Edmund M. Higgins, MD
Clinical associate professor, Psychiatry and Behavioral Sciences, Medical University of South Carolina. Co-author of The Neuroscience of Clinical Psychiatry: The Pathophysiology of Behavior and Mental Illness, 3rd ed. (Wolters Kluwer).
Dr. Higgins has disclosed that he has no relevant financial or other interests in any commercial companies pertaining to this educational activity.
TCPR: One of the reasons we wanted to interview you was to get insight into how we can talk to patients about the neuroscience behind their disorders. A lot of us know some of the science, but why is it good for us to learn more? Dr. Higgins: I think it’s important because having patients understand the neuroscience not only better educates them, but also can help them understand why it’s important to stay on their treatments.
TCPR: Let’s begin by talking about educating patients in terms of what’s really going on in their brain when they have a heroin use disorder. How can we help patients understand that process, which can then help them with recovery? Dr. Higgins: Well, I’d start by saying to the patient, “All the opioids (heroin, morphine, oxycodone, fentanyl, etc) function in the brain because they simulate naturally occurring brain molecules (eg, endorphins). Typically, we only get a little squirt of endorphins when we get a reward like earning a good grade, winning a race, or being kissed. The opioids hijack this naturally occurring reward system, and people can feel GREAT without having to exert any effort. However, the brain, in all its wisdom, recognizes this is a problem and recalibrates the system by reducing the number of receptors on the neurons. Consequently, it takes more endorphins (or heroin) to get the same good feeling.”
TCPR: That sounds like a straightforward approach, but how do you then further explain to the patient on heroin what you mean by receptors, and how they function? Dr. Higgins: If we think of the molecules (the endorphins or the opioids) as “keys” and the receptors on the neurons as “locks,” then one needs the right key in the lock to get the reward—to turn on the good feelings. The brain likes to keep things in equilibrium—like keeping body temperature at 98.6 degrees. So, to not overwhelm the reward system, the brain starts reducing the number of locks. It does this by turning off the DNA that makes the receptors. Consequently, one needs more of the keys (molecules) to open the ever-decreasing locks (receptors); for someone with a substance use disorder, this impairs the experience of normal life. Because there are fewer locks to open in response to life’s simpler, more subtle pleasures, life becomes gray (when not on drugs).
TCPR: As clinicians, how can we better understand this process? Dr. Higgins: Instead of allowing the naturally occurring neurotransmitter chemicals to do their job, heroin binds to and activates specific mu-opioid receptors in the brain, causing an unnatural release of the neurotransmitter dopamine (see: https://www.drugabuse.gov/publications/research-reports/heroin/how-heroin-used). Heroin does this while causing a reduction in the number of brain receptors, which the neurons need to properly function (Chorbov WM et al, J Opioid Manag 2011;7(4):258–264). I tell the patient, “Once you stop the heroin, you will go through withdrawal, but if you then stay clean and sober, those receptors will rejuvenate and get your brain back to a more normal level.”
TCPR: So, you’re saying that, if a patient is abstinent for a while, the receptor factory will get revved up again? Dr. Higgins: Exactly. I tell the patient, “Your genes will get turned back on and they’ll start manufacturing more receptors (or “locks,” if you’re following my earlier metaphor). In due time, you won’t feel as horrible as you feel now.” However, trying to find joy in normal life can be a struggle for someone with substance dependence. This is the curse of heroin. But I think we need to tell patients that, if they can stay clean and sober long enough, other avenues are going to open up; that they’ll become involved in more positive and healthier activities, including jobs and relationships. But the first step is getting through this withdrawal and then staying clean and sober. This may be why the faith-based programs are more effective than “just say no.” A spiritual belief gives the abuser something to hang on to while the brain resets.
TCPR: Another topic we often find ourselves discussing with patients is selective serotonin reuptake inhibitors (SSRIs). Although these are probably the most common medications we discuss when it comes to depression, we don’t know a lot about how SSRIs work. From a neuroscience standpoint, what should we know here? Dr. Higgins: The most interesting aspect of the neuroscience of antidepressants is the growth factor proteins, such as brain-derived neurotropic factor (BDNF). For whatever reason, depression seems to reduce BDNF, which in turn causes a shrinking of the neurons. SSRIs, like any effective treatment for depression, can stimulate the DNA to produce more BDNF (Lee BH and Kim YK, Psychiatry Investig 2010;7(4):231–235). We’ve seen in studies with rats and postmortem research with humans that BDNF is increased with SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), as well as lithium, transcranial magnetic stimulation, and electroconvulsive therapy. We imagine psychotherapy does it as well, but we just don’t know—nobody can get a rat model for psychotherapy, and we obviously can’t conduct this sort of testing on the brains of living people.
TCPR: Let’s imagine a patient says to you, “You’re saying that my depression is due to my neurons shrinking? What does that mean, doc? Will the medication I’m taking (the SSRI) help get me well?” What would you tell the patient? Dr. Higgins: I would tell that patient, “Yes, since neurons control brain function, the reason for your depression appears to be a small shrinkage of some neurons.” It’s not dementia, or a neuronal loss; more like a thinning of the neuron branches. The SSRI will increase the growth factor proteins or BDNFs. A good way to put this in simple terms for the patient might be to say that sertraline (Zoloft), or any other antidepressant, can be like brain fertilizer—like throwing fertilizer on a lawn that’s gotten a little thin and brown. SSRIs, of course, are not exactly like fertilizer, but they do stimulate your neurons to grow and branch out.
TCPR: I thought SSRIs increase serotonin and possibly help restore the chemistry in the brain. Is that inaccurate? Do SSRIs work some other way? Dr. Higgins: Well, that was a very popular idea, and it’s really a simple way to explain treatment. Sertraline, for example, does block the serotonin reuptake inhibitor. The idea has been that maybe there’s not enough serotonin when a person is depressed and more when the person is treated, but research has failed to prove this true. What you can show is that antidepressants start a cascade of events in the cell that ultimately leads to the DNA and gene expression. So, it looks like the antidepressants are turning on something, such as BDNF, which explains why it takes weeks for antidepressants to be effective. They don’t simply replace serotonin in the sense of putting oil in your car. It takes some time for antidepressants to sink in, and that’s probably the process of getting down to the DNA and stimulating the growth factor proteins, which then stimulates nerve growth.
TCPR: We’ve been through a lot of theories about how antidepressants work, but is what you laid out here something that neuroscientists now hypothesize as a major part of the actual story? Dr. Higgins: I would say, as a general opinion, that there are many smart people who believe this kind of model. I’ve learned from them. I’m not out there doing the research; I’m just reading what they are writing. But not everybody accepts this. Depression is very confusing, and there is no general consensus in terms of what’s going on or even what’s wrong with the brain. For example, if you were going to biopsy the brain of a depressed person, where would you do it? Nobody really knows. It’s really hard to identify where the specific problem lies. So, a lot of this is speculation. The other complication is that we call it depression, but “depressions” might be more accurate—it’s probably a number of different kinds of illnesses. Mark George, MD, my colleague and co-author, likes to point out that a hundred years ago we used to simply call a cough a cough, but now we might call it tuberculosis or influenza. We believe that in the future we’ll have different names for different types of depression as we continue to learn more about the types of mechanisms that cause it.