Use of Atypical Antipsychotics

for Treatment-Resistant
Major Depressive Disorder
George I. Papakostas, MD, and Richard C. Shelton, MD

Corresponding author
George I. Papakostas, MD
Department of Psychiatry, Massachusetts General Hospital,
Harvard Medical School, 15 Parkman Street, WACC #812,
Boston, MA 02114, USA.
E-mail: gpapakostas@partners.org
Current Psychiatry Reports 2008, 10:481–486
Current Medicine Group LLC ISSN 1523-3812
Copyright © 2008 by Current Medicine Group LLC
Despite the progressive increase in the number of
pharmacologic agents with potential antidepressant
activity, many patients suffering from major depressive
disorder (MDD) continue to be symptomatic. Clearly,
an urgent need exists to develop safer, better tolerated,
and more effective treatments for MDD. Use of atypical
antipsychotic agents as adjunctive treatment for treat-
ment-resistant MDD (TRD) represents one such effort
toward novel pharmacotherapy development. Atypical
antipsychotic agents have been hypothesized to be
beneficial in treating mood disorders, including TRD, as
a result of their complex mechanisms of action. After an
initial series of positive case reports, series, and small
clinical trials, subsequent larger-scale projects have
yielded conflicting results. However, more recently,
larger-scale clinical trials have supported the effective-
ness of at least some of these medications. This review
summarizes the existing data regarding the effectiveness
of these medications in treating TRD, including bio-
chemical rationale and clinical data.
Introduction
Despite the progressive increase in the number of available
antidepressants, many patients suffering from depression
continue to be symptomatic. For example, in the fi rst
level of the Sequenced Treatment Alternatives to Relieve
Depression (STAR*D) study, only about 30% of patients
had achieved remission of their depressive episode after
up to 12 weeks of therapy with citalopram [1]. Moreover,
it was recently reported that as many as half of all patients
enrolled in two academic-based depression specialty clin-
ics did not achieve remission despite receiving a series of
adequate trials of antidepressant therapies [2]. To compli-
cate matters further, residual symptoms among remitters
are common and associated with poorer psychosocial
functioning [3] and increased relapse rates [4]. Yet little
consensus exists among psychiatrists regarding optimiz-
ing treatment for patients with incomplete response.
Generally, management of treatment-resistant major
depressive disorder (TRD) can involve pharmacologic and
nonpharmacologic interventions, such as the use of cog-
nitive-behavioral psychotherapy [5••], electroconvulsive
therapy [6], vagus nerve stimulation [7], and transcranial
magnetic stimulation [8]. Pharmacologic interventions
can involve increasing the dose of an antidepressant [9],
switching to a second antidepressant [10–13], or using
adjunctive pharmacotherapeutic strategies. When a sec-
ond antidepressant is added to an existing antidepressant,
this is termed combination pharmacotherapy. When
a nonantidepressant agent is added, this is termed aug-
mentation treatment. Combination strategies can involve
adding bupropion [14], mirtazapine [13,15], and tricyclic
antidepressants [9,16] to an antidepressant treatment
regimen. Augmentation strategies can involve adding
lithium [9,17,18], triiodothyronine [18], buspirone [14],
pindolol [19], omega-3 fatty acids [20], dopaminergic
agents [21,22], folates, or S-adenosyl methionine [23,24]
to an antidepressant treatment regimen. Nevertheless, as
described previously, despite the broad armamentarium
available to clinicians for managing TRD, many patients
remain symptomatic despite several adequate pharmaco-
logic and nonpharmacologic trials. Clearly, there is an
urgent need to develop safer, better tolerated, and more
effective treatments for major depressive disorder. Using
atypical antipsychotic agents as adjunctive treatment for
TRD represents one such effort toward novel pharmaco-
therapy development.
Mechanisms of Action
Atypical antipsychotics are a heterogeneous group, each
with a distinct and complex set of receptor affi nities
involving dopaminergic and serotoninergic receptors and
482 Mood Disorders
various effects on noradrenergic, histaminergic, and cho-
linergic systems. As a result, the receptor-binding profi le
of the atypical neuroleptics differs substantially from
that of other typical agents. This difference may provide
clinical advantages to the atypical antipsychotic agents in
therapeutic areas other than in schizophrenia.
