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Why Antidepressants Don’t Always Work – And What Can Make a Difference


Why Antidepressants Don't Always Work - And What Can Make a Difference

The presence of hope can be just as powerful as its absence. Just ask anyone with depression. Depression is a devastating illness that thrives on hopelessness. This sense of hopelessness can be worsened when medication, often taken as a last resort, fails to deliver any relief. New research finds clues as to why antidepressants don’t work for everyone.

There are a number of treatments for depression, and amongst the most common are SSRI’s (Selective Serotonin Reuptake Inhibitors). About 50% of people who take SSRI’s find that their depressive symptoms are halved within 8 weeks of taking the medication. Then there are the other 50%. For those people, antidepressants just don’t work. 

Out of the people who do find relief, half of them will see a return of the symptoms, taking the actual recovery rate to 25%.

The way we think about depression is changing. 

Though SSRIs are a lifeline for many people, their sketchy levels of effectiveness have put pressure on the idea that depression is caused by a lack of serotonin. The way we think about depression is changing. More recently, there has been a dramatic shift away from the serotonin theory of depression. There are a number of reasons for this:

  • If depression was caused by low serotonin, it would be expected that medication which increases serotonin would be more effective than the 50% strike rate of SSRIs.
  • A number of studies (including here and here) have found that in some depressed people, serotonin is elevated.
  • There are other treatments for depression, including therapy, a combination of meditation and exercise, and medication that has little effect on levels of SSRI, that can reduce depression as much as SSRI’s do.
  • The key argument in the serotonin theory of depression was the observation that increasing serotonin relieved depression. However, in the same way that a headache is not caused by low levels of paracetamol, the effectiveness of SSRI’s does not necessarily mean that depression is caused by low serotonin.
  • Recent research points to the possible role of oxidative stress in depression. 

SSRI’s seem to have some capacity to heal, but not reliably, and only in around half of the people who take them. Clearly something is missing. New research seems to have found some pieces that can start to fill out the picture.

Why Antidepressants Don’t Always Work – Let’s talk about the research. 

In a study published in the journal, ‘Brain, Behavior and Immunity,’ researchers found important clues about how SSRI’s work, and more importantly, what can be done to increase their effectiveness.

 ‘There is no doubt that antidepressants work for many people, but for between 30 and 50% of depressed people, antidepressants don’t work. No-one knows why. This work may explain part of the reason.’ – Silvia Poggini, researcher, Intituto Superiore di Sanita, Rome.

From the research, it seems that the effectiveness of SSRIs doesn’t happen directly by increasing serotonin. What seems more likely, it that SSRIs facilitate recovery by increasing the plasticity of the brain so it can be changed, healed and strengthened by environmental and lifestyle factors. (Plasticity refers to the brain’s capacity to change.)

‘In a certain way it seems that the SSRIs open the brain to being moved from a fixed state of unhappiness, to a condition where other circumstances can determine whether or not you recover’ – Silvia Poggini. 

The research was conducted in mice. (Mice are often used in research in place of humans because of their biological and genetic similarity to humans.) After the mice had been stressed for two weeks, they were all given SSRIs. They were then split into two groups. Half the mice continued to be exposed to stress while the other half were put in a calmer, less stressful environment.

The mice that were treated with SSRIs and put into the more comfortable environment showed an improvement in their depression symptoms. In contrast, the ones who were treated with the SSRIs and put into the stressful environment showed a distinct worsening of their symptoms.

What makes a difference?

When someone takes SSRIs, the environment and the things that person does, play a critical role in whether he or she will get better, stay the same, or get worse.

The research suggests that the effects of the SSRIs aren’t necessarily on serotonin, but on the brain’s capacity for change. The medication conditions the brain for recovery, and the environment drives the recovery – for better or worse. The environment has a heavy influence on how the person will respond to the antidepressants.  

‘This work indicates that simply taking an SSRI is probably not enough. To use an analogy, the SSRIs put you in the boat, but a rough sea can determine whether you will enjoy the trip. For an SSRI to work well, you may need to be in a favourable environment. This may mean that we have to consider how we can adapt our circumstances, and that antidepressant treatment would only be one tool to use against depression.’ –Silvia Poggini. 

What can help?

Environment seems to be key. Environments that are nurturing and supportive of healing are more likely to change and strengthen the brain in a positive way. This might be enhanced if SSRIs have prepared the brain for this. On the other hand, environments that are stressful and unsupportive, and a lifestyle that doesn’t nurture the body and the brain, will potentially fail to make the most of any benefits of SSRIs.

The research is in its early days, and more will be needed before we have a clearer picture. 

In the meantime, an abundance of research has found strong evidence for the effectiveness of various lifestyle and behavioral factors in easing the symptoms of depression. These include meditation, exercise, reduced stress, diet, sleep, and the company we keep. These have been found to change the structure and function of the brain in ways that promote a healthy brain.

The idea that healing is more likely through a combination of environment and medication is nothing new, but this research gives us evidence of the importance of environment and lifestyle in healing from depression.

And finally …

The hopelessness that is so characteristic of depression can be worsened when medication fails to bring any sort of relief. For at least 50% of people, medication makes no dent at all in their symptoms. From the research, it seems that the effect of antidepressants may be more indirect than once thought. More importantly, it seems that they might not be as effective on their own, as they can be when lifestyle and environmental factors are able to support the healing.

