Why Antidepressants Don’t Always Make You Feel Better
If you’ve ever experienced depression, then you already know how profoundly it can affect every aspect of life. It’s more than just feeling sad—it can make even the simplest tasks feel insurmountable, leaving you trapped in a fog that dulls your emotions, motivation, and sense of purpose. I’m no stranger to depression myself; it has come and gone at different points in my life, and each time, I’ve found myself questioning everything - Are antidepressants worth it? Is there a way out without medication? What is life like for people with depression who never find relief? Will I ever feel normal again?
The best way I can describe depression is like being in a lucid dream where you’re aware something isn’t right, but you don’t quite have the clarity or energy to wake yourself up. It’s as if you’re watching your life unfold from behind a glass wall—present, yet detached. You know you should be able to take control, to shake yourself free, but no matter how hard you try, the weight of depression keeps pulling you back into inertia. And while depression medication can be life-changing for some, others find themselves wondering whether the benefits outweigh the side effects, searching for alternative ways to reclaim their mental health.
As a chronic illness, it’s one of the most prevalent, affecting around 5% of adults worldwide, though this figure is higher in developed countries. It’s also the leading cause of disability worldwide and it’s increasing at a rapid rate of around 18% per year, though this number jumped up to 25% during the pandemic.
Without a doubt, it’s one of the biggest health issues we face. Yet, I would argue that it’s also one of the most poorly understood, at least by mainstream medicine. What I’m going to do in this post is dig into what we’ve learnt about genetic factors that contribute to depression over the last 30 years. I’m also going to outline why I think it’s about time the current theory about what depression is - and, therefore, how it’s treated - needs to be turned on its head.
Before we get to that bit, let’s talk about the history of depression treatment, so we can understand where we’re at now.
A Short History of Depression and Its Treatment
We’ve known about depression for a long time. Hippocrates wrote about “melancholia” as early as 400 BCE, and Freud became interested in its psychological underpinnings in the early 1900s. However, it didn’t become an official diagnosis (called a depressive reaction) until 1952, with the advent of the Diagnostic and Statistical Manual of Mental Disorders I (DSM). Since then, the field of psychiatry has blossomed. It was renamed “depressive neurosis” in 1968, then “major depressive disorder” in 1980, which has stuck around and is still used in diagnoses today.
Along with its naming came a theory about what it was: serotonin deficiency. At last, there seemed to be some sort of biological basis for depression. This theory gained prominence in the mid-20th century and provided a biological framework to explain the complex and multifactorial nature of depression. The chemical imbalance hypothesis emerged from early research linking neurotransmitter function to mood disorders, especially following the discovery that certain drugs could affect mood regulation by altering serotonin levels in the brain.
The most commonly prescribed drugs used to treat depression today are Selective Serotonin Reuptake Inhibitors (SSRIs), which were developed in the late 20th century as a direct response to this theory. The most well-known of these early SSRIs was fluoxetine (Prozac), which was first introduced to the market in 1987. Prozac, marketed by Eli Lilly, quickly became a household name and symbolised the shift towards a biological understanding of depression. The success of Prozac, in particular, was seen as a breakthrough in psychiatry, driven by the idea that increasing serotonin availability in the brain would help restore balance and alleviate symptoms of depression.
The widespread adoption of SSRIs was bolstered by evidence that these drugs could increase serotonin levels in the synaptic cleft by blocking the reuptake process, allowing serotonin to remain active for a longer period. At the time, clinical trials showed that SSRIs were “effective” in alleviating symptoms of depression, particularly when compared to earlier antidepressant classes, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), which had more severe side effects.
By the early 1990s, SSRIs like Prozac, Zoloft, and Lexapro became widely prescribed. The popularity of these drugs grew rapidly due to their relatively mild side effect profile compared to older antidepressants and the growing belief that depression could be managed through the regulation of serotonin levels.
Depression is More Complicated Than We’ve Been Told
There’s no doubt that SSRIs have helped many people. I’m close to people in my own life who swear by them and will never stop their use.
Yet, their effectiveness has always been limited. Research has shown that only 10% of SSRIs’ efficacy in the roughly 60% of people they help is due to biological mechanisms - the rest is due to the placebo effect. In fact, a 30-year prospective study showed that SSRI use increased the long-term risk of depression if taken at some point during those 30 years. Meanwhile, there are significant risks of side effects from taking SSRIs (which often go unreported in the literature and weren’t required to be reported until recently, nor are companies conducting studies on them well-policed ) - to the point where some research suggests they double the risk of suicide.
So, what’s actually going on here?
The notion of serotonin deficiency as the primary cause of depression has been increasingly questioned by research more recently. A strong case in point is research looking at possible genetic underpinnings of depression. When I first began exploring this topic eight years ago, over 500 genes had been correlated with depression. A study published earlier this year found that around 700 genetic variants across 300 different genes have been linked to depression. The last time I checked, there were only around 20-30 genes that we know to be directly involved in the serotonergic system. This means that even if all of these genes were involved, they contribute 10% at the most to the incidence of depression.
What’s more, when you look at data on which genes have the strongest association with depression, genetic variants involved in the serotonin system aren’t necessarily the greatest risk factor. For example, a variant involved in the secretion of Brain-Derived Neurotrophic Factor has one of the strongest known associations with depression. In people with the risk variant, secretion of BDNF is reduced, leading to decreased brain plasticity. Another gene, Neuronal Growth Regulator 1, has a variant that can lead to changes in how neural networks are formed, resulting in heightened vulnerability to stress. Catechol-O-Methyltransferase, colloquially known as COMT, is a gene involved in the breakdown of dopamine. Aside from having a strong association with Attention Deficit Hyperactivity Disorder (ADHD), it too is linked to depression. But here’s the catch: the variant with the strongest connection to depression and ADHD doesn’t lead to the brain not having enough dopamine. It leads to inefficient metabolism of dopamine, meaning that people with it tend to have higher dopamine levels than those without the variant.
