1. Please tell us about your career path. How did you come to be interested in the area of addiction?
My decision to become a doctor probably started when I was very young. It started really with a desire to help other people. I was fortunate to be accepted into the Johns Hopkins University as a natural sciences major and humanities major – I always kind of liked art and science combined. But at Hopkins, one really learned the rigors of academic thinking. Then I was fortunate again to be able to be accepted into the Johns Hopkins School of Medicine. I never thought in a million years that I would become a psychiatrist (which is ultimately what I did), but that experience was primarily through a mentor: J. Raymond Depaulo (now the Chair of the Department of Psychiatry there). He opened my eyes to the significance and fascinating interest in psychiatric illness. I always knew I wanted to be in academic medicine, so for my residency, because I had grown up in the northeast, I did a national search and wound up at the University of California, San Diego (UCSD). There again the influence of a mentor: Marc Schuckit (an alcohol researcher) really led me into the field of addiction psychiatry. My first experience was on the alcohol and drug treatment program, and I saw right away the role alcohol and drugs played in psychiatric patient's presentations. While there, I applied for and won a 2-year addiction psychiatry research fellowship, which I also completed at UCSD and San Diego VA Medical Center. Then I was fortunate again to be hired as Assistant Professor there for 4 years before leaving to go and run the programs in Cincinnati. I've been at the University of Cincinnati going on 13 years.
2. What is stress?
Any stimulus that disrupts the physiological homeostasis of an organism.
3. Does that include pleasurable things?
Well for some perhaps. There is actually a reward-stress interaction.
4. What are the components of the stress response system?
The stress that surrounds us is a part of daily living, all organisms' survival strategy is how to manage stress. So anytime a person is threatened, or there's a challenge to the homeostasis, it sets into cascade a stress system that starts in the brain and percolates throughout the body. The stress system originates in the hypothalamus, the pituitary gland, and the adrenal glands. This is known as the hypothalamic-pituitary-adrenal (HPA) axis. As stress comes in it leads to a release of two major stress hormones that originate in the brain: corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). These are released into the bloodstream and stimulate the pituitary gland to create adrenocorticotropic hormone (ACTH). ACTH stimulates the adrenal cortex to stimulate cortisol, the major stress hormone. Cortisol and other components released from the adrenal cortex and medulla such as epinephrine and norepinephrine are what really mediate the stress response. Sometimes people call it the 'fight or flight' response but that is really just a small component of the stress response. This system motivates speeding of the heart rate, dilatation of the pupils, environmental scanning, getting more blood to the muscles, etc.
5. How does this system relate to addiction or mental health?
As psychiatrists and addictionologists, we study the way that chronic stress through either psychiatric illness or addictive disorders perturbs that system. We do know that most stress-related psychiatric disorders (e.g., major depression, post-traumatic stress disorder [PTSD]) and certainly the addictive disorders (e.g., alcohol and cocaine dependence) all really perturb that system and might play a role in leading people to becoming vulnerable for those problems or certainly if they have a drug addiction, maybe relapsing.
6. What are the male to female differences?
Well this is an area that I have grown fascinated in over the last few years. The results of a 5-year National Institute on Alcohol Abuse and Alcoholism sponsored trial that we just finished demonstrate that stress responses are sexually dimorphic. Through a neuroendocrine test called combined dexamethasone-CRH challenge test we observed differential stress responses between women and men. In this particular stressor's case, women have a more robust response than men do. One other key element is that they are also stressor-specific. So what makes one individual respond more or less to a stress might be mediated through different neural circuits and those might differ by gender. So we've been looking at the ways men and women's stress response differ not only hormonally – the endocrine limb of the stress axis, but also the subjective behavioral portions, the cardiovascular catecholinergic – norepinephrine-epinephrine pathway.
7. Does this make the outcome worse for one gender vs. the other?
That's a good question. We think that might be the case. I'm particularly interested in alcoholism and we know that women who develop alcoholism typically have a more severe course through their disorder i.e., if they start drinking later – and usually later than a man does – their problems with the alcohol start sooner than a man's would. That phenomenon has been described as 'telescoping' and it is not just in alcohol its in many different substances of abuse. We also know that women might be more sensitive to alcohol's neurotoxic (brain damaging) effects. We would hypothesize that maybe the increased activation of the stress system might contribute to some of those phenomena. So yes, it does seem to have clinical relevance. The other important thing about this is we know that certain psychiatric disorders (especially the stress-related and even the addictive disorders) have sex prevalence. In the case of alcoholism, it is usually an illness of men. The gender gap has been shrinking over the last few decades, but it is now about a 2:1 prevalence (male to female). For stress-related disorders like major depression or PTSD, it is just the opposite. Women are more likely to suffer from those. So the basic gender or sex differences might help explain why. We would argue that the limbic-hypothalamic pituitary-adrenal axis and these different stress responses might play a pivotal role in understanding those kinds of differences.
