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
Zoltán Rihmera,⁎, Hagop Akiskalb
aNational Institute for Psychiatry and Neurology, Budapest, 27 POB 1, 1281, Hungary
bDepartment of Psychiatry and International Mood Center, University of California at San Diego, and Veterans Administration Medical Center,
San Diego, USA
Received 31 October 2005; accepted 29 March 2006
Available online 19 May 2006
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
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.
© 2006 Elsevier B.V. All rights reserved.
Keywords: Antidepressant; Suicide; Suicide attempt; RCT
The background of the antidepressant–suicidality controversy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Antidepressants and suicide at the level of general population. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Antidepressants and suicide in clinical samples of mood disorder patients . . . . . . . . . . . . . . . . . . . . . . .
Journal of Affective Disorders 94 (2006) 3–13
⁎Corresponding author. Tel.: +36 1 391 5353; fax: +36 1 391 5305.
E-mail address: firstname.lastname@example.org (Z. Rihmer).
0165-0327/$ - see front matter © 2006 Elsevier B.V. All rights reserved.
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Antidepressants and suicide in individual case studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Hypothesis: rare suicidality on antidepressants as iatrogenesis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Concluding remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1. The background of the antidepressant–suicidality
Untreated or unsuccessfully treated major mood dis-
orders are the main clinical substrates of suicidal behav-
ior (Angst et al., 1999; Rihmer and Kiss, 2002;
Baldessarini et al., 2003). Prospective and retrospective
studies clearly support the evident clinical observation,
i.e. if major mood disorder patients committ or attept
suicide, they do it mostly during a major depressive
episode (79–89%) and less frequently in dysphoric
mania (11–20%), but practically almost never during
euthymia (0–1%) (Rouillon et al., 1991; Isometsa et al.,
1994; Tondo et al., 1998). On the other hand, patients
with anxiety disorders, a population also frequently
exposed to antidepressant (AD) pharmacotherapy, expe-
depressive episode (Warshaw and Keller, 1996).
Therefore, to treat mood and anxiety disorders ef-
fectively, and to stabilize the period of well-being is
crucial for suicide prevention (Khuri and Akiskal,
1983). However, as it has recently been advised by
US Food and Drug Administration (FDA, 2004), anti-
depressants (ADs) could sometimes be related to sui-
cidal behavior, which in their database examined mainly
pertains to children and adolescents. New meta-analyses
have confirmed FDA's position for a modestly in-
creased risk of suicidality in juvenile patients in SSRI
trials (Hammad et al., 2006). We concur with Baldes-
sarini et al.'s (2006) commentary to the effect that this
claim is not based on prospectively “defined research
outcomes of the trial designs.” We also concur with
Cheung et al. (2006) that data on antidepressants in
children and adolescents should not be extrapolated
from adults. Nor should one be tempted to extrapolate to
adults from the FDA Advisory on juvenile patients.
Nonetheless, the problem is of broader public health
significance for all age groups. If suicidality potential of
(some) ADs does actualize, it must be small enough to
be masked by currently favorable trends in national
suicide rates. Even one case of an AD-related suicide is
one more than needed, and psychiatrists should identify
the vulnerable patients and develop effective prevention
strategies to avoid such iatrogenesis. We decided to
write this paper because the issues raised by the FDA
cannot be understood solely on the basis of the
methodology of the psychopharmacologic trials (Mann
et al., 2006) and require consideration of broader
epidemiologic and clinical parameters.
In the present review and clinical reformulation of
this public health problem, suicidality refers to suicide
proneness as evidenced by ideation, verbalization, writ-
ten communication, or attempt; suicide denotes the
completed act that results in death. It would be useful to
clarify at this early stage in this paper that what the FDA
advisory is warning about, is mainly whether antide-
pressants are involved in suicidaltiy in the broadest
sense, rather than completed suicide. After examining
all sides of this controversy, we will argue that the
proper use of the FDA advisory can nonetheless serve to
develop a rational prevention strategy of how to deal
with the suicidality even before it develops.
2. Antidepressants and suicide at the level of general
Since successful acute and long-term treatment of
unipolar depression and bipolar disorders substantially
reduces the suicide morbidity and mortality even in this
high-risk population (Angst et al., 2002; Baldessarini et
al., 2003; Rihmer and Kiss, 2002; Yerevanian et al.,
2003, 2004), it is logical to postulate that if the rate of
treated depression in the population increases gradually,
at a given point will result in a decrease of the suicide
rate. Indeed, a prospective trial on Gotland, a Swedish
island, showed that educating primary care physicians
on how to diagnose and treat depression does lead to a
significant decline of suicide rates over a 3-year period,
and that this decrease was a linear consequence of the
significant decrease of depression-related suicides (Rutz
et al., 1989; Rihmer et al., 1995).
However, since the effect of a given intervention
depends on the baseline condition (i.e. the effect is
greater when the baseline condition is more patholog-
ical), the role of more widespread treatment of de-
pression in reducing suicide rates can be easier to detect
in countries where the suicide rate is high and the rate of
treated depressions is low. Indeed, looking at the
countries with the highest suicide rate of the World 20
years ago (between 20 and 46 per 100,000 per year), the
4 Z. Rihmer, H. Akiskal / Journal of Affective Disorders 94 (2006) 3–13
Changes in national suicide rates between 1980/1981 and 2001/2003
Change in percent
3. Russian Federation
6. Slovenia (from 1985)
12. Belgium (1980–1997)
13. Czech Rep. (from 1986)
16. Germany (from 1990)
17. Slovakia (from 1992)
Countries are listed in decreasing order of their suicide rates at baseline (1980/1981). Suicide rates are expressed as number of siucudes per 100.000/
year. (To avoid the extremely busy nature of this table, only the total suicide rates were entered, i.e. the separate suicide rates of males and females are
not shown here).
Out of these 30 countries, 21 showed decrease and 9 showed increase in suicide rates.
Out of the 13 countries with high baseline suicide rates (20 or more), 10 countries showed decrease (in average 26.9%, range: 6–57%) and 3 showed
increase (Russian Fed., Lithuania, Ukraine, all of them are post-Soviet countries). Out of the 17 countrieswith low baselinesuicide rate (less than 20),
11 countries showed decrease (in average 15.0%, range: 9–31%) and 6 showed increase (Poland, Australia, Iceland, Portugal, Ireland and Spain).
