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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 乌鸦传媒視頻. "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 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 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 乌鸦传媒視頻. 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.

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