For treatment-resistant depression, knowing the options for combining therapies is a key challenge for healthcare providers.
“You don’t need to be a specialist, you don’t need to be someone who
is in an academic medical center to quickly fill up your clinic with
patients who have experienced treatment failure with one or more
antidepressants or patients who have outright treatment-resistant
depression — it’s very common,” George Papakostas, MD, of Massachusetts
General Hospital in Boston, explained during a presentation at the
Psych Congress 2019 meeting.
However, with all the available options, clinicians can face
difficulties when not only choosing which agents to start as first-line
therapies, but which to add as adjunctive treatment — and when.
“I believe it is important to keep in mind that there should be a
rationale behind the decision of combining medications,” Marsal Sanches,
MD, PhD, associate professor of psychiatry at McGovern Medical School
at UTHealth in Houston, told
MedPage Today. “The number of
available psychiatric medications has increased dramatically over the
past 20 years and, while combining agents may result in potential
benefits for the patients — especially for those with
treatment-resistant conditions — some criteria should be adopted during
the decision-making process of combining medications.”
Strategies for Treatment Combinations
During another session at the Psych Congress 2019 meeting, Michael
Thase, MD, of the Perelman School of Medicine at the University of
Pennsylvania in Philadelphia, pointed attendees to the
American Psychiatric Association’s antidepressant treatment algorithm to help guide providers through the steps of prescribing antidepressants.
First-line antidepressant treatment should begin with an “adequate
trial” of one medication, he explained, typically a selective serotonin
reuptake inhibitor (SSRI) — such as escitalopram (Lexapro), fluoxetine
(Prozac), or sertraline (Zoloft) — or a serotonin-norepinephrine
reuptake inhibitor (SNRI), like duloxetine (Cymbalta), desvenlafaxine
(Pristiq), or venlafaxine (Effexor). If this first drug proves
ineffective, the provider should see if the patient was adherent to the
treatment, as well as ensure that the original diagnosis of major
depression was accurate and not actually bipolar disorder, PTSD, OCD, or
another condition that shares symptoms with depression.
The next step is to try another first-line antidepressant or
different class of medication, such as mirtazapine (Remeron, Remeron
SolTab).
Not until the third level in the treatment algorithm are combination
and adjunctive treatments advised. Add-ons might include an atypical
antipsychotic; some popular choices are aripiprazole (Abilify),
brexpiprazole (Rexulti), olanzapine (Zyprexa), or quetiapine (Seroquel).
Other adjunctive approaches, said Papakostas, include lithium,
omega-3 fatty acids, triiodothyronine (T3), L-methylfolate,
S-adenosyl-L-methionine (SAMe), and scopolamine infusions — none of
which are FDA-approved for major depressive disorder.
Also at this stage, other treatment options may include older
antidepressants like tricyclics or monoamine oxidase inhibitors (MAOIs).
If remission still isn’t achieved with combination pharmacological
therapies, the fourth step in the algorithm advises trying nondrug
neuromodulation strategies like electroconvulsive therapy or
transcranial magnetic stimulation. Still other options for
treatment-resistant depression at this level include the recently
approved
intranasal esketamine (Spravato)
— used in combination with an existing antidepressant — or ketamine
infusions. The final step in the treatment algorithm involves
experimental, unproven treatment strategies, or vagus nerve stimulation.
Papakostas warned against trying one monotherapy after another after
another, in an effort to avoid combination therapy. The landmark
Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial
showed how ineffective that can be. In this 2006 study, 67% of
treatment-naïve patients with major depression did not achieve remission
after monotherapy with the SSRI citalopram (Celexa). Then, those
patients who didn’t achieve remission who were then switched to another
antidepressant monotherapy — sertraline, bupropion-SR (Wellbutrin), or
venlafaxine-XR — in which 75% didn’t achieve remission. These
nonresponders were then switched to a third monotherapy — mirtazapine or
nortriptyline — where 90% failed to achieve remission. This was then
succeeded by a switch to a fourth antidepressant, where almost 90% still
failed to achieve remission.
“One of the big lessons of STAR*D is if antidepressant monotherapy
doesn’t work the first, or even the second time, it’s time to consider
building blocks — augmentation, combination — as being a more viable
option,” Papakostas underscored.
The specific treatment combinations should be carefully selected, however, as the
risk for drug-drug interactions
and side effects increases with polypharmacy, Manish Jha, MBBS,
assistant professor of psychiatry and neuroscience at the Icahn School
of Medicine at Mount Sinai in New York City, told
MedPage Today.
He continued, stating that metabolic side effects are some of the most
common events seen especially when combining antidepressants and adjunct
atypical antipsychotics. Metabolic side effects can present with weight
gain, glucose, and lipid changes. Other risks with these agents include
extrapyramidal symptoms like tardive dyskinesia, QTc prolongation, and
neuroendocrine issues.
Sanches agreed with this sentiment, stating: “while the combination
of medications may be a valuable strategy when properly utilized,
sometimes ‘less is more.'”
“In cases where a patient is already taking multiple medications and
still not responding well, it might be a good idea to stop and consider
replacing one or more of the medications in question if alternatives are
available,” he advised. “Of course, that needs to be carefully
balanced, taking into account the peculiarities — as well as the
preferences — of each patient.”
When prescribing combination treatments, another factor to keep in
mind is “the fact that some medications have very similar mechanisms of
action and combining them might not produce much improvement but
increase the risk of side effects,” Sanches added. “It is also important
to keep in mind that, sometimes, the same medication may be effective
to treat more than one condition, and that may be utilized to mitigate
the risk of polypharmacy.”
Jha advised providers shouldn’t be shortsighted when managing
patients with depression, recommending that, before prescribing a drug,
clinicians should think about what will happen when a patient stops it.
“If it’s continued for a long time, will there be any discontinuation
symptoms? And when the medication is stopped, what will be the risks?”
Combination treatment strategies for managing depression don’t stop
only with pharmacology, though. Sanches noted, “It is important to
remember the potential benefits of non-pharmacological treatments, such
as psychotherapy, which should always be considered, again depending on
the patient, the condition under treatment, and other factors,” he
suggested.
Papakostas reinforced this recommendation, urging consideration of
cognitive behavioral therapy as part of any depression treatment plan.
