Selective serotonin reuptake inhibitors (SSRIs) have been the holy grail of psychiatry for quite some time. To some extent, they still are as the number of prescriptions is still rising. However, recent years brought a very heated discussion on SSRIs and their efficacy in treating depression. Multiple studies have been conducted in order to confirm that the drugs improve patients’ moods. Analyses have also been done to understand the effectiveness. Some provide results against SSRIs (Ioannidis, 2008; Moncrieff et al., 2022), while others are pro (Cipriani et al., 2018). Some say that SSRIs are not better than placebo (Simons, 2022). Others say that it’s only 1/3rd of patients who actually benefit from it, with another 1/3rd benefiting mildly, and the rest not at all (Psychiatrist Tells the Truth About Anti Depressants – YouTube). One-third is not much, given the side effects of the drugs and the popularity of depressive disorders, which according to WHO affect 280 million people worldwide and are constantly rising, despite the wonder drugs. 

If SSRIs work for you, by all means, continue using them. This post is not aimed at discouraging you from it. However, if you are in the 2/3rds who are either immune to SSRIs or feel not much different, you may want to explore alternatives. The process should start with understanding why the serotonin deficiency theory is not perfect, followed by understanding what less popular and less often talked about reasons for depression are. This is exactly what this article is about. 

SSRI issues

The problems with the SSRI studies

The serotonin deficiency theory (aka the chemical imbalance) was developed in the 60s and became very popular instantly. It states that depression is caused by lower serotonin levels in the brain. Serotonin, which is a neurotransmitter, is responsible for neuron communication. Lower levels negatively impact communication and increasing the levels should make the issue go away.  But one thing to remember is that the theory was only as good as the researchers and their studies at that time, which – in the field of psychology – was a very long time ago. The serotonin deficiency theory was actually just a theory developed by accident, not by any actual research. Since then, brain scans or postmortem brain autopsies have been used to “look into” neurotransmitter levels in the brain. Unfortunately, postmortem or rat brain autopsies are still popular diagnostic tools, as we are pretty limited in methods here. Most of the research, however only compares the “healthy brains” with the “unhealthy brains” which in my opinion is not enough. When seeing some differences between healthy and depressed people, we can only deduce that those may be correlated with depression. However, we don’t know if they are biological in nature (i.e. genes) and have nothing to do with depression, if they happened before and caused depression or happened as a result of depression. Long-term studies of healthy people who later get depressed are a must to understand more about “tendency” or biological predispositions to depression. And nothing like that has been done so far.

Similarly, I’m not fond of deriving conclusions based on rat studies. Depression is a complex issue and we are not able to find out how rats “feel”. We can only see how they behave. We can observe if they are more or less lethargic after being administered SSRIs (the behavioural element of the issue) or check what their neurotransmitter levels are (postmortem). The problem with the latter however is that SSRIs sometimes lower the serotonin levels rather than increase them (France et al., 2007), and that serotonin levels differ among depressed humans. Hence, we should not evaluate a drug based on neurotransmitter level information in rat brains. Having no access to the subjective element, such as mood, makes it impossible to derive conclusions from such studies. We need both elements to make any conclusions, feelings and serotonin levels accompanying those. And we need those in humans.

Regression to the mean

Patients who are prescribed SSRIs are told that it takes a few weeks (up to 8) for the drugs to start working. The problem that I have with it is that when we experience a stressful or traumatic event in our lives, the stress and depression related to it lowers over time. Our bodies (and brains) have a tendency to heal themselves naturally when the adverse factor is removed. Otherwise, we would not be able to live to 100. 😉 The process of getting back to the most natural state is called regression to the mean, and it’s pretty well described here: https://www.madinamerica.com/2019/04/impact-regression-mean-psychiatric-drug-studies/ 

So after those 8 weeks, without a very complex test of the serotonin levels in the patient’s brain, or any kind of measure of the efficiency of neuron connectivity conclusions are made based on subjective measures of “how a patient feels”. Just we have no idea if the improvement is caused by the SSRIs, placebo effect (Kirsch, 2014) or regression to the mean, we can only believe it’s the drug. 

