The role of Serotonin and SSRI’s in the treatment of depression: was this more junk science to make pharma billions of dollars?

https://www.nature.com/articles/s41380-022-01661-0.pdf

I will start by saying this.  Major Depressive Disorder is woefully over diagnosed.  Remember yesterday, we discussed what the DSM definition of true major depressive disorder is.  Yes, FEELINGS of depression happen A LOT.  The majority of the time, they are situational induced.  Someone lost a job, has financial stressors, legal issues, kid issues, parent issues, divorce, separation, loss of a loved one, loss of a pet, empty nest syndrome, hates their job, abusing alcohol or marijuana, abuse, current trauma, childhood trauma, etc.  SO MANY THINGS go into “feeling depressed”.  Are there true clinical depression patients out there?  Absolutely.  Are there many who fail treatment after treatment?  YEP!  This is not to diminish the truly categorically diagnosed major depressive disorder patients at all.  This is to discuss how the invention of the SSRI led to the belief that a “little happy pill” was going to fix ALL depression, including the types that are not chemical balance related.   Many of us who have worked in mental health for years on end will talk about it to each other. Most of us readily admit that achieving depression remission with a SSRI is not typical.  They are not my favorite go-to medication.  Because I see them fail over and over.  They have side effects like weight gain and lowered sex drive/anorgasmia.  Some people feel suicidal when they take them.  They are not the guaranteed “happy pill” we were sold on 30+ years ago.

We see failure after failure with SSRI’s.  Patients try 2-3 of them, feel no better, try an SNRI and or add Wellbutrin, still feel no better, and then its labeled “treatment resistant” which jumps you into another category of treatment.  Then you go to the Abilify, the Rexulti, Spravato, Ketamine, and TMS treatments.  Treatment resistant depression is a big business in and of itself, just like SSRI’s were in the late 1980’s.  And lets be honest here.  Patients have been indoctrinated into this “I need a pill to fix my ill” mentality.  Pharma has ensured this.  I cannot count the number of times EVERY week that a patient will say “well I saw this med on TV can I try that? I still feel depressed and I haven’t tried THAT med yet”.  Well played pharma.  Well played.  And remember back to my posts in April when I discussed that pharma hires physicians to sell their drugs; psychiatry is NO different!  You can find a psychiatrist who will happily collect their $2500 from a pharma company to tell you how amazing Rexulti, Vraylar, Trintellix, Spravato, and Caplyta are.  Which, yes, sometimes they ARE good meds for people.  But they also cost on average $300-1200 per month and are ONLY required to show that they work AS GOOD as their predecessors that are generics.  They don’t have to show they work BETTER.  Just AS GOOD.  With a hefty price tag.  MOST of these drugs are used for, you guessed it, “treatment resistant depression” when a patient failed other treatments.  Just add one of these baby’s to their regimen and voila, depression is better.  Or so they claim.

But what if the SSRI treatments we were told to give patients never had any clinical basis to back it up?  That is exactly what we are finding out now.  Ponder this for just a moment:  If the SSRI class was so fantastic, why did they come out with new improved SNRI and NDRI (Effexor and Wellbutrin) that mimic the tricyclic antidepressants shortly after the arrival of the SSRI to the market?  If the SSRI was the magic bullet they wanted us to believe it was, why were those other drugs even created?

So back to the paper I linked above.  The serotonin theory of depression.  80% or more of the population believe that depression is “chemical imbalance” based.  WOW.  Zero mention of life stressor psychosocial causes.  Which I hammer on pretty hard in my office.  I discuss with EVERY patient that medications only work IF there is a neuro chemical component to their mental health issue, and a mix of therapy, life changes, diet, exercise, boundaries, etc are all just as important.

“It is often assumed that the effects of antidepressants demonstrate that depression must be at least partially caused by a brain-based chemical abnormality, and that the apparent efficacy of SSRIs shows that serotonin is implicated. Other explanations for the effects of antidepressants have been put forward, however, including the idea that they work via an amplified placebo effect or through their ability to restrict or blunt emotions in general.”  This is where SSRI’s are in the news right now, the blunting restricting of emotions that could lead to teenagers attempting suicides or committing acts of violence with zero remorse while taking these medications.

