Embed Size (px)
Citation preview
DISEASE MANAGEMENT
Consider augmentation or switching strategies when first-lineantidepressants are unsuccessful in major depressive disorder
When treating major depressive disorder that has not
responded to an adequate trial of a first-line antidepressant,
the current evidence most strongly supports switching to
another first-line antidepressant or augmentation with the
atypical antipsychotics aripiprazole or quetiapine. Lithium
and liothyronine (triiodothyronine) may be used to augment
tricyclic antidepressants, but further studies of their use to
augment newer antidepressants are needed.
If initial treatment does not succeed ...
Major depressive disorder (MDD) is a common disorder
that reduces health-related quality of life, results in poorer
overall health, impairs the ability to work and is associated
with considerable economic costs to society.[1,2] Although
there have been numerous advances in the pharmacological
treatment of MDD, initial treatment with first-line anti-
depressants (e.g. selective serotonin reuptake inhibitors
[SSRIs], serotonin and norepinephrine [noradrenlaine] reup-
take inhibitors [SNRIs], bupropion and mirtazapine) does not
provide an adequate clinical response in many patients.[1]
After an initially unsuccessful treatment of MDD, it is
vital that the next agent is chosen with care, as a good choice
can improve outcomes and resolve illness, whereas a poorer
choice may lead to persistent depression with a more
chronic and morbid disease course.[3,4] This article provides
a summary of a recent review by Connolly and Thase[1] of
the current evidence regarding second-line treatment of
adults with MDD who have not had an adequate clinical
response to their first antidepressant medication treatment.
y try, try again with another approach
Many guidelines offer recommendations for the initial
management of MDD; however, guidance as to which
option is best for patients with treatment-resistant MDD
is more limited.[1] After the failure of an initial anti-
depressant trial that has been optimized in dose and dura-
tion, current evidence-based clinical guidelines[5-8] recom-
mend improving efficacy with the following main pharma-
cological strategies:� switching to another antidepressant;[5-8]
� augmentation or adjunctive therapy with another agent
(which is not thought to be an antidepressant itself) to the
antidepressant regimen.[5-8] Agents that are recom-
mended to augment antidepressant therapy include
atypical antipsychotics,[6,8] lithium[5-8] and liothyronine
(triiodothyronine).[5-8]
Although other pharmacological strategies, such as
combination therapy with two antidepressants and aug-
mentation with stimulants or buspirone, are commonly used
in clinical practice, there is a lack of evidence to support
their use.[1,5-8] Nonpharmacological therapies, such as the
addition of psychotherapy to pharmacological treatment and
the use of neurostimulation therapies (electroconvulsive
therapy or transcranial magnetic stimulation) may have
beneficial effects in treatment-resistant MDD;[1] however, a
discussion of their use is beyond the scope of this review.
Switch to a different antidepressant
In patients who have not responded to an adequate trial of
an antidepressant, the antidepressant agent used may be
switched to another agent,[1,2,5-8] which produces a response
in 18–60% of patients.[1] Strategies include changing to
another class of newer-generation antidepressant (generally
considered to be the favoured option), or changing to an-
other agent in the same class or an older-generation anti-
depressant.
Unfortunately, the few high-quality studies that have in-
vestigated this issue have generally not shown consistent
and/or clinically significant differences between various
switching strategies (table I).[1] Therefore, guidance on the
class of agent that offers a unique clinical advantage after
treatment failure with an SSRI or another first-line anti-
depressant agent cannot yet be provided. Further studies are
clearly needed to determine the best approach with regard to
this important and common treatment step.[1]
Augment with atypical antipsychotics
Of the augmentation strategies, adjunctive treatment with
atypical antipsychotics has been the most systematically and
rigorously studied, with current data supporting their use in
patients with treatment-resistant MDD.[1] In a meta-analysis
of data from 16 randomized controlled trials (RCTs) of
atypical antipsychotic versus placebo augmentation in 3480
patients with treatment-resistant MDD, the addition of an
atypical antipsychotic was significantly (p < 0.0001) more
1172-0360/11/0012-0007/$19.95 ª 2011 Adis Data Information BV. All rights reserved.