8. So it's possible that this will open the door for different preventive measures and sex-specific treatment options?
Perhaps yes. I think there is a possibility that if we were to learn that women were more sensitive to alcohol stress-producing effects we would consider targeting pharmacotherapy that might work better or worse in women and men. There is actually some emerging literature demonstrating that one of the FDA-approved drugs for alcohol dependence: naltrexone seems to work better in men compared with women. It turns out that the opiate system is involved in modulating the stress response. It has been proposed that maybe the way naltrexone works in the brain is through its effects on the HPA axis or the extra hypothalamic stress system. So given these sex differences, one could speculate that maybe some of the ways that medicines may or may not work may differ between the sexes based on some of these underlying sex differences. There's also a possibility that women might respond differently to the different psychosocial interventions. Alcohol-dependent women (or substance-abusing women) are more likely to have suffered child maltreatment, specifically child sexual abuse compared with alcohol-dependent men and control groups. We know that experiencing those childhood adversities sets one up for the risk of not only addictive disorders but also other psychiatric disorders. Understanding how that might work and hopefully intervening earlier in people who have been traumatized might be another potential therapeutic route that differs between the sexes. So we're very excited by these findings and it is really kind of a neglected area in our field. When you go back and look at the endocrinology studies in alcoholics they are almost exclusively done in men. When women are included usually its small numbers and no consideration of the menstrual cycle which is incredibly important to regulating the brain's milieu.
9. So there's a linkage between early trauma and vulnerability and vulnerability and relapse. What role does early history play in the HPA axis?
It is true, the question becomes, what comes first in the sequence? We would like to explore those interactions in these models and disentangle the effects. It does get tricky because of the number of interactions. Added into that is the genetics – the gene-environment interactions are very interesting here. Christina Barr and colleagues have done some very nice work using a non-human primate model, looking at various genes which might be associated with some sort of stress vulnerability and the gene-environment interactions in animals who were stressed versus not and whether that predicts drinking and/or relapse. As we go forward in this research it would be interesting to look at populations where people have been traumatized but yet aren't alcohol-dependent, i.e., an at-risk population and doing a prospective study.
10. What is known about using stress inoculation (or stress management or coping skills) approaches to reduce some of this vulnerability?
That is a very important part of treatment for addiction. Lisa Najavits is a psychologist who developed a cognitive behavioral therapy specifically designed for women comorbid alcohol and/or drug problems and anxiety and/or mood disorders. One empirically-tested instrument she developed is called 'seeking safety' and it is delivered in a group to try to look at anxiety and stress as well as alcohol and drugs in one context and using cognitive behavioral strategies to address coping skills tied together with use of alcohol as a maladaptive strategy. I think we will begin to see more of these sorts of manual-guided treatments coming out that people can use.
11. In the research you were very careful to control for a certain phase of the menstrual cycle among the female participants. Are you concerned that you are not accurately capturing the whole picture because you are disregarding the importance of other aspects of the menstrual cycle?
Yes, but its one of those things where you can only do so much. But it would be interesting to look at menstrual cycle effects on these changes. Some studies have done this in healthy populations and found differences, mostly in the luteal vs. follicular phase, so it could be a follow-up study that we do. However, in reviewing the literature on PTSD it was interesting that only two controlled for menstrual cycle phase and I think the field has to decide, we're just not going to do that anymore. We can keep doing a lot of studies, but if we know something is important and might affect the outcome, we certainly need to take the time to address it. Believe me, it is a pain in the neck and it is expensive too! We struggled because the women would have to call us and tell us when they were starting their menstrual period. We would have to do everything in our power to get them into the lab that day [or soon thereafter].
12. What else can you tell us about the citalopram challenge?
Well the data surprised us. Previously we gave alcohol-dependent men a fenfluramine challenge test and found that compared with the controls, the alcohol-dependent group had a more robust and prolonged response to the fenfluramine, which we thought, might be a state-dependent marker. When fenfluramine was no longer available we began using citalopram. Suffice it to say that there does seem to be a sex difference and in the opposite direction.