Out of the first 10 countries with the highest baseline suicide rates (From Hungary to Switzerland) 2 showed increase (Russian Fed. and Lithuania) and
and more marked decline, and the majority of countries with increasing suicide rates come primarily from countries with low baseline rates.
In the 21 countries with decreased suicide rate, the decrease was greater in females in 19 countries (19/21=90%), while in the 9 countries with
increasing suicide rates the increase was higher in males in 8 countries (8/9=89%, chi-square with Yates correction: 14.46, p=0.0001). This is in
good agreement with the findings of Gotland Study, showing that the decreased number of depressive suicides was almost exclusively the
consequence of the decrease in female depressed suicides (Rihmer et al., 1995;Rutz et al., 1997). It has been also repeatedly demonstrated that among
suicide victims, females contact much more frequently their GPs or psychiatrists some weeks or months before their death (Rutz et al., 1997; Luoma
et al., 2002). It has been also demonstrated that the increase in the utilization of SSRIs is more and less pronounced in females in several countries
including Sweden, the United States and Australia (Isacsson, 2000; Hall et al., 2003; Grunebaum et al., 2004).
The detailed analysis of the recent increase of SSRIs and other newer antidepressants in different countries is beyond the scope of this review.
However, there is no doubt that the greatest increase can be detected in North America and in Western and nordic Europe (as well as in Hungary)
where it has been accompanied by the greatest decrease in the national suicide rates.
5 Z. Rihmer, H. Akiskal / Journal of Affective Disorders 94 (2006) 3–13
24–57% decline in national suicide rates of Denmark,
Hungary, Germany, Austria, Estonia, Switzerland, Swe-
den and Slovenia in the last 2 decades is quite im-
pressive, and a marked (6–8 fold) increase of AD
prescription during the same period has been also
reported from Denmark, Hungary, Sweden and Finland
(Isacsson, 2000; Rihmer, 2001, 2004, see also Table 1).
Unemployment and alcohol consumption did not
correlate with suicide rates in Sweden (Isacsson, 2000)
and in Hungary (Rihmer, 2001), in the two countries
where these data were also reported.
Iceland and Italy, the increased utilization of ADs (5-fold
increase or less) has not been accompanied by any or
marked decline in overall national suicide rates (Barbui
et al.,1999; Hallet al.,2003; Kelly et al.,2003; Helgason
et al., 2004). Nonetheless, the study from Australia (Hall
significantly associated with exposure to ADs indifferent
age cohorts between 1990 and 2000: the higher the
exposure to ADs, the larger the decline of the suicide rate
in a given subpopulation. Moreover, the study from
Northern Ireland (Kelly et al., 2003) also demonstrated a
significant association between increased AD prescribing
and fall in suicide rate in the population over 30 years of
age. Unemployment (but not alcohol consumption) was
also positively correlated with the suicide rate in this age
From 1985 to 1999 the national suicide rate of the
United States fell from 12.4 per 100,000 to 10.7 per
100,000 (a 13.5% decline), while the prescription of
ADs (mainly SSRIs and other second-generation ADs)
increased over 4-fold (Grunebaum et al., 2004). The
decline in suicide rate was more pronounced for females
(22.5%) than for males (12.8%), consistent with the
finding that females received twice as many AD pre-
scription compared with males. Prescription rates for
SSRIs and other second-generation ADs in United
States between 1985 and 1999 were both inversely and
significantly correlated with suicide rates. However, the
independent effect of changing rates in unemployment
and alcohol consumption has not been demonstrated in
this study (Grunebaum et al., 2004). Investigating the
relationship between AD utilization and suicide mortal-
ity in adolescents, another study from the United States
also revealed a significant negative correlation between
regional change in AD (mainly SSRIS) utilization and
suicide mortality between 1990 and 2000. Doubling in
adolescent use of ADs was associated with a decrease of
23 suicides per 100,000 adolescents per year (Olfson et
al., 2003). It is important to keep in mind that the
foregoing considerations pertain to completed suicide,
because at least one epidemiologic survey in U.S. adults
failed to detect changes in other suicide-related be-
haviors and/or ideation in the decade of the 1990s
(Kessler et al., 2005). Whatever the reasons for this
discrepancy–i.e. such behaviors and/or ideation often
occur before antidepressants are prescribed–we wish to
restate that our main focus in this section is national
suicide rates, not the complex and heterogeneous mix of
related behaviors and/or ideation.
Investigating the suicide mortality of the 27 countries
with data on annual sales of all SSRIs (and other ADs)
between 1980 and 2000, Ludwig and Marcotte (2005)
have found that after controlling for several socio-
demographic factors (unemployment, GDP, gender, age-
groups, divorce rate), an increase of one SSRI pill per
capita (a 13% increase over 1999 levels) was associated
with a 2.5% reduction in suicide rates, a significant
relationship that was more pronounced in adults than
children. The detailed analysis of these 27 countries also
showed that the faster was the growth in SSRI sales per
capita, the larger was the decline in suicide rates (Lud-
wig and Marcotte, 2005).
Of course, the significant negative correlation be-
tween increasing AD utilization and decreasing national
suicide rates does not automatically suggest a causal
association, but considering the strong (and causal)
relationship between untreated major mood disorder and
suicidal behavior (Angst et al., 2002; Rihmer and Kiss,
2002; Baldessarini et al., 2003; Yerevanian et al., 2003,
2004), all the above mentioned pharmaco-epidemiolog-
ical studies strongly suggest that more widespread and
effective treatment of mood disorders is a significant,
but not the only factor in decreasing suicide mortality at
the level of the general population. The progressively
(and significantly) lowering of suicide rates of depressed
patients through the “pretreatment era” (1900–1939),
“ECT era” (1940–1959), and “AD era” (1960–1992)
(6.3, 5.7, and 3.3 per 1000 patient year, respectively:
O'Leary et al., 2001), also support such a connection.
