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Use of Atypical Antipsychotics

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

Corresponding author ics did not achieve remission despite receiving a series of
George I. Papakostas, MD
Department of Psychiatry, Massachusetts General Hospital, adequate trials of antidepressant therapies [2]. To compli-
Harvard Medical School, 15 Parkman Street, WACC #812, cate matters further, residual symptoms among remitters
Boston, MA 02114, USA. are common and associated with poorer psychosocial
E-mail: functioning [3] and increased relapse rates [4]. Yet little
Current Psychiatry Reports 2008, 10:481–486 consensus exists among psychiatrists regarding optimiz-
Current Medicine Group LLC ISSN 1523-3812 ing treatment for patients with incomplete response.
Copyright © 2008 by Current Medicine Group LLC
Generally, management of treatment-resistant major
depressive disorder (TRD) can involve pharmacologic and
nonpharmacologic interventions, such as the use of cog-
Despite the progressive increase in the number of
nitive-behavioral psychotherapy [5••], electroconvulsive
pharmacologic agents with potential antidepressant
therapy [6], vagus nerve stimulation [7], and transcranial
activity, many patients suffering from major depressive
magnetic stimulation [8]. Pharmacologic interventions
disorder (MDD) continue to be symptomatic. Clearly,
can involve increasing the dose of an antidepressant [9],
an urgent need exists to develop safer, better tolerated,
switching to a second antidepressant [10–13], or using
and more effective treatments for MDD. Use of atypical
adjunctive pharmacotherapeutic strategies. When a sec-
antipsychotic agents as adjunctive treatment for treat-
ond antidepressant is added to an existing antidepressant,
ment-resistant MDD (TRD) represents one such effort
this is termed combination pharmacotherapy. When
toward novel pharmacotherapy development. Atypical
a nonantidepressant agent is added, this is termed aug-
antipsychotic agents have been hypothesized to be
mentation treatment. Combination strategies can involve
beneficial in treating mood disorders, including TRD, as
adding bupropion [14], mirtazapine [13,15], and tricyclic
a result of their complex mechanisms of action. After an
antidepressants [9,16] to an antidepressant treatment
initial series of positive case reports, series, and small
regimen. Augmentation strategies can involve adding
clinical trials, subsequent larger-scale projects have
lithium [9,17,18], triiodothyronine [18], buspirone [14],
yielded conflicting results. However, more recently,
pindolol [19], omega-3 fatty acids [20], dopaminergic
larger-scale clinical trials have supported the effective-
agents [21,22], folates, or S-adenosyl methionine [23,24]
ness of at least some of these medications. This review
to an antidepressant treatment regimen. Nevertheless, as
summarizes the existing data regarding the effectiveness
described previously, despite the broad armamentarium
of these medications in treating TRD, including bio-
available to clinicians for managing TRD, many patients
chemical rationale and clinical data.
remain symptomatic despite several adequate pharmaco-
logic and nonpharmacologic trials. Clearly, there is an
urgent need to develop safer, better tolerated, and more
Introduction effective treatments for major depressive disorder. Using
Despite the progressive increase in the number of available atypical antipsychotic agents as adjunctive treatment for
antidepressants, many patients suffering from depression TRD represents one such effort toward novel pharmaco-
continue to be symptomatic. For example, in the fi rst therapy development.