Specifically, similar to the typical antipsychotic agents,
atypical antipsychotics act as dopamine-2 (D2)–receptor
antagonists [25]. However, unlike typical antipsychotic
agents, atypical antipsychotics, including olanzapine;
quetiapine; risperidone; ziprasidone [25]; and, to a
much lesser extent, aripiprazole [26], act as serotonin-2
(5-HT2)–receptor antagonists. Ziprasidone [25] and
aripiprazole [26] also act as serotonin-1A (5-HT1A)–recep-
tor agonists, whereas ziprasidone and risperidone [25]
act as serotonin-1D (5-HT1D) agonists. Antagonism of
5-HT1D, a presynaptic autoreceptor inhibiting serotonin
release, indicates potential efficacy in major depression
[27], whereas selective 5-HT1A–receptor partial agonists,
such as gepirone [28], have shown antidepressant effects
in clinical trials. Similarly, 5-HT2 –receptor antagonists,
such as trazodone [29] and nefazodone [30], also have
shown antidepressant effects.
Aripiprazole and ziprasidone have other unique
neurochemical properties that distinguish them from
the other atypicals. Aripiprazole is a potent dopamine
D2-receptor partial agonist, blocking D2 receptors under
hyperdopaminergic conditions while acting as a D2
agonist under hypodopaminergic conditions [31–35].
Ziprasidone has been shown to inhibit the neuronal
uptake of 5-HT and norepinephrine in a way comparable
to the antidepressant imipramine [36].
Clinical Effects of Atypical Antipsychotics in
Treatment-Resistant Depression
The neurochemical effects described previously led to the
testing, initially, of atypical antipsychotics for cognitive
and mood symptoms associated with schizophrenia. This
subsequently led to the evaluation of atypicals for mood
symptoms in TRD and bipolar depression. This section
reviews the data supporting effects of these drugs individ-
ually and focuses primarily on controlled clinical trials.
Olanzapine
The fi rst controlled test of the effects of an atypical in
TRD was a small study with olanzapine that compared
the effects of olanzapine alone (ie, olanzapine + placebo),
olanzapine plus fluoxetine, and fluoxetine alone in treat-
ing TRD [37]. All participants had previously failed
adequate trials of a selective serotonin reuptake inhibitor
(SSRI) and a non-SSRI antidepressant, as well as a pro-
spective treatment period with fluoxetine alone (up to 60
mg/d). Nonresponders (n = 28) to this run-in treatment
then were randomly assigned to one of the three condi-
tions in a double-blind fashion. The average maximum
doses in the double-blind period were as follows: 12.5
mg/d for olanzapine alone; 52 mg/d for fluoxetine alone;
and 13.5 and 52 mg/d, respectively, for the olanzapine and
fluoxetine combination. The continuation of fluoxetine
for this period yielded essentially no further improve-
ment. Olanzapine administered alone achieved a modest
benefit over fluoxetine, whereas the olanzapine plus fluox-
etine combination resulted in robust and significantly
greater improvement in depressive symptoms than either
monotherapy. Remission, defi ned as a 17-item Hamilton
Depression Rating Scale (HAM-D) score of 7 or less,
was achieved in 60% of patients receiving the combina-
tion, 25% receiving olanzapine alone, and 20% receiving
fluoxetine alone.
Two large-scale clinical trials testing the effects of the
olanzapine plus fluoxetine combination were undertaken
next. In the fi rst, 500 patients were prospectively treated
with nortriptyline; responders were excluded, leading into
the double-blind phase [38]. Patients then were randomly
assigned to one of four treatment groups for 8 weeks:
olanzapine plus placebo, fluoxetine plus placebo, a com-
bination of olanzapine plus fluoxetine, or a continuation
of nortriptyline. Olanzapine was dosed in groups at 6 to
12 mg/d and fluoxetine at 25 to 50 mg/d. The combina-
tion of olanzapine and fluoxetine produced a rapid effect
relative to the other groups. However, the groups did not
differ at end point. Several design and execution factors
may have affected these results. Patients had failed only
one adequate trial of an SSRI before entry. The doses of
olanzapine and fluoxetine were lower than in the previous
study (mean maximal dose of olanzapine, 8.5 mg/d; mean
maximal dose for fluoxetine, 36.5 mg/d). Furthermore, the
use of nortriptyline may have been problematic. Although
the mean dose in the initial phase was respectable (104.6
mg/d), many patients achieve their maximum dose rela-
tively late in phase 1. Given the delay until maximum
response to antidepressant treatment, the response to the
dose achieved before phase 2 may have been experienced
after the start of this period. A second study [39] using
venlafaxine as a comparator suffered from many of the
same design problems and is not reviewed in detail here.
