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What are antidepressants, how do they work?

In the early 1960’s the “monoamine hypothesis” of depression was first proposed and this remains largely unchallenged. Monoamine is an enzyme which quickly destroys serotonin and noradrenaline (also called norepinephrine), chemicals which are the neurotransmitters which operate in synapses in the brain. This hypothesis forms the basis for our understanding of depression at a psychopharmacological level. Most researchers believe that the benefits of antidepressants stem from how they affect certain brain circuits and the neurotransmitters that pass along signals from one nerve cell to another in the brain. The action of antidepressants results in higher concentrations of neurotransmitters at the synapse.  

Different antidepressants achieve this in different ways.


Tricyclics seem to block the reabsorption of serotonin and epinephrine back into nerve cells after these chemicals are released into a synapse. Monoamine oxidase inhibitors (MAOIs) inhibit (or prevent) the action of monoamine oxidase which results in higher levels of serotonin and noradrenaline in the synapse.  These are among the oldest forms of antidepressant and neither tricyclic medication nor MAOI’s are permitted forms of antidepressant therapy for EASA certification purposes.  


MAOI’s can take up to three weeks to build up their effect to work fully. MAOI’s include moclobemide (e.g. Manerix), phenelzine (e.g. Nardil), and older types of MAOI’s such as isocarboxazid (e.g. Marplan) and tranylcypromine (e.g. Parnate) which are no longer widely prescribed.  MAOI’s have more unpleasant side effects than newer forms of antidepressant therapy, for example they can cause dizziness, drowsiness, and there can be significant withdrawal symptoms when medication is stopped. You cannot drink alcohol or eat food that contains tyramine (for example, cheese, liver, yoghurt or Marmite®) while you are taking an MAOI. You cannot take some cough and cold medicines while you are taking an MAOI. 


MAOI’s and tricyclic antidepressants tend to be used when newer antidepressants have not worked.


Newer antidepressants act by blocking the reuptake of Noradrenaline and/or serotonin at the synapse, again resulting in higher concentrations of neurotransmitters at the synapse.  There are various forms, which are named after the neurotransmitter they affect. 

Serotonin and norepinephrine reuptake inhibitors (SNRIs) are among the newer types of antidepressant. As the name implies, they block the reuptake of both serotonin and noradrenaline.


Norepinephrine and dopamine reuptake inhibitors (NDRIs) are another class of reuptake inhibitors which affect the reuptake of noradrenaline and dopamine (another nuerotransmitter).


Selective serotonin reuptake inhibitors (SSRIs) selectively inhibit the reuptake of serotonin in central nervous system (CNS) synapses, thus increasing the intra-synaptic concentration of serotonin. SSRI’s have been found to be at least as effective as MAOI’s or tricyclic antidepressants but have far fewer side effects and are better tolerated by most people.

Certain SSRIs are permitted for EASA medical certification.  These are Sertraline (e.g  Zoloft), Citalopram  (e.g. Celexa) and Escitalopram e.g. Lexapro).  These have very few side effects but like all antidepressant medication their effects are not immediate and a normal course of antidepressants lasts at least six months after symptoms ease.  

Antidepressants do not work for everyone. St John’s Wort (SJW) is an over the counter herbal remedy that has also been compared to antidepressants - in particular SSRIs. SJW use was associated with greater depressive symptom reduction and fewer adverse effects compared with SSRIs (paroxetine) in some studies. However, a recent meta-analysis studies of SJW failed to find a substantial benefit over other forms of therapies. It may be that SJW is a safe and effective in the short-term relief of depression. SJW may be more useful in milder depression. The National Institute for Health and Clinical Excellence (NICE) provides independent evidence based guidance for the NHS on the most effective ways to treat disease and NICE does not recommend its use given the uncertainty in its effectiveness.  STW is also not permitted for EASA certification.

Experimental and developing treatments

Almost a third of people with depression do not respond to antidepressant medications and this has led to the investigation of alternative therapeutic approaches. Deep brain stimulation (DBS) is one of these approaches. It was first used with success for treating movement disorders and has since been extended to the treatment of psychiatric disorders. It involves major invasive brain surgery and presents many ethical challenges, therefore DBS remains a treatment which requires much more investigation before it can be used more widely.  However, it is showing promising efficacy and safety in preliminary trials in some patients with treatment-resistant depression (TRD).

Ketamine, a drug which is licensed as an anaesthetic but is also used illegally as a “party drug” has been trialled recently (2016/17) in people who have not responded to other antidepressant treatment with promising results.  However there are still signifiant gaps in our knowledge about how to use ketamine safely in treating depression.


Most researchers believe that the benefits of antidepressants stem from how they affect certain brain circuits and the neurotransmitters that pass along signals from one nerve cell to another.

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