Reanalysis of Popular Antidepressant Trial Uncovers Reporting Flaws

A reanalysis of a study found that fluoxetine alone showed no measurable benefit over placebo in treating adolescent depression after 12 weeks

by Dr. Joseph Mercola

Story at-a-glance

• A reanalysis of a study found that fluoxetine alone showed no measurable benefit over placebo in treating adolescent depression after 12 weeks

• Researchers uncovered 11 additional suicide-related events that were hidden or misclassified, bringing the total to 21 serious incidents

• Statistical tactics and selective reporting made fluoxetine appear safer and more effective than it really was in clinical trials

• A different reanalysis mentioned that adverse events and many side effects were minimized or excluded from the original reports

• Improving gut health, getting regular exercise, undergoing therapy, and optimizing vitamin D are viable approaches for treating depression

Once in a while, the findings of a particular study make such a big impact in the medical industry that it influences recommendations for many years to come. One notable example is the Treatment for Adolescents with Depression Study (TADS), which was published in 2004.¹

More than two decades after TADS was published and shaped how doctors prescribe fluoxetine (Prozac) to teens, investigative journalist Maryanne Demasi, Ph.D., has sounded the alarm regarding new evidence showing that the original findings dramatically underreported serious adverse events.²

A Landmark Trial Reexamined from the Ground Up

In a study published in the International Journal of Risk & Safety in Medicine, researchers uncovered major flaws in TADS. This was a large, publicly funded study that shaped prescribing habits for fluoxetine, making it the default first-line treatment for adolescents diagnosed with major depressive disorder. TADS included 439 adolescents aged 12 to 17, all diagnosed with major depressive disorder.³

The original trial split them into four groups — fluoxetine only, cognitive behavioral therapy (CBT) alone, a combination of CBT and fluoxetine, and placebo. The reanalysis showed that while the combination of fluoxetine plus CBT produced the biggest drop in depression scores, fluoxetine by itself had no measurable benefit over placebo by the end of the 12-week acute phase. That’s the exact opposite of how the original study presented its findings.

•New findings have been uncovered — In this new study, the team reviewed the raw trial data — not just published outcomes — and reaudited everything using the original study protocol. They applied the RIAT model (Restoring Invisible and Abandoned Trials) to see what the results would look like if all the data were handled transparently and without statistical manipulation.

What they found turned the original TADS conclusion on its head — fluoxetine alone didn’t perform better than a placebo after 12 weeks of treatment. On top of that, over two-thirds of all serious adverse events happened in kids who took fluoxetine.

•Fluoxetine didn’t benefit participants as time went on — The original TADS researchers published that fluoxetine worked quickly and clearly by Week 6, but the reanalysis found no meaningful advantage at all by Week 12. Specifically, on the main outcome measure — the Children’s Depression Rating Scale-Revised (CDRS-R) — the difference between fluoxetine and placebo was statistically insignificant.

What’s worse, the original study authors had emphasized suicidal thoughts and behaviors as rare. But the reanalysis team identified 11 additional suicide-related events that were either hidden or misclassified in the official TADS reporting. This brings the total number of suicidal events up to 21 — two of which were actual suicide attempts, one completed and the rest were severe self-harm or ideation. That’s a major correction to the record and radically alters the risk-benefit result.

•Adverse events were abundant — The reanalysis noted that 369 adverse events occurred for 171 participants, and 66% of those occurred in the fluoxetine group. These weren’t limited to suicide-related episodes.

The team found hospitalization for chest pain, severe mood swings, and cognitive disturbances, among others. Some were documented clearly in case report forms but never made it into the official journal articles. Others were downgraded in severity or simply not included because they didn’t meet arbitrary thresholds set by the original researchers.

•Even the combination of CBT with fluoxetine was misleading — While it did show the strongest symptom drop, the reanalysis points out a problem — those therapy sessions weren’t blinded. Therapists and participants both knew who was receiving treatment.

That opens the door for expectancy bias, meaning they expected themselves to improve, so they reported feeling better, regardless of whether the drug helped. That calls into question how much of that symptom improvement came from the medication itself.

•Data was manipulated to make the findings look good — The reanalysis also exposed how fluoxetine’s risks were obscured through statistical tactics. In the original trial, multiple comparisons were made between groups without correcting for how that inflates the chance of false positives.

Essentially, the more statistical tests you run, the higher the odds you’ll find something significant just by chance. That’s exactly what the RIAT team believes happened with the original results, and it’s how the drug ended up being declared a success.

