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Asian Journal of Psychiatry xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Asian Journal of Psychiatry

journal homepage: www.elsevier.com/locate/ajp

Review

Emerging antidepressants to treat major depressive disorder

Samantha G. Block a,*, Charles B. Nemeroff b,1
a
Department of Psychiatry and Behavioral Sciences, Jackson Memorial Hospital, University of Miami Hospital, Leonard M. Miller School of Medicine,
1695 N.W. 9th Avenue, Miami, FL 33136, USA
b
Department of Psychiatry and Behavioral Sciences, Center on Aging, Jackson Memorial Hospital, University of Miami Hospital, Leonard M. Miller School of
Medicine, University of Miami, 1120 Northwest 14 Street, Suite 1455, Miami, FL 33136, USA

A R T I C L E I N F O A B S T R A C T

Article history: Depression is a common disorder with an annual risk of a depressive episode in the United States of 6.6%.
Received 8 June 2014 Only 30–40% of patients remit with antidepressant monotherapy, leaving 60–70% of patients who do not
Received in revised form 3 September 2014 optimally respond to therapy. Unremitted depressive patients are at increased risk for suicide.
Accepted 6 September 2014
Considering the prevalence of treatment resistant depression and its consequences, treatment
Available online xxx
optimization is imperative. This review summarizes the latest treatment modalities for major
depressive disorder including pharmacotherapy, electroconvulsive therapy, repetitive transcranial
Keywords:
magnetic stimulation and psychotherapy. Through advancements in research to better understand the
Antidepressants
Major depressive disorder
pathophysiology of depression, advances in treatment will be realized.
Treatment ß 2014 Published by Elsevier B.V.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2. Pharmacology currently used to treat depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2.1. Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2.2. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) . . . . . . . . . . . . . . . . . . . . 000
2.3. Atypical antidepressants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2.4. Nefazodone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2.5. Vortioxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3. Antidepressants approved for use outside the United States. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.1. Tianeptine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.2. Moclobemide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.3. Reboxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.4. Agomelatine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4. N-methyl-D-aspartate (NMDA) receptors and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5. The HPA axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5.1. Monotherapy targets of the hypothalamic pituitary axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5.2. Augmentation therapy with hypothalamic–pituitary–adrenal axis targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6. Omega-3 fatty acids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
7. Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
8. Atypical antipsychotics (olanzapine, quetiapine, aripiprazole, and risperidone) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
8.1. Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
8.2. Thyroid hormone augmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
8.3. Buspirone augmentation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

* Corresponding author. Tel.: +1 305 355 8264.

E-mail addresses: sblock@med.miami.edu (S.G. Block), CNemeroff@med.miami.edu (C.B. Nemeroff).
1
Tel.: +1 305 243 6400/+1 305 243 8532.

http://dx.doi.org/10.1016/j.ajp.2014.09.001
1876-2018/ß 2014 Published by Elsevier B.V.

Please cite this article in press as: Block, S.G., Nemeroff, C.B., Emerging antidepressants to treat major depressive disorder. Asian J.
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8.4. Stimulant augmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000

8.5. Atypical antipsychotics as augmenting agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
8.6. Other augmenting strategies: Pindolol, yohimbine, testosterone/estrogens, and lamotrigine. . . . . . . . . . . . . . . . ............... . 000
8.6.1. Pindolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
8.6.2. Yohimbine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
8.6.3. Testosterone/estrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
8.6.4. Lamotrigine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
8.6.5. Mianserin, mirtazapine, and desipramine: Combination therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
9. Substance P . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
10. Electroconvulsive therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
11. Focal brain stimulation: Vagus nerve stimulation, transcranial magnetic stimulation, magnetic seizure therapy, deep brain stimulation . 000
11.1. Vagus nerve stimulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
11.2. Transcranial magnetic stimulation (TMS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
11.3. Theta burst stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
11.4. Magnetic seizure therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
11.5. Deep brain stimulation (DBS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
11.6. Transcranial direct current stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
12. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
13. Expert opinion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... . 000

1. Introduction 2. Pharmacology currently used to treat depression

Depression is a common disorder affecting nearly 16% of the 2.1. Tricyclic antidepressants (TCAs) and monoamine oxidase
population over the course of a lifetime with an annual risk of a inhibitors (MAOIs)
depressive episode of 6.6%. The condition is nearly twice as
common in women as in men. Only 30–40% remit with a single Tricyclic antidepressants were the first medication class used to
antidepressant treatment leaving nearly 60–70% of patients treat depression. Their primary mechanism of action is inhibition
who do not optimally respond (Kato and Chang, 2013a). Even of the reuptake of norepinephrine and/or serotonin. Monoamine
more problematic is the fact that the disease tends to recur, oxidase inhibitors block the enzymatic degradation of serotonin,
with greater than 75% of patients experiencing more than 1 norepinephrine and dopamine resulting in increased levels of
episode in a 10 year period. It is also responsible for the these neurotransmitters within the synaptic cleft. A large number
majority of almost 40,000 suicides per year in the United of randomized controlled clinical trials and meta-analyses confirm
States. Because of a lack of any validated predictors of response that both of these classes of drugs are effective in treating
to any of the evidence-based treatments for depression depression. However, the TCAs anticholinergic and antihistami-
including various approved antidepressants and psychothera- nergic side effect profiles limit their use (Holtzheimer and
pies, there is a trial and error approach to treating major Nemeroff, 2006) the TCAs can be lethal at 10 times or less the
depressive disorder. This concatenation of facts has led to a daily recommended dose, and can cause cardiotoxicity or seizures
large number of patients who have failed one or more FDA- as well (Schatzberg and Nemeroff, 2009). Additionally, problem-
approved treatments for depression, so-called treatment atic to the MAOIs, are their interaction with tyramine (and other
refractory depression (TRD). sympathomimetic amines) containing products. The selegiline
Older treatment modalities focus on three monoamine patch, a MAOI, is also FDA approved for the treatment of
neurotransmitter systems: serotonin, dopamine, and norepineph- depression. Unfortunately, as a class, these drugs have not shown
rine. Tricyclic antidepressants, selective serotonin reuptake increased efficacy in treatment refractory depression compared to
inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors first-line therapy and their side effect profile may limit their use.