7
effective than that of placebo with regard to rates of response
(odds ratio [OR] 1.69; 95% CI 1.46, 1.95) and remission
(OR 2.00; 95% CI 1.69, 2.37).[17] However, it remains to be
seen how the clinical risks and benefits of these agents
translate into real-world outcomes. The optimal duration of
augmentation therapy and the cost effectiveness of this
strategy relative to other strategies remain unknown.[1]
The rationale for the use of these agents to augment
treatment with SSRIs or SNRIs is largely based on the broad
receptor binding profiles of this medication class.[18] Atyp-
ical antipsychotics bind strongly to serotonin 5-HT2A re-
ceptors, aripiprazole and ziprasidone are also 5-HT1A partial
agonists, and ziprasidone and quetiapine (via its N-desalkyl
metabolite) inhibit norepinephrine reuptake. Different atyp-
ical antipsychotics may be beneficial in different patient
groups or may be more useful when used to augment treat-
ment with different antidepressants, but further study into
this area is required.[1]
Evidence supports the use of aripiprazole orquetiapine
The strongest available clinical data supports the use of
aripiprazole or quetiapine to augment antidepressant treat-
ment.[1] In 6-week RCTs in patients with a history of non-
response to adequate trials of antidepressant monotherapy,
aripiprazole[19-21] and quetiapine[23,24] (particularly at a do-
sage of 300 mg/day) appeared to be effective augmentation
strategies (table II). It is unclear if augmentation with que-
tiapine is of use in patients who are resistant to treatment
with more than one prior course of antidepressant therapy.[1]
Table I. Summary of the evidence for switching antidepressant medications in patients (pts) with majordepressive disorder (MDD) who do not respond to first-line antidepressant therapy, as reviewed byConnolly and Thase[1]
Switching to venlafaxine
In four RCTs in SSRI nonresponders,[3,9-11] a significant benefit with regard to response[11] and/or remission[9,11] was shown in pts switched to
venlafaxine vs a second SSRI in two trials
Overall, venlafaxine appears to be an effective and useful agent after the failure of an SSRI, but whether it is markedly more effective than other
options seems doubtful
Switching to a newer SNRI
Studies are needed to determine the role of newer SNRIs in treatment-resistant MDD, as no available RCTs have investigated switching to newer
SNRIs (e.g. duloxetine, desvenlafaxine and milnacipran) in treatment-resistant pts
Switching to bupropion
Although switching from an SSRI to bupropion is a commonly used strategy in the US, well designed trials of this strategy are lacking
A STAR*D study did not support any preference for switching to bupropion over either SSRIs or venlafaxine in pts with SSRI-resistant MDD[3]
Switching to mirtazapine
Although more studies are needed, the limited available evidence suggests that this agent may hold promise for effective and perhaps more rapid
remission after an SSRI failure, but does not indicate that it is more or less effective than other second-line options
In a large RCT in SSRI nonresponders,[12] remission rates in pts switched to mirtazapine were not significantly different than that in pts switched
to a second SSRI (sertraline) [38% vs 28%]; however, mirtazapine was associated with significantly faster times to response and remission
In the ARGOS comparison of mirtazapine with a second SSRI or venlafaxine as a second-line agent after an SSRI failure,[11] response and
remission rates with mirtazapine were numerically similar to those for SSRIs and lower than those with venlafaxine (statistical analysis not
performed)
In the STAR*D study in pts who had not responded to two consecutive antidepressants,[13] remission rates were similar when switched to
mirtazapine or nortriptyline (12.3% vs 19.8%)
Switching to a tricyclic or related antidepressant
Very little data support the use of a tricyclic or related antidepressant instead of another second-line treatment strategy
In an RCT in fluoxetine nonresponders, no significant difference was seen between the addition of mianserin (a tetracyclic antidepressant)
to ongoing fluoxetine treatment vs fluoxetine alone[14]
In pts who had failed to respond to either imipramine or sertraline, treatment with the opposite medication resulted in significantly improved