Despite these discouraging results, two subsequent
large-scale trials undertaken [40] were of similar design
to the original study by Shelton et al. [37]. In each,
patients with a single drug failure were treated prospec-
tively with fluoxetine. Those who did not respond were
randomly assigned to continuation fluoxetine (+ placebo),
olanzapine (+ placebo), or the olanzapine and fluoxetine
combination. In one (n = 638), combined olanzapine/fluox-
etine produced no greater effect than either monotherapy.
However, the fluoxetine monotherapy condition produced
a robust effect by study’s end, indicating another failed
trial. However, the second project (n = 675) confi rmed the
more robust effect of combined olanzapine/fluoxetine in
treatment-resistant unipolar major depression compared
 Atypical Antipsychotics for Treatment-Resistant Major Depressive Disorder Papakostas and Shelton
with olanzapine or fluoxetine monotherapy. The pooled
analysis of both studies also showed a significantly supe-
rior effect of the combination. Meanwhile, a successful
trial of the combination was tested in bipolar I depression
(non–treatment-resistant), leading to US Food and Drug
Administration (FDA) approval for this indication [41].
Risperidone
The fi rst published report of the effectiveness of an atypi-
cal antipsychotic in TRD was with risperidone [42]. In
this case series, eight patients who failed to respond to
an adequate trial of an SSRI were given risperidone in
an open fashion, and all experienced a rapid and robust
effect. However, there were no controlled clinical trial
data with risperidone in TRD until recently. In one study
[43], 489 patients with one to three prior documented
failures were treated prospectively with citalopram, 20
to 60 mg/d. Those who experienced greater than 50%
improvement were excluded. The remainder (n = 390)
were given 4 to 6 weeks of open-label risperidone, 0.25 to
2.0 mg/d, in combination with citalopram. Patients with
17-item HAM-D scores of 7 or less or a Clinical Global
Impression Severity Scale score of 2 or less (ie, “much
improved” or “very much improved”) were randomized to
risperidone or placebo augmentation (n = 243 remitters,
241 randomized). The primary end point, time to relapse,
did not differ between groups. The median time to relapse
was 102 days for risperidone plus citalopram and 85 days
for placebo plus citalopram. Relapse rates were 53.3%
with the combination and 54.6% with continuation of
citalopram alone. These data indicate that continuation
of risperidone plus citalopram was no more effective for
preventing relapse than citalopram alone.
In a second controlled trial [44], 463 depressed patients
were treated with an optimized trial of an antidepressant.
The 274 patients who did not respond were randomized
to receive risperidone, 1 to 2 mg/d, or placebo combined
with the initial antidepressant for 6 weeks. Mean HAM-D
scores dropped from 24.2 to 15.2 in the risperidone group
and from 24.6 to 17.5 in the placebo group, a statistically
significant difference.
In a third controlled trial, Keitner et al. [45] studied 97
outpatients who met the DSM-IV criteria for a unipolar,
nonpsychotic major depressive episode and failed to respond
or only partially responded to at least a 5-week trial of an
adequate dose of antidepressant monotherapy. Patients were
randomized to receive adjunctive risperidone or placebo for
a total of 4 weeks of treatment. The odds of remitting were
significantly better for patients treated with adjunctive ris-
peridone than placebo (52% vs 24%, respectively).
