Psychobiology of Anxiety and Anxiety Disorders

Symposium on Anxiety Disorders

Psychobiology of Anxiety and Anxiety Disorders

john M. Rainey, Jr., M.D., Ph.D.,* and Randolph M. Nesse, M.D. t

The first biologic model of fear and rage based on experimental evidence was described by Cannon and his colleagues in a series of investigations carried out between 1910 and 1935. 6 They used a procedure in which young, physically healthy cats were held on their backs and confronted by a barking dog. Under these conditions, the cats bared their teeth, laid back their ears, hissed, and made attempts to escape and to claw the dogs .. Cannon was able to show that the tachycardia, pupillary dilatation, piloerection, and decreased visceral activity that accompanied these intense behavioral displays were associated with the release of epinephrine from the adrenals and could be produced by the intravenous administration of epinephrine. These findings led to investigations of anxiety states associated with intramuscular injections of epinephrine in man. 75 The earliest studies were prompted by the close resemblance of the symptoms of anxiety attacks to hyperthyroidism. Then, in 1935, Lindemann and Finesinger began to systematically study the effects of epinephrine on neurotic patients. 45-.n They found that many patients with histories of anxiety attacks experienced anxiety attacks after injections of epinephrine, whereas control subjects did not. Since that time, there have been many other clinical studies of the relationships between stress, catecholamine turnover and release, and neuroendocrine function. These studies have generally used poorly defined clinical populations and assumed either that pathologic anxiety is related to abnormally increased adrenergic or noradrenergic activity or to a neuroen docrine defect in stress adaptation as proposed by Selye and his colleagues in their work on the general adaptation syndrome.6s While the adrenergic and neuroendocrine models have continued to *Assistant Professor and Director, Research Administration; Co- Director, Anxiety Disorders Research Program, Wayne State University and Lafayette Clinic, Detroit, Michigan tAssistant Professor and Director of Residency Education, Department of Psychiatry, Univer sity of Michigan, Ann Arbor, Michigan

Psychiatric Clinics of North America-Vol.

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No. 1, Ylarch 1985

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occupy the attention of investigators interested in anxiety, there have been major changes in the methods and assumptions used to investigate these relationships. Among them are the operational definitions of anxiety disor ders provided by D SM-111, 1 evidence that at least some anxiety disorders may be genetically transmitted, 14 the pharmacologic control of panic attacks using antidepressants, 39 advances in receptor and endocrine physiology and biochemistry,30 the development of a noradrenergic model of anxiety based on the electrical stimulation of specific brain areas, "4· 6·5 and new techniques for the chemical induction of anxiety states that resemble spontaneously occurring panic attacks in man. Recent developments in the diagnosis, genetics, and treatment of anxiety disorders are described in other articles in this volume. In this article, we will review the recent neuroendocrine and biochemical findings in anxiety, the evidence for a noradrenergic model of anxiety, and the precipitation of anxiety states by psychological, pharmacologic, and physi ologic methods. Because only brief reviews of these subjects are provided here, the references have been selected to provide more comprehensive discussions of each topic.

NEUROENDOCRINE STUDIES Brain Receptors There have been only a few studies of receptor changes in anxious patients. It is not feasible to perform direct assays on brain receptors in patients. Therefore, assays of receptors on blood platelets have been performed in the hope they may provide an indirect indicator of receptor status in the brain. Platelet alpha-2 receptors were found to be decreased in patients with panic attacks compared with normal and depressed control subjects when yohimbine was the assay ligand, but depressed patients did not differ from normal controls. When clonidine was the ligand, patients with panic disorder did not differ from controls, but in depressed patienfs, alpha-2 receptors were increased in comparison with control subjects.5 Patients with panic disorder and control subjects also have similar blood pressure responses to a cold-pressor test. 29 However, beta-receptor respon siveness is decreased in patients with panic attacks when assessed by heart rate responses to graded doses of intravenously administered isoproterenoP3 or by isoproterenol-stimulated lymphocyte cyclic AMP. 44 This suggests that beta-receptors are down-regulated in patients with panic disorder, which may be a result of elevated plasma and urine catecholamine levels. 53 Patients with panic disorder have minimal responses to naloxone that are identical to the responses of control subjects, suggesting both groups have normal opiate receptor function. 32 There have been no direct assays of benzodiaze pine (BZ) receptors in anxious patients. 59 However, mice selectively bred for "emotionality" have fewer numbers of brain BZ receptors than normal mice.66

