TCPR: Dr. Pine, can you describe the background on the two new categories for anxiety disorders in DSM-5: Obsessive-Compulsive Disorders and Trauma- and Stressor-Related Disorders?
Dr. Pine: First, I will say that the overall changes from the standpoint of the day-to-day practice of a clinician are pretty mild and minor. The biggest change to anxiety disorders in DSM-5 is taking a collection of syndromes that were all grouped together in DSM-IV and splitting them into these three groups. One group, the obsessive-compulsive and related disorders, has OCD as its signature condition; a second, the trauma- and stressor-related disorders, contains PTSD and adjustment disorders; and a third comprises all the other anxiety disorders. When you look at the external validators—or the things besides the symptoms, such as the patterns of comorbidity, longitudinal associations, familial aggregation, or biology—the three groups of disorders kind of fall out in terms of how closely related they are to each other.

TCPR: What are some of the relationships among anxiety disorders that help to shape these new categories?
Dr. Pine: One of the most striking associations is the relationship between tic disorders and obsessive-compulsive disorders, which is uniquely strong, and there is some hint that they also follow the same familial pattern. Similarly, from a longitudinal perspective, particularly when OCD has an onset in childhood, I think the disorder is more stable. It is less likely to have a spontaneous remission. There is also some suggestion that the treatment approach is different in that there tends to be a pretty low placebo response rate and response rate to some of the antidepressants, such as imipramine (Tofranil). There are some hints from neuroscience to suggest that obsessive-compulsive disorder, much like the tic disorders, involves a certain type of dysfunction in the prefrontal cortical striatal-thalamo-cortical loops that is different from the kind of dysfunction that one sees in phobias, generalized anxiety disorder, or panic disorder, where there is thought to be a more prominent amygdala component. 

TCPR: What new data have come up since DSM-IV in terms of treatment? 
Dr. Pine: One important message to come out since DSM-IV is that in different clinical scenarios there is different evidence for the relative advantages and disadvantages of various combinations of serotonergic antidepressants and cognitive behavioral therapy (CBT). For instance, in pediatric anxiety disorders there are probably the clearest findings that combination treatment worked better than either therapy alone (Walkup JT et al, NEJM 2008;359(26):2753–2766). For the other anxiety disorders, there hasn’t been a greater advantage for combination therapy, and if anything, I think that particularly for obsessive-compulsive disorder, both in children and adults, cognitive behavioral therapy has emerged as a really solid treatment (see for example, Simpson HB et al, JAMA Psychiatry 2013;Sept 11, online first). Overall, there is a real success story in terms of both the range of treatments that are available for people with anxiety disorders and their durability or ability to get people with anxiety well.

TCPR: What is new on the treatment horizon for anxiety disorders?  
Dr. Pine: There has been a great interest in using what we have learned about neuroscience to come up with new treatments. And there really are two main exciting avenues. One is through extending what we know about the underlying neurocircuitry of extinction. Extinction is a process that is usually studied in rodents where a rodent learns to overcome a fear that has been acquired through learning. There is a great interest in using our knowledge of the underlying neural architecture, and the associated molecular targets of that architecture, to come up with better ways to enhance cognitive behavioral therapy. D-cycloserine is the agent where there has been the most interest, and there are some suggestions that it enhances cognitive behavioral therapy, though maybe not as much as we had hoped when the first set of studies came out. But more important, this is a different approach in that it generates hypotheses about novel treatments that are based on what we have learned in neuroscience. The other really good example refers to aspects of cognitive perturbations where we have mapped the underlying neurocircuitry and then we have used that knowledge to come up with novel ways to train cognition. The major interest has been on attention, and the observation has been that people with anxiety disorders have a very rapidly deployed bias in their attention that is thought to at least partially reflect perturbations in the amygdala. And the idea here is that this bias is deployed incredibly rapidly, so rapidly that patients aren’t even aware of it. So there has been interest in computer-generated training to shift patients’ biases. And again there is a hint that this might be a way to develop new efficacious treatments. Again, it is early, and like in d-cycloserine I don’t think we are ready to broadly apply these clinically, but it does kind of point to a path where basic neuroscience gives us ideas about novel treatments that can then be tested.