Quetiapine
Quetiapine has received FDA approval for treating bipo-
lar depression as monotherapy. However, there are now
483
three controlled trials in unipolar TRD. One study (n =
40) evaluated the effects of quetiapine for SSRI/(SNRI)
partial response [46]. In this 8-week, double-blind, pla-
cebo-controlled study, patients were randomized (2:1
ratio) to receive quetiapine, 200 to 400 mg/d, or placebo
along with their previous SSRI/serotonin–norepinephrine
reuptake inhibitor (SNRI). Twenty-one of 26 quetiapine-
treated patients (80.8%) completed the study, compared
with 11 of 14 (78.6%) in the placebo group. At the end
of 8 weeks, the quetiapine group had significantly lower
17-item HAM-D scores than the placebo group (8.3 vs
14.7) plus higher response (67% vs 27%) and remission
rates (43% vs 15%).
In a separate study, McIntyre et al. [47] studied 58
patients who did not experience sufficient symptom
improvement after adequate treatment with an SSRI or
venlafaxine. Patients were randomized in double-blind
fashion to receive adjunctive treatment with quetiapine
or placebo for 8 weeks. Eighteen of 29 quetiapine-treated
and 16 of 29 placebo-treated patients completed the study.
A greater resolution of depressive symptoms was reported
among patients treated with adjunctive quetiapine than
placebo (mean difference in the reduction in HAM-D
scores during treatment was 5.7 points in favor of que-
tiapine, P < 0.01).
Finally, in a third trial, Khullar et al. [48] studied 15
outpatients with TRD (to SSRIs or SNRIs) who under-
went augmentation with quetiapine or placebo for 8
weeks. Quetiapine was more effective in reducing depres-
sive symptoms than placebo, as 37% of patients remitted
after adjunctive treatment with quetiapine, whereas none
remitted after treatment with placebo. Additional larger-
scale studies of quetiapine therapy for TRD recently have
been completed by the manufacturer, although results are
not yet available in the published literature.
Ziprasidone
An initial open trial supported the effects of ziprasidone
in TRD. In this study, 20 patients who had an incomplete
response to a trial of an SSRI were treated with ziprasi-
done in an open fashion [49]. Thirteen (65%) completed
the trial; of this group, eight (61.5%) were responders, as
defi ned by a 50% improvement in 17-item HAM-D score.
Of all the patients randomized, 10 were responders (50%),
and 5 remitted (25%).
In a second randomized, open trial, adult outpatients
who had not responded to a prior trial with an antide-
pressant were treated prospectively with sertraline, 100 to
200 mg/d, for 6 weeks [50]. Those who failed to achieve a
30% or greater change in Montgomery-Asberg Depression
Rating Scale score were randomly assigned to continua-
tion with sertraline; sertraline plus ziprasidone, 80 mg/d
(mean dose, 78 mg/d); or sertraline plus ziprasidone, 160
mg/d (mean dose, 129.9 mg/d) for 8 weeks. The mean
change from baseline was greater in the two ziprasidone
484 Mood Disorders
Figure 1. Aripiprazole augmentation for antidepressant-resistant
major depressive disorder: results of two identical randomized,
double-blind, phase 3 trials (P < 0.05, aripiprazole augmentation vs
antidepressant monotherapy for both trials).
augmentation groups (80 mg/d: -5.98 points; 160 mg/d:
-8.27 points) than in the sertraline monotherapy group
(-4.45 points), although this did not achieve statistical
significance. Respective response rates were 19%, 32%,
and 10%, and remission rates were 5%, 21%, and 5%.
Although these results suggest possible benefit, they did
not conclusively support ziprasidone augmentation.
Aripiprazole
Until recently, aripiprazole had received relatively little
attention in this area. In one open-label trial, 12 patients
who had failed to respond sufficiently to an adequate
trial of an SSRI were treated with adjunctive aripipra-
zole in an open fashion for 8 weeks [51]. Nine patients
(75%) patients completed the trial; five (55.6%) achieved
response (mean change in HAM-D score > 50%), whereas
seven of the total group (58.3%) responded.