remission and response rates; although these results are of little value in indicating a preferred strategy, they do suggest that switching
antidepressants in general can improve outcomes, and that imipramine may be a promising second-line treatment after SSRI failure[15]
Switching to an MAOI
Because of their dietary restrictions and potentially dangerous medication interactions, MAOIs are typically reserved for more severely refractory
MDD
No RCTs have studied the use of MAOIs vs other available options for the treatment of MDD resistant to SSRIs or other first-line antidepressants
In a STAR*D study in pts resistant to three antidepressants, no clear advantage in remission rates was seen in pts receiving tranylcypromine over
those receiving mirtazapine plus venlafaxine (6.9% and 13.7%), and the MAOI was tolerated less well[16]
MAOI = monoamine oxidase inhibitor; RCT = randomized, controlled trial; SNRI= serotonin and norepinephrine (noradrenaline) reuptake
inhibitors; SSRI = selective serotonin reuptake inhibitors.
8
Drugs Ther Perspect 2011; Vol. 27, No. 12
More data needed for other agents
In 4-week RCTs,[25,26] the addition of risperidone was
beneficial in improving outcomes in patients with treatment-
resistant MDD, but there was no significant advantage with
risperidone over placebo with regard to the proportion of
patients remaining relapse-free at the end of a 24-week
trial[27] (table II). The lack of sustained benefit in this
trial[27] casts doubt on the utility of this adjunctive strategy;
risperidone is not currently recommended as a first-line
augmentation option.[1,2]
To date, olanzapine has only been studied in combination
with fluoxetine.[1] Patients who did not respond to two trials
of SSRIs, including fluoxetine as the second agent, bene-
fited from the addition of olanzapine in an 8-week RCT[22]
(table II). Whether olanzapine/fluoxetine offers comparable
benefits in patients who do not respond to other treatment
sequences has not been evaluated.[1]
No large RCTs have evaluated the use of ziprasidone or
other recently approved antipsychotics (e.g. paliperidone,
iloperidone, asenapine) to augment antidepressant medica-
tions in patients with treatment-resistant MDD.[1,2] Although
ziprasidone has a favourable pharmacodynamic profile and
perhaps the best tolerability profile for minimizing weight
gain and related metabolic effects among the atypical anti-
psychotics, there is currently insufficient empirical support
to recommend the addition of ziprasidone to antidepressant
therapy.[1,2]
Must weigh risks versus benefits
Augmentation with an atypical antipsychotic should be
initiated only after careful appraisal of its potential benefits
and risks of adverse effects.[1,2,28] These agents are asso-
ciated with increased risks of metabolic adverse effects and
complications, including weight gain, lipid abnormalities
and impaired glucose tolerance, as well as tardive dyskinesia
and acute extrapyramidal syndromes.[28] In the meta-analysis
of placebo-controlled trials, atypical antipsychotics were
associated with an increased risk of discontinuation due to
Table II. Summary of the key efficacy results of augmentation with atypical antipsychotics in randomizedcontrolled trials in patients (pts) with major depressive disorder resistant to treatment with first-lineantidepressants. Pts continued to receive treatment with a first-line antidepressant with the addition of anatypical antipsychotic or placebo. Only results from trial arms relevant to augmentation therapy are reportedAugmentation regimensa (no. of pts) Durationb Results (antipsychotic vs comparator)
(wk) response ratec (% of pts) NNTd
Aripiprazole
Aripiprazole (182) vs placebo (176)[19] 6 33.7* vs 23.8 10
Aripiprazole (191) vs placebo (190)[20] 6 32.4*** vs 17.4 6.7
Aripiprazole (177) vs placebo (172)[21] 6 46.3*** vs 26.7 5
Olanzapine
Olanzapine (198) vs control (203)[22]e 8 40.4** vs 29.6 9.3
Quetiapine
Quetiapine 150 mg (166) or quetiapine 300 mg (166) vs placebo (160)[23] 6 55.4 and 57.8* vs 46.3 8.7f
Quetiapine 150 mg (143) or quetiapine 300 mg (146) vs placebo (143)[24] 6 51.7 and 58.9* vs 46.2 7.8f
Risperidone
Risperidone (106) vs placebo (112)[25] 4 46.2** vs 29.5g 8.3
Risperidone (64) vs placebo (30)[26] 4 54.7* vs 33.3 4.6
Risperidone (122) vs placebo (119)[27] 24 46.7 vs 45.4h No significant
advantage
a Unless otherwise indicated, dosages were titrated based on response and tolerability.