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 Mechanisms of Action
up to 12 weeks of therapy with citalopram [1]. Moreover, Atypical antipsychotics are a heterogeneous group, each
it was recently reported that as many as half of all patients with a distinct and complex set of receptor affi nities
enrolled in two academic-based depression specialty clin- involving dopaminergic and serotoninergic receptors and
482 Mood Disorders

various effects on noradrenergic, histaminergic, and cho- tions in a double-blind fashion. The average maximum
linergic systems. As a result, the receptor-binding profi le doses in the double-blind period were as follows: 12.5
of the atypical neuroleptics differs substantially from mg/d for olanzapine alone; 52 mg/d for fluoxetine alone;
that of other typical agents. This difference may provide and 13.5 and 52 mg/d, respectively, for the olanzapine and
clinical advantages to the atypical antipsychotic agents in fluoxetine combination. The continuation of fluoxetine
therapeutic areas other than in schizophrenia. for this period yielded essentially no further improve-
Specifically, similar to the typical antipsychotic agents, ment. Olanzapine administered alone achieved a modest
atypical antipsychotics act as dopamine-2 (D2)–receptor benefit over fluoxetine, whereas the olanzapine plus fluox-
antagonists [25]. However, unlike typical antipsychotic etine combination resulted in robust and significantly
agents, atypical antipsychotics, including olanzapine; greater improvement in depressive symptoms than either
quetiapine; risperidone; ziprasidone [25]; and, to a monotherapy. Remission, defi ned as a 17-item Hamilton
much lesser extent, aripiprazole [26], act as serotonin-2 Depression Rating Scale (HAM-D) score of 7 or less,
(5-HT2)–receptor antagonists. Ziprasidone [25] and was achieved in 60% of patients receiving the combina-
aripiprazole [26] also act as serotonin-1A (5-HT1A)–recep- tion, 25% receiving olanzapine alone, and 20% receiving
tor agonists, whereas ziprasidone and risperidone [25] fluoxetine alone.
act as serotonin-1D (5-HT1D) agonists. Antagonism of Two large-scale clinical trials testing the effects of the
5-HT1D, a presynaptic autoreceptor inhibiting serotonin olanzapine plus fluoxetine combination were undertaken
release, indicates potential efficacy in major depression next. In the fi rst, 500 patients were prospectively treated
[27], whereas selective 5-HT1A–receptor partial agonists, with nortriptyline; responders were excluded, leading into
such as gepirone [28], have shown antidepressant effects the double-blind phase [38]. Patients then were randomly
in clinical trials. Similarly, 5-HT2 –receptor antagonists, assigned to one of four treatment groups for 8 weeks:
such as trazodone [29] and nefazodone [30], also have olanzapine plus placebo, fluoxetine plus placebo, a com-
shown antidepressant effects. bination of olanzapine plus fluoxetine, or a continuation
Aripiprazole and ziprasidone have other unique of nortriptyline. Olanzapine was dosed in groups at 6 to
neurochemical properties that distinguish them from 12 mg/d and fluoxetine at 25 to 50 mg/d. The combina-
the other atypicals. Aripiprazole is a potent dopamine tion of olanzapine and fluoxetine produced a rapid effect
D2-receptor partial agonist, blocking D2 receptors under relative to the other groups. However, the groups did not
hyperdopaminergic conditions while acting as a D2 differ at end point. Several design and execution factors
agonist under hypodopaminergic conditions [31–35]. may have affected these results. Patients had failed only
Ziprasidone has been shown to inhibit the neuronal one adequate trial of an SSRI before entry. The doses of
uptake of 5-HT and norepinephrine in a way comparable olanzapine and fluoxetine were lower than in the previous
to the antidepressant imipramine [36]. 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
Clinical Effects of Atypical Antipsychotics in the mean dose in the initial phase was respectable (104.6
Treatment-Resistant Depression mg/d), many patients achieve their maximum dose rela-
The neurochemical effects described previously led to the tively late in phase 1. Given the delay until maximum
testing, initially, of atypical antipsychotics for cognitive response to antidepressant treatment, the response to the
and mood symptoms associated with schizophrenia. This dose achieved before phase 2 may have been experienced
subsequently led to the evaluation of atypicals for mood after the start of this period. A second study [39] using
symptoms in TRD and bipolar depression. This section venlafaxine as a comparator suffered from many of the
reviews the data supporting effects of these drugs individ- same design problems and is not reviewed in detail here.
