William C. Menninger

Transcription

[APPLAUSE] [Dr. Nora Volkow Speaking] Good afternoon. It’s a pleasure. It’s an honor. It’s a privilege for me to be here with all of you and to celebrate all of the fellows. And I want to thank the APA and Dr. Summergrad for giving me the opportunity to share this moment with you. I devoted all of my life to study the effects of drugs in the human brain. To try to understand what is it that they do to our brains that in some people that are vulnerable that leads them to the complete loss of control with severe catastrophic consequences. But, before I actually go into that and what I’ve learned I want to share with you. I want to share a personal story that perhaps can help you put it in perspective. As Dr. Summergrad mentioned, I was born in Mexico City, and many, many years ago, when I was five or six years old, I remember having dinner with my family, with my parents and my three sisters, and there was a man that came to deliver a telegraph to my mother. I remember my mother crying after she read the telegraph. I had never seen my mother cry, and I wanted to console her. But she did not want us to see her cry, and she left the room and locked the door behind her. The next morning, my father told us that the father of my mother had died. It was many, many years later, when I had gone to medical school, when I had completed my residency training in psychiatry, when I had already been working for many years in brain imaging to investigate what drugs do to our brains and how we become addicted. At the time when my mother was dying of cancer, she called me and said, “Nora, I need to tell you something I have never spoken to you about.” And she told me that my grandfather, her father, had been an alcoholic, and that in his distress at not being able to control his strong urges to drink alcohol, he had killed himself. And I was taken aback by this, because I never knew my grandfather was an alcoholic and I had always thought that he died from cardiac complications. But I was also taken aback by the fact that my mother had kept this a secret from me, even though she knew that my professional life was devoted to trying to understand what drugs do to the brain. She had heard me speak of addiction as a disease of the brain. So I wondered how I had miscommunicated, how could I have not made her realize, that it was okay to speak about addiction. And then as I think about these words I’ve gone over many times in my brain, and I realize that describing addiction as a brain disease, describing addiction as a chronic brain disease, is sort of a theoretical concept. Say that you have two parents with a very sick child, and they go to the hospital, and the doctor says, “Your child is in a coma because he has diabetes.” And he explains to them that diabetes is a disease of the pancreas, a chronic disease of the pancreas. This does not explain why that child is so severely ill. What explains it is the understanding that the cells in the pancreas can no longer produce insulin, and we need insulin in order to be able to use glucose as an energy source, so without it, the cells in our body are energy-deprived—which explains why this child is so sick. So when we speak of addiction as a chronic disease of the brain, what does it mean? How does it help us explain the devastating changes in behavior of a person that’s addicted, where even the most severe threat of punishment is insufficient to have them stop taking drugs, where they are willing to give up everything they care for in order to take a drug? How does “a dysfunction in the brain” help us understand that? Well to start with, we’ve known for many years that all the drugs of abuse that produce addiction, all of them, whether it’s legal or illegal, all of them increase dopamine in brain reward regions, activating them—and that, in turn, motivates our actions. Which explains why behaviors that are rewarding have been used by nature in order to ensure that we survive, as an individual, and as a species. That is why food is so rewarding. That’s why sex is rewarding so we can survive and procreate. Drugs hijack that system. So it made perfect sense that one of the first theories regarding why a person that’s addicted will take drugs was because in them their brains was much more sensitive to the rewarding effects of drugs. In other words, in them the drugs will produce much larger increases in dopamine than in a person that was not addicted. Which will then explain their enhanced motivation for taking the drug. Except that the research shows that was not the case. In fact, it showed that the opposite appeared to be true, that people who are addicted to drugs, showed much lower increases in dopamine when they were given the drug, than those who were not addicted. This was completely counterintuitive. It was counterintuitive. You’re addicted. The addicted person has less increases in dopamine with a drug and we are saying that the ability of drugs to increase dopamine in reward regions is why we take them? So why would an addicted person even bother to take the drug? As counterintuitive as this may seem, it was actually very consistent with what we had started to learn about how the dopamine cells in our brains responds to reward. This was actually a very, very unexpected finding. It was first reported by Wolfram Schultz, who showed that in animals, when you give an animal a reward, their dopamine cells fire, but with repeated administration of that reward, the dopamine cells stop firing to that reward. But instead, fire when they get exposed to the condition stimulant that predicts the reward. What is a condition stimulant? A condition stimulant is that one that has been associated by its temporal circuits or by its spatial presence with the actual experience of the reward, and this condition stimulant by itself increases dopamine. When we increase dopamine that activates the motivation and drive that leads you to want to consume that particular reward. Now, things when we look at them scientifically retrospectively can make a lot of sense and when I think about this particular finding, I just marvel at the extraordinary design of nature. Why do I say this? I say this because increasing dopamine in reward regions is what motivates our behavior. What nature is aiming for us to do is to ensure that we do the behaviors that will allow us to survive. In the case of food, to consume it. But it wants you to be motivated to engage in the behaviors that will allow you to get the food so you can consume it. So, by being conditioned, you will engage that motivational system that is anticipating to receive a reward so that you can ensure to do the behaviors and procure the reward. This