SSRIs and Suicide

A meta-analysis in the BMJ, August 2009.
Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration
Stone et al. 339 (112): b2880. (2009) Full text pdf.

There is a debate in the Feb 2009 issue of the Canadian Journal of Psychiatry

IN DEBATE

Are Selective Serotonin Reuptake Inhibitors a Risk Factor for Adolescent Suicide?
David Healy. Full-text.

Selective Serotonin Reuptake Inhibitors and Suicidality: A Guide for the Perplexed
David A Brent. Full-text.

Perplexity Is Our Product
David Healy. Full-text.

Youth Depression and Suicide: Selective Serotonin Reuptake Inhibitors Treat the Former and Prevent the Latter
David A Brent. Full-text.

Selective serotonin reuptake inhibitors and risk of suicide: a systematic review of observational studies
Corrado Barbui, MD, Eleonora Esposito, MD and Andrea Cipriani, MD
CMAJ • February 3, 2009; 180 (3) 291-297. Full-text.

Background: It is unclear whether the use of selective serotonin reuptake inhibitors (SSRIs) and other antidepressant drugs reduce the risk of suicide in people with depression. We explored the association between exposure to SSRIs and risk of suicide completion or attempt.

Methods: We conducted a systematic review of observational studies that reported completed or attempted suicide in depressed individuals who were exposed to SSRIs compared with those who were not exposed to antidepressants. We assessed the overall risk of completed or attempted suicide.

Results: Eight studies involving more than 200 000 patients with moderate or severe depression were included in the meta-analysis. Although exposure to SSRIs increased the risk of completed or attempted suicide among adolescents (odds ratio [OR] 1.92, 95% confidence interval [CI] 1.51–2.44), the risk was decreased among adults (OR 0.57, 95% CI 0.47–0.70). Among people aged 65 or more years, exposure to SSRIs had a protective effect (OR 0.46, 95% CI 0.27–0.79). Sensitivity analyses did not change these findings. In particular, for studies that used completed suicide as an outcome, exposure to SSRIs was associated with increased risk among adolescents (OR 5.81, 95% CI 1.57–21.51) and decreased risk among adults (OR 0.66, 95% CI 0.52–0.83) and older people (OR 0.53, 95% CI 0.26–1.06).

Interpretation: Based on data from observational studies, use of SSRIs may be associated with a reduced risk of suicide in adults with depression. Among adolescents, use of SSRIs may increase suicidality.

'We found that the relation between exposure to SSRIs and the risk of suicide is influenced by age. Exposure to SSRIs decreased the risk of suicide by over 40% among adults, and decreased the risk by over 50% among elderly people. However, among adolescents, exposure to SSRIs almost doubled the risk of suicide.'

The authors attempted to see if some antidepressants were more risky of suicide than others.

They comment: 'Paroxetine and venlafaxine may be better avoided based on the increasing evidence from randomized and observational studies that the risks might outweigh the benefits for most adolescents.'

There is some literature suggesting that the self-harm impulses associated with SSRI use may be related to 5-HT2 receptors. 10

Results of a MEDLINE Search by Ivan Goldberg, M.D.
Revised 18 November 2006
http://www.psycom.net/depression.central.ssri-suicide.html

Am J Psychiatry. 2006 Nov;163(11):1898-904.
The relationship between antidepressant prescription rates and rate of early adolescent suicide.
Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
Center for Health Statistics, University of Illinois at Chicago, 1601 W. Taylor, Chicago 60612. rdgib@uic.edu.

OBJECTIVE: In 2002, 264 children and adolescents ages 5-14 died by suicide in the United States, the fifth leading cause of death. Of these suicides, 260 were in the 10-14 year age group, making suicide the third largest cause of death behind accidents and malignancy. Although 60% of suicides in the general population occur in the midst of a mood disorder, usually untreated, little is known about the relationship between treatment of mood disorders and youth suicide. The FDA recently linked adverse event reports of suicidal ideation among children and adolescents in randomized controlled trials to selective serotonin reuptake inhibitors (SSRIs) and consequently required a change in labeling that included a black box warning regarding SSRI use for all age groups. Given that the age-adjusted suicide rate is about six times higher in 15-19 year olds compared with 10-14 year olds, the risk-benefit ratio may be different in younger children. Therefore, this study examined the association between antidepressant medication prescription rate and suicide rate in children ages 5-14 prior to the FDA findings by analyzing associations at the county level across the United States. METHOD: National county-level suicide rate data among children ages 5-14 were broken down by sex, income, and race during the period 1996-1998. National county-level antidepressant prescription rate data were expressed as number of pills prescribed per person. The primary outcome measure was the suicide rate in each county expressed as number of suicides for a given population size. RESULTS: After adjustment for sex, race, income, access to mental health care, and county-to-county variability in suicide rates, higher SSRI prescription rates were associated with lower suicide rates in children and adolescents. CONCLUSIONS: The aggregate nature of these observational data precludes a direct causal interpretation of the results. More SSRI prescriptions are associated with lower suicide rates in children and may reflect antidepressant efficacy, treatment compliance, better quality mental health care, and low toxicity in the event of a suicide attempt by overdose.

Aust N Z J Psychiatry. 2006 Nov;40(11-12):941-50.
How have the selective serotonin reuptake inhibitor antidepressants affected suicide mortality?
Hall WD, Lucke J.
School of Population Health, University of Queensland, Herston, Queensland, Australia.

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.

Presse Med. 2006 Oct;35(10 Pt 2):1507-15.
[Safety of selective serotonin reuptake inhibitor antidepressants in children and adolescents]
[Article in French]
Bailly D.
Service hospitalo-universitaire de psychiatrie, Hopital Sainte-Marguerite, Marseille (13). daniel.bailly@ap-hm.fr

Some behavioral side effects of selective serotonin reuptake inhibitor (SSRI) antidepressants have been known for a long time. Since the introduction of these drugs in the 1990s, publications have regularly reported behavioral side effects in children and adolescents, including excitation, motor restlessness, social disinhibition, and above all self-injurious ideation and behavior. Clinical trials provide only limited data. Although these data suggest that some self-injurious and suicidal behavior may indeed occur in children and adolescents receiving SSRIs, they are too disparate to specify the frequency of these acts. Clinical trials provide useful data about drug efficacy, but their methodology is inappropriate for determining the frequency of such side effects. SSRI and suicidality: the data are difficult to read. Although some epidemiologic data suggest that SSRIs may increase the risk of occurrence of self-injurious and suicidal behavior in children and adolescents, other epidemiologic data show that the rate of suicide mortality in children and adolescents has decreased since the introduction of SSRIs. No known mechanism explains how SSRIs might increase the risk of these behavioral side effects. It is clear, however, that these effects are not particular to children and adolescents but may also be observed among adults. SSRIs must be used rationally and carefully in children and adolescents. They should not be administered routinely in youth with obsessive-compulsive or depressive disorders. Their use should be reserved for severe disorders or when psychotherapy alone has been shown to be inadequate, and when they are used, efficacy and side effects must be monitored carefully and frequently.

Nervenarzt. 2006 Jun 22; [Epub ahead of print]
[Antidepressants and suicidality : Risk-benefit analysis.]
[Article in German]
Hegerl U.
Abteilung fur Klinische Neurophysiologie, Psychiatrische Klinik der Ludwig-Maximilians-Universitat, Nussbaumstrasse 7, 80336, Munchen, ulrich.hegerl@psy.med.uni-muenchen.de.

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.

Clin Trials. 2006;3(2):73-90; discussion 91-8.
Do antidepressants cause suicidality in children? A Bayesian meta-analysis.
Kaizar EE, Greenhouse JB, Seltman H, Kelleher K.
Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15217, USA.

BACKGROUND: To quantify the risk of suicidal behavior/ideation (suicidality) for children who use antidepressants, the FDA collected randomized placebo-controlled trials of antidepressant efficacy in children. Although none of the 4487 children completed suicide, 1.7% exhibited suicidality. The FDA meta-analyzed these studies and found sufficient evidence of an increased risk to require a black-box warning on antidepressants for children. PURPOSE: The FDA considered different drug formulations and psychiatric diagnoses to be equivalent in their effect on suicidality. If this assumption does not hold, the FDA analysis may have underestimated the variance of the risk estimate. We investigate the consequences of relaxing these assumptions. METHODS: We extend the FDA analysis using a Bayesian hierarchical model that allows for a study-level component of variability and facilitates extensive sensitivity analyses. RESULTS: We found an association between antidepressant use and an increased risk of suicidality in studies where the diagnosis was major depressive disorder (odds ratio 2.3 [1.3, 3.8]), and where the antidepressant was an SSRI (odds ratio 2.2 [1.3, 3.6]). We did not find evidence for such an association in the complement sets of trials. Although the results based on the hierarchical model are insensitive to model perturbations, the robustness of the FDA's meta-analysis to model assumptions is less clear. These data have limited generalizability due to exclusion of patients with baseline risk of suicide and the use of relatively short duration trials. CONCLUSIONS: Because of model specification and interpretation issues raised in this paper, we conclude that the evidence supporting a causal link between antidepressant use and suicidality in children is weak. The use of Bayesian hierarchical models for meta-analysis has facilitated the incorporation of potentially important sources of variability and the use of sensitivity analysis to assess the consequences of model specifications and their impact on important regulatory decisions.

PLoS Med. 2006 Jun;3(6):e190. Epub 2006 Jun 13.
Modeling of the temporal patterns of fluoxetine prescriptions and suicide rates in the United States.
Milane MS, Suchard MA, Wong ML, Licinio J.
Center for Pharmacogenomics and Clinical Pharmacology, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, USA.

