Abstract: Learning Objectives:

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1 Title of Course: PTSD Treatment I: CBT, Neurobiology & Pharmacotherapy CE Credit: 3 Hours Learning Level: Intermediate Authors: Josef I. Ruzek, PhD & Matthew J. Friedman, MD, PhD Abstract: Part I of this course provides an overview of cognitive-behavioral interventions for PTSD. It describes some basic aspects of CBT, outlines cognitive-behavioral theories of PTSD, discusses key trauma-focused CBT interventions, and provides some tips for using CBT to encourage behavior change. Additional resources related to the topic are identified. Part II has two principal objectives. First it will review the psychobiology of the human response to stress in order to establish the pathophysiological rationale for utilizing different classes of medications as potential treatments for PTSD. Second it will review the current literature on evidence-based pharmacotherapy for PTSD. New medications currently being tested will also be discussed. Learning Objectives: 1. List the key elements of four major cognitive-behavioral theories of PTSD 2. Identify concrete ways of increasing compliance with between-session task assignments and reducing treatment dropout 3. Describe the major neurotransmitters, pathways and their implications in the development and treatment of PTSD 4. Report the major pharmacological interventions and their likely mechanisms of action in the care of clients with PTSD/combat stress reactions 2007 National Center for PTSD Professional Development Resources PTSD Treatment I Page 1 of 37

2 PTSD Treatment I: CBT, Neurobiology & Pharmacotherapy This course is based on one of a series of activities from the Department of Veterans Affairs National Center for Post- Traumatic Stress Disorder PTSD 101 curriculum. PTSD 101 is a web-based curriculum of diverse topics focusing on issues related to combat stress/ptsd. Courses are presented by a faculty of recognized experts in the field of traumatic stress. Most of the information available from NCPTSD s site is within the public domain and, unless otherwise noted, may be freely downloaded and reproduced. NCPTSD requests giving source credit to the National Center for PTSD, including the publication name, the URL, and the date the document was accessed. The speakers original lectures included in this course are transcribed verbatim with minor editorial modifications. Accessed May 15, Part I: Cognitive-Behavioral Interventions for PTSD Josef I. Ruzek, PhD Hello, welcome to our PTSD 101 presentation on cognitive-behavioral interventions for PTSD. I am Joe Ruzek; I am associate director at the national center for PTSD and the Palo Alto Health Care System. Cognitive-behavioral interventions for PTSD are very important in our work with veterans with this disorder because cognitive-behavioral methods are much used in the Veterans Administration Health Care System and also within our Readjustment Counseling Service. They are a complex set of tools for clinicians that help clinicians deal with many issues and many different kinds of problems that we face. And they are becoming increasingly important in the sense that many of the best evidence-based interventions for PTSD are in fact cognitive-behavioral in their design. Topics in this Presentation As you will appreciate, this is a very broad topic, and therefore I won t be able to do justice to all of the details, but today, I am going to attempt to give you an overview of the topic. In this presentation, I will be covering some basic aspects of cognitive-behavioral interventions to therapy, cognitive-behavioral theories of PTSD because these theories are practical tools that help us think more effectively about what we re seeing in front of us and what our patient needs. Then I m going to talk in a bit of detail about some key cognitive-behavioral interventions, namely therapeutic exposure and cognitive therapy. And finally, I m going to talk a bit about how to use cognitive-behavioral methods to encourage behavior change to help our clients actually begin to change their actions in the community rather than sitting in our sessions and merely talking. CBT: Some Basic Propositions There are some basic propositions to the cognitive-behavioral intervention approach that I would like to lay out very briefly. First is that it is fundamentally an educational model of behavior change. That is, it focuses on giving the client information, involving them as a learner, the role of the counselor himself or herself is that of a teacher. Mental health problems, including post traumatic stress disorder are seen as adaptive learned responses. Not so much as psychopathology. They are seen as reflecting the same kinds of laws of human behavior and learning that lead to effective behavior. But in this case, these laws lead to behavior that creates problems for an individual. Cognitivebehavioral methods have a rich grounding in theories and research on human behavior, especially learning theories of classical conditioning and operant conditioning or instrumental conditioning and also in cognitive science research. They are grounded as well in empirical research in the effectiveness of interventions, and a strong cornerstone of cognitive-behavioral therapy is that it s important to continuously evaluate our treatment progress and the outcome that our patients are getting out of our care National Center for PTSD Professional Development Resources PTSD Treatment I Page 2 of 37

3 CBT Includes: Cognitive-behavioral therapy is an umbrella term which actually includes a number of things. It includes the therapies that would be called behavior therapy. It also includes the therapies that are often labeled cognitive therapy. And it has interventions within it that focus on a number of main areas of human behavior. Some of those of course are to try and reduce physiological arousal. Methods like relaxation training try to induce relaxation and challenge the physiological arousal part of human behavior. Other interventions focus on what people say to themselves, how they think their cognitions. Still other approaches work on helping people change their actions, their overt behaviors, what they say, what they do around other people. And then finally, some of the interventions themselves focus on helping people change the environments in which they are living so that those environments will have an impact that s helpful on their own behavior and their own emotions. Range of CBT Change Tools/Processes Cognitive-behavioral therapy is actually a very vast set of change tools and change processes for clinicians. In this slide you can see some of the major change processes and treatment methods that can be included under the heading of cognitivebehavioral therapy and these include things like therapeutic exposure and cognitive therapy or cognitive restructuring. But a lot of the things that we are familiar with emerge from cognitivebehavioral approaches, like relaxation training and anxiety management training in general. A whole range of skills, training, approaches, communication skills and so on. Problem solving, helping people break down their problems, tackle them one by one and also generate alternative, select the best alternatives. Motivational enhancement methods that will be familiar to some. Methods of behavioral activation, getting people to go and engage in more rewarding activities in their daily life is a way of combating depressed mood. And very concrete things like goal setting, self monitoring in which we encourage our patients to keep records of their specific behaviors and issues that they re working on. Modeling, trying to expose people to models who are using some of the behaviors that we hope that our patients themselves will learn. And a series of other things, and you can see some of these here. CBT PTSD-Related Treatment Targets Cognitive-behavioral therapy for PTSD also has a range of treatment targets. Some of those of course are PTSD symptoms themselves, as when we do exposure therapy hoping to reduce re-experiencing symptoms or reduce hyperarousal symptoms. Sometimes they focus on distressing from a related thinking or beliefs, as when we cognitive therapy to help a veteran who is troubled by guilt related to his actions or her actions in the war zone. Sometimes they try not so much to eliminate symptoms, but to help people manage their symptoms more affectively. And that might result from a better understanding of your symptoms, a better sense of what elicits your symptoms, and anxiety management methods. And cognitive-behavioral approaches can help us deal with a lot of the other associated problems or targets of our therapy that go along with PTSD like alcohol or other substance use, social isolation, conflict and anger management, panic management, marital and family problems, and also changing health behavior. So, we can use cognitive-behavioral methods in many different ways and there are a lot of things we can choose from National Center for PTSD Professional Development Resources PTSD Treatment I Page 3 of 37

4 CBT-Derived Methods are Much Used in VHA/RCS PTSD Services It s probably worth noting here that cognitive-behavioral methods are currently much used in our Veterans Health Care Administration or Readjustment Counseling Services for PTSD. That is, we see for example wide spread use of relaxation training and other anxiety management methods. We see in our systems a lot of communication skills training, anger management training. We see some use of methods of exposure therapy and cognitive therapy, which seem to be increasing, and we also see some of the trappings of cognitive-behavioral interventions, like the use of between session task assignments, the use of role playing as a way of teaching skills, the use of diary keeping as a way of helping people understand their own behavior more effectively. CBT: Phases of Treatment Today I m going to talk a bit about the trauma focused cognitivebehavioral interventions, that is exposure in cognitive therapy. The parts of the cognitive-behavioral intervention repertoire that focus on the experience of trauma itself, the memories of trauma, and the trauma emotions that emerge when an individual is experiencing his or her symptoms in the face of trauma reminders or trauma cues. But it s worth taking a moment to make the point that these trauma focus CBT, and the there are the cognitive-behavioral methods that receive most attention are only part of the set of tools that cognitive-behavioral intervener can use and that they are embedded in a series of phases of treatment. And here you can see Dr. Terrence Keane s brief listing of some formal phases of treatment which are useful for us to think about. And we first develop a relationship with a client, form a therapeutic alliance, and works towards stabilization of emotional and behavioral reactions. We then engage in the process of educating the person in front of us about his or her reactions, what happens at time of trauma, what they need to do to recover and so on to make their experience more comprehensible and more predictable to them. We probably are going to help them learn some coping skills, particularly stress management skills, relaxation, breathing, things like that. Which get them ready for the process of treatment and help prepare them perhaps for trauma focused work. At some point, we want to work on the trauma memories themselves with folks if our clients are appropriate for this kind of treatment. And after we ve worked on these various arenas, we want to take steps to minimize the likelihood that an individual would relapse, so we ll try to do some relapse prevention. And we ll gradually follow up with a person, perhaps we ll decrease that over time, but we ll attempt to help them maintain their gains that they get with us. Therapist-Client Relationship Therapist-client relationship is a very important part of this. You can see it in Dr. Keane s emotional stabilization first phase because the therapist client relationship is very important to that goal. Having a good client relationship is necessary for delivery of cognitive-behavioral interventions. Often cognitive therapy assumes a set of techniques, but this isn t really the best way to look at it. It s better to look at it as a set of principles for understanding, conceptualizing a person in front of us, and a set of methods for more affectively changing emotions and behavior. But in order to deliver these particular tools, we need to have a good relationship, an empathic cognitive-behavioral therapist is going to be far more affective than a non-empathic therapist. The therapist sees himself or herself as an education and as a coach, and it s a mutual relationship that is established to develop goals, to mutually evaluate the impact of treatment and rethink where treatment is going as a collaborative enterprise. And that s a core part of cognitive-behavioral therapy National Center for PTSD Professional Development Resources PTSD Treatment I Page 4 of 37

5 Assessment Cognitive-behavioral therapists also have a whole set of assessment approaches that are specific to cognitive-behavioral therapy. I won t be able to outline them in detail here, but suffice it to say that the approach focuses on identifying problems in very specific terms, trying to conceptualize what are the factors that have lead to their development and that are maintaining them now. A lot of effort is put into determining the client s needs, how he or she sees the problem, and to build treatment goals around those needs in ways that are informed by the therapist input, but also are informed by the client s views, judgments, and preferences. And often a treatment contract is negotiated out of this assessment process. Sources of Assessment Information Assessment itself is based on a variety of sources of information because behavior therapy and cognitive behavior therapy recognizes that our patient s verbal self report of what he or she is doing in the community environment is not necessarily always the best account or the most useful one for guiding treatment decisions. Individuals often do not recognize the influences on their behavior or describe it in ways that might differ from that of an external observer. So, we also try to supplement our assessment information that we gain from talking to the patient with discussion with significant others and gaining their perspectives. With attempting to observe the behavior of the client, certainly in session with us but when possible in the natural environment or in his or her other interactions with people in the environment. We use questionnaires that help give us systematic information. And also we encourage individuals to self monitor their own behavior, complete diary forms for us that direct attention to the goals of treatment, whether that be anger issues or new skills that are being learned, or cognitions and beliefs that are occurring in different situations. That self monitoring data can be very valuable in the assessment process. Some CBT Assessment Foci These assessment efforts from cognitivebehavioral therapy focus on a variety of different things, but very often they focus on getting very specific about what are the triggers for emotional upset, what are the stimuli which set off the problem emotions and behaviors that we re working on. We think that by identifying those very specifically, we ll be better placed to understand the behavior of the person in front of us, but also better placed to help them begin to respond differently in the face of those triggers. And another cornerstone of this cognitive-behavioral assessment process is to get very clear on what the person is experiencing, to describe their responses in considerable detail. What are they doing, what are they feeling, what are they experiencing, and what are they saying to themselves in the situation, what actual behavior are they engaging in, what s happing in their body, in their physiology. And finally, assessment focuses on what happens after the person behaves, that is, if an individual avoids a trauma reminder, what happens? What happens to his or her symptoms? What happens to his or her emotions? And how are other people responding because often other people s responses are one influence on behavior. Are they rewarding maladaptive behavior? Are they rewarding constructive coping? 2007 National Center for PTSD Professional Development Resources PTSD Treatment I Page 5 of 37

