We’ve all heard of the “chemical imbalance” explanation for mental illness, and in particular, depression. While this term has supported the argument that mental illness is actually an illness, it’s also a gross simplification of mental illness in terms of what’s actually going on in the brain. I wonder if perhaps this terminology is no longer serving us.
Where “chemical imbalance” came from
The idea of a chemical imbalance didn’t come about because of observations of what was happening in the brain; rather, it was an attempt to explain depression based on the way antidepressants worked.
Isoniazid and other early drugs that demonstrated antidepressant activity were known to slow the breakdown of the catecholamine neurotransmitters (serotonin, norepinephrine, and dopamine). Based on this activity of the drugs, it was hypothesized that a deficit in catecholamines led to depression. This hypothesis was first proposed in the 1960s.
The serotonin element in particular became a popular bandwagon, leading to the development of new drugs. Eventually, this led to the development of the first selective serotonin reuptake inhibitor (SSRI), Prozac, which ushered in an era marked by heavy direct-to-consumer advertising by drug companies that leaned heavily into the notion of a chemical imbalance (Pies, 2019). “Chemical imbalance” was also a handy metaphor to explain to patients that depression involved biology.
The real story
Current understanding is that depression is complex and multi-factorial. The idea that there’s a simple serotonin deficit, or catecholamine deficit more broadly, is inaccurate. Science can get a much more detailed view of what’s happening in the brain now compared to the 1960s, and there simply isn’t a shortage of neurotransmitters.
However, that doesn’t mean we throw the baby out with the bathwater. There are clearly biological elements to depression and other mental illness, and multiple factors that have been implicated.
Signalling between neurons via catecholamine neurotransmitters
This is much more complex than absolute amounts of these neurotransmitters. Regulation of neurotransmitter receptors and transporters on nerve cell membranes has a major impact on signal conduction. A potential reason the delayed onset of action of antidepressants relates to the time it takes to adapt the regulation of these receptors via changes in the expression of genes encoding for them.
The neurotransmitter glutamate can cause what’s referred to as “excitotoxicity,” and this may have a role in depression. Inflammation is suspected to be a key contributing factor. Ketamine affects the glutamate signalling system via its effect on NMDA receptors.
Speaking of ketamine, it promotes the production of brain-derived neurotrophic factor (BDNF), which is involved in neuroplasticity. BDNF’s potential role in depression continues to be investigated.
Genetic variants affecting such things as serotonin transporters and methylation processes are thought to potentially play a role. Variants in the SERT (serotonin transporter) gene are associated with different patterns of response to treatment than those with the “normal” SERT gene. Significantly more research is needed in this area to gain a greater understanding of the role of genetics.
Epigenetics refers to when and how often our genes are translated into the proteins that they code for. Multiple environmental factors are thought to affect this, and this is where adverse childhood experiences can have a huge impact. There is still much, much more to be learned in this area.
In Johann Hari’s book Lost Connections, he argues that the serotonin hypothesis is untrue, and therefore biology should be kicked to the curb, and depression is all psychosocial. That’s quite the leap, but the notion of a chemical imbalance is the starting point.
The idea of a chemical imbalance is sometimes described as being literally true. One way this can be done is to validate the existence of biological illness. For example, an article in VeryWellMind titled The Chemistry of Depression mentions a deficit in neurotransmitters as a contributor to depression. References to deficits in serotonin and other neurotransmitters can be seen in graphics on Pinterest and other corners of the internet, along with advice on how to “naturally” boost neurotransmitter levels.
I’m inclined to think that at this stage of the game “chemical imbalance” may have outlived its usefulness. In a time when it’s so easy for people to look things up online, if we’re using terminology that oversimplifies to the point that it’s not really accurate, we may just be shooting ourselves in the foot by hanging onto it. I’m not sure what would work better. I could suggest “complex, multifactorial, biopsychosocial illness” but that’s rather long-winded.
What do you think is the best way to characterize mental illness?