AnxietyDisorders - Journal of Psychopharmacology 5(4)...

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Unformatted text preview: Journal of Psychopharmacology 5(4) (1991) 281-285 @1991 British Association for Psychopharmncology CRITIQUE Psychology and pharmacology in the treatment of anxiety disorders: co-operation or confrontation H. C. Middleton Cambridge University Department of Psychiatry, Addenbroohe's Hospital, Hills Rd, Cambridge CBZ ZQQ, UK 5-HT;, and cholecystokinin receptor antagonists with anxiolytic properties threaten a further round of the ‘tranquilizers or treatment’ debate. Tricyclic antidepressants have been shown to enhance the efi‘ect of exposure therapy upon agoraphobic patients, and it can be argued that the therapeutic success of cognitive therapy in the treatment of anxiety disorders depends upon guided exposure to threatening situations. A consideration of the efi'ects of agents already in use for the treatment of anxiety, and experimental and neuroanatomical findings, suggests that pathological anxiety might well include relatively independent abnormalities of autonomic regulation and psychological reactivity. Proper evaluation of these new compounds is therefore going to require careful evaluation of their cognitive and behavioural effects, as well as their physiology. This work should, therefore, draw the contributions of clinical pharmacology and clinical psychology closer together rather than drive them further apart. With the demonstration that 5-HT; and cholecystokinin receptor antagonists have anxiolytic properties (Jones et al., 1988; Hughes et a]. , 1990), and their introduction into clinical trials, there is serious risk of a further round in the sterile debate about the relative merits of drug or psychological treatments for anxiety. The debate has its roots in the use of barbiturates for the alleviation of disabling anxiety during the first half of the century. It received further impetus in the 1970s, when it became apparent that the equally anxiolytic but considerably less toxic benzodiazepines also had abuse potential, and that focussed psychological treatments such as exposure therapy could be equally effective. This public debate, - which on the one hand discredits the long-term efficacy of drug treatments for anxiety disorders and on the other hand emphasizes the narrow application of effective psychological treatments, has had widespread and deleterious clinical consequences. At the beginning of their clinical career the benzodiazepines were greeted with enthusiasm. There have been many casualties since then, not only among the disabled addicted but also in the pharmaceutical industry and among the reputations of psychiatrists and established behavioural scientists. This has resulted in many patients resisting appropriate drug treatment without access to a satisfactory psychological alternative. These difficulties and the apparently conflicting aims of psychological and pharmacological treatment have tended to polarize opinion and treatment strategies. Psychological and pharmacological treatments are usually given on an either/or basis, with the former construed as confrontational and aimed at habituation and the latter as palliative with the risk of dependence. As a result little has been done to explore the potential for interaction between psychological and pharmacological treatments, a line of enquiry which could shed considerable light on the biochemical bases of anxiety disorders as well as promising considerable clinical benefit. What little work that has been done in this area shows promise. Egan et al. (1988) showed that the administration of naloxone inhibited habituation during controlled exposure of agoraphobic patients, suggesting a role for the endogenous opiate system in the process of habituation. A number of studies (Zitrin, Klein and Woemer, 1980, 1983; Mavissakalian, Michelson and Dealy, 1983; Telch, Agras and Taylor, 1985; Mavissakalian and Michelson, 1986) demonstrate additive effects when imipramine and exposure are combined in the treatment of agoraphobia and it has been suggested (Akiskal, 1985) that under these circumstances imipramine and repeated exposure to phobic stimuli may share a common biochemical mode of action. One of the major restrictions to this approach has been the narrow focus of clearly effective psychological treatments. Until recently the only effective psychological treatment for anxiety disorders was graded exposure, and as the application of this is limited to conditions in which a phobic stimulus can be clearly defined, the successful application of clearly effective psychological treatment has been limited to the treatment of phobic disorders. 