(SNRIs), and monoamine oxidase inhibitors (MAOIs) are all However, there is some evidence that clomipramine may be more
effective antidepressants that increase the availability of one or effective than the SSRIs (Duval et al., 2006).
more of these monoamines. Although pharmacotherapy is often
chosen based on which symptoms predominate in an individual 2.2. Selective serotonin reuptake inhibitors (SSRIs) and serotonin
including changes in sleep, appetite, interest, guilt, energy, norepinephrine reuptake inhibitors (SNRIs)
concentration, psychomotor behavior, and suicidality, there is
little evidence to suggest that such symptoms predict response to Currently first-line treatments of depression include the SSRIs
one antidepressant versus another. and SNRIs. The SSRIs (including fluoxetine, sertraline, paroxetine,
More recent attempts have sought to identify genetic citalopram, and escitalopram) were introduced into the United
predictors of response or nonresponse to individual treatment. States between the years of 1987–2003, while the SNRIs
For example, the serotonin transporter gene (5HTTLPR) may (duloxetine, venlafaxine and desvenlafaxine) were introduced
predict response to some SSRIs and the gene coding a between 1995 and 2008. As the name suggests, their mechanism of
glucocorticoid co-chaperone protein, FKBPS, may predict re- action involves inhibiting the reuptake of serotonin, or serotonin
sponse to antidepressant treatment (Binder et al., 2004). This and norepinephrine, respectively, increasing the concentration of
review will not summarize the genetics of depression treatment these neurotransmitters within the synaptic cleft. Some (fluoxe-
which is reviewed elsewhere (Ozomaro et al., 2013), but instead tine and paroxetine) are potent inhibitors of the cytochrome P450
focuses on the newest treatment modalities for major depressive IID6 isoenzyme. Both classes of these drugs in men and women are
disorder including pharmacotherapy, electroconvulsive therapy, associated with sexual dysfunction and similar to all other
repetitive transcranial magnetic stimulation (TMS), and psycho- antidepressants take 6 to 8 weeks to become effective (Berton
therapy. and Nestler, 2006). The STAR*D trial was an effectiveness trial

Please cite this article in press as: Block, S.G., Nemeroff, C.B., Emerging antidepressants to treat major depressive disorder. Asian J.
Psychiatry (2014), http://dx.doi.org/10.1016/j.ajp.2014.09.001
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which assessed the response to various treatments after failure to
achieve remission with citalopram. Remarkably, less than a third of
depressed patients in this open trial achieved remission after doses
of up to 40 mg of the SSRI. One question of interest is whether a
nonresponder to an SSRI, would respond to an SNRI? The literature
is meager. The ARGOS and the STAR*D trials assessed this issue.
ARGOS showed an 8% advantage in achieving remission when
switching to a SNRI (venlafaxine), and the STAR*D trial showed a
7% advantage when using a SNRI; however neither of these
differences were statistically significant (Baldomero et al., 2005;
Rush et al., 2006). It is important to note that venlafaxine has been
reported to have the highest rate of lethality after overdose among
all of these agents, as well as a number of cardiovascular side
effects including hypertension and decreased heart rate variability.
2.3. Atypical antidepressants
The atypical antidepressants, a heterogeneous group, also
reportedly affect monoamine neurotransmitters, receptors, or
transporters. These include bupropion, mirtazapine, nefazodone
and trazodone, as well as several others not approved for use in the
US, but approved for use in other countries (mianserin, reboxetine,
and tianeptine). The mechanism of action of bupropion remains
obscure, as it is a very weak dopamine and norepinephrine
reuptake inhibitor. It has the advantage of lack of sexual
dysfunction. It is also approved for smoking cessation and has a
relatively favorable side effect profile, though unlike the SSRIs and
SNRIs it is not effective in treating syndromal anxiety disorders
(Schatzberg and Nemeroff, 2009). Mirtazapine increases the
release of noradrenaline, is a mild reuptake inhibitor and blocks
a-2 and 5HT receptor subtypes. It is approved for use in depression
and is reportedly particularly effective in elderly patients.
Mirtazapine has also shown efficacy in the treatment of dysthymia,
PTSD, social phobia, OCD, sleep disorders and chronic or recurrent
pain (Schatzberg and Nemeroff, 2009). A related drug, mianserin,
has a similar mechanism of action, but is not approved for use in
the US. Several meta-analyses, demonstrated the efficacy of both
mirtazapine and mianserin (Lopes Rocha et al., 2013); the major
drawback of mirtazapine is weight gain and sedation. Trazodone
both antagonizes the 5HT2 receptor and mildly inhibits the
reuptake of serotonin or noradrenaline. Side effects of trazodone
include sedation, orthostatic hypotension, and priapism, but the
latter is a rare event (Holtzheimer and Nemeroff, 2006; Schatzberg
and Nemeroff, 2009).
2.4. Nefazodone
Nefazodone is approved for the treatment of depression in the
United States by virtue of its efficacy in numerous placebo-
controlled trials. Similar to trazodone, it has potent selective
5HT2 antagonistic properties and weakly inhibits the reuptake of
serotonin and norepinephrine (Feiger et al., 1999). A study that
assessed nefazodone, psychotherapy, as well as a combination of
psychotherapy and nefazodone in chronically depressed patients
revealed response rates of 55% in the nefazodone group, 52% in the
psychotherapy group, and 85% in the combined-treatment group
(Keller et al., 2000). Side effects include nausea, headache, dizziness,
asthenia, dry mouth, constipation and somnolence (Schatzberg and
Nemeroff, 2009; Baldwin et al., 2001). More serious rare adverse
events include hepatotoxicity (Park and Ishino, 2013), which may
be fatal and resulted in an FDA black box warning.
2.5. Vortioxetine
Vortioxetine, a serotonin reuptake inhibitor, as well as an
antagonist at 5HT1D, 5HT3A and 5HT7 receptors and a partial
Please cite this article in press as: Block, S.G., Nemeroff, C.B., Emerging antidepressants to treat major depressive disorder. Asian J.