BACKGROUND: To study the potential association of antidepressant use and suicide at a population level, we analyzed the associations between suicide rates and dispensing of the prototypic SSRI antidepressant fluoxetine in the United States during the period 1960-2002. METHODS AND FINDINGS: Sources of data included Centers of Disease Control and US Census Bureau age-adjusted suicide rates since 1960 and numbers of fluoxetine sales in the US, since its introduction in 1988. We conducted statistical analysis of age-adjusted population data and prescription numbers. Suicide rates fluctuated between 12.2 and 13.7 per 100,000 for the entire population from the early 1960s until 1988. Since then, suicide rates have gradually declined, with the lowest value of 10.4 per 100,000 in 2000. This steady decline is significantly associated with increased numbers of fluoxetine prescriptions dispensed from 2,469,000 in 1988 to 33,320,000 in 2002 (r(s) = -0.92; p < 0.001). Mathematical modeling of what suicide rates would have been during the 1988-2002 period based on pre-1988 data indicates that since the introduction of fluoxetine in 1988 through 2002 there has been a cumulative decrease in expected suicide mortality of 33,600 individuals (posterior median, 95% Bayesian credible interval 22,400-45,000). CONCLUSIONS: The introduction of SSRIs in 1988 has been temporally associated with a substantial reduction in the number of suicides. This effect may have been more apparent in the female population, whom we postulate might have particularly benefited from SSRI treatment. While these types of data cannot lead to conclusions on causality, we suggest here that in the context of untreated depression being the major cause of suicide, antidepressant treatment could have had a contributory role in the reduction of suicide rates in the period 1988-2002.

J Affect Disord. 2006 Aug;94(1-3):3-13. Epub 2006 May 19.
Do antidepressants t(h)reat(en) depressives? Toward a clinically judicious formulation of the antidepressant-suicidality FDA advisory in light of declining national suicide statistics from many countries.
Rihmer Z, Akiskal H.
National Institute for Psychiatry and Neurology, Budapest, Hungary. rihmer.z@opni.hu

Given that suicidality is a well-known symptom and outcome of untreated or inadequately treated depressive illness, the United States (US) Food and Drug Administration (FDA) warning of emergent suicidality in children and adolescents based on the antidepressant arm of placebo-controlled randomized trials (RCTs) has created understandable concern in clinical practice. The issues involved are of broader public health importance for all age groups. As in other branches of medicine, psychiatrists must always be vigilant of the rare risk of iatrogenesis when prescribing potent agents like antidepressants for patients with depressive disorders where the risk of suicidality is inherent. The overall evidence we review suggests that the widespread use of antidepressants in the new "SSRI-era" appear to have actually led to highly significant decline in suicide rates in most countries with traditionally high baseline suicide rates. The decline is particularly striking for women who, compared with men, seek more help for depression. Recent clinical data on large samples in the US too have revealed a protective effect of antidepressant against suicide. We argue that the discrepancy between RCTs (in children) and national and clinical suicide statistics (in adults) may reside in new provocative data documenting high rates of unrecognized pseudo-unipolar mixed states particularly in juvenile, but also in adult, clinical populations. Such an interpretation accords well with equally provocative data that bipolar II (which is often "mixed" in nature) may well represent a particularly vulnerable clinical substrate for suicidality. In this respect, the widespread (at least in the psychiatric sector) augmentation of antidepressants with benzodiazepines, atypical antipsychotics or mood stabilizers may represent one situation where current practice is superior to evidence-based medicine. We conclude that rather than being a threat, the judicious clinical use of antidepressants actually does serve to effectively treat and indeed protect depressed patients from suicidal outcome. The fact of being in treatment with regular clinical follow-up appears beneficial as well. Full text available here.

Encephale. 2005 May-Jun;31(3):309-16.
[Selective serotonin reuptake inhibitors in major depressive disorder in children and adolescents (ratio of benefits/risks)]
[Article in French]
Hjalmarsson L, Corcos M, Jeammet P.
Departement de Psychiatrie des Adolescents et Adultes jeunes, Institut Mutualiste Montsouris, 42 boulevard Jourdan, 75014 Paris.

Major depressive disorder in children and adolescents is associated with high risk of suicide and persistent functional impairment. While psychological treatments are used as a first line treatment in mild and moderately severe depression in this age group, the number of prescriptions for antidepressant medication (SSRI) has grown in recent years. Recently, FDA and MHRA advised that most of SSRI should not be used to treat MDD under the age of 18 years. They may increase the risk of suicidal thoughts and self harm. We reviewed the recent literature on efficacy and suicide risks of SSRI in depressed young people. Conflicting findings of SSRI efficacy have been reported in clinical studies. The discrepancies could be related to the heterogeneous samples and the absence of a standard definition of treatment effectiveness. In randomised placebo-controlled antidepressant clinical trials (RCT), the assessment of treatment effectiveness is commonly made with the CDRS-R (improvement of 20% or 30% or 40%) and CGI. SSRI demonstrated significantly, but modest, improvement compared with placebo in CGI score of 1 or 2: 10% more for sertraline, 16.8% more for paroxetine and between 16 to 24% more for fluoxetine. In adults, RCT studies have shown placebo response rates of 30% to 50%, drug response rates of 45% to 50% and drug-placebo differences of 18% to 25%. The highest placebo response rates, in young people, may be related to the highly selected group not representative of the general population of depressed patients and/or to the high youths' sensibility of psychotherapy. Patients participating in antidepressant clinical trials have a low BDI and CDI in Emslie's study for example (2002). In adults, previous reports suggest that SSRI use is associated with increased suicidal risk. But the analyse of 48 277 depressed patients participating in RCT for nine FDA approved antidepressants fail to support an overall difference in suicide risk between antidepressants (SSRI) and placebo treated subjects. An inverse relationship between regional change in use of antidepressants (increased) and suicide (decreased) is found in young -people in United States from 1990 and 2000. We can not draw a conclusion from few studies with few -participants. None suicide have been reported in pharmacological studies. And the link between "suicidality" and MDD can not be excluded. The instruments of assessment in depressed young patients are based on extensions of adult procedures. Whereas clinical picture of MDD in children, adolescents and adults have some differences. Depressed youngsters have more pronounced mood lability. Depressed adolescents have more anhedonia than depressed children. Future investigations into the efficacy and safety of treatments for children and adolescents depression should use specific instruments directly built on phenomenological and clinical picture of depressed children and adolescents. Comparison studies of pharmacotherapy, specific psychotherapies (not only CBT) and combined therapies are necessary to identify the adolescents who will benefit the most from specific or combined therapies. Further studies into the factors that influence treatment outcome including clinical picture (clinical dimensions, severity, duration, co morbidity), genetic factor, age, and i-llness course may help identify appropriate treatments for children and adolescents with MDD. Studies should include patients more severely ill, with associated psychiatric troubles, treatment resistance, history of relapses... In clinical studies, the link between "suicidality" and some clinical dimensions (which take part in clinical picture or not) must be analysed by assessing anhedonia, hopelessness feel, impulsive trait, borderline personality, familial inter-action, biological indices. New treatment should be expand and their efficacy and safety must be study: St John's worth, Bright light therapy, Trans-cranial Magnetic Stimulation. In practice: suicide and MDD have a strongest relation and it must be investigate syste-matically during the course of MDD. The suicide risk increases in the context of past history of suicide attempts, hopelessness, psychosis, impulsivity traits, substance abuse, familial dysfunction, life events, open access of arms. The use of SSRI in depressed children and adolescents is also the question of the quality and the support of the consultant and the mode of the prescription.

Pharmacoepidemiol Drug Saf. 2005 Jun;14(6):367-72.
Comment in: Pharmacoepidemiol Drug Saf. 2005 Jun;14(6):365-6.
Prevalence of risk factors for suicide in patients prescribed venlafaxine, fluoxetine, and citalopram.
Mines D, Hill D, Yu H, Novelli L.
Global Safety Surveillance and Epidemiology, Wyeth Research, Collegeville, PA 19426-3930, USA. minesd@wyeth.com

PURPOSE: Three recent observational studies reported that the risk of fatal overdose is greater with venlafaxine than SSRI use. It is not clear whether patient factors could account for this finding. We evaluated whether risk factors for suicide are more prevalent among patients prescribed venlafaxine than patients prescribed fluoxetine or citalopram. METHODS: Using data from the UK General Practice Research Database (GPRD), we identified patients who were first prescribed any of the three drugs between January 1995 and April 2002. We ascertained risk factors for suicide documented in the 1 year before that first prescription. Separate analyses compared venlafaxine (N = 27 096) and fluoxetine (N = 134 996) cohorts, and venlafaxine and citalopram (N = 52 035) cohorts. RESULTS: Previous suicidal behaviors were documented for 1.0% of the venlafaxine cohort compared to 0.4% of the fluoxetine cohort (OR 2.8, 95%CI: 2.4, 3.2) and 0.4% citalopram cohorts (OR 2.4, 95%CI: 2.0, 2.9). 72.5% of venlafaxine patients had been prescribed at least one other antidepressant compared to 27.6% of fluoxetine (OR 6.9, 95%CI: 6.7, 7.1) and 39.5% of citalopram (OR 4.0, 95%CI: 3.9, 4.2) patients. Venlafaxine patients were also four to six times as likely to have been previously hospitalized for depression. CONCLUSION: In the UK, venlafaxine has been selectively prescribed to a patient population with a higher burden of suicide risk factors than patients prescribed fluoxetine and citalopram. Unless baseline population differences are accounted for, observational studies that compare the risk of suicide in patients receiving these agents may produce biased results.

Curr Psychiatry Rep. 2005 Apr;7(2):87-90.
The selective serotonin reuptake inhibitors controversy in the treatment of depression in children.
Weller EB, Tucker S, Weller RA.
2619 B Executive Place, Biloxi, MS 39531, USA. clinneurochemist@msn.com.
Antidepressants are widely prescribed for children and adolescents, although data regarding their safety and efficacy are limited. The objective of this article is to review the origins of the controversy regarding the current use of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents. Two chief concerns drive the controversy: 1) the discovery of an increased risk of suicidal behaviors in those treated with SSRIs and 2) the efficacy of SSRIs in childhood and adolescent major depression is unclear. Various factors may account for the reported differences in outcomes for SSRI treatment in children and adolescents compared to adults. The past decade has shown a significant drop in the rate of adolescent suicide, which coincides with the onset of the use of these medications. Therefore, a reduction in the use of SSRIs in children and adolescents should be considered carefully.