More recently, results of two positive, double-blind,
placebo-controlled trials investigating the use of adjunc-
tive aripiprazole in major depressive disorder were
published. In the fi rst such study, Berman and colleagues
[52••] focused on the use of aripiprazole augmentation
for patients resistant to up to three “retrospective” (his-
torical) antidepressant trials. To “confi rm” treatment
resistance, those patients underwent an 8-week, open-
label trial with an SSRI (fluoxetine, sertraline, paroxetine,
or escitalopram) or an SNRI (venlafaxine). The patients
who made insufficient symptom improvement had aripip-
razole or placebo added to their SSRI or SNRI regimen
under double-blind conditions for a total of 6 weeks. A
statistically significant difference in remission rates was
also observed, with 26% remission for aripiprazole, com-
pared with 15.7% remission for placebo (P < 0.05). This
study also reported relatively low rates of discontinuation
due to intolerance in the two treatment groups (2% for
aripiprazole, 1.7% for placebo; P > 0.05). The results of
a separate study of identical design also demonstrated
greater remission rates for adjunctive aripiprazole than
placebo-treated patients [53••]. The results of these
two trials led to FDA approval of a new indication for
aripiprazole as adjunctive treatment to antidepressants for
antidepressant-resistant major depressive disorder (Fig. 1).
This was the fi rst approval for an adjunctive treatment in
major depressive disorder and the fi rst FDA approval for
the use of any medication for TRD.
Conclusions
TRD is a common clinical occurrence, and its manage-
ment poses a formidable clinical challenge for clinicians
and patients alike. Despite several pharmacologic and non-
pharmacologic treatment options for TRD, many patients
remain symptomatic. Thus, there is an urgent need to
develop novel treatments for TRD. From the evidence
available to date, it appears that augmenting antidepres-
sants with atypical antipsychotics (specifically aripiprazole,
olanzapine, quetiapine, and risperidone) can be effective in
some patients, at least during the acute phase of treatment.
However, the long-term efficacy, tolerability, and safety of
this treatment are not yet understood. In particular, the
risk of metabolic (weight gain and hyperlipidemia or dys-
lipidemia), endocrine (hyperprolactinemia), cardiac (QTc
prolongation and arrhythmogenesis), and central nervous
system (akathisia, parkinsonism, tardive dyskinesia,
neuroleptic malignant syndrome) adverse events during
treatment with these agents in major depressive disorder
needs to be better quantified. Further research also is
required into how this compares with other augmentation
strategies and other strategies for addressing TRD.
Acknowledgments
This work was supported in part by National Institute of
Mental Health grant K24 MH01741 (to Dr. Shelton).
Disclosures
Dr. Papakostas has received research support from Bris-
tol-Myers Squibb, Forest Pharmaceuticals, the National
Institute of Mental Health, Pamlab, Pfi zer, and Precision
Human BioLaboratories; has served as a consultant for
Bristol-Myers Squibb, Eli Lilly and Company, Evotec,
GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Phar-
maceuticals, Pamlab, Pfi zer, Pierre Fabre Medicament,
Shire Pharmaceuticals, and Wyeth; has received hono-
raria from Bristol-Myers Squibb, Eli Lilly and Company,
Evotec, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz
Pharmaceuticals, H. Lundbeck A/S, Pamlab, Pfi zer, Pierre
Fabre Medicament, Shire Pharmaceuticals, Titan Phar-
maceuticals, and Wyeth; and has served on the speakers’
bureau for Bristol-Myers Squibb and Pfi zer.
 Atypical Antipsychotics for Treatment-Resistant Major Depressive Disorder Papakostas and Shelton
Dr. Shelton has received grant/research support
from Eli Lilly and Company, GlaxoSmithKline, Jans-
sen Pharmaceutica, Pfi zer, Sanofi-Aventis, Wyeth-Ayerst
Laboratories, AstraZeneca Pharmaceuticals, and Abbott
Laboratories; has served as a paid consultant for Pfi zer,
Janssen Pharmaceutica, and Sierra Neuropharmaceuticals;
and has served on the speakers’ bureau for Bristol-Myers
Squibb, Eli Lilly and Company, Janssen Pharmaceutica,
Pfi zer, GlaxoSmithKline, Wyeth-Ayerst Laboratories, and
Abbott Laboratories.
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