The results of this study indicate that, after eliminating the effects of long-term linear trends, annual changes in antidepressant prescribing in Japan since the introduction of SSRIs are negatively associated with annual changes in suicide rates. It does not follow that an annual increase in SSRI prescriptions will correspond to a decrease in the suicide rate because other long-term linear trends may affect the suicide rate. For example, unemployment increased during this time period, but because the increase was nearly linear, this confound was eliminated in our differenced analysis. It might be argued that factors associated with risks of antidepressants are lost by eliminating these trend effects. However, if increased antidepressant treatment caused increased suicide rates, then in years in which the increase in prescriptions is especially great the increase in the suicide rate should also be especially great. Instead, we found evidence to support our hypothesis of an inverse relationship. This appeared to be strongest among males, who have the highest suicide rates and experienced a greater increase in antidepressant treatment.
Our findings are consistent with most studies in other countries,17–23
and in particular with those studies17,23
that found that demographic groups with the largest increases in antidepressant treatment had the greatest decrease in suicide rates. Using U.S. regional data, Gibbons et al.18
and Olfson et al.25
showed that counties with the greatest increase in SSRI and newer antidepressant prescriptions had the biggest declines in suicide rates.
Analysis of data not stratified by age and gender may have contributed to premature reports that Japan is an exception to these findings in other countries.29
This is the first national study in an Asian country with a high annual suicide rate of more than 20 per 100,000 persons using a differenced, age/sex-stratified analysis. The results support the notion that increased use of newer antidepressants, mainly SSRIs, may have had a protective association to suicide rates in Japan.
The most likely explanation for this protective association is improved treatment of depressive disorders. Substantial literature demonstrates the efficacy of anti-depressants for major depressive disorder.12,51,52
Major depressive disorder accounts for approximately 60% and anxiety disorders for 20% of antidepressant prescriptions in Japan.53
Greater use of antidepressants for depression and other disorders with elevated suicide risk54
may have a beneficial effect on suicide rates.
Improved side effect profiles of newer antidepressants may have increased prescribing by general practitioners55
and reduced negative perceptions.56
Educational programs on depression treatment can change general practitioners’ clinical knowledge and attitudes,57,58
and reduce suicide rates.59
Improved side effect profiles may have also increased patients’ treatment adherence.60,61
Selective serotonin reuptake inhibitors are safer on overdose compared with TCAs.62
Clinical contact and psychosocial interventions associated with prescribing may also have beneficial effects.63,64
A study in an isolated rural village in Japan with an aged population and very high suicide rate showed that better diagnosis and treatment of depression led to a substantial fall in suicide rates.65
Meta-analyses of effects of SSRIs on rates of suicide, attempts, and ideation in clinical trials report inconsistent results.66–74
Some report that SSRIs may increase the risk of attempts, specifically in youth, on the basis of clinical trial adverse event reports,66–69
but suicide item scores on rating scales in the same studies do not indicate such a risk.70,71
There is a need for randomized controlled trials measuring the effects of antidepressants on suicidality, particularly in children, adolescents, and young adults.
We found a trend for a stronger protective association of both SSRIs and all newer antidepressants among males compared to females. A similar effect was found by Olfson et al.25
Age-adjusted mortality rates from suicide are about 2-fold higher for Japanese males compared with U.S. males.75
More widespread antidepressant treatment might be expected to more strongly affect males, since they have higher suicide rates and also experienced a greater relative increase in antidepressant prescribing during this time period compared to females. There could also be effects on impulsivity and aggression in depressed men.76–80
We did not find evidence of an interaction effect of age. Unlike the United States, where suicide rates are highest among elderly males, in Japan, they are highest among middle-aged males. Yamasaki et al.81
reported that from 1970 to 1990 in Japan, low income was associated with suicide in middle-aged males, but that study did not consider the role of mood disorders. In a cohort study of 57,714 Japanese males aged 40 to 69 years, cigarette smoking was associated with an increased risk of suicide.82
We and others have discussed the relationship of cigarette smoking to aggressive personality traits, lower serotonin function in the brain, and the risk for suicide and nonfatal attempts.79,82,83
In our analysis, adjusting for alcohol consumption and unemployment rates did not significantly alter the inverse relationship between SSRIs and suicide rates. This is consistent with similar evidence from the United States,17
This study has limitations associated with an ecological analysis. We cannot infer causality from statistical associations. A fundamental limitation of this type of analysis is the lack of individual level data. It is not possible to know whether individual suicides were associated with use or nonuse of antidepressant medication. Nor is it possible to control for all variables that may contribute to observed associations, such as drug abuse and access to lethal means. However, prevalence of illicit drug use and common methods of suicide, mainly hanging, did not change during the study period.84,85
The differenced analysis of annual changes in rates eliminates the effect of long-term linear trends. Another limitation is the relatively short time period. The use of separate datasets for prescription volume and to estimate age/sex stratification of prescriptions may have introduced some error, though this method has been used by others.23
The large national datasets allow us to estimate rates relatively accurately. We could not stratify by diagnosis since we did not have these data. Suicides tend to be underreported,86
whereas the dose of antidepressant that patients take may be overestimated in that studies show low adherence.87,88
However, it is unlikely that underreporting of suicides or inadequate adherence changed markedly during this time period.
In conclusion, the introduction of newer antidepressants in Japan, beginning in 1999, was associated with increased antidepressant prescribing, mainly of SSRIs. After eliminating the effects of long-term linear trends, we found annual increases in antidepressant treatment were associated with annual decreases in suicide rates. This may be a consequence of improved treatment of anti-depressant-responsive psychiatric illnesses that increase suicide risk, mainly depression. Randomized controlled trials are needed to prove whether these medications have actual antisuicidal effects.