6 Trauma Education Out of this assessment process and relationship building comes trauma education. A cornerstone again of cognitivebehavioral therapy is to have an educated consumer who understands his or her experience. We are going to ask a lot of our clients in cognitive-behavioral treatment because they have to do a lot. So we need to make sure that they are provided with a very strong rational and understanding for everything we re going to ask them to do. We only want to ask them to be doing things if it makes good sense to them. That educational process needs to help them understand in considerable detail in ways that work for them, how does trauma affect them, what are the impacts of traumatic stress on individuals generally and on themselves? What is post traumatic stress disorder? And what does recovery involve? What s going to happen in treatment, what do they need to do, how is it that recovery will work? Our goal again is to have an educated, active, and motivated patient, and trauma education is central to that goal. Stress Management Stress management will be something that is familiar to many of you. We very often deliver relaxation training or breathing training. These are very useful skills for clients and often cognitivebehavioral therapists will deliver these treatments to PTSD patients early in treatment partly because they are very practically useful. They give the client a very rapid tool that can be use to calm them in difficult situations, can also be used to help with sleep, can be used to help with relaxing on general basis, even when not in the presence of a trauma cue. It s also useful to do this early because it enables the client to get an early win. Most clients that we teach relaxation to can master the skill and get quick benefits. They see usefulness of coming to us for treatment. So often cognitive-behavioral therapists will do stress management and relaxation training fairly routinely with PTSD patients. And it s also important to recognize that the larger group of stress inoculation training methods you can see here, breathing, relaxation, thought stopping, self talk, covert modeling, which means imagining yourself behaving in the ways that you wish to again to behave. Those things have been found in some research to be affective with some types of PTSD. Trauma-Focused Intervention Processes Now often, core parts of cognitive-behavioral intervention for PTSD are focused on the trauma themselves, and particularly this trauma-focused work focuses on direct therapeutic exposure as a healing process and on cognitive therapy. CB Theoretical Models of PTSD Before I go into these treatments, I want to spend a bit of time telling you about some of the cognitive-behavioral theoretical models of PTSD because in fact exposure therapy and cognitive therapy are really emerged from these theoretical models. Now, there are many theoretical understandings of PTSD, even within cognitive-behavioral psychology. Here I am going to highlight a behavioral model, a basic behavioral model that s been laid out, and three variants of cognitive models of PTSD, which I think are useful because each complements the other and help us think about the patient in front of us and what it is we re trying to do in revisiting the traumatic memory National Center for PTSD Professional Development Resources PTSD Treatment I Page 6 of 37

7 Behavioral Model of PTSD The basic behavioral model of PTSD is one that s been around for some time. Terry Keane and colleagues and others have adapted this model based on much earlier learning theory models put forward by O. Hobart Mowrer and his famous two factor learning theory. So this proposed that two processes are often going in the formation of PTSD. The first is classical conditioning. And this is the kind of relatively automatic learning that all organisms are capable of, and the idea here is that when a traumatic event is occurring in a person s experience, it is being pared with many neutral stimuli in the environment. That is sight, smell, sounds in the environment, all kinds of cues that are present at the time that the person is being traumatized. Now, those cues themselves, the sight of a red haired person, the sight being in a particular kind of terrain, having a particular sound going on, those kinds of things that might happen at the time the trauma occurs are of course themselves not dangerous. They are neutral. But through classical conditioning, those previously neutral cues can become triggers. We call these things condition stimuli that can now pull for trauma related stress so that later when an individual encounters those same cues, reminders, or stimuli in his or her environment, he can find himself experiencing panic, anxiety, intrusive thoughts about the event, namely the same kinds of physical, mental, and emotional reactions that took place at the time of trauma itself. Hence we see an individual who was sexually assaulted in a cafeteria now experiencing panic anxiety when she is in the vicinity of a cafeteria. We see a veteran who travels in particular kinds of terrain that are reminiscent of Vietnam or Iraq now begin to experience similar reactions to what he may have experienced in Iraq and himself. That happens and that leads to a set of, a process by which a person is very frequently being triggered by environmental queues and stimuli. But factor two, the second thing that s operating is good old fashioned reward learning. And the idea here is that now an individual is now experiencing these triggers in the environment is a very unpleasant thing. And the individual therefore begins to learn to avoid those triggers, or to leave situations where those triggers are present. And that is rewarded because a person s anxiety decreases. So, it feels better to be avoiding these kinds of situations. We see that in our veterans who may now avoid the conversations and talking about what happened in their trauma, but they may actually begin to avoid all kinds of situations and begin to stay in their garage and not go out very often. So, the idea here is that classical condition lays in these kinds of reactions. But then this process of avoidance means that a person cannot learn that these situations and queues and reminders are no longer dangerous because he or she is not experiencing exposure to these queues and therefore has no opportunity to learn that things are different than they were at the time of trauma. So, the idea is this reward learning, this avoidance, can lead to a failure to extinguish the emotional responses that were learned in the trauma and which are now attached to the queues in a person s natural environment. Treatment Implications of Behavioral Model So this model tells us several things. It highlights for us that we need to therapeutically induce repeated exposure to trauma triggers or reminders in the absence of a bad thing happening of the trauma. And this repeated exposure with no trauma taking place in a safe situation, in a deliberate situation, can help us extinguish the learned emotional response, that is the conditioned emotional reaction, which is being tied to various trauma triggers. This is called habituation. It s the process by which trauma related stress triggers can become less intense over time. And through this kind of treatment, the individual begins to recognize and be able to better discriminate between dangerous and safe situations. But one of the implications of this is we need to block avoidance behaviors because avoidance behaviors will prevent this new learning from taking place National Center for PTSD Professional Development Resources PTSD Treatment I Page 7 of 37

8 Emotion Processing Therapy Now a more recent cognitive interpretation of what s happening in PTSD is provided by Edna Foa and colleagues, and this is called emotion processing theory. And this theory focuses on the way in which a memory is laid down, and PTSD is here conceptualizes impaired emotional processing of the trauma due to the laying down of a memory that has a number of characteristics that make it difficult to change, called the pathological fear structure in memory. It contains aspects of memory that relate to what happened, the stimuli that were present at the time of the trauma, the persons own reactions at the time of trauma, their responses, and their judgments and interpretations of what was going on. These PTSD related memories are held to be very easily activated and disruptively intense. They are relatively disorganized relative to memories for non-traumatic experiences. They have many unrealistic elements and in which harmless stimuli or harmless circumstances are associated with escape or avoidance reactions that the person may have engaged in at the time of the trauma. And they contain a series of erroneous evaluations or judgments. My anxiety will go on forever unless I escape. This fear is dangerous to me, I m going to go crazy. These things are terrible. Treatment Implications of Emotion Processing Theory of PTSD This concept of emotion processing highlights a few things for us. One is that we need to activate the fear structure. We need to activate the fear memory in order to change it. Otherwise it remains in a form that is not amenable to change. So, exposure therapy itself is aimed in part at activating the fear memory, and one of our ways of knowing we ve activated is that we do see emotional arousal taking place in the therapeutic situation in front of us. But also, we want to activate the fear structure, but also help the person incorporate new corrective information that does not fit and contradicts the pathological elements of the fear structure, and that might be the fact that the person can now relax and feel more physiologic comfort in the face of the trauma memory. Or it might be something that the therapist says, or it might be the fact that other people are reacting with support rather than rejection. But new information needs to be provided because after all, for folks with PTSD, the fear memories are often triggered, but that doesn t lead to recovery because very often the memories are unpredictable and extremely upsetting and they are just turned off by some kind of escape or avoidance. Therefore, there s no new therapeutic information coming in to change that memory. Emotion processing also directs our attention to the way that they narrative account of trauma changes as a person goes through it over and over again in the exposure process. There is a better organization of memory, the reading level may increase in complexity, there are fewer unfinished thoughts and repetitions. Dual Representation Theory Brewin and his colleague s dual representation theory also helps us with some ideas that are useful. He distinguishes between two types of memory that are laid down in traumatic experiences. Some are verbally accessible. These verbally accessible memories, he calls them VAM s, are the kinds of things that a person can tell us about trauma if we can ask them. So, what happened to you during your trauma? The person can give us an account and describe things that happened National Center for PTSD Professional Development Resources PTSD Treatment I Page 8 of 37

9 So these are representations of their conscience experience of the trauma. The can deliberately remember or retrieve these memories when we ask them about the trauma. And that especially includes meanings. I don t know why I didn t fight my attacker. I froze, I was a coward in the situation. Those judgments the person made are very often verbally accessible memories. But very important, they are also memories of trauma that cannot be deliberately accessed. These are what Dr. Brewin calls situationally accessible memories. That is, the memories are accessed automatically when individuals are in the presence of trauma queues or reminders. And these are the same things that we talked about in classical conditioning. So now when I am walking down the street and I see someone that resembles my attacker, or I see a car that looks similar to a car that was present when a bomb was detonated, I might have a whole series of internal, physiological and emotional reactions that are automatically queued, but I might have been able to remember that experience or describe that car when asked consciously what happened in my trauma. So these situationally accessible memories are the ones that are associated with the strong classically conditioned emotional responses. And it s useful to distinguish between those two types of memory. Dual representation theory is also useful in terms of its information about three different kinds of end points of working through the trauma or emotional processing of the trauma. One of course would be the best outcome, completion and integration in which a person thinks about their trauma, revisits it, engages in a process of reexperience in trauma emotions perhaps so that the habituation process takes place. But some kind of positive working through the experience. Some individuals, however, get stuck in chronic emotional processing, a kind of a rumination process in which they think over and over about aspects of what happened, a permanent preoccupation with the consequence. But not practical problem solving and nothing that is leading to any kind of resolution. And finally we have what we would call premature inhibition of processing, and when people avoid, for example, when they become a workaholic, they may find a reduction in some symptoms and some improvement in function, but they continue their fearful avoidance of trauma reminders and triggers. They may experience physiological symptoms, i.e. somatizing symptoms. And we think that they may be more vulnerable to reactivation later in life is when a veteran who has been a workaholic for many years retires and finds that the thoughts begin to become more prominent and more intrusive. Treatment Implications of Dual Representation Theory of PTSD Dual representation theory directs our attention to some things in treatment. The first is that it focuses on what are called the hotspots of a memory, the situationally accessible memories. We want to identify what kinds of things trigger those memories and what s going on with a person. We wanted to get them to talk about those and transfer the situationally queued memories into verbal memories by putting the experience into words and thinking about it, we hope that we change the representation of the memory itself. And that s in essence what happens in exposure therapy. A person remembers what happens, they are triggered by those reminders, but they are encouraged to keep talking about the process. The idea is that these new verbally accessible memories will then be easier to manage for the person and when a person experiences a trigger in the future, they will be better able to respond to that trigger because the trigger will elicit their verbally accessible memory rather that just the situationally accessible, emotional, conditioned emotional response. Cognitive Theory of PTSD Finally, Ehlers and Clark s cognitive theory of PTSD makes some similar points, but directs us to some additional aspects. Ehlers and Clarks hypothesize that there are two key processes that lead to a sense of ongoing threat after trauma, and it s this sense of ongoing threat that is responsible for maintaining acute stress reactions and helping to turn them into more chronic post traumatic stress disorder National Center for PTSD Professional Development Resources PTSD Treatment I Page 9 of 37