Acta Psychiatr Scand. 2005 Apr;111(4):286-90.
Comment in: Evid Based Ment Health. 2005 Nov;8(4):113.
Selective serotonin reuptake inhibitor antidepressants and the risk of suicide: a controlled forensic database study of 14,857 suicides.
Isacsson G, Holmgren P, Ahlner J.
Neurotec, Division of Psychiatry, Karolinska Institute, Stockholm, Sweden. goran.isacsson@neurotec.ki.se

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.

BMJ. 2005 Feb 19;330(7488):389.
Comment in: BMJ. 2005 Feb 19;330(7488):373-4.
Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study.
Martinez C, Rietbrock S, Wise L, Ashby D, Chick J, Moseley J, Evans S, Gunnell D.
General Practice Research Database Division, Medicines and Healthcare products Regulatory Agency, London SW8 5NQ.

OBJECTIVE: To compare the risk of non-fatal self harm and suicide in patients taking selective serotonin reuptake inhibitors (SSRIs) with that of patients taking tricyclic antidepressants, as well as between different SSRIs and different tricyclic antidepressants. DESIGN: Nested case-control study. SETTING: Primary care in the United Kingdom. PARTICIPANTS: 146,095 individuals with a first prescription of an antidepressant for depression. MAIN OUTCOME MEASURES: Suicide and non-fatal self harm. RESULTS: 1968 cases of non-fatal self harm and 69 suicides occurred. The overall adjusted odds ratio of non-fatal self harm was 0.99 (95% confidence interval 0.86 to 1.14) and that of suicide 0.57 (0.26 to 1.25) in people prescribed SSRIs compared with those prescribed tricyclic antidepressants. We found little evidence that associations differed over time since starting or stopping treatment. We found some evidence that risks of non-fatal self harm in people prescribed SSRIs compared with those prescribed tricyclic antidepressants differed by age group (interaction P = 0.02). The adjusted odds ratio of non-fatal self harm for people prescribed SSRIs compared with users of tricylic antidepressants for those aged 18 or younger was 1.59 (1.01 to 2.50), but no association was apparent in other age groups. No suicides occurred in those aged 18 or younger currently or recently prescribed tricyclic antidepressants or SSRIs. CONCLUSION: We found no evidence that the risk of suicide or non-fatal self harm in adults prescribed SSRIs was greater than in those prescribed tricyclic antidepressants. We found some weak evidence of an increased risk of non-fatal self harm for current SSRI use among those aged 18 or younger. However, preferential prescribing of SSRIs to patients at higher risk of suicidal behaviour cannot be ruled out. Full text.

Expert Opin Pharmacother. 2005 Jan;6(1):147-50.
Fluoxetine--do the benefits outweigh the risks in adolescent major depression?
Doggrell SA.
The University of Queensland, School of Biomedical Sciences, Australia. s_doggrell@yahoo.com
Major depressive disorder probably occurs in approximately 5% of adolescents. In these adolescents, selective serotonin re-uptake inhibitors (SSRIs), other than fluoxetine, have shown limited benefit and may increase the risk of suicide. In the Treatment for Adolescents with Depression Study, treatment with fluoxetine of adolescents diagnosed with major depressive disorder, or with the combination of fluoxetine and cognitive behavioural therapy, was superior to placebo. Cognitive behavioural therapy alone was not shown to be superior to placebo. Of the patients in the study, 27% had at least minimal suicidal ideation at baseline, and this reduced to 9% at the end of the treatment period, with the reduction being similar in each of the treatment groups. There were more suicide-related adverse events in the patients treated with fluoxetine (15 of 216) than in patients not treated with fluoxetine (9 of 223). There were no actual suicides. Although further investigation of any association between fluoxetine and suicidal tendencies is clearly required, at present, fluoxetine is the only SSRI for which benefit has been clearly shown, and the benefits seem to outweigh the risks. Thus, fluoxetine should generally be the first choice drug of clinicians if they decide that antidepressant drug treatment is indicated in adolescents with major depressive disorder.

Arch Gen Psychiatry. 2005 Feb;62(2):165-72.
The relationship between antidepressant medication use and rate of suicide.
Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
Center for Health Statistics, University of Illinois at Chicago, USA.

BACKGROUND: Approximately 30 000 people die annually by suicide in the United States. Although 60% of suicides occur during a mood disorder, mostly untreated, little is known about the relationship between antidepressant medication use and the rate of suicide in the United States. OBJECTIVE: To examine the association between antidepressant medication prescription and suicide rate by analyzing associations at the county level across the United States. DESIGN: Analysis of National Vital Statistics from the Centers for Disease Control and Prevention. SETTING: All US counties. PARTICIPANTS: All US individuals who committed suicide between 1996 and 1998. MAIN OUTCOME MEASURES: National county-level suicide rate data are broken down by age, sex, income, and race for the period of 1996 to 1998. National county-level antidepressant prescription data are expressed as number of pills prescribed. The primary outcome measure is the suicide rate in each county expressed as the number of suicides for a given population size. RESULTS: The overall relationship between antidepressant medication prescription and suicide rate was not significant. Within individual classes of antidepressants, prescriptions for selective serotonin reuptake inhibitors (SSRIs) and other new-generation non-SSRI antidepressants (eg, nefazodone hydrochloride, mirtazapine, bupropion hydrochloride, and venlafaxine hydrochloride) are associated with lower suicide rates (both within and between counties). A positive association between tricyclic antidepressant (TCA) prescription and suicide rate was observed. Results are adjusted for age, sex, race, income, and county-to-county variability in suicide rates. Higher suicide rates in rural areas are associated with fewer antidepressant prescriptions, lower income, and relatively more prescriptions for TCAs. CONCLUSIONS: The aggregate nature of these observational data preclude a direct causal interpretation of the results. A high number of TCA prescriptions may be a marker for those counties with more limited access to quality mental health care and inadequate treatment and detection of depression, which in turn lead to increased suicide rates. By contrast, increases in prescriptions for SSRIs and other new-generation non-SSRIs are associated with lower suicide rates both between and within counties over time and may reflect antidepressant efficacy, compliance, a better quality of mental health care, and low toxicity in the event of a suicide attempt by overdose. Full text.

J Clin Psychiatry. 2004 Nov;65(11):1456-62.
Antidepressants and suicide risk in the United States, 1985-1999.
Grunebaum MF, Ellis SP, Li S, Oquendo MA, Mann JJ.
Department of Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA. mfg14@Columbia.edu

BACKGROUND: The role of antidepressants in suicide prevention is a major public health question. An association was hypothesized between the increase in the use of non-tricyclic antidepressant medications in the United States and the decline in the suicide rate during the years 1985-1999. METHOD: The relationships between the suicide, antidepressant prescription, unemployment, and alcoholic beverage consumption rates were studied using generalized linear models. Suicide rates by antidepressant overdose were compared in selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). RESULTS: From 1985 to 1999, the suicide rate fell 13.5%, with a greater decline among women, and antidepressant prescription rates increased over 4-fold, with the increase mostly due to SSRIs. Prescription rates for SSRIs and other second-generation antidepressants were both inversely associated with suicide rates (p = .03 and p = .02, respectively). In a multivariable analysis adjusting for unemployment and alcoholic beverage consumption rates, SSRI antidepressant prescription rates remained inversely associated with the national suicide rate (p = .03). Females received twice as many antidepressant prescriptions compared with males. The commonest prescription indication was mood disorders, the condition most often associated with suicide. SSRIs were associated with a lower risk of suicide by antidepressant overdose compared with TCAs. CONCLUSION: The decline in the national suicide rate (1985-1999) appears to be associated with greater use of non-tricyclic antidepressants. Treatment of a greater proportion of mood disorders with SSRIs and other second-generation non-tricyclic antidepressants may further reduce the suicide rate. Controlled studies of the antisuicidal properties of antidepressants are needed in high-risk depressed patient populations.

Acta Psychiatr Scand. 2004 Dec;110(6):452-8.
Antidepressants and suicidal behaviour in unipolar depression.
Yerevanian BI, Koek RJ, Feusner JD, Hwang S, Mintz J.
Sepulveda Ambulatory Care Center, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA. byerevan@ucla.edu

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.

Lancet. 2004 Apr 24;363(9418):1341-5.
Comment in: Evid Based Ment Health. 2004 Nov;7(4):115. Evid Based Nurs. 2004 Oct;7(4):106. Lancet. 2004 Apr 24;363(9418):1335. Lancet. 2004 Aug 21-27;364(9435):659-60; author reply 661. Lancet. 2004 Aug 21-27;364(9435):660-1; author reply 661. Lancet. 2004 Aug 21-27;364(9435):660; author reply 661. Lancet. 2004 Jun 19;363(9426):2088. Lancet. 2005 Feb 5-11;365(9458):469.
Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data.
Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E.
Centre for Outcomes Research and Effectiveness, Subdepartment of Clinical Health Psychology, University College London, 1-19 Torrington Place, London WC1E 7HB, UK. c.whittington@ucl.ac.uk

BACKGROUND: Questions concerning the safety of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression in children led us to compare and contrast published and unpublished data on the risks and benefits of these drugs. METHODS: We did a meta-analysis of data from randomised controlled trials that evaluated an SSRI versus placebo in participants aged 5-18 years and that were published in a peer-reviewed journal or were unpublished and included in a review by the Committee on Safety of Medicines. The following outcomes were included: remission, response to treatment, depressive symptom scores, serious adverse events, suicide-related behaviours, and discontinuation of treatment because of adverse events. FINDINGS: Data for two published trials suggest that fluoxetine has a favourable risk-benefit profile, and unpublished data lend support to this finding. Published results from one trial of paroxetine and two trials of sertraline suggest equivocal or weak positive risk-benefit profiles. However, in both cases, addition of unpublished data indicates that risks outweigh benefits. Data from unpublished trials of citalopram and venlafaxine show unfavourable risk-benefit profiles. INTERPRETATION: Published data suggest a favourable risk-benefit profile for some SSRIs; however, addition of unpublished data indicates that risks could outweigh benefits of these drugs (except fluoxetine) to treat depression in children and young people. Clinical guideline development and clinical decisions about treatment are largely dependent on an evidence base published in peer-reviewed journals. Non-publication of trials, for whatever reason, or the omission of important data from published trials, can lead to erroneous recommendations for treatment. Greater openness and transparency with respect to all intervention studies is needed.

