increased national suicide rates. From this data, we conclude that there is a clear signal that suicides and suicidal acts may be linked to antidepressant usage. It would seem likely that explicit warnings and monitoring in the early stages of treatment could greatly minimize these hazards.     

Antidepressant drug use & the risk of suicide

There have been longstanding concerns about the propensity of antidepressants to precipitate suicidality in vulnerable individuals. To investigate this further, first we have analyzed all clinical trials, and in particular trials submitted to regulators for evidence on the relative risk of antidepressants versus placebo for this hazard. Second, we have compiled current epidemiological evidence germane to the issue. Third, we have constructed a model (Investigative Medication Routine; IMR) to shed light on the interactions between drug uptake, patient numbers on treatment and suicidal events. The clinical trial data gives rise to a relative risk of suicide on antidepressants over placebo of the order of a 2.0–2.5 times greater risk with treatment. These figures are supported by epidemiological findings. Investigative Medication Routine translates such findings into estimates of likely adverse outcomes, and explains why apparently increasing consumption of antidepressants would not be expected to lead to increased national suicide rates. From this data, we conclude that there is a clear signal that suicides and suicidal acts may be linked to antidepressant usage. It would seem likely that explicit warnings and monitoring in the early stages of treatment could greatly minimize these hazards.     

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.     

Treatment of depression in children and adolescents

Depression occurs in children and adolescents, although it may appear differently in younger patients. Research suggests juvenile depression may respond to psychotherapy and to pharmacologic agents, and that antidepressants remain a valuable treatment for juveniles with depression. Diagnostic considerations in juveniles with mood symptoms are discussed. A brief overview is provided of the evidence supporting psychotherapy for juveniles with depression. Controlled antidepressant trials in juveniles with depression provide some support for the use of some selective serotonin reuptake inhibitors and little support for atypical antidepressants, tricyclic antidepressants, or monoamine oxidase inhibitors. Evidence from suicide rates over time, autopsy findings among juvenile suicides, and impacts of antidepressant prescribing trends are related to the current controversy over suicidality and antidepressant use in juvenile patients. Based on this evidence, practical guidelines for treatment of juvenile depression are provided.     

Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration data sets

OBJECTIVE: In late 2006, a U.S. Food and Drug Administration advisory committee recommended that the 2004 black box warning regarding suicidality in pediatric patients receiving antidepressants be extended to include young adults. This study examined the relationship between antidepressant treatment and suicide attempts in adult patients in the Veterans Administration health care system. METHOD: The authors analyzed data on 226,866 veterans who received a diagnosis of depression in 2003 or 2004, had at least 6 months of follow-up, and had no history of depression from 2000 to 2002. Suicide attempt rates overall as well as before and after initiation of antidepressant therapy were compared for patients who received selective serotonin reuptake inhibitors (SSRIs), new-generation non-serotonergic-specific (non-SSRI) antidepressants (bupropion, mirtazapine, nefazodone, and venlafaxine), tricyclic antidepressants, or no antidepressant. Age group analyses were also performed. RESULTS: Suicide attempt rates were lower among patients who were treated with antidepressants than among those who were not, with a statistically significant odds ratio for SSRIs and tricyclics. For SSRIs versus no antidepressant, this effect was significant in all adult age groups. Suicide attempt rates were also higher prior to treatment than after the start of treatment, with a significant relative risk for SSRIs and for non-SSRIs. For SSRIs, this effect was seen in all adult age groups and was significant in all but the 18-25 group. CONCLUSIONS: These findings suggest that SSRI treatment has a protective effect in all adult age groups. They do not support the hypothesis that SSRI treatment places patients at greater risk of suicide.     

Antidepressant drug use and suicide prevention

Depression has been identified as occurring in the majority of people who commit suicide. Effective antidepressant medications have been available for over half a century. It seems logical to conclude that treatment of depression with antidepressants would have a suicide preventive effect. This has been difficult to demonstrate due to the infrequency of suicide and methodological problems in prospectively testing the hypothesis. Pooled data from controlled clinical trials of antidepressants have not demonstrated a suicide preventive effect, but patient selection and the brief time of most trials limits the power of the data. Some reports from either long-term or very large databases have provided evidence that antidepressants prevent suicide. All but one study using aggregated data from naturalistic settings have shown inverse relationships between use of antidepressants and suicide rates in various populations. Definite conclusions cannot be drawn from naturalistic studies since unknown confounders cannot be excluded. The number of geographically widespread studies reporting positive results with varying methods leads us to conclude, however, that antidepressants do exert a suicide preventive effect.     