282 Partly in response to this clinical shortcoming, and partly in response to theoretical developments, the practice of clinical psychology has undergone a ‘cognitive revolution’ (Salkovskis, 1986). This has not been a uniformly comfortable development, but it has led to treatments of proven efficacy and provides a model for the pyschological treatment of anxious patients with a much wider application than can be offered by graded exposure to identified phobic stimuli. As a result it widens the opportunity to investigate the complementary roles of drug and psychological treatment. Central to the cognitive formulation of anxiety disorders is the view that attribution, or meaning, is an important intervening variable, influencing the relationship between stimulus and response. Cognitive formulations emphasize the importance of the affective state provoked by stimuli. Whatever the provoking stimulus might be, if for some reason it is perceived as threatening, certain predictable behavioural, physio- logical and perceptual changes will take place. The abnormality found in patients suffering an anxiety disorder is understood to be one of appraisal; threat or danger is perceived where it is not present. It is argued that this abnormal appraisal of threat is due to specific and identifiable ‘misinterpretations’ of the significance of identifiable stimuli, and cognitive therapies are designed to identify and correct these ‘misinterpretations’. This cognitive formulation of anxiety disorders is probably most clearly illustrated by that proposed by Clark (1986) for panic disorder. This has now been successfully tested in the clinic (Michelson et (11., 1990) and it is also supported by several investigations demonstrating relevant and predictable psychological differences between panic patients and other anxious subjects. The formulation used in treatment argues that certain critical bodily sensations are wrongly appraised as evidence of impending catastrophic illness. Examples include ‘My heart is racing: I am going to have a heart attack’ ‘I am overbreathing: I am going to suffocate’ ‘I am feeling lightheaded: I am going to pass out'. These particularly threatening interpretations are associated with an understandable anxiety response, including physiological perturbations that amplify the very same symptoms that provoked the initial inaccurate appraisal of threat. The result is positive feedback causing a paroxysm of intense anxiety, or a panic attack. In support of this model, laboratory experiments have shown that patients suffering recurrent panic attacks attend to cues that suggest sudden, severe illness more readily than they do cues suggesting neutral events, unlike normals or other types of anxious patient (Clark et al., 1988). Application of this model is no longer restricted to panic disorder. Warwick and Salkovskis (1990) have proposed an essentially identical formulation for hypo- - chondriasis; Lucock and Salkovskis (1988) have offered H. C. MIDDLETON a cognitive formulation of social phobia; Salkovskis (1989) has applied the model to the treatment of obsessional ruminations; and Wessely (1989) has published a similar formulation of much of the disability suffered by victims of the so-called chronic fatigue syndrome. .- The framework common to all of these cognitive models of anxiety disorder is a vicious cycle. Initial stages involve the misinterpretation of sensations or other cues leading to an excessive appraisal of threat and a consequent anxiety response. The anxiety response itself causes increased attention to cues signalling threat and a reduced appreciation of safety signals. It also involves physiological changes which generate further potentially threatening sensations or cues. It is argued that the ‘misinterpretation’ persists because it is reinforced by this amplification of the provoking stimuli. Although this model has considerable face validity when applied to panic disorder in hypochondriasis, chronic fatigue or social phobia, where the provoking stimulus is one that is less likely to be amplified by increased arousal, such a model is less credible. It is difficult to see how not uncommon hypochondriacal complaints such as chest pain, pudenda! discomfort or lassitude can be attributed to the anxiety response. Attempts to do so based on muscle tension, disordered