Br J Psychiatry. 2004 Jan;184:41-7.
Comment in: Br J Psychiatry. 2004 Dec;185:518; author reply 518.
Antidepressant-related deaths and antidepressant prescriptions in England and Wales, 1998-2000.
Cheeta S, Schifano F, Oyefeso A, Webb L, Ghodse AH.
Department of Addictive Behaviour and Psychological Medicine, St George's Hospital Medical School, London, UK. scheeta@sghms.ac.uk

BACKGROUND: Deaths from antidepressants continue to account for a substantial proportion of drug-related deaths. AIMS: To investigate the relative toxicity of the major classes of antidepressant drugs, with the specific objective of assessing this in relation to the cause of death; and to analyse the deaths where there were multiple mentions of antidepressant drugs or other psychoactive drugs with antidepressants. METHOD: Mortality data were collected from the National Programme of Substance Abuse Deaths, and antidepressant prescription data were collected. RESULTS: Most deaths from antidepressant drugs were suicides (80%). Tricyclic antidepressants (TCAs) accounted for more drug mentions than did other antidepressant drugs (12 per million prescriptions). Selective serotonin reuptake inhibitors (SSRIs) were associated with a significantly lower risk of toxicity, but 93% of deaths from SSRIs occurred in combination with other drugs, especially TCAs (24.5%). In 'combination' deaths patients were significantly more likely to have had a history of drug misuse. CONCLUSIONS: The efficacy and safety of augmentation therapy with TCAs in SSRI-resistant patients should be monitored carefully, and patients prescribed antidepressants should be screened for drug use/misuse.

J Psychiatry Neurosci. 2003 Sep;28(5):340-7.
Comment on: J Psychiatry Neurosci. 2003 Sep;28(5):331-7.
Suicidality with selective serotonin reuptake inhibitors: Valid claim?
Lapierre YD.
Journal of Psychiatry & Neuroscience. lapierreyd@aol.com

The red flags raised by the 1990 clinical reports of increased suicidality associated with treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine were followed by anecdotal reports of similar symptoms with other antidepressants of the same class. Recent discussions by Healy have argued in favour of a suicidogenic potential of the SSRIs. This paper reviews the relevant literature addressing the epidemiological data of Western populations and the data accumulated from clinical trial databases in several countries. The evidence currently available does not support the hypothesis that antidepressants or, more specifically, SSRIs cause increased suicidality in patients with depression, nor do they appear to do so in patients treated with these drugs for other reasons. Full text.

Am J Psychiatry. 2003 Apr;160(4):790-2.
Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports.
Khan A, Khan S, Kolts R, Brown WA.
Northwest Clinical Research Center, Bellevue, Washington, USA. akhan@nwcrc.net

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. Full text.

PMID: 12668373 [PubMed - indexed for MEDLINE]
Sci Eng Ethics. 2003 Jan;9(1):59-71.
In the grip of the python: conflicts at the university-industry interface.
Healy D.

North Wales Dept of Psychological Medicine, University of Wales College of Medicine, Hergest Unit, Bangor LL57 2PW, United Kingdom. Healy_Hergest@compuserve.com
When the University of Toronto withdrew a contract it held with me in December 2000, it initiated a sequence of events that led to a public letter to the University from senior figures in the world psychopharmacology community protesting against the infringement of academic freedom involved and a first ever legal action, undertake by this author, seeking redress for a violation of academic freedom. The issues of academic freedom surrounding this case have been intertwined with a debate about the possibility that the selective serotonin reuptake inhibitor (SSRI) group of antidepressants have the potential to trigger suicidality in a subgroup of patients. Whether the SSRIs do trigger suicidality or not, exploration of this issue has given rise to a number of worrying sets of observations. First, in my view, there is evidence that pharmaceutical companies have miscoded raw data on suicidal acts and suicidal ideation. Second, this author also maintains that there is a growing body of examples of ghostwriting of articles in the therapeutics domain. Many of the tensions evident in this case, therefore, can be linked to company abilities to keep clinical trial data out of the public domain--this is the point at which the pharmaceutical python gets a grip on academia.

Psychother Psychosom. 2003 Mar-Apr;72(2):71-9.
Lines of evidence on the risks of suicide with selective serotonin reuptake inhibitors.
Healy D.
North Wales Department of Psychological Medicine, University of Wales College of Medicine, Bangor, UK. healy_hergest@compuserve.com

BACKGROUND: There has been a long-standing controversy about the possibility that selective serotonin reuptake inhibitor (SSRI) antidepressants might induce suicidality in some patients. METHODS: Starting from the clinical studies that gave rise to this issue, this paper reviews an unselected cohort of randomized clinical trials (RCTs), a series of meta-analyses undertaken to investigate aspects of the problem, studies in recurrent brief depressive disorders, epidemiological studies and healthy volunteer studies using SSRIs to shed light on this issue. RESULTS: The original clinical studies produced evidence of a dose-dependent link, present on a challenge, dechallenge and rechallenge basis, between SSRIs and both agitation and suicidality. Meta-analyses of RCTs conducted around this time indicate that SSRIs may reduce suicidal ideation in some patients. These same RCTs, however, yield an excess of suicides and suicide attempts on active treatments compared with placebos. This excess also appears in the best-controlled epidemiological studies. Finally, healthy volunteer studies give indications that SSRIs may induce agitation and suicidality in some individuals. CONCLUSIONS: The data reviewed here, which indicate a possible doubling of the relative risk of both suicides and suicide attempts on SSRIs compared with older antidepressants or non-treatment, make it difficult to sustain a null hypothesis, i.e. that SSRIs do not cause problems in some individuals to whom they are given. 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. Copyright 2003 S. Karger AG, Basel

Dtsch Med Wochenschr. 2002 Oct 4;127(40):2053-6.
[Increasing significance of antidepressants in deliberate self-poisoning]
[Article in German]
Von Mach MA, Weilemann LS.
Klinische Toxikologie und Beratungsstelle bei Vergiftungen, II. Medizinische Klinik und Poliklinik, Klinikum der Johannes Gutenberg-Universitat Mainz, Germany. marcm@giftinfo.uni-mainz.de

BACKGROUND AND OBJECTIVE: Antidepressant drugs are frequently used in deliberate self-poisoning resulting in a major risk for the patients due to their cardiac and central-nervous toxicity. In the present study the cases of intoxications consulting our Poison Center should be analysed illustrating recent results and trends about self-poisoning with antidepressants. PATIENTS AND METHODS: During the study period from 1995 to 2001 35 394 inquiries concerning deliberate self-poisoning were registered in our Poison Center. The substance used, age and gender of the patient as well as the degree of the observed symptoms were documented. Thereby, antidepressant drugs were grouped in tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI) and other antidepressants. RESULTS: The use of antidepressants in deliberate self-poisoning continuously increased during the study period from 17.3 % to 22.9 % with SSRI and other antidepressants being observed more frequently as compared to TCA. Antidepressant drugs were mainly used from female patients and in the age group between 35 and 54 years. Antidepressant drugs caused severe intoxications and deaths more frequently as the remainder substances with TCA showing higher rates of complications as compared to SSRI and other antidepressants. CONCLUSIONS: In recent years, an increasing importance of antidepressant drugs in deliberate self-poisoning was determined particularly concerning female and middle-aged patients. Due to the changing prescribing patterns larger numbers of intoxications with SSRI and other antidepressants were observed representing an advantage with respect to the reduced rate of complications known for these substances as compared to TCA. Nevertheless, the averagely more severe symptoms present in the three groups of antidepressants in comparison to the remainder drug overdoses demonstrated the need for hospitalization and monitoring of intoxications with antidepressants.

Nervenarzt. 2002 Jul;73(7):629-36.
[Fatal poisonings with antidepressive drugs and neuroleptics. Analysis of a correlation with prescriptions in Vienna 1991 to 1997]
[Article in German]
Frey R, Schreinzer D, Stimpfl T, Vycudilik W, Berzlanovich A, Kasper S.
Klinische Abteilung fur Allgemeine Psychiatrie, Universitatsklinik fur Psychiatrie, Wahringer Gurtel 18-20, A-1090 Wien. richard.frey@akh-wien.ac.at

As a result of the increasing use of selective serotonin reuptake inhibitors (SSRI), the number of antidepressants (AD) prescribed in Vienna doubled from 1991 to 1997. In the same period, autopsies and chemical analyses performed at the Institute of Forensic Medicine, University of Vienna, revealed a total of 164 fatal intoxications by means of AD. In this study, the number of fatal intoxications per million defined daily doses prescribed was determined and referred to as the fatal toxicity index (f-index). For both single- and multiple-substance intoxications, it proved to be significantly (p < 0.001) lower with SSRI than with tricyclic antidepressants (TCA). Single-substance intoxications (n = 30) were seen exclusively in TCA. Concerning neuroleptics (NL), the increase in prescriptions observed in the study period (plus 30%) was less pronounced, and they were found to be involved in 85 fatal intoxications. Also in NL, those of the tricyclic type (TCNL) showed a significantly (p < 0.001) higher f-index than other groups. Out of a total of 17 single-substance intoxications, 14 were caused by TCNL and none by butyrophenones or haloperidol. The present study demonstrates that the prescription of TCA or TCNL involves a relatively high risk of fatal intoxication.

Perspect Biol Med. 2002 Spring;45(2):250-63.
Conflicting interests in Toronto: anatomy of a controversy at the interface of academia and industry.
Healy DI.
North Wales Department of Psychological Medicine, University of Wales College of Medicine, North Wales, UK. Healy_Hergest@compuserve.com

In December 2000, the University of Toronto breached a contract it held with me, initiating a sequence of events that has led to a public letter to the University from a large number of senior figures in the psychopharmacology community, protesting against the infringement of academic freedom involved, and a first-ever legal action seeking redress for violation of academic freedom. This case has been intertwined from the start with a longer running debate about the possibility that the SSRI group of antidepressants may have the potential to trigger suicidality or other serious effects in a subgroup of takers. And this specific issue connects to concerns about conflict of interest in the domain of therapeutics, as well as in science in general, the ghostwriting of scientific articles, and a series of other hot-spots on the interface between academia and industry.