is exactly why people that are addicted to drugs have the enhanced motivation to take them because they have been conditioned. They have been conditioned to the place where they take drugs. They have been conditioned to the dealer that sells them their drugs, to the friends with whom they get high. They have been conditioned to the emotional state that precedes the anticipation of getting that drug. This drives their behavior. But addiction does not end there in the reward motivation conditioning system. Drugs, by their chemical nature, activate dopaminergic pathways and the repeated administration of these drugs triggers neurotic adaptations on those pathways rendering them much less sensitive to normal physiological stimuli. But the dopamine pathways are not limited as I say to reward and motivation. In fact, in psychiatry for many years we already knew that the dopamine system was fundamental in the function of the prefrontal areas of the brain. In studies, first of all, by work in part by Dr. Patricia Goldman-Rakic, we’re actually trying to understand the role of dopamine in Schizophrenia and was able to document that it is indispensible for the proper function of the prefrontal areas in our brains that enable us to exert executive function, self-control, self-revelation, working memory, decision-making, and judgment. More recent work has shown that disrupted dopaminergic signaling into the prefrontal cortex helps us explain the impulsivity in patients that suffer from Attention Deficit Hyperactivity Disorder. We have also learned, in part by research in other psychiatric diseases, that the dopamine system is also extraordinarily important in regulating the function of limbic areas of the brain, such as the amygdala and the hippocampus, that are processing emotions, that are processing our reaction to stressful stimuli. We have known of their involvement in Schizophrenia, and more recently we have also come to recognize their fundamental role in Post Traumatic Stress Disorder, where again, just as in addiction, dopamine enables that conditioning. Conditioning in this case to a negative stimuli in contrast to conditioning to a rewarding stimuli. All of these pathways get disrupted by the repeated administration of drugs. So what is the clinical significance? Dopamine enables us to emulate our behavioral choices, our ability to change our behavior when the environment changes so that we can optimize our actions to sustain effort, to resist immediate rewards, to delay gratification, to be able to conceive a goal for our future, and to carry it through. Drugs disrupt that. But these networks that are disrupted by drugs do not belong uniquely to addiction. As I already mentioned, they contribute to the psychopathology of multiple psychiatric diseases. I mentioned Schizophrenia, ADHD, Post Traumatic Stress Disorder, among others. Which of course gives us an explanation about why these individuals with mental illness are more vulnerable to taking drugs. Because the dopamine enhances the effects of drugs, this will temporarily relieve some of the symptoms. The problem is that with repeated administration it will downregulate their function, exacerbating the clinical presentations of the patients. It also highlights to us as we think of addiction as a disease of multiple networks being disrupted, that our therapeutic approaches should follow a multi-prong strategy. We should aim to enhance the motivation for other non-drug behaviors in addicted people so that they have alternative actions. We should aim to strengthen prefrontal cortical circuits so that they can exert cognitive control over their desires, their emotions, so that they can predict situations where they may be at greater danger of taking drugs and avoid them. Interventions to decrease the strength of condition stimuli; to decrease the enhanced sensitivity to stressors, to improve their negative emotions, so we can help them and prevent them from relapsing. I think a lot and I go back a lot to that conversation with my mother, and I always of course wonder what did I miss. I missed. Of course I failed because she kept the story of her father a secret from me. But I also realize that her shame or her fear, was not just because my grandfather had been an alcoholic, but because he had committed suicide. He had committed suicide out of hopelessness and helplessness at the inability to control the strong urges to drink, and then relapse, and the inability to stop taking the alcohol, and then relapse again, and again, and again, until there was one last moment of self-hatred, and he killed himself. This should have not happened. But, it’s too late. My grandfather had died. My mother died five months later… and it’s the past. It’s my story and I live with it. But I wanted to share it with you so that this does not happen to our future patients. So that this does not happen to our current patients. We psychiatrists have an obligation to treat substance use disorders in our patients. Whether they are by themselves, or as they frequently emerge comorbid with other mental illnesses, you can treat substance use disorders, and in so doing, you will improve the outcomes of the patients, for the substance use disorder, but also the other comorbid psychiatric disease. You will decrease the suffering in the families and the health care system will win. All of the averted cost associated with adverse medical consequences, averted cost associated with accidents, averted cost from criminal behavior… if we in psychiatry embrace addiction as a chronic disease of the brain, where the pathology is the disruption of the areas of the circuits that enables us to exert free will. That enables us to exert free determinations. Drugs disrupt these circuits. The person that is addicted does not choose to be addicted; it’s not a choice to take the drug. Many times they take it and they’ll say it’s not even pleasurable. “I just cannot control it.” Or they’ll say, “I have to take the drug because the distress of not having the drug is so difficult to bear.” If we embrace the concept of addiction as a chronic disease where drugs have disrupted the most fundamental circuits, that enable us to do something that we take for granted—make a decision and follow it through—we will be able to decrease the stigma, not just in the lay public, but in the health care system, among providers and insurers. So that patients with mental illness do not have to go through obstacles to obtain the evidence-based treatments, so that they don’t have to feel that shame, they don’t have to feel inferior, and perhaps we will be able to feel empathy for a patient suffering from a disease we call addiction. Thank you very much. [APPLAUSE]