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.     

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.     

Selective serotonin reuptake inhibitor antidepressants and the risk of suicide: a controlled forensic database study of 14,857 suicides

OBJECTIVE: To test the hypothesis that selective serotonin reuptake inhibitor (SSRI) antidepressants may have a suicide emergent effect, particularly in children and adolescents. METHOD: Detections of different antidepressants in the forensic toxicological screening of 14 857 suicides were compared with those in 26,422 cases of deaths by accident or natural causes in Sweden 1992-2000. RESULTS: There were 3411 detections of antidepressants in the suicides and 1538 in the controls. SSRIs had lower odds ratios than the other antidepressants. In the 52 suicides under 15 years, no SSRIs were detected. In 15-19-year age group, SSRIs had lower relative risk in suicides compared with non-SSRIs. CONCLUSION: The hypothesis that treatment of depressed individuals with SSRIs leads to an increased risk of suicide was not supported by this analysis of the total suicidal outcome of the nationwide use of SSRIs in Sweden over a period of 9 years, either in adults or in children or adolescents.     

Risk of Suicidality in Depression with Serotonergic Antidepressants

Since depression is a risk factor for suicidal thoughts and behaviors, and since suicidal behaviors are associated with low serotonin activity, are selective serotonin reuptake inhibitors (SSRIs) more effective than other antidepressants in treating suicidality in depressed patients? There is inconclusive evidence for and against this hypothesis. However, all studies suggest that antidepressants are effective treatments of suicidal ideations and behaviors, and SSRIs have been shown to have prophylactic effects in preventing suicidal behaviors. Although some reports suggest that SSRIs might increase suicidal ideations and behaviors, the results of large, double-blind studies do not suggest a causal relationship between pharmacotherapy and the emergence of suicidality. Undertreatment of depression and therapeutic failure are more significant problems with the use of antidepressants in suicidal patients than the risk of using antidepressants in overdose. Prescribing inadequate doses of antidepressants is therefore a source of overlooked risk.     

Is there evidence for negative effects of antidepressants on suicidality in depressive patients?

The role of antidepressants in suicide prevention is a major public health question given the high prevalence of both depression and depression-related suicidality. Therefore all available means should be utilised to clarify the influence of antidepressants on suicidality, especially in view of the ongoing intensive debate about possible suicidality-inducing effects of antidepressants that may outweigh their traditionally hypothesised beneficial effects. This paper gives a systematic and comprehensive review of the empirical data which might indicate that antidepressants have negative effects on suicidality. First, principal methodological issues related to this research question are discussed. Thereafter, the results of controlled trials and epidemiological and cohort studies are presented. Altogether, there seems to be only a small amount of evidence from different research approaches that antidepressants, not only serotonin reuptake inhibitors (SSRIs), might induce, aggravate or increase the risk of suicidal ideation and suicide attempts. As to suicide, there are no hints in this direction. TCAs have a higher risk of fatal outcome in overdose compared to SSRIs, which, in case of mono-intoxication, carry almost no risk of lethal consequences. The ongoing discussion about suicidality-inducing effects should not prevent physicians from prescribing SSRIs and other antidepressants to their patients if they are clinically indicated. However, they should take into account potential risks and manage them by good clinical practice.     

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.     

Do SSRIs or antidepressants in general increase suicidality?

In the past few years several papers have reported critically on the risk of suicidal thoughts and behaviour associated with antidepressants, primarily SSRIs. The risk-benefit ratio of antidepressant (AD) treatment has been questioned especially in children and adolescents. The critical publications led to warnings being issued by regulatory authorities such as the FDA, MHRA and EMEA and stimulated new research activity in this field. However, potential harmful effects of antidepressants on suicidality are difficult to investigate in empirical studies because these have several methodological limitations. Randomised controlled trials (RCTs) are the most reliable way to test the hypothesis that AD have such side effects. In addition to meta-analyses of RCTs, complementary research methods should be applied to obtain the most comprehensive information. We undertook a comprehensive review of publications related to the topics ADs, suicide, suicidality, suicidal behaviour and aggression. Based on this comprehensive review we conclude that ADs, including SSRIs, carry a small risk of inducing suicidal thoughts and suicide attempts, in age groups below 25 years, the risk reducing further at the age of about 30–40 years. This risk has to be balanced against the well-known beneficial effects of ADs on depressive and other symptoms (anxiety, panic, obsessive-compulsive symptoms), including suicidality and suicidal behaviour. According to the principles of good clinical practice, decision making should consider carefully the beneficial effects of AD treatment as well as potentially harmful effects and attempt to keep the potential risks of AD treatment to a minimum. It is the major problem facing efforts to identify the possible ‘suicidal effects’ of antidepressants.