Antidepressant drug use and suicide prevention

Depression has been identified as occurring in the majority of people who commit suicide. Effective antidepressant medications have been available for over half a century. It seems logical to conclude that treatment of depression with antidepressants would have a suicide preventive effect. This has been difficult to demonstrate due to the infrequency of suicide and methodological problems in prospectively testing the hypothesis. Pooled data from controlled clinical trials of antidepressants have not demonstrated a suicide preventive effect, but patient selection and the brief time of most trials limits the power of the data. Some reports from either long-term or very large databases have provided evidence that antidepressants prevent suicide. All but one study using aggregated data from naturalistic settings have shown inverse relationships between use of antidepressants and suicide rates in various populations. Definite conclusions cannot be drawn from naturalistic studies since unknown confounders cannot be excluded. The number of geographically widespread studies reporting positive results with varying methods leads us to conclude, however, that antidepressants do exert a suicide preventive effect.     

Antidepressant sales and regional variations of suicide mortality in Germany

Suicides account for over one million deaths per year worldwide with depression among the most important risk factors. Epidemiological research into the relationship between antidepressant utilization and suicide mortality has shown heterogeneous and contradictory results. Different methodological approaches and limitations could at least partially explain varying results. This is the first study assessing the association of suicide mortality and antidepressant sales across Germany using complex statistical approaches in order to control for possible confounding factors including spatial dependency of data. German suicide counts were analyzed on a district level (n = 402) utilizing ecological Poisson regressions within a hierarchical Bayesian framework. Due to significant spatial effects between adjacent districts spatial models were calculated in addition to a baseline non-spatial model. Models were adjusted for several confounders including socioeconomic variables, quality of psychosocial care, and depression prevalence. Separate analyses were performed for Eastern and Western Germany and for different classes of antidepressants (SSRIs and TCAs). Overall antidepressant sales were significantly negatively associated with suicide mortality in the non-spatial baseline model, while after adjusting for spatially structured and unstructured effects the association turned out to be insignificant. In sub-analyses, analogue results were found for SSRIs and TCAs separately. Suicide risk shows a distinct heterogeneous pattern with a pronounced relative risk in Southeast Germany. In conclusion, the results reflect the heterogeneous findings of previous studies on the association between suicide mortality and antidepressant sales and point to the complexity of this hypothesized link. Furthermore, the findings support tailored suicide preventive efforts within high risk areas.     

Suicide risk and symptom reduction in patients assigned to placebo in duloxetine and escitalopram clinical trials: analysis of the FDA summary basis of approval reports.

BACKGROUND: We assessed suicide and suicide attempt risk as well as symptom reduction among 3,282 depressed patients participating in duloxetine and escitalopram clinical trials assigned to either an antidepressant or placebo. METHODS: We reviewed the FDA Summary Basis of Approval reports for data regarding safety and efficacy for duloxetine and escitalopram. Furthermore, we compared suicide risk among antidepressant clinical trials in this study with our two previous analyses on seven antidepressant clinical trials. RESULTS: Suicide and suicide attempt risk varied considerably among the three analyses, showing up to ten fold differences. Interestingly, the variability exists across the three reports, rather than between treatments (antidepressants versus placebo). CONCLUSIONS: These findings suggest caution in generalizing suicide risk even from a relatively large number of participants and thus, firm conclusions can only be drawn if the number of participants is overwhelmingly large (approximately two million patients). We also noted similar magnitude of response to placebo and antidepressants among the three studies.     

Kopfschmerzen und Migräne

Reanalyses of placebo-controlled trials reveal an increased risk of suicidal ideations or parasuicidal acts in children and adolescents under treatment with selective serotonin reuptake inhibitors (SSRI) or other antidepressants. Although no completed suicide was shown, these findings are the more important because, with the exception of fluoxetine, an evidence base for the efficacy of antidepressants is weak or lacking in this age group. For adults, there is no reason to doubt that antidepressants help to reduce suicides by shortening depressive episodes and preventing recurrence. A general and pronounced suicide-inducing effect of SSRI or other antidepressants can largely be excluded. On the other hand, in some vulnerable patients the risk of suicidal acts can increase, especially during the first days of antidepressant treatment. There is no evidence that this risk is higher with SSRI than with other antidepressants or nonpharmacological treatments. Safety in case of overdose is a strong argument favouring newer antidepressants over tri- and tetracyclic antidepressants in outpatients with unclear suicidality. The current widespread public discussions concering the risks of antidepressants is a risk in itself because confidence in treatment, compliance, and help seeking behaviour may get influenced negatively.     

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.     

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.