The bulk of the evidence is against the use of psychotropic medications for anxiety and depression. Studies show that in many cases, effects of SSRIs and benzodiazepines are no better than placebo for mild to moderate depression–indeed, some studies showed that SSRIs were less than half as effective as placebo! It also appears that according to the major medical journals, the concept of a chemical imbalance underlying at least depression has been debunked.

Heritability of Depression

And yet, there’s a flip side—which is probably why the concept of neurotransmitter imbalance persists. We know that clinical depression runs in families: those with major depressive disorder (MDD) are three times more likely to have a family member with depression than the rest of the population.

Which genes are actually responsible for this is still a bit of a debate—this study shows that six genes have been implicated, including MTHFR, but other studies disagree, not finding the data for this association particularly compelling.

What Antidepressants Do

We also know that antidepressants are more effective than placebo for MDD (though the relapse rates while medicated are still up to 60%, and long-term treatment may, in fact, make the condition worse).

Still, this tells us that the drugs must be doing something. Since the target of SSRIs is serotonin (and sometimes dopamine, epinephrine, and norepinephrine too), neurotransmitters must have something to do with the pathology of depression (and potentially other mental/emotional disorders as well), despite the contradictory studies that say there is no evidence for neurotransmitter involvement.

Any Evidence for the Neurotransmitter Imbalance Theory?

Could it be that studies haven’t found neurotransmitter imbalance in depressed patients because of the way in which the neurotransmitters are measured?

This study shows no difference in the cerebrospinal fluid (CSF) of serotonin metabolites between depressives and non-depressives. CSF is often the measurement of choice in studies of neurotransmitter levels, as it is assumed to be the most accurate.

And yet, urinary neurotransmitter measurements have shown low levels of serotonin and catecholamines in those with depression compared to those without. We likewise see high levels of urinary catecholamines in PTSD, and low PEA in ADD. It has also shown that those with depression treated with 5-HTP (the biochemical precursor of serotonin) improved, as long as urinary serotonin metabolite levels also increased.

So at least by the urinary standard of measurement, there is evidence for the imbalance theory. But again, this doesn’t establish a causal relationship.

Is it possible that neurotransmitter imbalance might not be a cause, but an effect—and that’s why the relapse rates are so high for those who are medicated? Because they are only treating a symptom of the problem, rather than the problem itself?

Neurotransmitter Imbalance and Depression: Which Comes First?

This study from way back in the early 80s postulates the idea that stressful events, known risk factors for depression, might cause neurotransmitter imbalance (raising some and depleting others). Many of the studies nowadays are looking at the association between genetics and stressful life events as combined predictive risk factors for depression: that is, when a trigger event occurs, perhaps (and I’m extrapolating here) your enzymes for neurotransmitter metabolism (such as MTHFR, COMT, and MAO, to name a few) might be overwhelmed, and temporarily unable to restore balance. Perhaps those with “healthy” genes for those enzymes can play catch-up faster than those with inherited defects. That has yet to be clearly established, though.

But I’ve certainly seen patients with genetic mutations in especially these enzymes for whom nutritional cofactor support (such as activated folate – MTHF – and methylcobalamin – B12) have been game-changers. This certainly suggests that these enzymes play a role in the pathology of depression in those cases—and indeed, low folate levels have been implicated in various types of psychiatric disorders. Studies have linked low folate with neurotransmitter imbalance, particularly low serotonin, lending credence to this theory.

The Upshot

First, it’s amazing to me how little we still know about the brain, and how much controversy there still is around the pathology of depression. This is probably because there are so many potentially diverse root causes.

Second, while I certainly don’t care for long-term antidepressant therapy, I can’t deny that I have seen some patients respond to meds when they have not responded to anything else. That said, the studies strongly caution against using those meds as a monotherapy, or as a long-term treatment. Even if neurotransmitter imbalance is part of the symptomatic process, and if the drugs provide temporary relief, it’s important to find and treat the cause while using a short course of them. Does the problem involve gut inflammation (which can lower serotonin production)? Do your hormones need recalibrating—adrenals, thyroid, or sex hormones, which in turn influence neurotransmitter levels? Are you in a toxic environment or reliving old trauma? Reprogramming toxic thoughts, and/or Cognitive Behavioral Therapy (CBT) are great adjunctive therapies to help deal with the root issues in these cases.

It’s also possible, and advisable in less severe cases, to run urinary neurotransmitter testing and feed the deficient biochemical pathways with neurotransmitter precursors. Given the relapse rates and potential for creating more imbalance than before, antidepressants should certainly not be the first line therapy for treatment.