Nerochemical and cognitive aspects of anxiety disorders

0301-0082/89/$0.00+ 0.50 Copyright © 1989PergamonPress plc

Progressin NeurobiologyVol. 32, pp. 391 to 402, 1989 Printed in Great Britain. All rights reserved

NEUROCHEMICAL A N D COGNITIVE ASPECTS OF ANXIETY DISORDERS ANTONY KIDMAN Neurobiology Unit, University of Technology, Sydney, Gore Hill, N.S.W. 2065, Australia

(Recewed 12May 1988)

CONTENTS 1. Introduction 2. Definition of anxiety 2.1. Anxiety states 2.1. I. Phobias 2.1.2. Generalized anxiety disorder (GAD) 2.1.3. Panic disorder 2.2. Anxiety--state versus trait 2.3. Epidemiology of anxiety disorders 2.4. Diagnosis and assessment 3. Anxiety models and theories 3.1. Psychoanalytic model 3.2. Behavioural model 3.3. Humanistic and existential models 3.4. The cognitive behavioural model 3.5. Neurochemical model 4. Treatment 4.1. Drugs 4.1.1. Major tranquilizers 4.1.1.1. Undesirable effects 4.1.2. Minor tranquilizers 4.1.2.1. Benzodiazepines 4.1.2.2. Undesirable effects 4.1.3. Barbiturates 4.1.3. I. Undesirable effects 4.1.4. Beta-blockers 4.1.4.1. Undesirable effects 4.1.5. Antidepressants 4.1.6. Alcohol, nicotine and other drugs 4.2. Psychotherapy 4.2.1. Psychoanalytic therapy 4.2.1.1. The opening phase 4.2.1.2. Development of transference 4.2.1.3. Working through 4.2.1.4. The resolution of the transference 4.2.2. Person-centred therapy 4.2.3. Behaviour therapy 4.2.3.1. Social anxiety 4.2.3.2. Systematic desensitization 4.2.3.3. Flooding 4.2.3.4. Paradoxical intention 4.2.4. Cognitive behaviour therapy 4.2.4.1. Cognitive elements of anxiety 5. Conclusion References

1. I N T R O D U C T I O N As a neurobiologist who became interested in behaviour and undertook training in clinical psychology, I wish to discuss models and treatment of anxiety from a holistic and reductionist perspective. The reductionist or medical model approach attempts to reduce phenomena to smaller and smaller parts

391 392 392 392 392 393 393 393 393 394 394 394 394 395 396 396 396 397 397 397 397 397 397 397 397 397 397 397 397 398 398 398 398 399 399 399 399 399 399 40O 4O0 40O 401 401

(organism ~ tissue ~ cell ~ molecules) and to unify explanations of a range of observations. The holistic approach argues that the whole organism system is greater than the sum of its parts and, in the case of psychology, the behaviour of the organism as a whole must be considered in the light of treatment. The reductionist model has been challenged and the basis of behavioural medicine is that perceptions, attitudes

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and behaviours of the organism influence disease states (Lazarus and Folkman, 1984; Valentine, 1982; Jessor, 1958). This is the interaction between the mind and the body. Anxiety disorders are a good example of this. Anxiety is a state which affects almost all people at some time in their lives. This review is written in an attempt to bring some of the latest cognitive/ behavioural techniques to the attention of neuroscientists; already some have become interested, as shown by the emergence of a new discipline known as psychobiology and an even more specialized sub-discipline, psychoneuroimmunology (Solomon, 1985). Behaviour and biology have attracted workers who have in general pursued separate paths. The time now appears right for studies that integrate both disciplines with a practical therapeutic objective. I hope this article will stimulate neuroscientists to consider joining this growing field.

2. DEFINITION OF ANXIETY Anxiety is a universal, human experience which is characterized by fearful anticipation of a possible unpleasant event. It is important to distinguish between anxiety and fear because they are often used interchangeably. Fear is the assessment of danger; anxiety is the unpleasant feelings and symptoms evoked when fear is stimulated. A person suffering from anxiety experiences an unpleasant emotional state characterized by tension, nervousness, heart palpitations, tremor, nausea, dizziness, inability to think clearly and on some occasions inability to even speak; other symptoms may include backache, headache and diarrhoea. The Diagnostic and Statistical Manual of the American Psychiatric Association (American Psychiatric Association, 1987) has classified anxiety disorders as shown in Table 1. 2.1. ANXIETYSTATES I would like to focus on three categories of anxiety disorders: 2.1.1. Phobias

A phobia is a persistent anxiety reaction that is grossly out of proportion to the stimulus and the reality of the danger. There are a variety of things or activities in the world which produce inordinate and irrational fear in many people--flying, snakes, spiders, mice, water, having to talk with strangers, elevators and crowded spaces. The problem is that some relatively non-harmful object or activity produces these feelings. Even though there is the possibility of a plane crash or of being bitten by a spider, the chance of it happening is so low that the emotional response is totally out of proportion to the risk of being harmed. 2.1.2. Generalized anxiety disorder (GAD) Generalir~l anxiety is chronic and may last for months on end but the elements of anxiety are more

TABLE

1.

