Antidepressants in suicide prevention

Antidepressants are the cornerstone of treatment of depressive disorders in health care. Their efficacy in treating depression is undisputable, although it leaves room for improvement. However, recent reports also suggest that antidepressants might, in some rare cases, actually worsen suicidal tendencies instead of alleviating them. As a consequence, research has intensified to clarify this issue, and regulatory authorities in many countries have reconsidered their cost-benefit ratio. While there is no doubt that such potential side-effects of antidepressant therapy are a very serious issue, it is important to obtain a balanced view of all the clinical and epidemiological facts pertaining the effect of antidepressant therapy in relation to suicidal behaviour.

Depression and risk of suicidal behaviour

Suicide is a significant public health issue. The World Health Organization (WHO) estimates that annually about one million people worldwide complete suicide. Thus, worldwide significantly more people die by suicide than e.g. in armed conflicts or as victims of terror, or tragic natural disasters such as earthquakes. Furthermore, completed suicides represent only a tip of the iceberg of suicidal behaviour, as for every completed suicide, there is more than ten-fold number of non-fatal suicide attempts, and as many as almost one tenth of individuals worldwide, also in the EU, report having had suicidal ideation over their lifetime (Bernal et al., 2007; Nock et al., 2008).

In numerous psychological autopsy studies conducted worldwide, more than 90% of subjects completing suicide were shown to have suffered from mental disorders. Suicides have multiple causes and should therefore not be seen as merely consequences of mental disorders. Nevertheless, for health care, the strong relationship between mental disorders and suicides involves an obligation for prevention. Mood disorders, principally major depression and bipolar disorder, are associated with about 60% of completed suicides (Mann et al., 2005). More than half of the subjects completing suicide during major depression communicate their intent during the final 3 months, and almost all patients attempting suicide report suicidal ideation (Isometsä et al., 1994; Sokero et al., 2003). This communication of intent allows prevention by appropriate treatment and other measures. However, the problem faced by psychiatrists is a high number of suicidal patients and the difficulty of identifying those at highest risk of completion among them.

Among psychiatric patients with major depression, non-fatal suicidal behaviour is remarkably common. Almost half (about 40%) have attempted suicide, and one half to two thirds of them (47%-69%) have suicidal ideation (Sokero et al., 2003; Malone et al., 1995) when depressed. The risk for suicide attempts is closely intertwined with the commonly recurrent course of depression; the risk is about eightfold during a major depressive episode compared to periods of full remission (Sokero et al., 2005). The more time a patient spends in a depressed state, the higher is the risk of suicidal acts over time. Among depressed patients having suicidal ideation, decline in suicidal ideation is predicted by declines in the levels of both depressive symptoms as well as hopelessness (Sokero et al., 2006).

Thus, reducing the severity and the duration of a depressed state by antidepressant treatment is likely to be an effective preventive measure for suicidal acts, and alleviation of depression and hopelessness can be reasonably expected to result in disappearance of suicidal thoughts.

Suicide prevention strategies

Depression is present in more than half of suicides, but in the majority of these suicides it has remained untreated at time of death (Isometsä et al, 1994; Henriksson et al., 2001). Even after a suicide attempt, depression often remains unrecognized, untreated or undertreated (Oquendo et al., 2002).

The role of targeting depression for suicide prevention has been highlighted in a worldwide review and consensus of leading authorities in suicide research, in which the effectiveness of specific suicide-preventive interventions was examined: Only physician education in recognition and treatment of depression as well as restricting access to lethal means were clearly identified to prevent suicide, other interventions still need more testing (Mann et al., 2005). Thus, treating mood disorders and other psychiatric disorders is a central component of suicide prevention.

Improved recognition and treatment of depressed patients in primary care alongside improved access to psychiatric services is a key prevention strategy for suicide.

Antidepressants and suicide risk: what is the evidence?

In numerous short-term randomized clinical trials (RCTs) of antidepressants for depression in children and adolescents (<19 years), antidepressants are found to be associated with a slightly higher proportion (0.7%) of patients reporting suicidal ideation or a suicide attempt than control patients receiving placebo (Bridge et al., 2007). It is important to note that there are no completed suicides in these studies. Adults treated with SSRI antidepressants in randomized clinical trials have a similar risk of either non-fatal self harm or suicidal thoughts than those on placebo (Gunnell et al., 2005 & 2006). It is undisputable that at least among children and adolescents, antidepressants have some potential of causing harm to a small subgroup of vulnerable patients, at least in the beginning of treatment. However, there are several reasons why such trials are likely to create a distorted view of the total balance of benefits and harms of antidepressants:

• First, short-term clinical trials are designed to produce statistical evidence of efficacy for regulatory purposes, and their duration is only as long as necessary to produce this evidence. Thus, the trial ends when the drug response has evolved. During the trial patients spend most of their weeks with possible side effects, but not yet full antidepressant response. With regard to suicidal behaviour, the benefits come with the response, gradually over time.

• Second, for ethical reasons, subjects who are severely suicidal at the time of evaluation for the trial must be excluded, since they might receive placebo. This changes the balance between observed negative and positive effects with regard to suicidal behaviour in these trials. Worsening of mild pre-existing or newly emerging suicidal behaviour can be usually detected. However, as most severely suicidal patients must be excluded before a trial starts, it remains unknown whether they would benefit from the active treatment. As naturalistic studies do suggest such improvement, this bias is not merely hypothetical. Antidepressant trials have not been designed to investigate suicidal behaviour, and they cannot provide unbiased information on their overall effects related to it.

• Third, factors resulting in short-term suicidal ideation, or even less severe suicide attempts do not necessarily result in significantly increased risk for completed suicide, as mental disorders and their symptoms related to completed suicides are usually more severe. There is no evidence of increased rates completed suicides in antidepressant trials (Khan et al, 2003).

