Trapped in Treatment: How Antidepressant Research Ignores Withdrawal

Over 30 years ago we wrote that the number of people suffering a mood disorder was “staggering” (Graedons’ Best Medicine, Bantam Books, 1991). Back then it was estimated that 20 million people would experience bipolar disease or depression sometime during their lifetime. Now, public health experts estimate that over 20 million people experience major depression annually. We suspect the number is much higher. Based on the most recent data regarding antidepressant prescriptions, we estimate that over 44 million Americans are taking drugs for depression. Sadly, most antidepressant research has seemingly ignored the downsides of antidepressant medications. Are withdrawal symptoms making it hard for many of these people to stop such antidepressant drugs?

Shackled By Sadness:

Depression is a devastating condition. Life loses its luster. People often complain of hopelessness and helplessness. Some folks describe low energy, as if they are moving in slow motion. Many individuals have trouble with sleep and appetite. Food no longer has much appeal. Concentrating can be difficult and decisions can be overwhelming.

Psychotherapy can be helpful, but it takes time. Insurance companies often prefer a quick prescription for an antidepressant such as sertraline, escitalopram, trazodone, fluoxetine, duloxetine, venlafaxine, paroxetine or citalopram.

The promise is quick relief from depression at a low cost. All these antidepressants are now available generically. Patients don’t need to commit to talking therapy that might take months or years. Swallow a pill daily for a few weeks and depression should lift and life resume. At least that is the expectation if not the promise.

The Truth About Antidepressant Research:

How well do antidepressant drugs work to relieve depression? That is a question that has been bumping around for decades and the answer is surprisingly confusing.

Let’s start with your tax money ($35 million) at work. One of the biggest and best clinical trials was a government-sponsored trial called STAR*D. That stands for Sequenced Treatment Alternatives to Relieve Depression (New England Journal of Medicine, March 23, 2006).

The STAR*D Study:

In my opinion, STAR*D was one of the most comprehensive assessments of antidepressant drugs ever conducted. It was complicated, so I need you to be patient and hang in with me to understand what these researchers did and what they discovered.

They started with 727 patients with major depression who had not responded to the SSRI antidepressant citalopram (Celexa). As you will shortly read, such antidepressant failures are not uncommon. When that happens, doctors frequently prescribe another antidepressant. The assumption is that if at first you don’t succeed, try, try again!

In the STAR*D antidepressant research trial, patients who had not responded to citalopram were assigned to receive either bupropion (Wellbutrin), sertraline (Zoloft) or venlafaxine (Effexor). Here are the results of that research:

“The Conclusions:

“After unsuccessful treatment with an SSRI, approximately one in four patients had a remission of symptoms after switching to another antidepressant.”

So, only about one out of four depressed patients actually recovered after taking one of the other antidepressants for 14 weeks. That is not a very good outcome.

Other Antidepressant Research:

Other analyses conclude that drugs for depression work about 50% of the time. That sounds pretty good compared to 25% of the time. But that 50% number must be compared to placebo. When depressed patients received a placebo pill instead of an active antidepressant the placebos are effective on average between 31 to 45% of the time (Walsh et al, JAMA, April 10, 2002; Stolk et al, Annals of Pharmacotherapy, Dec. 2003). That is not a very impressive outcome. If the patients taking a sugar pill got relief about 30 to 45% of the time and antidepressants worked about 50% of the time, most researchers would say that the drugs were only 5 to 20% effective.

A study of SSRI antidepressants in older people produced even more disappointing results (Journal of Affective Disorders, Nov. 15, 2016):

“Background: There has been a steady increase in the prescription of antidepressants for the elderly. This study comprises a systematic review of randomized, placebo-controlled trials of antidepressants for treatment of depressive disorder in people aged 65 years or more.”

“Results: Twelve trials met the inclusion criteria. For patients with major depressive disorder, selective serotonin re-uptake inhibitors (SSRI) were not superior to placebo in achieving remission or response  after 8 weeks of treatment (three trials).”

“Discussion: On a group level, SSRI treatment of MDD [major depressive disorder] in people 65 years of age and older may not offer any benefits over a placebo in acute treatment trials of up to 8 weeks’ duration.”

Most physicians maintain that they practice something called EBM (“Evidence Based Medicine”). In other words, they adhere to strict guidelines that depend upon randomized, placebo-controlled clinical trials. Rarely do they tell patients how effective a particular treatment is. As long as it is statistically superior to placebo, it is considered effective and protected under the umbrella of “evidence based medicine.”

We have seen that with statin-type cholesterol-lowering drugs. Here is my most recent take on statins. It demonstrates statistical significance, but the clinical benefits are surprisingly small when it comes to primary prevention of heart attacks.