10 These key processes associated with ongoing threat are related to the way the memory is laid down, the nature of the memory and its link to other memories. And this is very similar to what Dr. Foa is talking about in the pathological fear memory. And Ehlers and Clark also talk about the appraisal of trauma and its sequelae, that is, how a person talks to themselves about their symptoms, their reactions, and their experience. Those judgments they make, judgments of personal weakness, of guilt, of lack of trust in others, and those are held to play a role and also maintaining a sense of ongoing threat. And finally, this cognitive theory also highlights the behavioral and cognitive responses, the avoidance responses that we ve talked about just now, that can prevent cognitive change, prevent habituation from taking place and therefore maintain the disorder. Though the cognitive theory of PTSD really, again, directs our attention to the nature of trauma memories, especially when PTSD is present. The idea is that these trauma memories are laid down as primarily sensory impressions, sight, smell, sounds. There s a sense with these memories that they are happening right now, that they are very intense and they are taking place now, not that they are located in the past. In actual fact, the idea is that many of the original sensory impressions and emotions that were experienced in the traumatic situation itself are now being felt in the memory. And that is they are involuntarily being triggered by a wide range of stimuli and situations. This is the same idea again of situationally accessible memories and conditioned emotional responses. Very often, these things, these same intense emotions and bodily sensations may be triggered automatically so that the person will experience the affect and emotion, but not necessarily even remember the trauma in detail, or even connect that set of reaction with the trauma itself. As I mentioned, Ehlers and Clark focus our attention on the personal negative appraisals of the events, in the sequelae, which can relate to setting a continuing sense of threat. So for example, if you make the judgment that I can t protect myself, the world is extremely dangerous, other people are going to take advantage of me. Those judgments suggest that the world is going to continue to be dangerous for you because if you can t protect yourself, it means bad things may happen to you in the future. And so those negative appraisals maintain a sense of ongoing threat, which are held to, and lead to the maintenance of traumatic stress reactions. Treatment Implications of Cognitive Theory of PTSD The treatment implications of this cognitive model are several. They are that the trauma memory itself needs to be laid out in more detail, elaborated, and then integrated into the context of the individuals experience before the trauma happened, and afterwards. The idea here is that very often a person may have a traumatic memory that is very, very brief and sensory. For example, the person might remember having a gun held to his or her head. But that memory doesn t include what happened shortly after that. For example, the person struggled with or escaped from his or her attacker. That resolution and the fact that the person did get back into a situation of safety is not included with the traumatic memory just related to having the gun held at the head. So, there is usefulness in organizing the narrative to include many elements of traumatic memory. The Ehlers and Clark model also says that we need to identify the problematic judgments or appraisals that maintain a sense of threat and help the person challenge those. And then finally, as with other cognitive-behavioral methods, it says that we should try to intervene with dysfunctional coping strategies, like drinking, like extreme emotional avoidance that can prevent recovery National Center for PTSD Professional Development Resources PTSD Treatment I Page 10 of 37

11 Therapeutic Exposure These cognitive-behavioral models really lead rather inescapably to the idea of therapeutic exposure. And this is the key treatment element which is embedded in many of the best cognitive-behavioral evidence based treatments. Therapeutic exposure goes under many terms, prolonged exposure, flooding, systematic desensitization is a form of exposure in which a person is exposed gradually to more and more difficult or anxiety eliciting aspects of the traumatic experience. But very important for us here is the concept of imaginal exposure and real world exposure. Most exposure with trauma memories is done through having the person imaginally re-experience the event. And this is done through the person telling us in great emotional detail on a repeated basis what happened in their experience. And the idea is that with multiple tellings, the person becomes better able to tolerate the emotions and the emotions become associated with gradually decreasing the stress. In vivo or real-world exposure is different, and that s the process by which we encourage the person to go out and confront feared situations or triggers. And to do this repeatedly until fear diminishes. And it s often done in a gradual way by creating a fear hierarchy in which a person takes on progressively more difficult elements in the real world. Research has suggested that treatment is actually more affective with the combined imaginal and in vivo exposure. A resource for you, probably the most detailed explanation of therapeutic exposure is the textbook by Edna Foa and Barbara Rothbaum, which I have reproduced here for you, and I recommend that you go and read this book in some detail. Imaginal Exposure Tactics Imaginal exposure is done in a way that it makes it different than ordinary helping conversations. The first thing that s important is that exposure itself takes some time. Exposure is not conducted in five or ten minute increments because the idea is we need to maintain the person in the emotional presence of the trauma memory, that is feeling the feeling s associated with the memory. For long enough, for their anxiety to increase and be maintained by the experience and then gradually to fall, and that takes some time. So, typically, imaginal exposure is delivered in sessions of forty five to ninety minutes of actual exposure for a person. We also are, as therapists, very directive in this kind of therapy and we do things like asking for sensory details of the scene, what were you smelling, what were you hearing, what could you see in the situation, what was happening in your body. And this process helps to increase queues for retrieval and help them to better access their memories. We ask them for details of the scene, we ask them to recount the experiences. If it s happening now perhaps to close their eyes. I am walking down the street. I look over and I see a vehicle and he s rolling down the window. Present tense is thought to increase the emotional access to the memory and to increase the activation of the memory that is important in Edna Foa s model of emotion processing. Imaginal exposure encourages a slow attention to the emotional aspects of the memory. That is, we unpack the hotspots, the pieces that are most associated with physiological fear and terror and anxiety. The parts that are most associated with negative appraisals like personal guilt and so on National Center for PTSD Professional Development Resources PTSD Treatment I Page 11 of 37

12 The job of the therapist is to watch for emotional avoidance because we want to bring the person into close experience of their emotions and feelings at the time of the trauma because that s what we want to have the person habituate to. One of the tools in doing that is to ask the person to monitor their own distress and to tell us how distressed they are and that gives us another indicator about whether or not we are activating the memory, that is the numbers should go up if the person rates his subjective units of distress as a nine or a ten out of a scale of ten, we know we are getting activation. Exposure Therapy Points Exposure therapy has some other points to remind us of, and these are taken from Barbara Rothbaum s guidance about exposure therapy, that our patients should remain in the exposure situation long enough for their anxiety to decrease. So, for example, if they were going out on a community exercise, we don t want them to experience anxiety then flee the situation. Just as if they are telling us about their trauma, we don t want them to experience strong anxiety and then run out of the room and leave the situation. We want them to remain in emotional contact with their memory long enough for their anxiety to gradually come down. We want them to progress through their tellings at their own pace or through their visits to previously avoided situations in the real world and to progress through those at their own pace, and we have to give them a lot of encouragement, to praise them for the exposure s completed, help them push themselves. Help them understand how this is going to benefit them. And acknowledge how difficult this experience is. Therapeutic Comments during Imaginal Exposure Here are some of the kinds of therapeutic comments that are useful doing the exposure process. You re doing fine, stay with the image. You ve done very well. It took some courage to stick it out. Stay with your feelings. I know this is difficult. You re doing a good job. Stay with the image, you are safe here. Feel safe and let go of the feelings. Therapist in Imaginal Exposure So the therapist has a very directive role in imaginative exposure. He or she provides a strong rationale for treatment. Remember, this is very unpleasant for many clients. If they are going to do this, they need to fully understand what s going to happen and why they re doing it and how it s going to benefit them. We are playing a very important role in encouraging the patient to continue with the process. It s a common experience for many patients to feel that they re getting worse, not better in this kind of treatment because we are stopping years of emotional avoidance, and we re bringing them into close emotional contact with their memories. Therefore, we need to help hold them in that situation and encourage them to continue in the treatment. Our job is to prevent emotional avoidance, whether it s through distraction or talking about elements of the trauma that are not emotionally evocative, or whether it s leaving out details of the trauma. We want to help them access and activate their memory by probing and asking them about what s happening in their body, what s happening in their feelings and emotions. We also want to help them control their level of arousal. We don t want them to become completely overwhelmed and dissociated; lose awareness of their present circumstances. So we can do that by helping them keep their eyes open, orient to us and so on National Center for PTSD Professional Development Resources PTSD Treatment I Page 12 of 37

13 In Vivo Exposure Real world exposure, as I ve said, is very important. The therapy that combines both in vivo real world exposure and emotional exposure is likely to be more effective. But these planned visits to previously avoided situations are things that need to be structured very carefully. We need to suggest the situations that they will approach carefully to make sure they map onto the things that are really being avoided by them. And of course they have to be safe, that is, we only want people to approach situations which are objectively safe. We typically do this in very planful, deliberate ways of discussing with a client whether they are ready for this, making a systematic list of situations that are avoided, often arranging those in a hierarchy of difficulty, giving people forms to record their progress on these tasks, and sometimes using a buddy system to help them to approach these avoided situations initially and then gradually fade out the interpersonal supports. And of course, as mentioned, we give people clear instructions to remain in the situation until their anxiety diminishes. Selection Consideration for Exposure It s not well established in a research sense--- what are the selection criteria that we should use to determine whether or not to give someone exposure therapy. And ultimately this requires clinical judgment. It s not a cookbook issue. The clinician needs to think about a number of things, and here are some of them. Certainly it s good practice, especially with our veterans whose health may not be very good to get a sign off from a physician that this person is a suitable candidate for a therapy which may be stressful. So someone with a very severe heart condition might not be a good candidate for this. We want to check and make sure that the person is in stable remission if they have had a previous substance abuse problem, or we need to take steps to arrange supports for them with their substance abuse. We want to check into their environment, is it a stable environment and they re living on the street and things like that, obviously we re not going to do this. Or if they are going through a divorce we may decide that now is not the right time. We want to look at their emotional stability. Most importantly, we want to look at the motivation of the veteran. For this kind of treatment, we need a highly motivated individual. And so, and that s one of the important determinants. We want to talk about this kind of treatment with a client in considerable detail, educate them about that, and then take a reasoned decision. In many treatment programs, it is also useful to look at how well the person has previously engaged in treatment, how well they are participating in treatment. This is a labor intensive, emotionally challenging intervention that might be best used with individual who previously have perhaps been educated about their problems and have demonstrated a commitment to therapy by showing regular attendance and so on. Role of Cognition in Failures of Exposure I ve talked a bit about exposure therapy, but I want to talk about the second major trauma focus treatment. That is cognitive therapy. Now, we ve heard what some of the models have said about this, particularly the model proposed by Ehlers and Clark, which directs strong attention to the appraisals of a traumatic experience, and their role in maintaining a sense of continuing threat. Here s a quote I like from Roger Pitman, one of the major researchers in psychophysiology of PTSD. And he was trying to think about why exposure therapy sometimes fails, and he said going over the situation again and again is called for in the exposure procedure didn t improve but rather worsened the anger, shame, guilt, self accusation, feelings of failure, and what if? ruminations associated with the traumatic experience. Note that anger, shame, guilt, self accusation, feelings of failure, what if? ruminations are appraisals, judgments, beliefs, thought cognitions, they are self-taught. Those are different in some ways than the physiological and pure emotional reactions that are queued by trauma reminder National Center for PTSD Professional Development Resources PTSD Treatment I Page 13 of 37