DSM-III-R CLASSIFICATION OF DISORDERS*

ANXIETY

Anxiety disorders (or anxiety and phobic neuroses) (235) 300.21

300.01 300.22

300.23 300.29 300.30 309.89 300.02 300.00

Panic disorder (235) with agoraphobia Specify current severity of agoraphobic avoidance Specify current severity of panic attacks without agoraphobia Specify current severity of panic attacks Agoraphobia without history of panic disorder (240) Specify with or without limited symptom attacks Social phobia (241) Specify if generalized type Simple phobia (243) Obsessive compulsive disorder (or obsessive compulsive neurosis) (245) Post-traumatic stress disorder (247) Specify if delayed onset Generalized anxiety disorder (251) Anxiety disorder NOS

* From the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised, p. 7. American Psychiatric Association (1987), Washington D.C. or less continually present. Emotionally the individual feels jittery and tense, vigilant and constantly on edge. Cognitively, the person expects something awful but does not know what. The most common symptom, inability to relax, appears to represent an over mobilization of the nervous system and incorporates anxious feelings and mind racing. The most common symptom of cognitive impairment is difficulty in concentration (86.2%). The high frequency of confusion, mind blurring and inability to control thinking, indicates that cognitive impairment is an important aspect of GAD. The most common symptom referable to the theme of danger is the fear of losing control which occurs in 75.9% of sufferers and thus is an unexpectedly important feature of GAD. The fear of being rejected (72.4%) is almost as common (see Table 2). TABLE 2, FREQUENCY OF COGNITIVE AND BEHAV1OURAL SYMPTOMS IN GENERALIZEDANXIETYDISORDER*

Frequency Symptom (%) Difficulty in concentration 86.2 Fear of losing control 75.9 Fear of being rejected 72.4 Inability to control thinking 72.4 Confusion 69.0 Mind blurred 65.5 Inability to recall important things 55.2 Sentences broken or disconnected 44.8 Blocking in speech 44.8 Fear of being attacked 34.5 Fear of dying 34.5 Hands trembling 31.0 Body swaying 31.0 Body shaking 27.0 Stuttering 24. l * Taken from Beck et al. (1985). Anxiety Disorders and Phobias: A Cognitive Perspective, p. 88.

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2.1.3. Panic disorder

How many of us at some time have been suddenly overcome with intense apprehension? Physically we feel jumpy. Cognitively we expect that something bad is going to happen. Such an attack comes out of nowhere; no specific object or event sets it off and the attack gradually subsides. However some people have frequent severe attacks; these people suffer from panic disorder. Emotionally the individual is overwhelmed with intense apprehension, dread or terror. Physically, symptoms appear--rapid heartbeat, muscle tension, perspiration and trembling. Cognitively the person thinks he may die, go mad or lose control of himself. Such an attack usually lasts for a matter of minutes subsiding rather gradually. What distinguishes a panic attack from a phobic disorder is that a panic attack comes out of nowhere rather than in response to a specific threatening situation. Some individuals who suffer from phobias, particularly agoraphobics (those with fear of crowded places), are subject to panic attacks before their phobic disorder develops and the agoraphobia may in fact begin with a panic attack. There is no definitive data on the frequency of panic attacks although they are quite common. Clinical experience indicates they occur more frequently in women than in men. 2.2. ANXIETY--STATEVERSUSTRAIT Some individuals have acute attacks of anxiety and do not have them again for some time (panic disorder); others seem to feel anxious all of the time (generalized anxiety disorder). Some have suggested there is a State-vs-Trait distinction that makes plain this observation. That is, many individuals at one time or another may feel panic whether or not they understand what it was in the situation that brought it on, they fall into a state of anxiety. But others, those who feel anxious all of the time, may have a predisposition to anxiety. They are always ready to feel anxiety; they are chronically anxious. We say they have a trait of anxiety. Various tests have been designed to determine whether one is in a state of anxiety, whether one has trait for anxiety or if neither measure applies. The most well known is Charles Spielberger's State-Trait Anxiety Inventory (Spielberger et al., 1970). 2.3. EPIDEMIOLOGYOF ANXIETYDISORDERS Weissman (1985) has recently reviewed the epidemiology of anxiety disorders and states that the rates and risks for different anxiety disorders in adults vary. A rough estimate for all anxiety disorders is about 4 to 8 per 100 annual prevalence. A study carried out in 1979 during the national survey of psychotherapeutic drug use (Uhlenhuth et aL, 1983) shows the rates for different diagnostic groupings (see Table 3). The main findings of Weissman's reviews are as follows: (a) Anxiety disorders in adults are common, heterogenous and familial. (b) In the studies available using precise diagnostic techniques, there are some agreements that

TABLE3. ANNUALPREVALENCERATESFROM1979 NATIONAL SURVEYOFPSYCHOTHERAPEUTICDRUOUSE* DSM-III diagnoses derived from symptom checklist

Rates/100 Male

Female

Total

Agoraphobia/panic 0.5 1.8 1.2 Other phobia 1.3 3.1 2.3 Generalized anxiety 4.3 8.0 6.4 *Taken from Weissman (1985). The Epidemiology of Anxiety Disorders, p. 281.

G A D is the most common, and panic disorder the least common of the anxiety disorders; anxiety disorders are most common in women, younger populations (although this varies) and in the less educated (again this varies). (c) There is an increased probability that a person with one anxiety disorder will have another, or will have a major depression during his/her lifetime. (d) Only about a quarter of people with anxiety disorders receive treatment for these problems. However, these persons are high users of health care facilities for reasons other than emotional problems. People with panic disorders have the highest use of psychotropic drugs. (e) Current studies show that first degree relatives of individuals with anxiety disorders have increased rates of anxiety disorder and of depression. 2.4. DIAGNOSISAND ASSESSMENT Diagnosis is essential to a clinician because it succinctly describes what is wrong with the client, it suggests appropriate treatment and it may assist in determining the cause of the condition and scientific investigations. The diagnosis of anxiety states would normally include a clinical interview (Spitzcr and Williams, 1983) together with a self report or observer rated instruments. A group of observer rated instruments is designed primarily to quantify levels of pathology in cliagnosing patients. This group includes the Hamilton anxiety scale (Hamilton, 1959) and the Covi anxiety scale (Lipman, 1982). Self report instruments include the Minnesota Muitiphasic Personality Inventory (MMPI) (Hathaway and McKinley, 1943) and the Spielberger State-Trait Anxiety Index (STAI) (Spielberger et al., 1970). The 550-item MMPI was developed in 1940 and contains nine clinical scales including measures of anxiety. More recent measures such as the Beck Anxiety Inventory and the SCL90 (DeRogatis, 1977) have also proved Very useful. The Diagnostic and Statistical Manual of the American Psychiatric Association, the third edition revised (DSM-III-R), which is used by many clinicians in North America, is not a single classifying statement but rather it consists of multi-dimensional diagnostic guides. All told, there are five dimensions or axes that should be used, not only to classify a disorder but to help plan treatment and predict outcome, this is an advance over former diagnostic systems that we use merely to classify individuals.

