Antidepressant-associated chronic irritable dysphoria (ACID) in
Rif S. El-Mallakha,⁎, S. Nassir Ghaemib,c, Kemal Sagduyud, Michael E. Thased,
Stephen R. Wisniewskif, Andrew A. Nierenbergg, Hong Wei Zhangf,
Tamara A. Pardob, Gary Sachsb,c,f
for the STEP-BD Investigators
aMood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine,
501 East Broadway, MedCenter One, Suite 340, Louisville, Kentucky 40202, United States
bBipolar Disorder Research Program, Emory University, Atlanta, GA 30322, United States
cDepartment of Psychiatry, Harvard Medical School, Boston, MA, United States
dUniversity of Missouri, Kansas City, MO, and Mercer University, GA, United States
eDepartments of Psychiatry, University of Pennsylvania School of Medicine and Philadelphia Veterans Affairs Medical Center,
Philadelphia, PA and University of Pittsburgh Medical Center, Pittsburgh, PA, United States
fEpidemiology Data Center, University of Pittsburgh, Pittsburgh, PA, United States
gHarvard Bipolar Disorder Research Program, Massachusetts General Hospital, Boston, MA, United States
Received 10 January 2008; accepted 25 March 2008
Available online 20 June 2008
Background: It has been proposed that antidepressants can induce a chronic, dysphoric, irritable state in bipolar patients (called
ACID for antidepressant-associated chronic irritable dysphoria). This phenomenon has only been described in case series format,
and has not been prospectively validated.
Methods: Prospective data from the first 1500 patients (62.7% with bipolar I, 30.1% with bipolar II, and 7.2% with NOS) treated in
the STEP-BD database were examined and those who were euthymic for at least one month at study entry, subsequently developed
a depressive episode, and were then followed for one year were identified. Outcome of those who received an antidepressant for
this depressive episode (n=27) was compared to those who did not (n=56), with particular attention given to the presence of the
proposed symptom triad of ACID, namely dysphoria, irritability, and middle insomnia.
Results: Patients treated with antidepressants were ten times more likely to develop ACID than those who were not (Hazard
ratio=9.95, CI=1.103–89.717, P=0.04). However, the hazard ratio dropped to 1.05 (P=0.99) when corrected for significant
covariates, notably past antidepressant-related manic switch and sex.
Discussion: This study does not support the existence of ACID as an independent phenomenon. Rather, ACID appears to be part of
a broader spectrum of antidepressant treatment-emergent affective switches.
© 2008 Elsevier B.V. All rights reserved.
Keywords: ACID; Antidepressants; Bipolar; Depression; Dysphoria; STEP-BD
Journal of Affective Disorders 111 (2008) 372–377
E-mail address: firstname.lastname@example.org (R.S. El-Mallakh).
0165-0327/$ - see front matter © 2008 Elsevier B.V. All rights reserved.
Bipolar disorder is associated with episodes of mania/
hypomania and depression. However, whereas the manic
and hypomanic episodes define the illness, the depressive
episodes typically dominate the clinical course and, on
average, people with bipolar disorder spend between one
third to one half of their lives with depressive symptoms
(Ghaemi et al., 2000; Judd et al., 2002, 2003; Post et al.,
2003a,b). For example, in a prospective study of weekly
symptoms in 146 people with a history of mania (i.e.,
bipolar I disorder), only 15% of the time was spent in
mania/hypomania/cycling as compared to 32% of the time
spent with syndromal or subsyndromal depressive symp-
toms (Judd et al., 2002). A similar study of 86 people with
bipolar II disorder found that only 3% of the time was
time spent with depressive symptoms (Judd et al., 2003).
Subjectively, bipolar subjects are more likely to complain
of depression and are more commonly prescribed antide-
pressants than mood stabilizers (Ghaemi et al., 2000).
Moreover,severalgroups havefoundthatthe psychosocial
impairments and vocational disability associated with
bipolar disorder are much more closely linked to the
depressed pole of the illness than the manic or hypomanic
episode (Altshuler et al., 2006; Simon et al., 2004).
The role of antidepressants in the treatment of bipolar
illness continues to be defined. Interestingly, while
antidepressants added to a mood stabilizer do not appear
to be better than a mood stabilizer alone, antidepressant
monotherapy(Amsterdam 1998; Amsterdametal.,1990)
or cotherapy with an atypical antipsychotic (Tohen et al.,
2004) appear to be effective, suggesting that either mood
stabilizers maximize the antidepressant benefit, or they
have an interfering effect that renders antidepressants less
effective (El-Mallakh, 2007). Some authors interpret the
data as supporting the use of antidepressants in depressed
bipolar patients (Gijsman et al., 2004), but an increasing
number of randomized studies are failing to find anti-
depressants effective in bipolar depression (Sachs et al.,
2007; Post et al., 2003; Nemeroff et al., 2001) and most
experts arguing that antidepressants complicate matters
by induction of mania and rapid cycling (El-Mallakh and
Karippot2002; Ghaemi and Goodwin2005) withthe risk
appearing higher with multimodal antidepressants (Post
et al., 2006; Nemeroff et al., 2001).
