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Proof of the pill: cutting out the guesswork in prescribing antidepressants

Voltaire was right when he said “doctors prescribe medicines of which they know little, to cure diseases of which they know less". Almost 300 years later, this still rings true for depression. Antidepressants…

Antidepressants lift the mood but we don’t know exactly how they work.

Voltaire was right when he said “doctors prescribe medicines of which they know little, to cure diseases of which they know less". Almost 300 years later, this still rings true for depression.

Antidepressants are one of the most commonly prescribed classes of medication in Australia. And while their efficacy has been established – though debated – research remains speculative about how the effects of these drugs are produced.

Other questions, such as why they take so long to have an effect and why a certain drug may work for some patients, but not others, also remain unanswered.

Researchers are frantically trying to answer these questions to cut out some of the guess work out of prescribing antidepressants.

And though we don’t yet have definitive answers, we’re certainly making headway.

Depression, emotion and mood

Depression is one of the most common and disabling illnesses in the world, affecting one in five Australians at some point in their life.

It ultimately affects people’s ability to function at home and work, and is characterised by low mood, loss of interest in doing pleasurable things, and disturbances with sleep, appetite, thoughts and movement.

People who experience depression have difficulty regulating their emotions and display increased activity in the amygdala, a key region of the brain that processes emotional stimuli outside conscious awareness.

Depressed patients are likely to have heightened negative views of themselves and believe statements such as “I’m worthless”, “the world is unfair” and “I have no future”.

Thankfully, this hyper-responsivity, and subsequent negative self-assessment, generally resolves with antidepressant treatment.

Behavioural and physiological studies have also shown that depressed individuals show less reaction to positive stimuli than those without depression. This is known as anhedonia.

Again, antidepressants have been shown to counter anhedonia and increase responses to positive stimuli.

So how do antidepressants work?

Doctors will tell you that antidepressants increase the level of certain neurotransmitters, such as serotonin, in your brain. After three or four weeks, you should start to feel better.

There are a variety of explanations for why antidepressants take so long to have an effect but the prevailing view goes something like this:

  • Selective serotonin re-uptake inhibitors (SSRIs) - an antidepressant class frequently prescribed by GPs - increase the amount of serotonin available in the brain.

  • This triggers a series of intra-cellular mechanisms, which occurs in a time period consistent with the three to four week delay in response to treatment.

  • The brain’s regulation of emotions alters and the patient’s depressive symptoms subside.

However, as our understanding of antidepressants improves, this explanation of how antidepressants work is becoming increasingly unlikely.

A promising new theory, based on neuroimaging research (scanning the brain and its activity), suggests antidepressants may trigger initial and immediate changes in the way emotions are processed and regulated.

Neuroimaging studies show that after antidepressants are absorbed into the body, there’s an immediate reversal of the negative emotional bias. This means positive emotions aren’t held back and negative emotions are properly regulated.

Interestingly, people aren’t even aware of these early changes in their brain and it certainly isn’t observed by the treating clinician.

Genetics and antidepressants

Common genetic differences underpin the way we process and regulate emotion. But we’re still unsure of how these genetic differences impact on emotion and its regulation.

We’ve just begun a neuroimaging study at the University of Sydney to examine the impact of genetic differences and a commonly prescribed antidepressant on emotion processing and regulation of healthy young women.

In the study, participants will be given a single dose of an antidepressant or a placebo and have their DNA sequenced. Then, while in a functional Magnetic Resonance Imaging (fMRI) scanner, they will be asked to perform tasks that require them to process and regulate positive and negative emotions.

The aim of the study is to determine whether common genetic differences impact on the antidepressant’s ability to shift a negative bias to a positive bias, which will alleviate the symptoms of depression.

We’re also examining the effects of antidepressants and genetics using brain electrical activity (or EEG) and body function during resting and stressful tasks. This will tell us whether antidepressants help to adapt to stress after a single dose.

We hope we’ll be able to answer some of the long-standing questions about antidepressants, especially how genetic differences impact on the brain’s response to particular therapies.

And if we can find the answer, it’s likely we’ll be able to reduce some of the trial and error that occurs when prescribing antidepressants.

Join the conversation

6 Comments sorted by

  1. Dennis Alexander

    logged in via LinkedIn

    Interesting and promising research which might ultimately benefit myself and others I know.

    At the same time, I note that "sleep disturbance" is symptomatic and that most antidepressants have an immediate affect of increasing the amount of less disturbed sleep and even warn of drowsiness as a side effect. Is there any research on potential cyclical interaction of sleep/disturbed sleep and mood disorders and depression?

    1. Andrew H Kemp

      Associate Professor at University of Sydney

      In reply to Dennis Alexander

      Thanks for your interest Dennis. This is a very important issue. You may be interested in another piece we did for The Conversation at:

      In particular, we noted that:

      "melatonin-based therapies such as agomelatine, usually used to treat sleep disorders, may have antidepressant effects and fewer side-effects than antidepressants, as well as improved sleep quality."

      This was based on a recent article published in The Lancet by Ian Hickie and colleagues.


  2. Tim Allman

    Medical Software Developer

    I have personal experience with some of these drugs and agree that a lot more needs to be learned and clinicians, at least in my bit of the world, need to be better educated in their use.

    If they really do work (, then from the clinical point of view it would be useful to know the mechanism. Ideally one could better match the drug to the patient so as not to put him through the long process of finding…

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    1. Tim Outhred
      Tim Outhred is a Friend of The Conversation.

      PhD Candidate at University of Sydney

      In reply to Tim Allman

      Hi Tim,

      Thank you for your comment. The thing is that at the moment it is very difficult to predict who will respond to a particular antidepressant and to predict the time frame when symptoms will begin to reduce. We hope that something will come out of our research or our future research that will help us to predict this.

      Psychotherapy is a costly exercise and is now funded by the government to some degree through the Better Access scheme. This has been a positive change for medical practice when it comes to holistic approaches to treatment. We hope to conduct similar research where we combine psychotherapy and antidepressant treatments.


  3. Michael Bending


    There is such a thing as proceeding in the totally wrong direction with the best of intentions, utmost speed and precision. I’m sure most psychologists believe they are trying to do good things, helping people with psychiatric drugs, but there are other possible therapies that don’t have the dangerous side effects. Common and well-documented side effects of psychiatric drugs include mania, psychosis, hallucinations, depersonalization, suicidal ideation, heart attack, stroke and sudden death. According…

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  4. Lewis Rassaby


    I take issue with your assertion that the efficacy of antidepressants has been established. The issue of efficacy is contested and much of the literature suggests that SSRI antidepressants are no more effective than placebo. As you correctly point out the neurotransmitter theory is quite suspect. A number of antidepressants decrease serotonin and are just as effective/ineffective as those that increase it. I repeatedly ask colleagues why they prescribe medication that have so little empirical or theoretical basis for their use.