Clearly, depression is far more complex than simply not having enough serotonin.
This isn’t to say that there’s no place for the serotonin hypothesis for depression. There’s a reasonable amount of evidence to suggest that, in some people, a shortage of serotonin may indeed contribute to depressive symptoms. For instance, variants in the Monoamine Oxidase-A gene that lead to rapid metabolism of serotonin have been found to be more prevalent in people with a depression diagnosis compared to controls. But here’s the rub - that particular genetic variant is relatively common and is found in 30-50% of many populations, while even a less common variant that leads to even lower serotonin levels is found in 10-20% of the population. This means that anywhere from 40-70% of the population have a genetic predisposition to depression if this variant is truly as powerful as we’ve been told.
So here we have another revelation. Not only is serotonin not the exclusive culprit in depression, but many of us - likely the majority - also have some of the genetic material needed for it to manifest. That’s if we believe that it’s all about genetics, anyway.
Depression Isn’t a State of Mind, But a State of Being
So why is this serotonin theory of depression so popular - to the point where it’s taught to the clinicians meant to help us when we experience it? Firstly,it likely became popular because SSRIs presented a seemingly simple solution to a problem. Every researcher wants to be the one to solve a big problem for society and have their name forever associated with their achievement. But it wasn’t just researchers driving its popularity. Significant commercial interests were also involved, and they needed to get a return on their investment.
Over the last few years, a more nuanced understanding of depression has been developing, one that acknowledges the complex interactions between genetics, environment, lifestyle, and brain chemistry. More recent theories suggest that depression may not solely be a disorder of serotonin deficiency but instead involves multiple systems, including dopamine, glutamate, and neuroplasticity pathways, as well as an interplay with inflammation and stress hormones.
This last piece of information is important: inflammation and stress hormones are involved. I can’t understate the relevance of this piece of information. Not only are we starting to shift away from the hypothesis of serotonin being the only neurotransmitter directly involved in depression, but we’re also moving away from thinking that the brain is the only organ involved. Moreover, we’re also starting to move away from the idea of depression being something that happens primarily in the nervous system. Neurotransmitters and peptides are the main currency by which the nervous system (which includes the brain) communicates. But hormones and inflammatory molecules can also act on the nervous system, despite being classified as parts of the endocrine and immune systems, respectively.
For years, since the time of Descartes, we’ve had this bizarre idea that the brain and body are somehow separate when, in fact, they’re part of a system. Each of the parts within that system work synchronistically towards a common goal: to keep us alive and (hopefully) thriving. They’re connected by a complex communication and exchange network, one that involves the nervous system but also gap junctions, cell adhesion molecules, exosomes and microvesicles, chemical signals, and more. They’re talking to one another constantly. As Dr Ellen Langer said on Huberman Lab recently, anything that happens anywhere in the body happens everywhere in the body.
It’s not just your brain that’s depressed: it’s your entire being.
A Different Way to Think About Depression
According to Polyvagal Theory, there are three main states of the nervous system:
Rest and digest
Fight or flight
Freeze (or fawn)
While the accuracy of Polyvagal Theory is still questioned, it presents itself as an interesting model to consider different states of an organism. We can actually correlate the three states of the autonomic nervous system with different emotional states by measuring heart rate variability (HRV). What’s interesting is that, when you then integrate what we know about the inflammatory reflex (which I explained in my recent seminar), we can start to understand how our energy state changes depending on how our immune, nervous, and endocrine systems are working. In fight or flight mode, we’re not only hyper-aroused and feeling emotions like fear or anger, our cells are also mobilising resources so that we can fight or flee the moment that we need to. The immune system is also more active in stages of it. Basically, our entire body is gearing up for war.
But when we’ve spent a long time in fight or flight mode with no resolution of the threat, the inflammatory reflex doesn’t play out the way it should. When adrenaline and cortisol are raised indefinitely, they can play havoc with our body’s metabolism. Our mitochondria, the tiny organelles that generate energy in almost all of your cells, experience more stress and can eventually sustain so much damage that they malfunction. This then increases stress on the body and contributes to the onset and pathology of depression. Your body effectively goes into retreat mode because it doesn’t have the energetic resources to meet the challenge that its facing.
This can be an external stressor, like your boss constantly telling you that your work isn’t up to scratch with no constructive feedback or encouragement to do better next time, your parents yelling or being violent towards you as a child, or even simply the stress of being socially isolated in an uncertain world during the pandemic. Or it can be getting infected with some sort of virus like COVID-19, too little sleep, or too much exercise. Whether the stress is psychosocial or physical, your body reacts in a very similar way.
The result, when it feels like it’s run out of other (fight or flight) options? To freeze resources and ride out the storm, aka depression.
This means that depression is a metabolic issue just as much as a psychological issue. To me, this is the reason why antidepressants, according to the data, just don’t work very well. It’s like to trying to chop down a tree with a pocketknife; despite being well-intentioned, you won’t get very far with it. It’s just not the right tool for the job.
We need a far more comprehensive approach to this issue, one that takes into account the biopsychosocial factors that impact how a person thinks and feels and how that affects them at a biochemical level.
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