Psychiatry (2014), http://dx.doi.org/10.1016/j.ajp.2014.09.001
3
agonist at 5HT1A and 5HT1B receptors, has recently been approved
by the FDA for the treatment of major depression. Several studies
have been conducted assessing its efficacy at different dosages.
While not always statistically effective at under 5 mg (n = 611)
(Mahableshwarkar et al., 2013; Henigsberg et al., 2012; Katona
et al., 2012), at dosages between 10 and 20 mg, the drug
significantly reduced MADRS scores. There is evidence that
vortioxetine may have cognitive enhancing effects (Boulenger
et al., 2014). Side effects include nausea, headache, diarrhea, dry
mouth and dizziness.
3. Antidepressants approved for use outside the United States
3.1. Tianeptine
Tianeptine, approved for the treatment of depression in Europe
and Asia, but not in the United States, has an unknown mechanism
of action, though it reportedly increases serotonin reuptake and in
animal models restores neuroplasticity by increasing gene
expression of BDNF and nerve growth factor in the hippocampus
and the amygdala. It also has been shown to decrease dendritic
atrophy while normalizing glutamatergic neurotransmission
(Kasper and McEwen, 2008).
Tianeptine is as effective as amitriptyline, clomipramine,
imipramine and paroxetine in treating depression. Not only is
this drug beneficial in treating depression, but it has anti-anxiety
properties as well (Wagstaff et al., 2001).
A meta-analysis involving two studies showed no adverse
effects on libido. Adverse effects most commonly included
headache, nausea, constipation, abdominal pain, dizziness, dream
alterations, and dry mouth. The side effect profile is clearly
superior to that of TCAs (Wagstaff et al., 2001).
3.2. Moclobemide
Moclobemide, a reversible inhibitor of monoamine oxidase A,
increases the concentration of monoamines in the synaptic cleft. A
meta-analysis found moclobemide (OR = 6.98) to be significantly
more effective than placebo. Additionally, pairwise comparison
found moclobemide superior to fluoxetine (OR = 2.38) (Kriston
et al., 2014). Four large comparative trials have been published of
moclobemide treatment in depression. Silverstone (2001) demon-
strated its efficacy in bipolar depression Additionally, bipolar
patients treated with moclobemide were less likely than those
treated with imipramine to switch to a manic episode. Similar to
other MAOIs, moclobemide was shown to be effective in patients
with atypical depression (Sogaard et al., 1999). It has also been
shown to be effective in the treatment of dysthymia; 57% of the
patients responded after 8 weeks of treatment (Versiani et al.,
1997). Side effects include dry mouth and tachycardia, but the drug
appears to be well tolerated in the majority of patients (Tanghe
et al., 1997).
3.3. Reboxetine
Reboxetine is a potent and selective inhibitor of the norepi-
nephrine transporter, markedly inhibiting norepinephrine reup-
take. It has been approved for use in several European countries
including the United Kingdom and Germany since 1997. Several
meta-analyses have shown it to be effective in the treatment of
major depression. Papakostas et al. (2008) reported similar
response rates between SSRIs (63.9%) and reboxetine (59.2%). A
2013 Cochrane review suggested that reboxetine is less tolerable
than SSRIs (fluoxetine) and had a higher dropout rate in clinical
trials (Magni et al., 2013). Remarkably, a 2010 meta-analysis
combined both published and unpublished data and questioned its
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efficacy. Analysis of 13 trials that were placebo controlled, SSRI
controlled, or both, revealed no significant difference in remission
rates between placebo and drug (odds ratio 1.17, 95% confidence
interval 0.91 to 1.51; P = 0.216). Additionally, the published
literature, the authors suggested, overestimated the effect of drug
by 115% compared to placebo, suggesting significant bias (Eyding
et al., 2010). Reboxetine’s major side effects are constipation,
difficulty with urination in men, tachycardia and insomnia.
3.4. Agomelatine
Because depression is associated with alterations in circadian
rhythm and sleep disruption, agents that modify biological
rhythms have been suggested as novel antidepressants. Agome-
latine is an agonist at melatonin MT(1) and MT(2) receptors and an
antagonist at serotonin 5-HT2C receptors. It is approved for the
treatment of depression in Europe. Agomelatine has been shown to
improve sleep latency and sleep efficiency over a six week period
compared to sertraline (Kasper et al., 2010). A recent meta-analysis
suggests that agomelatine was comparable in efficacy to other
antidepressants including SSRIs and venlafaxine (Guaiana et al.,
2013). However, agomelatine was superior to placebo in the acute
treatment of depression (nine studies) (Koesters et al., 2013).
Another meta-analysis involving six studies and a total of 1997
patients (1001 agomelatine; 996 SSRI/SNRI) found a significant
advantage for agomelatine compared to SSRIs and SNRIs in
HAM-D total scores and the Clinical Global Impression-
Improvement scale (Kasper et al., 2013). Relapse prevention is
an important advantage of antidepressants. During a 6-month
period, relapse was significantly lower in patients on continued
agomelatine therapy compared to placebo (Goodwin et al.,
2009). Additionally, this drug has less sexual side effects than
SSRIs (Montejo et al., 2010). However, problematic are the
transient elevations in liver enzymes, which is one reason why
agomelatine is not approved for use in the US. Nausea and
vomiting are also less of a problem with agomelatine compared
to SSRIs (Guaiana et al., 2013).
4. N-methyl-D-aspartate (NMDA) receptors and depression
Glutamate, a neurotransmitter present in more than 80% of
neurons, binds to NMDA, AMPA and kainate receptors. There is
evidence for a role of glutamate in the pathophysiology of
depression (Mathews et al., 2012). Ketamine, an NMDA receptor
antagonist has been used as an anesthetic for more than
40 years. It was originally created as a similar but safer drug to
phencyclidine (Howland, 2013). Murrough et al. (2013) assessed
the effect of intravenously administered ketamine on patients
with treatment resistant depression; 64% of patients responded,
with one-third (NNT = 2.8) responding specifically to ketamine.