Pharmacoepidemiol Drug Saf. 2001 Oct-Nov;10(6):525-30.
Antidepressant medication and suicide in Sweden.
Carlsten A, Waern M, Ekedahl A, Ranstam J.
Department of Social Medicine, University of Goteborg, Sweden. anders.carlsten@telia.com

OBJECTIVE: To explore a possible temporal association between changes in antidepressant sales and suicide rates in different age groups. METHODS: A time series analysis using a two-slope model to compare suicide rates in Sweden before and after introduction of the selective serotonin reuptake inhibitors, SSRIs. RESULTS: Antidepressant sales increased between 1977-1979 and 1995-1997 in men from 4.2 defined daily doses per 1000 inhabitants and day (DDD/t.i.d) to 21.8 and in women from 8.8 to 42.4. Antidepressant sales were twice as high in the elderly as in the 25-44-year-olds and eight times that in the 15-24-year-olds. During the same time period suicide rates decreased in men from 48.2 to 33.3 per 10(5) inhabitants/year and in women from 20.3 to 13.4. There was significant change in the slope in suicide rates after the introduction of the SSRI, for both men and women, which corresponds to approximately 348 fewer suicides during 1990-1997. Half of these 'saved lives' occurred among young adults. CONCLUSION: We demonstrate a statistically significant change in slope in suicide rates in men and women that coincided with the introduction of the SSRI antidepressants in Sweden. This change preceded the exponential increase in antidepressant sales.

Acta Psychiatr Scand. 2001 Aug;104(2):84-91.
Selective serotonin reuptake inhibitors and violence: a review of the available evidence.
Walsh MT, Dinan TG.
Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin 2, Ireland.

OBJECTIVE: To provide a clinically useful analysis of the relationship between selective serotonin reuptake inhibitors (SSRIs), in particular fluoxetine and violent or suicidal behaviour. METHOD: All published papers on Medline and other databases linking serotonin, SSRIs and aggression were reviewed. RESULTS: A small proportion of patients treated with SSRIs may become akathisic and others may show increases in anxiety in the initial phase of treatment, but no increased susceptibility to aggression or suicidality can be connected with fluoxetine or any other SSRI. In fact SSRI treatment may reduce aggression, probably due to positive effects on the serotonergic dysfunction that is implicated in aggressive behaviour directed towards oneself or others. CONCLUSION: In the absence of convincing evidence to link SSRIs causally to violence and suicide, the recent lay media reports are potentially dangerous, unnecessarily increasing the concerns of depressed patients who are prescribed antidepressants.

J Child Adolesc Psychopharmacol. 2000 SUMMMER;10(2):91-102.
Efficacy and safety findings from naturalistic fluoxetine drug treatment in adolescent and young adult patients.
Dittmann RW, Czekalla J, Hundemer HP, Linden M.
Psychosomatic Department, Children's Hospital, University of Hamburg, Germany. DITTMANN_RALF_W@Lilly.com

This article reports on the efficacy and safety of the selective serotonin reuptake inhibitor, fluoxetine, in 213 patients (ages 11-23 years) treated by psychiatrists/neurologists (PN) or general practitioners/internists (GPI). Data were derived from naturalistic drug utilization observation (DUO) studies with fluoxetine (n = 18,759 patients). Data collection--at the start and the end of the observation period (< or =6 weeks)--included patient characteristics, diagnoses, medication, co-medication, efficacy, and adverse events (AEs). Nonparametric statistics and descriptive p values (two-tailed) were used. Analyses revealed various differences between PN (n = 56) and GPI (n = 157) samples as to patient and treatment characteristics (p < 0.001-0.08). Based on both Clinical Global Impression (CGI; all p < 0.001) and self-assessment (total n = 47; Zung SDS, all p < or = 0.003), both PN and GPI patients showed improvements in their symptomatology over time, including suicidality (all p < 0.001; there were no group differences). Overall AE rates were higher in PN patients (p < 0.01; 17.9% vs. 4.5%); the frequency and type of AEs in both subgroups were typical for fluoxetine and the total DUO samples. In fact, AE rates were lower compared to controlled trials. Findings suggest that PN patients were more severely ill at observation start and suffered a more complicated treatment course. However, clinical efficacy showed highly significant improvements in both subgroups; AE rates were low in both--although higher in PN patients. Thus, results support a positive benefit/risk ratio of fluoxetine use for this young patient population.

Soc Psychiatry Psychiatr Epidemiol. 1999 Nov;34(11):609-14.
Suicides by drug poisoning among the elderly in Sweden 1969-1996.
Carlsten A, Waern M, Allebeck P.
Department of Social Medicine, University of Gothenburg, Vasa Hospital, Sweden. anders.carlsten@telia.com

BACKGROUND: Previous studies have shown an association between the rates of suicide employing certain types of medications and the availability of those drugs. During recent years, prescription patterns of psychoactive drugs commonly used in suicides have undergone some major changes. This study examines whether altered prescription patterns are associated with changes in the rates of drug-related suicides in the elderly. METHODS: An ecological study was performed, in which rates of suicide by drug poisoning were related to prescription sales of different psychotropic drugs, derived from the National Prescription Survey (1987-1996). RESULTS: Benzodiazepines were the dominant drug type used by elderly persons who committed suicide by drug poisoning. Rates of suicide using benzodiazepines increased despite decreasing prescription sales. Decreasing tricyclic antidepressant sales and increasing SSRI (selective serotonin reuptake inhibitors) sales were paralleled by decreasing rates of suicides employing antidepressants. The fatality ratio (FR) decreased for the antidepressant group, increased for benzodiazepines and remained more or less unchanged for analgesics among the elderly during the study period. CONCLUSIONS: Rates of suicide using benzodiazepines increased in the elderly despite decreasing prescription sales. Benzodiazepines should be prescribed restrictively to this age group.

Am J Psychiatry. 1999 Feb;156(2):195-201.
Prospective study of fluoxetine treatment and suicidal behavior in affectively ill subjects.
Leon AC, Keller MB, Warshaw MG, Mueller TI, Solomon DA, Coryell W, Endicott J.
NIMH Collaborative Depression Study, USA. acleon@mail.med.cornell.edu

OBJECTIVE: There has been speculation in the literature about a link between fluoxetine use and suicidal behavior. The authors of this study hypothesized that there is no elevation in risk of suicidal behavior associated with use of fluoxetine. METHOD: The data come from the National Institute of Mental Health Collaborative Depression Study, a prospective, naturalistic follow-up of persons who presented for treatment of affective disorders. The analyses included data on 643 subjects who were followed up after fluoxetine was approved by the Food and Drug Administration in December 1987 for the treatment of depression. RESULTS: Nearly 30% (N = 185) of the study group was treated with fluoxetine at some point during the follow-up period. Relative to the other subjects, those who were subsequently treated with fluoxetine had onset of affective illness at a younger age and, after intake into the study and before 1988, had elevated rates of suicide attempts before fluoxetine treatment. A mixed-effects survival analysis that incorporated treatment exposure time, multiple treatment trials, and multiple suicide attempts per subject showed that relative to no treatment, use of fluoxetine and use of other somatic antidepressants were associated with nonsignificant reductions in the likelihood of suicide attempts or completions. Severity of psychopathology was strongly associated with elevated risk, and each suicide attempt after intake into the Collaborative Depression Study was associated with a marginally significant increase in risk of suicidal behavior. CONCLUSIONS: The results do not support the speculation that fluoxetine increases the risk of suicide. Rather, there was a nonsignificant reduction in risk of suicidal behavior among patients treated with fluoxetine, even though those subjects were more severely ill before treatment with fluoxetine.

J Clin Psychiatry. 1996 Sep;57(9):415-21.
Suicidal risk during controlled clinical investigations of fluvoxamine.
Letizia C, Kapik B, Flanders WD.
Solvay Pharmaceuticals, Marietta, GA 30062, USA.

BACKGROUND: Suicide is a serious risk factor in major depressive disorder. Paradoxical emergence of suicidal ideation or behavior during antidepressant treatment has been reported in isolated cases. An evaluation was undertaken to assess the risk of suicidality during treatment with fluvoxamine, a serotonin selective reuptake inhibitor. METHOD: Meta-analyses were conducted on pooled data from double-blind, randomized, placebo-controlled, parallel-group clinical trials. The primary outcome measure was the suicide item of the Hamilton Rating Scale for Depression. Tests for emergence of substantial suicidal ideation and improvement or worsening in suicidal ideation were performed using the Mantel-Haenszel adjusted incidence difference. The Breslow-Day test was used to test for lack of homogeneity across trials. Secondary analysis, which consisted of Pearson's chi-square test, was used to confirm the Mantel-Haenszel result. RESULTS: In comparison to placebo, fluvoxamine was associated with significantly greater improvement in suicidal ideation (p = .01) and significantly less worsening of suicidal ideation (p < .01). No differences were found in the emergence of substantial suicidal ideation. CONCLUSION: These findings demonstrate that fluvoxamine is not associated with an increased risk of emergence of substantial suicidal thoughts among depressed patients. On the contrary, the results are suggestive of a protective effect of fluvoxamine upon the risk of suicidal ideation.

Depress Anxiety. 1997;6(1):31-9.
Fluoxetine and concomitant centrally acting medication use during clinical trials of depression: the absence of an effect related to agitation and suicidal behavior.
Wernicke JF, Sayler ME, Koke SC, Pearson DK, Tollefson GD.
ELLYN Inc., League City, Texas, USA.