Fourteen different serotonin receptors have been identified, with most research on depression focusing on the 5-HT1A receptor. 5-HT1A receptors, known as auto-receptors, inhibit the release of serotonin pre-synaptically, therefore, if depression is the result of reduced serotonin activity in the 5-HT1A receptor, people with depression would be expected to show increased activity of 5-HT1A receptors compared to those without. Two meta-analyses were evaluated, the majority of results across the two analyses suggested either no difference in 5-HT1A receptors between people with depression and controls, or a lower level of these inhibitory receptors, which would imply higher concentrations or activity of serotonin in people with depression. Both meta-analyses were based on studies that predominantly involved patients who were taking or had recently taken (within 1–3 weeks of scanning) antidepressants or other types of psychiatric medication, and both sets of authors commented on the possible influence of prior or current medication on findings. In addition, one analysis was of very low quality including not reporting on the numbers involved in each analysis and using one-sided p-values, and one was strongly influenced by three studies and publication bias was present.

The serotonin transporter protein (SERT) transports serotonin out of the synapse, thereby lowering the availability of serotonin in the synapse.  Animals with an inactivated gene for SERT have higher levels of extra-cellular serotonin in the brain than normal and SSRIs are thought to work by inhibiting the action of SERT, and thus increasing levels of serotonin in the synaptic cleft.  Although changes in SERT may be a marker for other abnormalities, if depression is caused by low serotonin availability or activity, and if SERT is the origin of that deficit, then the amount or activity of SERT would be expected to be higher in people with depression compared to those without.

Three overlapping meta-analyses based on a total of 40 individual studies.  Overall, the data indicated possible reductions in SERT binding in some brain areas, although areas in which effects were detected were not consistent across the reviews. In addition, effects of antidepressants and other medication cannot be ruled out, since most included studies mainly or exclusively involved people who had a history of taking antidepressants or other psychiatric medications. Only one meta-analysis tested effects of antidepressants, and although results were not influenced by the percentage of drug-naïve patients in each study, numbers were small so it is unlikely that medication-related effects would have been reliably detected. If the results do represent a positive finding that is independent of medication, they would suggest that depression is associated with higher concentrations or activity of serotonin.

And now the discussion of findings.  Our comprehensive review of the major strands of research on serotonin shows there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity. Most studies found no evidence of reduced serotonin activity in people with depression compared to people without, and methods to reduce serotonin availability using tryptophan depletion do not consistently lower mood in volunteers.  The chemical imbalance theory of depression is still put forward by professionals.  The general public widely believes that depression has been convincingly demonstrated to be the result of serotonin or other chemical abnormalities and this belief shapes how people understand their moods, leading to a pessimistic outlook on the outcome of depression and negative expectancies about the possibility of self-regulation of mood.  The idea that depression is the result of a chemical imbalance also influences decisions about whether to take or continue antidepressant medication and may discourage people from discontinuing treatment, potentially leading to lifelong dependence on these drugs.  This review suggests that the huge research effort based on the serotonin hypothesis has not produced convincing evidence of a biochemical basis to depression. This is consistent with research on many other biological markers.  We suggest it is time to acknowledge that the serotonin theory of depression is not empirically substantiated.

This paper is one of those aha moments where you realize that everything you were taught about antidepressants probably had a pharma agenda behind it…….and you have to unlearn what you thought to be true, and go back to the basics of how to better treat patients with unipolar depression. Because if the goal of antidepressants are to increase serotonin in the synapse, but studies found that HIGHER levels of serotonin existed in people who are depressed, then it begs the question: do antidepressants, namely SSRI’s, actually cause more depressive symptoms? Are we increasing serotonin with the opposite outcomes we are supposed to get? Are we overdiagnosing depression? Are we truly looking at the comorbid life issues contributing to mood dysregulation? Has the “happy pill” era just had a huge elephant sized dump landed on it? Yes.