Table 1 provides greater detail on the foregoing
national statistics. Countries with the highest baseline
suicide rates (except some post-Soviet countries) show
the most pronounced declines in their suicide rates. It is
also important to highlight that the decline in suicide
rates has been striking particularly in females. The same
was found in the Gotland trial (Rutz et al., 1989, 1997;
Rihmer et al., 1995). These observations accord with the
well-known fact that women, compared with men, seek
help in greater proportions (Rutz et al., 1997; Luoma et
al., 2002). Obviously being in treatment and regular
6 Z. Rihmer, H. Akiskal / Journal of Affective Disorders 94 (2006) 3–13
follow-up by mental help clinicians and general prac-
titioners trained to recognize and treat depression is a
necessary ingredient of the therapeutic regimen of
clinically depressed patients, especially so when they
3. Antidepressants and suicide in clinical samples of
mood disorder patients
Several large-scale, retrospective and/or prospective,
naturalistic observational, long-term clinical studies,
including severely ill, hospitalized, frequently suicidal
mood disorder patients showed that compared to no
treatment, the risk of completed suicide among unipolar
and bipolar patients on long-term pharmacotherapy
(mood stabilizers, ADs) is 2–19 fold lower (Leon et al.,
1999; Kallner et al., 2000; Angst et al., 2002; Bal-
dessarini et al., 2003; Yerevanian et al., 2003, 2004).
However, since these studies could not exactly discern
the successfully and unsuccessfully treated patients as
well as medication adherence immediately before the
suicide, the difference between successfully treated and
unsuccessfully treated nonadherent patients might be
In spiteofthefactthat actively suicidalpatients are not
included into AD drug-studies, randomized controlled
trials (RCTs) could provide some useful, albeit limited,
information on this topic. Analyzing the committed
suicides on the basis of patients exposure years of phase
2–3 RCTs, it has been found that the annual rates of
committed suicide were 0.6–0.9% with ADs and 0.3–
0.5% with placebo (Rouillon et al., 1991; Kahn et al.,
2000, 2001). Comparing the SSRIs, other ADs, and
placebo in FDA summary reports of phase 2–3 RCTs
(N=48,277, 77 of which completed suicide), the results
patients on SSRIs, on other ADs and on placebo were
The most recent meta-analysis of 702 RCTs, in-
cluding more than 87,000 depressive and other psy-
chiatric patients, Fergusson et al. (2005) have found a
significant increase of suicide attempts for patients
taking SSRIs compared with placebo (OR: 2.28).
However, focusing on fatal suicide attempts, they did
not detect any significant difference between SSRIs and
Much of the recent focus on ADs and suicidal
behavior has involved children. The analysis of 25
outpatient pediatric AD-trials, including more than 4000
patients showed that 3.2% of the children taking AD
become “suicidal,” compared with 1.7% of those taking
placebo, but most importantly, no patients in these drug-
trials completed suicide (Culpepper et al., 2004;
Whittington et al., 2004).
The (nonsignificantly) higher frequency of suicidal
behavior on ADs than on placebo in RCTs on unipolar
depressives raises several questions. Does it mean that
ADs provoke more suicide events than placebo? Does
placebo prevent more suicide events than ADs? Do both
ADs and placebo provoke suicidal behavior, but this
effect is less frequent among patients taking placebo?
What would be the frequency of suicidal behavior in this
patient population without ADs or placebo (i.e. during
the naturalistic course of the illness)? The “evidence-
based” findings of the mentioned RCTs in this respect
are in sharp contrast with the “evidence” based on the
everyday clinical practice, since no clinical guidelines
recommend to treat severely ill, acutely suicidal patients
with placebo monotherapy! The bizarre nature of this
(otherwise logical) conclusion indicates that the basic
question (“Do ADs increase or decrease suicidality
among depressives?”) in this general form is counter-
productive and unscientific.
Indeed, short-term RCTs in adults also showed that
newly emerged suicidal ideation was rare (3.6% for
TCAs, 1.2% for fluoxetine and 2.6% for placebo), and
that in 70–72% of the cases, ADs (primarily SSRIS)
markedly decreased the suicidal tendencies (that were
present in one-third of the patients at baseline), while the
same rate for placebo was “only” 55% (Beasley et al.,
1991; Montgomery et al., 1995). More recent larger
clinical studies, in both adults (Simon et al., 2006) and
children (March et al., 2004), have confirmed the pro-
tective effects of antidepressants against suicidality. The
ACNP task force, which reviewed large RCT database
(Mann et al., 2006), also found no evidence that SSRI's
were involved in adult suicidality.
Since severely ill, actively suicidal patients, who
have the highest lifetime risk of suicide (Bostwick and
Pankratz, 2000) as well as DSM-IV diagnosed bipolar
depressives, are excluded from AD drug-studies, RCTs
are not representative for suicidal depressives. In ad-
dition, recent meta-analyses of RCTs have not con-
sidered several important factors, such as the time of
suicide event (first 3 weeks vs. week 4. or more), the
actual clinical condition (nonresponse, response/remis-
sion, relapse, etc.), adherence failure (hidden drug-
discontinuation before suicide event), and some phar-
macokinetic parameters (e.g. excessive metabolization
that results in a suboptimal serum-drug level, that can
basically influence the drug response, but not the pla-
Viewed in perspective, the almost double frequency
of suicidal behavior (much of it not fatal) of patients on
7 Z. Rihmer, H. Akiskal / Journal of Affective Disorders 94 (2006) 3–13
ADs than on placebo in RCTs (Rouillon et al., 1991;
Kahn et al., 2000, 2001, 2003; Whittington et al., 2004)
is surprising. Considering the strong anti-suicidal effect
of long-term antidepressant pharmacotherapy in open
clinical studies on severe unipolar, frequently suicidal
depressives (Leon et al., 1999; Angst et al., 2002;
Yerevanian et al., 2004), one would have expected a
great difference in the opposite direction. The fact that
the suicidal behavior of AD-treated unipolar patients in
RCTs is just nonsignificantly higher than those of on
placebo does not constitute an appropriate answer, as
one would have asked “why not much lower”? Does it
mean that ADs prevent suicide more frequently among
severely ill, frequently suicidal unipolar major depres-
sives, but provoke such behavior sometimes (or prevent
less frequently) in less severe, actually nonsuicidal
unipolar patients? To answer this, one should look at the
complex relationship between ADs and suicide at the
4. Antidepressants and suicide in individual case
As of 1990, several individual case studies appeared
in the literature suggesting a link between use of ADs
(particularly SSRIs) and suicidal behavior. The dose–
response relationship and the challenge–dechallenge–
rechallenge nature of these suicidal events suggested
that in these cases, the postulated relationship might be
real. Most of the authors related the “SSRI-induced
suicidal behavior” to the generation of akathisia or
agitation (Healy, 2003). The actual clinical condition of
the patients at the time when they become suicidal while
taking ADs is usually an activated state which is well-
known since Kraepelin (“increasing activity before im-
provement of mood”), but only recently has been termed
“an activation syndrome (AS),” that occurs mainly in the
initial phase of treatment (Culpepper et al., 2004).
