LAS VEGAS (FRONTLINE MEDICAL NEWS) Only about 1 in 3 depressed patients achieve remission on the first antidepressant, and 4 in 10 subsequently relapse, according to Dr. Jonathan E. Alpert.

To complicate matters, no universally accepted definition or staging system exists for treatment-resistant depression. The definitions range from “failure to remit after a course of one antidepressant of adequate dose and duration” to “failure to respond to three or more courses of antidepressants as well as other treatments such as psychotherapy or electroconvulsive therapy,” Dr. Alpert said at the annual psychopharmacology update held by the Nevada Psychiatric Association.

“If broadly defined, treatment-resistant depression is the norm, rather than the exception. If more narrowly defined, it is still a very common clinical scenario,” he said. Known factors associated with nonremission include a history of chronic or recurrent depression; anxious, melancholic, or psychotic features; comorbid psychiatric and general medical conditions; socioeconomic adversity; minority ethnic/racial status; and having a lower quality of life and function prior to treatment.

When patients with major depressive disorder (MDD) do remit, revisit “the basics,” including adherence, diagnosis, comorbidities, and pharmacokinetics, Dr. Alpert advised. “I need to remind myself of these basics each time, because in the press of clinical practice, it’s compelling to just go on to the next antidepressant when somebody comes in and says, ‘Dr. Alpert, thank you very much, but the medication you gave me hasn’t touched my depression,’ ” he said. “There are over two dozen FDA [Food and Drug Administration]-approved antidepressants. There are all kinds of combination strategies and adjuncts that we can try, many of them off label but certainly in common use.”


Just because patients receive a medication doesn’t mean they’re taking it. “They might be sharing it with their son or with their grandmother, or they might not have been able to afford the copayments,” said Dr. Alpert of the department of psychiatry at Massachusetts General Hospital and Harvard Medical School, both in Boston. “There might be stigma when they go to their local pharmacy, and they were reluctant to fill the prescription. They may have been confused about what they were supposed to be taking.”

Primary diagnosis

It’s possible that the primary diagnosis is incorrect. For example, a patient with MDD might have occult psychotic features that were not asked about during previous office visits. It’s also possible that the patient has bipolar disorder or dementia. “There might be a CNS lesion if things don’t quite fit into the DSM-5 definition of depression,” he added.


Investigate possible comorbidities such as substance abuse, obsessive-compulsive disorder, posttraumatic stress disorder, or other medical conditions such as hypothyroidism that could complicate depression treatment strategies if not brought to light.


According to Dr. Alpert, many patients are rapid metabolizers of medications and require higher doses. Then there’s the potential for drug-drug interactions. “Some patients might be smokers or might be on Tegretol [carbamazepine] or phenobarbital, potent inducers of metabolism causing a need for higher levels of other medications in order [for patients] to respond,” he explained.

Three pharmacological approaches to treatment-resistant depression include switching, augmentation, and combination strategies. “We’re always thinking about cost, risk, and benefit, as with all clinical decision making,” said Dr. Alpert, who is also director of the depression and clinical and research program at Massachusetts General Hospital. “We try to share the decision making with our patients; it’s very important for them to be invested and knowledgeable about the decisions we’re making. Perseverance is a major feature of dealing with treatment-resistant depression. It’s not always the smartest psychopharmacologist who gets somebody better, but often it’s the psychopharmacologist who is willing to stick with a patient step by step and not blame them for not responding to treatment.”

Regarding a strategy to switch medications, little evidence exists for a differential benefit of one class over another, he said, with the following exceptions: selective noradrenergic reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) are superior to SSRIs for MDD with comorbid pain such as fibromyalgia and diabetic neuropathy. Bupropion is superior to SSRIs and SNRIs for MDD with antidepressant-related sexual dysfunction, nicotine dependence, or attention-deficit/hyperactivity disorder. Monoamine oxidase inhibitors are superior to TCAs in MDD with atypical features such as oversleeping, carbohydrate craving, rejection sensitivity, and mood sensitivity. “More complex agents such as SNRIs and TCAs may be superior to simpler agents such as SSRIs for more severely ill populations,” he said.

For patients who partially respond to an antidepressant, consider an augmentation strategy “in an effort to broaden the pharmacological profile as well as to target side effects such as sedation or sexual dysfunction,” Dr. Alpert said. Evidence is strong for atypical antipsychotics, particularly for olanzapine, aripiprazole, quetiapine, risperidone, ziprasidone, and brexpiprazole. “There is less good evidence for dopamine agonists and stimulants, though they are used widely,” he said.

Other augmentation options include lithium, buspirone and pindolol, as well as naturally occurring agents such as l-methylfolate, S-adenosylmethionine, creatine, omega-3 fatty acids, and cycloserine.

Combination strategies for MDD involve pairing two FDA-approved antidepressants. According to Dr. Alpert, the most common combinations are an SSRI or SNRI plus bupropion, or an SNRI plus mirtazapine, an approach “which I personally like very much.”

New approaches

There are some new approaches to treating MDD in the pipeline. “Since the 1950s, when antidepressants were discovered, we’ve focused on developing new agents that can better affect the monoamine, norepinephrine, and dopamine [pathways],” he said. “Much of our thinking has had to do with modulating monoaminergic mechanisms. Our animal models are geared toward testing monoamine drugs. It’s exciting that we’re on the cusp of looking at nonmonoaminergic mechanisms.”

Recent targets in the development of new antidepressants include mitochondrial function, inflammation processes, and neurogenesis, he said. Nonmonoaminergic mechanisms including kappa-opioid and neurokinin-1 receptor antagonists and a range of glutamatergic-modulating agents are a growing focus. In addition, rapid-acting antidepressants such as intravenous ketamine and scopolamine promise novel strategies for jump-starting treatment. “This could change the paradigm for how we think about depression treatment,” he said.

Dr. Alpert reported that in the past 12 months he has served as a consultant to Luye Pharma.


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