PHM302 – Oct 14 Part 1Anxiety Disorders

Learning Objectives By the end of this lecture/case discussion students will be able to:

o Differentiate between normal vs. pathological anxiety - What you’re going to need to be able to do is understand the role of anxiety for all of us normally; it actually plays a purpose in our life on a regular basis; and when do you actually cross the line from what is normal to when you actually have a pathological anxiety disorder?

o List the different types of anxiety disorders (AD) and key defining features that allow you to distinguish between e.g. Generalized Anxiety Disorder or Social Anxiety Disorder

o Recognize the diagnostic criteria – I only expect you to know the DSM criteria for Generalized Anxiety Disorder and clinical presentation of generalized anxiety disorder (GAD), but you need to know to be aware of the key clinical features of the other disorders that we’ll talk about

o Justify the place in therapy for the following medications (i.e. benzodiazepines, antidepressants, Buspirone, and Pregabalin) in the treatment of GAD

o Differentiate between the time course of anxiolytic effect of benzodiazepines, antidepressants, and Pregabalin in terms of how long does it take these drugs to work in different types of anxiety disorders

So today, we’re actually going to do a case in the context of all of you being here vs. your workshops; this is your patient, her name is Ellen, and she has an anxiety disorder; and hopefully by the end of the class today, you’re actually going to be able to help maximize her treatment and improve her anxiety

Importance of Anxiety Disorders as a Group = extremely important The most common mental/psychiatric disorders, so there are a lot of pts that actually suffer from anxiety

disorders who you will come into contact with in your daily practiceo Lifetime prevalence for any AD = Anxiety Disorder is 24.9% ~25%; so a quarter of the people in this

room will suffer from some sort of pathological anxiety disorder at some point in their life; so those numbers are fairly startling

Tend to be chronic (more chronic i.e. they last a person in most cases the majority of their life and non-remitting than major depression)

Have substantial comorbidity – both medical comorbidity as well as psychiatric comorbidity; most patients that have an anxiety disorder also have depression; so they actually co-exist; also a significant number of patients with anxiety disorders also have substance use disorders

Carry a burden of distress and impairment similar to chronic medical disorders – has a significant impact on quality of life and functional abilities, occupational abilities, etc.

High social cost – these result in a lot of missed work, missed school, missed activities; people actually often give up many things because it’s easier to give something up than to deal with the anxiety that’s associated with it

Normal vs. Pathological Anxiety A biological warning system that is activated by perceived danger Distressing and usually associated with bodily discomfort

o Normal levels prepare – protective responseo High levels can be disorganizing, counter-productive, and cause impairment

Abnormal when disproportionate to the potential for harm or when it occurs in situations reasonably deemed to be harmless

so what is anxiety and what do I mean by normal anxiety? Well our entire biological systems is set up to have a warning mechanism that is actually activated when we think we’re in danger – that’s a good thing; so again, this dates back to pre-historic times when everyone hears about hunters and gatherers and you were out and about, you needed to be aware if you were about to be chased by a bear or something of that nature; here I guess in Toronto we don’t have any bears chasing us, but there are times when you’re walking down the street in the dark and all of a sudden your heart starts to race and/or you heard a noise and/or you perceived some sort of danger or threat that started to cause physiologic changes in your body; anyone ever been there and done that? And sometimes it’s a cat or something crazy, and you’re freaking about where you’re going to go next, and then you realize that, “okay, it’s nothing”; but your body got completely reactive;

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your heart was racing, you were ready to run if you had to; so that’s the whole fight or flight response that is in place to protect us; and it’s there so that we’re able to get ourselves out of a dangerous situation

however, when this becomes overactive and/or the response that’s being generated by your body is greater than the actual perceived danger or that the danger actually presents, then it starts to become concerning and potentially pathological; so again, you’ve crossed the threshold between being normal and abnormal when your response is disproportionate to the potential harm; so if you’re walking down an alley and you get afraid because you hear a noise and it’s dark and you’re in a part of the city or somewhere you don’t know, your heart starts to race, you start to feel anxious and you’re thinking about what you’re going to do next – that’s normal; if however, you then discover that that was a cat and everything is good, but your response to that is, “I’m no longer ever going to walk outside at night by myself ever and now I’m so scared that I’m actually never going to leave my house and now I can’t even get groceries”…that’s a bit disproportionate to the cat that jumped out of the garbage bin behind you; so for some folks this actually continues to perpetuate and it has a huge impact on their ability to function

Risk Factors Female gender: F:M ~ 2:1 (except OCD M=F) – gender difference; in general, more females than males

suffer from anxiety disorders roughly about 2:1; with the exception of Obsessive Compulsive Disorder (OCD), which we think is relatively equal between genders

Family history: Odds ratio 4-6; family history is a strong predictor of anxiety; so if you’ve got family members that have pathological anxiety disorders, there’s a higher likelihood that you will; and again, the closer the degree of the relative, the higher the likelihood

Trauma (abuse, assault, accidents, etc.) also increases the risk of anxiety disorders; and we’ll talk about a specific type of trauma-induced disorder which is Post-Traumatic Stress Disorder

Stressful life events (unemployment, illness, death of loved one, marital conflict, etc.) also can contribute to the development of an anxiety disorder

Take note that most of these are actually the same risk factors that you see in Major Depressive Disorder; and again, that’s not uncommon because as I mentioned, >50% of patients that have anxiety disorder also have Major Depressive Disorders, and so they tend to co-occur; and sometimes it’s hard to tease out one from the other, so there’s a lot of overlap

Medical Causes of Anxiety “Anxiety Disorder Secondary to…” In terms of medical causes, this is one area in psychiatry where you really have to have a good history; so

there are a lot of medical causes or contributing factors to anxiety, and this is where you hear somebody has an anxiety disorder or anxiety secondary to [insert medical condition] and/or [something that’s not necessarily biologic in the brain]

Substances:o So we know that substances can cause anxiety disorders and anxiety symptoms, so things like…o Use of pseudoephedrine, nicotine, caffeine, marijuana, LSD, cocaine, MDMA (ecstasy), herbal

supplements can all cause symptoms and present like anxiety disorderso Withdrawal from ETOH, opiates or benzodiazepines

Medical Disorders:o Cardiac arrhythmias (SVT), congestive heart disease, hyperthyroidism, vertigo, congenital adrenal

hyperplasia, hypoglycemia, pheochromocytoma Medications (so not necessarily just substances, but things that may have been prescribed for other

disorders):o Stimulants, Theophylline, others (there’s a table in DiPiro)

Missing Slide So what’s actually happening in anxiety disorders and what do we know that’s actually going on in the brain?