Nearly two decades ago, in a clinical report, Akiskal
and Mallya (1987) described a group of an “overzea-
lously” tricyclic antidepressant and MAOI treated out-
patients who had developed a refractory agitated
symptoms, including panic and suicidality, they
subsequently responded to lithium- or neuroleptic-
augmentation. Another clinical study (Haykal and
Akiskal, 1999) also showed that among double
depressives given fluoxetine and those who switched
from their dysthymic baseline to hyperthymia, eventu-
ally mood instability and suicidality emerged; most of
these patients had bipolar family history and responded
to lithium augmentation. A similar clinical condition
has been described by Koukopoulos et al. (1992).
Interestingly, the vast majority of the 10 symptoms of
AS, such as agitation, irritability, hostility, impulsivity
(and by definition hypomania/mania) are the typical
non-euphoric hypomanic symptoms during major
depressive episode (i.e. depressive mixed state, Kou-
kopoulos and Koukopoulos, 1999; Benazzi, 2002;
Benazzi et al., 2002; Akiskal and Benazzi, 2003; Maj
et al., 2003; Sato et al., 2003; Akiskal et al., 2005),
while other symptoms like anxiety and panic can reflect
the high rate of comorbid anxiety disorders found in
unipolar but most commonly in bipolar patients
(Kessler, 1999; Rihmer et al., 2001). Agitated depres-
sion and depressive mixed state (3 or more hypomanic
symptoms during major depression) appear to be
almost identical conditions (Benazzi et al., 2002;
Akiskal and Benazzi, 2003; Akiskal et al., 2005), and
the clinical cluster of agitated depression/depressive
mixed state is associated with increased risk of suicidal
behavior (Maser et al., 2002; Benazzi, 2003; Busch et
al., 2003; Maj et al., 2003; Akiskal et al., 2005; Akiskal
and Benazzi, 2005; Balázs et al., 2006). It is therefore
very likely that the AS and AD-induced depressive
mixed state–frequently seen in AD-treated depressives
with threshold or subthreshold bipolarity (Akiskal and
Mallya, 1987; Koukopoulos et al., 1992; Haykal and
Akiskal, 1999; Ghaemi et al., 2002; Bottlender et al.,
2004)–are the phenomenologic descriptions of the
same clinical state from two different angles.
Since the officially diagnosed (DSM-III/IV Type I and
unipolar major depression, whereas major depressives
with subthreshold hypomania and bipolar spectrum
depressives (Akiskal and Mallya, 1987; Akiskal and
Pinto, 1999; Ghaemi et al., 2002; Dunner, 2003), as well
bipolar disorder, Akiskal et al., 2005) are regularly
included, we submit results in a substantial proportion
of bipolar spectrum patients in the “unipolar” samples in
RCTs. In line with these considerations, we wish to cite
the landmark study of Rouillon et al. (1991) on
prophylactic efficacy of maprotiline and placebo in
unipolar depression, where only bipolar I (but not bipolar
II) patients were excluded, the rate of all suicidal events
during the 1-year follow-up was very much (6-times)
higher on maprotiline than on placebo (1.8% vs. 0.3%
among all RCTs. This may well represent the largest and
most systematic database in support for the rare occur-
rence of suicidality on an antidepressant.
Worsening the clinical picture under treatment with
ADs has been recently observed in pediatric population.
8 Z. Rihmer, H. Akiskal / Journal of Affective Disorders 94 (2006) 3–13
Wilens et al. (2003) found that 7% of pediatric patients
treated with SSRIs for depression or OCD become
manic and 10% become psychotic. Others have reported
that the rates of aggressivity, self-injured behavior and
homicidal ideation in pediatric patients who developed
treatment-emergent mania were 77%, 20% and 6%
respectively (Faedda et al., 2004), indicating that the 3–
4% of the “depressed” children who become suicidal
while on antidepressant (Culpepper et al., 2004;
Whittington et al., 2004), should come primarily from
early-onset bipolar population (Akiskal, 1995), where
the frequency of mixed states is over 70%, a rate being
much higher than reported in adult bipolar patients
(Dilsaver and Akiskal, 2005).
5. Hypothesis: rare suicidality on antidepressants as
In light of the foregoing literature, we submit that the
suicidality-antidepressant link appears mediated by de-
pressive mixed states (3 or more hypomanic symptoms
during major depressive episode). When ADs worsen
substrate might well reside in an agitated, excited, or
mentally aroused–anxious depressive mixed state (Akis-
kal et al., 2005; Akiskal and Benazzi, 2005). AD mono-
therapy, unprotected by mood stabilizers or (atypical)
antipsychotics, particularly in bipolar and bipolar spec-
trum disorder (including “unipolar” depressive mixed
state) can favor not only hypomanic/manic switches and
or generate de novo mixed conditions at the depressive
state or temperament level (Akiskal and Mallya, 1987;
Haykal and Akiskal, 1999; Bottlender et al., 2001;
Ghaemi et al., 2002; Benazzi, 2003; Dunner, 2003).
Recent work, showing that 80% of AD-resistant “uni-
polar” depressives have threshold and subthreshold
bipolar disorder (Sharma et al., 2005), and that among
AD-treatedoutpatients the rateofpriorsuicide attemptsis
three-times higher in the case of unrecognized versus
recognized bipolarity (Shi et al., 2004) also support this
Another important aspect in the AD-suicidality
connection might reside in different neurotransmitter-
activity of different (classes of) ADs. Antidepressants
with marked norepinephrine reuptake inhibiting potential
(e.g. maprotiline, venlafaxine and some TCAs), seem to
be associated with more frequent suicidal behavior than
SSRIs and placebo (Rouillon et al., 1991; Kahn et al.,
2003; Whittington et al., 2004). Analysing almost 15000
suicides in Sweden between 1992 and 2000 that were
subjected to forensic toxicological screening, Isacsson et
al. (2005) found that when compared with the average of
all antidepressants, the odds ratios showed highly
significant underrisks for SSRIs, average risks for
TCAs, and overrisks for venlafaxine and mirtazapine.