A. KIDMAN

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The DSM-III-R provides useful information for the functional diagnosis on the following axes: Axis 1. Clinical syndromes Axis 2. Personality disorders and specific development disorders Axis 3. Physical disorders and conditions Axis 4. Psychosocial stressors Axis 5. Highest level of adaptive functioning during the past year

3. ANXIETY MODELS AND THEORIES 3.1. PSYCHOANALYTICMODEL Sigmund Freud was concerned with anxiety from the beginning to the end of his psychological studies. He proposed that the conflicts between various personality processes regularly give rise to a kind of psychic pain that he termed anxiety. He explained that anxiety emerged because of an accumulation of undischarged excitation (libido) and that this was transformed directly into anxiety (Freud, 1894). Freud reformulated his theory in terms of a structural organization of the mind. Mental functions were grouped according to the role they played in conflict. The three major subdivisions of the psychic apparatus he called the ego, id and the superego. The ego comprises a group of functions that orient the individual toward the external world and mediates between it and the inner world. It acts in effect to satisfy drives with a proper regard for the conscience and the world of reality. The id represents the organization of the sum total of the instinctual pressures on the mind, especially the sexual and aggressive impulses. The id operates to seek pleasure and avoid pain (pleasure principle) without regard for reality. The ego, according to the theory, represents more coherent organization whose task is to avoid unpleasurable activities and pain by opposing or regulating the discharge of instinctual drives in order to conform with the demands of the external world. In addition to the discharge of id impulses, the ego is opposed or regulated by the third component, the superego, which contains the moral values and influences of parental images. In Inhibitions, Symptoms and Anxiety (1926), Freud replaced the earlier notion of anxiety as a product of frustrated sexual libido with a new concept of anxiety as a signal of approaching internal danger. In contrast to anxiety, fear according to Freud is a signal of approaching external danger. Anxiety rather than sexuality now became the most powerful determinant of the neuroses and the importance of the "ego" slowly began to overshadow the earlier emphasis on the unconscious. Anxiety serves as a warning signal, alerting the ego to the danger of overwhelming anxiety or panic that may supervene if a repressed, unconscious wish emerges into consciousness. Once warned the ego may undertake a wide array of defences to protect itself. This new view had far reaching implications for both theory and practice.

3.2. BEHAVIOURALMODEL This model grew out of the conditioning studies carried out by Pavlov (1927) and Watson (1970). Further developments occurred with the work of Skinner (1953) and his radical behaviourism relying on operant conditioning, the fundamental assumption of which is that behaviour is a function of its consequences. Thus we have a stimulus response model (S-R) which proposes that anxiety is a learnt response to a particular stimulus, such as a threat of attack and the anxiety mobilizes the body's defences in order to deal with that threat. However, when the anxiety level is excessive because you enter an elevator or have to talk with a stranger, then this model would suggest that this inappropriate response has been learnt during the past because it was associated with a stimulus which was anxiety provoking. For example, being trapped in an elevator on one occasion and as a result the person has a profound anxiety whenever he enters an elevator. Alternatively the response was reinforced during childhood; a child is told by its parents not to talk to strangers or they will be beaten, injured or kidnapped and as a result the anxiety towards any stranger as an adult has been inappropriately heightened and reinforced. The behavioural model was very appealing to scientists because it specified particular behaviours and treatment procedures based on altering relationships between overt behaviours and their consequences. The model incorporates techniques based on rewards (positive reinforcement), punishment (negative reinforcement), extinction of behaviours, stimulus control and other procedures derived from laboratory research originally with animals. It also allowed scientific analysis of outcome which the psychoanalytic model did not permit readily. The behavioural model sees the cause of anxiety as the learning of maladaptive habits. It aims to discover by laboratory experiment what aspect of the environment produced this learning and it sees successful therapy as learning new and more adaptive ways of behaving. 3.3. HUMANISTICAND EXISTENTIALMODELS The humanistic and existential approaches to abnormality seem less radical because they are centrally concerned with conscious human experiences, experiences with which all of us are familiar. This model rejects the narrow determinism that often characterizes earlier theories. The psychoanalytic notion that early feeding experiences during the oral stage are forever stamped on mature personalities in oral ways is fundamentally abhorrent to humanists and existentialists alike. This model acknowledges that some aspects of human experience are determined by genetic constitution, by age and gender and by the very times in which people live. However there are many situations in which people have control or at least believe they have control. Human beings can imagine, dream, engage in reflective thought, use symbols and create and manipulate meanings. These abilities allow people to plan and choose among alternative courses of action, rather than simply performing rigidly prescribed actions, or