Recently, El-Mallakh and Karippot (2005) described a
new potential complication of long-term antidepressant
treatment. In a case series of six patients on antidepressant
for an average of 9.7 years, a clinical picture of a chronic,
irritable, dysphoric state was noted (El-Mallakh and
that manifested specifically as middle insomnia (disturbed
sleep or multiple awakenings). None met full criteria for
either depression or (hypo)mania. Invariably, there was
significant social and occupational dysfunction. The
continuous nature of the dysphoria was clearly different
from the pre-antidepressant exposure course of episodic
depressions. All antidepressant classes were used by these
or atypical antipsychotic medication. Discontinuation of
antidepressant treatment, as the only intervention, was
associated with remission of most of these symptoms and
resolution of the dysfunction in all subjects. A sympto-
matic triad of dysphoria, irritability, and middle insomnia,
was common to all subjects and believed to be the core of
this syndrome. Because of the chronic nature of these
symptoms and their apparent relationship to antidepres-
sants, the phenomenon was labeled antidepressant-asso-
ciated chronic irritable dysphoria (ACID).
Due to the case series nature of that initial report, the
true nature of the relationship to antidepressant treatment
could not be fully elicited. Furthermore, the existence of
ACID as a true complication of antidepressant therapy
could not be confirmed in the original case series. To
examine this phenomenon, we studied subjects who
participated in the Systematic Treatment Enhancement
Program for Bipolar Disorder (STEP-BD) study. We
compared one-year outcome in depressed bipolar subjects
who received antidepressants with those who had never
been exposed to antidepressants. We found that ACID
appears to be associatedwithantidepressant treatment,but
1.1. Study overview
Data as were collected from participants in the STEP-
BD study. STEP-BD is a prospective, longitudinal,
naturalistic outcome multicenter study (10). Participants
andstatistics manual (DSM-IV) criteria for either bipolar I,
bipolar II, cyclothymia, bipolar NOS, or schizoaffective
disorder, manic or bipolar types. The diagnosis is made
after a Mini-International Neuropsychiatric Interview
(MINI) (11) and history and illness characteristics were
the first 1500 patients to enter STEP-BD.
92.6% were Caucasian (3.4% African–American, 1.1%
373 R.S. El-Mallakh et al. / Journal of Affective Disorders 111 (2008) 372–377
Asian–American, 0.4% Native American, and 2.8% as
40.6±SD 12.7 years and mean duration of bipolar illness
was 13.1±12.9 years. Seventy one percent were type I,
24% were type II, four were not otherwise specified, and
the remaining 1% were schizoaffective or cyclothymic.
The primary treating clinician used a Clinical Monitor-
the severity of selected symptoms, and assign as clinical
function score (GAF) during every visit. These visits
occurred as clinically indicated rather than a fixed
schedule. All treating psychiatrists had to be certified in
the use of the CMF and were periodically monitored to
first year, participants completed 9.34±SD 7.31 CMFs.
by ADE), subsequently developed a depression, and then
recovered, were evaluated for the study (as defined by
CMF). Excluding patients with ongoing depression was
necessary so that ACID could be reliably identified.
Similarly, all patients who switched to mania, hypomania,
or mixed states were excluded. Characteristics of the
excluded subjects were not recorded. This was not a
randomized, nor a controlledstudy. Treatmentreceived by
the participants was naturalistic, and patients who did not
receive an antidepressant may have received a non-
antidepressant treatment for their depression. While the
data were collected prospectively, the analysis is post hoc.
There were 83 patients who fulfilled criteria. These
were classified into two groups: those who used an
antidepressant during the depressive episode, and those
who were never exposed to an antidepressant through-
out the observation period of one year.
Outcome was evaluated over the time subsequent to
the resolution of the depressive episode. Individuals
who experienced significant irritability (N30% of the
time), significant dysphoria (N30% of the time), and a
significant reduction in sleep (b−1 on CMF scale), and
who were not either depressed, manic, hypomanic, or
mixed were defined as having an ACID-like state.
