“Bipolar! I’m not really Bipolar… am I?” How Modifying the Expression of CACNA1C, ANK3, MTHFR, and SLC6A4 Genes Can Help You Recover from Bipolar Depression

Don’t Let Anyone Ever “Label” You – Including Yourself!

Reader, first and foremost, I want to welcome you into the New Year, the time when millions of people all around the globe have finished taking stock of the year that’s passed and are ready to step into a bold new future. The most common “resolution” on most peoples’ minds after weeks of holiday overindulgence is health—usually of the physical kind. If you’ve been following my series on genetics, you already know that our physical health can indeed have a strong impact on our mental wellbeing. But this year, I want to challenge you to expand your resolutions around health to include your mental health, too. There are a million ways in which to get started thinking about your own mental health, but today I want to focus on one specific question, which I hope you’ll take the time to consider as you plan out your resolutions for the rest of the year: What beliefs do you hold about who and how you are—and how might they be holding you back? It’s so easy to get stuck in a “personality trap”, if you will—assuming that the way our mind works, for better or worse, is just “who we are”. To a certain extent, that may be true. But I want to be clear: nobody should be defined by a “label,” by their mental illness… and nobody should settle for intractable symptoms of mental illness, either. A correct diagnosis and treatment plan can open up your world in ways you might have never known to be possible. One of my patients, Jimmy*, experienced exactly this. After realizing he had bipolar disorder, his life began to change. Behind his illness was a Jimmy he never knew existed. And today, I want to tell you his story.

Depression, Substance Use, and Racing Thoughts: Is this really “Just Who I Am”?

Jimmy first came in to see me with his wife, Amy. It was clear in the initial session that Amy had “twisted his arm” to get him to come in, and he was pretty resistant to opening up. She began, “Dr. Bruce, I love Jimmy but I just can’t take it anymore.” The couple was in deep distress and on the verge of separation. She went on, “He is very depressed and refuses to get help anymore. He has given up on seeking treatment and I had to drag him in here by putting our marriage on the line. We have two young children and they keep asking me, ‘What’s wrong with Daddy?’ and it is breaking my heart. Can you help us?” I could see by her body language that Amy was in clear distress. Jimmy, however, was the picture of resistance. With his arms crossed and his brow furrowed, he jumped in before I could say a word: “You shrinks don’t know what you are doing. It seems like voodoo to me. Talk, talk, talk and nothing good ever comes out of it. This is a waste of time and money. Nothing personal, Doc.” And with that Jimmy clammed up once again.

I soon learned that Jimmy was suffering through a deep depression. Although he had been a successful personal trainer, he’d become so depressed he was no longer able to work. Meanwhile, he hardly slept and was spending excess amounts of money gambling on online sports betting sites. He was smoking marijuana on a daily basis and had a prior history of excessive alcohol intake and cocaine abuse. Tellingly, he also had a family history of bipolar disorder. There were also some other atypical features of his depression such as racing thoughts. These details painted a clear portrait of mental illness—but none of it was new information to Jimmy. I wondered why he was so quick to assume nothing could be done to treat his symptoms and make him feel whole again. Why was he resigned to these warning signs just being “who he is”?

It turned out that Jimmy had reason to be cynical about further treatment. He reported prior trials on Zoloft, then Lexapro, and finally Cymbalta, and Jimmy believed—and Amy concurred—that each of these medications seemed to make him worse. This is something that is described not infrequently with my new patients during their first visit: the trial-and-error process of finding which medication works for them and their symptoms has been excruciatingly painful for many. I wanted Jimmy to know that precision medicine could help him—and sooner than he may have thought.

SLC6A4, MTHFR, and “Bipolar Genes” CACNA1C and ANK3: “Am I really Bipolar?”

I knew that Jimmy was so much more than his symptoms—and that’s why I got started right away administering some precision medicine tools to figure out what was really going on beneath his cynical demeanor. First, I administered a PHQ9 depression scale and he scored severely depressed. We also administered a Mood Disorder Questionnaire (MDQ) which was positive for 8 signs of possible bipolar disorder. Suddenly, the picture was becoming clearer.

“I understand how frustrated you both are, and why you feel so negative about seeking help, Jimmy,” I explained as I shared with them my conclusions. “I believe that you are suffering from Bipolar Depression, which has been misdiagnosed as an agitated, anxious depression. This is why you got worse on those SSRI and SNRI medications, and is related to symptoms of hypomania (racing thoughts, gambling impulses, sleeplessness, the disparagement that Amy reports), and depression (low energy, low self-esteem, difficulty concentrating, suicidal feelings, crying spells). In addition you were diagnosed with ADHD as a child, and we will get to that, but first we need to address your crippling mood symptoms. Let’s try a more targeted approach, using the precision medicine that comes from genetic testing.”

After determining the preliminary diagnosis, we performed Genomind's Pharmacogenetic (PGx) Test. I order genetic testing on every new patient, as I believe strongly that in the 21^st century it is not enough to diagnose someone using just the DSM-5 – to be most effective as psychiatrists, we also need a “genetic diagnosis.” His SLC6A4 variant revealed a higher likelihood of an exaggerated stress response, and the benefit of a more nurturing environment to reduce stress. He also had variants in his MTHFR, ANK3, and CACNA1C genes, and his 5HT2C and MC4R genes were positive for greater difficulty feeling sated, particularly if I were to prescribe certain types of mood stabilizer antipsychotics. Armed with this information, I prescribed Rexulti and l-methylfolate, and asked him to return in two weeks. At his next visit his mood was a little brighter, but he continued to complain of mood swings, racing thoughts and sleeplessness. To address these symptoms in the context of his CACNA1C and ANK3 variants, I added Memantine and Omega 3, and asked him to return in two weeks once again. At the next visit he reported that many symptoms were improving, but his troubles with focus, concentration and distractibility remained crippling, and so we added Wellbutrin.

Genetic Testing: Making Sense of your Bipolar Depression, One Gene at a Time

Over the next few months as we adjusted the doses of these medications and supplements, Jimmy began to feel better, and returned to work part-time. As he was about 80% recovered and my goal is always 100%, I administered Genomind’s Mindful DNA, particularly to address his ongoing fatigue, and his social and generalized anxiety symptoms. The results were most interesting, as he had genetic variants in 6 additional stress-response genes, FKBP5, CHRNA5/3, MIR181, OXTR, MEIS1, CRHR1; and the aforementioned CACNA1C, ANK3, SLC6A4 and MTHFR genes. Many of these genes help govern the fight, flight or freeze response (the so-called hypothalamic-pituitary-adrenal axis or HPA Axis), and are associated with PTSD symptoms. Armed with this information we added N-Acetylcysteine (NAC), a Mediterranean Diet, and Ashwagandha in sequence over the next three months.

It is now one year later, and Jimmy is back at work full-time. His marriage is improving, and his children no longer ask, “What is wrong with Daddy?” There are occasional relapses when he goes off his medications, “I hate coming in here, Doctor Bruce, and hate these medications and supplements even more. I feel like an old person!” And so in therapy we are working in how ashamed he feels about needing the medications and my emotional support, and how this ties into early childhood traumatic experiences with his mother. We both remain hopeful for his full recovery.

Reader, Jimmy discovered through the process of genetic testing that he was so much more than his disease—but for years, he had bought into the limiting belief that his symptoms were just part of his personality. This New Year’s, please take a moment to reflect on whether any part of Jimmy’s story sounds familiar. If it does, I urge you to seek the help of a trusted psychiatrist who uses precision medicine to reveal what might really be causing your pain, and then intervene with greater precision to help you ease emotional pain and find self-love.

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