If Statins Save Lives, Why Is Heart Disease Still #1 Killer?
Heart disease remains our # 1 killer, even after decades of statin therapy. Why don’t statins save lives when it comes to primary prevention?

Why don’t prescribers tell patients how effective antidepressant medications really are and how challenging it can be to stop taking them?

Antidepressant Research: Drugs Tested for Weeks but Taken for Years:

Vinay Prasad, MD, MPH, is a provocative critic of the pharmaceutical industry. He and his colleagues have recently posted their analysis of medication use as a pre-print to medRxiv (Feb. 28, 2025).  It is titled:

“Antidepressant Trial Duration versus Duration of Real-World Use: A Systematic Analysis.”

In his commentary, Dr. Prasad captured the essence of this research:

“Anti-depressants: The trials last 8 weeks; People take them for 8+ years.”

These scientists describe the results from 52 placebo-controlled trials with a total of 10,116 participants. They were interested in comparing the duration of the trials to how long people actually take such medications in real life.

Antidepressant Research is Shocking!

The median trial duration was just eight weeks. The vast majority of studies lasted 12 weeks or less. Using data from the National Health and Nutrition Examination Survey (NHANES), the investigators found that most people take their antidepressant for many years.

The authors write that:

“The analysis revealed a striking disparity between the duration of clinical trials and real-world use patterns. According to NHANES data, 25% of antidepressant users have taken them for over 10 years.”

The investigators point out that the FDA approves such drugs after relatively short trials, despite the fact that most patients will take these medications for indefinite periods of time.

Their antidepressant research showed that few trials investigated withdrawal symptoms and hardly any reported post-treatment outcomes. This makes it very difficult for doctors to make wise decisions about prescribing antidepressants.

The authors conclude:

“Publicly funded randomized controlled trials comparing antidepressants to placebo with long duration, which also monitor for withdrawal, sexual side effects and relapse on treatment discontinuation are necessary to determine the optimal duration of therapy.”

Patients Do Their Own Antidepressant Research:

Readers of this website have shared their struggles stopping antidepressants.

One person wrote:

“I have been taking sertraline for 10 years. Two weeks ago, I stopped, not knowing that there would be any withdrawal problems.

“I felt like there were electrical currents going through my brain. I also spent a lot of time in the bathroom. My heart is skipping beats, and it takes almost nothing to get me angry. Even my dogs make me mad. I’m sweating, tired, nervous, sick and shaking. My blood pressure is up. I had no idea stopping an antidepressant could be this bad. Had I known, I would never have started taking it.”

Maddie was not told about antidepressant withdrawal symptoms:

“I was prescribed Effexor in the late 1990’s. No mention was made of any kind of withdrawal symptoms. My prescription was renewed year after year for over twenty years, even though, to my knowledge, there is no research to show that long-term use is safe.

“In 2014, I suspected that the venlafaxine XR 75 mg I was taking was giving me unpleasant side effects as well as debilitating withdrawal symptoms if I missed a dose by as little as four hours – brain zaps, nausea, dizziness. One night I woke up and found that when I moved my eyeballs, I heard a distinct ‘click’ with each movement – this happened over several months any time I was late taking my dose. I also didn’t think I needed an antidepressant any more.

“I decided I would open up the capsule and take one less pellet every two weeks. I did this for over a year and finally reduced my dosage to 37.5 mg. After a couple of months stabilizing myself at the lower dosage, I started back reducing it by 1 pellet a week.

“I ended up having withdrawal symptoms even with this tiny reduction. Now I’m stuck at that dosage. It makes me furious that a drug company can market a drug like this with no warning, and even with a denial that the drug is addictive. Of course it works well for them, since I’m still buying their poison pills!”

Many readers have described their own antidepressant research in trying to wean themselves off such medications.

Jan shares her very gradual tapering process:

“After many years of taking a low dose of Effexor following some depression, a physiatrist (a doctor who also treats patients for pain) switched me to Cymbalta to help relieve lower back pain following an ineffective double spinal fusion. I experienced brain zaps during the whole time (4 yrs) while taking Cymbalta. I told my internist about the brain zaps and was basically ignored. If I had been warned about the real side effects of this drug, I never would have taken it.

“Cymbalta did nothing for my pain. The brain zaps became so frequent, along with periods of brain fog and hot flashes (I’m in my 70’s), I decided to wean myself off of it by opening up the generic capsules and removing 3 of the 12 balls inside, taking the remaining little balls each day for one week. The next week I removed 3 more and stayed on that dose for one week. By the end of one month, I had gotten off of the drug completely.