Comparisons of the baseline characteristics across the
groups were conducted by chi-square test for character
variables, and ANOVA for continuous variables. Survival
analysis to the time of developing ACID was performed.
of ACID with and without adjustment for the covariates
(covariates examined are listed in Table 1). This method
have developed ACID.
sample at study entry. Fifty-two (62.7%) had bipolar I, 25
(30.1%) had bipolar II, and the remaining 6 (7.2%) were
age of onset of illness was 19.8±SD 9.0 years of age.
Women were more likely to receive an antidepressant
(43.5%) than men (19.4%) (P=0.02). The average age of
the patients was 43.8±13.1 years.
proposed criteria ACID, as compared to only one (1.8%)
patient who did not receive an antidepressant. Fig. 1 is the
Kaplan–Meier survival curve to time of onset of ACID.
Patients receiving antidepressants developed ACID sig-
nificantly earlier than those not receiving antidepressants
Theoddsratio ofdevelopingACIDwhenreceiving an
antidepressant is 6.8 compared to 0.15 for those not
receiving an antidepressant. In terms of relative risk,
patients prescribed antidepressants were nearly 10 times
more likely to develop ACID than those who did not take
antidepressants (estimate hazard ratio 9.95, CI 1.103,
89.717; P=0.04). However, the maximum likelihood
dropped to 1.05 when the model included the significant
covariates (P=0.99). While the regression analysis
suggested that the risk for developing ACID was almost
entirely explained by a history of at least one antidepres-
sant-induced affective switch and female sex, this test is
Characteristics of the study population
Character variables (n) No
Female gender (46)a
Age at onset (years)
History of affective switch (27)a
Bipolar type I (52)
Bipolar type II (25)
History of suicide attempt (30)
Lifetime substance Dep/abuse (36)
Current substance Dep/abuse (4)
History psychosis (28)
Rapid cycling previous year (7)
aOnly female gender and history of affective switch are statistically
related to ACID (P=0.02 and 0.005, respectively).
374 R.S. El-Mallakh et al. / Journal of Affective Disorders 111 (2008) 372–377
(Peduzzi et al., 1995). Viewed differently, the fraction of
patients who did not develop ACID after receiving an
antidepressant (85.2%) is significantly less that those
who did not develop ACID without an antidepressant
(98.2%, z=2.01, Pb0.05 utilizing a test for proportional
data [El-Mallakh et al., 1994]).
The current study observed that about one in eight
patients with bipolar depression will develop a chronic
irritable dysphoric state after beginning antidepressant
antidepressants for an acute depressive episode (i.e.,
14.8% of the antidepressant-treated patients versus 1.8%
of those not receiving antidepressants), it was also true
that approximately 85% of the patients treated with
antidepressants did not develop a chronic irritable
The risk of developing ACID was almost entirely
related to a previous history of antidepressant-induced
affective switch and female gender. Without these
predisposing factors, there is no increase in the risk of
developing ACID. It appears that other factors such as
prior sensitization to the destabilizing effect of antide-
and Whiteside, 2003).
ACID has been independently described by different
investigators a generation apart (Akiskal et al., 1977; El-
Mallakh and Karippot 2005). The original description in
1977 (Akiskal et al., 1977) was in first degree relatives of
patients. ACID may explain why long-term antidepres-
sant treatment is associated with more depressed days
than avoidance of antidepressants (Bauer et al., 2005).
ACID is a syndrome that has been previously defined as
occurring in either type I or type II bipolar patients after
prolonged antidepressant exposure. It manifests with the
triad of irritability, dysphoria, and middle insomnia (El-
Mallakh and Karippot, 2005). Almost always, it is
associated with social or occupational dysfunction. The
chronic natureofthese symptomsdistinguish ACIDfrom
the more episodic major depressive or mixed manic
syndromes. Marked improvement in function and the
ACID symptoms is seen with antidepressant discontinua-
tion (El-Mallakh and Karippot 2005).
It is important to note that the current study was not
designed to capture ACID symptomology. ACID symp-
toms were gleaned from the CMF data entered by the
STEP-BD investigators. Furthermore, the original case
series of ACID patients described an average duration of
antidepressant treatment of 6.6 years (range 3–7 years)
(El-Mallakh and Karippot 2005), in the current study
we evaluated ACID symptoms after only one year of
antidepressant treatment. The small sample, and the small
of a biased regression coefficient (Peduzzi et al., 1995),
thereby precluding sweeping conclusions regarding the
effect of antidepressant treatment on the development of
chronic irritable dysphoria. Stated simply, while the Cox
proportional hazards model appears to be accurate, the
analysis of confounding covariates is not reliable.
