A landmark teen antidepressant trial has been reanalysed. Here’s why it matters.

Written by Dr Libby

When a teenager’s mood changes noticeably, it’s understandable that parents want answers. Is it hormones? Stress? Something happening at school or online? Challenges with friends? A lack of exercise? Are they simply exhausted? These are important questions. Yet there can be more to consider.

Because a symptom is information. It tells us something is going on, but it doesn’t tell us what. A recent reanalysis of one of the most influential studies of antidepressant treatment in adolescents is a timely reminder of just how important that distinction can be.

The antidepressant trial that shaped treatment for two decades

In 2004, the results of the Treatment for Adolescents with Depression Study, known as TADS, were published in JAMA. The trial involved 439 adolescents aged 12 to 17 who had been diagnosed with major depressive disorder. They were randomly assigned to receive fluoxetine, cognitive behavioural therapy (CBT), a combination of fluoxetine and CBT or placebo. The study became enormously influential. Its original publication concluded that the combination of fluoxetine and CBT offered the most favourable balance of benefits and risks. Fluoxetine alone was also reported to produce a higher response rate than placebo on one of the trial’s primary measures.

More than 20 years later, independent researchers have gone back to the data. And their findings raise important questions.

What did the reanalysis find?

Published in 2025 as part of the Restoring Invisible and Abandoned Trials initiative, the reanalysis sought to evaluate TADS according to the trial’s original protocol. On the Children’s Depression Rating Scale–Revised, one of the trial’s primary measures, the researchers found that fluoxetine alone was not statistically superior to placebo. On another primary measure, Clinical Global Impressions–Improvement, fluoxetine did show a greater response than placebo.

The researchers also identified substantially more adverse events than had been reported in the original publications. They documented 369 adverse events, 66 per cent of which occurred among participants taking fluoxetine. Of 32 serious adverse events, 22 occurred in those receiving fluoxetine. The reanalysis also identified 11 suicide-related events that had not previously been reported.

Please note: Anyone concerned about their teenager’s mental health should seek appropriate professional support and prescribed medication should never be stopped or changed without guidance from the prescribing healthcare professional.

These are significant findings and they deserve attention. And it also offers us a lesson about the questions we ask in the first place.

A change in mood is information

Mental health can be complex. A young person can be experiencing genuine psychological distress while also having physical, nutritional, hormonal, environmental or social factors contributing to how they feel. These things aren’t mutually exclusive. Yet it can be easy to begin with the symptom and work forwards. They’re exhausted. They’re irritable. They can’t concentrate. They’re withdrawn. Their mood is all over the place. The temptation is to find the label that best explains what we can see. I prefer to get curious about what might sit underneath it.

What is happening in their life – at school, home and online? How are they sleeping? Are they eating enough to meet the extraordinary nutritional demands of growth? Are they active? Are they outside, getting enough sunshine? What is happening hormonally? Are there signs of a nutrient deficiency? Do they need psychological support? And, importantly, could more than one thing be true at the same time?

Where does iron fit?

Iron is one piece of this much larger picture. During adolescence, the body’s demand for iron increases substantially to support growth and development. For girls who have begun menstruating, regular blood loss adds another demand. Iron is also about far more than preventing anaemia. The brain requires iron for numerous processes, including energy metabolism and neurotransmitter function. When iron stores become depleted, symptoms can include fatigue, difficulty concentrating, heart palpitations, and hair loss.

Research has also explored associations between iron deficiency and what are often approached as purely psychological symptoms, including anxiety and depression. That doesn’t mean low iron is the cause of every change in mood, but it does mean iron status is worth investigating as part of the wider picture, particularly when other symptoms of iron deficiency are present. A blood test that includes ferritin can help establish whether iron stores are low or at the lower end of the normal range. If they are, poor iron status is a likely contributor or causal factor in how the person is feeling and/or behaving.

Sometimes the foundations deserve investigating too

One of the reasons I keep returning to this conversation is that the human body does not divide itself neatly into ‘physical health’ and ‘mental health’. It is one interconnected system. This is also why a recent message from OnBlends customer Deb Druce stood out to us. Her teenage daughter had been taking Iconic Iron for three weeks when Deb wrote:

“Her moods have levelled out completely, none of the big highs or low lows. The whole family can see a positive change in her wellbeing.”

That is one family’s experience. Yet, her story does highlight a question I believe is worth asking:

When a young person isn’t themselves, have we looked at the whole picture?

Stay curious

None of this is about choosing nutrition instead of mental healthcare. It’s about resisting the idea that we always need to choose one explanation. Nutritional therapy and psychological therapy can coexist in a treatment plan. I can’t help but wonder though how much misdiagnosis is out there, and how many times iron deficiency has been missed when something is approached in a purely psychological way. Sadly, nutrition, and nutrient deficiencies, aren’t considered enough (or addressed) prior to the diagnosis of depression and anxiety.

The reanalysis of TADS is important because science should always remain open to scrutiny, particularly when the decisions being made affect young people. But perhaps there is a broader lesson here too. Before we rush to explain a symptom, stay curious. Ask what has changed. Ask what else is going on. Ask what their body might need. Because sometimes the symptom is only the beginning of the story.