•Possible reason why side effects occur — The reanalysis didn’t focus on molecular pathways of fluoxetine, but it strongly criticized the mismatch between real-world reactions and the theory that selective serotonin reuptake inhibitors (SSRIs) are uniformly safe.

SSRIs are thought to work by increasing serotonin levels in the brain, which is linked to mood. But that theory doesn’t explain why so many teens on fluoxetine reported agitation, insomnia, or even psychotic symptoms.

•Complete disclosure is required for the public’s safety — The study called for full access to clinical trial data moving forward, emphasizing that hidden harms in TADS were not accidental but preventable. The team concluded that if the original TADS data had been reported accurately and honestly, fluoxetine would never have become the go-to antidepressant for adolescents. As summarized by the team’s closing words:⁴

“Our reanalysis confirms the original reported findings that superiority over placebo was not demonstrated for fluoxetine. Contrary to original TADS Team’s reporting, we have uncovered a higher, clinically significant level of harm, including 11 additional suicide-related adverse events.”

These findings raise a larger question — if this “landmark” study was manipulated, what else has been misrepresented? Whatever the case, the reality is that manipulated data led to flawed guidelines that are still harming teenagers today.

Widespread Gaps in Side Effect Reporting of TADS Is Exposed

The featured study above isn’t the only publication pointing out the flaws of TADS. In a different study, published in BMJ Open, researchers investigated how adverse effects were documented across all published materials from the TADS trial.⁵ In the end, the team found that safety data was not just incomplete — it was selectively presented in ways that have misled doctors, patients, and regulators for years.

Rather than focusing solely on original trial data, this review investigated how the TADS researchers reported — or failed to report — side effects when writing up results over the years. Out of the 48 papers investigating TADS, only eight mentioned adverse events at all, and most of those provided limited or vague descriptions of the harm associated with fluoxetine treatment.

•The side effects of fluoxetine are downplayed — While previous reports have mostly emphasized fluoxetine's effects on depressive symptoms, the BMJ Open team turned the spotlight to what was missing. For example, despite well-known risks like insomnia, appetite changes, and sexual dysfunction in SSRI use, nearly all those side effects were either absent or minimized in TADS-related publications.

Only suicidal behavior was consistently tracked through the 36-week period, leaving out a wide array of common and distressing adverse experiences that could have shaped treatment decisions for families and clinicians.

•A deceptive manipulation was exposed — The researchers discovered misclassifications of patients who had dropped out. In the TADS data set, several participants who attempted suicide while on fluoxetine but discontinued before the end of the treatment phase were counted in the placebo group, not the fluoxetine group.

That single tactic — placing the harmed participants into the wrong category — artificially reduced the appearance of risk tied to the drug and falsely increased placebo-related harm numbers. This allowed the drug's safety profile to appear cleaner than it truly was.

•Another issue was the reporting threshold itself — The researchers noted that the TADS team only included pre-classified adverse events that led to severe disruption. That means dozens of mild but still disruptive events were excluded entirely:⁶

“In the TADS, adverse events were defined as an unfavourable medical change that occurred after beginning or during the study that might or might not be related to or caused by the study drug or CBT treatment.

This was further specified as any medical event that caused clinically significant interference with functioning (e.g., headache that caused school absence or otherwise caused clinically significant activity restriction), any event that required medical attention, and any medical event associated with impairment in functioning and induced the patient to take a concomitant medication.

Conditions that did not lead to clinically significant interference with functioning or did not require medical attention were not defined as adverse events.”

•There was a deliberate exclusion — The definition of what constitutes a serious adverse event in TADS was never explained in most of its publications. This lack of transparency made it impossible to understand which symptoms crossed that invisible threshold and which ones were ignored:⁷

“The TADS protocol included a threshold limit on what would be considered an adverse event, specifying that the event must cause clinically significant interference with functioning, require medical attention or cause a need to take medication. As an example, emerging mania was not recorded unless symptoms exceeded this threshold.

It must be assumed that this reduced the number of reported adverse effects, which may not have been severe enough to reduce daily functioning or cause a need for additional treatment.”

•There’s also the issue of long-term follow-up — Even though the TADS trial lasted for 36 weeks, most publications only focused on the 12-week acute treatment phase. After that, side effect monitoring all but disappeared:⁸

“Due to its long duration (36 weeks) and follow-up (1 year), the TADS could have provided valuable information on the long-term occurrence of adverse effects both in frequency and severity. The adverse effects profile of FLX [fluoxetine] in the TADS has only been reported in detail for stage 1, where approximately 200 patients received FLX for 12 weeks.”