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NEUROCHEMICAL AND COGNITIVEASPECTS OF ANXIETYDISORDERS

suffering the consequences of thoughtless actions. Human experience moreover is characterized by reciprocal determinism (Bandura, 1977), that is we interpret our environment and therefore control our responses to it. We affect the environment quite as much as it affects us. When there are constraints on perceived freedom, there may be psychological reactants, the tendency to react against constraints rather than making free choices. Humanistic psychologists stress that people are naturally good. Given the kinds of psychological conditions that are necessary for psychological development, people will grow and fulfil themselves. In short they will self-actualize. According to Rogers (1961), the self is that aspect of personality that embodies a person's perceptions and values. There are two kinds of values: those that are acquired from experience and those that are introjected or acquired from others. Values that arise from experience are usually labelled by the individual and therefore easily accessible to the individual. They are the kinds of values that contribute to personal growth and self knowledge. Values that arc introjectcd, however, are confusing, for they often require that a person deny his or her own feelings in order to conform to the desires of another. Existentialist psychologists assert that the central human fear and the one from which most psychopathology develops is the fear of dying. Anxiety about death is most prominent in, and best recalled from childhood. Perhaps because children are vulnerable and because their worst imaginings are detached from reality, their fears are stark, vivid and memorable. For them, the idea of death does not involve mere biological process. It is terrifyingly full of awful meanings. Death means being forgotten, being left out. Death means helplessness, aloneness, finiteness. This approach stresses the role of unconditional positive regard, empathy and warmth in enabling people to overcome their defensiveness and to begin to self-actualize. Conscious experience and feelings are stressed and the past is only important in so far as it has implications for the present. Another well known approach that is included in this model is that of the Gestalt technique developed by Fritz Pearls (1970). This approach has little interest in the past except as it impacts on the immediate present. When it does, Gestalt therapists seize upon it, open it up and make it extraordinarily vivid. People are urged to re-experience their emotions as vividly and as violently as is necessary, the objective being to teach people that they can know, control and be responsible for their feelings rather than allow their feelings to control them.

belief system, that is the perceptions and subsequent evaluation of external events which takes place in an individual's central nervous system, is the feature which distinguishes this model from all others. Ellis' formulation which he calls "Rational-Emotive Therapy" places great emphasis on challenging and disputing irrational thoughts and in teaching people to re-evaluate and restructure their perception of the world so that their emotional responses are more appropriate. Beck et al. in their book on anxiety and phobias (Beck et al., 1985), argue that an individual's automatic negative dysfunctional thoughts, which can be triggered by an external event or arise spontaneously, generate inappropriate feelings of anxiety because the thoughts are characterized by erroneous assessment of the danger associated with a particular situation. They are usually due to one or more of the following: (1) Overestimating the chance of a dangerous event, e.g. "the bus in which I am being driven is likely to crash". (2) Overestimating the severity of the feared event, e.g. "if I lose my job I will be finished and I can't see anything else for me". (3) Underestimating coping resources (what you can do to help yourself). (4) Underestimating rescue factors (what other people can do to help you). These perceptions can include bodily sensations such as a quickening heartbeat or a feeling of anxiety in the stomach due to autonomic response so that an anxiety cycle develops where one has anxiety about anxiety: this is shown in Fig. 1. Donald Michenbaum (1977) places great emphasis on inner speech or internal self dialogue and that the cognitions associated with this are crucial to the generation of anxiety, and that people can learn self instructional training which will enable them to reduce the feelings of anxiety. This will be dealt with in a later section. A very important contribution to the cognitive behavioural model was made by Albert Bandura (1977) in his book Social Learning Theory. The

EXTERNAL EVENTS

l

NEGATIVE T H O U G H T S

(A)

(13)

3.4. THE COGNITIVEBEHAVIOURALMODEL This is the most recently developed model as exemplified by the work of Ellis (1962), Michenbaum (1977), Beck et al. (1985) and Clarke (1986). The crux of this model is the primacy of cognition in determining emotions and subsequent behaviour. Albert Ellis has developed his A, B, C model which states that specific events (A) interact with one's belief system (B) and this leads to feelings (C). Importance of the

(UNPLEASANT BODILY SENSATIONS)

FIG. 1. Anxiety cycle. Events cause negative thoughts, or automatic negative thoughts arise spontaneously. This triggers feelings of anxiety and unpleasant bodily sensations. This in turn leads to more negative thoughts and increased feelings of anxiety. Thus an ever-worsening cycle is generated. Alternatively a bodily sensation, quickening heart beat or slight pain in the chest or stomach is misinterpreted by the mind and triggers an escalating cycle of anxiety.

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A. KIDMAN

influence of environmental events on behaviour is largely determined by cognitive processes which govern what environmental influences are attended to, how they are perceived and how the individual interprets them. Bandura (1977) put it as follows; "Personal and environmental factors do not function as independent determinants, rather they determine each other. Nor can persons be considered independent of their behaviour. It is largely through their actions that people produce the environmental conditions that affect their behaviour in a reciprocal fashion. The experiences generated by behaviour also partly determine what individuals think, expect and can do; which in turn affects their subsequent behaviour." Cognitive factors and anxiety disorders have been reviewed recently in a special issue of Cognitive Therapy and Research (Ingram and Kendall, 1987). 3.5. NEUROCHEMICALMODEL Proponents of this model argue that some abnormality in the nervous system produces the feelings and symptoms associated with the anxiety state and that the abnormality should be investigated, identified and treated. Support for this model comes from the surgical lesion work in the brains of animals by Gray (1982) and the known anti-anxiety effects of certain drugs which act on the central nervous system (CNS). Animals that have been subjected to punishment, non reward or abnormal stimuli react with increased arousal, attention and behavioural inhibition and this has been equated to anxiety in humans. Anti-anxiety drugs that are effective for humans, such as benzodiazepines and barbiturates, produce behavioural changes in animals such that inhibition, arousal and attention are modified, and it was concluded that these drugs were acting on that part of the CNS that was responsible for these behaviours. Gray proposed that this particular system was located in the septo-hippocampal region of the brain, because when he lesioned this part of the brain in a variety of animals ranging from goldfish to monkeys, he replicated the behavioural change produced by the anti-anxiety drugs. On the bases of these and other experiments Gray suggests that the critical action of anti-anxiety drugs consists of a reduction in the flow of noradrenergic and serotonergic impulses to the septo-hippocampal system under conditions of stress. This hypothesis is not in conflict with the biochemical and neurophysiological evidence indicating that these drugs enhance GABA-ergic transmission. Such enhancement might inhibit the firing of cells in the locus coeruleus and/or the raphe nuclei both of which probably receive GABA-ergic afferents. Important work by Costa (1985) suggests the function of some GABA-ergic synapses is related to an endogenous mechanism that regulates anxiety. Reduction of GABA-ergic function facilitates anxiety. A range of behavioural states from tension and panic to relaxation and calm can be brought about by various chemicals acting as ligands of benzodiazepine recognition sites. Whether or not this recognition site for benzodiazepines located on the GABA receptors has a physiological rote is still controversial. Costa has