Both of the later mentioned antidepressants have strong
regulation”) appear strongly involved in the pathogenesis
of depression, but only the hyperactivity of norepineph-
rine/dopamine (but not serotonin) system is characteristic
for (hypo)manic states (Goodwin and Jamison, 1990;
that monotherapy with norardenergic ADs is the primary
substrate for AS/mixed states (and ultimately aggressive/
suicidal behavior). On the other hand, much of the FDA
advisory is based on data on selective serotonin re-uptake
inhibitors. An earlier related hypothesis formulated by
Nutt (1999) proposes that SSRI's do provoke the
“activation syndrome,” whereas such agents as mirtaza-
pine with combined noradrenergic 5-HT2mechanism of
action might protect form such arousal in the form of
anxiety and insomnia, thereby according greater comfort
to the acutely depressed patient.
Bipolar disorders, and particularly bipolar II and
bipolar spectrum disorder are highly underdiagnosed or
misdiagnosed as unipolar depression (Akiskal, 1996;
Akiskal and Pinto, 1999; Akiskal et al., 2000; Ghaemi et
al., 2002; Dunner, 2003). The very low rate of mood
stabilizer treatment in bipolar II patients has also been
demonstrated among suicide victims (Rihmer et al.,
1990) and among suicide attempters (Balázs et al.,
2003). The fact, that out of the three different clinical
manifestations of official (DSM-IV, APA, 2000) major
bipolar II illness), bipolar II diagnosis carries the highest
risk for both committed and attempted suicide (Rihmer
and Kiss, 2002) further underlines the importance of the
correct identification of subthreshold bipolarity among
depressed patients (Akiskal and Pinto, 1999).
Worsening medical state, in which the given drug-
therapy is effective in general, but could at times be
problematic, is also a problem in other fields of med-
icine. Emergence of resistance to antimicrobial agents is
a well-known phenomenon complicating the clinical use
of such agents. Provocation of a new arrhythmia or
increase in the frequency of preexisting arrhythmia
occurs with all antiarrhythmic agents in 6–25% of cases:
This so-called “pro-arrhythmogenic” effect can be seen
mainly in cardiac patients who have evidence of on-
going overt or silent cardiac ischemia (Podrid, 1999).
The frequently observed association between lowered
serum cholesterol and depression and irritability as well
9 Z. Rihmer, H. Akiskal / Journal of Affective Disorders 94 (2006) 3–13
as suicidal behavior (Kim et al., 2002; Golomb et al.,
2004) might be another example that illustrates the
potential of rare harm in an otherwise widely used
medically beneficial preventive strategy.
6. Concluding remarks
Like other medical fields then, where the risk of
iatrogeny is ever present, psychiatry should identify
persons who might be threatened by a given interven-
tion. Those depressives who are labile and agitated or
otherwise in a mixed state, or give such early warning
signs upon antidepressant treatment, must be protected
form antidepressant monotherapy (Akiskal et al., 2005;
Dilsaver and Akiskal, 2005). Incorporating such ob-
servations into everyday clinical practice is urgently
needed, as our responsibility in the clinical management
of depression is to treat rather than be a threat to the
mental health of our patients. This is further discussed in
a companion article in this issue of the journal (Benazzi
and Akiskal, 2006-this issue). Overall, the data
reviewed in this paper justify the claim that the increased
use of antidepressants has reduced depressive morbidity
and suicidal mortality. The formal recognition of
depressive mixed states in our official diagnostic system
will help to red-flag those pseudo-unipolar mixed
depressives for whom antidepressant monotherapy is
contra-indicated, and benzodiazepine, mood stabilizer
and/or atypical antipsychotic augmentation indicated on
clinical grounds (reviewed in Akiskal and Benazzi,
2003). Indeed, this is often what experienced clinicians
do worldwide (Fawcett et al., 1997; Akiskal and Pinto,
1999; Furukawa et al., 2001; Smith et al., 2002; Viner et
al., 2003; Barak et al., 2006). Because such augmenta-
tion is almost never part of research protocols, probably
explain why in placebo-controlled trials of antidepres-
sants modest increase in suicidality has been observed.
This is an instance where clinical wisdom surpasses
evidence-based medicine! However, it is presently
unknown to what extent such combined treatment
occurs in the general medical sector, where the largest
number of depressive patients are treated. Data on this
subject will be instructive.
It will be ethically forbidding to attempt to test pro-
spectively the antidepressant–suicide risk potential for
the vulnerable few. Psychiatry, like the rest of medicine,
is an art based on scientific methodology. Pending fur-
ther developments in the psychopharmacology and so-
matotherapy of depressive illnesses, for now the
prevention framework outlined herein from various
sources of data can be considered the most judicious
approach for the clinician. It is encouraging–and in line
with the overall thrust of our argument in this review–
that a large dataset deriving from clinical practice has
upheld the protective effectiveness of antidepressants
against suicide (Simon et al., 2006). Another such study
has failed to indicate any suicidality associated with
antidepressants (Bauer et al., 2006).
Suicide and suicidal behavior are multi-factorial
phenomena. We could not obviously cover all relevant
biologic and psychosocial factors in the origin and
Obviously clinical vigilance, regular clinical follow-up
and supportive therapeutic relationship with physicians
and mental health professionals are essential ingredients
of suicide prevention.
This review would be incomplete without making
reference tolithium.Lithium iswellknown for its suicide
preventive effectiveness in bipolar disorder (see Baldes-
sarini et al., 2003 for a review). Whether such effec-
tiveness extends to the broader spectrum of all affective
disorders is a worthy topic offurther investigation. To the
best of our knowledge–and given its declining use over
the past decade–it is unlikely to have had any impact on
national suicide rates discussed in the present review.
We wish to sign off with the remark that we earnestly
hope that the recently documented decline in the use of
antidepressants–at least in American psychiatry
(Rosack, 2005)–represents restraint in their use of an
understanding of the negative potential of such use in
pseudo-unipolar patients. Otherwise such decline in
their use could undermine the recent gains in the treat-
ment of depression and, we daresay, in suicide pre-
vention. Whether lithium, mood stabilizer combinations
and/or atypical antipsychotics are preferable in such
patients are beyond the scope of this commentary.
onset depressions pre-bipolar? J. Am. Acad. Child Adolesc. Psych.
Beyond DSM-IV. J. Clin. Psychopharmacol. 16 (suppl 1), 4s–14s.
therapeutic significance. Clini. Approaches Bipolar Disord. 2, 41–47.
Akiskal, H.S., Benazzi, F., 2005. Psychopathologic correlates of
suicidal ideation in major depressive outpatients: is it all due to
unrecognized bipolar depressive mixed states? Psychopathology
Akiskal, H.S., Mallya, G., 1987. Criteria for the “soft” bipolar spectrum:
treatment implications. Psychopharmacol. Bull. 23, 68–73.