     

Do SSRIs or antidepressants in general increase suicidality? WPA Section on Pharmacopsychiatry: consensus statement

In the past few years several papers have reported critically on the risk of suicidal thoughts and behaviour associated with antidepressants, primarily SSRIs. The risk-benefit ratio of antidepressant (AD) treatment has been questioned especially in children and adolescents. The critical publications led to warnings being issued by regulatory authorities such as the FDA, MHRA and EMEA and stimulated new research activity in this field. However, potential harmful effects of antidepressants on suicidality are difficult to investigate in empirical studies because these have several methodological limitations. Randomised controlled trials (RCTs) are the most reliable way to test the hypothesis that AD have such side effects. In addition to meta-analyses of RCTs, complementary research methods should be applied to obtain the most comprehensive information. We undertook a comprehensive review of publications related to the topics ADs, suicide, suicidality, suicidal behaviour and aggression. Based on this comprehensive review we conclude that ADs, including SSRIs, carry a small risk of inducing suicidal thoughts and suicide attempts, in age groups below 25 years, the risk reducing further at the age of about 30-40 years. This risk has to be balanced against the well-known beneficial effects of ADs on depressive and other symptoms (anxiety, panic, obsessive-compulsive symptoms), including suicidality and suicidal behaviour. According to the principles of good clinical practice, decision making should consider carefully the beneficial effects of AD treatment as well as potentially harmful effects and attempt to keep the potential risks of AD treatment to a minimum. It is the major problem facing efforts to identify the possible 'suicidal effects' of antidepressants.     

Antidepressants and suicidal behavior in bipolar disorder

Patients with bipolar disorder are at very high risk for suicidal ideation, non-fatal suicidal behaviors and suicide and are frequently treated with antidepressants. However, no prospective, randomized, controlled study specifically evaluating an antidepressant on suicidality in bipolar disorder has yet been completed. Indeed, antidepressants have not yet been shown to reduce suicide attempts or suicide in depressive disorders and may increase suicidal behavior in pediatric, and possibly adult, major depressive disorder. Available data on the effects of antidepressants on suicidality in bipolar disorder are mixed. Considerable research indicates that mixed states are associated with suicidality and that antidepressants, especially when administered as monotherapy, are associated with both suicidality and manic conversion. In contrast, growing research suggests that antidepressants administered in combination with mood stabilizers may reduce depressive symptoms in patients with bipolar depression. Further, the only prospective, long-term study evaluating antidepressant treatment and mortality in bipolar disorder, although open-label, found antidepressants and/or antipsychotics in combination with lithium, but not lithium alone, reduced suicide in bipolar and unipolar patients (Angst F, et al. J Affect Disord 2002: 68: 167–181). We conclude that antidepressants may induce suicidality in a subset of persons with depressive (and probably anxious) presentations; that this induction may represent a form of manic conversion, and hence a bipolar phenotype, and that lithium's therapeutic properties may include the ability to prevent antidepressant-induced suicidality.     

Suicide seasonality and antidepressants: a register‐based study in Sweden

Objective: Seasonality of completed suicides with a peak in spring and early summer is a well‐documented finding. The circannual serotonergic functioning is hypothesized to be central in this phenomenon. Antidepressant medications exert their pharmacological action mainly by regulating serotonin. Our aim is to study the amplitude of the seasonal effect among suicide victims positive for different classes of antidepressants or without any antidepressants at the time of death. Method: By using Swedish Registers, 12 448 suicides with forensic data for antidepressive medication and information on in‐patient‐treated mental disorder were identified during 1992–2003. Seasonality was estimated with a Poisson regression variant of the circular normal distribution of completed suicides. Results: Higher suicide seasonality was found for individuals treated with selective serotonin reuptake inhibitor (SSRIs) compared to those with other antidepressant treatment or without any antidepressant treatment. The finding is more evident for men and violent suicide methods and those without history of in‐patient treatment. Conclusion: Our results provide preliminary support for the serotonergic hypothesis of suicide seasonality and raise the question of a possible accentuation of the natural suicide seasonality in patients treated with SSRIs, a hypothesis that warrants further investigation.     