TCPR: Let’s talk basics: We all have a lot of people come into our offices with complaints of “anxiety,” but what exactly is clinical anxiety?
Dr. Pine: Anxiety is the way the body responds to danger, and there are many aspects of this response. There are changes in physiology that prepare the body to respond to danger; there are hormones, neurochemicals, and autonomic responses that normalize the body to cope with danger; there are behavioral responses, such as avoidance; and there are subjective responses, such as the feeling of being afraid. While anxiety involves increases in all of these things, they don’t always go together. So in some situations people might have a very robust autonomic or physiologic response, but they might not feel particularly afraid. In other situations, they might have a robust behavioral response, but they might not have such changes in physiology. Having an anxiety response is something that is adaptive, functional, and allows people to live safe and productive lives. In fact, people who don’t have anxiety responses can be thought of as suffering from a problem. But the question is: How exactly do we draw a line between where normal anxiety ends and abnormal anxiety starts? It is easiest to recognize anxiety as a problem when it is interfering with an individual’s ability to do something that they really have to do, such as the daily activities in their social life with their family or at work. When anxiety is so high that it prevents an individual from performing those duties, that is when we can think about anxiety as a problem that needs to be treated.

TCPR: You talked about the three aspects of anxiety being the autonomic, behavioral, and subjective. If we are able to differentiate those symptoms as they present in our patients, does that dictate treatment as well?
Dr. Pine: I think that is where people want to get, but we’re not there yet. There is interest in biomarkers or tests that we can use to guide treatment. However, as of now there really is no test using brain imaging, genetics, or any other measure that can tell us that this patient with anxiety that presents in this way will respond to this treatment vs that treatment.

TCPR: Do you recommend any clinical scales or questionnaires for diagnosis or evaluating treatment?
Dr. Pine: There are many research scales, such as the Hamilton rating scale, that as a clinician I use. I like to use both clinician-based measures and self-report measures. However, I think that there is no substitute for a careful, thorough clinical assessment performed by the clinician. So I think rating scales are helpful to guide the clinician’s thinking, but ultimately decisions about diagnosis and the appropriate way to treat have to be based on a clinical assessment that comes from sitting down with patients and hearing their stories and having the chance to question them about the kinds of things that they might fill out on a rating scale.

TCPR: In your paper in the journal Depression and Anxiety (Craske MG et al, Depression Anxiety 2009;26:1066–1085) you draw an interesting distinction between the anxious misery disorders and the fear disorders. Can you summarize those differences?
Dr. Pine: Generalized anxiety disorder shows a particularly strong association with major depressive disorder, which is something that was recognized at DSM-IV. And there was a lot of thought about how this uniquely strong connection might be reflected in the nosology: might these two syndromes be part of this broader group of conditions that we can think of as “anxious misery disorders,” which are different from things like panic disorder or the phobias. In the end, the data were not strong enough to justify making a change in DSM-5 that would have grouped generalized anxiety and major depressive disorder in the same group of such “anxious misery” disorders. 

TCPR: Is there any particular way to tackle the problem of comorbid depression and anxiety versus how we might treat a straightforward major depressive disorder?
Dr. Pine: Depression with concurrent anxiety is a common and particularly severe and worrisome condition. Unfortunately, there are no treatments that have definitively been established to work particularly well for major depression with anxiety disorders as opposed to without. 

TCPR: What are some ways that practicing psychiatrists can learn CBT techniques for anxiety?
Dr. Pine: It is possible to learn, and it is a wonderful skill to have. To get started, you can find resources online. (See Dr. Pine’s “recommended resources” box for more information.) ADAA (Anxiety and Depression Association of America) and ABCT (Association for Behavioral and Cognitive Therapies) both hold wonderful conferences where people can also start to learn all about CBT. The bigger question is the economics of it all. I think that the way reimbursement is going, it is not clear that psychiatrists are going to be reimbursed, at the rates that they desire, to deliver CBT. Unfortunately, CBT is the kind of thing where, if you are going to be good at it, you need to do it a lot. These economics issue could make it hard for psychiatrists to do a lot of CBT and get paid at the rates that they might be used to being paid.

TCPR: Thank you, Dr. Pine.