We know for sure with imaging that there are a lot of brain regions and structures that are involved; we know that the amygdala is fairly heavily involved; but we’re not exactly clear all of the biochemical mechanisms that are actually contributing to the development of full-fledged anxiety disorders, and we’re not completely sure what makes them all different; we do know that different types of anxiety disorders, when you look at PET scans, have different parts of the brain lit up; but again, this is still an area of fairly active research

however, in terms of neurochemical theories, what do we know? We know for sure that there is noradrenergic involvement; why do we know that? Because you get an autonomic nervous response; so there has to be some role for noradrenaline; and we know for sure that the autonomic nervous system in anxious patients is actually hypersensitive and it overreacts to stimuli

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The GABA receptor model; we also know that GABA plays a role; how do we know that? Why do we know that GABA is involved? Because of how the drugs work i.e. we get a response to drugs that bind to these receptors or subtypes of the receptors; so we know that there is an involvement, but we don’t know exactly what’s happening and we don’t know all of the intricacies of the role of the different subtypes of the receptors at this point

And we also know that there is a serotonin model, and we know that there is a role for serotonin; again, because we use serotonergic drugs and because a variety of animal models have suggested that; but it’s actually not clear - and there’s data to support that the role of serotonin is significant, and then there’s other data that suggests that it’s not so significant; so it may in fact be some sort of interaction between serotonin and some of the effects that serotonin has on other neurochemicals in the brain; so again, these things are not well articulated, we know that these things are all involved, but there’s no clear picture or mechanism that clearly explains exactly what’s happening in these individuals – again, which makes treatment difficult

Structural Changes in the DSM-5: Anxiety Disorders

So here again, because you guys are living in a hybrid world between the DSM-IV and the DSM-V, I want to highlight some of the differences so that you can get an understanding in practice of kind of where we’re working in the DSM-IV, but also where we’re going towards with the DSM-V

So here you can see in this category are all of the anxiety disorders that are listed in the DSM-IV; so the list is big, so you can see all of the different things that we think about for anxiety

What looks different in the DSM-V? well one of the things that is different is that Obsessive Compulsive Disorder has actually been removed from the list of anxiety disorders and is actually given its own chapter; so it’s no longer grouped in the anxiety disorders chapter i.e. it has its own section in the DSM-V; and included there, you can also see the categories for the other disease states that are listed in the Obsessive-Compulsive and Related Disorders chapter in the DSM-V; and they’re all somewhat similar to what you think of when you think of OCD – so Body Dysmorphic Disorder, Hoarding, etc.; but again, you can get a sense here for a number of different disorders that actually have diagnostic classification or have been medicalized

Also you can see here that any of the trauma and stress-related anxiety disorders have been pulled out into their own chapter as well; so PTSD just used to be a subcategory of anxiety disorders, and again, it now has its own chapter which is called Trauma- and Stressor-Related Disorders; and again, you can see a few other disorders listed there as well, but again, the main one that we’ll talk about is Post-Traumatic Stress Disorder

And again, Appendix B, has actually been removed and we no longer have this Mixed Anxiety Depressive Disorder category

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Obsessive-Compulsive and Related Disorders Chapter So here again, you can see these are all of the different types of disorders that fall into that new chapter on

OCD and Related Disorders Obsessive-Compulsive Disorder Body Dysmorphic Disorder Hoarding Disorder Trichotillomania (Hair-Pulling Disorder) Excoriation (Skin-Picking Disorder)

Main DSM-5 Anxiety Disorders And here you can see what remains in the DSM-V category or chapter called Anxiety Disorders Panic Disorder Agoraphobia Social Anxiety Disorder [a.k.a. Social Phobia] Specific Phobia – this is where you get all of those specific fears of things like spiders e.g. arachnophobia;

and a whole variety of things where a person has an anxiety but it’s associated with only one thing, often an animal

Generalized Anxiety Disorder, which is what we’ll spend most of our time talking about and certainly what our case will be about

Separation Anxiety Disorder Selective Mutism And then what’s interesting is that Separation Anxiety Disorder and Selective Mutism are actually now in the

Anxiety Disorder category; so these are additions; in the DSM-IV, these two categories of diagnoses used to be in the chapter that was related to diseases most often diagnosed in infancy or early childhood; so at one time, in order to get a diagnosis of Separation Anxiety Disorder, it had to be made when you were a child or at least prior to the age of 18 – those age specifiers have now been removed, and they’re now being categorized as anxiety disorders and in theory, now you can actually diagnose somebody with Separation Anxiety Disorder when they’re >18; now I’m not sure that it’s actually separation anxiety to the parent when you’re >18, but there are other things that when you’re separated from, you can develop anxiety disorders from

Generalized Anxiety Disorder (1) Generalized Anxiety Disorder is probably the one that’s most commonly discussed; it’s the one that occurs

most frequently CORE = Chronic, difficult-to-control WORRY causing functional impairment/distress – they have so

much WORRY that they can’t control it and it actually pre-occupies their entire existence; again, a little bit of worry is okay it’s normal; but when it starts to cause functional impairment and distress, it becomes pathologic; excessive anxiety