14 Cognitive Therapy or Restructuring Cognitive therapy, sometimes called cognitive restructuring, tries to help an individual challenge and change his or her interpretations of the trauma, which are thought to be playing a role in maintaining distress and PTSD symptoms themselves. And there are a number steps here simplified at three that we identified dysfunctional ways of thinking, that we help the person rethink and evaluation the validity of those thoughts and challenge them, and we are trying them to help them replace those dysfunctional thoughts and beliefs with more helpful ones that relate to their recovery. Examples of Negative Cognitions Here are some examples of the kinds of negative beliefs or appraisals that we often see in our patients: I should have prevented the trauma. I m going to be attacked again. I m going crazy. I m weak. I turned my back on God. My life is ruined. I attract disaster. I deserve that bad things happen to me. I m dead inside. I cannot rely on other people. Sometimes these beliefs relate to spirituality, sometimes they are observations on how I am reacting or about the future. Sometimes they relate to other people. We can think of the negative beliefs or cognitions as relating to two key areas, the dangerousness of the world, and sense of personal incompetence. That is, I can t protect myself, I can t make myself safe. I can t trust my own instincts, et cetera. And those are the kinds of cognitions, and there are many types, specific cognitions that would relate to these things that we want to pay attention to. Changing Cognitions The point to make here is that changing cognitions is not simply having a brief discussion with someone. That may be helpful. But cognitive therapy itself involves an extended systematic effort to change beliefs. That goes through a number of sessions that take time. We educate the person about how beliefs cause distress; we identify common distressing beliefs related to post traumatic experience for survivors. We help an individual identify his or her own personal distressing beliefs. We discuss review evidence; generate alternative beliefs that are more helpful. This involves training a person in how to step back from their beliefs and rethink them. Then we have them engage in a process of practice by which a person makes those revised ways of looking at the situation their own, that weaves them into their daily life National Center for PTSD Professional Development Resources PTSD Treatment I Page 14 of 37

15 Resick s Cognitive-Processing Therapy for PTSD Probably the most detailed application of cognitive therapy to PTSD is seen in Patricia Resick s cognitive processing therapy for PTSD. And this is a treatment which I also recommend that you might want to read about. Here is the citation of the treatment manual for cognitive processing therapy, originally developed for rape survivors with PTSD, but the manual itself is suitable for all trauma populations with sensible modifications that you would make based on your patient population. So, we re using variants of this quite often now with active duty and veterans with PTSD, male and female. But this particular treatment includes cognitive therapy, a lot of cognitive therapy, and also exposure therapy. And it s worth noting that although we have a distinction between exposure therapy and cognitive therapy, most of the efficacious treatments and best treatment actually combines both approaches. It s rather artificial that we distinguish between them because in the real world, we re going to be providing both. Cognitive-Processing Therapy I just want to show you, here s a nice list of some of the goals of cognitive processing therapy which resonate to some of the themes that I ve been talking about. It s developed to help victims of trauma understand how their thoughts and emotions are accepted, accept and integrate the trauma as an event that actually occurred and should not be denied, to experience fully the range of their trauma related emotions, to analyze and confront their maladaptive ways of thinking about the situation, and to explore how prior experiences, beliefs affected their reactions and were affected by trauma itself. Cognitive processing therapy actually visits a number of different themes, cognitive themes are important in trauma survivors related to safety, trust, power and control, self and other esteem and intimacy. Can Trauma-Focused CBTs Be Disseminated? These treatments are challenging treatments that require some skill and practice and mentoring to learn well. So we have a big question for our field, and that is, can we, as practitioners, master enough of these treatment elements of cognitive therapy and exposure therapy to be effective with our clients? Much of the research of course is being conducted in special laboratories with specially trained individuals. But we are beginning to see demonstrations from research in the field that ordinary clinicians can learn these methods and achieve the same kinds of quality results that are found in the research trials. So here s just an example of a study by Gillespie and colleagues conducted with ninety one individuals who developed PTSD when they were victims of a Northern Ireland Omagh terrorist bombing. In this study, national health service providers who were nurses, some psychologists, but a variety of helping professions, but not trauma specialists or people previously knowledgeable about cognitive-behavioral therapy were trained via workshops and then in face to face, but mostly telephone supervision, and in an evidence- based treatment based on Ehlers and Clark s model, which incorporated both exposure and cognitive therapy, and then some reduction of negative avoidance behaviors, negative coping behaviors. And the treatment effectiveness in this approach was as much as that found in the pristine research trials of cognitive-behavioral therapy. So this is the good early demonstration, and there are now some other demonstrations that community practitioners, if properly trained to supervise, can achieve big results for some types of trauma survivors National Center for PTSD Professional Development Resources PTSD Treatment I Page 15 of 37

16 Veterans with Chronic PTSD The point is worth making here that with our veterans with chronic PTSD, if our exposure and cognitive therapy is useful for them, we nonetheless will then need to use it as a springboard to tackle additional issues. So a person now is better with their trauma memories, we are going to want to follow through and help them reconnect socially with other people, reconnect with their family, rebuild their life generally so again, cognitive therapy, exposure therapy are parts of a much more comprehensive treatment package, not stand alone treatments for themselves. Of course, if someone has recent PTSD, there may be occasions when using these things to focus on trauma memories start a cascade of changes and may result in improved family function and other things. But in general, as therapists, we want to tackle a number of targets, not just the traumatic memories. Other CB Treatments As a point of disclosure, it should be noted that there are many cognitive-behavioral treatments, and here is a list of some of the better-known ones. This is not a complete list. Eye movement desensitization processing has a strong support base and incorporates some of these elements of exposure in cognitive therapy. There are variants on cognitive therapy for guilt, like that developed by Edward Kubany. We have some cognitive-behavioral combined PTSD substance abuse treatments, like Seeking Safety, developed by Dr. Lisa Najavits, which is being much applied in our VA and Readjustment Counseling Service systems, and there are many others here. CBT-ing Treatment I also would just talk broadly for a moment about how to cognitive-behavioralize treatment so that it might have more impact. One of our challenges in our system of care for veterans is to ensure that we are not just talking shop in our therapy, but that we are actually engendering behavior change, an actual action in which a patient is taking responsibility for his or her change and going out and doing things differently to try to rebuild his or her life. A climate of action, not just talk. Coping Skills Training We do this a lot with coping skills training. That is, we teach people to do things and we have them go out and do them differently. And there are some underlying assumptions in the cognitive-behavioral model of coping skills training. The fundamental one is that in therapy, we don t want to just get people to stop doing something that s an old, unhealthy, or maladaptive behavior. The theory is, we re going to be more affective if we give them something different to do. We want to have them replace an old, ineffective behavior or response with something that s more adaptive and useful for them. We are going to replace their old ways of behaving with new ones. Sometimes there s a skills deficit. A person doesn t know how to be assertive, doesn t know how to reduce their anxiety and we re going to teach them skills for that National Center for PTSD Professional Development Resources PTSD Treatment I Page 16 of 37

17 Sometimes it s just a motivational problem and by giving them skills training they are going to be better able and more likely to do something which they already can do to some degree. The issue here is knowing what to do. We can tell people go out and interact with people more, don t be so socially isolated. That s easy. What we need to do is show individuals how to do that and that s where skills training comes in. How do you manage your anxiety in a social situation, how do you carry on conversations? How do you invite somebody out for an activity? And we know that one showing is worth a thousand tellings, so we want to show behavior, not just talk about it. And coping skills training involves this cycle of talking about something, identifying the behavior, instructing them in it. Then demonstrating for them, engaging in behavioral rehearsal or practice through role-play or other ways, and then finally the task assignments to go out and try it in the real world. Come back, get feedback on it, look at what worked, what didn t, polish it a little bit, go out and try it again. And in that that way, develop this thing as a skill and a habit. Examples of Skills Here are some examples of the kinds of skills we train for anxiety reduction, for anger management, conflict resolution and so on. And the challenge for the therapist is to decide which skills are going to add value for a person, and within these skills what the highlights what communication skills we can teach a person to listen better we can teach a person to reflect back what another individual said, we can teach them to smile, we can teach them to invite other people out. So, there are a lot of things you can teach them and this therapeutic skill comes in deciding what skill. if I help the client learn this, would actually have a real world impact on their life? Behavioral Task Assignments A core part of using skills training to get more action out of our clients is to give behavioral task assignments, that is between session assignments that involve asking the person to go out and do something. And as I ve said, that involves thinking carefully about what skills, if used, would create significant benefit for our client or significant change. We want to, when we give a task assignment, especially early, give an assignment which is easy to do, which is not going to create lots of opposition on the part of the client, and that we think is very likely to ensure early success. So, if we re teaching our client to better express love for a significant other and to get around emotional numbing, a good skill, of course, would be to go and embrace your partner, look her in the eye and tell her you love her. However, that s high on the hierarchy of difficulty. A simple one, an easy one, would be to simply purchase a card for her, write I love you or thank you for standing by me honey and to leave that on her pillow. So, we want to map these behavioral task assignments onto the central goals of the client and arrange them in such a way that we think they are likely to meet with significant success. And we have to expect completion of behavioral task assignments from individuals because this often involves a change in therapy from simply talking about things to asking for real work out of our clients. Methods for Enhancing Between-Session Task Compliance Cognitive-behavioral therapy has methods for increasing the likelihood that people would do these things between sessions. The big one is that we want to actively reward completion of these tasks, and we want to do that in some very real ways. The most central one, of course, is to use that information in session, to spend a significant amount of time in treatment reviewing the task assignments to looking at how it went, thinking about how it might be improved next time, drawing lessons learned from that experience. Therapists also can reward behavioral task assignments if a person comes in with a written task assignment by actually writing comments on their forms and then handing them back to them National Center for PTSD Professional Development Resources PTSD Treatment I Page 17 of 37

18 To get compliance with these between session tasks, it s very important in the beginning to involve our client significantly in formulating the task, and showing them how those things made sense for their own personal goals. A client who has input into the design of the tasks or an ability to select from several possible tasks is far more likely to complete those tasks. Of course, we want to give written instructions in the tasks to people, if you re running an anger management group, you can have these things pre-created and give the person a piece of paper that lays out the between session task, and we want to give them task forms in which they can record their experience. That makes it more concrete and again more likely they ll complete these things. We want to explore and problem solve obstacles to task completion that can be done ahead of time if we anticipate difficulties, but it should certainly be done if a person comes back in not having completed the task. And we want to do this in a supportive way, a way that underlines the importance and the centrality to therapy of actually going out and practicing things between sessions. Self-Monitoring Another useful tool for turning words into action is called self monitoring. In self monitoring, we assign our clients to keep written records of their behavioral tasks or something they are working on in therapy. This could be simply a diary, but often it s within behavior therapy or cognitive-behavioral therapy it s much more concrete than that because it s particularly targeted at looking at whatever the person is working on. So, if they are working on learning relaxation training, we might ask them to keep a daily relaxation log with their rate, their physical attention both before and after their experiences in practicing the relaxation exercise. If we re trying to train them to better understand the influence of their own appraisals, judgments and beliefs on their emotions, we might have them complete an ABC form in which they write down the activating event in one column of what set off their emotional reaction, in the C column they write down their consequences, that is the emotions they experienced, and in the middle column, the B column, they identify the thoughts they had about the activating event which helped to lead to the emotional consequences. Self monitoring has been shown in research to be a powerful change method in its own right. So when we get people to complete these kinds of daily task monitoring, we re more likely to deceptively change their own behavior. It s also a major way used in cognitive-behavioral therapy to gather assessment information because now we re getting up close to when a person has a conflict and when a person is trying to use a tool we re teaching them. They re writing down what happened at the time. And that s very valuable because we don t have to ask the person to remember back to what happened five days ago during a confrontation. If they have written it down closer in time to when the actual confrontation took place. We want to encourage self monitoring primarily by giving people forms that are pre made to do this for us. And again, as I ve said, we want to collect these forms and talk about their self monitoring experiences and make the results of their self monitoring a central part of treatment. Reducing Dropout We also have cognitive-behavioral approaches to reducing dropout and increasing motivation. These things I d like to mention briefly because they are important. They are especially important in some of the more challenging parts of cognitive-behavioral therapy like the trauma focused elements because trauma focused work brings up strong emotions, as does much therapy and the risk of dropout is ever present. Dropout from any kind of therapy is a significant factor. So, the cognitive-behavioral repertoire for reducing dropout includes a number of things. As I said before, presenting a very clear and repeated rational for why we re doing what we re doing, how it connects up with the personal goals of the veteran. To obtain a verbal commitment from the person and emphasize the importance of commitment to change, to problem solve obstacles, to participating in the therapy National Center for PTSD Professional Development Resources PTSD Treatment I Page 18 of 37