Akiskal, H.S., Pinto, O., 1999. The evolving bipolar spectrum:
prototypes I, II, III, IV. Psychiatr. Clin. North Am. 22, 517–534.
Akiskal, H.S., Bourgeois, M.L., Angst, J., Post, R., Moller, H.J.,
Hirschfeld, R.M.A., 2000. Re-evaluating the prevalence of and
10 Z. Rihmer, H. Akiskal / Journal of Affective Disorders 94 (2006) 3–13
diagnostic composition within the broad clinical spectrum of
bipolar disorders. J. Affect. Disord. 59 (Suppl 1), 5s–30s.
Akiskal, H.S., Benazzi, F., Perugi, G., Rihmer, Z., 2005. Agitated
“unipolar” depression re-conceptualized as a depressive mixed state:
implications for the antidepressant–suicide controversy. J. Affect.
Disord. 85, 245–258.
American Psychiatric Association, 2000. Diagnostic and Statistical
Manual of Mental Disorders, 4th ed., Text Revision(DSM-IV-TR).
American Psychiatric Association, Washington, DC.
Angst, J., Angst, F., Stassen, H.H., 1999. Suicide risk in patients with
major depressive disorder. J. Clin. Psychiatry 60 (suppl 2), 57–62.
Angst, F., Stassen, H.H., Clayton, P.J., Angst, J., 2002. Mortality of
patientswith mood disorders:follow-up over 34–38years. J.Affect.
Disord. 68, 167–181.
Balázs, J., Lecrubier, Y., Csiszér, N., Koszták, K., Bitter, I., 2003.
Prevalence and comorbidity of affective disorders in persons making
and bipolar II diagnoses. J. Affect. Disord. 76, 113–119.
Balázs, J., Benazzi, F., Rihmer, Z., Rihmer, A., Akiskal, K.K., Akiskal,
H.S., 2006. The close link between suicide attempts and mixed
(bipolar) depression: implications for suicide prevention. J. Affect.
Disord. 91, 133–138.
Baldessarini, R.J., Tondo, L., Hennen, J., 2003. Lithium treatment and
suicide risk in major affective disorders: update and new findings.
J. Clin. Psychiatry 64 (suppl 5), 44–52.
Baldessarini, R.J., Pompili, M., Tondo, L., 2006. Suicidal risk in
antidepressant drug trials. Arch. Gen. Psychiatry 63, 246–247.
Barak, Y., Olmer, A., Aizenberg, D., 2006. Antidepressants reduce the
risk of suicide among elderly depressed patients. Neurophycho-
pharmacology 31, 178–181.
Barbui, C., Campomani, A., D'Avanzo, B., Negri, E., Gorattini, S.,
1999. Antidepressant drug use in Italy since the introduction of the
SSRI's: national trends, regional differences and impact on suicide
rates. Soc. Psychiatry Psychiatr. Epidemiol. 34, 152–156.
Bauer, M.S., Wisniewski, S.R., Marangell, L.B., Chessick, C.A.,
Allen, M.H., Dennehy, E.B., Miklowitz, D.J., Thase, M.E., Sachs,
G.S., 2006. Are antidepressants associated with new-onset
suicidality in bipolar disorder? A prospective study of participants
in the systematic treatment enhancement program for bipolar
disorder (STEP-BD). J. Clin. Psychiatry 67, 48–55.
Beasley, C.M., Dornseif, B.E., Bosomworth, J.C., Sayler, M.E.,
Rampsey Jr., A.H., Heiligenstein, J.H., Thompson, V.L., Murphy,
D.J., Masica, D.N., 1991. Fluoxetine and suicide: a meta-analysis
of controlled trials of treatmentfor depression. BMJ303,685–692.
Benazzi, F., 2002. Which could be a clinically useful definition of
depressive mixed state? Prog. Neuro-psychopharmacol. Biol. Psy-
chiatry 26, 1105–1111.
Benazzi, F., 2003. Depression with racing thoughts. Psychiatry Res.
Benazzi, F., Akiskal, H.S., 2006-this issue. Assessing the FDA's
probablecorrelates of suicidality associated with antidepressants in
adult clinical sample J. Affect. Disord. doi:10.1016/j.jad.04.002.
Benazzi, F., Helmi, S., Bland, L., 2002. Agitated depression: unipolar?
Bipolar? Or both? Ann. Clin. Psychiatry 14, 97–104.
Bostwick, J.M., Pankratz, V.S., 2000. Affective disorders and suicide
risk: a reexamination. Am. J. Psychiatry 157, 1925–1932.
Bottlender, R., Rudolf, D., Strauss, A., Möller, H.-J., 2001. Mood-
stabilizers reduce the risk of developing antidepressant-induced
maniform states in acute treatment of bipolar I depressed patients.
J. Affect. Disord. 63, 79–83.
Bottlender, R., Sato, T., Kleindienst, N., Strausz, A., Moller, H.-J.,
2004. Mixed depressive features predict maniform switch during
treatment of depression in bipolar I disorder. J. Affect. Disord. 78,
Busch, K.A., Fawcett, J., Jacobs, D.G., 2003. Clinical correlates of
inpatient suicide. J. Clin. Psychiatry 64, 14–19.
Cheung, A.H., Emslie, G.J., Mayes, T.L., 2006. The use of antidepres-
sants to treat depression in children and adolescents. CMAJ 174,
Culpepper, L., Davidson, J.R.T., Dietrich, A.J.M., Goodman, W.K.,
Kroenke, K., Schwenk, T.L., 2004. Suicidality as a possible
side effect of antidepressant treatment. J. Clin. Psychiatry 65,
Dilsaver, S.C., Akiskal, H.S., 2005. High rate of unrecognized bipolar
mixed states among destitute Hispanic adolescents referred for
“major depressive disorder”. J. Affect. Disord. 84, 179–186.
Dunner, D.L., 2003. Clinical consequences of under-recognized
bipolar spectrum disorder. Bipolar Disord. 5, 456–464.
(accessed 13 October 2004).
Faedda, G.L., Baldessarini, R.J., Glovinsky, I.P., Austin, N.B., 2004.
Treatment-emergent mania in pediatric bipolar disorder: a
retrospective case review. J. Affect. Disord. 82, 149–158.
Fawcett, J., Busch, K.A., Jacobs, D., Kravitz, H.M., Fogg, L., 1997.
Suicide: a four-pathway clinical–biochemical model. Ann. N. Y.
Acad. Sci. 836, 288–301.