In order to make the diagnostic criteria for Generalized Anxiety Disorder, you need to have Excessive anxiety for 6 months about a number of areas i.e. you have to be anxious about a lot of different things (and you have to have more days with anxiety than without)

You also need to have what’s defined as Difficult to control the worry (a “worrier”):o Symptoms have to be so significant that they impact your social/occupational/family role e.g. your

ability to go to work, your ability to act as a parent, your ability to go to school or be a student; so again, they have to have some profound impact on your actual life

And they also have to be Associated with 3 or more of the following:o Restlessness, edgyo Easily fatiguedo Difficulty concentratingo Irritabilityo Muscle tensiono Sleep disturbance (so oftentimes, it starts off with initial insomnia and/or fragmented sleep – you

can’t fall asleep because you’re so worried about something and then when you do fall asleep and you wake up, which happens to all of us, the worry comes back the minute your eyes open and then you can’t fall back to sleep – so you don’t get any sort of consistent, restful sleep)

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Generalized Anxiety Disorder (2) The other issues with Generalized Anxiety Disorder is that it’s: Very Common, chronic Uncontrollable, pervasive anxiety – telling somebody that has an anxiety disorder to relax actually doesn’t

help; they actually will tell you when they describe it to you, “I’m so worried and I know that it makes no sense, but I can’t stop”; if they can’t find a switch to shut it off; and many of them are very aware that their worry is well beyond where it should be, but they just can’t figure out how to turn the light off on it; and it gets to be really problematic for them and it’s really frustrating, especially for folks that keep saying, “I know I shouldn’t be worried but…”

Psychological Symptoms (e.g. excessive worry) The other thing that you’ll often also see are Somatic Symptoms (e.g. muscle tension); and this can be

problematic because sometimes people will voice these somatic symptoms e.g. upset stomach, headache, fatigue, they feel yucky; they go to the doctor presenting with these vague somatic symptoms; the doctor tells them that there’s nothing wrong with them, “you must have the flu, you must have this, go home, it’s a virus, whatever”; they go home, they don’t feel better; but they’re not associating the worry with the physical symptom; so when they go to the doctor, they’re only presenting the physical symptoms, but they’re not also presenting those psychological or worry type symptoms, and again, it can take a long time to actually accurately diagnose these folks

High degree of Psychiatric comorbidity very common: so lots of the patients also have:o Depressiono Other Anxiety Disorders – many of them have multiple anxiety disorders, so more than oneo SUDs – and again, some of them also have substance use disorderso And all of these things muddy the picture in terms of diagnosing

GAD – Questions (1) So there’s some questions that you can ask people; again, these are questions that psychiatrists often ask

when they’re interviewing somebody, screening for anxiety; but these are questions that a pharmacist can ask as well to help you get a sense for, does this person have an anxiety disorder? Do I need to refer them somewhere?

Have you frequently been worried or anxious about a number of things in your daily life?o Do people say you worry about things too much?o Do you think your anxiety is unrealistic or excessive? Many patients will say yes; so again, they

often have a very strong sense of awareness Is it hard for you to control or stop your worrying? Yes So again, here if you think about a mom who worries; you’ve got somebody that worries that their kids are

going to be hurt when they’re out past curfew or that they’re not going to come home on time; that’s probably to a certain extent a normal parenthood worry

however, for patients that have anxiety disorders, you could have a teenager who has never been late for their curfew ever, they’re home early in fact for the time that you set for them; yet, the entire time they’re gone, you sit at the window worrying that they’re not going to be on time; and in your mind, you have no evidence to support that i.e. nothing has ever gone wrong before, but you still can’t shut off the worry and you can’t do anything else for the 6 hours that they’re out because you’re waiting at the door for them to get home to make sure that they’re okay and on time; so it’s a very nasty cycle for some folks and it really impacts their productivity

GAD – Questions (2) and then after you get a sense for some of those psychological worry type symptoms, you then move into

asking about the physical symptoms Now I’m going to ask you about physical symptoms that often go along with anxiety and nervousness?

o …feel restless, fidgety, jittery, keyed up? Like that fight or flight response is always on and you can’t shake it?

o …get tired easily?o …feel irritable?

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o …feel tension, aches, or soreness in your muscles; again, if you can imagine…when you experience that fight or flight…; can you think of a time when you’re afraid of something or you felt anxious about something and you had a deadline and you thought “I’m never going to get this done” and your heart was racing; but you also get so keyed up that you start to actually tense yourself up, and you get sore muscles or you get stiff; so can you imagine if you felt like that 20 hours out of the day? After a while, you end up with this chronic tension, and it can cause significant back and neck pain

o …have problem falling asleep or staying asleep o and the combination of those symptoms together would help to again come up with a high likelihood

of anxiety, and then you would then begin applying that to the diagnostic criteria in the DSM and come up with a Generalized Anxiety diagnosis

Panic Disorder: The Panic Attack so the next disorder that I want to talk about is actually panic disorder; and panic disorder is a disorder with

or without panic attacks; now panic disorder has a number of panic attacks; but a person can suffer from panic attacks, and not actually go on to develop a full-fledged disorder

a panic attack is a Discreet period of fear or anxiety, intense feeling of fear common And oftentimes you feel 4 or more of the following types of symptoms: Fear of Dying, Fear of Losing Control (usually people describe either a fear of dying and/or a fear of losing control), Sweating, Derealization, Trembling, Nausea, SOB = shortness of breath, Choking feeling, Parasthesias, Hot flashes, Chest pain – this is one of the common causes of a trip to the ER with chest pain and you think you’re having a heart attack but in fact you’re having a panic attack – but again as you can imagine, this leads to a lot of costly tests i.e. anybody that goes to the ER with chest pain is probably going to get at minimum an ECG and if they have a panic attack, you’re probably not going to see very much, Palpitations, Dizzy, unsteady and an overall sense of feeling unwell