“The brain zaps are still there but have diminished in intensity. The same with the hot flashes. The muscle pain is worse. I have been experiencing wide emotional swings and general feelings of anger and hostility. I have been Cymbalta-free for 2 weeks now and refuse to take this drug again.

“Drug makers are able to get away without disclosing all of the true side effects of their drugs, and I am grateful for sites that enable patients to warn others as well as educate themselves about what big Pharma is doing to us!”

Alice was “saved” by a friendly pharmacist:

“I was situationally depressed. My GP put me on Zoloft (sertraline). It was on a very low dose. Once the situation improved I talked to the doctor about coming off of it. He said just stop it but the brain zaps drove me crazy so I went back on it.

“Every time I had it refilled, I talked to the pharmacist at my little local pharmacy about coming off of it. I cut the dose in half but the brain zaps were still terrible and I couldn’t function. After being on Zoloft for 5 years the pharmacist must have taken pity on me. He spent hours dividing the contents of the capsules into incremental smaller and smaller doses. It took six months but I was able to come off it with no problem. I will be forever grateful! I will never go on an antidepressant again!”

Short Trials, Lifelong Pills: The Hidden Flaws in Antidepressant Research!

Dr. Vinay Prasad and his colleagues have revealed a huge shortcoming in antidepressant research compared to clinical practice.

Here is their conclusion:

“The evidence base of antidepressants, particularly their duration of use, is an important public health question as 13.2% of adults are taking antidepressants. The efficacy of commonly prescribed antidepressants is largely based on trials of 8-12 week duration, and yet, we find, the median duration of therapy in the real world is 5 years.

“Regardless of duration, trials rarely monitored participants for withdrawal or relapse upon completion of treatment…Publicly funded randomized controlled trials comparing antidepressants to placebo with long duration, which also monitor for withdrawal, sexual side effects and relapse upon treatment discontinuation are necessary to determine the optimal duration of therapy.”

Getting Off Antidepressants?

Neither drug companies nor the FDA provide doctors or patients detailed guidance on discontinuing antidepressants. As you have read above, visitors to this website have come up with their own strategies for discontinuing drugs.

We have written extensively about the Ashton Manual. Dr. Heather Ashton developed detailed protocols to help patients withdraw safely from benzodiazepines and antidepressants. Here is an article you may find of interest with links to the Ashton Manual:

Do Doctors Know How to Help Patients Stop Medications?
Why don’t drug companies, doctors or the FDA tell patients how to stop medications? This is a problem with benzos, antidepressants and PPIs.

Other Options:

CBT (Cognitive Behavioral Therapy) vs. Drugs for Depression:

There was a time when psychotherapy was an option for people who were depressed or anxious. Then the pharmaceutical industry convinced physicians that psychological depression was a chemical imbalance. Just rearrange the neurotransmitters, correct the chemical imbalance and all would be fine.

We recognize that many people benefit from antidepressant medications. Numerous individuals have told us such drugs make a huge difference in the quality of their lives. We do not doubt them for a moment. If such antidepressants work, great! And if the side effects are minimal or nonexistent, even better.

No one should ever stop an antidepressant, or any medication for that matter, without close consultation with the prescriber. As you have learned, stopping an antidepressant suddenly can lead to some major complications.

What else can people do if they are suffering from depression? Because psychotherapy has become a bit of a dinosaur and insurance companies don’t like paying for it, many people have given up on talk therapy. There’s also the problem of a shortage of health professionals. Many now refuse to take insurance. As a result, patients in need may find themselves at a loss for non-drug therapeutic options.

Some people doubt that such non-drug treatment is even effective. An analysis published in the Annals of Internal Medicine (Oct. 29, 2019) showed that cognitive behavior therapy (CBT), while more expensive to start with, actually saves money after five years. The authors noted that medications and cognitive behavioral therapy were about equal in effectiveness. So far as we are aware, there are no withdrawal symptoms for people who stop CBT.

Final Words:

It troubles me that the FDA has not required drug companies to do the kind of antidepressant research that would determine long-term effectiveness. In my opinion, 8 weeks or even 20 weeks is not nearly long enough. I would like to see trials that last much longer because that is what happens in real life.

The idea that such medications could be tested for weeks but taken for years is distressing. Some people are never able to stop their antidepressant because of unbearable withdrawal side effects. Dr. Prasad and his colleagues correctly point out that this serious flaw in the drug approval process needs correcting.

Please share your own experience with antidepressant medications. Have they worked well? If so, we want to hear your story. Have you experienced side effects or withdrawal symptoms upon stopping? Please describe that experience in the comment section below. If you think this article has merit, please share it with friends or family. And if our newsletter provides helpful information not readily available elsewhere, please encourage your acquaintances to sign up at this link. Thank you for your support.