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Antidepressants: Pros and Cons

by Wellness Letter

Think of depression as part of a spectrum of moods, ranging from ordinary unhappiness, disappointment, and grief, to persistent depressive mood, to major depressive disorder. Different medications may help with the latter two categories along this spectrum. Because response to any particular treatment varies from one person to another, people who do not improve with the initial medication may respond to a different one.

Today about 12 percent of American adults take antidepressants, compared to 6.5 percent in 1999. And the number of people taking antidepressants long-term—more than 24 months—has doubled, from 3 percent to more than 6 percent. Americans are more likely to take antidepressants than people in any other country (Iceland is a close second).

In part this is because the diagnosis of depression has increased significantly. Also, the development—and marketing—of a newer generation of antidepressants has increased their acceptability to the public.

Developing antidepressants

The first modern antidepressants—monoamine oxidase inhibitors (MAOIs) and tricyclics—were developed in the 1950s. MAOIs such as phenelzine are rarely used these days because they can produce a sudden increase in blood pressure when combined with a large consumption of tyramine, an amino acid found in certain foods such as soy sauce. Tricyclics such as amitriptyline sometimes cause side effects like sedation and weight gain. (See inset below for other types of drugs.)

A newer class of antidepressants—selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, and paroxetine—hit the market in the 1980s and 1990s. They are thought to work by targeting serotonin receptors, raising levels of this mood-boosting neurotransmitter. SSRIs were followed by serotonin norepinephrine reuptake inhibitors (SNRIs), which also target receptors for norepinephrine, another neurotransmitter that’s important for emotions and attention.

Related medications called serotonin antagonist and reuptake inhibitors (SARIs) appear to act in two ways. They prevent the reuptake of serotonin and prevent serotonin from binding at certain undesired receptors.

Then there’s bupropion, which is thought to work on receptors for both norepinephrine and dopamine, a neurotransmitter involved with pleasure and many other important processes. Classified as a norepinephrine and dopamine reuptake inhibitor (NDRI), bupropion is often used as an augmenting medication in cases of incomplete response to an SSRI.

These newer drugs are not necessarily more effective than first generation MAOIs and tricyclics. But they often have fewer side effects and are safer.

The ABCs of Antidepressants

Here's a look at the nine classes of drugs used to treat depression, from monoamine oxidase inhibitors (MAOIs) and tricyclics to selective serotonin reuptake inhibitors (SSRIs) and serotonin modulators.

Side effects

For major depressive disorder, antidepressants—specifically SSRIs—are often a first treatment choice (frequently combined with psychotherapy). Most people tolerate these medications well, but they can cause side effects, including tremors, agitation, weight loss or gain, slowed heartbeat, sexual dysfunction, and falls leading to fractures. Most of these side effects go away in a week or 10 days. Side effects may be severe in older adults who are frail or ill. Another downside is a possible interaction with other drugs.

Antidepressants can produce a significant improvement within 4 to 8 weeks, al­­though it may take 12 to 16 weeks to see the full benefit.

Overall, studies seem to suggest that one-third of people get full remission on antidepressants, a third get some positive response, and a third don’t improve. About two-thirds of older adults with major depressive disorder won’t respond to initial treatment, so your health care provider may switch you to another class of antidepressants.

Finding the right drug

Identifying the best antidepressant treatment remains partly a process of trial and error. A 2017 study in the Journal of the American Medical Association offered evidence for one approach: Patients with major depression at 35 Veterans Health Administration medical centers who did not respond to at least one antidepressant were randomly assigned to one of three groups: one in which participants’ current antidepressant was replaced with bupropion, a second in which the current antidepressant was augmented with bupropion, or a third in which the current antidepressant was augmented with an antipsychotic drug (aripiprazole).

After 12 weeks, nearly 1,300 people had completed the treatment phase. In the group that switched to bupropion, slightly more than 22 percent experienced remission. Almost 27 percent of those who augmented their current treatment with bupropion went into remission. Of those who augmented their antidepressant with aripiprazole, nearly 29 percent experienced remission.

Finding the best treatment means weighing both the benefits and potential side effects. In this study, bupropion was associated with more reports of anxiety, and aripiprazole with sleepiness, weight gain, and a movement disorder called akathisia.

If your medication isn’t working or you are experiencing side effects, talk with your doctor about making a change.

Antidepressant Placebo Effect?

Virtually all drugs work at least in part via the placebo effect, and antidepressants apparently more so than most—at least for mild or moderate depression and in the short term.

This article first appeared in the UC Berkeley Wellness Letter.