characteristic for panic attacks is that it Comes on suddenly “it comes out of nowhere”, reaches peak within 10 minutes – why does this peak matter? What is the treatment for panic attacks? What do we give people for panic attacks? Often they’re PRNs; the answer was something like sublingual Lorazepam i.e. something with a very quick onset of action; how quick is the onset? 30min; and how fast is the panic attack? 10min; the panic attack is usually over before you get any benefit from any drug; now, that doesn’t counteract the fact that placebo effect has a huge role and probably there is something to that, but it’s food for thought when you’ve got a patient who’s got a lot of panic attacks; because as soon as you start the cycle of giving them PRN benzodiazepine…they feel panicked, you give them an Ativan, and all of a sudden 15 min, they feel good – what made them better? In their mind, the benzodiazepine; and now, you’re never going to be able to take it away; what actually made them better? Is that this is a self-limiting condition i.e. the panic attack itself is always gone in <20min, and that’s true of all panic attacks; now if a person has a panic disorder and the attacks are frequent i.e. they happen several times a week and they are something that is not situational…for some folks, panic attacks happen in very predictable circumstances e.g. some people are afraid to fly and they actually get a panic attack the minute the plane door closes; so they’re okay at the airport, they’re okay when they get on the plane as long as they feel like they can get out; but as soon as the doors close and the pilot says “here we go”, they often get panicked, because now they’ve lost their sense of escape; so for those cases, it’s usually an isolated event and the panic attack will be gone in 20min; even though the plane has left, those 20min are horrid for the patient, they feel terrible, but usually they go away; it’s different if they’re happening with your everyday life with multiple activities, and that’s when we go on to talk about Panic Disorder

Panic Disorder so if you go beyond just having 1 or 2 panic attacks or panic attacks with specific situations, you go on to

develop a panic disorder, again which can be chronic Common, often chronic Repeated and unexpected = not predictable panic attacks agoraphobia = fear of spaces i.e. open spaces

and fear of not being able to exit Again with panic disorders, you can see the same Psychiatric comorbidity common:

o Depressiono Other anxiety disorderso SUDs

High medical utilization – these folks use the medical system a lot because many of the symptoms are very intense e.g. sudden onset, chest pain; so these folks often go to the ER, especially early on when they don’t

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know that they’re panic attacks; and so here you’ll see more medical utilization than with some of the other disorders, again because of the rapid onset and the intensity of the symptoms

Panic – Medical Presentations Common medical presentations in an ER department or a clinic include: Cardiac panic = when you get chest pain, rapid heart rate, sometimes numbness in one arm i.e. all of those

signs that you’ve been told that sounds like stroke and/or heart attack Pulmonary panic = when a person can’t breathe; so they often feel like they’re going to choke, they get really

short of breath; sometimes they describe a real tightness across their chest that’s impairing their ability to get air

GI panic = when you get a lot of GI symptoms, so lots of nausea, some patients actually throw up; so they have this overwhelming sense of discomfort in their GI system

Neurological panic (vertigo) – this is not common, but usually it presents as vertigo Panic exacerbatic medical illness – so you’ve got a person who has an underlying cardiac history, they now

have this panic attack, their blood pressure goes up, and they start to get a whole variety of exacerbated cardiac symptoms that they may have experienced because of another illness

Panic Disorder – Questions (1) So how do you start to get at whether or not a person has a true medical illness, and they’re actually having

a heart attack or a panic attack? So you ask them things like… Have you had a sudden rush of intense fear, anxiety, or discomfort that came on from out of the blue, for no

apparent reason, or in situations where you did not expect them to occur? And many patients describe that they were just interacting or sitting on the sofa, and then all of a sudden, these symptoms just appeared; there seems to be no apparent reasons and you didn’t expect them; the problem when you start to get a panic disorder though is the next question…

Do you worry a lot about having more of them? So then the worry becomes, “when’s the next one going to happen?”; so if you have 1 or 2 panic attacks, you can probably manage; if they’re expected or predictable because you have a panic disorder in a plane, you can manage your life around it; if they start to happen frequently and unexpectedly, you start to get scared – “when are they going to happen next?” “what if I’m driving a car?” “what if I’m taking my kids somewhere” “what if I’m…”; and the “what if” list gets huge, and then people start to change their life to manage the fear of having another panic attack; so this is when you start to see people no longer leaving their house – “I don’t want to have a panic attack on the subway because if I’m underground and on the TTC, I can’t get out, and I don’t have a cell phone signal, and so to prevent that, I better just stop taking the TTC”; and as you can imagine if this keeps going, people all of a sudden have had huge impairment to their life, many people have lost jobs, etc.; and again, those two questions go together i.e. you worry about having more of them and then what kind of behavioral changes have you made again because of these attacks?

Have you changed your behavior since these attacks began?

Panic Disorder – Questions (2) You can also ask them to Think back to the last attack that they had:

o When was it?o Where were you at the time?o Would most of the symptoms ever come on quickly, within 10 minutes after the attack began?

Did you experience any of the following?o …feel your heart racing, pounding, fluttering, or skipping beats?

Panic Disorder – Questions (3) …sweat? …tremble or shake? Again, you’re trying to get a sense for their physical symptoms that are occurring with

their specific attacks to get a sense of what’s going …have trouble catching your breath, or feel like you were being smothered? …feel like you were choking?

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…have chest pain, pressure, tightness, or discomfort? …feel nauseated, sick to your stomach, or like you might have diarrhea?