patterns of breathing or mental confusion strain the model and discredit the theory. Another problem that has hindered the integration of these cognitive formulations of anxiety into the thinking of those pursuing a more pharmacological interpretation of the disorder is the language they are couched in. Cognitive formulations depend upon ‘misinterpretations’ which are notoriously difficult to measure in the rat, and even in humans have to be inferred from the results of reaction time tests demonstrating a particular perceptual bias (e.g. Mathews and Macleod, 1986). Although these ‘misinterpretations’ have considerable subjective validity, they are not available to direct empirical scrutiny and do not relate to other relevant scientific corpuses such as those embodying information processing or decision theory. This inhibits any integration with other disciplines and threatens continuing sterile debate. Differing ways of conceptualizing the compelling psychological contribution to our understanding of anxiety disorders have to be considered if a more integrated approach is to be found. Lang conceptualized human pathological anxiety in terms of three components; a view that has acquired considerable support among psychological practitioners and theorists (Rachman and Hodgson, 1974). It is suggested that pathological anxiety is made up of independently identifiable disturbances of cognition, physiological reactivity and behaviour (Lang, 1967). Most attention has been focussed, to date, on how these differing features of anxiety disorder might operate PSYCHOLOGY AND PHARMACOLOGY IN ANXIETY DISORDERS 283 independently. From the perspective of an investigation of the complementary roles of psychological and drug treatments it is probably more productive to consider how they might interact. The hallmark of the behavioural abnormalities found in pathological anxiety is that they are behaviours that reduce the risk of encountering a presumed threat. Classically this is overt avoidance, as found in phobic disorders, but risk-reducing strategies such as the ensuring of an escape route by panic patients, checking and reassurance seeking in hypochondriasis, and neutralizing rituals among obsessionals can all be understood in the same way. Threat avoidance has a critical effect upon the appraisal of threat. If high buildings or aeroplanes are consistently avoided because they are felt to be unsafe, then there is no opportunity to discover with sufficient conviction that this is an inaccurate appraisal. In conditions characterized by overt avoidance behaviour the relationship between avoidance behaviour and maintenance of the disorder is clear and this is firmly supported by the success of exposure therapy. In conditions lacking overt avoidance behaviour, this association is less clear. Scrutiny of the process of successful cognitive therapy for such conditions does, however, reveal such an association. The process of cognitive therapy for anxiety disorders begins with the identification of inaccurate anxiety- provoking interpretations of identified stimuli, usually by the use of a diary to establish patterns of co-occurrence of anxiety, particular experiences and the threatening meaning attributed to these experiences. The initial assessment also involves identifying overt and covert behaviours that serve to avoid or reduce threat. Examples include holding onto the furniture when light-headedness is interpreted as impending collapse, talking loudly and assertively to minimize the risk of social embarrassment or taking a pill to prevent anticipatory anxiety escalating into panic. In identifying these ‘misintcrpretations’ and risk-reducing strategies the cognitive therapist constructs a precisely tailored and individualized threat/avoidance model. The explicit aim of cognitive therapy for anxiety disorders is to extirpate inaccurate and threatening attributions of meaning. The three main techniques used in this exercise are behavioural provocation in the consulting room, diary-based reappraisal and behavioural experimentation. Behavioural provocation in the consulting room involves the deliberate evocation of stimuli that form the basis of the threatening ‘misinterpretation’. This involves exposure to the relevant stimuli while resisting habitual risk-reducing strategies, supported by the reassuring presence of the therapist. A well-known example of this is the provocation of symptoms frequently interpreted as threatening by panic patients, by deliberate hyperventilation. Diary-based