• Fourth, clinical trials do not reflect usual treatment. In usual care, the attending doctor can promptly discontinue antidepressants that involve intolerable side-effects, adjust dosage, and switch and combine agents. Antidepressants are only part of treatment, which should always include a trustful relationship between the doctor and the patient, with necessary support and psychosocial treatments.

The most important test for the role of antidepressants in suicide prevention is real life: In contrast to these randomized clinical trials, observational studies of antidepressant treatment, which typically include abundantly highly suicidal patients, demonstrate a marked alleviation of suicidal behaviour in the vast majority of patients. In clinical practice, the benefits of treatment are seen over time as the drug response consolidates. Patient population studies of adolescents report lower rates of suicide attempts and of adults both attempts and completions over time as treatment continues (Valuck et al., 2004; Jick et al., 2004; Simon et al., 2007; Sokero et al., 2006; Simon et al., 2006).

In many western countries (e.g. Korkeila et al., 2007), increasing use of antidepressants on the national and regional level expectedly correlates with declining suicide mortality. Of course, such ecological studies do not prove that antidepressants have caused the observed decline in suicides, but nevertheless, they are consistent with a positive or at worst, neutral net effect on suicides. Most importantly, there is no evidence for increased national suicide rates due to increased use of antidepressants.

Antidepressants reduce the severity, and the time a patient spends in a depressive state, which are credible factors in reducing the risk for suicidal acts.

Clinical implications

• Depression is the most important single factor predisposing to suicide, and more than half of all subjects completing suicide are known to have suffered from depression. Thus, any treatment that is widely available, safe and efficacious in alleviating depression is plausible for purposes of suicide prevention.

• Register-based and observational studies have provided individual-level information on depressed subjects on and off antidepressants in real life conditions: Compared to randomized clinical trials these studies give a more realistic account of risk of suicidal behaviour, and suggest antidepressants to be beneficial for suicide prevention.

• While antidepressants likely have a potential for provoking suicidal behaviour in some vulnerable individuals in the early phases of treatment, from a public health perspective, the epidemiologically much more important effect of antidepressants is to alleviate depression and thus reduce the risk of suicide.

References

1. Bernal M, Haro JM, Bernert S, et al.; ESEMED/ MHEDEA Investigators. Risk factors for suicidality in Europe: results from the ESEMED study. J Affect Disord. 2007;101:27-34
2. Nock MK, Borges G, Bromet EJ, et al. Cross-national prevalence and risk factors for suicidal ideation, plans and attempts. Br J Psychiatry. 2008;192:98-105
3. Mann JJ, Apter A, Bertolote J, et al. Suicide prevention strategies. A systematic review. JAMA 2005;294:2064-2074
4. Isometsä ET, Henriksson MM, Aro HM, et al. Suicide in major depression. Am J Psychiatry 1994;151:530-536
5. Sokero TP, Melartin TK, Rytsälä HJ, et al. Suicidal ideation and attempts among psychiatric patients with major depressive disorders. J Clin Psychiatry 2003;64:1094-1100
6. Malone KM, Haas GL, Sweeney JA, et al. Major depression and the risk of attempted suicide. Journal of Affective Disorders 1995;34:173-185
7. Sokero P, Melartin TK, Rytsälä HJ, et al. Prospective study of risk factors for attempted suicide among patients with DSM-IV major depressive disorder. Br J Psychiatry 2005;186:314-318
8. Sokero P, Eerola M, Rytsälä H, et al. Decline in suicidal ideation among patients with MDD is preceded by decline in depression and hopelessness. Journal of Affective Disorders 2006;95:95-102
9. Henriksson S, Boethius G, Isacsson G. Suicides are seldom prescribed antidepressants: findings from a prospective prescription database in Jamtland county, Sweden, 1985-95. Acta Psychiatr Scand 2001;103:301-306
10. Oquendo MA, Kamali M, Ellis SP, et al. Adequacy of antidepressant treatment after discharge and the occurrence of suicidal acts in major depression: a prospective study. Am J Psychiatry 2002;159:1746-1751
11. Bridge JA, Iyengar S, Salary CB, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment. A meta-analysis of randomized controlled trials. JAMA 2007;297:1683-1696.
12. Gunnell D, Saperia J, Ashby D. Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo-controlled, randomised controlled trials submitted to the MHRS's safety review. BMJ 2005;330:385-8 (updated in BMJ 2006;332:1453)
13. Khan A, Khan S, Kolts R et al. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: Analysis of FDA reports. Am J Psychiatry 2003;160:790-792
14. Valuck RJ, Libby AM, Sills MR, et al. Antidepressant treatment and risk of suicide attempt by adolescents with major depressive disorder: a propensity-adjusted retrospective cohort study. CNS Drugs 2004;18:1119-1132
15. Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA 2004;292:338-343
16. Simon G, Savarino J. Suicide attempts among patients starting depression treatment with medications and psychotherapy. Am J Psychiatry 2007:164:1029-1034.
17. Simon G, Savarino J, Operkalski B, et al. Suicide risk during antidepressant treatment. Am J Psychiatry 2006;163:41-47.
18. Korkeila J, Salminen JK, Hiekkanen H, et al. Use of antidepressants and suicide rate in Finland: an ecological study. J Clin Psychiatry. 2007;68:505-11.

Correspondence:
Professor Erkki T. Isometsä, M.D., Ph.D.
Institute of Clinical Medicine,
Department of Psychiatry,
P.O. Box 22, 00014 University of Helsinki, Finland
E-mail: erkki.isometsa@hus.fi