Panic Disorder – Questions (4) …feel dizzy, light-headed, unsteady, or like you might faint? …feel like things around you were unreal, like you were in a dream, like part of your body were unreal or

detached from you… …fear you were going crazy or might lose control? …fear you might die? …feel numb or tingling in your fingers or feet? …have hot flashes? **I won’t ask you to memorize all of these questions; these are really just for you to get a sense of what are

the kinds of questions that folks ask when you’re trying to tease out or when you’re trying to think of all of the differential diagnoses on the table; what are the kinds of questions you can ask to get a sense of, could there be a panic element to what they’re feeling

Now, panic attacks often occur with agoraphobia but it’s not a requirement

Agoraphobia – Questions (1) Agoraphobia = Some people have very strong fears of being in certain places or in certain situations. They

often are also afraid of going places where they cannot exit – planes being a common example; so here you can get a sense for when patients are describing their phobias…Do any of the following make you feel very fearful, anxious, or nervous?

o Being in places or situations where the exit is perceived as difficult?o Being in places or situations where getting help is perceived as difficult?o Being away from home?o Being in wide open space like a park? Some people are afraid of small spaces – so again, it’s very

individual; but these are the kinds of questions you can ask

Agoraphobia – Questions (2)o Being in crowded places like a movie theater, supermarket, shopping mall, church, restaurant, etc.?

and again, here getting more specific because here you can start to isolate, is it everywhere? Or is it specific things?

o Being on a bridge or in a tunnel?o Traveling in a bus, train or plane? Some people actually stop flying which is fine for some folks but

other folks find that hugely problematico Driving in a car?o Being home alone?

Posttraumatic Stress Disorder (PTSD) Is not super Common, but I think it’s worth highlighting because it gets a lot of press; where do you hear

about PTSD? Vets, right? You hear a lot about it in America because many of them are still involved in active combat somewhere in the world; and then they come back to the United States and many of them experience what we call PTSD after returning from some sort of active combat; again, it can also happen when folks have experienced any kind of life-threatening, overwhelming experiences; and again, this is a very complicated disease and I don’t want to get into all of the details; but patients often experience different types of symptoms that usually fall into 1 of these 3 categories:

Symptom categories:o Re-experiencing an event; so the fearful event they relive in their mind over and over again and they

can’t seem to let it go; often that occurs through nightmares and it impacts their ability to sleep; sometimes they don’t want to go to bed because that’s when these visions come back; again, the other thing that’s really important is that the patient has to have felt usually that their life was in danger but that doesn’t actually mean that their life was in danger necessarily; so there’s an element of the perceived danger to the patient; again, so you can imagine obviously if somebody’s in active combat, that fair enough their life is probably in danger i.e. they run the risk of some sort of negative outcome by virtue of the fact that they’re in the military, if they’re actually engaged in some sort of activity in certain parts of the world; but a person who has been abused or a person who’s life has been threatened by a family member or whoever, that person may never have acted out and actually

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ended their life, but the person was so afraid that it could happen, that it actually results in the development of this disorder as well

o Avoidance – another category of symptoms is Avoidanceo Increased arousal – and then something else that we call Hyperarousal or Increased arousal, and I’ll

show you some questions thereo but again sometimes patients have experienced symptoms in all of these domains, other times they

are more troubled by one than another

PTSD – Stressor Criteria Questions again, the first thing that’s important when you’re looking at the possibility of a diagnosis of PTSD is the

stressor criteria, so what is the stressor that the person was exposed to, so… Have you ever seen or experienced a traumatic event in which your life was actually in danger or you

thought your life was in danger? Have you ever witnessed an event in which someone else’s life seemed to be in danger? How did you react to the trauma?

o Were you frightened or horrified?o Did you feel helpless and out of control?

Not everybody who goes to war for example gets PTSD, right? if that was the case, we’d have huge numbers, and we don’t; so an active area of research in this field is, what kind of protective mechanisms do people have? Because for some people, they can go and maybe even have their own life threatened, maybe have lost a limb, and they can come back and they’re perfectly fine i.e. they’re able to go back to work, they’re able to interact with their family, friends, and live their life as normal as possible having experienced traumatic events; yet somebody else may have experienced something that when you read/hear about it seems less traumatic – yet that person had such a response that they actually can’t go back to work, that they can’t form relationships with their family, friends or their loved ones; so why does one person respond one way and somebody else respond totally different? And we have no idea, so that’s something currently being explored; but these questions are important because it’s the person’s reaction or how they felt in response to the event that contributes to the development of the actual disorder

PTSD – Re-experiences Questions Do memories about the [war, event, trauma, etc.] still bother you?

o Do you see images of the trauma?o What about dreams?o What about flashbacks where you relive the event? Flashbacks do happen, and some patients

actually flashback to the event; sometimes a smell or a sound can cause a person to have a flashback and bring them back so that they feel like they’re actually in that moment where the event actually happened

o Are there different things that remind you of the [event] that get you upset?o Do the reminders make you tremble, break you in a sweat, hyperventilate or have a racing heart?

What is your physical response to these things?

PTSD – Avoidance Questions Do you try to block out thoughts or feelings related to the [event]?

o Do you try to avoid activities, situations, or places that remind you of the [event]? So Vets will tell you sometimes that they don’t want to do anything with anybody from the military e.g. they don’t want to go to hospitals where they might have contact with another military person because they’re trying to avoid any association to anything that resembles or relates back to the event

o Are there aspects of the [event] that you can’t recall?o Since the [event] have you lost interest in some things you used to enjoy?o …do you feel distant and cut off from people?o …have you lost the ability to feel certain emotions?o Has the [ ] changed how you feel about the future?o So all of these things again can be a sign that a person is trying to build up mechanisms to avoid

any sort of memory of the event

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PTSD – Hyperarousal Questions Hyperarousal is when a person is truly in a hyperaroused state, so… Since the trauma have you…

o …problems sleeping?o …more irritable or lost your temper more easily?o …problems concentrating?o …been on the alert, always keeping your guard up with an eye out for possible trouble? So this is an

over-activated fight response; so you’re trying to protect yourself all the time, and again as you can imagine, this becomes very tiring, very stressful, and it can have huge impact on relationships with folks in your life

o …been kind of jumpy and easily startled by everyday ordinary noises? So people will explain that they can hear something that reminds them of a gunshot that brings them back to the trauma, and they’ll jump 2 feet in the air

so PTSD, I think is something important to be aware of; a whole variety of things go into making a diagnosis, but there has to have been some kind of trauma and a over-exaggerated response to the trauma that impacts functioning; and again because it gets a lot of press, I think it’s important; and we’re not going to talk about treatment; but it’s certainly a valid mental health diagnosis