shown that a brain peptide, diazepam binding inhibitor (DBI), can displace various ligands from the benzodiazepine recognition site and can cause anxiety and conflict in rats. While the work with the benzodiazepines seems to generate a useful model, work with the barbiturates which produce almost the same anti-anxiety effect in man and their interaction with catecholaminergic neurons and receptors is much more confusing (Gershon and Eison, 1987). The role of lactate in inducing panic attacks was first reported by Pitts and McClure (1967). They stated that spontaneous episodes of panic can be precipitated by the infusion of sodium lactate in patients prone to such attacks. They postulated that anxiety symptoms may have a common biochemical mechanism involving the binding and thus decreased availability of ionized calcium at the surface of excitable membranes by excess lactate. This hypothesis has been challenged by a number of people, including Grosz and Farmer (1972) and clearly further investigation is warranted.

4. TREATMENT Anxiety states, as noted earlier in the epidemiological section, are common. Yet only 25% of people get treatment (Weissman, 1985). The most common form of treatment, as in the case of depression which I noted earlier, is medication (Kidman, 1985). The reason for this is the widespread availability of information to general practitioners from drug companies about the efficacy of their anti-anxiety drugs and the subsidies received from the Government by patients for these preparations. It is also time saving to treat people suffering from anxiety conditions with medication and it can produce dramatic results for acute conditions. However, if the underlying causes of anxiety lie in a person's thinking processes then that is where the treatment needs to ultimately focus. 4.1. DRUGS Drugs that are used to treat anxiety encompass a wide range of compounds. I have selected a number of groups that include the most frequently used anti-anxiety medications. The groups are: (1) (2) (3) (4) (5)

Major tranquilizers Minor tranquilizers Barbiturates Beta-blockers Antidepressants.

There is a continuous search for the ideal anxiolytic, one that should selectively decrease anxiety without causing sedation or other undesirable physical or mental effects (Gershon and Eison, 1987). Just as certain chemicals seem to be able to decrease anxiety, others appear to be able to induce it. The compound ~.carboline-3-carboxylic acid ethyl ester (~-CCE) has been shown to induce a striking behavioural and physiological syndrome suggestive of anxiety when administered intravenously to primates. These effects can be attenuated in primates by pretreatrnent with diazepam (Ninan et al., 1982).

NEUROCHEMICALAND COGNITIVEASPECTSOF ANXIETYDISORDERS

4.1.1. Major tranquilizers This group includes the phenothiazines, such as chlorpromazine (Largactil), thioridazine (Melleril) and butyrophenones such as haloperidol (Serenace). What makes this group of drugs different from other anti-anxiety agents is that they are primarily used to treat major psychiatric problems such as schizophrenia and severe emotional disorders. However they may be prescribed for anxiety and tension.

4.1.1.1. Undesirable effects By taking a major tranquilizer one may feel drowsy. However, even after very large doses of major tranquilizers, they are unlikely to produce a deep sleep or coma. They rarely cause addiction, therefore withdrawal symptoms are not common. However, neurological problems such as shaking and uncontrolled movements of certain muscles occur in a small proportion of patients (Baldessarini, 1985, p. 402).

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They can produce unexpected excitement in the elderly. They also effect the enzymes of the liver by increasing the rate at which other drugs are utilized by the liver; they may interfere with other treatments the patient may be having, e.g. a person may be on a drug to reduce blood clotting and if barbiturates are taken for anxiety, this can change the effectiveness of the blood clotting drug and cause serious problems. 4.1.4. Beta-blockers These drugs have aroused interest recently, as they relieve two of the common symptoms of anxiety-palpitations and shakiness. They are mainly used for treating high blood pressure. They are called betablockers because of their neurotransmitter action on the peripheral adrenergic receptors, which results in a slower heart rate and thus a lowered blood pressure. If the main symptoms of the patient's anxiety are rapid heart beat and shakiness, beta-blockers may be helpful. One advantage is the low risk of dependency. Drugs such as propranolol (Inderal) and metoprolol (Betaloc; Lopressor) are in this group.