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Autonomic and Hormonal Function The autonomic and hormonal changes that occur during anxiety states are the subject of an extensive literature. In a variety of species, stressors induce increases in sympathetic tone and plasma catecholamines, cortisol, and growth hormone.48 Changes in plasma prolactin, thyroxine, testoste rone, and insulin have also been reported. In patients with panic attacks, urinary MHPG levels are elevated after attacks are precipitated by exposure to situations that previously resulted in panic attacks. 40 Plasma and urinary levels of epinephrine and norepinephrine are elevated in resting patients with panic disorder, 53 whereas patients with generalized anxiety disorder have normal or increased plasma epinephrine and norepinephine levels. 49 Subjects with Type A behavior show increased plasma epinephrine, norepinephrine, and cortisol responses to mental work as compared with those with Type B behavior. 76 In depressed patients, elevated plasma catecholamine levels are highly correlated wih anxiety level (r 0.691, p-w which increases the release of norepinephrine and the ethyl ester of beta-carboline-3-carboxylic acid (BCEE)3 6 can also induce severe anxiety in primates. The findings with yohimbine suggest there may be a presynaptic abnormality involving the control of norepinephrine release. Both these agents have been used to induce anxiety states in man and are discussed in the following section.

PROVOCATION OF ANXIETY STATES Much more rigorous experimental procedures are possible when the subjective experience and physiologic changes occurring during anxiety states can be studied under laboratory conditions. The use of provocative tests to study anxiety states in the laboratory is a particularly useful strategy for this purpose. The methods currently being used to induce anxiety states in man are ( 1) in vivo exposure to a phobic stimulus and (2) infusions of sodium lactate, isoproterenol, and beta carbolines, orally administered caffeine and yohimbine, inhalation of COb and hyperventilation. In addi tion, the effects of sodium lactate and isoproterenol have been studied before and after treatment with imipramine, which effectively supressses spontaneously occurring panic attacks and decreases the effects of lactate and isoproterenol. 4·1· m

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There is no unifying hypothesis that explains why this second group of procedures is able to produce anxiety states that resemble spontaneously occurring panic attacks. However, some investigators have proposed that the locus ceruleus is involved. Others have proposed that medullary chemoceptors may be responsible for the symptoms, regardles of the initial stimulus. 7 · 6 4· &o In Vivo Exposure In vivo exposure treatment for simple phobia induces severe anxiety that permits the study of endocrine responses under carefully controlled conditions. Plasma levels of norepinephrine, epinephrine, insulin, cortisol, and growth hormone apparently increase during the intense phobic anxiety states that occur using this method, whereas there are no detectable changes in thyroid stimulating hormone, prolactin, glucagon, or pancreatic polypeptide. t.s, 17-19· 54-56 The patterns of hormone response during severe phobic anxiety vary considerably between and within subjects in these studies. Cortisol and growth hormone levels are particularly erratic. Al though the method shows that there are endocrinologic effects of psycho logical anxiety, there are intensely anxious subjects who have essentially normal hormone levels. 56 Sodium Lactate Pitts and McClure were the first investigators to report that sodium lactate induces anxiety states resembling spontaneously occurring panic attacks in patients with anxiety neurosis but not in nonpsychiatric control subjects. 60 Their results have been replicated by seven laborato ries.2· 3• 23· 27 · 28· 38· 41· 43· 61-'33, 70 In these studies, approximately 70 to 90 per cent of patients with panic disorder and 0 to 30 per cent of control subjects experienced anxiety states meeting operational criteria for panic attacks. · It is not clear why sodium lactate produces panic attacks. There have been suggestions that lactate complexes calcium, causes an increase in epinephrine levels, produces a metabolic alkalosis, increases locus ceruleus firing, and affects the redox state of cells controlling respiration on the ventral medullary surface. 7· 29· 6 1 There is at least fragmentary evidence and a logical rationale for each of these possibilities. In fact, any or all of these mechanisms may be involved in the pathogenesis of sodium lactate panic attacks. Isoproterenol There have been three open studies of the effects of isoproterenol on anxious patients.4• 22· 24 In the first study, nine of 14 patients with labile hypertension became hysterical during isoproterenol infusions of 1 to 3 J-Lg per minute but quickly responded to intravenous injections of 10 mg of propranolol. The second study involved five patients with spontaneous anxiety attacks who had anxiety attacks during infusions of 0. 5 to 2.0 J-Lg per minute of isoproterenol and responded to 4 mg of intravenously administered doses of propranolol. In the third study, 16 patients with mitral valve prolapse (MVP) syndrome developed symptoms of anxiety,