Obsessive Compulsive Disorder (OCD) (1) Obsessive Compulsive Disorder – this is the disorder where you think about people that wash their hands

too much – and that’s certainly one form of the disorder Obsessions: Persistent ideas, thoughts, impulses, or images that are experienced as intrusive,

inappropriate, and increase anxiety – and obsessions are often accompanied by compulsions Compulsions: Repetitive behaviors or mental acts that are aimed at preventing or reducing the anxiety and

distress caused by the obsessions So the most common ones that you see are hand washing – so people are obsessed about germs, and the

potential to develop an illness or to get germs from other people, and the compulsion becomes washing their hands to try to reduce the anxiety and reassure themselves that they’re not going to get the germs; and again, these things get so out of control that patients sometimes lose the skin on their hands because they’ve washed their hands so many times

Another common one is locking the door; so you’re leaving your house, and you know that when you leave your house, you lock the door; so you go and you lock the door and then you walk down the street; and then you start saying to yourself, “did I lock the door? Because if I didn’t lock the door, somebody could steal and take my notes for PCT-7 and that would be a tragedy because the exam is coming up; did I really lock the door? Because I can’t lose those notes”; so you walk back home and you put your key back in the door, you unlock it and you relock it – you say to yourself, “okay, I’ve locked the door – I checked twice, I locked door”; you start walking to the bus because you’ve got to go to class, and then you’re like “did I really lock the door? Because if somebody stole those notes, that’s a really big problem, I better go back and check if I locked the door” – it’s not uncommon if somebody goes back and checks if they’ve locked the door 100 times; and it’s now taken 2 hours to leave their front step

I had a patient who needed to count his pills; he was a Clozapine patient and he came every week; and he needed to count his pills because he was obsessed about decompensating and getting re-admitted to the hospital; so he needed to know that there was enough tablets there to last until his next blood work; so he used to come and we would give him a corner of the dispensing counter because we knew that he was going to be there always for 2 hours counting and re-counting his Clozapine; and he would pour them out and count them, put them all back in the bottle, put the child cap back on, look at it, read the instructions, undo it, pour them all back out, and do it again – 2 hours; he counted them 303 times – he had a number, and he couldn’t stop; so it’s not just about saying “yes I counted them for you; I counted them twice; they’re all here”; he needed to do it and not just do it once – it becomes so repetitive

Same thing happens with people that are afraid that they didn’t shut off the stove – it’s hugely problematic, and often leads to patients being hospitalized

Obsessive Compulsive Disorder (OCD) (2) OCD is not as common as some of the other anxiety disorders Not frequently diagnosed in primary care setting Patients are often secretive about this and have increased shame - Most people are very aware (in fact 95%

of the time) that this is a problem and they do whatever it takes to hide it; e.g. they know that washing their

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hands does not make sense because they can see that their skin is falling off and that they’re bleeding and that their hands hurt, but they can’t stop; they know that nobody really wants their PCT-7 notes and they don’t need to check their door 500 times, but they can’t actually stop; so there’s a functioning issue with all of these anxiety disorders is that most people know that they’re way too far on one side and that this doesn’t make sense, but all of them describe it as “but we can’t shut it off” and that becomes really distressing to folks; and again, a lot of patients that have OCD are very high functioning e.g. they’re students, they work, they have jobs, they have families, and they don’t want to admit that they have a problem; but sometimes the problem starts to impact their ability to get to work on time, to get to class, etc.

Starts early in life – it often starts in kids, and in adolescence or early adulthood, it becomes really problematic and can lead to hospitalization

Another interesting element of OCD is that it can actually also be caused by medications; Clozapine as a side effect can actually induce OCD in individuals that are susceptible, and then you’ve got a huge problem because you’ve got a patient with treatment-refractory schizophrenia, on the best drug we have, the last line i.e. Clozapine and now they’ve got OCD; and now we need to back the dose off to try to get the OCD in check, but in doing that, many of their psychotic symptoms come back and you’ve got to find a balance; so that’s probably one of the strongest evidence for drug-induced causes of OCD is Clozapine; and I’ve seen several cases of Clozapine-induced OCD and it’s a real challenge to the treatment

Social Phobia (Social Anxiety Disorder) Social phobia, again, is one that we all think about e.g. the guy that can’t give the speech or doesn’t want to

interact with people Common, potentially disabling depending on the person and depending on how severe the disorder Intense fear of scrutiny or being ridiculed by others Avoidance of social interactions Specific and Generalized subtypes Rarely recognized in Primary Care And usually these patients have a variety of issues that nobody can quite pinpoint and they often get

referred to psychiatry where they get a more comprehensive review and diagnosis

Social Phobia – Questions So again, some of the questions that we would ask in a patient who is suspected to have social phobia… Some people have very strong fears of being watched or evaluated by others. Do you worry that you might

do or way something that would embarrass you in front of others, or that other people might think badly of you?

