Lecture 7 Anxiety Disorders: Etiology Biological Factors Lecture Outline I. Introduction II. Biological Factors A. Neurobiology 1. Benzodiazepine 2. Other neurotransmitters B. Genetics C. Preparedness D. Physiology 1. Mitral Valve Prolapse 2. Hyperventilation III.Conclusions ------------------------------------------- I. Introduction Today we continue our discussion of Anxiety Disorder etiology with an examination of the role of biological factors: neurobiology, genetics, biological predispositions, and physiology. II. Biological Factors A. Neurobiology A promising area of research has been the study of the brain in an attempt to discover neurological mechanisms that may underlie anxiety responses. This research goes hand in hand with developments in drug treatments for anxiety: If a drug can be found that inhibits anxiety, and if it can be determined how that drug works in the brain, then we've learned something about the neurobiology of anxiety. Similarly, work with brain damaged individuals sheds light on this neurobiology: We can see how the damage effects the person's behavior, and thus learn what that part of the brain does in a normal individual. 1. Benzodiazepine: A major class of antianxiety drugs (eg: librium, xanax). Although its antianxiety effects have been known since the 60's, it's only recently that benzodiazepines have been vigorously investigated (Agras, 1985). These investigations were largely spurred on by the discovery of specific receptor sites in the brain that are set up to react to benzodiazepines.
Before we continue, let's review some of the basics of neurobiology and the functioning of the brain (see Grebb, Reus & Freimer, 1988 for much more detail). The brain is made up of billions of neurons (or nerve cells). These cells bring information to the brain, store memories, process information, and send out directions for responses. This information is carried as electrical impulses along each neuron (see Handout 7-1). This impulse moves down the axon, to the nerve terminals (terminal but- tons), where it stimulates the release of chemical sub- stances called neurotransmitters (of which there may be over 200! [Snyder, 1980]). These chemicals flow out into the space existing between every neuron - the synaptic cleft - and activate the nearby neurons "telling" them to fire an electrical impulse. The manner in which these chemicals do their job is unique: Like a key into a lock, only a neurotransmitter with the proper molecular shape will fit into the receptor sites of the adjacent neuron. Each neurotransmitter must seek out the receptor sites specifically attuned to it. Once found, the chemical will stimulate an electrical impulse in this adjacent neuron, and the message continues on. Thus, information flows through the nervous system as electrical impulse, transformed to a chemical, back to an impulse, and so.Specific receptor sites have been found for benzo- diazepines. This had the fascinating implication that there might be naturally occurring substances in the brain with anti-anxiety effects. These chemicals have only recently been discovered (Greist & Jefferson, 1988). Such substances may have important implications for future developments in anxiety treatment techniques. How benzodiazepines work: The benzodiazepines cause the secretion of a neurotransmitter called Gamma Aminobutyric Acid (GABA) which inhibits anxiety responses (Agras, 1985), especially those associated with Generalized Anxiety (Barlow, 1988). Research indicates that the region of the brain known as the septo-hippocampal region (a very old part of the brain) receives the messages from the benzodiazepine sites (Agras, 1985). We thus know what part of the brain is responsible (at least in part) for anxiety responses. This finding is supported by experiments where this region of the brain is directly stimulated or damaged. It appears that oversensitivity of this region will result in anxiety responses and symptoms. 2. Other Neurotransmitters have also been found to play an important role in anxiety, especially noradrenalin and serotonin. These chemicals increase when a person is under stress and are especially associated with panic (Barlow, 1988). Like the benzodiazepines, they seem to effect the older part of the brain. B. Genetics Genetic studies suggest that certain people inherit autonomic nervous system traits that make them vulnerable to anxiety (eg: overly responsive, reactive, strong alarm tendencies, overly emotional) (eg: Eysenck, 1967; McGuffin & Reich, 1984; Rose & Chesney, 1986). It is possibly because of this inherited vulnerability that even minor events trigger anxiety. In other words, the person is predisposed to anxiety. But such a predisposition won't be realized without there also being a sufficient amount of stress to activate it (Selye, 1976): Environmental conditions + Inherited vulnerable nervous (stress) system = ANXIETY This should look familiar, it is the diathesis stress model we discussed in the third lecture Despite the fact that some genetic factor seems to be present (Carey & Gottesman, 1981; Barlow, 1988, for reviews), it remains to be seen to what degree and in what specific manner genetics plays a role. It's much more complex than simply passing on an "anxiety gene". C. Preparedness (Barlow, 1988; McNally, 1987; Mineka, 1985; Ohman, 1986; Ohman, Dimberg & Ost, 1985; Ohman, Erixon & Lofburg, 1975; Seligman & Hager, 1972): There is some evidence that what we learn may be controlled in part by our inherited biology: We seem to be "prepared" to