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OPINION

From lab to clinic: hope for those suffering from depression

For many, when despair becomes depression, or untenable anxiety, the standard answers are not enough to assuage suffering. It’s time to close the interminable lag time between what’s happening in the lab and what’s happening in the clinic.

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As we look back over the past decade, one thing is disturbingly apparent: We are increasingly a people in despair. For many, when despair becomes depression, or untenable anxiety, the standard answers — antidepressants with a dose of therapy — are not enough to assuage suffering.

We know this because the rates of mental health disorders and suicide are rising. Nearly a third of the 264 million people who suffer from major depression around the world don’t respond to any antidepressant treatments, and many who do find that medications stop working over time. A surprising number of young people who attempt suicide are already taking antidepressants. Dr. Gregory Plemmons of Children’s Hospital at Vanderbilt put it recently, pediatric beds in hospitals used to be for kids fighting off pneumonia; now they’re full of kids who don’t want to live.

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As other areas in medicine move rapidly forward with findings in their fields — for instance, targeted cancer therapies are extending the lives of oncology patients — psychiatry lags decades behind in providing new answers. The options we give a patient today are largely the same ones we offered a patient 30 years ago.

That’s frustrating and disappointing not only from the patient perspective but also from a scientific one. The past decade has been a golden era in brain research, one in which scientists have offered extraordinary hope for today’s mental health crisis by rewriting our basic understanding of how disorders of the human brain develop, and by using that science to offer novel possibilities for preventing and treating depression, anxiety, and cognitive decline.

In 2012, Harvard researchers Beth Stevens and Dori Schafer used new visual tools to unmask the behavior of previously little understood cells, called microglia, mapping their actions in the brain in exquisite detail. Under the right circumstances, microglia keep the brain healthy; they twirl around neurons like tiny dancers stretching out their long, elegant limbs, soothing and bathing neurons in anti-inflammatory factors that help protect the brain’s all-important neural circuitry.

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But microglia also have a dark side. When they sense incoming threats — the same triggers that can overwhelm our body’s immune system, including environmental toxins, trauma, infections, physical or emotional abuse, or chronic stressors — microglia can morph from angels into frenzied assassins. They spit forth inflammatory toxins and engulf and destroy the very neural synapses they once protected — those fundamental to our mind state, mental processing, mood, behavior, and memories. Indeed, the root causes of depression and anxiety stem not so much from chemical imbalances but from microglia gone rogue — when microglia spit out inflammation that alters levels of dopamine and serotonin.

These revelations that microglia function as a kind of “holy grail” cell, one that serves as both the assassin and the guardian of the self, gives a stymied field new hope that extends beyond the serotonin hypothesis. Neuroscientists are racing to offer up novel, noninvasive ways to gently manipulate microglia to protect and restore the brain to health.

In 2016, neuroscientist Li-Huei Tsai, director of the Picower Institute for Learning and Memory at MIT, programmed software so that LED lights on a handheld wand flickered at the frequency of gamma brain waves, which are compromised in Alzheimer’s, and delivered pulses of light from outside the brain, noninvasively, to mice with a version of Alzheimer’s. This treatment caused microglia to stop spitting out inflammatory toxins and attacking synapses. Instead, microglia bathed neurons in neuroprotective factors, repaired vulnerable synapses, and stimulated new neurons to grow — all while scouring the brain for plaques and tangles and clearing those away, too. Mice showed improvements in memory tasks, with results lasting for up to a week. Human clinical trials are well underway.

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Another brain-hacking method, transcranial magnetic stimulation, or TMS, introduces gentle, brief magnetic pulses from the scalp’s surface to the brain areas where synapses have gone offline. These pulses induce a mild electrical current that hands microglia and neurons a fresh, proper set of signals. In 2016, Harvard researcher Alvaro Pascual-Leone demonstrated that TMS can restore healthy brain circuitry in depressed patients who have not responded to medications. Some patients who experienced significant relief after 30 treatments with TMS never experienced a relapse of depression, even years later.

Microglia also communicate with the over 100 trillion nerve cells that line our gastrointestinal tract. Unhealthy alterations in the gut’s microbiota can contribute to depression and other mood disorders in the brain. Valter Longo of the University of California and Mark Mattson of Johns Hopkins unveiled in 2014 and in 2018 that one way to influence both the gut and microglia is through intermittent fasting and fasting-mimicking diets, which help increase the resistance of neurons to overpruning. With fasting, we may have some ability to influence microglia to turn from the dark side to the light again.

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The discovery that microglia are like one giant light switch through which many signals related to diseases of the brain pass is one of the most remarkable in the history of science. As a result, a sea change is coming to psychiatry — that is, if psychiatrists are ready to step up to the plate and help close the interminable lag time between what’s happening in the lab and what’s happening in the clinic.

Psychiatrists have great agency here, as do patients. Big Pharma and psychiatry have long functioned hand in glove — pharma funds research, then markets successful drugs to psychiatrists — in a more symbiotic relationship than in any other field of medicine. Big industry has little to gain if we put someone on a fasting diet or refer them to gamma light flicker therapy, so these modalities have little chance of being made known and available to patients unless patients and psychiatrists push for them out of a desire to help relieve suffering.

For those caught in the liminal space of despair — between wanting and not wanting to live this life — the clock is ticking.

Donna Jackson Nakazawa is a science journalist and the author of six books, including “The Angel and the Assassin: The Tiny Brain Cell That Changed the Course of Medicine,” which publishes this week.

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