Additionally, it is not likely that past antidepressant-
associated mood switch and female gender are simply
confounding factors which negate the validity of ACID
as a phenomenon. Rather re-exposure to antidepressants
seems relevant with effect modification perhaps mainly
in those with past antidepressant exposure (often
females) and manic responses to them.
Depression in bipolar illness is a very important
syndrome. It occupies a large fraction of the patients'
lives and is related to significant morbidity and mortality.
Yet these are very few studies examining its treatment
directly. Efficacy and safety of antidepressant treatment,
particularly long-term treatment, in bipolar patients needs
Role of funding source
Funding for this project was provided by a grant and a contract
from the NIMH. For the STEP-BDcontract NIMH had input regarding
safety issues in study design. NIMH did not dictate the design of data
collection, management, or analysis.
Fig. 1. Kaplan–Meier survival curve to time of onset of ACID. bTop line=no antidepressant treatment, bottom line=with antidepressant treatment.
375 R.S. El-Mallakh et al. / Journal of Affective Disorders 111 (2008) 372–377
Conflict of interest
No conflict declared.
This project has been funded in whole or in part with
Federal funds from the National Institute of MentalHealth
(NIMH), National Institutes of Health, under Contract
N01MH80001. Also supported, in part, by NIMH
Research Career Award (MH-64189) (SNG). Any opi-
nions, findings, and conclusions or recommendations
not necessarily reflect the views of the NIMH. This article
was approved by the publication committee of the
Systematic Treatment Enhancement Program for Bipolar
for STEP-BD are:
Gary S. Sachs, M.D. (PI), Michael E. Thase M.D.
STEP-BD Clinical Coordinating Center
Gary S. Sachs, M.D.; Leslie Leahy, Ph.D.⁎; Jane N.
Kogan, Ph.D.; Ellen B. Dennehy, Ph.D.; Jennifer A.
Conley, M.A.; Jaimie L. Gradus B.A.; Stephen M. Gray
B.A.; Jacqueline Flowers, B.A.; Mandy Graves, B.A.
STEP-BD Data Coordinating Center
Stephen Wisniewski, Ph.D.
STEP-BD Site Principal Investigators and Co-
Lauren B. Marangell, M.D. and James M. Martinez,
M.D. at Baylor College of Medicine; Joseph R.
Calabrese, M.D. and Melvin D. Shelton, M.D. at Case
Western Reserve University; Michael W. Otto, Ph.D.⁎/
Massachusetts General Hospital and Harvard Medical
School; R. Bruce Lydiard, M.D. at the Medical
University of South Carolina⁎; Joseph F. Goldberg,
M.D. at New York Presbyterian Hospital and Weill
M.D. and Joshua Cohen, DO at New York University
School of Medicine; John Zajecka, M.D. at Rush —
Presbyterian St. Luke's Medical Center⁎; Terence A.
Ketter, M.D. and Po W. Wang, M.D. at Stanford
University School of Medicine; Uriel Halbreich, M.D. at
State University of New York at Buffalo⁎; Alan Gelen-
berg, M.D. at University of Arizona⁎; Mark Rapaport,
M.D. at University of California, San Diego⁎; Marshall
Thomas, M.D., Michael H. Allen, M.D., and David J.
Miklowitz, Ph.D at University of Colorado Health
Sciences Center; Rif S. El-Mallakh, M.D. at University
ofLouisville School ofMedicine; Jayendra Patel, M.D. at
University of Massachusetts Medical Center;⁎Kemal
Sagduyu, M.D. at University of Missouri — Kansas City,
School of Medicine. Western Missouri Mental Health
at University of Oklahoma College of Medicine; Laszlo
of Pennsylvania Medical Center; Michael E. Thase, M.D.
Western Psychiatric Institute and Clinic; Peter Hauser,
M.D. at Portland VA Medical Center; and Charles L.
of Texas Health Science Center at San Antonio.
STEP-BD Executive Committee
Mark S. Bauer, M.D., Charles L. Bowden, M.D.,
M.D., Ellen Frank, Ph.D., Terence A. Ketter, M.D., Jane
N. Kogan, Ph.D., David Kupfer, M.D., Leslie Leahy,
Ph.D., Michael W. Otto, Ph.D., Jerrold, F. Rosenbaum,
M.D., Matthew V.Rudorfer,M.D., GaryS.Sachs, M.D.,
Linda Street, Ph.D., Michael E. Thase, M.D., Sean Ward
and Stephen Wisniewski, Ph.D.
NIMH Liaisons to STEP-BD
Matthew V. Rudorfer, M.D., Joanne Severe, MS,
Linda Street, Ph.D.
⁎No longer participating in this role in STEP-BD.
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