Concomitant use of psychoactive medications is a common practice in most clinical trials of antidepressant medications. However, the relative therapeutic impact of such use on trial results has not been the subject of much attention. We conducted a meta-analysis to determine whether concomitant use of psychoactive medications confounded the efficacy or safety results of a series of fluoxetine trials. Data were evaluated from 25 randomized, double-blind clinical trials comparing fluoxetine with placebo or a tricyclic antidepressant (TCA) in 4,016 patients with major depression. We compared incidence rates of concomitant use of anxiolytics, sedatives, and antipsychotics between treatments. In addition, we compared the change in total score for the 21-Item Hamilton Depression Rating Scale (HAMD21): incidence rates of any worsening, emergence, or improvement in psychomotor agitation; and incidence of suicidal acts and any worsening, emergence, or improvement in suicidal ideation between treatment groups among patients taking/not taking a sedative. Anxiolytic and antipsychotic drug use was uncommon (8.3% and 0.9% overall use, respectively) and did not substantially increase over time. Sedative drugs were used most often (29.6% overall), but only 29.8% of the fluoxetine-treated patients took one or more doses. Regarding efficacy, fluoxetine was superior to placebo in decreasing HAMD21 total scores among patients taking/not taking sedatives. Effects on safety were assessed by examining agitation and suicidal ideation. Use of sedatives did not affect the change in the HAMD agitation score; scores were similar in patients receiving fluoxetine, placebo, and TCAs. In all treatment groups, anxiolytic use tended to increase as the HAMD anxiety score increased. Fluoxetine was superior to placebo in treating suicidal ideation, and the concomitant use of sedatives did not influence this effect. Overall, concomitant use of psychotropic medications in the fluoxetine depression clinical trials was uncommon. Our meta-analysis demonstrated that the clinical efficacy and safety of fluoxetine were not confounded by the concomitant use of medications.

Encephale. 1997 May-Jun;23(3):218-23.
[Fluoxetine, akathisia and suicide]
[Article in French]
Lancon C, Bernard D, Bougerol T.
Service hospitalo-universitaire de Psychiatrie, CHU Sainte-Marguerite, Marseille.

Several cases of suicidal thinking or suicidal behavior during fluoxetine treatment are described in the literature. Akathisia or dysphoric extrapyramidal reactions may explain the emergence of suicidal ideation during fluoxetine treatment. Retrospective and controlled studies found no relationship between fluoxetine and the emergence of suicidal ideation. Some cases reports of akathisia or suicidal ideation with other selective serotonin reuptake inhibitors (SSRIs) suggest that same mechanisms (pharmacokinetic or pharmacodynamic interactions) are involved in extrapyramidal effects during treatment with SSRIs. The clinical use of SRIs is discussed.

J Clin Psychiatry. 1996 Apr;57(4):158-66.
The relationship between fluoxetine use and suicidal behavior in 654 subjects with anxiety disorders.
Warshaw MG, Keller MB.
Brown University School of Medicine, Providence, RI 02912, USA.

BACKGROUND: In the past few years, there has been controversy over the relationship between suicidal behavior and fluoxetine use. This report examines the relationship between fluoxetine use and suicidal behavior in the Harvard/Brown Anxiety Disorders Research Program (HARP). METHOD: HARP is a naturalistic, prospective, longitudinal anxiety disorders study. Probabilities of suicidal behavior for 654 subjects were examined using life table analysis for the study group as a whole and stratified by depression status at intake. RESULTS: Subjects not using fluoxetine during follow-up had almost twice the probability of making a suicide attempt or gesture during the follow-up than subjects who were using fluoxetine, although this difference was not statistically significant. Subjects having episodes of major depressive disorder (MDD) at intake were more likely than those not having an episode to receive fluoxetine during follow-up (74/166 [45%] vs. 118/488 [24%], chi squared= 24.85, df= 1, p < .0001). Among those subjects having episodes of MDD at intake, there was a statistically significantly lower probability of suicide attempts/gestures for those taking fluoxetine than for those not using fluoxetine during follow-up (log-rank chi squared= 5.10, df= 1, p= .02). CONCLUSION: We found no evidence that fluoxetine use is associated with increased risk of suicide attempts or gestures. However, we did find that subjects with more suicide risk factors at intake were more likely to use fluoxetine than those without these risk factors.

Eur Neuropsychopharmacol. 1995 Mar;5(1):5-13.
Reduction of suicidal thoughts with paroxetine in comparison with reference antidepressants and placebo.
Montgomery SA, Dunner DL, Dunbar GC.
St Mary's Hospital Medical School, London, UK.

In order to determine whether paroxetine was associated with any increase in suicidal thoughts or acts all controlled studies of paroxetine were examined in a series of metanalyses. Paroxetine showed an advantage in reducing suicidal thoughts in all analyses compared with placebo. On the MADRS there was a significant advantage compared with active controls at weeks 1, 3, 4 and 6 (P < 0.01). There were significantly fewer emergent suicidal thoughts on paroxetine compared with placebo in all analyses, and a significant advantage for paroxetine compared with active controls on the MADRS. A significant advantage for active controls compared with placebo was seen only on the HAMD. In the analysis of the data from controlled studies and open extension studies of paroxetine calculated by patient year of exposure there were 2.8 times fewer suicides in the paroxetine-treated group compared with active control and 5.6 times fewer compared with placebo.

BMJ. 1995 Jan 28;310(6974):215-8.
Antidepressants and suicide.
Jick SS, Dean AD, Jick H.
Boston Collaborative Drug Surveillance Program, Boston University Medical Center, Lexington, MA 02173.

OBJECTIVE--To estimate the rate and means of suicide among people taking 10 commonly prescribed antidepressant drugs: dothiepin, amitriptyline, clomipramine, imipramine, flupenthixol, lofepramine, mianserin, fluoxetine, doxepin, and trazodone. DESIGN--Open cohort study with a nested case-control analysis. SETTING--General practices in the United Kingdom that used VAMP computers to maintain their patient records from January 1988 to February 1993. SUBJECTS--172,598 people who had at least one prescription for one of the 10 antidepressants during the study period. MAIN OUTCOME MEASURE--Suicide confirmed by general practitioner or on death certificate, or both. RESULTS--143 people committed suicide. The overall rate of suicide was estimated to be 8.5 per 10,000 person years (95% confidence interval 7.2 to 10.0). Rates of suicide were higher in men than women (relative risk 2.8 (95% confidence interval 1.9 to 4.0)), people with a history of feeling suicidal (19.2 (9.5 to 38.7)), and people who had taken several different antidepressants (2.8 (1.8 to 4.3)). People who received high doses of antidepressants and those who had had a prescription in the 30 days before they committed suicide were also at higher risk than those who had received low doses and had had their prescriptions 30 or more days previously (2.3 (1.4 to 3.7) and 2.3 (1.6 to 3.4)) respectively. Rates of suicide were higher in patients who received fluoxetine, but this may be explained by selection biases which were present for those drug users. CONCLUSION--Several factors correlate with the risk of suicide in people taking antidepressants. After controlling for these factors, the risk of suicide was similar among the 10 study antidepressants. Overdose with antidepressants accounted for only 14% of the suicides. Full text.

Isr J Psychiatry Relat Sci. 1995;32(1):44-50.
Serotonin and suicidality: the impact of fluoxetine administration. II: Acute neurobiological effects.
Anderson GM, Segman RH, King RA.
Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA.

Despite the demonstrated anti-depressant efficacy of the selective serotonin reuptake inhibitors (SSRIs), increased suicidal ideation and/or agitation have been reported in a small proportion of individuals receiving fluoxetine or other SSRIs. Part II of this review examines fluoxetine's acute effects on serotonergic functioning. Although acute fluoxetine administration produces a short-term compensatory decrease in the firing of 5-HT neurons, the neurobiological data reviewed suggests that this decrease probably does not lead to an over-compensatory net decrease in 5-HT functioning. The implications of fluoxetine's complex effects on the 5-HT systems are discussed with respect to clinical practices and future research.

J Emerg Med. 1994 Sep-Oct;12(5):685-7.
Revisiting fluoxetine (Proxac) and suicidal preoccupations.
Tueth MJ.
Department of Psychiatry, University of Florida, Gainesville 32608.

Several reports were published in the psychiatric literature in 1990 and 1991 documenting fluoxetine (Prozac) causing patients to consider or attempt suicide. During the following 2 years, retrospective studies appeared in the medical literature that seemed to indicate that suicidal preoccupation was not related to the antidepressant fluoxetine (Prozac) but was probably a symptom of the depressive illness. Recent studies have suggested, however, that fluoxetine (Prozac) may in fact lead to suicidal behavior because the drug appears to adversely affect serotonergic neuronal discharge and induce an akathisia-like extrapyramidal reaction. While fluoxetine (Prozac) has a very favorable side effect profile compared to the tricyclic antidepressants, it may cause akathisia and induce a small subset of patients to consider or attempt suicide.

J Clin Psychopharmacol. 1994 Jun;14(3):163-9.
Absence of a relationship between adverse events and suicidality during pharmacotherapy for depression.
Tollefson GD, Rampey AH Jr, Beasley CM Jr, Enas GG, Potvin JH.
Psychopharmacology Division, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285.

This study tested the hypothesis that some patients treated with an antidepressant who develop adverse events (e.g., activation, akathisia) experience emergent suicidality specifically associated with such events. Seventeen double-blind, controlled clinical trials conducted in the United States and Canada with 3,065 patients with major depression were evaluated for treatment-emergent adverse events (events that first occurred or worsened during therapy) and suicidality (a suicidal act or emergence of substantial suicidal ideation or both) with fluoxetine, placebo, and tricyclic antidepressants. Nine relevant adverse event clusters were evaluated: activation, sedation, activation and sedation, decreased libido, mania, psychosis, psychosis and mania, acute brain syndrome, and violence. Incidence rates were determined for suicidality that was and was not temporally associated with an adverse event cluster and were analyzed within and across treatments (incidence difference method). Most patients experienced neither a cluster event nor suicidality. Where suicidality was reported, it generally was not in temporal association with an adverse event cluster. In no cluster was the incidence of suicidality statistically significantly higher when reported in temporal association with an event than when not. Suicidality was associated infrequently with treatment-emergent activation and at comparable rates across treatments. No increased risk of suicidality associated with an adverse event cluster was observed between the treatment groups (fluoxetine versus tricyclic anti-depressants; fluoxetine versus placebo). These results from double-blind, placebo- and comparator-controlled fluoxetine clinical trials in patients with major depression do not suggest a relationship between a treatment-emergent adverse event pattern and suicidality in this population.