19 Before going into an exposure therapy group or a cognitive processing therapy group, it can be very helpful to conduct an individual assessment and discuss up front what will be demanded of the person in treatment to predict for them that their emotions may become activated, that their PTSD symptoms might become more troubling, more distressing, more frequent, or more intense. But help them by explaining why that s a therapeutic process and a good sign in the context of these treatments. To let them know about the homework and work they ll need to be doing so they have a realistic up front expectation, and then to get commitment. To discuss non attendance with individuals, and when individuals don t show up for a session to follow up with them on the phone rapidly, research has suggested that by telephoning someone if they miss a session, we can really reduce the rate of dropout. The final thing, and this is especially going to be important for our Iraq war returnees and Afghanistan war returnees who are currently employed, is to be flexible and try to arrange our clinics so that we can offer these groups at times that are comfortable to the patient, perhaps in the evenings. Monitoring Treatment Outcomes A final point to make about cognitive-behavioral treatments generally is finally just to say that the centrality of evaluating how we re doing in treatment, of monitoring treatment outcomes. This is a core activity in cognitivebehavioral therapy. It is something that s stressed in our clinical practice guideline, our department of defense and VA clinical practice guideline for management of traumatic stress, which is our official doctrine with out to do treatment of PTSD. And it helps us, it gives us the ability to get better in care and to recalibrate our treatment. By knowing how treatment is working, we can decide how to modify treatment. It helps the patient review his or her progress and see concrete indicators of change. It enables us to get better over time at providing treatment because we see if we re not doing well, it spurs us to change. And then it moves in line with our evolving VA policy of the importance of accountability and care and evaluation and care. And just as an advertisement I ll mention that there has been a recently created veterans administration military stress treatment assessment, VAMSTA, questionnaire which is a brief measure for evaluation outcomes, that if you re interested in, please contact me. Some CBT Resources Today, we ve talked about a number of things, and I want to leave you just with some cognitive-behavioral resources. These resources are several. In the talk today, we ve tried to make you aware of some general cognitive-behavioral concepts and models that I think can be quite practical in helping you think about what you want to do with the client in front of you. These theories are tools for thinking about the client and thinking about what needs to be accomplished in revisiting the trauma memories. We ve highlighted exposure and cognitive therapy as some of the most powerful change processes and change methods open to a therapist. We talked a little bit about how some of the cognitive behavior can be harnessed to make our therapies more action oriented and less focused just on talk between task assignments, with self monitoring and so on. I hope that this has been a useful set of ideas and principals to lay out to you today. I welcome you to contact me and to contact us all at the National Center for PTSD Education Division if you d like to follow up on some of these issues. Some notable cognitive-behavioral resources are listed in the slide for you, there is an Association for Behavioral and Cognitive Therapies, which is the premier professional organization for individuals interested in these things. This used to be called the Association for the Advancement of Behavioral Therapy. The name has been changed to reflect the fact that it includes both behavior therapies and cognitive therapies National Center for PTSD Professional Development Resources PTSD Treatment I Page 19 of 37

20 There is a useful instructional video on exposure therapy that is being created by the Australian Center for Posttraumatic Mental Health. This costs some money, but nonetheless, it s a useful tool if individuals wish to pursue this in more detail. Our National Center for PTSD Clinical Training Program is available to give you more help in mastering some of these methods. And finally, I highlight for you three pragmatic texts that are useful for further reading. Thank you for your attention today and good luck with cognitive-behavioral interventions. Part II: Neurobiology & Pharmacotherapy for PTSD Matthew J. Friedman, MD, PhD Hello. My name is Matt Friedman. I m the Executive Director of the National Center for PTSD and I m going to talk about pharmacotherapy for PTSD. The Stress System The stress system is really the biological context in which we can understand both the pathophysiology of PTSD and the target sites for any of the medications that I m going to discuss in the course of this discussion. Basically, the stress system is a marvelous system that has developed through evolution, and it really has evolved for survival of the species, and I think for that reason, it s very complicated. It has many, many different brain centers, both cortical and subcortical, and many different neurotransmitters and neuromodulators and/or peptides and/or hormones that play a role. The main components of the stress system are the hormonal part of that, which is the HPA system, or hypothalamicpituitary-adrenocortical system, which is activated by corticotropin-releasing hormone or CRF, as I ll refer to it during the course of this lecture. And as I ll show, CRF also activates the noradrenergic component, the locus coeruleusnorepinephrine sympathetic nervous system action. There s a third important part of the stress system that we won t be discussing today, although maybe some time in the future we will. That is the immunological system, which is also activated during moments of stress and is activated by CRF, and I think that the mobilization of the immunological system is one reason why PTSD is a risk factor for medical problems. But that is a subject for another talk. Central and Peripheral Components of the Stress System This slide begins to show you what the stress system looks like. You ll see on the left-hand side something that says CRH. That is corticotropin-releasing hormone. CRH and CRF are the same thing. I generally use the term CRF. On the left part of the slide you can see the hormonal aspect (CRH), which is produced in the hypothalamus. Looking at the arrow that goes directly below that, ACTH (adrenocorticotrophic hormone) is released from the pituitary gland, and the ACTH in turn releases a glucocorticoid, particularly cortisol, from the adrenal cortex. Those dotted lines are a negative-feedback loop. When a sufficient amount of glucocorticoid is produced, it turns off the release of CRH National Center for PTSD Professional Development Resources PTSD Treatment I Page 20 of 37

21 Now, in PTSD this system is altered. It is functioning at an abnormal level. Also, if you look back at the CRH blue ball, which basically is the hypothalamus amygdala, you can see that there is a direct line over to the right-hand side of the slide that says LC/NC, which stands for the locus coeruleus noradrenergic system the sympathetic nervous system. The locus coeruleus is that part of the brain that contains most of the noradrenergic neurons. One of the marvelous design features of the stress system is that CRH acts both as a hormone, releasing ACTH and cortisol on the one hand, and as a neurotransmitter, releasing norepinephrine from the locus coeruleus on the other. Those neurons go downstream to the sympathetic nervous system and upstream to the many key brain structures, such as mesocortical and mesolimbic systems, as well as subcortical systems such as the amygdala, hippocampus, etc. And in the middle of all of these arrows you can see a bunch of different neurotransmitters are mentioned: serotonin, acetylcholine, GABA-benzodiazepine, dynorphin, which is an opiate, etc. So there are many, many different neurotransmitters that are involved in this system. This slide is a simplified version, and you can see on the left part the HPA system; hypothalamus-pituitary-adrenocortical system, producing CRH, ACTH and on the right side the locus coeruleus having noradrenergic neurons. But the main point of the slide is in the upper part, towards the left side, showing you the main brain nuclei involved in the stress system. You can see the amygdala, which is that part of the brain that is developed to process emotional information, threatening information, and dangerous information. The amygdala is activated during traumatic exposure. The hippocampus, which is right next door to the amygdala in the limbic system, is that part of the brain that will remember the context, in which a threat occurred. You know in prehistoric times - where the saber tooth tiger was so you ll remember not to go to that place again. Now, to the upper left-hand corner you ll see something that s says orbitofrontal inhibition of the amygdala mediates extinction. This indicates the only major way that the amygdala can be brought under control; because in PTSD the amygdala is in hyper-drive. It is dysregulated. It is activated to an excessive degree, and that s a major part of the problem. It s the prefrontal cortexorbitofrontal cortex all of those structures, the anterior cingulate, that are the major part of the brain that can rein in the amygdala. Indeed, cognitive behavioral therapy and other psychotherapies are mediated through cortical neurons. The route by which they can get to the amygdala is through the prefrontal cortex. So that s a very important part of the circuitry. The next slide is really more of the same, only it emphasizes the more adrenergic part. You can see the locus coeruleus, which has 2/3 of the noradrenergic neurons. You can also see that it has synapses that go all over the place, particularly to the amygdala, hippocampus, hypothalamus, etc National Center for PTSD Professional Development Resources PTSD Treatment I Page 21 of 37

22 HPA/Norepinephrine Pathway This slide focuses more on the relationships between the locus coeruleus and the amygdala, and you can see that there are reciprocal interactions. So, the amygdala is basically the ignition switch for the stress response. It goes to the hypothalamus to get CRF involved in both activating noradrenergic neurons from the locus coeruleus and releasing ACTH from the pituitary gland. But part of the purpose of this slide is to show you the various reciprocal relationships of this system. This is an oversimplification, but the bottom line is what you would expect from all that I ve shown you so far, that norepinephrine is a key part of the problem, that there s excessive norepinephrine, and that the HPA system is dysregulated as well. Norepinephrine and PTSD We have to recognize whether it s substances that are produced endogenously by the brain or substances that are administered pharmacologically that there is an effective dose and there is a toxic dose, and there is also an inadequate dose. So, on the left-hand side, what I m showing you is that you need norepinephrine to survive. The Fight-flight or freeze response, first described by Walter Cannon in the early part of the 20th century, is essentially a sympathetic activation, in which mobilizing norepinephrine during dangerous, threatening situations enables you to run to safety and to protect yourself. It involves the emotional signal of fear telling you that there s something that you better pay attention to. It also helps you consolidate the memory of those events so that you re not going to repeat dangerous behaviors in the future. And that s all adaptive. So we need norepinephrine to survive, to function. But when there s too much norepinephrine that is in play, as the right-hand column shows, what was an adaptive response becomes maladaptive. The hypervigilance, the autonomic arousal, exaggerated startle response even flashbacks, which can be produced by increasing noradrenergic activity as well as the intrusive memories. So, the point of the slide is to indicate that, in PTSD, an adaptive response is excessively produced, and that becomes maladaptive. Another piece of this and this is important in terms of PTSD is that what may be adaptive for survival in a dangerous situation can be maladaptive in a safe situation. For example, hypervigilance: anyone who s returned from Iraq will tell you that you need to be hypervigilant in order to be able to protect yourself and function in a combat zone. But when you re in a safe situation and you re still hypervigilant that s not adaptive. That s part of the problem that we have in PTSD, and part of that is related to excessive noradrenergic activity. Serotonin Pathways This slide shows you some of the serotonergic pathways. So serotonin is an important piece of the puzzle as well, and if you look at the bottom part of this slide, you ll see two little yellow boxes; one says MR and one says DR. That s the median rafae and the dorsal rafae nuclei, which are the parts of the brain where most of the serotonergic neurons live. The point of the slide is, number 1, to show you that these neurons, like the adrenergic neurons emanating from the locus coeruleus, have many, many connections all over the brain. They affect subcortical limbic structures, such as the amygdala and the hippocampus, also going into the association cortex, etc. Number 2, there is a direct relationship between serotonin and the locus coeruleus and adrenergic neurons National Center for PTSD Professional Development Resources PTSD Treatment I Page 22 of 37

