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Why Aren’t Antidepressants Better By Now?

In addition to the side effects they often impart, it’s not even clear if SSRIs really work. Where are our better drugs?

Taking an SSRI can sometimes feel like running through a labyrinth. One path erases your sex drive. Another numbs your emotions, including the good ones. Then, after bumping into unexpected side effects for weeks, you realize that the maze you’re in is made up entirely of dead ends, because you were prescribed the wrong SSRI to begin with. All you can do now is try another one and hope it makes you feel better.

Why is it that SSRIs are so fickle like that? Don’t we have the know-how to make psychiatric drugs that aren’t side-effect slot machines, and instead work in predictable ways for the people who take them? 

Well, it’s complicated.

For starters, we’re still not entirely sure how SSRIs function. It’s believed that they increase serotonin levels in the brain, which is thought to enhance a person’s mood, but even experts can’t agree on that. The disagreements don’t stop there — some argue that SSRIs are no better than placebos, while others say they work quite well. Many agree that the side effects are serious — and that withdrawal can be a slog — but a prominent few, including Wendy Burn, former president of the Royal College of Psychiatrists, have at times considered them to be fleeting (Burn has since walked back her comments). A significant number (27 percent, according to one study) of people who take SSRIs also claim that they’re addictive, a concept that’s ripe for stormy Twitter debates. (Doctors don’t consider them to be addictive in the traditional sense, but stopping treatment — especially abruptly — can spur unpleasant withdrawal symptoms.)

One reason for all this controversy is that on the whole, psychiatric research has some problems. To start, it relies heavily on industry-funded studies, which is a major conflict of interest — for instance, the makers of SSRIs like Prozac and Paxil misled doctors and consumers between 1987 and 2004 by deliberately suppressing research that was less-than-complimentary of their medications. While published studies show that 60 percent of people who take these drugs experience relief from depression, that percentage shrinks when unpublished reports are included.

Furthermore, a 2010 report called Profitable Failure: Antidepressant Drugs and the Triumph of Flawed Experiments describes the many weaknesses of psychiatric trials, regardless of whether they’re performed by pharmaceutical companies. Psychiatrists have inconsistent approaches to diagnosing disorders, patient’s responses are subjective — i.e., happiness isn’t easily measured — and the real-world value of drugs that prosper in clinical settings is often exaggerated.

To make matters more complicated, mood disorders like depression aren’t fully understood, either. If SSRIs really do work by increasing serotonin levels, chemical imbalances are only one piece of the depression puzzle anyway. Genetics, stressful life events and trauma all contribute to the development of emotional ailments, and they may require more comprehensive treatment than a mere boost of serotonin.

This explains why there are multiple forms of depression — for example, persistent depressive disorder (which is mild but long-term); clinical depression (which is more palpable and interferes with your daily life); and treatment-resistant depression (which is the bane of psychiatrists everywhere). It also helps to explain why people react to SSRIs so differently.

“I didn’t like the later generation of drugs — Effexor and Lexapro — because I got ‘zaps’ [shock sensations in the brain] with them,” Mark, 51, says. I’ve personally taken Lexapro, and I experienced no such thing.

Now Mark prefers Zoloft. “I can forget about taking it for a few days and not feel terrible like I would with Effexor or Lexapro,” he explains. “The only real side effect I’ve experienced — and this isn’t a negligible one — is delayed ejaculation.” On the flip side, Isa, 18, tells me she’s been taking a generic form of Zoloft for years without any side effects whatsoever. “I’m quite sure it’s only ever helped,” she says.

Then there’s Alex, 29, who says high doses of Zoloft make him virtually “asexual.” When I ask Mark if he’s experienced anything similar, he says, “No real libido issues for me with Zoloft, fortunately.” It only impacts his ejaculation.