Do you think you are much more anxious than other people? …what about the situation bothers you? Now social phobia itself is considered a diagnosis or some folks refer to it actually as a specific phobia i.e. a

phobia to social situations, but there are a lot of other specific phobias

Specific Phobia And again, to meet the criteria for any kind of specific phobia i.e. a fear of one particular thing usually is that

you have A marked, excessive fear provoked by the presence or anticipation of a specific object or situation; so not only are you actually anxious about the social event, you’re actually anxious thinking about the possibility of the social event

Generally, the phobic object is either avoided or endured with intense anxiety and distress Five subtypes of most people’s specific phobias:

o (1) Animal = one of the most common; spiders are the most common, so arachnophobiao (2) Natural environment (storms, heights, water)o (3) Blood-Injection-Injury (MDs, hospitals, dentists) – so the fear of getting contaminated and/or

when you’re giving an injection and/or taking blood from another individual; this didn’t used to be a problem for pharmacists because they didn’t touch people but now we touch; and now we fall into the category of we might potentially have fears of blood-injection-injury because now we also inject

o (4) Situational (public transportation, flying, enclosed spaces)o (5) Other (space, loud noises)

Health care-related Phobias Examples of health care-related phobias:

o Needles

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o The sight of blood or open woundso Pain o Anesthesiao Dental procedures

And again, the health care-related phobias are real and they’re something to be aware of because for some people, it may impact their ability to keep their job; so if you’ve got a severe phobia that you can’t give an injection and you’re a nurse, it’s hard to find work; so again, trying to find ways to help folks manage these is really important

Goals of Therapy for Anxiety Disorders? Anxiety can be a profoundly limiting disease to people’s life; it’s one of the disorders that people often have a

lot of misconception and don’t realize how severe it can be for some folks (1) Improve their quality of life (2) Reduce their symptoms - and what that means for each person is different so when a patient presents to

you their anxiety symptoms, you want to reduce them; so that would be fair at the beginning of treatment is to reduce them; what would be the ultimate goal? To get rid of them; so you can’t cure the disorder, but it can wax and wane; for many people, it is chronic and we usually treat people at minimum for a year, but it’s not uncommon to stop therapy in somebody to see if they can have a prolonged period of remission; but it’s important to be aware that the goal for anxiety is a full remission i.e. you want people to be asymptomatic and return to their previous level of function; now that doesn’t happen for everybody, but that’s the ultimate broad goal – you’d have to look at your individual patient to know if that’s feasible

Treatment Options Pharmacological:

o Benzodiazepineso Antidepressantso Buspironeo Pregabalin

Non-pharmacological: o Pyschotherapy:

Group therapy CBT = Cognitive Behavioral Therapy Individual therapy Exposure therapy – so that can work for folks that have specific phobias that you actually

expose them to the thing that they’re afraid of in a controlled setting, and help them build up a tolerance or an ability to manage their anxiety when confronted by those specific situations or things

Evolution of Anxiolytics

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This is to show you the evolution of anxiolytics; not unlike other mental health disorders, how we treat folks with anxiety disorders has certainly evolved; and as we get a better understanding of the neurobiologic aspects of the diseases, our treatment modalities do change

so we no longer use barbiturates to treat anxiety disorders – again, we’ve talked about the safety issues with barbiturates

but we still do use benzodiazepines and we started to use them in the 60’s; but again, what we’re trying to do now is to see if we can actually develop benzodiazepines that actually bind to different types of the GABA-A receptor, and even more selectively to get better control

we also use antidepressants – again, lots of different types of antidepressants; I would say the most common are the SSRIs and the SNRIs; but we certainly sometimes use TCAs and I would say the one in terms of anxiety that has the strongest evidence is Clomipramine, specifically for OCD – it has great data for OCD

and then Buspirone – it has a different mechanism – it’s a 5HT1a agonist and then there’s some new drugs we’ll talk about now; we’re not going to talk about Agomelatine because

it’s not yet available in Canada; but they are using it in Europe to treat anxiety disorder and also in the United States and there is some positive data, and so that’s an up and coming antidepressant that I would imagine Health Canada will approve sometime in the new future; but for now, it’s not part of our toolkit

and then we’ll talk about Pregabalin because it has a wealth of new evidence and it seems to be quite a good anxiolytic – however, it’s not indicated for this in Canada or the United States but it is in European guidelines, and it’s gaining a lot of momentum in the UK

Benzodiazepines and Z-Drugs

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Benzodiazepines and the Z-drugs are certainly options for the management of anxiety And you can see the different categories The ones in red are the ones that have some potential data and/or are being used in anxiety; the other ones

are not But you can see the approved indications for benzos in Canada in the corner there – they are approved for

anxiety disorders; and mostly when we’re talking about anxiety disorders, really we’re talking about Lorazepam and Clonazepam – those are where we’re at with benzodiazepines in general

And again, Zoplicone is not covered; we’re using it predominantly for sleep; there are some studies that have looked at it for anxiety, and again it probably has some efficacy, but I wouldn’t say in Canada that that’s taken off at this point, other than to help insomnia which may or may not be associated with the anxiety disorder

Benzodiazepines & SSRIs Compared

This is a graph that’s going to show you the differences between benzodiazepines and SSRIs; and I like this graph because it helps to give you a sense for where they might be useful

So here you can see that the average Treatment period for anxiety, sort of 0 to 6 weeks to start to get some effect, and then out past 12 weeks potentially; but you can see why benzos are often prescribed because they actually work sooner; so you actually get a response to symptoms that patients can feel usually within the first couple of days to the first week that you don’t actually see with antidepressants unfortunately; and so sometimes, people like to go quick to the benzo because they are trying to get a quicker onset of symptom improvement for their patient

5HT and Anxiety – Drug Types 5HT reuptake blockers:

o TCAs (especially Clomipramine)o SSRIs – we use most of them as an optiono SNRIs – there is data with Duloxetine and Venlafaxine as well

5HT receptor blockers:

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o Mirtazapine – there is some data in anxiety although it’s still quite limited; where you see this drug more often used in is somebody that has anxious depression; so if you look at the CANMAT guidelines for depression, there are patients that have Major Depressive Disorder and anxiety features, and often Mirtazapine is given to these individuals; but it’s not always or commonly used as a first-line option to treat somebody with for example, just a Generalized Anxiety Disorder

o Trazodone – is always listed; and again there is a bit of evidence; but at this point in time, mostly used for sedation or for sleep, and very limited use clinically speaking for anxiety disorders

o Agomelatine (not available in Canada yet) – is in this category of drugs; it actually does have promising data for the treatment of anxiety disorders, but again at this point in time, it’s not available in Canada