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Great article! This is timely as my son *who has anxiety has asked me a lot of questions about medication. I take an SSRI as does my daughter and we find that it is not a cure for depression, but prevents us from slipping into the depths. Medication is just one tool in our toolbox that also includes a walking, running, gym classes (good for social support), healthy diet, sleep, gratitude, and prayer.


This is so true. I have been taking antidepressants before, with no effect, apart from feeling an un-emotional shell of a person.
It appears I lived with a person who triggers my depression, and the first time I was truly happy and ALL signs of depression have lifted, was when I was so far away from her that there was no way she could follow me.
Now planning for a new life away, feeling more hopeful than ever before. All my other relationships improved nearly instantly. I’m still undergoing psychotherapy, but of course it will take time to be fully recovered.
Thank you for such a timely article – it strengthens my resolve not to take antidepressants.

Carole Lyden

Hey Karan, I just love this site, when I have time to sit down to read. Always such sensible information. Depression is so unique and complex to each sufferer. It’s great to read a balanced article for a change.


I sometimes say that I was born depressed. Actually, it kicked in big time as I entered my teens and have been wrestling with it since. My opinion is that mine is half genetic, half situational.

That said, anti-depressants can lift my mood. My experience showed St. John’s Wort to have the exact same effect as the pharmaceuticals, though now I can’t take it due to a medication interaction. So they do work, but not all that much. Hardly worth the effort of taking them.

Because the situational part is so stressful and shows little hope of being resolved, I’ve found that my “escape” is medication and visualization. My mind can be taken to a much nicer place. Also, writing my feelings down helps quite a bit.

Perhaps the SSRI I’m taking does help my brain do these things better. Showing this article to my husband as he decided to stop his anti-depressant due to making him feel like a zombie.

Another very pertinent and informative article. Much appreciated.


What if taking an SSRI makes you feel worse? That happened to me 8 years ago, then as a result I was diagnosed with Bipolar 2 and set off on a road that ultimately led to taking a LOT of strong medications. Finally in the last year I have been able to take a wean off most of them and at last discovered how to be more mindful and grateful. I still don’t know how to make sense of that initial event where the SSRI made me feel worse and what else could have been done or how else it could have been interpreted.

Karen - Hey Sigmund

A worsening of symptoms is definitely a potential side effect of SSRI’s, which is why finding the right medication can sometimes take a bit of experimenting. It’s not clear why this is, but one explanation according to this new research, is because SSRI’s work by making the brain more plastic, which means more open to change. The problem is that sometimes the conditions or the environment you are in might not necessarily support the change happening in a positive direction. In this study, the mice that were used showed a worsening of symptoms when they were put in the stressful environment. This is just one theory as to why SSRI’s lead to a worsening of symptoms. There are no definitive answers for this, just that it’s clear that it happens. It’s difficult to say what else could have been done because we don’t know exactly why it happens. It might just be something to do with the way the medication interacted with your particular chemistry. It’s like any side-effect – we don’t always know someone is going to have a reaction until they’re actually having the reaction.

It sounds like you’ve worked hard to get to where you are now. That can’t have been easy but you’re doing it. All the best to you.


I don’t know why they jumped to the conclusion that it was bipolar with not a lot of other evidence. 8 years of serious meds and still weaning. Yes I was in therapy before the SSRI and 7 years after but somehow never got the message that moods are normal and not to panic and keep asking for more meds. Oh well, like you said I am on a really good path now and need to be grateful!!


Thanks for sharing your story. I was also given the diagnosis of “soft bipolar” after 8 years on Cipralex (medication made me a bit hypomanic until I reduced my dose). Now the psychiatrist wants to start me on another round of stronger medications to stabilize my mood. Like you I am using visualization, yoga, meditation and social support to stay on track.

Riza Sukman

I think the importance of increasing the range of someones ability to handle and be present with over-whelming “bad” emotions needs to be mentioned as relevant for curing depression. As is mentioned in Theodore I. Rubin’s book “The Angry Book” unacknowledged and unfelt anger is often a big player in the cause of depression and symptoms. Often times avoiding the “bad” emotions in order to feel better can prolong and worsen the condition. I think that medication can help us get out of the depth of depression but then we need to do work to get in touch with all of the suppressed emotional pain that we really don’t want to feel which will help to release stuck energies that create depressive symptoms.


That’s because the reason for depression isn’t due to Serotonin.

Mine was a lack of Dopamine. They offered me wellbutrin (it’s like an SSRI but works on another pathway and doesn’t make you gain weight).

I decided to use a natural adaptogenic from iherb (or any vitamin shop) and it fixed it. I no longer have depression. I dont even have PMS anymore. It’s called Vitex and it stops prolactin, increases dopamine and progesterone.

Who would have thought my depression was caused by my female hormones? It was by fluke I stumbled upon an article on the internet that saved me. I still love this website even though I’ve fully recovered (in just 3 months!)

NB if you’re male then this is not an option for you, it will dampen your testosterone making your situation worse. It’s also not recommended for women who are menopausal.

I truly hope you stumble upon your answer. I know where you are. It’s painful, scary and dark! If you are reading this then you are still better off than many and you still have hope of finding the light. It’s there waiting for you. You may have forgotten what happiness feels like just ask for help. Whatever is out there is watching over you. It’s a kind beautiful spirit.

It’s real, joy after depression.


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