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    Double Helix Depression: There’s No Such Thing as “Depression” But there is “CACNA1C + MTHFR Depression”

    “Any sufficiently advanced technology is indistinguishable from magic.”

    – Bruce Alan Kehr, M.D.

    Reader, what is “normal”? In my profession, I speak with a lot of folks who have trouble answering that question. “Is what I’m feeling normal?” “Am I really depressed or is this just a phase?” “Is something wrong with me, or does everybody secretly feel as bad as I do, and they just don’t talk about it?” When it comes to mental health and wellbeing, it’s normal to look for a “norm” or a baseline for how we think we should feel—yet most of us have a hard time trying to define what that baseline really looks like. And please believe me, those eternally happy pictures posted on Facebook are not the “norm” for anyone (and are the source of emotional pain for many). However, if “What is normal?” is a difficult question to answer, its opposite is often as clear as day: “I don’t know what normal is,” some of my patients say, “but what I’m feeling isn’t it.” Unfortunately, this answer can lead to a deep feeling of helplessness: for those who are suffering mental illness, nothing’s worse than knowing something’s wrong, but not knowing if anything can be done about it. Some people feel this sense of helplessness for months, or even years. Some, like my patient Martin, have felt it their entire lives. This is not as uncommon as you may think. Luckily, thanks to major advances in genetic testing, Martin and those like him have a way out of their suffering. Today, I want to explain how I used precision medicine to tweak Martin’s genes and help him feel better after nearly four decades of deep depression.

    When Martin* came to see me, one of the first things he mentioned was the longevity of his depression and anxiety, which dated back to his childhood. Like many with these illnesses, he was baffled that despite having the trappings of a “normal” life—including success as a real-estate broker, a loving wife, and two young children—he continued to feel empty inside. How was that possible, he wondered? Why hadn’t these milestones filled him with joy or contentment? In fact, rather than experiencing  these positive feelings, his symptoms seemed to be worsening by the month despite adequate doses of Sertraline (an SSRI antidepressant) and Alprazolam (an anti-anxiety medication). His PHQ (Patient Health Questionnaire) depression scale score was 20, suggesting a severe major depressive disorder. He fantasized about leaving his family to become a wilderness guide, given his love of nature, and stated, “Dr. Bruce, I just want out of it all. I am not suicidal, but I can’t take it anymore. The pressures of my job, marriage, and raising a family are just too much. I have lost interest in everything, can’t sleep, overeat, and feel that I am a failure in life. I know that I have everything that matters in life but I just feel so empty—and so overwhelmed. And the meds aren’t helping. Is there hope for me? Can you give me one of those genetic tests I keep reading about?”

    Genetic Testing is the Frontier of Medicine – it is Precision Medicine

    I empathized with how badly he was feeling. Over 16 million Americans suffered from major depression last year, and the prevalence of the disease is on the rise. Martin was not alone in how he was feeling—and his curiosity about genetic testing demonstrated how serious he was about finding a solution. “Martin,” I told him, “Genetic testing is at the cutting-edge of medical science. It is the frontier, the future. This test allows me to ‘read’ your genes to better understand what medicines and supplements your body will respond to—and what it won’t. I can help you feel better—and that process begins with a simple cheek swab to send away for your results.” He felt encouraged as he left the office but remained skeptical that anything could help him. I didn’t blame him—four decades is a long time to suffer. And yet I felt excited to get to work in helping him feel whole again. I knew the genetic test would make a difference.

    Genetic Testing Reveals Your Personal Genome, and How to Epigenetically Modify It

    One week later we met again, and I presented the results of his testing. “Martin, your test results indicate that Sertraline is not the best choice for you, as your SLC6A4 gene predicts an average response to SSRIs, and a higher rate of side effects.” As you may remember, for individuals with certain variants on their SLC6A4 gene, SSRIs can in fact be ineffective or create adverse events—and given how prevalent SSRIs are in the treatment of depression, this is crucial to test for via a genetic test.

    CACNA1C and MTHFR Gene Variants

    “In addition,” I continued to Martin, “you have mutations in two other genes—CACNA1C and MTHFR—which we will need to address.” With three genes in play, we had a lot of epigenetic levers we could work with to help Martin feel better. Not wanting to make too many changes at once, I began by making modifications to each gene in turn: I addressed his SLC6A4 variant by reducing his dosage of Sertraline, which as an SSRI was likely responsible for a number of his side effects. I addressed his CACNA1C variant by adding lithium. If you recall from our prior blog on this gene, CACNA1C is responsible for encoding the calcium ion channels in our brain cells, which help our neurons communicate messages between cells and within brain circuits. A particular mutation on this gene can lead to these channels remaining open for an extended period of time—leading to too much “excitatory signaling” which negatively impacts our mood and anxiety levels (for a refresher click this link!) Lithium blocks the calcium channels, and can thus drastically improve wellbeing for those patients with a CACNA1C gene variant. For Martin’s MTHFR mutation, I added l-methylfolate (Deplin, Enlyte) which helps to produce more serotonin, dopamine and norepinephrine in the brain. (I wrote about l-methylfolate treatment on a prior blog found at this link, which I highly encourage you to read for more information.)

    After I explained to Martin this new treatment regimen to see how it sounded to him, he looked at me with even more skepticism. Most of it sounded fine, but one aspect of the proposed treatment plan shocked him. “Lithium? Really!? Isn’t that for crazy people? Do you think I’m crazy?” This is a common reaction from patients when I recommend Lithium, until I point out that municipalities with higher levels of lithium in their supplies of drinking water are correlated with lower rates of suicide and violence in adolescents and adults. When I shared this information with him he reluctantly agreed.

    One month later, his reluctance had transformed into pure joy. Martin came into my office with a big smile on his face and said, “Doc, It was like magic! At the end of the first week I began to feel better, and now I feel the best I have in decades! It’s a miracle!” With Martin, it was one of those days where I actually felt like a surgeon—that I had removed from him some diseased tissue and restored him to health. It was a great feeling.

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