However approximately half of those treated relapsed within
one week of treatment (Murrough et al., 2013). Additionally, 17%
of those treated with ketamine had dissociative symptoms.
Ketamine has also been reported to be effective for bipolar
depression. In a double blind, placebo controlled, crossover study,
depression improved 40 min after infusion. 71% responded to
ketamine compared to 6% to placebo. Ketamine’s effect was
greatest at day 2 (Diazgranados et al., 2010). Shiroma et al. (2014)
reported that infusions of ketamine over a 12-day period resulted
in a 91.6% response rate and 66.6% remission rate in 12 patients
with treatment resistant depression. This was an open study with
no placebo or active comparison group. Recently, Naughton et al.
(2014) have reviewed the literature and suggested that there was
evidence for efficacy but needed additional study (Naughton et al.,
2014).
Please cite this article in press as: Block, S.G., Nemeroff, C.B., Emerging antidepressants to treat major depressive disorder. Asian J.
Psychiatry (2014), http://dx.doi.org/10.1016/j.ajp.2014.09.001
Although ketamine has been shown in small placebo-
controlled trials and meta-analyses to improve symptoms of
depression short-term, some concerns regarding the drug
include: safety, optimal dose, route of delivery, its effects on
perception and cognition (likely secondary to NMDA and AMPA’s
involvement in cognition), and duration of its antidepressant
effect (Mathew et al., 2008; Sanacora et al., 2012). Adverse effects
may be serious including damage to the kidneys, liver, and
neurotoxicity. There is significant potential for abuse and not all
patients are responders. Some non-responders carry the Val66-
Met single nucleotide polymorphism (SNP) associated with the
brain derived neurotrophic factor (BDNF) gene (Murrough et al.,
2013). Schatzberg (2014) has recently provided a thoughtful
commentary on the extant database, the lack of true ‘‘blindness’’
in the clinical trials and the concerns of creating a new epidemic of
drug abuse. Despite the problems with the drug, the NMDA
receptor shows promise as a novel target for antidepressant
development. Therefore other antagonists are under investigation
(including memantine, AZD6765, traxopridil, MK/0657, GLYX-13,
riluzole, RO4917523, and N-acetylcysteine) some of which will be
described below. Memantine exhibited no antidepressant effect
in a large double-blind trial despite its similar mechanism of
action to ketamine (Zarate et al., 2006). Whether this is because of
the higher affinity of ketamine for the NMDA receptor, or another
yet obscure pharmacological effect or the fact that it is
administered intravenously, is unknown and requires further
research (Mathew et al., 2008). CP-101,606, which blocks the
receptor-gated ion channel, was studied in 30 patients that were
randomized in a parallel study to receive paroxetine titrated up to
40 mg with either IV placebo or IV treatment medication. Patients
were found to have a greater decrease in depression with active
drug (60% response rate) from baseline compared to placebo (20%
response rate) (Preskorn et al., 2008). Additionally, MK-0657, a
selective NR2B antagonist, is being studied in patients who have
failed two other antidepressant treatment modalities (clinical
trials 2008). It has been analyzed in terms of efficacy for the motor
symptoms of Parkinson’s disease, with no benefit, and has been
shown to cause blood-pressure variability (Addy et al., 2009).
Independent of its efficacy in treating depression, there are
concerns with its safety profile. In summary, although there are
several drugs that target the NMDA receptor, much additional
research is necessary.
5. The HPA axis
5.1. Monotherapy targets of the hypothalamic pituitary axis
Corticotropin releasing factor (CRF) is secreted from the
hypothalamus and enters the hypothalamic–hypophyseal portal
circulation where it stimulates the release of ACTH from the
anterior pituitary gland. ACTH in turn causes the release of cortisol
(Schatzberg and Nemeroff, 2009; Currier and Nemeroff, 2010). A
substantial number (40–60%) of severely depressed patients have
elevated cortisol levels and a disruption of the normal diurnal
cortisol rhythm. In addition to the elevated cortisol levels,
depressed patients also have elevated concentrations of CRF in
cerebrospinal fluid (CSF) (Nemeroff et al., 1984) much derived
from extra-hypothalamic sources. Thus, any strategy that reduces
HPA axis activity has been suggested to possess promise as a novel
antidepressant approach. Therefore, several anti-glucocorticoids
(metyrapone, aminogluthemide, mifepristone, ketoconazole)
have been studied (Schatzberg and Nemeroff, 2009; Kling et al.,
2009).
A Cochrane review included nine randomized controlled trials
that studied antiglucocorticoid (mifepristone, ketoconazole,
metyrapone or DHEA) treatment of depression. Five trials assessed
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non-psychotic depression, and there was a significant difference in
favor of antiglucocorticoid treatment. Psychotic major depression
was not significantly affected by antiglucocorticoid treatment.
Although a study with mifepristone using plasma concentrations
to assess drug exposure have been positive (Blasey et al., 2009),
several studies with CRH R1 receptor antagonists as monotherapy
have failed (Holtzheimer and Nemeroff, 2008).
5.2. Augmentation therapy with hypothalamic–pituitary–adrenal
axis targets
Additionally, medications that affect the HPA axis have been
studied as augmentation agents in the treatment of depression.
Patients treated with either nefazodone or fluvoxamine received
either placebo or metyrapone. More patients responded to
treatment when metyrapone was added ((day 21: 23 of 33
patients) and day 35: 19 of 33 patients) compared with placebo
(day 21: 13 of 30 patients; Fisher exact P = 0.031; day 35: 10 of 30
patients; Fisher exact P = 0.047). Additionally, patients treated
with drug, had a faster response starting in the first week (Kaplan-
Meier analysis; log-rank test P < 0.006) (Jahn et al., 2004).
Remarkably, no studies using CRHR1 antagonists added to SSRI
non-responders have been conducted.
6. Omega-3 fatty acids
Studies have suggested that cultures with diets higher in
omega-3 fatty acids have lower rates of depression, whereas
cultures with diets lower in omega-6 fatty acids have higher rates
of depression. Meta-analyses studying omega-3 fatty acids and
their efficacy on depression have been questioned because of bias
and lack of consistency between studies. Additionally, some
smaller studies have found no significant difference between
omega-3 fatty acid treatment and placebo (Rakofsky et al., 2009).