4.1.2. Minor tranquilizers 4.1.2.1. Benzodiazepines Statistics indicate that one in five Americans has been at some time on a psychotrophic medication, of which two-thirds are in this class. Interestingly, prescriptions for such agents are written largely by general practitioners. The benzodiazepines are the main class of drugs in the minor tranquilizer group. These include: diazepam (Valium), chlordiazepoxide (Librium), nitrazepam (Mogadon) and oxazepam (Serepax). At higher doses these drugs can be used as hypnotics (sleeping pills). At lower doses they act as anti-anxiety agents. They can reduce acute anxiety when given intravenously. 4.1.2.2. Undesirable effects They can induce drowsiness, they relax the muscles which make some people feel weak in the legs and they also affect memory. They have a good margin for safety and overdose problems are rare. However, large doses of these drugs over a long period can lead to staggering movements, slurred speech and double vision (especially in the elderly). Many people who take benzodiazepines for long periods can become dependent upon them (Baldessarini, 1985).

4.1.3. Barbiturates These drugs cause relaxation by day and induce sleep at night. They have the longest history in the treatment of anxiety and date back to the beginning of this century. Drugs in this group include amobarbital (Amytal), sodium amobarbital (Sodium Amytal) and sodium secobarbital (Seconal). However they have been largely replaced by the much safer benzodiazepines.

4.1.3.1. Undesirable effects The use of these drugs has been increasingly restricted because of their toxicity following overdose.

4.1.4.1. Undesirable effects Since they suppress many of the stimulating effects of adrenaline, beta-blockers may cause faintness and wheezing, particularly in asthma sufferers. 4.1.5. Antidepressants A recent development in psychopharmacology has been a number of reports of the efficacy of antidepressants in helping people suffering from agoraphobia with panic attacks, in particular the tricylic antidepressant, imipramine (Tofranil). The dosage required has been reported as much lower than the dosages for treating depression. The anti-anxiety drugs and their actions are listed in Table 4. 4.1.6. Alcohol, nicotine and other drugs There is no doubt that people smoke and drink to relieve anxiety and it is often appropriate to have a glass of beer or wine to ease tension and reduce anxiety. However, the problems of becoming dependent upon alcohol to reduce anxiety are well known. A person who smokes may find that a cigarette is helpful in anxiety-provoking situations. However, because of the health risks associated with this habit, it would be wiser to consider using some other method to reduce anxiety. People use other drugs such as cocaine, heroin and marihuana to help cope with their anxiety. These have many undesirable effects including physical and psychological addiction that are well documented. My personal observations, together with evidence from the literature, suggest that substance abuse including over-eating is frequently initiated and maintained to relieve anxiety (Kidman, 1986). 4.2. PSYCHOTHERAPY

Psychotherapy is the term applied to the therapeutic interaction between two or more people, one

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A. KIDMAN

Class of compound Major tranquilizers

Minor tranquilizers (Benzodiazepines) Barbiturates

Beta-blockers

Tricyclic anti-depressants

TABLE4. ANTbANxmTY DRUGS Generic name Trade name Side effects Drowsiness, neurological Chlorpromazine Largactil problems in small number Thioradazine Melleril of people. Not addictive Haloperidol Serenace Drowsiness, some people Diazepam Valium get addicted over long periods Chlordiazepoxide Librium Nitrazepam Mogadon Drowsiness, overdose can Amobarbital Amytal Sodium amobarbital Sodium amytal be very serious Sodium secobarbital Seconal Slower pulse rate. Propranolol Inderal Can cause wheezing in asthma Metoprolol Lopressor sufferers Dry mouth, constipation, Imipramine Tofranil drowsiness

usually professionally trained. The objective is to help the client, at his request, to change certain undesirable behaviours; primarily by talking to help him overcome the negative feelings that are upsetting him and the subsequent behaviours which interfere with effective living. It does not include drug therapy and usually follows a systematic procedure to help accomplish the agreed goals. Many psychotherapeutic techniques have been developed since Freud's day and I would like to review some of these, including more recent approaches to the treatment of anxiety. For a more comprehensive review of a wider range of psychotherapies, refer to Corsini's books (Corsini, 1981, 1984). The question of outcome in psychotherapeutic treatment has been debated (Eysenck, 1966; Prioleau et al., 1983) but there is substantial evidence supporting the efficacy of many therapeutic techniques (Lambert, 1982; Smith et al., 1980). The mere fact that a client talks over his problems and feelings with someone is often very beneficial in itself. Many come to therapy after drug treatment because they do not like the side effects produced by drugs and that their moods are controlled by external chemical agents.

4.2.1. Psychoanalytic therapy This was developed by Sigrnund Freud, the father of modern psychotherapy, and although there have been many developments, including the outfight rejection of psychoanalysis by many therapists, most behaviour scientists would agree that Freud's work has had a profound impact on virtually all therapies. People undergoing classical analysis are only accepted after evaluation because analysts consider only those with a relatively strong ego outside the area affected by the neurosis can benefit from treatment. This usually consists of 4 to 5 visits per week with a 50 minute session each time and can continue for months or even years. There are four phases: (1) the opening phase, (2) the development of transference, (3) working through and (4) resolution of the transference.

4.2.1.1. The opening phase Everything the patient says and does is noted for possible significance and use later in the treatment. The analyst attempts to learn as much as possible about the patient, his current life situation and difficulties, what he has accomplished, how he relates to others and the history of his family background and childhood development. After a few sessions the patient assumes the couch. Then the analyst continues to learn more about the patient's history and development. He gets to understand the broad outline of the nature of the patient's unconscious conflicts and he has an opportunity to study the ways in which the patient resists revealing himself. This initial phase of treatment in ordinary cases lasts from 3 to 6 months. 4.2.1.2. Development of transference At a certain stage in the treatment when it appears the patient is just about ready to relate his current difficulties to unconscious conflicts from childhood, concerning wishes over some important person or persons in his life, a new and interesting phenomenon emerges. Emotionally, the person of the analyst assumes a major significance in the life of the patient. The patient's perception of and demands upon the analyst become quite inappropriate, out of keeping with reality. The professional relationship becomes distorted as he tries to introduce personal instead of professional considerations into their interactions. This is transference. Freud claimed that in transference the patient was unconsciously re-enacting a latter day version of forgotten childhood memories and repressed unconscious fantasies. Analysis of transference helps the patient understand how he misperceives, misinterprets and misresponds to the present in terms of the past. 4.2.1.3. Working through This phase of treatment coincides with and continues the analysis of transference. The patient's insight into his problems by way of the transference