ually and focuses primarily on controlled clinical trials. 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,
Olanzapine patients with a single drug failure were treated prospec-
The fi rst controlled test of the effects of an atypical in tively with fluoxetine. Those who did not respond were
TRD was a small study with olanzapine that compared randomly assigned to continuation fluoxetine (+ placebo),
the effects of olanzapine alone (ie, olanzapine + placebo), olanzapine (+ placebo), or the olanzapine and fluoxetine
olanzapine plus fluoxetine, and fluoxetine alone in treat- combination. In one (n = 638), combined olanzapine/fluox-
ing TRD [37]. All participants had previously failed etine produced no greater effect than either monotherapy.
adequate trials of a selective serotonin reuptake inhibitor However, the fluoxetine monotherapy condition produced
(SSRI) and a non-SSRI antidepressant, as well as a pro- a robust effect by study’s end, indicating another failed
spective treatment period with fluoxetine alone (up to 60 trial. However, the second project (n = 675) confi rmed the
mg/d). Nonresponders (n = 28) to this run-in treatment more robust effect of combined olanzapine/fluoxetine in
then were randomly assigned to one of the three condi- treatment-resistant unipolar major depression compared
Atypical Antipsychotics for Treatment-Resistant Major Depressive Disorder Papakostas and Shelton 483

with olanzapine or fluoxetine monotherapy. The pooled three controlled trials in unipolar TRD. One study (n =
analysis of both studies also showed a significantly supe- 40) evaluated the effects of quetiapine for SSRI/(SNRI)
rior effect of the combination. Meanwhile, a successful partial response [46]. In this 8-week, double-blind, pla-
trial of the combination was tested in bipolar I depression cebo-controlled study, patients were randomized (2:1
(non–treatment-resistant), leading to US Food and Drug ratio) to receive quetiapine, 200 to 400 mg/d, or placebo
Administration (FDA) approval for this indication [41]. along with their previous SSRI/serotonin–norepinephrine
reuptake inhibitor (SNRI). Twenty-one of 26 quetiapine-
treated patients (80.8%) completed the study, compared
Risperidone with 11 of 14 (78.6%) in the placebo group. At the end
The fi rst published report of the effectiveness of an atypi- of 8 weeks, the quetiapine group had significantly lower
cal antipsychotic in TRD was with risperidone [42]. In 17-item HAM-D scores than the placebo group (8.3 vs
this case series, eight patients who failed to respond to 14.7) plus higher response (67% vs 27%) and remission
an adequate trial of an SSRI were given risperidone in rates (43% vs 15%).
an open fashion, and all experienced a rapid and robust In a separate study, McIntyre et al. [47] studied 58
effect. However, there were no controlled clinical trial patients who did not experience sufficient symptom
data with risperidone in TRD until recently. In one study improvement after adequate treatment with an SSRI or
[43], 489 patients with one to three prior documented venlafaxine. Patients were randomized in double-blind
failures were treated prospectively with citalopram, 20 fashion to receive adjunctive treatment with quetiapine
to 60 mg/d. Those who experienced greater than 50% or placebo for 8 weeks. Eighteen of 29 quetiapine-treated
improvement were excluded. The remainder (n = 390) and 16 of 29 placebo-treated patients completed the study.
were given 4 to 6 weeks of open-label risperidone, 0.25 to A greater resolution of depressive symptoms was reported
2.0 mg/d, in combination with citalopram. Patients with among patients treated with adjunctive quetiapine than
17-item HAM-D scores of 7 or less or a Clinical Global placebo (mean difference in the reduction in HAM-D
Impression Severity Scale score of 2 or less (ie, “much scores during treatment was 5.7 points in favor of que-
improved” or “very much improved”) were randomized to tiapine, P < 0.01).