When you compare stories like these, it’s clear that SSRIs are a gamble, and nobody has quite the same odds. Combine the dissonance between psychiatric research with the complexities of mental disorders, and you can see why. In fact, it’s almost surprising that SSRIs work for so many people (about 40 to 60 percent of those who take them experience some relief, according to various studies).

But before you walk away thinking that psychiatry is a hoax and SSRIs are all over the map, we’ve actually come a long way in a short period of time. There’s evidence that humans have been suffering from depression for as long as we’ve been around, but we didn’t even begin to treat it appropriately until the 1950s. That’s when we developed one of the first generations of antidepressants (tricyclic antidepressants) and pursued psychopharmacology that addresses the source of a person’s mental ills, rather than merely masking their problems with powerful sedatives and hypnotics. 

And if you think SSRIs are temperamental, tricyclic antidepressants are even more likely to cause side effects like drowsiness, lightheadedness and a reduced sex drive. That’s because they affect chemical messengers beyond just serotonin, so in the process of making you happier, they run amok in your brain and cause all sorts of trouble.

It’s fortunate, then, that in 1988, 14 years after the first report on an SSRI was published, Prozac was released to the market, and many others followed. As the name “selective serotonin reuptake inhibitor” suggests, they’re much more selective than tricyclic antidepressants, which is why SSRIs have fewer side effects than and fewer harmful interactions with other drugs.

Other antidepressant medications have been released since then. For instance, serotonin-norepinephrine reuptake inhibitors (SNRIs) were introduced to the U.S. market in 1993. They prevent the reuptake of serotonin and norepinephrine, another chemical that’s believed to improve one’s mood, but much like everything we’ve discussed up until this point, nobody’s certain whether SNRIs are any better than SSRIs, which is why the latter are still commonly prescribed.

While it may seem like our nation’s psychopharmacological journey ends there, we’ve actually seen some movement in recent years, in part because our understanding of depression has developed. For example, we now know that the neurotransmitter glutamate and its interactions with the N-methyl-D-aspartate (NMDA) receptor play a role in mood disorders, which is why ketamine is currently being pursued as a treatment: It blocks the NMDA receptor.

There’s also a new drug called brexanolone, which was approved to treat postpartum depression in 2019. It’s the product of research into the GABA receptor system, which appears to play a role in depression as well.

These medications aren’t free of side effects either (both ketamine and brexanolone can cause drowsiness, for example). But the key point is that we’re widening our scope of depression and coming up with a multitude of options, which may very well be the best we can do when it comes to treating such a complex condition.

Among these options is genetic testing that matches a person’s biochemistry to a particular medication. As licensed mental health counselor Jacquelyn Tenaglia tells me, it “can help narrow down which psychiatric medications might align better with someone’s brain and body, decreasing the likelihood of side effects.” GeneSight Psychotropic, for example, performs DNA tests that they claim “can inform your doctor about how you may break down or respond to certain medications commonly prescribed to treat depression, anxiety, ADHD and other psychiatric conditions.”

These tests are (surprise!) controversial. In 2018, the FDA put out a warning about them, stating that they may produce inadequate results that potentially steer patients toward the wrong medications or doses, and studies on their accuracy have produced mixed results.

In a similar statement, the International Society of Psychiatric Genetics says the existing evidence is “inconclusive,” and they note that if a dozen patients were to take such a test for antidepressants, only one would benefit. Regardless, some insurance providers cover them, which is good news, because they’re expensive: GeneSight Psychotropic charges $2,000 per test.

They clearly need to work out the kinks, but this could be a major boon for the future of psychiatric drugs.

If you’re still not convinced of how far we’ve come, consider this: Lobotomies, which are now recognized to be both illogical and gruesome, earned their inventor the Nobel Prize in Physiology and Medicine in 1949, just over 70 years ago.

So, while SSRIs may kill your sex drive or make you gain a few pounds, they’re still better than some dude whisking your brain. And if we can go from lobotomies to SSRIs, ketamine and brexanolone in 70 years, just imagine what options we’ll have available in another 70.

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