Why does it matter that depression as a medical diagnosis is questionable? Well, because if depression is not a disease, we can’t really treat it like a typical disease. Consider this, if depression is a medical condition in the way that a broken ankle is, then it stands to reason that you would want to treat the condition with “medication” and different types of procedures. Which is what we’ve done in the United States.

However, if it isn’t a medical condition, then we would need to address it differently. If it’s a social problem, a mindset problem, a spiritual problem, then medication would do little to treat the condition and may even serve to mask the issue.

Going back to the so-called “chemical imbalance theory,” Americans have been taught that the primary neurotransmitter responsible for depression is serotonin. I can’t tell you the number of patients who are shocked when I explain to them that the idea that serotonin plays a defining role in depression has been debunked.[2] In what is known as a systematic umbrella review (basically the highest of the highest levels of scientific evidence) evaluating decades of research pertaining to the serotonin theory of depression, the authors reported in their summary conclusion:

The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that, long-term antidepressant use reduces serotonin concentration.[2]

These findings came to be quite controversial in the psychiatric community. There was so much criticism and critique of this paper that the authors felt compelled to write their own response addressing the major contradictions found among those in the field of psychiatry. [3]

Why is this lack of evidence supporting the role of serotonin in depression important? Well, let’s continue with the ankle example to understand.

When you injure your ankle, whether you sprain it or break it, that injury results in a cascade of events known as inflammation. Inflammation is not a disease, it’s a normal process mediated by your immune system designed to help you heal. To avoid a long lecture on the inflammatory process, I’m going to jump ahead by saying that one of the net results of inflammation is the production of prostaglandins which cause pain and swelling. Therefore, in order to help our patients manage the pain and swelling caused by inflammation, we use non-steroidal anti-inflammatories (NSAIDs) to block the enzymes that are necessary for the production of prostaglandins. In other words, if the problem we’re targeting is inflammation, we target the chemicals responsible for producing the inflammation.

In the case of depression, the vast majority of ADPs are ultimately designed to increase serotonin levels. Different ADPs accomplish this through varying mechanisms and by targeting different proteins. But the net result, in general, is to increase serotonin levels. Now, let’s think about this, if serotonin is not found to be a key player in depression, why then is serotonin the key target of ADPs? Does it make sense to prescribe something that increases serotonin when serotonin isn’t the problem? Wouldn’t that be like prescribing insulin to help manage inflammation in an ankle injury?

But if all this is true why do some people benefit from them?

It’s worth noting that in the studies that report improvement of symptoms with ADPs, the placebo groups also substantially improve. These studies end up reporting that ADPs are statistically superior to placebo, but that doesn’t change the fact that placebo was effective for many in the control group. The placebo effect is real, and it should not and cannot be discounted.

Additionally, it’s also kind of like treating a fever with acetaminophen, brand name Tylenol. The fever is not the result of decreased levels of acetaminophen. Still, taking acetaminophen generally reduces the fever. Great! No fever. That’s good right? Well, that is good if it wasn’t for the fact that fevers are normal physiologic responses the body uses to help deal with diseases. “Treating” the fever may actually cause harm![4] And in the same way, treating depression with drugs that blunt normal sensations may reduce the “fever” of depression, but in no way does it seem to actually treat the real problem.

“But research shows that ADPs are effective!” Actually, a careful analysis of the research raises some eyebrows.

In 2018, Cipriani et al published a systematic review and network meta-analysis, again the highest of high levels of evidence, reviewing the effectiveness and safety of 21 ADPs for acute treatment of adults with major depressive disorder (MDD).[5] The authors of the study reported that the evidence reviewed indicated that ADPs were more effective than placebo. In a Time Magazine interview, the chief author of the study stated:

“We were open to any result… This is why we can say this is the final answer to the controversy.”[6]

That’s a bold statement that warrants careful evaluation. For starters, the authors pointed out in their study that 78% (409 out of 522) of the studies that were reviewed in their analysis were funded by pharmaceutical companies (I’ll explain why this is important in a second). 9% (46) had a high risk of bias and 73% (380) had a moderate risk of bias. Only 18% (96) were rated as low risk. That’s less than one-fifth.

To contextualize this, imagine the difference between a high level of pain, moderate level of pain, and a low level of pain. Using a scale from 1-9 where 1-3 is low, 4-6 is moderate, and 7-9 is high, do you think moderate pain is real pain? Do you think it’s the kind of pain you would expect a medical practitioner to take seriously? I think you would. I certainly would. And I think a moderate risk of bias is a very real risk of bias that warrants cautious interpretation of the reported results.

Particularly when we consider that Dr. Andrea Cipriani, the chief author, was supported by the National Institute for Health Research (NIHR) Oxford Cognitive Health Clinical Research Facility.