Fergusson, D., Doucette, S., Glass, K.C., Shapiro, S., Healy, D.,
Hebert, P., Hutton, B., 2005. Association between suicide attempts
and selective serotonin reuptake inhibitors: systematic review of
randomised controlled trials. BMJ 330, 396–402.
Furukawa, T.A., Strener, D.L., Young, L.T., 2001. Is antidepressant–
benzodiazepine combination therapy clinically more useful? A
meta-analytic study. J. Affect. Disord. 65, 173–177.
Ghaemi, S.N., Ko, J.Y., Goodwin, F.K., 2002. “Cade's Disease” and
beyond: Misdiagnosis, antidepressant use, and proposed definition
for bipolar spectrum disorder. Can. J. Psychiatry 47, 125–134.
Golomb, B.A., Kane, T., Dimsdale, J.E., 2004. Severe irritability
Goodwin, F.K., Jamison, K.R., 1990. Manic–Depressive Illness.
Oxford University Press, New York.
Grunebaum, M.F., Ellis, S.P., Li, S., Oquendo, M.A., Mann, J.J., 2004.
Antidepressants and suicide risk in the United States, 1985–1999.
J. Clin. Psychiatry 65, 1456–1462.
Hall, W.D., Mant, A., Mitchell, P.B., Rendle, V.A., Hickie, I.B.,
McManus, P., 2003. Association between antidepressant prescrib-
ing and suicide in Australia, 1991–2000: trend analysis. BMJ 326,
Hammad, T.A., Laughren, T., Racoosin, J., 2006. Suicidality in
pediatric patients treated with antidepressant drugs. Arch. Gen.
Psychiatry 63, 332–339.
Haykal, R., Akiskal, H.S., 1999. The long-term outcome of dysthymia
in private practice: clinical features, temperament, and the art of
management. J Clin. Psychiatry 60, 508–518.
Healy, D., 2003. Lines of evidence on the risk of suicide with selective
serotonine reuptake inhibitors. Psychother. Psychosom. 72, 71–79.
Helgason, T., Tómasson, H., Zoéga, T., 2004. Antidepressants and
public health in Iceland. Time series analysis of national data. Br. J.
Psychiatry 184, 157–162.
Isacsson, G., 2000. Suicide prevention—a medical breakthrough?
Acta Psychiatr. Scand. 102, 113–117.
Isacsson, G., Holmgren, P., Ahlner, J., 2005. Selective serotonin
reuptake inhibitor antidepressants and the risk of suicide: a
controlled forensic data based study of 14857 suicides. Acta
Psychiatr. Scand. 111, 286–290.
11Z. Rihmer, H. Akiskal / Journal of Affective Disorders 94 (2006) 3–13
in bipolar disorder in Finland. Am. J. Psychiatry 151, 1020–1024.
Kahn, A., Warner, H.A., Brown, W.A., 2000. Symptom reduction and
suicide risk in patients treated with placebo in antidepressant
clinical trials. An analysis of the Food and Drug Administration
Database. Arch. Gen. Psychiatry 57, 311–317.
Kahn, A., Kahn, S.R., Leventhal, R.M., Brown, W.A., 2001. Symptom
reduction and suicide risk in patients treated with placebo in anti-
depressant clinical trials: a replication analysis of the Food and Drug
Administration Database. Int. J. Neuropsychopharmacol. 4, 113–118.
Kahn, A., Kahn, S., Kolts, R., Brown, W.A., 2003. Suicide rates in
clinicaltrials of SSRIs,other antidepressants,andplacebo:analysis
of FDA reports. Am. J. Psychiatry 160, 790–792.
Kallner, G., Lindelius, R., Petterson, U.J., Stockman, O., Tham, A.,
2000. Mortality in 497 patients with affective disorders attending a
lithium clinic or after having left it. Pharmacopsychiatry 33, 8–13.
Kelly, C.B., Ansari, T., Rafferty, T., Stevenson, M., 2003. Antide-
pressant prescribing and suicide rate in Northern Ireland. Eur.
Psychiatr. 18, 325–328.
Kessler, R.C., 1999. Comorbidity of unipolar and bipolar depression
with other psychiatric disorders in a general population survey. In:
Tohen, M. (Ed.), Comorbidity in Affective Disorders. Marcel
Dekker, New York, pp. 1–25.
Kessler, R.C., Berglund, P., Borges, B., Nock, M., Want, P.S., 2005.
Trends in suicide ideation, plans, gestures, and attempts in the
United States, 1990–1992 to 2001–2003. JAMA 293, 2487–2495.
Khuri, R., Akiskal, H.S., 1983. Suicide prevention: the necessity of
treating contributory psychiatric disorders. Psychiatr. Clin. North
Am. 6, 193–207.
Kim, Y.-K., Lee, H.-J., Kim, J.-Y., Yoon, D.-K., Choi, S.-H., Lee, M.-S.,
2002. Low serum cholesterol is correlated to suicidality in a Korean
sample. Acta Psychiatr. Scand. 105, 141–148.
Koukopoulos, A., Koukopoulos, A., 1999. Agitated depression as a
mixed state and the problem of melancholia. Psychiatr. Clin. North
Am. 22, 547–564.
Koukopoulos, A., Faedda, G., Proietti, R., D'Amico, S., de Pisa, E.,
Simonetto, C., 1992. Mixed depressive syndrome. Encephale 18,
Kujawa, M.J., Nemeroff, C.B., 2000. The biology of bipolar disorder.
Bipolar Disorders—100 Years after Manic–Depressive Insanity.
Kluwer Academic Publishers, Dordrecht, pp. 281–314.
Coryell, W., Endicott, J., 1999. Prospective study of fluoxetine
treatment and suicidal behavior in affectively ill subjects. Am. J.
Psychiatry 156, 195–201.
Ludwig, J., Marcotte, D.E., 2005. Anti-depressants, suicide, and drug
regulation. J. Policy Anal. Manage. 24, 249–272.
Luoma, J.B., Martin, C.E., Pearson, J.I., 2002. Contact with mental
health and primary care providers before suicide: a review of the
evidence. Am. J. Psychiatry 159, 909–916.
Maj, M., Pirozzi, R., Magliano, L., Bartoli, L., 2003. Agitated de-
pression in bipolar I disorder: prevalence, phenomenology, and
outcome. Am. J. Psychiatry 160, 2134–2140.