Isr J Psychiatry Relat Sci. 1994;31(4):271-9.
Serotonin and suicidality: the impact of acute fluoxetine administration. I: Serotonin and suicide.
King RA, Segman RH, Anderson GM.
Yale Child Study Center, Yale School of Medicine, New Haven, CT 06520-7900.

The general enhancement of central serotonin (5-HT) neurotransmission following long-term administration of serotonin-selective reuptake inhibitors (SSRIs) appears to play an important role in these drugs' anti-depressant efficacy. Because suicide and/or aggression appear linked to diminished levels of brain 5-HT and its metabolites, it has been suggested that SSRIs may be particularly effective in reducing suicidality. Case reports of increased or new suicidal ideation following administration of fluoxetine and other SSRIs, however, raise questions about how these potential side effects may relate to the SSRI's acute effects on 5-HT transmission. Part I of this review examines fluoxetine's effects on suicidality and related behaviors and reviews the relationship of suicidality to serotonergic dysregulation.

Acta Psychiatr Scand. 1993 Oct;88(4):235-7.
Emergence of depressive symptoms during treatment for panic disorder with specific 5-hydroxytryptophan reuptake inhibitors.
Fux M, Taub M, Zohar J.
Beersheva Mental Health Center, Ben Gurion University, Israel.

Selective serotonin reuptake inhibitors (SSRI) have been established as effective drugs in the treatment of depressive and anxiety disorders. However, there are also reports that they can induce depressive symptoms and suicidal thoughts in patients. Eighty of 230 patients who met the DSM-III-R criteria for panic disorder received, during the course of treatment, fluvoxamine (a selective serotonin reuptake inhibitor) at a dose level between 50-200 mg/day. The patients were clinically evaluated for a history of affective disorder and for the presence of affective symptoms before the treatment and for emergence of depressive symptoms during the treatment. Seven of the 80 patients (9%) developed symptoms of depression despite a good antianxiety response. Five of the 7 patients received fluvoxamine as second choice after tricyclic antidepressants (TCA). These patients had no history of affective disorder, and no symptoms of depression were present before the treatment with fluvoxamine. The depressive symptoms abated after the fluvoxamine was discontinued and TCA or clonazepam was prescribed. The depressive symptoms reappeared when fluoxetine was administered. None of these 7 patients developed depressive symptoms while treated with TCA or clonazepam. Among the 150 patients treated with TCA and benzodiazepines, not a single case of depression was seen in patients without a previous history of depression. These results suggest a vulnerability among some of panic disorder patients to noradrenergic-serotonergic imbalance caused by SSRI, which has to be taken into clinical consideration.

J Clin Psychiatry. 1993 Aug;54(8):309-16.
Analyses of suicidality in double-blind, placebo-controlled trials of pharmacotherapy for weight reduction.
Goldstein DJ, Rampey AH Jr, Potvin JH, Masica DN, Beasley CM Jr.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.

BACKGROUND: The obese who seek therapy may also have depression and thus a risk for suicidality (suicidal acts and ideation). For this reason and because of interest in the potential impact of a medication with antidepressant properties on suicidality in a population without a primary diagnosis of depression, we performed a comprehensive analysis of suicidality data from clinical trials in patients seeking weight-reduction therapy. METHOD: Suicidality data from 11 double-blind controlled trials in the United States Investigational New Drug fluoxetine obesity clinical trial data base (3819 randomized outpatients) were reviewed. Trials lasted 6 to 60 weeks (continuous and intermittent therapy designs). They included obese men and women (median body mass index, 35.0 kg/m2). Trials excluded patients treated with antidepressants. Incidence of suicidality was analyzed by the incidence difference method. RESULTS: No fatal suicidal acts occurred. One suicide attempt was reported in a patient receiving placebo after prior fluoxetine therapy (intermittent therapy trial). The overall incidence of suicidal ideation among fluoxetine-treated and placebo-treated patients in the obesity clinical trials was 0.24%. The difference in incidence of emergent suicidal ideation in fluoxetine-treated (0.23%) and placebo-treated patients (0.27%) was not statistically significant. CONCLUSION: Based on these analyses of controlled clinical trials, suicidality occurs but has a low incidence rate in the obese who seek pharmacologic weight-reduction therapy. Fluoxetine-treated and placebo-treated patients did not differ statistically significantly in the incidence of suicidality either during or after discontinuation of therapy.

Int J Neurosci. 1993 Jan;68(1-2):73-84.
Fluoxetine and suicidal ideation--a review of the literature.
Crundwell JK.
Department of Psychology, University of Lancaster, Bailrigg, England.

The emergence of suicidal ideation has been noted in some case studies, where fluoxetine administration appears to be the precipitating agent. However, these observational claims are not supported by the clinical trial literature. A review of some of the trials and the case histories is followed by an assessment of the evidence, and possible explanations for the discrepancy. It is concluded that a definite link between fluoxetine and emerging suicidal ideation cannot be ascertained, but that further research is indicated. Vigilance in prescribing any antidepressant medication, including fluoxetine, is recommended.

J Clin Psychiatry. 1992 Nov;53(11):401-6.
Akathisia, suicidality, and fluoxetine.
Hamilton MS, Opler LA.
Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York.

BACKGROUND: The propose link between fluoxetine and suicidal ideation is explained by fluoxetine-induced akathisia and other dysphoric extrapyramidal reactions. METHOD: The following literature is reviewed: (1) the subjective response of schizophrenics to akathisia, including evidence that akathisia gives rise to suicidal ideation; (2) the subjective reports of patients taking fluoxetine; and (3) preclinical studies describing the role of serotonin in the extrapyramidal system and suggesting a mechanism whereby fluoxetine can induce extrapyramidal side effects. RESULTS: The literature suggests that fluoxetine-induced extrapyramidal reactions may be a mediator of de novo suicidal ideation. CONCLUSION: We propose a syndrome which we name Extrapyramidal-Induced Dysphoric Reactions, one extreme manifestation of which is the emergence of suicidal ideation. We further propose a heuristic "Four Neuron Model of the Extrapyramidal Motor System" in which increased serotonin activity, by inhibiting the nigrostriatal dopamine tract, is capable of inducing extrapyramidal side effects.

J Clin Psychiatry. 1992 Jul;53(7):235-41.
Lack of association between fluoxetine and suicidality in bulimia nervosa.
Wheadon DE, Rampey AH Jr, Thompson VL, Potvin JH, Masica DN, Beasley CM Jr.
Division of Clinical Neurosciences, Eli Lilly and Company, Indianapolis, Ind 46285.

BACKGROUND: The coincidence of major depressive disorder in bulimia nervosa ranges from 35% to 80%. Because of this comorbidity and because suicidality (suicidal acts and ideation) is an inherent part of depression, assessment of the risk of suicide in patients with bulimia nervosa is of considerable interest. METHOD: Data from United States Investigational New Drug double-blind, placebo-controlled fluoxetine clinical trials in bulimia nervosa were analyzed comprehensively to assess the potential association between fluoxetine treatment and suicidality in 785 patients with DSM-III-R bulimia nervosa. Patients were predominantly women (98%), aged 17 to 63 years; of the randomly assigned patients, 16.9% exhibited 17-item Hamilton Rating Scale for Depression (HAM-D) total scores of 17 or greater at baseline (range, 0-31). Incidence of suicidality was analyzed by the incidence difference method. RESULTS: No fatal suicidal acts occurred; 9 (1.15%) of 785 patients made nonfatal attempts; 24 (3.06%) experienced emergent (text-defined) suicidal ideation. No statistically significant increases in the incidence of suicidal acts or suicidal ideation were observed among fluoxetine-treated compared with placebo-treated patients. A smaller percentage of fluoxetine-treated (2.0%) than placebo-treated (3.8%) patients experienced emergence of substantial suicidal ideation (change in baseline HAM-D Item 3 [suicide item] score of 0 or 1 to 3 or 4 during therapy). A statistically significantly greater proportion of fluoxetine-treated than placebo-treated patients experienced improvement in suicidal ideation (decrease in HAM-D Item 3 score) from baseline to endpoint (p = .026). CONCLUSION: Analyses of the incidence of suicidal acts and suicidal ideation did not indicate an increased risk of suicidality in patients with bulimia nervosa treated with fluoxetine compared with those treated with placebo.

J Anal Toxicol. 1992 Mar-Apr;16(2):142-5.
A possible association between fluoxetine use and suicide.
Bost RO, Kemp PM.
Southwestern Institute of Forensic Science, Dallas, Texas.

Fluoxetine has been available for use as an antidepressant since early 1988. Numerous reports have indicated that it is at least as good as some of the tricyclic antidepressants and that it does not produce as serious toxicity as the tricyclics. Recently, however, case reports have suggested that it may produce suicidal tendencies in some patients. The present report provides data from a medical examiner's office regarding the number of cases in which fluoxetine has been detected and the proportion certified as suicides.

J Affect Disord. 1992 Jan;24(1):1-10.
Fluoxetine: no association with suicidality in obsessive-compulsive disorder.
Beasley CM Jr, Potvin JH, Masica DN, Wheadon DE, Dornseif BE, Genduso LA.
Division of Clinical Neurosciences, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis 46285.

Since (a) obsessive-compulsive disorder (OCD) may involve serotonergic neural transmission abnormalities also though to be related to regulation of suicide and aggression, (b) comorbidity between OCD and depression is substantial, and (c) depression is a major risk factor for suicide, a comprehensive analysis of clinical trial data was undertaken to assess the potential association of fluoxetine, a serotonin uptake inhibitor, and suicidality (suicidal acts and ideation). Pooled data from clinical trials comparing fluoxetine (n = 266) and placebo (n = 89) in patients with DSM-IIIR OCD were analyzed retrospectively. No suicidal acts occurred during placebo lead-in or double-blind therapy. Mean Hamilton Depression Scale item 3 (suicide item) scores improved statistically significantly with fluoxetine compared with placebo. Worsening in suicidal ideation was statistically significantly more frequent with placebo than with fluoxetine. Emergence of substantial suicidal ideation (change in baseline item 3 score of 0 or 1 to 3 or 4) was numerically greater with placebo than with fluoxetine (3.6% vs. 1.7%; not statistically significant). The incidence of suicidality in fluoxetine-treated patients with OCD was low, compared favorably with rates in corresponding placebo-treated patients, and was well within the range of estimates in previous studies of patients with OCD. These controlled clinical trial results suggest no undue risk of suicidality in patients with OCD treated with fluoxetine.