b Length of double-blind augmentation phase.
c Defined as 50% reduction in Montgomery-Asberg depression rating scale score, unless otherwise indicated.
d As reported in Connolly and Thase.[1]
e Preplanned analysis of two identically designed studies, in which previous nonresponders received fluoxetine for 8 wk; pts who did not respond
to fluoxetine were randomized to 8 additional wk of olanzapine plus fluoxetine or fluoxetine alone.
f Quetiapine 300 mg vs placebo. No significant advantage for quetiapine 150 mg vs placebo.
g Response defined as 50% reduction in Hamilton Depression Rating Scale score.
h Response defined as remaining free of depressive relapse at 24 wk.
NNT = number needed to treat for one clinical response; * p < 0.05, ** p < 0.01, *** p < 0.001 vs comparator.
9
1172-0360/11/0012-0009/$19.95 ª 2011 Adis Data Information BV. All rights reserved.
adverse events relative to placebo (OR 3.91; 95% CI 2.68,
5.72).[17] As the risk of various adverse effects vary be-
tween these agents, treatment should be tailored to the in-
dividual.[28] For example, of the two recommended first-line
augmentation options, the risk of metabolic adverse effects
appears to be greater with quetiapine than with aripiprazole.
Longer-term studies are needed to fully evaluate the benefit-
risk profiles of these agents when used as augmentation
strategies in treatment-resistant MDD.[1]
No response to a tricyclicantidepressant? Try adding lithium ...
Lithium, which has shown efficacy as an augment to
antidepressant therapy, is postulated to act by increasing
serotonergic neurotransmission.[1] In a meta-analysis of ten
RCTs of lithium augmentation of various antidepressants
(including tricyclic antidepressants [TCAs], SSRIs and other
antidepressants) in 269 patients with depressive disorder, the
overall OR for response with lithium relative to placebo
was 3.1 (95% CI 1.8, 5.4), which corresponds to a number
needed to treat (NNT) to achieve one clinical response of
5.[29] The mean response rate was significantly higher with
lithium augmentation than with placebo (41.2% vs 14.4% of
patients; p < 0.001).The evidence for the efficacy of lithium augmentation is
strongest for patients whose MDD has been inadequately
treated by an initial trial of a TCA.[1] However, there are
little data for lithium augmentation of SSRIs or other newer
antidepressants. Lithium, which has comparatively weaker
effects on serotonergic neurotransmission, may have little po-
tential to benefit patients who have not responded adequately
to antidepressants that affect serotonergic neurotransmission,
as responses to enhancing serotonergic neurotransmission
would likely have already been seen.[1] In an open-label,
randomized STAR*D (Sequenced Treatment Alternatives to
Relieve Depression) trial in patients who did not respond to
two sequential trials with newer antidepressants, 15.9% of 69
patients who received lithium augmentation achieved the pri-
mary endpoint of remission.[30]
The relevance of lithium augmentation in contemporary
clinical practice is less clear than might be assumed from the
recommendations found in current guidelines.[5-8] The effi-
cacy of adding lithium to TCAs is well established; how-
ever, the use of TCAs is typically reserved for patients with
more advanced levels of treatment resistance. In contrast,
lithium should be used to augment SSRIs and other newer
antidepressants with caution; however, these agents are the
most commonly recommended first-line antidepressants.[1]
Lithium is associated with a relatively low therapeutic index
and its use is associated with long-term risks of thyroid and