What happens when SSRI does not work? Patients are usually told to try another drug. And another… Instead of exploring alternative reasons for their depression. 

Alternative causes of depression

Virus infection

‘Well,’ demanded Doctor Haydock of his patient. ‘And how goes it today?’ 

Miss Marple smiled at him wanly from pillows. 

‘I suppose, really, that I’m better,’ she admitted, ‘but I feel so terribly depressed. I can’t help feeling how much better it would have been if I had died. After all, I’m an old woman. Nobody wants me or cares about me.’ 

Doctor Haydock interrupted with his usual brusqueness. ‘Yes, yes, typical afterreaction of this type of flu. What you need is something to take you out of yourself. A mental tonic.’

[The Case of the Caretaker, Agatha Christie]

The story was written in the 40s, long before the serotonin deficiency theory was developed. I wonder if Christie would have written it differently in the 60s or 70s, ignoring the surprisingly wise and insightful diagnosis and prescription of Dr. Hatdock’s. 

France et al., 2007 reviewed reasons for depression alternative  to chemical imbalance and came back with the following list:

• Recent or ongoing stressful circumstances
• Difficult childhood experiences
• Excessive drug/alcohol use
• Genetic/inherited problem
• Character
• Virus/infection

Although least likely (viral infection is deemed to cause only about 22% of cases). According to the authors, the chemical imbalance alone is not the reason for depression. However, combined with one of the above, it becomes one. 

The viral infection as a cause for depression became more popular after COVID-19. And so, we have a lot more recent research on the likelihood. For example, Renaud-Charest et al., 2021, claim that “The frequency of depressive symptoms +12 weeks following SARS-CoV-2 infection ranged from 11 to 28%. The frequency of clinically-significant depression and/or severe depressive symptoms ranged from 3 to 12%.” 

Just the thing is that COVID is not the only virus linked with depression. Much more popular EBV is another one and it turns out that “a diagnosis of infectious mononucleosis was associated with a 40% increased risk of subsequently developing depression” (Vindegaard et al., 2021) There are many more viruses we live with and cope with during our lives… So next time, when you get an infection, especially a persistent one, difficult to get rid of, bear in mind that your mood can be affected by it for a few months afterwards. 

It is not well understood why viruses cause depression and mood disorders. It could be the inflammation and the immune system going mad when a virus gets in. It could be the gut microbiome that gets disrupted by the virus and additionally by medication. No matter what it is, the correlation is real. As real as 11-40%, which is a lot. 

Atrophy and loss of neurons due to stress

There is a thing called neuroplasticity and it’s both good and bad. It’s good because it means that our brains and neurons can, to some extent, fix themselves, rebuild and rewire. The same mechanism can also cause neurons to shrink, and change function for the worse. It is a well-known fact that stress (especially chronic stress), PTSD, and childhood traumas cause neuroplasticity impairment (Pittenger & Duman, 2008). Problems with learning and memory are just some of the side effects. Depression and anxiety are another one. 

Since neuron shrinking is related to the worsening of neuron connectivity, SSRIs can actually help (serotonin is a neurotransmitter after all and more serotonin can make up for the atrophy). It can also stop the process (Duman & Li, 2012). Nevertheless, it’s not a complete solution, just a workaround since it does not remove the root cause. 

The problem with neuroplasticity is that it makes the neural paths adjust to the way we think. So if we think negatively most of the time, our brains get used to it and the paths are more available. Other paths just disappear. I often use the bobsleigh metaphor here. The more you use a track, the faster you can go and vice versa – if you don’t use it often enough, snow will cover it. At first, it will slow you down but eventually will cover the track completely. So depression can make you think more negatively, starting a vicious circle of negativity. Eventually, happiness and joy are unlikely to be experienced. You have to re-learn them and consciously make an effort to “rebuild the connections”. Or build them from scratch as some personality types are more prone to depression. For example, high neuroticism is linked with more negative thinking, worry and rumination. Add an adverse experience on top of that, spice it up with chronic stress and a toxic environment, and you have a good chance for depression.