risperidone or placebo augmentation (n = 243 remitters, Finally, in a third trial, Khullar et al. [48] studied 15
241 randomized). The primary end point, time to relapse, outpatients with TRD (to SSRIs or SNRIs) who under-
did not differ between groups. The median time to relapse went augmentation with quetiapine or placebo for 8
was 102 days for risperidone plus citalopram and 85 days weeks. Quetiapine was more effective in reducing depres-
for placebo plus citalopram. Relapse rates were 53.3% sive symptoms than placebo, as 37% of patients remitted
with the combination and 54.6% with continuation of after adjunctive treatment with quetiapine, whereas none
citalopram alone. These data indicate that continuation remitted after treatment with placebo. Additional larger-
of risperidone plus citalopram was no more effective for scale studies of quetiapine therapy for TRD recently have
preventing relapse than citalopram alone. been completed by the manufacturer, although results are
In a second controlled trial [44], 463 depressed patients not yet available in the published literature.
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 Ziprasidone
with the initial antidepressant for 6 weeks. Mean HAM-D An initial open trial supported the effects of ziprasidone
scores dropped from 24.2 to 15.2 in the risperidone group in TRD. In this study, 20 patients who had an incomplete
and from 24.6 to 17.5 in the placebo group, a statistically response to a trial of an SSRI were treated with ziprasi-
significant difference. done in an open fashion [49]. Thirteen (65%) completed
In a third controlled trial, Keitner et al. [45] studied 97 the trial; of this group, eight (61.5%) were responders, as
outpatients who met the DSM-IV criteria for a unipolar, defi ned by a 50% improvement in 17-item HAM-D score.
nonpsychotic major depressive episode and failed to respond Of all the patients randomized, 10 were responders (50%),
or only partially responded to at least a 5-week trial of an and 5 remitted (25%).
adequate dose of antidepressant monotherapy. Patients were In a second randomized, open trial, adult outpatients
randomized to receive adjunctive risperidone or placebo for who had not responded to a prior trial with an antide-
a total of 4 weeks of treatment. The odds of remitting were pressant were treated prospectively with sertraline, 100 to
significantly better for patients treated with adjunctive ris- 200 mg/d, for 6 weeks [50]. Those who failed to achieve a
peridone than placebo (52% vs 24%, respectively). 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
Quetiapine (mean dose, 78 mg/d); or sertraline plus ziprasidone, 160
Quetiapine has received FDA approval for treating bipo- mg/d (mean dose, 129.9 mg/d) for 8 weeks. The mean
lar depression as monotherapy. However, there are now change from baseline was greater in the two ziprasidone
484 Mood Disorders

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.

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-
Figure 1. Aripiprazole augmentation for antidepressant-resistant
major depressive disorder: results of two identical randomized, pharmacologic treatment options for TRD, many patients
double-blind, phase 3 trials (P < 0.05, aripiprazole augmentation vs remain symptomatic. Thus, there is an urgent need to
antidepressant monotherapy for both trials). develop novel treatments for TRD. From the evidence
available to date, it appears that augmenting antidepres-
augmentation groups (80 mg/d: -5.98 points; 160 mg/d: sants with atypical antipsychotics (specifically aripiprazole,
-8.27 points) than in the sertraline monotherapy group olanzapine, quetiapine, and risperidone) can be effective in
(-4.45 points), although this did not achieve statistical some patients, at least during the acute phase of treatment.
significance. Respective response rates were 19%, 32%, However, the long-term efficacy, tolerability, and safety of
and 10%, and remission rates were 5%, 21%, and 5%. this treatment are not yet understood. In particular, the
Although these results suggest possible benefit, they did risk of metabolic (weight gain and hyperlipidemia or dys-
not conclusively support ziprasidone augmentation. lipidemia), endocrine (hyperprolactinemia), cardiac (QTc
prolongation and arrhythmogenesis), and central nervous
system (akathisia, parkinsonism, tardive dyskinesia,
Aripiprazole neuroleptic malignant syndrome) adverse events during
Until recently, aripiprazole had received relatively little treatment with these agents in major depressive disorder
attention in this area. In one open-label trial, 12 patients needs to be better quantified. Further research also is
who had failed to respond sufficiently to an adequate required into how this compares with other augmentation
trial of an SSRI were treated with adjunctive aripipra- strategies and other strategies for addressing TRD.