renal compromise.[1]
y or liothyronine
For augmentation of antidepressant therapy, the preferred
form of thyroid hormone is liothyronine.[31] It is recom-
mended instead of levothyroxine, which is used to treat
hypothyroidism, because liothyronine is thought to have
activity within the CNS and a rapid onset of action.[31]
Liothyronine augmentation has shown efficacy in pa-
tients who have not responded to TCAs.[1] In a meta-anal-
ysis of eight controlled trials in 292 TCA nonresponders,
patients who received liothyronine augmentation were twice
as likely to respond than those who received controls
(relative response 2.09; 95% CI 1.31, 3.32; p = 0.002). This
corresponds to an absolute increase in response rate of
23.2% (95% CI 4.5, 41.9; p = 0.02), and an NNT to achieve
one clinical response of 4.3.[32]
Questions remain as to whether the findings with TCAs
can be generalized to treatment with newer antidepressants.
In the STAR*D trial, 24.7% of 73 patients receiving lio-
thyronine augmentation of newer antidepressants achieved
remission (no significant difference relative to lithium aug-
mentation).[30] Moreover, an RCT in 36 patients nonresponsive
to SSRI therapy failed to find that liothyronine augmentation
had a significant benefit over that with placebo.[33]
Although liothyronine may appear to be a better option for
use in combination with SSRIs and other newer antidepressants
than lithium because of its generally better tolerability profile,
the remission rate observed in STAR*D was not significantly
better than with lithium, prolonged use of adjunctive thyroid
hormone was associated with adverse effects such as osteope-
nia, and the only placebo-controlled study of augmentation of
newer antidepressants with liothyronine did not shown a sig-
nificant benefit.[1] Further RCTs, therefore, are needed before
liothyronine can be recommended for euthyroid patients who
have not responded to first-line antidepressant treatment.
More evidence needed for augmentationwith psychostimulants
The use of traditional psychostimulants would seem to
be a rational strategy to improve depressive symptoms, as
these agents promote wakefulness, reduce fatigue and im-
prove mood by increasing levels of synaptic dopamine,
norepinephrine and serotonin to varying degrees.[1] Indeed,
methylphenidate and amfetamines are prescribed by some
psychiatrists to treat depressive symptoms, based on clinical
experience, case series and open-label trials. However, only
a few well designed studies of stimulant augmentation of
10
Drugs Ther Perspect 2011; Vol. 27, No. 12
antidepressants have been published and a systematic review
failed to establish the efficacy of this approach.[34]
Modafinil, a wakefulness-promoting agent, is thought to
act primarily on dopamine and norepinephrine neuro-
transmission.[1] Pooled data from the two RCTs in patients
with partial benefit with SSRIs indicated that modafinil
augmentation modestly improved symptoms of depression,
sleepiness and fatigue relative to placebo.[35] Of note, as
these studies were in ‘enriched’ samples (i.e. all patients had
fatigue and sleepiness at baseline),[35] evidence is lacking
that modafinil augmentation would be of benefit in anti-
depressant nonresponders without fatigue or sleepiness.[1]
The potential for tolerance of therapeutic effects and abuse,
as well as the current lack of strong efficacy data, should be
taken into account when the off-label use of psychostimu-
lants or modafinil is being considered to augment anti-
depressant therapy.[1]
Lack of benefits with adjunctivebuspirone ...