associate certain stimuli with aversive events/stimuli. That is, it is easier to learn to be afraid of a snake than a flower. This "preparedness" seems to be "hard-wired" into us - an evolutionarily selected predisposition to learn certain fears. A predisposition doesn't mean we will necessarily develop the fear, only that if the conditions are right we are likely to do so. Research by Ohman: Shock (US) associated with two classes of CS: (i) snakes, spiders, (ii) flowers, geometric shapes. The association was made much quicker with (i), often with a single pairing. In addition, the CR to (i) was highly resistent to extinction, just like actual phobias. If guns (and other modern-day threats) were substituted for the snakes and spiders, the effect was lost. And if a nonaversive stimulus replaced the shock, spiders and snakes did not show preparedness. Looking at all the research in this area, this resistance to extinction most strongly suggests biological preparedness (McNally, 1987). The first finding, that certain associations are made more easily, doesn't have quite the same level of support. Nevertheless, this all suggests that at some level we may be innately set up to make certain associations that (at one time) were evolutionarily advantageous (eg: fear of snakes that might be poisonous). We aren't biologically prepared to be afraid of guns because they're too new in our evolutionary history. And fear of flowers would never have been selected for (no survival advantage). In summary: We may be vulnerable to develop certain fears which once developed are clearly resistent to extinction. D. Physiology In general, very few reliable physiological differences which would help explain the etiology of anxiety disorders have been found between normals and anxiety disorder patients (Barlow, 1988). We will discuss some of the physiological factors that have gained the most attention in recent years and that seem most promising. 1. Mitral Valve Prolapse: Although many people suffering panic attacks fear they have heart disease, this fear is usually unfounded. Nevertheless, the connection has been suspected to be real for some people. A high incidence of the heart disease known as mitral valve prolapse has been reported in some patients (eg: agoraphobics, Kantor, Zitrin & Zeldis, 1980). Mitral valve prolapse is an abnormality in one of the valves separating the chambers of the heart - the mitral valve fails to close properly, interfering with the heart's ability to empty when it contracts (see Handout 7-2). The symptoms of this disorder include chest pain, headaches, breathlessness and dizziness, all very similar to anxiety symptoms. For a number of years it was thought that this could be a major organic cause of Anxiety Disorders. The results of more recent studies bring this into some doubt (eg: Dager, Comess, Saal & Dunner, 1986), where the correlation between mitral valve prolapse and anxiety tends to be weak. Nevertheless, such a heart disorder may account for some anxiety sufferers. For example, Agras (1985) reviewed the research in this area, and concluded that as many as 40% of patients with panic have mitral valve prolapse, whereas only about 10% of people without panic have this heart abnormality. 2. Hyperventilation: i) Introduction: An increasing amount of attention is being placed on the possible role that abnormal respiration plays in the etiology of Anxiety Disorders, especially Panic Disorder (eg: Clark, Salkovskis & Chalkley, 1985; Ley, 1985, 1987). First, we shall begin with some background on respiration: The purpose of respiration is to remove CO2 and take in oxygen. But when hyperventilation or "overbreathing" occurs, the amount of air breathed exceeds the body's demand. The results: a) Too much CO2 is lost, which has two consequences: 1) blood pH level increases (pH is a measure of how acidic a solution is; when pH increases, it means the solution is less acidic - So, in this case the blood is becoming less acidic than it should be). The body is a very fine-tuned mechanism - for the body to make the most efficient use of the oxygen available to it, the pH level of the blood must remain in a very particular range (around 7.2 - 7.6 - although this depends on activity level). But as the pH level increases, the metabolism of the oxygen in the blood is impaired. As a result, less oxygen becomes available to the body. 2) the pressure of the CO2 in the arteries decreases. The finely tuned mechanism is also upset by this increased pressure. For the body to receive the necessary amounts of blood for its various organs, a particular pressure of CO2 must be present in the arteries. When this level drops, the result is an impeded flow of blood to the body. b) The result of all this is that the heart must pump faster and harder to compensate. In addition, CO2 plays an important role in triggering respiration: when a certain amount accumulates in the body, respiration reflexively occurs (hold your breath and you will eventually experience this reflex). But because too much CO2 has been lost through hyperventilation, this reflex is impaired, resulting in shortness of breath or difficulty breathing (dyspnea). What should readily stand out is that increased heart rate, inability to breathe, and many of the other effects of hyperventilation are the same symptoms associated with panic (see Barlow, Vermilyea, Blanchard, Vermilyea, DiNardo, Cerny, 1985). See Handout 7-3. ii) A hyperventilation theory of panic: a) The DSM-III-R lists these somatic complaints as