In 13 randomized, placebo-controlled trials studying omega-3
fatty acids (n = 731 participants), a meta-analysis of major
depressive disorder showed no significant benefit of omega-3
fatty acid treatment compared to placebo. Additionally, there
was heterogeneity and publication bias between studies (Bloch
and Hannestad, 2012). Freeman and Rapaport (2011) has
discussed this heterogeneity citing the short duration, varying
dosages, and fatty acids being adjunctive to other medications as
confounding variables. Some suggest genetic polymorphisms
(FADS1 and FADS2) may influence the rate at which omega-3
fatty acids are metabolized and that these genes can predict
response to omega-3 fatty acids in the treatment of depression.
Additionally, there is evidence that high ratios of EPA:DHA may
be associated with response to omega-3 fatty acids in major
depressive disorder and bipolar depression. The lack of consis-
tent results between studies, the small number of studies,
and the fact that the studies themselves have a small number
of subjects suggest that further research is necessary before
definitive recommendations can be made (Freeman and Rapa-
port, 2011; Freeman, 2009).
7. Inflammation
There is considerable evidence of a link between inflamma-
tory cytokines and depression. TNF, IL-1, and IL-6 have all been
shown to be elevated in plasma of depressed patients and
associated with nonresponse to conventional antidepressants.
Therefore, anti-inflammatory agents have been hypothesized to
represent a novel treatment for depression. Interferon-a
increases TNF, IL-1, and IL-6 plasma concentrations and 40–
50% of interferon-a treated patients exhibit depressive symp-
toms and develop syndromal major depressive disorder which is
Please cite this article in press as: Block, S.G., Nemeroff, C.B., Emerging antidepressants to treat major depressive disorder. Asian J.
Psychiatry (2014), http://dx.doi.org/10.1016/j.ajp.2014.09.001
5
responsive to antidepressant treatment (Musselman et al.,
2001).
Raison et al. (2013) studied the pharmacological inhibition of
TNF-a with infliximab and whether it possesses antidepressant
properties in SSRI-refractory patients. There was no significant
overall difference in the change of HAM-D scores with infliximab
versus placebo. However, there was a significant interaction when
assessing treatment, time, and log baseline CRP concentrations. In
fact, CRP concentrations greater than 5 mg/L at baseline was
associated with a positive treatment response (50% reduction in
HAM-D score at any point during treatment) of 62% (8 of 13
patients) with infliximab compared to 33% (3 of 9 patients) in
placebo-treated patients (Raison et al., 2013). Likewise, the TNF
antagonist, etanercept, previously shown to possess antidepres-
sant effects in patients with psoriasis (Tyring et al., 2006) has
recently been shown to possess anti-anxiety and antidepressant
effects in a rat model. Thus, rats treated with etanercept exhibited
decreased immobility time in the rat model of despair (Bayr-
amgurler et al., 2013). Another study assessed celecoxib, a Cox2
inhibitor, as an augmenting agent to reboxetine. Superior results
were found using celecoxib compared to placebo (Currier and
Nemeroff, 2010).
8. Atypical antipsychotics (olanzapine, quetiapine,
aripiprazole, and risperidone)
Although antipsychotics primarily target the dopamine D2
receptor, second-generation antipsychotics also target the seroto-
nin 5HT1A and 5HT2 receptors. Through these and other
mechanisms, atypical antipsychotics have been postulated to
possess antidepressant properties. The largest meta-analysis of
second-generation antipsychotics for major depressive disorder
and dysthymia found that quetiapine monotherapy was more
effective than placebo in treating depression symptomatology,
whereas olanzapine, compared to placebo had no benefit in
depressive symptom treatment of psychotic depression (n = 184,
2 RCTs, MD 2.86; 95% CI 6.19 to 0.47). Risperidone has not been
studied as monotherapy for the treatment of depression (Komossa
et al., 2010).
8.1. Lithium
In 1981, lithium was demonstrated to be effective as an
augmenting agent in the treatment of depression in patients who
failed to respond to TCAs. Although better studied in patients
treated with TCAs, meta-analyses have shown lithium to be
effective when combined with SSRIs as well. In a meta-analysis of
9 placebo controlled trials, lithium was effective as an
augmenting agent for conventional antidepressant therapy
compared to placebo (OR = 3.31) (Bauer and Dopfmer, 1999).
Another, more recent meta-analysis included 10 randomized
placebo-controlled trials and showed a higher response rate with
lithium augmentation (41.2%) compared to placebo (14.4%)
(OR = 3.11, NNT = 5). Additionally, there have been suggestions
that patients with the —50T/C SNP of the GSK3 gene may be more
responsive to lithium augmentation (Bauer et al., 2010). Part of
the difficulty prescribing lithium is the need to titrate its dosage,
the need for monitoring of blood levels and its side effect profile.
It often acts quickly but may take up to six weeks to become
effective. Dosages start between 600 and 900 mg/day with a
blood level of at least 0.5 mEq/L required to be effective (Chang
et al., 2013). The drug has a long-term effect on renal and thyroid
function and these should be monitored regularly. However, of
all of the augmentation strategies, lithium has perhaps the
strongest scientific evidence as an augmentation agent in the
treatment of depression.
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8.2. Thyroid hormone augmentation
Several studies have assessed the use of tri-iodothyronine (T3)
as an augmentation agent to TCAs and SSRIs for the treatment of
depression. A 2009 meta-analysis with 444 patients combined
results of 4 studies in which T3 combined with SSRIs was not
superior in efficacy to SSRI monotherapy. However, these patients
did not fulfill criteria for treatment resistant depression (TRD)
(Papakostas et al., 2009). The STAR*D trial, in contrast, compared
lithium and thyroid hormone as augmenting agents for patients
who failed 2 treatment regimens. Thyroid hormone was superior
to lithium, achieving remission in 24.7% of patients compared to
15.9% treated with lithium (Nierenberg et al., 2006). Our more
recent trial sought to determine whether T3 accelerated or
enhanced the effect of sertraline in 153 patients without treatment
refractory depression (Garlow et al., 2012). There was no added
benefit of thyroid hormone to sertraline, perhaps because the
sertraline dosage was increased to achieve optimal benefit. There
are few side effects of T3 in the doses utilized (25–50 mg/day).