reappraisal involves the use of a diary recording anxious episodes, provoking experiences and their associated threatening meaning. This involves repeated bibliographic exposure to the threatening possibility. The value of diary-keeping as a method of overcoming ‘denial’ is well- established in other disorders such as bulimia nervosa and alcohol abuse. Behavioural experimentation involves making predictions about the outcome of provoking experiences on the basis of identified ‘misinterpretations’, and arranging to test them in real life as part of a therapy session or as homework. A typical social phobic might predict that if they were to spill a drink in a public house they would immediately become the focus of withering public ridicule. The behavioural experiment would be to deliberately spill a drink in order to discover what really happens. This too is a method of achieving exposure to risk of the presumed threat. All three procedures involve the encouragement of risk- taking by the patient. This inhibits avoidance behaviour and risk-reducing strategies, and has the effect of furthering exposure to the threatening stimulus. Increased exposure to the threatening stimulus permits closer scrutiny, facilitates reappraisal and undemiines inaccurate misinterpretation. Foa and Kozak (1986) have argued that physiological activation and habituation within and across exposure sessions are invariable indicators of emotional processing and that the provocation of these responses by exposure to feared situations is common to many psychotherapies for anxiety. Physiological activation by and habituation to carefully elicited salient cues certainly appears to be an important common feature of both successful exposure therapy and effective cognitive therapy. Although the explicit aim of cognitive therapy is a change in the way otherwise innocuous stimuli are appraised, successful reappraisals of this sort appear to entail the same underlying processes that play an important role in exposure therapy, namely the provocation of arousal by the inappropriately threatening stimulus and its subsequent habituation. At this stage it is unclear whether reappraisal is a consequence of physiological habituation, or vice versa, but both are involved. Consideration of the effects of pharmaceuticals also suggests that anxiolysis may involve more than one mechanism. Drugs with an established record of alleviating anxiety include alcohol, barbiturates, benzodiazepines, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Of these the first three, in slightly different ways, potentiate the neuroinhibitory effects of y-aminobutyric acid (GABA). TCAs and MAOIs, in different ways, both increase the availability of intra- synaptic monoamines. There appears to be no overlap of pharmacological properties between the two groups of compounds even though both exert a similar therapeutic 284 effect. A recent review of the effects of TCAs, MAOIs and benzodiazepines upon neuroendocrine variables and circulating, cerebrospinal fluid (CSF) and urinary levels of monoamines and their metabolites (Hsiao and Potter, 1990) draws attention to the divergent physiological responses to these compounds. The acute administration of TCAs leads to a surge of prolactin, adrenocortico- trophic hormone and growth hormone secretion (e.g. Nutt, Middleton and Franklin, 1987) whereas the acute administration of benzodiazepines has no effect upon prolactin secretion, reduces cortisone levels and only in some cases stimulates growth hormone secretion (Risby et a1. , 1987). Chronic TCA or MAOI administration leads to a reduction in CSF, circulating and urinary monoamine metabolite levels (Charney et al., 1981; Linnoila, Karoum and Potter, 1982; Potter et al., 1985), whereas chronic benzodiazepine administration has no effect upon urinary monoamine or monoamine metabolite levels (Lydiard er al., 1986). Benzodiazepine administration leads to a reduction in circulating levels of adrenaline and noradrenaline (Stratton and Halter, 1985), and dampens the adrenaline and noradrenaline responses to physical and mental ‘stress’ (Ziegler, Ludwig and Klotz, 1984). Acute TCA administration increases circulating noradrenaline levels (Ross et (11., 1983). Finally, the clinical effects of these compounds differ in detail. Their effects upon anxiety follow different time courses and, when given acutely, TCAs and MAOls, unlike benzodiazepines, are anxiogenic rather than anxiolytic (Nutt and Glue, 1989). It is clear that although the outcome (anxiolysis) is the same for both groups of compounds, it is achieved in quite different ways. Studies of the distribution of receptors likely to be implicated in the actions of these two groups of compounds support the view that they are acting upon different structures (Hsiao and Potter, 1990). Regions of the brain that have been implicated in the processes that result in physiological arousal in response to external and visceral stimulation include the hippocampus, hypothalamus, periaqueductal grey, locus coeruleus and medullary nuclei directly influencing the activity of the autonomic nervous system including the dorsal motor nucleus of the vagus, nucleus prepositus hypoglossi and nucleus paragiganto- cellularis. There are dense populations of benzodiazepine receptors in the hippocampus and, to a lesser extent, in the hypothalamus and periaqueductal grey, but there is virtually no benzodiazepine binding in the above mentioned medullary sites. These medullary nuclei are, however, densely populated by noradrenergic, adrenergic and sero- tonergic neurones, the activity of which would be expected to be susceptible to the effects of TCAs and MAOIs. Hippocampus and periaqueductal grey influence physiological activity indirectly, via projections to these medullary nuclei. Although locus coeruleus does have spinal projections that might influence autonomic activity, H. C. MIDDLETON these do not appear to innervate directly autonomic pre- ganglionic neurones, unlike medullary nuclei (Blessing et al., 1981). Furthermore, experimental work has dem- onstrated that changes in locus coeruleus activity provoked by peripheral stimulation are not always accompanied by parallel changes in sympathetic activity (Elam, Svensson and Thoren, 1985), suggesting that medullary nuclei more directly responsible for autonomic control are capable of independent activation rather than being dependent upon higher centres. Given this pharmacological and neuroanatomical background it does seem reasonable to make a functional distinction between the parts played by structures mediating pathological anxiety which are likely to be susceptible to the effects of benzodiazepines, and those likely to be susceptible to the effects of TCAs and MAOIs. Physiological arousal is due directly to activation of relevant medullary nuclei which can act independently of higher centres and which are likely to be susceptible to the effects of T CAs and MAOIs, but which are relatively immune to the direct effects of benzodiazepines. Higher centres more susceptible to the effects of benzodiazepines are equipped to influence the activity and reactivity of these nuclei. They thus exert their effect upon physiological activity more indirectly. Furthermore, the activity of these higher centres, in particular the hippocampus, is much more likely to be influenced by ‘reappraisal’ arising from psychological treatment. Much of the research that forms the basis of these speculations is experimental and is derived from findings in laboratory animals. There is therefore only limited validity in extrapolations into an understanding of pathological human anxiety. Nevertheless these arguments do point to important areas of enquiry. At present it is not yet clear whether the primary abnormality (in pathological anxiety is abnormal noradrenergic regulation, destabilizing the activity of those nuclei directly responsible for autonomic regulation, psycho- logical abnormalities that lead to undue activation of such nuclei by higher centres, or a combination of these. It is also not clear whether or not the relative importance of these factors is the same throughout the spectrum of anxiety disorders. Although physiological arousal and habituation appear to play an important part in the success of psychological treatments, is this because, in order to be effective, psychological treatments have to exert an effect that changes the transmission properties of nuclei subserving physiological regulation, or is physiological habituation merely an epiphenomenon that accompanies psychological change? As new compounds are introduced it is important to establish whether they are exerting a ‘benzodiazepine’ or a ‘TCA/MAOI’ effect by exploring their physiology as well as their effects upon responses to ‘stress’. Finally, as it becomes clear that there may be complementary roles for drug and psychological PSYCHOLOGY AND PHARMACOLOGY IN ANXIETY DISORDERS 285 treatments, there is considerable scope for further exploring their potential for synergy. It