Do antidepressants precipitate youth suicide?

The association between treatment with Selective serotonin reuptake inhibitors (SSRIs) and suicide in children and adolescents on the individual and ecological level were examined in a nationwide Danish pharmacoepidemiological register-linkage study including all persons aged 10–17 years treated with antidepressants during the period 1995–1999 (n=2,569) and a randomly selected control population (n=50,000). A tripartite approach was used. In Part 1, changes in youth suicide and use of antidepressants were examined. In Part 2, we made an assessment of youth suicide characteristics. In Part 3, we analysed the relative risk (RR) of suicide according to antidepressant treatment corrected for psychiatric hospital contact to minimize the problem of confounding by indication. The use of SSRIs among children and adolescents increased substantially during the study period, but the suicide rate remained stable (Part 1). Among 42 suicides nationally aged 10–17 years at death, none was treated with SSRIs within 2 weeks prior to suicide (Part 2). There was an increased rate of suicide associated with SSRIs (RR=4.47), however, not quite significant (95% CI: 0.95–20.96), when adjusted for severity of illness (Part 3). Conclusively, we were not able to identify an association between treatment with SSRIs and completed suicide among children and adolescents.     

Ecological studies of antidepressant treatment and suicidal risks

Ongoing discussion of potential benefits and risks of antidepressant treatment with respect to suicidal behaviors includes many ecological, or population-based, correlational studies of temporal or regional trends in suicide rates and rates of usage of modern antidepressants including serotonin-reuptake inhibitors (SRIs). Since this body of research has not been compiled and evaluated, we used computerized literature searching to identify 19 relevant published studies. They yielded heterogeneous findings: only 8/19 found significant inverse correlations between rising sales of modern antidepressants in the 1990 s and falling suicide rates not anticipated in the 1980s. Average reductions in suicide rates in the 1990 s (10.7%) and 1980s (10.0%) differed little in 11 studies with data from both eras. Reduction of suicide rates in the 1990 s was unrelated to geographic region, population size, units of analysis, publication year, or growth in antidepressant usage, but was greater with higher initial suicide rates, in men, and in older persons. In the same decade, suicides rates decreased in only half of 79 large countries. Overall, these findings yield limited and inconsistent support for the hypothesis that increased use of modern antidepressants might limit suicide risk, and no evidence that the risk increased. Suicidal risk is determined by complex factors, including access to clinical services, in general, and more comprehensive treatment of depression, in particular. Overall, as with findings from randomized trials and cohort or case-control studies, evidence of specific antisuicidal effects of antidepressant treatment from ecological analyses remains elusive.     

Antidepressants and suicide: risk-benefit conundrums

There has been a long-standing controversy about the possibility that selective serotonin reuptake inhibitor (SSRI) antidepressants might induce suicidality in some patients. To shed light on this issue, this paper reviews available randomized controlled trials (RCTs), meta-analyses of clinical trials and epidemiological studies that have been undertaken to investigate the issue further. The original clinical studies raising concerns about SSRIs and suicide induction produced evidence of a dose-dependent link on a challenge-dechallenge and rechallenge basis between SSRIs and both agitation and suicidality. Meta-analyses of RCTs conducted around this time indicated that SSRIs may reduce suicidal ideation in some patients. These same RCTs, however, revealed an excess of suicidal acts on active treatments compared with placebo, with an odds ratio of 2.4 (95; confidence interval 1.6-3.7). This excess of suicidal acts also appears in epidemiological studies. The data reviewed here make it difficult to sustain a null hypothesis that SSRIs do not cause problems in some individuals. Further studies or further access to data are indicated to establish the magnitude of any risk and the characteristics of patients who may be most at risk.