8.3. Buspirone augmentation
Buspirone acts as a partial agonist at the 5HT1A receptor and
has been studied as both monotherapy and augmentation therapy
in the treatment of depression. In the STAR-D study, patients with
non-psychotic major depression treated with citalopram who did
not achieve remission were augmented with buspirone or
bupropion. HRSD-17 remission was achieved in 30.1% of patients
treated with buspirone (Trivedi et al., 2006). Despite the
improvement in depression, buspirone had a higher dropout rate
than bupropion. Other studies have suggested that although
buspirone may accelerate the antidepressant response resulting in
a significantly greater reduction in the MADRS score after 1 week of
treatment, there is no overall effect on depression compared to
placebo (Appelberg et al., 2001). Side effects of buspirone include
gastrointestinal symptoms, dizziness, insomnia, palpitations,
paresthesias and sweating (Kishi et al., 2013).
8.4. Stimulant augmentation
Anhedonia, the inability to experience pleasure, is a cardinal
feature of depression. The main neurotransmitter involved in the
brain’s reward system is dopamine (DA). Stimulants, approved for
the treatment of attention deficit disorder, increase the release of
DA and 5HT as well as weakly block the reuptake of these amines.
For this reason, researchers have suggested that stimulants may
have some utility in the treatment of depression. In one study,
patients who continued to have depressive symptoms after
therapy were assigned to receive either placebo or OROS
methylphenidate. There was no significant effect on MADRS
scores. However, OROS methylphenidate was more effective than
placebo in improving apathy and fatigue (Ravindran et al., 2008).
Two large randomized controlled trials of lisdexamfetamine in the
treatment of MDD in SSRI non-remitters revealed no efficacy of the
psychostimulant (Shrie, 2014). A double blind, placebo-controlled
study assessed adjunctive modafinil or placebo (to an SSRI) and
found that modafinil did not have any benefit (Dunlop et al., 2007).
A Cochrane review published in 2008 included 13 trials for meta-
analysis. Three trials (62 participants) suggested that psychosti-
mulant monotherapy significantly decreased depressive symp-
toms compared to placebo. However, modafinil and placebo were
not different. Additionally, the literature is primarily comprised of
small trials over short time periods. Atomoxetine, a norepineph-
rine (NE) reuptake inhibitor, used in the treatment ADHD, also has
shown no benefit in augmentation of sertraline. Similarly,
edivoxetine, another NE reuptake inhibitor, failed in three
Please cite this article in press as: Block, S.G., Nemeroff, C.B., Emerging antidepressants to treat major depressive disorder. Asian J.
Psychiatry (2014), http://dx.doi.org/10.1016/j.ajp.2014.09.001
randomized controlled trials to augment the effects of SSRIs
in MDD.
8.5. Atypical antipsychotics as augmenting agents
As noted above, atypical antipsychotics have been studied in
depression both as monotherapy and as augmentation agents.
Aripiprazole was the first of the second generation antipsychotics
to obtain approval by the FDA for antidepressant augmentation.
Since then, both quetiapine XR and olanzapine, when added to
fluoxetine, have been approved for the acute treatment of
depression (Kato and Chang, 2013b). Two major meta-analyses
have addressed the efficacy of second generation antipsychotics as
augmentation therapy with antidepressants (Nelson and Papa-
kostas, 2009; Komossa et al., 2010). Nelson and Papakostas
included 16 studies and calculated a pooled OR for response rate of
1.69 [95% confidence interval (CI) 1.46 to 1.95, P < 0.00001], with a
NNT equal to nine. For all antipsychotics studied there was an
improvement in response rate: Aripiprazole OR = 2.07, olanzapine
OR = 1.39, quetiapine OR = 1.60, and risperidone OR = 1.83. Side
effects of second-generation antipsychotics include sedation,
dizziness, insomnia, akathisia, weight gain, Q–T prolongation
and metabolic syndrome.
8.6. Other augmenting strategies: Pindolol, yohimbine, testosterone/
estrogens, and lamotrigine
8.6.1. Pindolol
Pindolol, a b-adrenoreceptor and 5HT1A somatodendritic
autoreceptor, antagonist has been studied as an augmenting agent
in depression. Patients treated with pindolol and citalopram had a
higher likelihood of continued remission (OR = 5.00, 95% CI 1.191–
20.989) and exhibited an earlier response, 65% less (22 days vs. 30
days) compared to placebo (Portella et al., 2011). These results
were largely confirmed with meta-analysis (Portella et al., 2011)
though negative findings of pindolol combined with paroxetine
have been reported (Geretsegger et al., 2008).
8.6.2. Yohimbine
Because a-2 adrenoreceptor blockade increases the firing rate
of 5HT neurons, this drug has been posited to augment the action of
antidepressants. Patients (n = 25/group) were assigned to receive
either fluoxetine 20 mg plus placebo (F/P) or fluoxetine 20 mg plus
yohimbine (F/Y), the latter titrated based on blood pressure
changes for 6 weeks. Clinical global impression ratings and the
Hamilton depression rating scales were used to monitor treatment
response. Response was achieved faster with F/Y compared to F/P
and the MDD patients had higher response rates; 18/26 (69%) vs.
10/24 (42%) in the yohimbine group using the CGI79. This suggests
that a-2 antagonism may serve some utility for the treatment of
depression. Surprisingly, other a-2 antagonists such as dazoxan,
have not been studied in this area.
8.6.3. Testosterone/estrogens
In a pioneering study, Pope et al. (2010) reported that men with
depression who had undiagnosed hypogonadism, when treated
with testosterone, experienced a clear improvement of
depression. A meta-analysis of seven studies found a significant
positive effect of testosterone therapy on HAM-D response when
compared with placebo (z = 4.04, P < 0.0001) (Zarrouf et al., 2009).