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chest pain, and breathlessness during 6-minute infusions of 2 J-Lg per minute of isoproterenol. Two of these patients reportedly experienced panic attacks. There has been one controlled study of the effects of isosproterenol on patients with panic disorders.61-63 In that study, 39 patients with panic disorder and 18 nonpsychiatric control subjects were administered infusions of 1 J-Lg per minute of isoproterenol for a maximum of 20 minutes. Twenty nine out of 39 patients and one out of 18 control subjects had panic attacks during the infusions of isoproterenol, whereas ten out of 39 patients and 0 out of 18 controls had panic attacks during infusions of 5 per cent glucose. These results suggest that a beta-adrenergic agonist such as isoprote renol can produce panic attacks in patients with panic disorder. However, stimulation of beta-adrenergic receptors is not necessary for chemically induced panic attacks to occur, as sodium lactate is not a beta-adrenergic agonist, and propranolol does not prevent sodium lactate-induced panic attacks.27 On the other hand, sodium lactate reverses beta-adrenergic blockade at doses 50 to 100 times less than those required to produce panic attacks, suggesting that sodium lactate may influence beta-adrenergic re ceptor responsiveness despite its lack of intrinsic beta-adrenergic activity. 6'3 There is evidence that anxious patients, particularly those with MVP syndrome or the characteristics of "hyperdynamic beta-adrenergic circula tory state," develop higher heart rates than control subjects in response to continuous infusions of isoproterenol. 4• 24 This suggests that there is in creased beta-adrenergic responsiveness to isoproterenol in these patients. At the same time, there is a decreased heart rate response to pulses of intravenously administered isoproterenol in patients with panic disorder compared with control subjects. 5'3 There is also evidence that isoproterenol induced lymphocyte cyclic AMP production is lower in severely anxious patients than control subjects, 44 suggesting that anxious patients have diminished beta-adrenergic responsiveness. However, there is an agonist-induced 80 to 90 per cent increase in lymphocyte beta-adrenergic receptor number during the first 30 to 60 minutes of continuous infusions of isoproterenol in normal human subjects. 72 The increase in beta-adrenergic receptor number following a 30 to 60 minute infusion of isoproterenol is paralleled by an increased heart rate response to pulses of isoproterenol. If the infusions are continued for 3 to 4 hours, the number of beta-adrenergic receptors decreases to below baseline levels. This biphasic response to beta-adrenergic stimulation may explain why patients with panic disorder, who have increased circulating levels of catecholamines, exhibit decreased responses to brief pulses of isoproterenol and do not develop panic attacks. At the same time, contin uous infusions of isoproterenol lasting between 5 and 20 minutes may produce panic attacks in these patients by causing a dramatic increase in the number and functional effectiveness of beta-adrenergic receptors. There are several reasons why this may not be so. The decreased response to beta-adrenergic stimulation in patients with panic disorder at rest suggests there would have to be a much greater increase in receptor number in the patients than the controls for this mechanism to explain the results. The increase in receptor number would have to be accompanied by a 10-fold increase in receptor effectiveness as well. It also seems unlikely


