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    The Future of Depression Treatment May Come from Inducing Worse Depression

    Written by

    Michael Byrne


    Treatment for major depression is currently an often miserable realm full of just almost drug therapies, line after line of psychopharmaceuticals that stem the bleeding without healing the wound(s). Behavioral interventions are often marvelous in efficacy—sleep, exercise, talk—but these aren’t cures in the sense that we’ve come to understand what a cure is. The disease waits, sometimes patiently, and this unvanquished depression remains the most disabling disease in the United States.  

    Put differently, existing depression drugs attempt to fix the brain’s errors as they occur, rather than repair the brain such that it can operate normally without those errors in the first place. It’s a peculiar distinction, one that's the difference between lifetimes of just almost and, well, freedom. There is no cure for depression, and like every other mental health condition, even tracing the disease all the way down to its purest physiological root is a distant dream. We just don’t understand enough about the brain’s wiring.

    Research out Thursday from a team based at Mount Sinai Hospital in New York City might not suggest a cure in its purest sense, but it offers something much closer to that than previously obtained: full alleviation, at least in mouse models (which are pretty good models for this sort of thing). What the authors describe in their study is a new and very unexpected target mechanism—the mechanism by which the brain corrects depression on its own in healthy humans or, more specifically, the way it naturally responds to stress. 

    The discovery points to two different ion channels in the brain—imagine wires—and group of neurons known as the ventral tegmentum (VTA), the part of the brain that handles neurological reward systems, motivation, cognition, and drug addiction. Naturally it follows that VTA dysfunction is also thought to be the locus of a number of psychiatric disorders. In depression, particularly, what’s seen is an elevation in VTA neural firing—overactivity. This is thought to be the result of an increase in incoming cation channel currents (Ih currents), which trigger the additional out-of-control firing (“dysregulation”), and a therapeutic focus has been on quieting that channel and the VTA.

    The Sinai researchers discovered something very strange about the VTA and its corresponding cation channel. If you increase the current in that channel to very high levels, higher than we would expect in a normal brain, the VTA stimulation effect switches into reverse and the opposite becomes true. The VTA quiets rather than dysregulates, and as a result, the depression bows out. Symptoms disappear. In the case of lab mice, the symptoms disappear completely, as stimuli that would normally cause depression are increased. The researchers attempted two different methods of increasing depression-causing features: using light to stimulate firing within the VTA itself and using drugs to increase current in the cation channel. The result of both was an increase in natural resistance, specifically as mediated by a third brain (and cardiac) feature, potassium ion (K+) channels.

    It bears reiterating that this is the opposite approach of a wide swath of current drug therapies for depression. It doesn’t invalidate those therapies—they are often very successful in managing symptoms—but it’s interesting to note. Prozac (fluoxetine) and its descendants all act to decrease these particular cation currents in the brain, decreasing bad VTA activity by limiting the current that stimulates said activity. The research here instead suggests a way of quelling that activity by triggering the brain’s natural K+ channel response, achieved by pushing in the precise opposite direction as fluoxetine. That’s a pretty weird revelation (and one that definitely does not mean everyone being helped by SSRIs should flush them down the toilet). Instead of treating pathology, this research suggests a method of building resilience.  

    “This is the overall strategy [of existing drugs]: find the bad part, try to reverse it,” lead researcher Han Ming-Hu told me last week. “Resilience works in totally different ways.”

    “Resilient animals we thought avoid pathogenic mechanisms,” Ming-Hu said. “Actually not. The bad changes in the brain [increased cation channel currents] are even worse. The good thing is that this bad thing activates a compensation function that counteracts. It finds a new balance. After they establish a new balance, they become stronger. Kind of like in a human if you experience a tough time or trauma, if you overcome it, you become stronger—even stronger than people that never experienced a tough time. We found this same phenomenon at the cellular level.”

    There is in fact something of an anti-Prozac already on the market, a drug that increases cation currents in a way similar to what the researchers observed in resilient animals. It’s called lamotrigine and its on-label use is as an anti-convulsant. Off-label, the drug has had success in treating the depressive aspect of bipolar disorder. In the brain, its function is to increase Lh currents and the Sinai study used it to do just that. In the past, the mechanism of the drug has been poorly understood, but Ming-Hu agrees that it may have a future in treating conventional unipolar depression.

    Even if they don’t “cure” depression, the new pharmacological treatments suggested by Ming-Hu et al’s research promise to at least be more effective and have less side effects. “The reason is that it’s mimicking natural resilience,” he said. “Enhancing the good mechanism.” Beyond lamotrigine, there are actually a large number of ways this can be done, particularly via channel potentiators (that increase the electric potential along a channel; it’s analogous to increasing the steepness and height of a ramp on which a ball rolls from point A to point B) and via cAMP activators, proteins that induce intracellular signaling.

    Ming-Hu also suggested that Ih is just one of many possible signaling pathways that might be exploited like this in the future. One could imagine a single drug targeting many different sorts of natural resistances at once. The promised result is not another “brand-new” variety of psychological bandage invented by a drug company to snag a new patent on something old, but a way of curing from within and, in the process, making the brain stronger.