There is clear evidence for a role for estrogen deficiency in
depression especially in the premenopausal and postmenopausal
period (Soares, 2008; Soares and Frey, 2010). Indeed our group was
involved in one of the first studies demonstrating a higher response
rate to fluoxetine in postmenopausal depressed women on
hormone replacement therapy (HRT) (Schneider et al., 1997).
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There is also evidence that estrogen may have a role in the
treatment of postpartum depression (Gregoire et al., 1996).
8.6.4. Lamotrigine
An inhibitor of voltage sensitive sodium channels, lamotrigine
has recently been approved for the prevention of episodes of
bipolar depression. There is no evidence that it is effective in the
treatment of unipolar MDD or in the acute management of mania
(Schatzberg and Nemeroff, 2009).
8.6.5. Mianserin, mirtazapine, and desipramine: Combination therapy
A combination approach to antidepressant therapy in non-
responders has been suggested on the basis of combining
antidepressants with different mechanisms of action. There are
two methods for this approach. Either two antidepressants can be
started on initiation of treatment, or a second agent can be added
after the first was unsuccessful in achieving remission. Lopes
Rocha et al. (2013) attempted to perform a meta-analysis on trials
using dual antidepressant therapy (Sanacora et al., 2004). They
reported only two small studies that suggested a benefit of treating
depression with an antidepressant combination (Ferreri et al.,
2001; Carpenter et al., 2002). The notion of combination therapy
was supported by Nelson et al. (2004) when his team found that
desipramine (dosed according to plasma adjusted level) plus
fluoxetine (20 mg/day) was more effective than either drug alone
(53.8%, 0% and 7.1% remission rates, respectively). Blier et al.
published two supportive studies. One assessed mirtazapine
(30 mg/day), paroxetine (20 mg/day), or a combination of both
mirtazapine and paroxetine. At day 42, there was a 10 point
difference in MADRS score when comparing monotherapy and
combination therapy, favoring combination therapy (Blier et al.,
2009). A later study confirmed these results. Remission rates were
higher with combination therapy versus fluoxetine monotherapy
(Blier et al., 2010). A large trial assessed the effect of monotherapy
or combination therapy for depression in patients with heart
disease. Neither depressed patients with heart disease or those
without heart disease exhibited any differences in response to
antidepressant monotherapy versus combination therapy (Kerber
et al., 2012).
9. Substance P
Substance P is a CNS neuropeptide neurotransmitter that acts
primarily on neurokinin (NK) receptors. Although an early study
(Kramer et al., 1998) suggested antidepressant efficacy of an NK1
antagonist, MK869 (aprepitant) later double blind studies failed to
confirm those findings (Keller et al., 2006).
10. Electroconvulsive therapy
Electroconvulsive therapy, usually used in cases of medication
refractory depression, induces a seizure in the patient and is widely
believed to be the most effective antidepressant treatment
(Matthews et al., 2013; Kellner et al., 2006). In fact, it is considered
first-line for major depressive disorder with severe suicidal
ideation or severe depression with psychotic features because of
its repeatedly proven efficacy and fast onset of action. Although in
almost all cases it is utilized after failure of one or more
antidepressant medications, a meta-analysis showed that the
overall remission rate was 48.0% (281/585) for patients with and
64.9% (242/373) for patients without prior pharmacotherapy
failure. The requirement for general anesthesia and a muscle
paralyzing agent prevents an overt tonic–clonic seizure. ECT’s
memory impairment is a major drawback, as well as the stigma
associated with its use.
Please cite this article in press as: Block, S.G., Nemeroff, C.B., Emerging antidepressants to treat major depressive disorder. Asian J.
Psychiatry (2014), http://dx.doi.org/10.1016/j.ajp.2014.09.001
7
11. Focal brain stimulation: Vagus nerve stimulation,
transcranial magnetic stimulation, magnetic seizure therapy,
deep brain stimulation
11.1. Vagus nerve stimulation
Vagus nerve stimulation (VNS) was first performed in the 1980s
and was FDA-approved for the treatment of pharmaco-resistant
epilepsy. Patients with epilepsy treated with VNS were noted to
exhibit improvements in mood. It was approved by the FDA in
2005 for the treatment of depression in patients over the age of
18 who failed two or more antidepressant treatment regimens. An
electrode is surgically attached to the left vagus nerve and a
generator that delivers a pulse is implanted into the chest wall.
Side effects include hoarseness, difficulty swallowing, or cough.
Part of the criticism of the vagus nerve stimulation data is the lack
of RCTs. In fact, a 10 week randomized controlled trial including
235 patients did not show a significant effect for vagus nerve
stimulation compared to placebo (OR = 1.61; P = 0.25) (Rush et al.,
2005). However, a meta-analysis conducted in 2012 showed a
significant reduction in Hamilton Depression Rating Scale scores,
with 31.8% of subjects becoming responders ([23.2% to 41.8%],
P < 0.001) (Martin and Martin-Sanchez, 2012).
11.2. Transcranial magnetic stimulation (TMS)
Transcranial magnetic stimulation (TMS) is FDA approved for
depression in patients who have failed to respond to one, but not
more than one, antidepressant trial. It is the least invasive of the
brain stimulation techniques and most frequently targets the
dorsolateral prefrontal cortex (DLPFC). A magnetic field is
produced around the brain and an electrical current is delivered
through the cortex. Frequencies vary from 1 to 50 Hz with low-
frequency pulses causing less excitability in the cortex than higher
frequency pulsations. This form of treatment has been shown in
several meta-analyses to be as effective as both an augmenting
agent and monotherapy for the treatment of major depression. A
2013 meta-analysis included 8 randomized controlled trials
comprised of 263 patients. After a mean of 12.6  3.9 rTMS
sessions, 38.2% and 15.1% of subjects receiving active LF-rTMS and
sham rTMS were responders, respectively (OR = 3.35) whereas 34.6%
and 9.7% of subjects were classified as remitters (OR = 4.76) (Berlim
et al., 2013). However, different meta-analyses have produced
conflicting results as to whether active rTMS is more effective than
sham rTMS. Most randomized controlled trials found active rTMS to
be more effective than sham rTMS. Problematic is the lack of
standardization of rTMS parameters with frequencies ranging
between 0.17 Hz and 40 Hz, treatments lasting between 5 and
20 days (magnetic stimulation requires daily treatment), and
between 30 and 4800 pulses applied per treatment session. For this
reason, clear guidelines are necessary.