NEUROCHEMICALAND COGNITIVE ASPECTS OF ANXIETY DISORDERS

is constantly deepened and consolidated by the process of "working through" a process that consists of repetition, elaboration and amplification. Usually the experience of successful analysis of a transference phenomenon is followed by the emergence into memory of some important event or fantasy from the patient's past. This reciprocal interplay between understanding the transference and recollecting the past consolidates the patient's insight into his conflicts. 4.2.1.4. The resolution of the transference The resolution of the transference is the termination phase of treatment. When the patient and the analyst are satisfied that the major goals of the analysis, such as overcoming anxiety hysteria, have been accomplished and the transference is well understood, a date is set for ending the treatment. Technically the analyst's aim is to resolve the patient's unconscious neurotic attachment to him. Many of Freud's original followers went on to develop their own psychotherapeutic approaches such as Carl Jung (1964) and Alfred Adler (1929a,b) and then there were many neo-Freudians who came to the United States such as Karen Horney (1937), as well as native sons such as Harry Stack Sullivan (1953) who developed their own approaches. 4.2.2. Person-centred therapy This was developed by psychologist Carl Rogers, whose best known book on the subject is entitled On Becoming a Person (1961). He identifies himself with the humanistic psychology movement and this is based on his advocacy of the dignity and value of the individual person in search for growth. Rogers sums up the basic difference between the views held by psychoanalysts and by "person-centred" therapists in this way: "I have little sympathy with the rather prevalent concept that man is basically irrational and that his impulses, if not controlled, will lead to destruction of others and self. Man's behaviour is exquisitely rational, moving with subtle and ordered complexity towards the goals his organism is endeavouring to achieve" (Rogers, 1961, pp. 194-196). The concepts of congruence, empathic understanding and unconditional positive regard are crucial in this treatment. The therapist tries to immerse himself in the feeling world of his client to experience that world within himself. He also shows non-possessive caring or acceptance of the client's individuality and this is called unconditional positive regard. Central to the person-centred approach is the belief in the self directing capacity of the individual. Rogers sees anxiety as a state of uneasiness or tension of unknown cause. It is this incongruence within the person which generates anxiety, contradictory behaviours, denial of certain thoughts or feelings and the idea that he cannot control his own behaviour. The therapy reduces the role of special technique and tries instead to reflect back to the client the feelings the client has expressed. In this way the person can re-evaluate, accept and finally integrate his own feelings within himself as he works to make his

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attitudes about himself more appropriate with his experiences. 4.2.3. Behaviour therapy Behaviour therapy, as stated earlier, is based on the learning theories of Pavlov, Skinner, Bandura and others. Basic assumptions of behaviour therapy are that disorders are learned and learned independently and that specific behaviours can be changed by application of certain principles of learning. Reviews of treatment methods that contain special sections on anxiety are found in books by Wolpe (1982), Rimm and Masters (1979) and Hersen and Bellack (1985). 4.2.3.1. Social anxiety Let us assume that an individual is suffering from anxiety whenever he meets strangers or has to deal with them on a regular basis. This would be an example of a social phobia. A number of behaviour therapy techniques will be described that may be used to help overcome this problem. 4.2.3.2. Systematic desensitization This is a core procedure developed by Wolpe and involves teaching the client progressive muscle relaxation (Jacobson, 1980). Then a hierarchy of scenes are generated in the client's mind, with each scene causing an increased amount of anxiety. In the case of the social phobic patient, it may range from chatting with a few close friends at home to approaching a complete stranger at a party and asking her for a date. Once the hierarchy has been construtted, then each scene is paired with progressive muscle relaxation and the anxiety generated by it is reduced in each case. Thus, the pairing of the relaxation response with the anxiety-provoking image in a sequence assists the individual to replace the anxiety with relaxation. Thus in each scene, after the client relaxes, the therapist describes the next anxietyproducing scene in the hierarchy and asks the client to imagine it. Once he can imagine the scene without any anxiety, the therapist moves to the next scene and repeats the procedure. This technique is followed in a series of sessions, until the client is able to imagine the scene that formerly produced the most anxiety without experiencing any rise in anxiety at all. 4.2.3.3. Flooding This involves real, not imaginary situations, although imagination may be used in conjunction with actual exposure. The technique has been particularly useful in the elimination of obsessive compulsive rituals. For example, if hand washing rituals are based on fear of contamination, flooding would require the clients to contaminate themselves by touching and handling dirt or whatever substance they are trying to avoid, and afterward to be prevented from carrying out their cleansing ritual. Over repeated trials the intense anxiety elicited by "contamination" without hand washing would be extinguished.

