Depression: The drugs don’t work, so what now?

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For years, psychiatrists have followed a strict four-step program of pharmaceuticals—but the approach is in tatters after new studies discovered it was based on bad science. Bryan Hubbard reports

How do we treat depression? Right now, modern psychiatry doesn’t know after its drugs approach—which involves ever-increasing levels of potency and combinations of antidepressants—has been found not to work.

Since 2006, psychiatrists around the world have followed the four-step program of juggling different doses and types of pharmaceuticals, convinced that the approach would achieve remission for around 70 percent of patients, but it does so for just half that many. And even those successes are suspect, a new study has found.

A psychiatrist who writes out a prescription for an SSRI (selective serotonin reuptake inhibitor) antidepressant will be pretty sure the drug won’t work. The dose could be too low, it could be the wrong SSRI for the patient or it may need to be taken along with another drug.

Just a quarter of antidepressant prescriptions get it right the first time, and even then, it’s more likely the result of the placebo effect than the effectiveness of the drug. The theory that a chemical imbalance is the cause of depression and that SSRIs right that imbalance has never been proven.

Most patients don’t even have a placebo response—and for these, the psychiatrist increases the dose after about six weeks.

If that fails to ease the depression, the psychiatrist will likely try Step 2: a different antidepressant. Or they may augment the first drug with another antidepressant, typically Wellbutrin (bupropion), or the anti-anxiety drug Buspar (buspirone).

Step 3 is basically the same as Step 2, another choice to either switch or try a different combination, usually including thyroid hormone. Lithium, an antipsychotic, used to be an option, but it has been abandoned because of the damage it can do to the kidneys and thyroid gland.

As a final throw of the dice, the psychiatrist may try, in Step 4, a combination of Remeron (mirtazapine) and Effexor (venlafaxine), although these have a poor safety track record.

An ill star

The four steps have been followed diligently by psychiatrists in the West for decades, partly because they are told to do so by their governing bodies and partly because they believe the influential STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study proves that this method works.

The study mapped out the sequence to follow and the likely success rate at each phase: 33 percent of patients respond to the first phase, an SSRI, often Celexa (citalopram), at an initial or higher dose. The response rate rises to 57–63 percent of patients when a different antidepressant is tried or another drug is added, and finally to 67 percent when the patient is switched to mirtazapine and venlafaxine.¹

Cognitive behavioral therapy (CBT), the so-called talking cure, was the trial’s only concession to a non-drug approach. But the therapy wasn’t any better than an SSRI, and any positive results were slower to achieve, the trial concluded.

STAR*D, funded by the US National Institutes of Health to the tune of $35 million, has been described as the largest prospective clinical trial of treatment of major depressive disorder ever conducted. It started in 2000 and was shaped over four years by the responses of more than 4,000 patients with major depression who were being treated at 41 psychiatric centers and clinics across the US. Psychiatry adopted its protocols in 2006.

Placebo, if you please

The STAR*D study’s authors pride themselves on grounding their work in “real-life” practice as psychiatrists worked with patients to navigate the best treatments. But while it may have been pragmatic, it was not scientific, as a new analysis of their method has demonstrated.

At no point did the participating psychiatrists test their protocols and methods against a placebo, so they had no way of knowing if what they were doing was any better than doing nothing at all—especially as the placebo response plays such a major part in antidepressants’ seeming effectiveness.

After two decades of the four-step process, researchers from Corporal Michael J. Crescenz VA Medical Center in Philadelphia were the first to point out the glaring omission. When they looked at other studies that had included a placebo control, they found none of the STAR*D protocols were supported by the evidence.²

Though it was the first to point out the lack of a control group, theirs was not the first dissenting voice. In 2023, Harvard University researchers took another look at the data from the original trial that inspired the four-step process.

The STAR*D researchers had estimated the process would achieve a remission rate close to 70 percent, but the Harvard team found it was just half that.

The STAR*D trial had included 99 people whose depression went into remission even before the trial began, and the psychiatrists taking part in the trial hadn’t followed the study protocol of using an independent and objective measure of remission, known as the Hamilton Rating Scale for Depression. Instead they had made their own assessments of the patients’ progress, which also inflated the rate of success.

The true remission rate was around 35 percent, well below the 67 percent recorded by STAR*D, the Harvard researchers estimate.³

Do I hear 35 percent?