symptoms of Panic Disorder. The definition for "Symptom" is "an observable manifestation of a disorder". That is, if you have disorder X, then you will eventually manifest certain symptoms, or in other words, the symptoms arise because you have the disorder. To say that the somatic complaints as listed in the DSM-III-R are symptoms implies that they are a consequence of anxiety: fear is primary, the symptoms arise from the fear. This is the basis of what has been called the "Fear of Fear hypothesis" (eg: Jacob & Rapport, 1984; Stampler, 1982). This hypothesis states: Panic Disorder is caused by the person fearing the sensations that accompany the fear. The process works this way: There is a sudden onset of anxiety ---> unexplainable somatic sensations ---> fear of sensations (eg: feel like you're going crazy, having a heart attack) ---> fear increases ---> somatic sensations increase...and so on, in a viscous circle, until a panic attack occurs. b) Problem with Fear of Fear Hypothesis: "symptoms" are often experienced prior to the experience of fear (Ley, 1985). That is, the somatic sensations occur first. This seems to indicate that the fear is a consequence to the sensations, not the other way around. To explain this, a Hyperventilation theory of Panic Disorder has been suggested (eg: Ley, 1987): 1) Initiation of panic attacks are caused by the unexpected and unexplainable sensations that accompany hyperventilation. This results in misattributions (danger, death, insanity) which further increases hyperventilation; and so on. 2) Certain people are chronic hyperventilators, through faulty respiratory behavior (caused by, for example, chronic stress, mouth breathing, physical disorder of the nasal passages, drug intoxication). This chronic condition does not mean they are always panicking, but that they are always "ready" to do so. There is a "threshold of tolerance" (Ley, 1987) below which we can tolerate increases in blood pH and decreases in CO2 pressure (the effects of hyper- ventilation) without experiencing anxiety. Chronic hyperventilators are closer to this threshold, so even a mildly arousing event or "false alarm" (Barlow, 1988) can "push them over" the threshold into panic (recall that panic attacks seem to come out of the blue). Handout 7-4 illustrates this. In sum: The tendency to hyperventilate may predispose certain people, or put them at risk, for developing Panic Disorder. iii) Lactate: Although often presented as an alternative explanation, support for the hyperventilation theory comes from "Lactate Models" of Panic Disorder (eg: Carr & Sheehan, 1984; Rainey, Frohman, Freedman, Pohl, Ettedgui & Williams, 1984). a) Early studies (eg: Jones & Mellersh, 1946): It was found that anxiety increases in Anxiety Disorder patients when they exercise. When you exercise, blood lactic acid increases. b) Later studies (eg: Liebowitz, Fyer, Gorma, et al., 1984; Pitts & McClure, 1967): Injections of lactate frequently lead to panic in patients, but not in nonpatients: 50 - 90% patients respond with panic, 0 - 25% nonpatients respond with panic (Ley, 1987). This has lead some researchers to suggest that abnormal blood lactate levels may cause panic in some individuals. c) Lactate and hyperventilation: The hyperventilation theory can incorporate these findings - hyperventilation, among its many other effects, produces lactate (Grosz & Farmer, 1972), as well as makes an individual more susceptible to the anxiety producing effects of lactate (Ley, 1987). iv) The Final Result: Chronic hyperventilators are highly susceptible to anxiety. The anxiety can be triggered by even mild events. The chronic hyperventilator is primed and ready to panic. III. Conclusions The more comprehensive theories of anxiety recognize that the etiology of anxiety is a complex psycho-biological process. These theories (eg: Lang, 1979) combine cognition, biology, predispositions, and learning. It's important to understand that it is very unlikely that the cause(s) of anxiety will be found to be a simple linear (straight line) process (where one thing leads to the next and so on like a one direction chain of events). Rather, to speak of causation we will undoubtedly need to explore complex, interactive, reciprocal processes. Handout 7-1 Diagram of neuron Handout 7-2 A drawing of the heart illustrating its structure, including the location of the mitral valve [To be added] Handout 7-3 Some Symptoms of Hyperventilation* Cardiovascular - palpitations, chest pain Neurological - dizziness, numbness, tingling Respiratory - shortness of breath, dryness of mouth Gastrointestinal - stomach pains, gas Musculoskeletal - muscle pains, cramps, tremors Psychological - anxiety, insomnia, nightmares *(Adapted from Ley, 1987, p. 197) =========================================================== Some DSM-III-R Symptoms of Panic Disorder Palpitations or accelerated heart rate, chest pain Dizziness, numbness, tingling Shortness of breath or smothering sensations Nausea, abdominal distress Trembling or shaking Fear of going crazy, fear of dying Handout 7-4 Death ...............................³0 ³ ³ Coma ............................ ³ . ³ Panic . ³ CO2 . ³ Threshold .................... . ³ . . ³ . . ³ Tolerance . . ³ . . ³40 . . ³ ÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ 7.4 7.8 Blood pH Note: This is a very sensitive process, indeed! The difference between a pH of 7.4 and 7.8 is quite slight. Water has a pH of 7.0, laboratory acids are on the order of 1.0, milk, ammonia, lye ***** [values to be added]