This is why it’s so important to pay attention to how you think and to remove the actual stressor and heal PTSD or your childhood traumas. 

Thyroid and hormone imbalance

This research surprised me immensely. The level and complexity of dependencies in our bodies are truly astounding.  

According to Chávez-Castillo et al., 2019, depression is a complex neuroendocrine disorder that involves multiple neurotransmitter systems, endocrine axes, neurotrophic factors, and inflammatory mediators. Some of the neurotransmitters that are mentioned are serotonin, norepinephrine, dopamine, glutamate, and GABA, which are involved in regulating mood, motivation, reward, cognition, and stress response.

The authors say that “subclinical thyroid pathology appears to be a significant risk factor for psychiatric disorders [105], with multiple studies demonstrating depressive symptoms to be significantly more frequent or severe in patients with subclinical hypothyroidism than in age- and sex-matched controls”. This means that even slight thyroid problems, not yet in the state to be properly diagnosed, are a significant factor for depression. In such cases, balancing neurotransmitters on their own has no effect. 

The list of causes of thyroid problems is not very different from the depression list compiled by France et al., 2007 and consists of: “Nutrition, radiation exposure, drugs, infectious agents, and environmental toxins” (Gonzalez et al., 2020) and Smoking, Viruses, Microbiota (Ferrari et al., 2017). Sounds familiar? The only factor missing on the two lists is stress… 

Gut microbiome issues

Although a few years back (more like a few decades than actually a few years), it was unthinkable, by now, we probably all know that serotonin and other neurotransmitters are (partly) synthesised in the gut and that the gut-brain axis works both ways (the gut affects the brain and vice versa). We know that the bacteria that live in us affect our moods, as it has already been proven multiple times (Berrill et al., 2013; Mayer & Tillisch, 2011; Simrén et al., 2013).

But the studies keep moving forward and now we even know that “individuals with major depressive disorder have higher levels of the genera Oscillibacter and Alistipes” (Naseribafrouei et al., 2014). This is much more specific than just “eat well and you’ll get better”.

Kumar et al., 2023 wrote a great article summarising other research and what we so far know about probiotics, prebiotics, and synbiotics. It also suggests micro- and macro-nutrients intake, supplementation, and diet changes. Last but not least, there is a huge table in the article listing bacteria strains and their effects on mood disorders. So, if you paid no attention to what you eat for years, this might be your cause. We are much more complex organisms than just brains and neurons. A small imbalance here and there can impact a different part of the body. Wrong gut bacteria can make you depressed or anxious. So go through the article and see what you can incorporate into your diet.

Summary

Again – if SSRIs work for you, keep taking them. But if you’re one of those who tried multiple drugs and, like me, experienced no change apart from side effects, you may want to go for other solutions.

Take care of your gut, microbiome and supplementation. Remove toxins from your environment and food. Take care of yourself after each virus infection for a few weeks up to a few months. Heal your traumas and try more positive thinking, no matter how difficult it will be at the beginning. 

I know it sounds like a simpleton’s advice. On the other hand, it only sounds easy. This is why more in-depth instruction on what to do to gradually heal will follow soon. For now, I’m leaving you with the extensive reading. 😉

References

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Berrill, J. W., Gallacher, J., Hood, K., Green, J. T., Matthews, S. B., Campbell, A. K., & Smith, A. (2013). An observational study of cognitive function in patients with irritable bowel syndrome and inflammatory bowel disease. Neurogastroenterology & Motility, 25(11), 918-e704. https://doi.org/10.1111/nmo.12219

Chávez-Castillo, M., Núñez, V., Nava, M., Ortega, Á., Rojas, M., Bermúdez, V., & Rojas-Quintero, J. (2019). Depression as a Neuroendocrine Disorder: Emerging Neuropsychopharmacological Approaches beyond Monoamines. Advances in Pharmacological Sciences, 2019. https://doi.org/10.1155/2019/7943481

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