Buspirone, an anxiolytic, is a partial agonist at 5-HT1A
receptors.[1] A potential role for buspirone augmentation in
treatment-resistant MDD was suggested by its effects on
serotonin neurotransmission, which may enhance the effects
of SSRIs and SNRIs. Although a number of open-label trials
suggested that buspirone augmentation was beneficial, there
is no convincing evidence from RCTs that buspirone has a
place in the treatment of patients with MDD, regardless of
whether or not they have high levels of baseline anxiety.[1]
y or pindolol in treatment-resistant disease
Pindolol, which was originally developed as a b-adrenergicreceptor antagonist, is a relatively potent 5-HT1A receptor
antagonist.[1] Interestingly, evidence from recent meta-anal-
yses[36,37] suggests that pindolol may accelerate and enhance
response to antidepressant therapy during the first 2–4 weeks
of therapy (particularly in patients with non-resistant MDD,
who are SSRI-naive or who are at the beginning of their
illness[36]). However, it appears to have little or no signif-
icant effect on longer-term (6 week) treatment outcomes.[36,37]
High-quality data suggesting that augmentation with this
agent can improve outcomes in patients with treatment-
resistant MDD are currently lacking.[1]
Cannot recommend combiningantidepressants
Although treatment with a combination of two different
antidepressant medications is frequent in patients with re-
sistant MDD in clinical practice,[1] current guidelines do not
recommend this strategy.[5-8]
High-quality evidence to support adding another anti-
depressant agent to the treatment of patients who are not re-
sponding to antidepressant monotherapy is lacking.[1] A recent
single-blind RCT in 665 patients with chronic or recurrent
MDD concluded that combination treatment (sustained-
release bupropion plus escitalopram, or extended-release
venlafaxine plus mirtazapine) did not offer clinical advantages
over escitalopram monotherapy, with the extended-release
venlafaxine plus mirtazapine combination possibly increasing
the risk of adverse events.[38] No significant differences in
remission and response rates and most secondary outcomes
were shown between treatment groups during the acute
(12 week) or long-term (7 month) treatment phases.[38]
Small RCTs suggest that mirtazapine[39] and mianserin,[14]
which have similar receptor profiles, may prove useful when
added to treatment with other first-line antidepressants in
patients who had not responded to an adequate trial of an
antidepressant. Further study on the use of antidepressant
combinations in patients with treatment-resistant MDD are
needed before this strategy can be recommended.[1]
Disclosure
This review was adapted from Drugs 2011; 71 (1): 43-64[1] by Adis
editors and medical writers. The preparation of these articles was not
supported by any external funding.
References1. Connolly KR, Thase ME. If at first you don’t succeed: a review of the
evidence for antidepressant augmentation, combination and switching
strategies. Drugs 2011; 71 (1): 43-64
2. Philip NS, Carpenter LL, Tyrka AR, et al. Pharmacologic approaches
to treatment resistant depression: a re-examination for the modern era.
Expert Opin Pharmacother 2010 Apr; 11 (5): 709-22
3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertra-
line, or venlafaxine-XR after failure of SSRIs for depression. N Engl
J Med 2006; 354 (12): 1231-42
4. Tranter R, O’Donovan C, Chandarana P, et al. Prevalence and out-
come of partial remission in depression. J Psychiatry Neurosci 2002;
27 (4): 241-7
5. American Psychiatric Association practice guideline for treatment of
patients with major depressive disorder, third edition. Arlington (VA);
American Psychiatric Association, 2010 Oct
6. Institute for Clinical Systems Improvement (ICSI) healthcare guide-
line: major depression in adults in primary care, thirteenth edition.
Bloomington (MN); ICSI, 2010 May
7. Malhi GS, Adams D, Porter R, et al. Clinical practice recommenda-
tions for depression. Acta Psychiatr Scand Suppl 2009; 119 (439): 8-26
8. Lam RW, Kennedy SH, Grigoriadis S, et al. Canadian Network for
Mood and Anxiety Treatments (CANMAT) clinical guidelines for the
management of major depressive disorder in adults. III: pharma-
cotherapy. J Affect Disord 2009; 117 Suppl. 1: S26-43
11
1172-0360/11/0012-0011/$19.95 ª 2011 Adis Data Information BV. All rights reserved.