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 Acknowledgments
seven of the total group (58.3%) responded. This work was supported in part by National Institute of
More recently, results of two positive, double-blind, Mental Health grant K24 MH01741 (to Dr. Shelton).
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 Disclosures
[52••] focused on the use of aripiprazole augmentation Dr. Papakostas has received research support from Bris-
for patients resistant to up to three “retrospective” (his- tol-Myers Squibb, Forest Pharmaceuticals, the National
torical) antidepressant trials. To “confi rm” treatment Institute of Mental Health, Pamlab, Pfi zer, and Precision
resistance, those patients underwent an 8-week, open- Human BioLaboratories; has served as a consultant for
label trial with an SSRI (fluoxetine, sertraline, paroxetine, Bristol-Myers Squibb, Eli Lilly and Company, Evotec,
or escitalopram) or an SNRI (venlafaxine). The patients GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Phar-
who made insufficient symptom improvement had aripip- maceuticals, Pamlab, Pfi zer, Pierre Fabre Medicament,
razole or placebo added to their SSRI or SNRI regimen Shire Pharmaceuticals, and Wyeth; has received hono-
under double-blind conditions for a total of 6 weeks. A raria from Bristol-Myers Squibb, Eli Lilly and Company,
statistically significant difference in remission rates was Evotec, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz
also observed, with 26% remission for aripiprazole, com- Pharmaceuticals, H. Lundbeck A/S, Pamlab, Pfi zer, Pierre
pared with 15.7% remission for placebo (P < 0.05). This Fabre Medicament, Shire Pharmaceuticals, Titan Phar-
study also reported relatively low rates of discontinuation maceuticals, and Wyeth; and has served on the speakers’
due to intolerance in the two treatment groups (2% for bureau for Bristol-Myers Squibb and Pfi zer.
Atypical Antipsychotics for Treatment-Resistant Major Depressive Disorder Papakostas and Shelton 485

Dr. Shelton has received grant/research support 13. McGrath PJ, Stewart JW, Fava M, et al.: Tranylcypromine
versus venlafaxine plus mirtazapine following three failed
from Eli Lilly and Company, GlaxoSmithKline, Jans- antidepressant medication trials for depression: a STAR*D
sen Pharmaceutica, Pfi zer, Sanofi-Aventis, Wyeth-Ayerst report. Am J Psychiatry 2006, 163:1531–1541.
Laboratories, AstraZeneca Pharmaceuticals, and Abbott 14. Trivedi MH, Fava M, Wisniewski SR, et al.: Medication
augmentation after the failure of SSRIs for depression. N
Laboratories; has served as a paid consultant for Pfi zer, Engl J Med 2006, 354:1243–1252.
Janssen Pharmaceutica, and Sierra Neuropharmaceuticals; 15. Carpenter LL, Yasmin S, Price LH: A double-blind,
and has served on the speakers’ bureau for Bristol-Myers placebo-controlled study of antidepressant augmentation
with mirtazapine. Biol Psychiatry 2002, 51:183–188.
Squibb, Eli Lilly and Company, Janssen Pharmaceutica,
16. Nelson JC, Mazure CM, Jatlow PI, et al.: Combining nor-
Pfi zer, GlaxoSmithKline, Wyeth-Ayerst Laboratories, and epinephrine and serotonin reuptake inhibition mechanisms
Abbott Laboratories. for treatment of depression: a double-blind, randomized
study. Biol Psychiatry 2004, 55:296–300.
17. Nierenberg AA, Papakostas GI, Petersen T, et al.: Lithium
augmentation of nortriptyline for subjects resistant to
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