Deep brain TMS (DTMS) over the prefrontal cortex has been
shown to help apathy and depression. Higher intensity stimulation
is likely more effective than lower intensity stimulation and
baseline apathy may help predict whether or not DTMS can lead to
remission (Levkovitz et al., 2009, 2011). Studies have also shown
that continuation of H-coil rTMS may help maintain an antide-
pressant effect following the acute treatment phase (Harel et al.,
2014). Side effects are relatively mild and include headaches,
dizziness, and scalp discomfort (Hovington et al., 2013).
11.3. Theta burst stimulation
Theta burst stimulation (TBS) is a form of TMS that affects
synaptic plasticity rapidly and can produce long-lasting effects on
corticospinal excitability. Whereas intermittent TBS causes a
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potentiation-like effect on cortical excitability, continuous TBS
causes a reduction in excitability. A 2014 study compared
continuous TBS, intermittent TBS, a combination of continuous
and intermittent TBS and sham TBS. Intermittent TBS combined
with continuous TBS was most effective for treating depression (Li
et al., 2014). Another study provided intermittent enhancing TBS to
the left dorsolateral prefrontal cortex (dlPFC) and inhibiting
constant TBS (cTBS) to the right dlPFC, or bilateral sham
stimulation. Bilateral TBS was a safe, more effective form of
treating MDD than bilateral sham stimulation (OR = 3.86) (Plewnia
et al., 2014).
11.4. Magnetic seizure therapy
Magnetic seizure therapy (MST), not FDA approved, uses a
device that causes a series of magnetic pulses to be delivered to the
patient while the subject is under general anesthesia. It can be
thought of as a hybrid of TMS and ECT in that it combines
the antidepressant effects of both therapies without causing the
cognitive impairment characteristic of ECT. Compared to ECT, MST
is more focal, stimulating primarily only cortical gray matter, as
opposed to both gray and white matter. Additionally, MST differs
from ECT in how it propagates the seizure. However, there is no
dosing algorithm or suggested coil configuration at this time. In a
2013 pilot study of 13 patients who received 18 treatments with
100-Hz MST, five patients met clinical response criteria, without
cognitive side effects (Fitzgerald et al., 2013). Trials are still limited
and relatively small; therefore, further research is required in this
area (McClintock et al., 2011).
11.5. Deep brain stimulation (DBS)
Deep brain stimulation is not FDA approved for the treatment of
refractory depression. The procedure involves implanting electro-
des into the brain bilaterally and delivering a pulse that alters the
activity of targeted circuits. It is approved for Parkinson’s disease
and has replaced ablative therapy because of its reversible nature
and therapeutic efficacy (Mayberg, 2007). Lozano et al. (2012)
studied 21 patients with subcallosal cingulate gyrus (SCG)
Brodman’s area 25 deep brain stimulation and found a 57%
response rate at 1 month, 48% at 6 months, and 29% at 12
months. Following completion of a one-year study of DBSadmi-
nistered bilaterally to the SCG, 20 patients were assessed at
baseline, year 1, year 2 and year 3; 62.5%, 46.2%, and 75.0%
responded after years 1, 2, and 3, respectively. HAMD scores
decreased significantly at all time points (Schlaepfer et al., 2013). A
recent industry sponsored trial of SCG directed DBS did not
demonstrate efficacy versus sham controls, a finding similar to an
internal capsule directed DBS study conducted earlier. Seven
patients with refractory depression had DBS delivered to the
supero-lateral branch of the medial forebrain bundle; 6/7 achieved
response criteria 7 days after stimulation with 6/7 continuing to
meet response at 6 months and 4/7 met remission (Bewernick
et al., 2010). DBS of the nucleus accumbens in 10 patients resulted
in 5 who were responders at 12 months. Compared to those
patients who were nonresponders, responders had deceased
metabolism in the amygdala. DBS also produced anxiolytic effects
(Kennedy et al., 2011).
11.6. Transcranial direct current stimulation
Transcranial direct current stimulation (tDCS) is a noninva-
sive treatment that modulates cortical excitability and neural
activity. Studies have disputed whether it is an effective
treatment for major depression. A 2012 meta analysis of six
RCTs found active tDCS more beneficial than sham tDCS (Hedges’
Please cite this article in press as: Block, S.G., Nemeroff, C.B., Emerging antidepressants to treat major depressive disorder. Asian J.
Psychiatry (2014), http://dx.doi.org/10.1016/j.ajp.2014.09.001
g = 0.743, 95% CI 0.21–1.27). However, results between studies
differed more than explained by chance (Kalu et al., 2012). A
2013 study assessed MADRS scores between sham and active
TDCS groups and found significant benefit in dysphoria for active
TDCS. Both active and sham tDCS improved vegetative and
retardation symptoms (Alonzo et al., 2013). Further research is
needed.
12. Conclusion
While there are many effective treatments for depression, many
patients continue to suffer with unrelenting severe depressive
symptoms. Unfortunately, a trial and error approach to therapy has
become the norm, rather than the exception. Some guidelines exist
to help physicians optimize therapy, but no significant recent
breakthroughs have been reported. However, as personalized
medicine is realized with its focus on genomics and imaging, a
patient-centered protocol tailored to each individual is an
attainable goal.
13. Expert opinion
For years, the treatment of depression has focused on drugs that
act on monoamine neurotransmitter systems. Recent develop-
ments in the field have addressed different neural pathways
involved in the etiology of depression. Despite these advances, few
breakthroughs have been realized. As in other branches of
medicine, an evidence-based, patient tailored approach must be
utilized. A better understanding of the pathophysiology of
depression is a prerequisite for further advances in the field.
Currently available antidepressants and augmenting agents are
clearly effective in the treatment of the majority of depressed
patients.
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