23 Serotonin and PTSD As this slide will show you, whereas we have probably too much norepinephrine in PTSD, we don t seem to have enough serotonin. So, again, the left-hand part of the slide shows you the adaptive types of serotonergic actions that are put into play during stressful or threatening situations: fighting response, aggressive retaliations, self-defense, etc. But again, when there is a deficiency of serotonin, you can see on the right-hand side that people with deficient serotonin may be suicidal, impulsive, aggressive, and violent. They may be depressed, and they may experience anxiety and panic. Looking ahead to where some of this is going to go that s why medications that increase serotonergic activity, such as selective serotonin reuptake inhibitors, are helpful. The SSRIs, are useful, not just in PTSD, but in other panic disorders and in depression. Summary of Findings in HPA and Monoamine Dysfunction in PTSD One of the things we see in PTSD is that there s too much CRF, and that leads to alterations in the amount of cortisol that s available. There is also too much norepinephrine, so there s increased noradrenergic tone, and too little serotonin. Something else that I won t be talking about today is that there seems to be a neurodegenerative aspect. Too much stress can produce neuronal death or dendritic defoliation. That may be an important reason why we see reduced hippocampic volume and other reductions in volume of key brain structures such as the anterior cingulate in PTSD. But we won t be talking about that very much. This is probably a good place to mention that almost all of the medications that are useful (most of the medications that work in PTSD are antidepressants), in addition to whatever they re doing at the synapse-adrenergic, or serotonergic, or dopaminergic level, also produce neurogenesis. In other words, they promote the development of new brain cells. In one study, people with PTSD were treated with the SSRI Paxil (paroxetine), for about nine months. In addition to their symptoms getting better, their hippocampus increased in volume, again proving the neuroregenerative aspects of some of these medications. This is an important area for future research. Some of our National Center scientists, such as Ronald Dumann at our Clinical Neuroscience Division, are doing ground-breaking research in this area. Monoamines and Amino Acid Neurotransmitters Most of you are probably familiar with norepinephrine, serotonin, and dopamine, etc., because we know a lot more about them because we ve been able to measure them in the brain for many decades. But actually they are really mostly modulators and are relatively slow to act. The real action comes from the fast-acting amino acid neurotransmitters: gamma-aminobutyric acid (GABA), which is the major inhibitory transmitter in the brain, and glutamate, which is the major excitatory neurotransmitter. We ll be talking a great deal about these. This is really, I think, where the cutting edge research is going on because a number of medications, particularly what we call anticonvulsants or mood stabilizers now either potentiate GABA or diminish glutamate. I will discuss this at much greater length as we move forward. It s important to emphasize that no medication does anything by itself. All a drug can do is either potentiate a normal activity or prevent it by blocking its actions. And so, in the case of PTSD, we want to basically increase GABA and reduce glutamate types of actions. GABA and Glutamate Homeostasis This slide shows the yin and yang of fast-acting neurotransmitters Glutamate in red, the major activating neurotransmitter and GABA in yellow, the major inhibitory neurotransmitter. In normal brain function, these two neurotransmitters are in a very good balance. Again, another remarkable design feature is that it s very, very easy to convert one to the other again for rapid change if that balance needs to be corrected National Center for PTSD Professional Development Resources PTSD Treatment I Page 23 of 37

24 As I said earlier, GABA is the major central nervous system inhibitory transmitter, and it acts at a ligand-gated chloride channel. Benzodiazepines, with which I m sure you re all familiar, act at the GABA-A receptor. There are also GABA-B receptors and GABA-C receptors that I will not be talking about. I ll be talking mostly about actions at GABA-A receptors today because that s where most of the information is, and that s where most of the medications in practice are. Glutamate is the major CNS excitatory neurotransmitter. There are many different kinds of glutamate receptors. There are the ionotropic receptors, which basically act at ion channels where both calcium and sodium are involved. And then there are the metabotropic receptors, which act through G-protein and other second messengers. I m going to talk mostly about ionotropic receptors. The most remarkable of these is the NMDA receptor, which stands for N-methyl d- aspartate, and the NMDA receptors are the receptors that mediate learning and extinction. You can actually see under an electron microscope alterations at the NMDA receptor site as learning takes place, in terms of little growths. Since fear conditioning is a major theory about PTSD, the NMDA receptor is extremely important. There s also evidence that NMDA receptors are important for regeneration of neurons. As I said earlier, I think that regeneration of neurons is a very, very important aspect of the effectiveness of a number of different medications. And finally, the NMDA receptor also mediates sensitization. Another important model of PTSD is that the limbic nuclei, the amygdala and associated areas, become sensitized to traumatic reminders. Activating those receptors by traumatic reminders can set off a PTSD relapse. Well that is also mediated by NMDA receptors, and a number of anticonvulsant/mood stabilizer medications act to inhibit those mechanisms. GABA and PTSD As in the case of serotonin, the problem here seems to be not enough GABA for appropriate balance. So again on the left-hand side, GABA is the body s own anxiolytic if you will. It s involved in neuromodulation, mediating cognition, and hormonal modulation. It can actually oppose the release of CRF. But, too little GABA, as with too little serotonin, is associated with anxiety and reexperiencing ( kindling ), another form of sensitization. Too little GABA can promote sensitization (not necessarily a good thing), impulsivity, and hyperarousal. GABA in HPA-Mediated Fear Responses This slide elaborates on what I just said, in that GABA can inhibit CRF release, and there is too much CRF in the brains of people with PTSD. Too much CRF will activate the stress system. Too little GABA will permit that to happen, and so what happens in acute stress is that the inhibitory action of GABA is sometimes compromised so that CRF, adrenergic activity, etc., are unopposed. There are a number of medications: Divalproex, which is a mood stabilizer, and benzodiazepines, which are anxiolytics. Both of these can inhibit stress-induced cortisol secretion in humans. And remember, cortisol is the hormonal result of the CRF activating ACTH activating the adrenal cortex. And that benzodiazepine (Alprazolam) reduces brain CRF. So, basically the argument that I m making is that we think that the balances are too much norepinephrine, maybe too much glutamate, maybe too much dopamine, maybe too little serotonin, and too little GABA National Center for PTSD Professional Development Resources PTSD Treatment I Page 24 of 37

25 Sensory Information about Harmful Stimuli This is a look at the amygdala with a higher power to show you where we think 3 different types of medications might be effective. What the slide shows is, coming from the top there is stressful information, in this particular slide it happens to be auditory information could be a saber tooth tiger roaring, or an AK-47 firing, or somebody screaming anyway auditory information that is emblematic of a dangerous situation. That information goes to the lateral nucleus of the amygdala, which is the sensory area of the amygdala. As you can see on the left, the lateral nucleus communicates with the central nucleus of the amygdala through a glutamate receptor. So the glutamatergic neuron is basically the conduit through which this frightening information is transmitted to the central nucleus of the amygdala, and the central nucleus of the amygdala really is the part of the amygdala that gets things going. In this particular slide it activates the hypothalamus, which releases CRF. As I said earlier, CRF can, on the one hand, get the HPA system in motion and, on the other hand, can get the adrenergic system in motion. The slide also shows that there is negative feedback. You can see that the negative-feedback-looking cortisol is activating the dorsal rafae nucleus, which is where the serotonergic neurons are. So you see a 5-HT serotonergic neuron and then you see a GABA-ergic neuron. The GABA-ergic neuron is inhibitory. So, there are three places where medication might be effective just inside the amygdala. The first would be to block the glutamate receptors so that the threatening information is not transmitted to the central nucleus of the amygdala and is unable to get things going. The second would be to increase GABA activity, since GABA is inhibitory and more GABA is going to inhibit the action at that glutamate receptor. The third would be to increase serotonin. Increased serotonin is going to activate GABA, which is going to produce more inhibitory information. So you can see that the medications that act at a glutamate receptor that potentiate GABA or that potentiate serotonin all of them might reduce amygdala activation. And so those are things that pharmacologists get very excited about. What the slide doesn t show is that another source of restraint on the amygdala, besides these internal synaptic processes, is restraint coming from the prefrontal cortex. Treatment Evolution for PTSD Going back to the early 1900s, people used barbiturates; by the middle part of the 20th century, meprobamate; and a bit later on benzodiazepines. Towards the end of the 20th century, we discovered that our antidepressants our tricyclics and MAO inhibitors, as well as our SSRIs in addition to being good antidepressants, were also very effective anxiolytics. In some head-to-head comparisons, antidepressants actually did as well as benzodiazepines in terms of anxiety reduction. This slide also shows that we now have two medications that have FDA approval as medications for PTSD. We only have two. Unlike depression, in which there are many medications, there are only two approved for PTSD right now, both SSRIs. I will show you data on other medications, including other SSRIs. We will talk about other medications that should be effective based on the pathophysiology of PTSD that I have just described. We will also look at the antiepileptic drugs, which, as I said earlier, will act either by blocking glutamate or increasing GABA or as in the case of topiramate doing both simultaneously National Center for PTSD Professional Development Resources PTSD Treatment I Page 25 of 37

26 Pharmacologic Treatment of PTSD The pharmacological treatment of PTSD involves drugs that act on key neurotransmitters: tricyclic antidepressants and monoamine oxidase inhibitors act on monoamines. SSRIs act on serotonin. We ll talk about a number of medications that decrease norepinephrine activity, and we ll talk about the GABA/glutamate, the antiepileptic drugs. This slide is the first of several that summarize this information, and what I would like you to do is just focus on the two left-hand columns. Don t pay any attention to the right-hand column for purposes of this lecture. So, the left-hand column is the system that we think is affected, and the middle column is the proposed abnormality. First, there is increased CRF in PTSD. The HPA system: there are variable cortisol levels and a number of investigators - particularly Dr. Rachel Yehuda who have data suggesting that the glucocorticoid receptors are suprasensitive or up-regulated in PTSD. This, interestingly, is the opposite of what you see in depression, where they are down-regulated or subsensitive. This might suggest some real differences between depression and PTSD, at least with regard to the HPA system, despite the fact that the two disorders often co-occur. We have talked a lot about the adrenergic system, locus coereleus, norepinephrine hyperactivity, and also neuropeptide Y, which is a neuropeptide which opposes the actions of CRF and opposes the actions of norepinephrine. And I think that that may be a very important system for the future. Pharmacological Treatment of PTSD - 2 In PTSD there is dysregulation of the serotonergic system, the opioid system. Substance P, which we used to think was a pain modulator, seems to be more intimately involved in the stress system, and substance P antagonists have shown to be as effective antidepressants as Paxil (paroxetine). So a lot of really interesting questions about substance P, but we don t have any research in PTSD. Controlled Trials in PTSD More Effective than Placebo This is a list of a number of successful trials in which a medication was more effective than a placebo. Every one of the medications listed is an antidepressant with proven efficacy. Most of these medications are SSRIs: paroxetine, sertraline, fluoxetine. There also are two tricyclic antidepressants on the list: amitriptyline, and imipramine. There is one monamine oxidase inhibitor: phenelzine. And Brofaromine, a very interesting drug that was never put on the market, had monoamine oxidase inhibitory actions and also worked at monoaminergic synapses National Center for PTSD Professional Development Resources PTSD Treatment I Page 26 of 37

27 Randomized Trial of Phenelzine, Imipramine and Placebo (N=60) This randomized trial of phenelzine, imipramine, and placebo was done at the West Haven, VA. In an 8-week trial, veterans with PTSD were randomized to placebo, imipramine, or the MAO inhibitor phenelzine. We are measuring results with the Impact of Events scale, and as you can see the two medications worked. Phenelzine worked much, much better than imipramine, but imipramine was better than placebo. This, unfortunately, is the only randomized trial of an MAO inhibitor, and it was published fifteen years ago. It s really a shame that we haven t had more good research with MAO inhibitors, but that s the way it is. I think that many investigators are more comfortable with drugs that do not have the side effects and dietary restrictions that MAO inhibitors have. But it is important to emphasize at this point that these are good medications, and if you have a person who hasn t responded to other drugs, you might want to consider an MAO inhibitor. Obviously, they need to stay off alcohol, stick to the diet, and get the other drugs out of the system, but don t forget MAO inhibitors. Amitriptyline vs. Placebo This study, also done with veterans, is about amitriptyline versus placebo. Amitriptyline did better than placebo. What was interesting about this trial was that up until this time, almost all successful trials with medications reduced the re-experiencing symptoms and the hyperarousal symptoms but did not touch the avoidance symptoms. In this trial, the amitriptyline did very well on the avoidance symptoms, but the big difference between amitriptyline and imipramine is that amitriptyline blocks a lot more serotonin than does imipramine. Both drugs are tricyclic antidepressants and both block the reuptake of both norepinephrine and serotonin presynaptically, but amitriptyline blocks a lot more serotonin. And so this was a first suggestion that maybe increasing serotonin was more important for the avoidant numbing symptoms than it was for the other class of some of the arousal or re-experiencing symptoms. Sertraline vs. Placebo This study was done by Kathleen Brady, and this is one of the two trials that led to the FDA s approval of SSRIs for PTSD. The CAPS is the Clinician Administered PTSD Scale. There were 187 patients who were randomized to one drug or the other. As you can see, the sertraline group did better than the placebo group at the end of 12 weeks. Paroxetine in PTSD The other drug approved by the FDA is Paxil (paroxetine), and this slide shows the data from that trial. This was a big trial 651 patients were randomized to either placebo, 20 mg of paroxetine, or 40 mg of paroxetine. You can see that the two medicated groups did much, much better than the placebo group. What is interesting is that the 20 mg group does just a tad better than the 40 mg group. It s not statistically significant, but we often see this with the SSRIs, that sometimes you don t need to go to the maximum dose to get 2007 National Center for PTSD Professional Development Resources PTSD Treatment I Page 27 of 37