9. Poirier MF, Boyer P. Venlafaxine and paroxetine in treatment-resistant
depression: double-blind, randomised comparison. Br J Psychiatry
1999 Jul; 175: 12-6
10. Lenox-Smith AJ, Jiang Q. Venlafaxine extended release versus citalo-
pram in patients with depression unresponsive to a selective serotonin
reuptake inhibitor. Int Clin Psychopharmacol 2008; 23 (3): 113-9
11. Baldomero EB, Ubago JG, Cercos CL, et al. Venlafaxine extended
release versus conventional antidepressants in the remission of de-
pressive disorders after previous antidepressant failure: ARGOS
study. Depress Anxiety 2005; 22 (2): 68-76
12. Thase ME, Kremer C, Rodrigues H. Mirtazapine versus sertraline
after SSRI non-response [abstract]. The Annual Meeting of the New
Clinical Drug Evaluation Unit (NCDEU) of the National Institute of
Mental Health; 2001 May 28-31; Phoenix (AZ)
13. Fava M, Rush AJ, Wisniewski SR, et al. A comparison of mirtazapine
and nortriptyline following two consecutive failed medication treat-
ments for depressed outpatients: a STAR*D report. Am J Psychiatry
2006; 163 (7): 1161-72
14. Ferreri M, Lavergne F, Berlin I, et al. Benefits from mianserin aug-
mentation of fluoxetine in patients with major depression non-re-
sponders to fluoxetine alone. Acta Psychiatr Scand 2001; 103 (1): 66-72
15. Thase ME, Rush AJ, Howland RH, et al. Double-blind switch study of
imipramine or sertraline treatment of antidepressant-resistant chronic
depression. Arch Gen Psychiatry 2002; 59 (3): 233-9
16. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus
venlafaxine plus mirtazapine following three failed antidepressant
medication trials for depression: a STAR*D report. Am J Psychiatry
2006 Sep; 163 (9): 1531-41
17. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in
major depressive disorder: a meta-analysis of placebo-controlled
randomized trials. Am J Psychiatry 2009 Sep; 166 (9): 980-91
18. Papakostas GI, Shelton RC. Use of atypical antipsychotics for treat-
ment-resistant major depressive disorder. Curr Psychiatry Rep 2008;
10 (6): 481-6
19. Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of
aripiprazole as adjunctive therapy in major depressive disorder: a
multicenter, randomized, double-blind, placebo-controlled study. J
Clin Psychiatry 2007; 68 (6): 843-53
20. Marcus RN, McQuade RD, Carson WH, et al. The efficacy and safety
of aripiprazole as adjunctive therapy in major depressive disorder: a
second multicenter, randomized, double-blind, placebo-controlled
study. J Clin Psychopharmacol 2008; 28 (2): 156-65
21. Berman RM, Fava M, Thase ME, et al. Aripiprazole augmentation in
major depressive disorder: a double-blind, placebo-controlled study in
patients with inadequate response to antidepressants. CNS Spectr
2009; 14 (4): 197-206
22. Thase ME, Corya SA, Osuntokun O, et al. A randomized, double-
blind comparison of olanzapine/fluoxetine combination, olanzapine,
and fluoxetine in treatment-resistant major depressive disorder. J Clin
Psychiatry 2007; 68 (2): 224-36
23. Bauer M, Pretorius HW, Constant EL, et al. Extended-release que-
tiapine as adjunct to an antidepressant in patients with major de-
pressive disorder: results of a randomized, placebo-controlled, double-
blind study. J Clin Psychiatry 2009; 70 (4): 540-9
24. El-Khalili N, Joyce M, Atkinson S, et al. Extended-release quetiapine
fumarate (quetiapine XR) as adjunctive therapy in major depressive
disorder (MDD) in patients with an inadequate response to ongoing
antidepressant treatment: a multicentre, randomized, double-blind,
placebo-controlled study. Int J Neuropsychopharmacol 2010; 13 (7):
917-32
25. Mahmoud RA, Pandina GJ, Turkoz I, et al. Risperidone for treatment-
refractory major depressive disorder: a randomized trial. Ann Intern
Med 2007; 147 (9): 593-602
26. Keitner GI, Garlow SJ, Ryan CE, et al. A randomized, placebo-con-
trolled trial of risperidone augmentation for patients with difficult-to-
treat unipolar, non-psychotic major depression. J Psychiatr Res 2009;
43 (3): 205-14
27. Rapaport MH, Gharabawi GM, Canuso CM, et al. Effects of risper-
idone augmentation in patients with treatment-resistant depression:
results of open-label treatment followed by double-blind continuation.