The latest critique from the Philadelphia researchers throws even the 35 percent remission rate into question as it was never tested against a placebo. In other words, would 35 percent of patients have gone into remission even without any treatment? Nobody knows.

These results have left psychiatrists very frustrated; the protocols they’ve been told to follow just don’t work. “Patients who don’t respond to the first antidepressant are often placed on a carousel of tweaks—higher doses, add-on pills, lateral switches—that produce side effects without providing real relief,” Dr Hannah Nearney, a clinical psychiatrist, has said.

The new findings suggest these treatment steps may be driven more by expectation and placebo effects than by real outcomes.

“This mirrors what we see every day in practice,” adds Dr Kultar Singh Garcha, a family doctor in the UK. “Patients are stuck in trial-and-error cycles not because we lack alternatives—but because those alternatives haven’t been prioritized in funding or regulation.”

Another psychiatrist, John Miller, agrees. “This is a huge setback, as all of the publications and policy decisions based on the STAR*D findings that became clinical dogma since 2006 will need to be reviewed, revisited and possibly retracted,” he said.⁴

It’s also forced psychiatrists down a narrow drugs-only path and blocked them from trying other approaches. Dr Miller, for instance, leads a meditation center, while Dr Nearney is CEO of Flow Neuroscience, a company that develops neuromodulation therapies for depression treatment.

“While tens of millions continue to cycle through barely effective drug combinations, validated neuromodulation therapies are still being overlooked or overregulated. We must give patients options grounded in science, and it must stay up to date. We’re living in a time where depression is becoming the next epidemic,” says Dr Nearney.

An epidemic it is. Some 280 million people around the world are suffering from depression, and in the US, this equates to around 8 percent of the population. During their lifetimes, one in six Americans will suffer from the problem.

Astonishingly, after researching the condition for the best part of a century, we still don’t know what it is—the fall of the chemical imbalance theory has been quietly ignored, so it’s still the most popular explanation—and now conventional psychiatry doesn’t know how to treat it. All we can be sure of is that the drugs don’t work.

Try this instead

Omega-3 fatty acids. A diet rich in omega-3 fats—which are in oily fish and nuts—can help ease depressive symptoms. Don’t take omega-3 supplements if you also have bipolar disorder as they may trigger manic episodes.

St John’s wort. This over-the-counter remedy is as effective as an antidepressant drug, new research from the Liverpool John Moores University discovered after assessing the efficacy of more than 60 OTC remedies for depression.¹

Saffron. The herb used in cooking interacts with serotonin in the brain and can ease depressive symptoms.¹

Meditation. Meditation and mindfulness practices have been shown to ease symptoms of mild depression.

Cognitive behavioral therapy (CBT). Known as the “talking cure,” it can help depressed people reframe the way they see the world and themselves.

Acupuncture. This traditional Chinese treatment with very thin needles can ease symptoms of depression and anxiety.

Exercise. Studies continue to show it works. One review of over 200 studies found walking, jogging, yoga and strength training were most effective. In a surprising twist, yoga worked best for men, and strength training worked best for women.²

Diet. Some believe depression is a response to a poor diet. Start eating a healthy diet with fresh fruits, vegetables and olive oil—close to the Mediterranean Diet—and your symptoms will ease, one study found. And cut out gluten, which could be an unsuspected culprit behind depressive symptoms.³

Magic mushrooms. A single dose of psilocybin, a naturally occurring psychedelic compound in mushrooms, can put depression and anxiety into remission for as long as two years, one study discovered.⁴

Light therapy. Bright light has a strong positive impact on mood because of the body’s many circadian and non-circadian processes. Bright light therapy has long been used to treat seasonal affective disorder (SAD), but it’s effective for chronic depression as well.

To treat depression and SAD, spend 30 minutes in front of a light source with an intensity of 10,000 lux (see below for where to buy light therapy lamps). Or expose most of your skin to the sun for about 20 minutes a day between 10 a.m. and 3 p.m.

Transcranial magnetic stimulation (TMS). This therapy, introduced in the 1990s, involves pulsing magnetic fields through a small electric coil. It produces electrical currents in specific areas of brain tissue related to different disorders and can ease depression and anxiety, several studies have established. Clinical trials have shown repetitive TMS (rTMS) is effective in around 66 percent of patients, although it should be used only as a last resort when other approaches have failed.