Pharmacotherapy. 1992;12(6):451-4.
Comparison of frequencies of suicidal tendencies among patients receiving fluoxetine, lofepramine, mianserin, or trazodone.
Jick H, Ulcickas M, Dean A.
Boston Collaborative Drug Surveillance Program, Boston University Medical Center, Lexington, Massachusetts 02173.

To evaluate whether fluoxetine causes an important increased risk of suicidal behavior, we compared the frequency of attempted suicide, suicidal ideation, and aggressive behavior in persons who received fluoxetine, lofepramine, mianserin, and trazodone, based on information available on general practitioners' computers provided by Value Added Medical Products, Ltd. The frequency of these events was higher in fluoxetine users in the year prior to first treatment than in users of the other three antidepressants. The frequency of these events in the 90 days after the study drug was started was similar for the users of all four drugs. These data indicate that fluoxetine does not directly cause suicidal behavior at a substantially higher frequency than do lofepramine, mianserin, and trazodone.

Int Clin Psychopharmacol. 1991 Dec;6 Suppl 3:49-55; discussion 55-6.
5-HT reuptake inhibitors, tricyclic antidepressants and suicidal behaviour.
Baldwin D, Bullock T, Montgomery D, Montgomery S.
Academic Department of Psychiatry, St Mary's Hospital Medical School, London, UK.

Antidepressant drugs undoubtedly reduce much of the morbidity and mortality associated with a variety of depressive disorders. Certain types of antidepressant drugs have been shown to exert a relative advantage in the reduction of suicidal thoughts, and it is interesting that recent reports have noted an association between the prescription of some antidepressants and the development of suicidal and aggressive thoughts and behaviour. An analysis of the data from double-blind controlled trials of fluvoxamine, fluoxetine and paroxetine indicates that 5-HT uptake inhibitors exercise some protective effects on the emergence of suicidal thoughts, whereas the data from the studies with maprotiline show an increase in suicidal thoughts compared with placebo.

J Clin Psychiatry. 1991 Dec;52(12):491-3.
Reexposure to fluoxetine after serious suicide attempts by three patients: the role of akathisia.
Rothschild AJ, Locke CA.
McLean Hospital, Department of Psychiatry, Harvard Medical School, Belmont, MA 02178.

Considerable controversy exists regarding the relationship between fluoxetine and the emergence of suicidal ideation. Three cases are presented of patients who were reexposed to fluoxetine after having previously made a serious suicide attempt during fluoxetine treatment. All three patients developed severe akathisia during retreatment with fluoxetine and stated that the development of the akathisia made them feel suicidal and that it had precipitated their prior suicide attempts. The akathisia and suicidal thinking abated upon the discontinuation of the fluoxetine or the addition of propranolol. The emergence of suicidal ideation during treatment with fluoxetine may be secondary to the development of akathisia. Gradual increments of fluoxetine dose and the prompt recognition and treatment of akathisia may reduce further the rare occurrence of suicidal ideation during fluoxetine treatment.

BMJ. 1991 Sep 21;303(6804):685-92.
Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression.
Beasley CM Jr, Dornseif BE, Bosomworth JC, Sayler ME, Rampey AH Jr, Heiligenstein JH, Thompson VL, Murphy DJ, Masica DN.
Division of Clinical Neurosciences, Eli Lilly and Company, Indianapolis, Indiana 46285.

OBJECTIVE--A comprehensive meta-analysis of clinical trial data was performed to assess the possible association of fluoxetine and suicidality (suicidal acts and ideation). DESIGN--Retrospective analysis of pooled data from 17 double blind clinical trials in patients with major depressive disorder comparing fluoxetine (n = 1765) with a tricyclic antidepressant (n = 731) or placebo (n = 569), or both. MAIN OUTCOME MEASURES--Multiple data sources were searched to identify patients with suicidal acts. Suicidal ideation was assessed with item 3 of the Hamilton depression rating scale, which systematically rates suicidality. Emergence of substantial suicidal ideation was defined as a change in the rating of this item from 0 or 1 at baseline to 3 or 4 during double blind treatment; worsening was defined as any increase from baseline; improvement was defined as a decrease from baseline at the last visit during the treatment. RESULTS--Suicidal acts did not differ significantly in comparisons of fluoxetine with placebo (0.2% v 0.2%, p = 0.494, Mantel-Haenszel adjusted incidence difference) and with tricyclic antidepressants (0.7% v 0.4%, p = 0.419). The pooled incidence of suicidal acts was 0.3% for fluoxetine, 0.2% for placebo, and 0.4% for tricyclic antidepressants, and fluoxetine did not differ significantly from either placebo (p = 0.533, Pearson's chi 2) or tricyclic antidepressants (p = 0.789). Suicidal ideation emerged marginally significantly less often with fluoxetine than with placebo (0.9% v 2.6%, p = 0.094) and numerically less often than with tricyclic antidepressants (1.7% v 3.6%, p = 0.102). The pooled incidence of emergence of substantial suicidal ideation was 1.2% for fluoxetine, 2.6% for placebo, and 3.6% for tricyclic antidepressants. The incidence was significantly lower with fluoxetine than with placebo (p = 0.042) and tricyclic antidepressants (p = 0.001). Any degree of worsening of suicidal ideation was similar with fluoxetine and placebo (15.4% v 17.9%, p = 0.196) and with fluoxetine and tricyclic antidepressants (15.6% v 16.3%, p = 0.793). The pooled incidence of worsening of suicidal ideation was 15.3% for fluoxetine, 17.9% for placebo, and 16.3% for tricyclic antidepressants. The incidence did not differ significantly with fluoxetine and placebo (p = 0.141) or tricyclic antidepressants (p = 0.542). Suicidal ideation improved significantly more with fluoxetine than with placebo (72.0% v 54.8%, p less than 0.001) and was similar to the improvement with tricyclic antidepressants (72.5% v 69.8%, p = 0.294). The pooled incidence of improvement of suicidal ideation was 72.2% for fluoxetine, 54.8% for placebo, and 69.8% for tricyclic antidepressants. The incidence with fluoxetine was significantly greater than with placebo (p less than 0.001) and did not differ from that with tricyclic antidepressants (p = 0.296). CONCLUSIONS--Data from these trials do not show that fluoxetine is associated with an increased risk of suicidal acts or emergence of substantial suicidal thoughts among depressed patients.

Biol Psychiatry. 1991 Jul 15;30(2):190-6.
Fluoxetine-induced suicidality, serotonin, and seasonality.
Brewerton TD.
Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston 29425-0742.

In spite of the complexities involved in suicide, fluoxetine has been prematurely and simplistically blamed for inducing this phenomenon. A variety of variables must be factored into such an interpretation. Nevertheless, given the complicated psychobiological circumstances involved, acute and rapid changes in serotonin (5-HT) function appear to be important to the understanding of changes in suicidal behavior. Such a mechanism may also explain the robust seasonal peak of suicides in spring.

J Am Acad Child Adolesc Psychiatry. 1991 Mar;30(2):179-86.
Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment.
King RA, Riddle MA, Chappell PB, Hardin MT, Anderson GM, Lombroso P, Scahill L.
Yale Child Study Center, Yale University School of Medicine, New Haven, CT 06510-8009.

Self-injurious ideation or behavior appeared de novo or intensified during fluoxetine treatment of obsessive-compulsive disorder in six patients, age 10 to 17 years old, who were among 42 young patients receiving fluoxetine for obsessive-compulsive disorder at a university clinical research center. These symptoms required the hospitalization of four patients. Before receiving fluoxetine, four patients had major risk factors for self-destructive behavior including depression or prior suicidal ideation or self-injury. Three hypotheses concerning the apparent association between fluoxetine and these self-injurious phenomena are discussed: (1) coincidence; (2) disorganization of vulnerable individuals secondary to drug-induced activation; and (3) a specific serotonergic-mediated effect on the regulation of aggression.

J Clin Psychiatry. 1991 Mar;52(3):108-11.
Suicidality and fluoxetine: is there a relationship?
Fava M, Rosenbaum JF.
Clinical Psychopharmacology Unit, Massachusetts General Hospital, Harvard Medical School, Boston 02114.

A recent report of six depressed patients who developed intense, violent suicidal preoccupation after 2 to 7 weeks of fluoxetine treatment prompted the authors to survey 27 psychiatrists who treated 1017 depressed outpatient with antidepressants during 1989: 3.5% (8/231) of those treated with fluoxetine alone, 6.5% (4/62) of those treated with fluoxetine and tricyclics, 1.3% (5/385) of those treated with tricyclics alone or with lithium, and 3.0% (3/101) of those treated with other antidepressants became suicidal only after treatment with these antidepressants was initiated. None of these patients, however, reported intense suicidal thoughts of the degree described in the previously reported six cases. The difference in incidence of suicidal ideation occurring only after initiation of treatment was not significant between patients treated with fluoxetine alone and those receiving the other antidepressant treatments.

Am J Psychiatry. 1990 Feb;147(2):207-10.
Emergence of intense suicidal preoccupation during fluoxetine treatment.
Teicher MH, Glod C, Cole JO.
Department of Psychiatry, Harvard Medical School, MA.

Six depressed patients free of recent serious suicidal ideation developed intense, violent suicidal preoccupation after 2-7 weeks of fluoxetine treatment. This state persisted for as little as 3 days to as long as 3 months after discontinuation of fluoxetine. None of these patients had ever experienced a similar state during treatment with any other psychotropic drug.