Neuropsychopharmacology 2006; 31 (11): 2505-13
28. Goodwin G, Fleischhacker W, Arango C, et al. Advantages and dis-
advantages of combination treatment with antipsychotics ECNP
consensus meeting, March 2008, Nice. Eur Neuropsychopharmacol
2009; 19 (7): 520-32
29. Crossley NA, Bauer M. Acceleration and augmentation of anti-
depressants with lithium for depressive disorders: two meta-analyses
of randomized, placebo-controlled trials. J Clin Psychiatry 2007; 68
(6): 935-40
30. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium
and T3 augmentation following two failed medication treatments
for depression: a STAR*D report. Am J Psychiatry 2006; 163 (9):
1519-30
31. Altshuler LL, Bauer M, Frye MA, et al. Does thyroid supplementation
accelerate tricyclic antidepressant response? A review and meta-anal-
ysis of the literature. Am J Psychiatry 2001; 158 (10): 1617-22
32. Aronson R, Offman HJ, Joffe RT, et al. Triiodothyronine augmenta-
tion in the treatment of refractory depression: a meta-analysis. Arch
Gen Psychiatry 1996; 53 (9): 842-8
33. Joffe RT, Sokolov ST, Levitt AJ. Lithium and triiodothyronine
augmentation of antidepressants. Can J Psychiatry 2006; 51 (12):
791-3
34. Candy M, Jones L, Williams R, et al. Psychostimulants for depression.
Cochrane Database Syst Rev 2008; (2): CD006722
35. Fava M, Thase ME, DeBattista C, et al. Modafinil augmentation of
selective serotonin reuptake inhibitor therapy in MDD partial re-
sponders with persistent fatigue and sleepiness. Ann Clin Psychiatry
2007; 19 (3): 153-9
36. Portella MJ, de Diego-Adelino J, Ballesteros J, et al. Can we really
accelerate and enhance the selective serotonin reuptake inhibitor anti-
depressant effect? A randomized clinical trial and a meta-analysis of
pindolol in nonresistant depression. J Clin Psychiatry 2011; 72 (7): 962-9
37. Whale R, Terao T, Cowen P, et al. Pindolol augmentation of serotonin
reuptake inhibitors for the treatment of depressive disorder: a sys-
tematic review. J Psychopharmacol 2010 Apr; 24 (4): 513-20
38. Rush AJ, Trivedi MH, Stewart JW, et al. Combining medications to
enhance depression outcomes (CO-MED): acute and long-term out-
comes of a single-blind randomized study. Am J Psychiatry 2011;
168 (7): 689-701
39. Carpenter LL, Yasmin S, Price LH. A double-blind, placebo-con-
trolled study of antidepressant augmentation with mirtazapine. Biol
Psychiatry 2002; 51 (2): 183-8
12
Drugs Ther Perspect 2011; Vol. 27, No. 12
