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When depression drugs stop working

For all sorts of reasons, people who have been taking medication for depression (or related conditions including anxiety and OCD) for many years may find that it seems to have stopped working. This is pretty dreadful for them, and presents a challenge for their clinicians. When I used to man a telephone helpline for an NHS Trust, I would sometimes get calls from people in this position and they were frequently extremely distressed and frustrated.

Statistics are hard to find for people suffering from antidepressant tachyphylaxis as it is known, or ‘poop out’ as it is called in the US. However, it is estimated that between 10-25 per cent of people taking antidepressants for major depression disorder do report that after several years their medication is no longer keeping their depression symptoms away. There are different theories as to why this happens but it could be that harmful metabolites of the drugs have built up to toxic levels or that the body has become resistant to the drug.

The first thing to ascertain is whether this is true antidepressant tachyphylaxis. A study carried out in the US found that around half of people who said that their antidepressant was becoming ineffective were failing to take them correctly and missing doses. It is also possible that someone who says that their symptoms are not being adequately controlled is suffering from a related condition such as bipolar depression which requires a different type of medication altogether. Another likely explanation is that the patient is experiencing more severe depression and the drug dosage is no longer adequate.

It is important to make sure that these factors are excluded. For this reason, one of the first things that can be done is to increase the drug dosage and see if that makes a difference. For many people, this has a remarkable effect and they are soon back on track.

Switching to another drug can often provide relief too. The newest antidepressant available in the UK is vortioxetine (Brintellix) which has two separate pharmacologic modes of action and also seems to improve memory and cognition. Another drug agomelatine, which is a melatogenic antidepressant developed by pharmaceutical company Servier, has had good results and also improves sleep without causing side effects like loss of appetite, nausea, sexual dysfunction or withdrawal symptoms. A meta-analysis published in the BMJ in 2014 looked at over 20 trials of the drug and found that it was as effective as standard antidepressants although it works in a totally different way to other antidepressants.  Agomelatine works by stimulating melatonin receptors and blocks some serotonin receptors, unlike SSRIs which work by blocking serotonin reuptake by the body, allowing an increase in the levels of serotonin, the chemical messenger in the brain that regulates mood.

Using another approach, patients can try to resensitize themselves to the drugs after a period of quitting them altogether. This can be a long and drawn out process and can be quite difficult since the patient may experience withdrawal or discontinuation symptoms with some antidepressants.

There is also research that suggests dietary and lifestyle changes can help improve depression symptoms as well as therapies like the ‘talking therapies’ such as Cognitive Behavioural Therapy.

However, the fact remains that for a small group of people, the symptoms can come back and persist. This is an area that needs more research. We still have more questions than answers about how the brain changes under the influence of depression and antidepressant drugs and if these changes are potentially harmful. Prolonged untreated depression has now been strongly linked with an increased risk of developing dementia later in life, so while there may be a risk from treating depression there is also a risk from not treating depression. Drug companies rarely invest in ‘last resort’ treatments as these are very expensive to research and test on a cohort that is difficult to identify and bring together. It doesn’t help that the NHS is reluctant to pay for more expensive drugs when cheaper alternatives are available. For this reason, very few CCGs offer agomelatine to patients because it costs around £30 per month per patient as opposed to £2 per month per patient for a standard SSRI.

There is light at the end of the tunnel, though. In my experience, most patients do improve and return to a steady state where they can enjoy life once more.


Professor Steve Bazire
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6 years ago

This is an excellent article because too many people do face this issue of their antidepressant medications that do stop working. With this conundrum for so many that is where I wanted to add some insight into Transcranial Magnetic Stimulation aka TMS Depression Therapy. TMS is a non-invasive treatment option for those with medication resistant depression and Major Depressive Disorder. TMS works be sending magnetic pulses to the center of the brain where depression occurs, activating the chemicals, therefore relieving the depression symptoms. TMS is now covered by most health insurance companies which is excellent as it can help more… Read more »

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