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that sodium lactate produces panic attacks in this fashion; rather, both isoproterenol and lactate-induced attacks may share a common mechanism that does not involve abnormal beta-adrenergic receptor synthesis, activa tion, or activity. Beta-Carbolines Beta-carbolines, which bind to BZ receptors, can apparently produce panic attacks in man. 20 Despite the limited amount of human pharmacologic data and the failure to identifY a naturally occurring beta-carboline that could be responsible for spontaneously occurring anxiety states, this model of anxiety is an important one because of the effects of the beta-carbolines on BZ receptors, the efficacy of BZs in the treatment of anxiety, and the ability of beta-carbolines to produce emotional states resembling fear in primates. 36· '57· 59 Yohimbine Unlike sodium lactate and isoproterenol, 0. 5 mg per kg of intravenously administered yohimbine delivered over 5 minutes results in anxiety symp toms in most subjects including nonpsychiatric controls, schizophrenics, and other psychiatric patients. 25• .>:l-3·5 However, 20 mg of orally administered yohimbine produces an increase in anxiety ratings in most patients with panic disorder but not in control subjects, suggesting that larger doses of lactate and isoproterenol might also produce panic attacks in controls and in patients with other psychiatric disorders.H-lo Yohimbine is 'm alpha-2-adrenergic antagonist that prevents inhibition of norepinephrine release. An increased release of norepinephrine following the administration of yohimbine may be responsible for the anxiety states produced by yohimbine and the associated increases in plasma MHPG that have been reported in anxious patients. Alpha-2 receptors are located presynaptically, whereas isoproterenol is a postsynaptic beta-adrenergic agonist. Yohimbine may exert its effects by increasing the release of norepinephrine, which then acts as an alpha- or beta-adrenergic agonist. However, there have been no attempts to block the anxiogenic effects of yohimbine using alpha- or beta-adrenergic blocking agents such as phen tolamine or propranolol. Propranolol administered intravenously in doses of 5 mg per kg does prevent the fearful behaviors produced by electrical stimulation of the locus ceruleus64 and reduces the effects of beta-carboline induced increases in heart rate in monkeys.36 Yohimbine also alters brain serotonin levels and may have anxiogenic actions that are unrelated to the noradrenergic system. 25 Caffeine Caffeine has been studied as a model for generalized anxiety disorder.74 However, more than 500 mg of oral caffeine results in panic attacks in both patients with panic disorder and control subjects. It is apparent that caffeine induced anxiety states can be quite severe, and that caffeine can induce panic attacks as well as generalized anxiety states. Clinically, this implies that decreases in dietary cafleine intake may reduce the incidence of panic attacks and generalized anxiety symptoms in some patients. Caffeine binds

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to both BZ and adenosine receptors, and the effects of caffeine on these receptors may be responsible for the anxiogenic effects of caffeine. 36· 7� Inhalation of C02 Intolerable hyperpnea associated with inhalation of C02 was first described in World War I soldiers complaining of irritable heart or the effort syndrome, predecessor terms for anxiety neurosis, panic disorder, and MVP syndrome. 21 Cohen and White used a rebreathing technique to increase C02 levels and found that approximately 80 per cent of patients with anxiety neurosis developed anxiety attacks during the procedure. 11 More recently, Gorman and his associates have used 5 per cent C02 to induce panic attacks in lactate-responsive patients with panic disorder. 28 The mechanism for C0 2-induced panic attacks is not known. Because C02 produces an acidosis and hyperventilation and sodium lactate produce an alkalosis, it is difficult to explain these findings on the basis of similar effects on acid-base balance. C02 does increase locus ceruleus firing and affects the ventral medullary chemoceptors, which may be related to its anxiogenic effects. 7· 28 Hyperventilation Hyperventilation can apparently produce panic attacks in agoraphobic patients. 26· 28 It is curious that procedures resulting in respiratory alkalosis (hyperventilation) and acidosis (inhalation of C0 2) can both produce panic attacks. In one of these studies, C02 was more effective than hyperventilation in producing panic attacks. 28 This may have been because of differences in the degree of hyperventilation, as subjects in the first study experienced a much higher proportion of panic attacks when the level of alveolar carbon dioxide achieved during hyperventilation was less than 1/2 of the resting value for at least 1.5 minutes. Again, the mechanism by which hyperven tilation produces panic attacks is not known, but hyperventilation results in a respiratory alkalosis and may have effects on ventral medullary chemoceptors and on locus ceruleus firing.

SUMMARY New techniques for studying receptor pharmacology, neurotransmitter activity, and neuroendocrine function in affective illness have made it possible to carry out sophisticated neurochemical and neuropharmacologic investigations of the anxiety disorders. Some important reasons for pursuing these strategies have been the high frequency of depression in anxious patients, the effectiveness of antidepressants in the treatment of panic disorder, and the availability of probes for studying the physiologic changes that occur during anxiety states in human subjects. In addition, the ability reliably to induce anxiety states in man has made it possible to study at least some clinical forms of anxiety under laboratory conditions. Although


14 1

animal models for simple phobia have been developed, there are currently no adequate animal models of panic disorder in man. If valid, reliable animal models. for panic disorder and other human anxiety disorders can also be identified, then a much better understanding of the nature and causes of anxiety and more effective diagnosis and treatment of clinically important anxiety disorders may be possible.

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Anxiety Disorders Research Program Wayne State University and Lafayette Clinic Detroit, Michigan 48207