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4.2.3.4. Paradoxical intention This was devised by Victor Frankl, the founder of logotherapy, and involves encouraging and persuading clients to gradually seek out and do the thing that they fear most (Frankl, 1975). An example of this technique was with a young woman who had fear of heights, of being alone, of eating in a restaurant in case she vomited and of going into supermarkets, subways and cars. She was instructed to try to expose herself to the conditions that she feared. She was to try to vomit while dining out with her husband and friends, so as to create the greatest possible disruption. She was to drive to supermarkets, hairdressers and banks, trying to get as panicky as possible. In six weeks she had lost her fears in her home situation and shortly thereafter drove all by herself to the therapist's office, about five miles from her home. 4.2.4. Cognitive behaviour therapy Treatment for anxiety using this therapy is based on the primacy of cognition (see Fig. 2). The approach is different to that of behaviour therapy, although it uses many of the same procedures as part of the treatment. Ellis (1962, 1982), Beck et al. (1985), Michenbaum (1972) and Lazarus and Folkman (1984) refer to the importance of cognitions, the need to identify them and to try to intervene initially at that level. This approach appeals to me as a neurobiologist, for humans are born with an unusually large and complex cerebral cortex; they not only have the power to think, as do other animals, but also to think about their thinking. This is enormously enhanced by their invention and use of language, of verbal, mathematical, symbolic and other forms of language. All human groups that we have any knowledge of appear to use language and cognition much more, and in many more complex ways, than do other animals. The importance of the interpretation of verbal and written symbols by the central nervous system and the meaning given to these symbols, and the subjective effect on physiological and emotional states was expounded in Korzybski's remarkable book Science and Sanity (1958).

Human biology seems to predispose people to social living. Individuals are suggestible and are greatly influenced by their parents, schools, churches, books, television shows, newspapers and other organizations and modes of mass communication. Since social learning largely takes place through language and verbal activities, the natural propensity of humans to think and to affect their emotions and behaviours by their thinking becomes greatly enhanced by cognitive means; and the influence of thinking on normal and pathological processes becomes even more profound. Even if reared by wolves on a desert island, people would probably think much more and differently than the wolves. When reared in families, clans and cultures, their cognitive processes take over more and more and tend to run much of their existence (Ellis, 1982). Human thinking, if it can be said to have a purpose, probably is mainly designed to help humans live longer and more succesfully, to be alive and to be happy. But it also has its liabilities: to a considerable degree it manages to help humans to live less long as when it addicts them to cigarettes, over-eating, alcohol and drugs, and it helps them to live less happily when it addicts them to anxiety, depression and hostility. 4.2.4.1. Cognitive elements of anxiety The terrifying negative, often automatic, thoughts that occur when people are undergoing a panic attack, or when confronted with some relatively harmless activity such as going to a supermarket or when they have to speak in public or meet strangers, are well known. As well as these situations, individuals' recall of previous anxiety attacks generate cognitions such as "I cannot stand the feelings of anxiety and will go mad if I have another attack". The first strategy by a therapist is to get people to identify and even write down these cognitions and then to dispute and challenge them and compare them with reality. A challenging and disputing statement would be "So what if I am having a panic attack, thousands of people are having them, this is not my first, I will not die, I have survived many

B. THOUGHTS You interpret the events with a series of thoughts that continually flow through your mind. This is called your "self talk".

A. ENVIRONMENT A sedes of positive, neutral and negative events.

~

C. MOOD Your feelings are created by your thoughts. All experiences must be processed through your brain and given a conscious meaning before you experience emotional response.

FIG. 2. The cognitive behavioural model.

NEUROCHEMICALAND C(K~N1TIVEASPECTSOF A~Ydgrv DISORDERS

others in the past and will do so with this one". As soon as the person challenges and disputes his negative thinking, there is a good chance that the anxiety levels will fall a little so that further disputing and challenging will occur and a cognitive restructuring takes place. The distorted perception of reality is the key to this approach. Ellis lists several irrational beliefs that are fundamental to maintaining an anxiety state and they include: (1) If something is or may be dangerous or fearsome, one should be terribly concerned about it and should keep dwelling on the possibility of it occurring. (2) Human unhappiness is externally caused and people have little or no ability to control their sorrows or disturbances. (3) It is easier to avoid than to face certain life difficulties and self responsibilities. The cognitive behavioural approach not only works on cognitions but on bchaviour, using behaviour therapy techniques such as flooding, systematic desensitization, relaxation and assertion training, and also on emotions using Rogerian and Gestalt techniques. The importance here in the treatment of anxiety is that there is a clear model which the therapist can refer to, together with techniques which are drawn from a range of other approaches. In my book From Thought to Action (Kidman, 1988) I have explained these techniques in clear, easily understandable terms.

5. CONCLUSION Anxiety disorders are widespread and debilitating for many people. In this review I have tried to look at the role of perception and cognition in anxiety disorders and how neurochemical and psychological concepts might be unified. It is clear that chemicals in the brain have a profound effect on anxiety, as shown by the section on anti-anxiety drugs. Anxiety can also be induced and reduced by conditioning methods, and a range of psychotherapeutic techniques are employed to overcome anxiety. They range from the psychoanalytic to the cognitive behavioural method. It is this last approach that I believe holds great promise and allows a reconciliation between the neurochemical and holistic models. Genetic studies suggest there are biological tendencies towards anxieties and biochemical evidence indicates that certain chemicals such as benzodiazepines can bind to receptors and reduce anxiety for limited periods of time, both in man and animals. However, humans with their highly developed central nervous system can reflect and store memories, imagine events, interpret written and verbal signals. Cognitive behavioural therapy argues that these higher centres can influence the lower part of the brain that is responsible for anxiety and is suggested by Gray to be in the septo-hippocampal region. It is a psychocducative process whereby people can learn to cognitively re-appraise external events, can learn to test reality and to reduce the symptoms of anxiety, such as palpitations, shakiness and sweating,

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with relaxation and systematic desensitization techniques. Thus, genetic or chemical influences that cause individuals to have biological tendencies towards inappropriate anxiety, together with learnt anxiety responses from past experiences, can be considered as unfortunate handicaps that can be overcome by learning and persistent effort, together with chemical intervention when appropriate, although the majority of individuals would prefer to minimize drug regimens.

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