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Some antidepressants work better than others – now we know why

For people with depression or anxiety, finding an effective medication can be a difficult task. Eddi van W.

Three million Australians are currently living with depression or anxiety, and antidepressants are now the third most commonly prescribed class of medication in Australia, after antibiotics and cholesterol-lowering drugs.

Doctors have up to nine different types of antidepressant medications at their disposal, each of which produces different changes in chemical levels in the brain and downstream changes.

Although we’ve long known that some antidepressants are more effective than others, we haven’t been clear about why. A study we recently published in the journal Neuroscience & Behaviours Review shows the answer might come down to changes in the activity of the amygdala, an almond-like region responsible for automatic vigilance.

Getting the right fit

For people with depression or anxiety, finding an effective medication is a difficult task, often requiring lengthy periods of trial and error.

During these periods, patients are prescribed a particular medication and dose, with the hope that it will be effective. If it’s ineffective, the dose may be changed or the patient will have to try a different medication altogether.

The longer these trial-and-error periods are, the longer the patient remains unwell. This may result in everyday struggles with work and family or, in more serious cases, the risk of suicide or other harmful behaviours.

Serotonin is involved in mood and emotion and noradrenaline is involved in stress and attention. Both are thought to be involved in depression and anxiety.

The more commonly prescribed medications increase levels of serotonin (serotonin selective reuptake inhibitors or SSRI) or noradrenaline (noradrenaline reuptake inhibitors or NRIs), and some produce increases in both (serotonin and noradrenaline reupatake inhibitors or SNRIs).

For the average patient, antidepressants that cause increases in serotonin (SSRIs) have been shown to be more effective than those that only increase levels of noradrenaline (NRIs).

However, NRIs are still prescribed as they may be effective in some patients, and they are sometimes used in combination with other medications.


Our research suggests that the varying effectiveness of SSRIs and NRIs may be underpinned by their different impacts on brain activity, which can be seen after just one dose.

We took brain activity data from nine different international studies. Five studies looked exclusively at SSRIs, two looked exclusively at NRIs, and the other two looked at both SSRIs and NRIs. A total of 152 patients participated in these studies: 103 received SSRIs while the other 81 received NRIs.

When participants were given an SSRI, the amygdala became less active. This indicates that our brains become less emotionally reactive after a single dose of an antidepressant.

SSRI treatment also increased activity in frontal regions of the brain, including a region of the prefrontal cortex involved in regulating emotions, suggesting that SSRIs may increase capacity to regulate our emotions.

In contrast, when participants were given an NRI, only frontal regions increased in activity, while amygdala activity did not change.

So, SSRIs may be more effective than NRIs for treating mood and anxiety disorders because SSRIs impacted the emotionally reactive amygdala, while NRIs did not.

Next steps

These findings are important because patients only begin to display observable changes in symptoms after six weeks of ongoing treatment. But if the increases in frontal lobe activity and decreases in amygdala activity follow a single dose of an SSRI, this could act as an early indicator of the effectiveness of treatment over the longer term.

The next steps in our research are to further investigate how these changes occur, and whether genetic differences play a role. More research is also needed on both healthy people and patient samples to better understand how antidepressant treatments work and to predict outcomes with different treatments.

Though we don’t yet have the answers or tests to predict whether a treatment will work for a particular patient, it’s important that we increase our understanding about why some antidepressants are more effective than others.

The authors acknowledge the assistance of Rachel Martin in the preparation of this article.

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