Wikimedia Commons
Source: Wikimedia Commons

Back in 2008, the National Institute of Mental Health said, in a nutshell, to heck with the old-fashioned DSM, we want to focus on the pathology of mental illness rather than studying disease based on groups of symptoms. With that, the NIMH launched the “Research Domain Criteria” initiative (or RDoC). The stated goal of this initiative was to develop research strategies based on observable behavior and neurobiological measures—that is, harder science than the typical surveys and lists and criteria we’ve been tied to using since the more organized and rigorous medical science studies began around the 1980s or so.

Nine years into the RDoC initiative, how far have we come in treatment for mental illness, particularly the most common such as clinical depression and anxiety? On the evidence-based treatment end, not very far. There’s very little new out there medication or therapy-wise in the last 25 years, with just a few add-ons and twists such as TMS. Research-wise, however, we are tantalizingly close to having some very real and clinically useful insights into the actual brain pathology of mental illness.

One of the criticisms of psychopharmacology is that a psychiatrist will use just about any class of drug for almost any illness. OCD, depression, anxiety, schizophrenia, head injury. One might try antidepressants, certain types of antipsychotics, or even mood stabilizers for any of these conditions provided the possible benefits outweighed the risks in the particular situation. What does that mean about the separate diagnostic categories that widely different-acting medications could all possibly help? Anti-psychiatry folks use this fact to suggest all/most the meds are placebo or even harmful, and that psychiatric diagnoses are, to put it politely, bull poop.

I would suggest (and don’t think any reputable psychiatrist would disagree with me) that the diagnostic categories we have are imperfect rather than flat-out wrong or entirely invented to enrich doctors and drug companies, but we did what we could with the tools we had available at the time. Now we have better tools: We can observe genetic differences and how they play out in living neurons. Suddenly there are scientific, reasonable pathways forward through the messy tangle of psychopathology in the brain.

One of the first things researchers did once genetic testing dropped in price was to run the entire genomes of lots and lots of people. With all that data, you can compare people with and without psychiatric illness and see what genes are shared by folks who have illness and not by those who don’t. These are called “genome-wide association studies” (GWAS) and just give you clues and interesting tidbits to look into down the line. One of the risk genes that came up for multiple psychiatric disorders (from autism to ADHD to major depression to schizophrenia and bipolar disorder) was a mutation in the CACNA1C gene. (I like pronounce it Caknak, but I may be the only one.) 

CACNA1C encodes the alpha 1c subunit of the L-type voltage-gated calcium channel. Just in case you just fell into a coma reading that last sentence, it’s actually really exciting. You see, we’ve had evidence for a long time that mental illness is associated with inflammation and a process in the brain known as “excitotoxicity.” Neurons communicate with each other via electrical charge with some help and signal modulation via neurotransmitters like serotonin. The charge happens when ions on one side of a membrane flow through an ion channel to the other side of the membrane. This action can depolarize a cell, sending a wave of electrical charge down the axon of a neuron to send a signal to the next neuron, a bit like turning on a light switch or pressing the gas pedal to release fuel to power an engine. In the brain, however, sometimes it seems there is too much charge, too many ions flowing across the membrane, and this can cause real problems. The extreme version of “excitotoxicity” is a seizure, but excitotoxicity in different forms and perhaps in different areas of the brain is thought to be the main mechanism behind migraine headaches, bipolar disorder, and even clinical depression and psychosis.

What does this have to do with the voltage gated gobbledy-gook Caknak gene shared by many families with mental illness? Well, researchers discovered that people with the disease mutation make neurons that have more voltage-gated ion channels than those who don’t have the mutation.* That means these people have the structural capacity to drive more charge into the neurons. There may well be an advantage to that excess capacity, but there may also be a clear disadvantage—it may leave these folks more vulnerable to developing chronic excitotoxicity and eventual symptoms of mental illness under stress.

Wikimedia Commons
Source: Wikimedia Commons

Okay, so what? Well, this news is super exciting for clinicians and researchers alike. Remember how it is annoying that drugs like mood stabilizers can be used for all sorts of psychiatric disorders? Most mood stabilizers didn’t even start out as psychiatric drugs; they began life and still are used as anti-seizure medications. These drugs, which are insulators protecting the brain from uncontrolled waves of electrical discharge (i.e., seizures) also can help prevent and end manic episodes and depression related to bipolar disorder. Some of these drugs are also used for migraines, along with some other calcium channel blocking drugs. We have three sets of brain diseases (bipolar disorder, migraines, seizures) that are all associated with excitotoxicity and can all respond to a class of insulating medications that reduce uncontrolled ion flow through membranes.

Add to that information the fact that we have a genetic mutation associated with increased risk of mental illness related to a particular type of excitotoxicity through a particular subtype of voltage-gated calcium ion channels. That means that we can take people with this gene and symptoms of the disease and study treatments based on a hypothesis of pathology that was never this clear before. It’s still a hypothesis, but there’s more data being generated along these lines every day. There’s even a fellow gene associated with bipolar disorder, ANK3, related to sodium channels.

That kind of research and those kinds of questions can yield real, actionable answers fairly quickly. Multiple pathways of brain pathology can lead to similar symptoms (LSD and high fevers can both cause hallucinations, for example, but stopping them requires a different solution in each case). But by using genetic testing or other research methods, combined with pathological know-how and existing lines of treatment, we can learn to subdivide and better ask research and clinical questions rather than artfully educated-guessing our way to appropriate and useful treatment.

We don’t have the Rosetta Stone quite yet—we’re still doing our best with imperfect tools. But it’s time to really pay attention to the latest research, because the next stage of psychiatry is on its way.

*It's unclear if CACNA1C is expressed the same in the prefrontal cortex as it is in the cerebellum, for example, so we can’t just up and declare “mystery solved,” but it’s still a really cool finding.

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