Feeling Down? Try These Natural Strategies Instead

Depression among the youth, or any age for that matter, is a serious concern, but taking a pill shouldn’t be the first course of action. If you’re depressed, these natural strategies can help you:

1.Strengthen your gut health — Improving your digestive health is a foundational step toward better mental well-being due to the gut-brain axis. To nurture this relationship further, incorporating homemade probiotic-rich foods and steering clear of ultraprocessed foods high in linoleic acid (LA) will positively influence communication between your gut and brain.

LA is especially toxic to your gut health. I recommend limiting your intake to less than 5 grams a day from all sources, but if you can get it below 2 grams a day, that’s even better. To help you monitor your intake, download the upcoming Mercola Health Coach app. It has a feature called the Seed Oil Sleuth, which calculates the LA in your food to a tenth of a gram.

In addition, limiting processed foods and reducing exposure to antibiotics and agricultural chemicals can further protect your gut microbiome. A nutrient-rich diet fuels cellular energy and supports metabolic functions — both of which are key for maintaining a stable mood and reducing symptoms of depression.

2.Embrace a lifestyle that supports mental resilience — Support your mental health through regular exercise and quality sleep. Physical activity enhances mitochondrial health and boosts natural energy levels. Even simple habits like walking each day and keeping a consistent sleep routine can dramatically uplift your mood.

3.Try non-pharmaceutical methods — Examples include counseling, talk therapy, and cognitive-behavioral therapy (CBT). These methods empower you to develop coping strategies, confront root causes of distress, and build mental resilience without depending on medications.

Another promising option is the Emotional Freedom Techniques (EFT), a form of psychological acupressure that has demonstrated benefits for reducing anxiety and depressive symptoms.

4.Prioritize healthy vitamin D levels — Ensuring your body has adequate vitamin D through safe sun exposure will make a meaningful impact on your mood. As noted in a previous article, there’s a strong link between low vitamin D and a higher risk of depression. Thus, increasing your levels naturally by spending time outdoors will help improve emotional well-being and reduce depressive symptoms.

However, it’s not advisable to get out in the sun right away, especially if you’ve been eating a diet high in LA. When sunlight hits your skin, the LA embedded there begins to metabolize and cause inflammation. To protect your health, it’s advisable to avoid midday sunlight, especially between 11 a.m. and 3 p.m. until LA is purged from your body. To hasten the process, I recommend getting C15:0 (pentadecanoic acid) from full-fat dairy.

Most people get only about 100 to 200 milligrams of C15:0 per day. I personally take 2 grams daily. At that level, research suggests your keratinocytes — the skin cells in your outermost layer — may start incorporating C15:0 in place of LA. For an in-depth guide on this process, read “The Fast-Track Path to Clearing Vegetable Oils from Your Skin.”

5.Foster honest dialogue with the youth — When supporting a young person’s mental health, creating a safe, non-judgmental space for open communication is important. Encouraging them to express their emotions and concerns helps them feel heard and understood. This approach also aids in detecting any early signs of distress, which can lead to timely, effective support or intervention.

6.Explore these other natural strategies — For those seeking natural relief from stress and anxiety, gamma-aminobutyric acid (GABA) is available as a supplement or herbal tea. It offers calming effects by regulating neuronal activity,⁹ and animal studies¹⁰ suggest it helps lower depressive behaviors by promoting a state of relaxation.

Methylene blue, the precursor for hydroxychloroquine and chloroquine, is another viable strategy. It supports mitochondrial energy production and has been observed in clinical trials to outperform placebos in improving severe depressive states within three weeks.¹¹

If you're currently on an antidepressant and want to get off it, you'll want to have the cooperation of your prescribing physician. With their guidance, start lowering the dosage of the medication you're taking. There are protocols for gradually reducing the dose that your doctor should be well aware of.

If you are feeling desperate or have any thoughts of suicide and reside in the U.S., please call the National Suicide Prevention Lifeline by dialing 988, or call 911, or simply go to your nearest hospital emergency department.

You cannot make long-term plans for lifestyle changes when you are in the middle of a crisis. U.K. and Irish helpline numbers can be found on TherapyRoute.com. For other countries, do an online search for “suicide hotline” and the name of your country.

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