This facility boasts of “strategic collaboration” with the following companies:

Akrivia, Angelini Pharma, AstraZeneca, Biogen, Biotekna, Boehringer Ingleheim, Cambridge Cognition, Covance, Exprodo, GSK, IXICO, Janssen, Johnson & Johnson, J&J Innovation, Lilly, Lundbeck, Merck, Mezurio, Novavax, Novo Nordisk, Pfizer, P1vital Ltd, P1vital Products Ltd, Roche, and Sanofi.[7]

Five of the 21 drugs assessed in the study are manufactured by four companies in this list of “strategic” collaborators: Angelina Pharm – Trazadone, GSK – Bupropion and Paroxetine, Lilly – Fluoxetine, and Pfizer – Reboxetine.

Three other authors in the study, one of whom helped conceive and design the study, and all three whom selected articles and extracted data, had ties with several pharmaceutical companies that manufactured another 10 of the 21 drugs covered in the study. That means that 15 out of the 21 drugs, reported to be effective compared to a placebo, were assessed by authors who have substantial financial ties to the companies manufacturing those drugs.

Now, maybe that’s a coincidence. Maybe it’s inconsequential. Maybe it doesn’t impact their findings and the results can be taken at face value. However, a 2008 literature review of 39 meta-analyses revealed that the 10 studies supported by industries (having funding from pharmaceutical or medical device companies) exhibited lower median quality (2.5 vs. 6 out of 7, p<0.01), greater bias in study selection, less comprehensiveness, and were less inclined to employ appropriate criteria. [8]

Most interesting, perhaps, is the study published in the Journal of Clinical Epidemiology that set out to “identify the impact of industry involvement in the publication and interpretation of meta-analyses of antidepressant trials in depression.” [9]

Out of the 185 meta-analyses considered in said study, 79% (141) were associated with some form of industry link. The authors classified an 'industry link' as either having sponsorship or authors who were industry employees, or having conflicts of interest, similar to our Cipriani study. Their findings highlighted that meta-analyses involving authors who were employees of the drug's manufacturer were 22 times less likely to present negative reports about the drug in the study (p<.001).

So, while it would be nice to take Dr. Cipriani at his word, the literature suggests we should be cautiously optimistic about the results of his study at best. And I am very cautious.

With all that said, the question still remains, “okay, if you don’t initiate pharmacotherapy for depression, what do you recommend?”

For starters, I’m a big proponent of a form of therapy called “Cognitive Behavioral Therapy” (CBT). This is a well-researched approach to therapy with a proven track record. A 2019 Network Meta-analysis published in the Journal of the American Medical Association (JAMA) showed that regardless of the specific medium, CBT was superior to “care as usual” for the treatment of depression in adults.[10]

CBT helps patients identify unhelpful thought patterns and their impact on mood and behavior, and helps patients modify those thoughts to better fit their reality, change behavior for the better, and improve mood. Even the APA endorses the use of CBT for depression. [11] In fact, they endorse several other forms of psychotherapy. Now, full disclosure, they also endorse the consideration of second-generation ADPs. Nobody is perfect.

As I mentioned at the beginning of this post, in my own practice I try to dive into the personal factors that are causing my patients to experience depressive symptoms. I ask about the important relationships in their lives. Want to know something interesting? Only one of my patients who has ever presented with depression reported strong familial ties or friendships and a strong sense of belonging in a local community. The rest explained that they don’t have deep relationships with other human beings. They endorse preferring to live isolated.

I discuss screen time. Specifically, I ask about the kind of content my patients are consuming. Many of us are exposing ourselves to things that promote negative thought patterns and lead to a depressed mood.

I also discuss spirituality. I personally believe that one’s own view of themselves and their relationship to the universe and its Creator plays an important role in our mood. This doesn’t mean that religious people are happier, although evidence does suggest this.[12] But people who have a sense of who they are beyond matter tend to perceive that life has greater value than just what the physical form offers. There are always exceptions to this, but, at least in my experience, this tends to be the rule.

And of course, I talk about my patients’ diet and exercise. Exercise specifically has been shown to be an effective treatment for adults with depression.[13] In a meta-analysis evaluating 41 studies and 2264 participants, the authors reported a statistically significant “large effect size” that favored exercise in the treatment of depression (standardized mean difference (SMD) = −0.946, 95% CI −1.18 to −0.71). When the authors specifically considered only the studies that had low risk of bias, they calculated that only three patients would need to be prescribed exercise for treatment of depression in order for one patient to benefit. That is a big deal! In their own words:

“Exercise is efficacious in treating depression and depressive symptoms and should be offered as an evidence-based treatment option focusing on supervised and group exercise with moderate intensity and aerobic exercise regimes. The small sample sizes of many trials and high heterogeneity in methods should be considered when interpreting the results.”[13]

Please note that small caveat at the end. That is an important limitation of the research. But the point remains. And it’s kind of intuitive right? We often feel better when we move. We feel more accomplished when we complete rigorous exercise routines. And it helps to reach physical milestones when one has been putting in the effort. It is an obvious mood booster.