28 the maximum effect. Paroxetine was effective in reducing symptoms in all three clusters: re-experiencing, numbing/avoidance, and hyperarousal. PTSD Remission Analysis This is, I think, one of the most important slides, because, you know, people say, Well, okay. I m glad to see that the people got better on the medications, but are they well? Because what happens often in clinical practice is people are better, but they re not well. So you get a partial response. What this slide shows and this is from the very big paroxetine trials with 651 participants is how many people had complete remission. By that, it means that their CAPS scores were below 20, which is normal. What you can see is that about 30% got better, but 16% of the placebo group got better. What that means is that 70% of these patients may have improved, but they re not better after 12 weeks. What the breakdown really looks like is maybe 20% will not have responded at all, another 50% will have had a partial response, and the final 30% will have had a complete remission. Fluoxetine vs. Placebo (N=53) There have been a number of good studies with Prozac (fluoxetine). Sertraline Continuation Treatment in PTSD Again, this is one of the most important slides that I m showing you. If you look at this slide, there are two graphs. They represent two different PTSD scales: the green one represents the Impact of Events Scale, and the dark triangle one the CAPS score. Looking at the horizontal axis, note this goes up to 36 weeks. At the 12-week point, that s where the drug trial ends, and you can see the improvement. But in this, the patients who were in the original two trials, were asked to stay on their sertraline for another 24 weeks; another 6 months. And what you can see is that they continue to show improvement over the next 24 weeks. The improvement is not as steep as it was in the first 12 weeks, but it s unmistakable. In point of fact, if you think back to the remission analysis, 55% of people who had not had a remission by 12 weeks did have a remission by 36 weeks. So, the good news is that if your patient has had a partial response after 12 weeks, you should encourage them to stay on the medication for another 6 months. However, you know, most patients are not going to just want to stay on another medication, but are probably going to want to have additional treatment. You might want to try something else, and I think that this is a point where, if you had a partial responder with an SSRI, that you might want to think of different augmentation strategies, whether it s augmentation with CBT, which is a very effective treatment. In fact it s more effective than medication. Whereas we get 30% remission with medication, we get about 50% remission with CBT. Or you might want to augment with another medication: anti adrenergic drugs, are some of the other medications that I ll be talking about. So it s important to remember that people who have a partial response at 12 weeks may continue to go on to full remission, but you need to keep the medication there, and you may want to also add something else to the mix National Center for PTSD Professional Development Resources PTSD Treatment I Page 28 of 37

29 Controlled Trials in PTSD Not More Effective Than Placebo The next slide shows that not all controlled trials have been successful. There was a multi-site trial in VA settings, which was not successful, and my own belief is that that s more about the chronicity of these veterans. I mean if you think about a veteran, a Vietnam veteran with PTSD who s still in VA 30 years after the war is over and is still symptomatic, that s a very chronic refractory individual. Most of the veterans who would have responded to PTSD treatment have responded and are no longer in our system. But this trial led people to think that you shouldn t use SSRIs for veterans or you shouldn t use them for males. And again, I strongly reject that conclusion. In fact, there is a trial that I don t have a slide for of European and Israeli and South African personnel who were given Prozac (fluoxetine), and not only did they respond very well, but participation in combat and having combat trauma as a source of the PTSD actually predicted a favorable outcome. So, I think it s really apples and oranges to compare chronic Vietnam veterans with PTSD 30 years later who don t respond to medication with newer cases of combat trauma from Iraq or Afghanistan or other U.N or NATO deployments. There is every reason to think that these people will respond to SSRI s. Negative Trials There have also been negative trials with benzodiazepines. Don t use benzodiazepines. A lot of people use them. There s no reason to use them, and I ll elaborate on that a little. Benzodiazepines are still widely prescribed because they re good anti-anxiety medications, but they have not proven effective on PTSD core symptoms. They will help people sleep better. They will reduce general anxiety, but they won t touch the re-experiencing or the avoidance symptoms. So, don t use them. Up here in White River Junction we did a trial with cyproheptadine. It is a serotonin blocker, and there had been some letters to the editor and case reports that this was a good drug for PTSD flashbacks or nightmares. So we did a randomized trial and found that not only did cyproheptadine not work, it made people worse. And to me this is a very reassuring finding because if SSRIs medications that increase the amount of serotonin make people better, then a drug that blocks serotonin activity should make them worse, and that s what cyproheptadine does. Buspirone is another anxiolytic that has not proven to be effective in PTSD treatment. Promising Open Trials in PTSD The next slide is about promising open trials in PTSD, and you can see this is a very long list. It s a list that I find very interesting, and I ll be talking about the mood stabilizers in a little bit. I think that the trials with the anti-adrenergic drugs, clonidine and guanfacine, which are Alpha-2 agonists, which decrease presynaptic release of norepinephrine, are medications that have been used clinically, but there has not been a good randomized trial yet; a couple of reports in the literature, but nothing to bet the farm on. Propranolol is another anti-adrenergic, this one works with beta-blockers. Again, one trial with kids that had promising results. A recent trial with acutely stressed people that looked promising. And finally, Prazosin, which is an Alpha-1 antagonist. Murray Raskin and his group in Seattle have been using Prazosin for PTSD, mostly to reduce nightmares, and what they found is that it also reduced global PTSD symptoms. Murray and his group are now testing Prazosin both in veterans and in returnees from Iraq at Fort Lewis, so stay tuned on that one. It s a very exciting possibility, particularly given what we know about the excessive adrenergic activity. Naltrexone is a narcotic antagonist and one trial with dual diagnoses subjects, which was not that conclusive. I m going to be talking about mood stabilizers, so let s move forward National Center for PTSD Professional Development Resources PTSD Treatment I Page 29 of 37

30 Antiepileptic Drugs in the Treatment of PTSD* So now we get into the antiepileptic drugs in the treatment of PTSD, and you can see there s a long list. And these have been small studies without control groups, so we really don t have a lot of really good information. There s only been one placebo-controlled study; a very small study with 15 patients given lamotrigine, and I ll show you some of that data. Antiepileptic Drugs and CNS GABA This slide shows the rationale for using these medications, given what I said earlier on. And what we re looking at is increased GABA concentrations as a result of treatment with three different antiepileptic drugs: topiramate, gabapentin, and lamotrigine. You can see that, although topiramate acutely increases GABA to a great extent, after 4 weeks of treatment, there s considerable increase from gabapentin and lamotrigine as well. So the evidence is that these medications will increase GABA in the brain and that may be a partial explanation for any effectiveness that they may prove to have. Carbamazepine Efficacy in PTSD* Carbamazepine (Tegretol), in an open trial, all 8 of 10 patients, vets, did well. In addition to PTSD symptoms, it also decreased impulsivity and some of the violent angry outbursts. Another study, 22 of 28 sexually abused children became better. So that there is evidence that carbamazepine is effective. We don t have any randomized trials, and it s an old drug. It has a lot of side effects, and my guess is we re probably not going to see any randomized trials with this medication. Lamotrigine Efficacy in PTSD* Lamotrigine (lamictol), is an antiepileptic. It also has an indication for use in bipolar disorder. One double-blind trial, 5 on placebo and 10 received the medication. In the study, 50% responded, according to the Duke PTSD scale. This data has been re-analyzed and there s some question about it. It was a small study. It s obviously important to repeat this trial. So the results are inconclusive. *Lamotrigine is not FDA approved for PTSD. Divalproex Efficacy in PTSD* Divalproex (valproate), again a good drug for bipolar illness, increases GABA levels and has some promising results. The thing to remember about divalproex is, you don t want to give this to pregnant women, particularly in the 1st trimester; it can result in teratogenic effects, poor outcomes. So that s one reason not to use divalproex. Also weight gain and some sedation. Some people don t like it. *Divalproex is not FDA approved for PTSD National Center for PTSD Professional Development Resources PTSD Treatment I Page 30 of 37

31 Response to Divalproex Here s some of the data from the open-label trial with divalproex looking at reduction in CAP scores at 4 and 8 weeks, and again there s no control group, but there s a significant reduction from the baseline values. Gabapentin Efficacy in PTSD* Gabapentin is another promising medication and there has been a retrospective chart review of 30 patients suggesting that this was a very good treatment, although most of them, 83%, also had an antidepressant on board. *Gabapentin is not FDA approved for PTSD. Topiramate Efficacy in PTSD* The next slide is on topiramate. Topiramate is one of my favorite drugs, and I m hoping that we re going to get more trials, because topiramate does what an ideal antiepileptic drug would do: it not only blocks glutamate, but it increases GABA activity. *Topiramate is not FDA approved for PTSD. I ll show you a study showing that topiramate not only reduced total PTSD symptoms, but seemed to have broadspectrum effects on re-experiencing, avoidance, and arousal symptoms. Again, an open- label trial. We need to do a randomized trial, but it is promising. Also, there s been a lot of really interesting research on topiramate in terms of impulsive disorders. Most of the medications that we use in psychiatry, with the exception of bupropion (Wellbutrin), cause weight gain. Topiramate is one medication that doesn t do that. In fact, it is also being considered for use in binge-eating disorders and other kinds of things, as well as substance-abuse problems. So, stay tuned. Hopefully, we ll have some better information on topiramate within the next year or so. In the topiramate trial, again it was an open trial, there were reductions in nightmares, flashbacks, etc., and it was well-tolerated. Vigabatrin Efficacy in PTSD* Vigabatrin, another antiepileptic drug, increases GABA, and in a case series with 5 patients, made people better. *Vigabatrin is not FDA approved for PTSD. Psychopharmacology I ve talked about the SSRIs and the dosages on here, and why people like the SSRIs. Besides their efficacy and their safety, they improve global improvement scores, that s what CGI stands for: Clinical Global Improvement-- that s a scale. They re also good for comorbid disorders. As you know, if you ve got PTSD, you ve got an 80% chance of having another comorbid disorder, and among people we see in the VA and in clinical settings, that percentage is higher. And SSRIs are good in major depressive disorder, panic disorder, obsessive-compulsive disorder, social phobia, and associated symptoms such as suicidality, impulsivity, and aggressiveness. So SSRIs are clearly the drug of choice. Two of them have FDA approval. I mentioned two other serotonergic-acting medications like Nefazodone, which is no longer available because of its liver toxicity, just to prove the point that drugs that work on the serotonergic system seem to be good for PTSD and also for, in this case, comorbid depressive disorder National Center for PTSD Professional Development Resources PTSD Treatment I Page 31 of 37