Goodwin, F.K.,Leon,A.C.,Meltzer, H.Y.,Ryan,N.D.,Shaffer,D.,
behavior in youth. Neuropsychopharmacology 31, 473–492.
March, J., Silva, S., Petrycki, s., Curry, J., Wells, K., Fairbank, J., Burns,
B., Domino, M., McNulty, S., Vitiello, B., Severe, J., 2004. Fluoxe-
tine, cognitive–behavioral therapy, and their combination for ado-
lescents with depression: treatment for Adolescents with Depression
Study (TADS) randomized cantrolled trial. JAMA 292, 807–820.
Maser, J.D., Akiskal, H.S., Zeller, P., Scheftner, W., Mueller, T.,
Endicott, J., Solomon, D., Clayton, P., 2002. Can temperament
identify affectively ill patients who engage in lethal or near-lethal
suicidal behavior? A 14-year prospective study. Suicide Life-
Threat. Behav. 32, 10–32.
Montgomery, S.A., Dunner, D.L., Dunbar, G.C., 1995. Reduction of
suicidal thoughts with paroxetine in comparison with reference
Nutt, D.J., 1999. Care of depressed patients with anxiety symptoms.
J. Clin. Psychiatry 60, 23–27.
O'Leary, D., Paykel, E., Todd, C., Vardulaki, K., 2001. Suicide in
primary affective disorders revisited: a systematic review by
treatment era. J. Clin. Psychiatry 62, 804–811.
Olfson, M., Shaffer, D., Marcus, S.C., Greenberg, T., 2003.
Relationship between antidepressant medication treatment and
suicide in adolescents. Arch. Gen. Psychiatry 60, 978–982.
Podrid, P.J., 1999. Proarrhythmia, a serious complication of antiar-
rhythmic drugs. Curr. Cardiol. Rep. 1, 289–296.
Rihmer, Z., 2001. Can better recognition and treatment of depression
reduce suicide rates ? A brief review. Eur. Psychiatr. 16, 406–409.
Rihmer, Z., 2004. Decreasing national suicide rates—Fact or fiction?
World J. Biol. Psychiatry 5, 55–56.
Rihmer, Z., Kiss, K., 2002. Bipolar disorders and suicidal behaviour.
Bipolar Disord. 4 (Suppl. 1), 21–25.
Rihmer,Z., Barsi,J., Arató,M., Demeter,E., 1990.Suicideinsubtypes
of primary major depression. J. Affect. Disord. 18, 221–225.
Rihmer, Z., Rutz, W., Pihlgren, H., 1995. Depression and suicide on
Gotland. An intensive study of all suicides before and after a
depression-training programme for general practitioners. J. Affect.
Disord. 35, 147–152.
Rihmer, Z., Szádóczky, E., Füredi, J., Kiss, K., Papp, Z., 2001.
Anxiety disorders comorbidity in bipolar I, bipolar II and unipolar
major depression: results from a population-based study in
Hungary. J. Affect. Disord. 67, 175–179.
Rosack, J., 2005. New data show declines in antidepressant
prescribing. Psychiatry News 40, 1 [source NCD Health, 2005].
Rutz, W., von Knorring, L., Walinder, J., 1989. Frequency of suicide
on Gotland after systematic postgraduate education of general
practitioners. Acta Psychiatr. Scand. 80, 151–154.
Rutz, W., Walinder, J., von Knorring, L., Rihmer, Z., Pihlgren, H.,
1997. Prevention of depression and suicide by education and
medication: impact on male suicidality. An update from the
Gotland study. Int. J. Psychiatry Clin. Pract. 1, 39–46.
Rouillon, F., Serrurier, D., Miller, H.D., Gerard, M.-J., 1991. Pro-
phylactic efficacy of maprotiline on unipolar depression relapse.
J. Clin. Psychiatry 52, 423–431.
Sato, T., Bottlender, R., Schroter, A., Moller, H.-J., 2003. Frequency of
mixed state’ as bipolar spectrum. Acta Psychiatr. Scand. 107,
Sharma, V., Khan, M., Smith, A., 2005. A closer look at treatment
Shi, L., Thiebaud, P., McCombs, J.S., 2004. The impact of unrecog-
nized bipolar disorders for patients treated for depression with
antidepressants in the fee-for-services California Medicaid (Medi-
Cal) program. J. Affect. Disord. 82, 373–383.
Simon, G.E., Savarino, J., Operskalski, B., Wang, P.S., 2006. Suicide
risk during antidepressant treatment. Am. J. Psychiatry 163,
Network, 2002. Is extended clonazepam cotherapy of fluoxetine
12Z. Rihmer, H. Akiskal / Journal of Affective Disorders 94 (2006) 3–13
Tondo, L., Baldessarini, R.J., Hennen, J., Floris, G., Silvetti, F., Tohen,
M., 1998. Lithium treatment and risk of suicidal behavior in
bipolar disorder patients. J. Clin. Psychiatry 59, 405–414.
Viner, M.W., Chen, Y., Bakshi, I., Kamper, P., 2003. Low-dose
risperidone augmentation of antidepressants in nonpsychotic
depressive disorders with suicidal ideation. J. Clin. Psychophar-
macol. 23, 104–106.
Warshaw, M.G., Keller, M., 1996. The relationship between fluoxetine
use and suicidal behavior in 654 subjects with anxiety disorders.
Am. J. Psychiatry 57, 158–166.
Whittington, C.J., Kendall, T., Fonagy, P., Cottrell, D., Cotgrove, A.,
Boddington, E., 2004. Selective serotonin reuptake inhibitors in
childhood depression: systematic review of published versus
unpublished data. The Lancet 363, 1341–1345.
Wilens, T.E., Biederman, J., Kwon, A., Chase, R., Greenberg, L.,
Mick, E., Spencer, T.J., 2003. A systematic chart review of the
nature of psychiatric adverse effects in children and adolescents
treated with selective serotonin reuptake inhibitors. J. Child
Adolesc. Psychopharmacol. 13, 143–152.
Yerevanian, B.I., Koek, R.J., Mintz, J., 2003. Lithium, anticonvulsants
and suicidal behavior in bipolar disorder. J. Affect. Disord. 73,
Yerevanian, B.I.,Koek,R.J.,Feusner, J.D.,Hwang,S.,Mintz,J., 2004.
Antidepressants and suicidal behaviour in unipolar depression.
Acta Psychiatr. Scand. 110, 452–458.
13 Z. Rihmer, H. Akiskal / Journal of Affective Disorders 94 (2006) 3–13