5HT 1A receptor agonists:o Buspirone = 5HT1A receptor agonist that’s a bit unique and it’s used only for anxiety disorders; but

its efficacy unfortunately is marginal at best

Efficacy of SSRIs across the Spectrum of Depression & Anxiety Disorders You can see that many of the different antidepressants have efficacy data to treat depression as well as

many of the different types of anxiety disorders that we’ve talked about Fluvoxamine also has data for many things, but in Canada, we rarely use it; so it’s not a go to drug for us

because of the significant number of drug interactions And here you’ll notice that Fluoxetine has a star beside it; but again, much of this data for Fluoxetine in GAD

is actually in adolescents – and we know that it is the go to drug for adolescent depression; it’s pretty much one of the only drugs that has positive evidence for adolescent depression; and so that’s really important

Efficacy of SNRIs across the Spectrum of Depression & Anxiety Disorders Here you can see where there’s data for SNRIs, specifically Venlafaxine and Duloxetine but again as you can see, Venlafaxine has efficacy data for essentially all of the disorders that are listed

there, but Duloxetine doesn’t; but again, that doesn’t mean that the Duloxetine doesn’t work, it just means it hasn’t been studied; i.e. it’s a newer drug, the company was looking for a different niche in marketing; so a lot of data that we have on Duloxetine other than some of the early depression studies is in neuropathic pain - fibromyalgia, a variety of pain disorders – that’s where the company did a lot of their marketing; so this doesn’t mean that Duloxetine won’t work for anxiety – certainly there is evidence in Generalized Anxiety Disorder, but it does mean that at this point in time we don’t have a wealth of evidence specific to anxiety

Efficacy of Tricyclics across the Spectrum of Depression & Anxiety Disorders Here you can see some Tricyclics – the three common Tricyclic antidepressants i.e. Imipramine,

Clomipramine, and Amitriptyline; and again here you can see that they all have evidence in depression; but their efficacy and the ability of studies in anxiety is much more sparse

and again, Clomipramine has the strongest data of any of the drugs for sure for OCD – it’s a great drug for that

However, you can see Amitriptyline – probably not that good for anything outside of PTSD, and has a wealth of side effects, so certainly not something we go to unless we’re trying to induce sleep

Do SSRIs Work the Same Way in Anxiety Disorders as in Depression? When you look at the guidelines, the first line treatment for anxiety disorders across the board is

antidepressants, and certainly SSRIs would be at the top of that list And so do SSRIs actually work the same way in anxiety disorders mechanistically as they do in depression?

Or is it different? Yes i.e. their mechanism is that they do prevent the reuptake of serotonin – but probably at different brain

sites; so patients that are depressed, the SSRI probably exerts its effect in one part of the brain that’s not necessarily the same as individual’s that have anxiety and/or different subtypes of anxiety

Different regions may have different sensitivities to antidepressant actions 2 main components to SSRI action:

o Increase 5HT = serotonin transmissiono Desensitize overactive receptorso ^ we do know that that’s true in both depression and anxiety

Role of 5HT 1A

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what about Buspirone? Because it’s the only drug that stands out as having a totally different mechanism i.e. it’s a 5HT1A agonist

5HT 1A KO mice are anxious – so there seems to be some role of 5HT1A in the regulation of anxiety because these knockout mice have symptoms consistent with anxiety

5HT 1A receptor binding availability in brain correlates inversely with anxiety in normal subjects including humans; so clearly there is a role for this serotonin subtype in patients with anxiety

Buspirone:o Primary action is on 5HT 1A, and so when we discovered that this subtype of serotonin receptors

was involved in anxiety, the makers of Buspirone had hoped that this drug would be really promisingo Acts as an agonist pre-synpaticallyo Acts as partial agonist post-synapticallyo No affinity for benzodiazepine complexo So the goal was that this drug would actually treat anxiety, but without many of the issues

associated with binding the GABA-A receptor and/or the benzo complexeso However to date, the Efficacy data is weak for benefit in anxiety disorders; this drug is NOT

commonly prescribed first-line; sometimes we use it as augmentation and/or in a patient who has not responded to other first-line options; but although we know that there is a role for this particular subtype of receptor, this particular drug does not have strong strong data to allow this theory to go further; and that’s why it is still the only drug in its class because clearly it didn’t work well enough and we have not developed more; so this is still being investigated i.e. what exactly is the role

Is there a ‘Middle Way’?

So, is there some sort of middle way between the benzodiazepines and the SSRIs? Again, because you get SSRIs working but it takes longer, however you get your benzos working up front but then you’ve got problems with actual Withdrawal and getting patients off of them, so what do you do?

Well that has been how Pregabalin has been niched as the in-between agent; it actually is an anticonvulsant that does have pretty good data i.e. positive trials that are pretty decent quality to show that it does help for sure in Generalized Anxiety Disorder

The Role of Pregabalin Anticonvulsant effective in GAD Mechanism of action not fully characterized currently Binds to a specific subunit of voltage-dependent calcium channels; reduces calcium influx in nerve terminals Also decreases release of noradrenalin, glutamate, and substance P – we’re not clearly sure what that does Efficacy data in anxiety is building; included now in UK guidelines for the treatment of anxiety, specifically

GAD and again, there is a big push for more studies and for it to be approved and to be used for this in

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Canada; they also talk about it in DiPiro, so if you do read the chapter in the book they do make mention of the up and coming role for Pregabalin

Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology These guidelines are pretty good from the British Association of Psychopharmacology; and you can see that

Pregabalin is mentioned there

Take Home Points So we’re going to go into the case… Anxiety disorders are common, common, common! There are significant comorbid psychiatric conditions associated with anxiety disorders! Screening questions can help identify or rule out diagnoses There are many effective treatments including psychotherapy and psychopharmacology There is a huge amount of suffering associated with anxiety disorders that we often don’t think about! But

this can be one of the most troubling disorders for patients

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