32 There are three different classes of antiadrenergic drugs, Clonidine and guanfacine being Alpha-2 agonists, which reduce presynaptic release of norepinephrine. In my own experience, and based on some research we did at the National Center, these medications may also be good for reducing dissociative symptoms. Yohimbine, which is an Alpha-2 antagonist, does the opposite of what clonidine does, can produce dissociation in about 40% of veterans with PTSD, and that s why I ve started using clonidine and guanfacine for dissociative symptoms with considerable success, although we don t have a randomized trial to prove that. I ve talked about the Propranolol, and what s missing from this slide is Prazosin, which is an Alpha-1 antagonist, which has had good results. Don t forget MAO inhibitors. I showed you the data from the one trial with phenelzine. Another trial with a selective MAO A inhibitor, moclobemide, also had promising results and these are good antidepressants, good for panic disorder. And tricyclic antidepressants are still available and they re inexpensive. Many of your patients cannot afford some of these more expensive drugs, and the tricyclics, we ve managed them for years, even though they do have more side effects than SSRIs, and they re good antipanic agents, and they re good for major depressive disorder, as well as being good on the B-cluster symptoms of PTSD. Finally, the benzodiazepines, which are not effective in PTSD symptoms. And they re not even good prophylactically. There are two studies now: An Israeli study by Gelpin and Associates and an American study by Tom Melman and his group, where they gave benzodiazepines in the acute aftermath of traumas. The idea was if we could help people get some sleep after exposure to a disaster or traumatic experience, maybe we could prevent the later development of PTSD. The benzos helped people sleep, but they didn t have any prophylactic value. So there s really no good rationale for using benzodiazepines when we have so many other drugs. I ve talked at length about anticonvulsants. And finally on this list, I have atypical antipsychotics and there are now about 6 studies with the atypical antipsychotics risperidone, alanzapine, and quetiapine or Seroquel. Not used by themselves but for treatment failures or partialresponders to SSRIs, given additional treatment. Keeping them on the SSRIs for the reasons I stated earlier, because they may continue to improve, but augmenting with an atypical antipsychotic. There are now 6 small studies indicating that this may be a very good strategy. There s a Cooperative Study at the VA that John Krystal and Bob Rosenheck of the National Center are now doing. It s a 15-site study in VA, which will be looking at augmentation of SSRI partial responders, or non-responders, with atypical antipsychotics. So that s a very, very important study to be looking at National Center for PTSD Professional Development Resources PTSD Treatment I Page 32 of 37

33 New Medications for PTSD A number of new medications some of them are not available for human use, but theoretically they ought to be important CRF antagonists, to basically reduce the important activation of the whole stress system by CRF. NPY agonists, which enhance NPY and which opposes the action. We talked about antiadrenergic agents, etc. We talked about glutamatergic anticonvulsants, etc. And the bottom of this slide mentions BDNF promoters and IGF-1 agonists. BDNF is brain derived neurotrophic factor, which is the mechanism through which antidepressants produce neurogenesis, and as I mentioned all antidepressants do that. Another substance that promotes neurogenesis is insulin-type growth factor-1. So this is my list of medications for the future that, hopefully, will be tested. Psychotherapies Found Effective in Controlled Trials in PTSD The point is just to emphasize that CBT works, in point of fact it even works better than medications, with remission rates of about 50%, as compared to the 30% remission rate. So I m showing slides with some data about exposure therapy and cognitive therapy, all of which work. The other advantage of cognotherapy, and as a pharmacologist I hate to have to admit this, is that after an intense session of CBT, trial people generally maintain their gains for months or years. Whereas with medication, if you stop the medication after there s been a successful treatment, people are probably going to relapse. So if a person has responded to medication, it s like treating a person with depression, you probably need to keep them on the medication. If they ve stayed asymptomatic for a year or so, you might want to slowly reduce the medication, see how well they can do without it. But many people who had good medication responses will lose their gains if you stop the medication. Treatment of Acute Stress Okay, so I ve gone through slides showing the good data on cognitive behavioral therapy, you have other modules in this series that will address that at length, even the one study showing brief psychotherapy for people with PTSD-but we ll skip over that and end this talk with a few slides talking about treatment of acute stress. Again, there s very little research out there. There are about 10 studies now. But the question is, is there a morning-after pill? In other words, if someone comes to your emergency room and he or she has just survived a traumatic episode, whether it s a motor vehicle accident, a rape, an assault, attack by a terrorist as in places like Israel, where we have a lot of the data National Center for PTSD Professional Development Resources PTSD Treatment I Page 33 of 37

34 What would we want a morning-after pill to look like? I mean, is this something we can give them that s going to reduce their immediate distress and prevent later development of PTSD? Well, I ve listed three things that a morning-after pill ought to do: 1. It ought to reduce excessive stress responses. You know, reduce the excessive CRF for example. 2. It should enhance inadequate stress responses if people are unable to meet the challenge psychobiologically. We need to help them. 3. And the other thing that people don t always realize is that to be a doctor is to be able to mobilize the necessary psychobiological responses when the need exists when there is a threat; fight or flight or freeze-whatever. But when the danger has passed, to be able to return to normality. The problem with PTSD is that many people are stuck, sometimes for decades, in a hyperactivated stress response there s no off switch for these people. So having some kind of an off switch when the danger has passed is an important characteristic of a morning-after pill. So what do we want this pill to do? Well some of the things we might want it to do would be reduce CRF activity, to normalize HPA function, to reduce excessive adrenergic activity, and to normalize the immunological function. Differential Efficacy at 1 Week of Imipramine vs. Chloral Hydrate for Children with Acute Stress Disorder Let s look at some data. This is a randomized trial that was done by Robert & Associates on a pediatric burn unit, so these are kids who had been burned severely enough to require hospitalization. If any of you have worked on a burn unit, as I have, it s a terrible place. The kids are in pain. The treatment to get rid of the to debride the tissue makes the pain even worse. So one of the things that the staff want to do is make sure they (burn patients) get a decent nights sleep. And this slide shows a trial where they compared a typical sleeping pill, chloral hydrate, with imipramine, that the imipramine, which is a tricyclic antidepressant, was very, very much more effective than the chloral hydrate in reducing the acute stress disorder symptoms, among these kids. Unfortunately, there s no follow-up, so we really don t know whether this prevented a later development of PTSD. And as you can imagine, any kid who has been burned badly enough to require hospitalization is certainly a very high risk to develop PTSD as a result of his or her traumatic exposure. β Blockade and PTSD Symptoms The next slide is a very interesting experiment that Roger Pittman did at the Mass General Hospital Emergency Room. Reasoning as I outlined earlier that excessive adrenergic activation may increase the risk for later PTSD, both through the sympathetic arousal and the potentiation of the encoding of traumatic memories, Roger gave randomized people, who came to the Mass General within several hours of their trauma, either a 10-day course of propanolol, a betaadrenergic blocking agent, or a placebo. And these are the results: Looking at CAP scores at 1 month and at 3 months after treatment. It s a small study, only about 21 patients in the study, so I have very, very low statistical power to detect differences. If you inspect this data, I mean, it looks like the propanolol group has an edge, but there s tremendous variance, particularly in the placebo group. Although these results were in the right direction, in terms of lower CAP scores for the propanolol group, they were not statistically significant National Center for PTSD Professional Development Resources PTSD Treatment I Page 34 of 37

35 β Blockade and Physiological Reactivity However, if you look at the next slide, which shows beta-blockade and physiological reactivity, we all know that one of the hallmarks of PTSD is that if you expose people to traumatic reminders, in this case scriptdriven imagery, where a narrative about the traumatic event is read to the individual by a female if it s a female subject or by a male if it s a male subject, that the PTSD subjects are going to have significantly greater increases in physiological indicators, such as heart rate, skin conductance, or electromyogram. In this slide, the propanolol-treated group is in black and the placebo-treated group is in pink. So you can see, in terms looking just at the pink slides for these four graphs, that all of the placebo group shows increased hyper-reactivity one month after exposure to the traumatic episode. If you look at the black however, it s less than the pink and, in the case of skin conductance, the upper right-hand corner, is significantly less. If you look at the lower right-hand corner, the corrugator electromyogram is almost significantly lower. This is a very, very promising trial, suggesting that acute administration of an antiadrenergic drug, in thins case propanolol, which is a beta-adrenergic blocker, may indeed be a prophylactic and preventive treatment for PTSD. This study is now being repeated, a much larger scale study done both here and in France. So stay tuned. It s a very important experiment. Plasma NPY: Baseline and Acute Stress My final three slides are about studies that the National Center s been doing at Fort Bragg, North Carolina. And we ve been doing studies with Special Forces, so SF stands for Special Forces, and Non-SF stands for Non-Special Forces. They have something called the SERE School training, which is a very, very stressful training experience in which troops are asked to evade capture for several days, or if they are captured and incarcerated, there is a mock interrogation. This is obviously to prepare them for possible capture following dangerous missions in places like Iraq or Afghanistan. The situation is so stressful these are macho men that, when you measure neurohormones, and we ve measured many of them, many more than I m showing in these slides, testosterone levels disappeared during the course of this. So this is a credible threat, even to Green Berets and Navy SEALS. If you look at the baseline neuropeptide Y levels for the Special Forces and the Non-Special Forces, the yellow boxes-yellow squares-you can see there s no difference. But if you look at the neuropeptide Y levels during the acute stressful situations, you can see that the Special Forces are much more able to mobilize the neuropeptide Y than are the Non-Special Forces. What this slide also illustrates is what I believe is the difference between PTSD and, say, depression is that PTSD is a disorder of reactivity, rather than of basal state. In order to really unmask the differences between PTSD and non-ptsd, or resilient versus non-resilient people, you really need to provoke them; in this case we re provoking them with the stressful situation of the SERE Training School. And what it looks like is the Special Forces, whatever the criteria by which the military selects its people for Special Forces, are different in some way. They re more able to mobilize neuropeptide Y National Center for PTSD Professional Development Resources PTSD Treatment I Page 35 of 37

36 Plasma NPY: Baseline and Recovery Here s another slide showing recovery period. You can see that the Special Forces people have recovered their baseline neuropeptide Y, whereas the Non-Special Forces are still quite depleted. Again, there s a difference. There is a biological capacity that s different for Special Forces and Non-Special Forces. I should say also that we found similar results with the adrenogluccorticoid DHEA; dehydroepiandrosterone, which opposes the actions of cortisol. Correlation Between Dissociation Scores and NPY Levels So here s my final slide. Why should we care about how much neuropeptide Y is released? Well, the horizontal axis plots the amount of neuropeptide Y that a given individual released, and the vertical axis is a dissociation scale, which is also equivalent to a functional scale. As you can see, the greater the neuropeptide Y, the less the dissociation, and the less the dissociation, the greater the function. So what this data suggests to us is that neuropeptide Y may be a biological marker for resilience, and it s one of the reasons that I ve been saying throughout this talk that I think we need to look at neuropeptide Y, and it may be drugs that can enhance neuropeptide Y function, particularly in vulnerable or non-resilient people; may be one pharmacological approach to PTS or acute stress problems. About the Speakers (Authors): Josef I. Ruzek, PhD, is Associate Director for Education at the Education and Clinical Laboratory Division of the National Center for Post-Traumatic Stress Disorder and Director of PTSD Education for the Sierra-Pacific MIRECC. He is an editor of the text Cognitive-Behavioral Therapies for Trauma, a writer for the Iraq War Clinician Guide, and co-chair of the Early Intervention special interest group of the International Society for Traumatic Stress Studies. Joe was a member of the team that developed the joint VA-DOD Clinical Practice Guideline for Management of Traumatic Stress. Matthew J. Friedman, MD, PhD, is Executive Director of the U. S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder (PTSD) and Professor of Psychiatry and of Pharmacology at Dartmouth Medical School. He has worked with PTSD patients as a clinician and researcher for thirty years and has published extensively on stress and PTSD, biological psychiatry, psychopharmacology, and clinical outcome studies on depression, anxiety, schizophrenia, and chemical dependency. He has written or co-edited fifteen books and monographs, 52 book chapters and 93 peer reviewed articles in scientific journals. Listed in The Best Doctors in America, he is a Distinguished Fellow of the American Psychiatric Association, past-president of the International Society for Traumatic Stress Studies (ISTSS), Chair of the scientific advisory board of the Anxiety Disorders Association of America and has served on many VA and NIMH research, education and policy committees. He has received many honors including the ISTSS Lifetime Achievement Award in National Center for PTSD Professional Development Resources PTSD Treatment I Page 36 of 37