is clear that success in these areas of enquiry is going to depend upon co-operation between the disciplines instead of a further round of sterile debate. References Akiskal HS (1985) Anxiety: definition, relationship to depression, and proposal for an integrated model. In Tuma A H, Maser J D (eds), Anxiety and the anxiety disorders. Erlbaum, Hillsdale, pp. 787-797 Blessing W W, Goodchild A K, Dampney R A L, Chalmers J P (1981) Cell groups in the lower brain stem of the rabbit projecting to the spinal cord, with special reference to catecholamine—containing neurons. Brain Res 221: 35-55 Chamey D S, Heninger G R, Stemberg D E, Roth R H (1981) Plasma MHPG in depression: effects of acute and chronic desipramine treatment. Psychiatr Res 5: 217—229 Clark D M (1986) A cognitive approach to panic. Behav Res Ther 24: 461—470 Clark D M, Salkovskis P M, Gelder M, Koehler C, Martin M, Anastasiades P, Hackmann A, Middleton H, Jeavons A (1988) Tests of a cognitive theory of panic. In Hand I, Wittchen H U (eds), Panic and phobias 2. Springer-Verlag, Berlin, pp. 149-158 Egan KJ, Carr J E, Hunt D D, Adamson R (1988) Endogenous opiate system and systemic desensitisation. J Consulting Clin Psychol 56: 287-291 Elam M, Svensson TH, Thoren P (1985) Differentiated cardiovascular afferent regulation of locus coeruleus neurons and sympathetic nerves. Brain Res 358: 77 -84 Foa E B, Kozak M J (1986) Emotional processing of fear: Exposure to corrective information. Psychol Bull 99: 20-35 Hsiao J K, Potter WZ (1990) Mechanisms of action of antipanic drugs. In Ballenger J C (ed.), Clinical aspects of panic disorder. Wiley-Lies, New York, pp. 297-317 Hughes J, Boden P, Costall B, Domeney A, Kelly E, Horwell D C, Hunter J C, Pinnock R D, Woodruff G N (1990) Development of a class of cholecystokinin type B receptor antagonists having potent anxiolytic activity. Proc Natl Acad Sci USA 87: 6728-6732 Jones B J, Costall B, Domeney A M, Kelly M E, N aylor R J, Oakley N R, Tyers M B (1988) The potential anxiolytic activity of GR38032F, a 5-HT3-receptor antagonist. Br, J Pharmacol 93: 985-993 Lang PJ (1967) Fear reduction and fear behaviours Problems in treating a construct. In Shlien J M (ed.), Research in psychotherapy, Vol. III. American Psych- ological Association, Washington. Linnoila M, Karoum F, Potter W Z (1982) Efl'ect of low-dose clorgyline on 24 hour urinary monoamine excretion in patients with rapidly cycling bipolar afi'eetive disorder. Arch Gen Psychiatr 39: 513-516 Luoock M P, Salkovskis P M (1988) Cognitive factors in sodal anxiety and its treatment. Behav Res Ther 26: 297—302 Lydiard R B, Ballenger J C, Laraia M, Potter W Z, Lake R (1986) Noradrenergic measures before and after treatment with tricyclics and benzodiazepines in agoraphobic and panic disorder patients. Presented at the American Psychiatric Association Meeting, Washington DC Mathews A, MacLeod C (1986) Discrimination of threat cues without awareness in anxiety states. J Abnormal Psychol 95: 1 3 1 - 1 38 Mavissakalian M, Michelson L (1986) Relative and combined effectiveness of therapist-assisted in vivo exposure and imipramine treatment of agoraphobia. Am J Psychiatr 143: 1106-1112 Mavissakalian M, Michelson L, Dealy R S (1983) Pharma- cological treatment of agoraphobia: imipramine vs imipramine with programmed practice. Br J Psychiatr 143: 348-355 Michelson L, Marchione K, Greenwald M, Glanz L, Testa S, Marchione N (1990) Panic disorder: Cognitive- behavioural treatment. Behav Res Ther 28: 141-151 N utt D, Middleton H, Franklin M (1987) The neuroendocrine effects of oral imipramine. Psychoneuroendocrinology 12: 1-9 N utt D J, Glue P (1989) Clinical pharmacology of anxiolytics and antidepressants; a psychopharmaoological perspective. Pharmacol Ther 44: 309-334 Potter W Z, Soeinin M, Golden R N, Rudorfer M V, Cowdry R, Calil HM, Ross RJ, Linnoila M (1985) Selective anti- depressants and cerebrospinal fluid. Arch Gen Psychiatr 42: 1171-1177 Rachman S, Hodgson R (1974) Synchrony and desynchrony in fear and avoidance. Behav Res Ther 12: 311-318 Risby E D, Hsiao J K, Golden R N, Potter W Z (1987) Intravenous alprazolam challenge in normal subjects. Presented at the Society for Biological Psychiatry, Chicago Ross R J, Zavadil A P, Calil H M, Linnoila M, Kitanaka I, Blombery P, Kopin IJ, Potter W Z (1983) Effects of desmethylimipramine on plasma norepinephrine, pulse and blood pressure. Clin Pharmacol Ther 33: 429-437 Salkovskis P M (1986) The cognitive revolution: New way forward, backward somersault or full circle? Behav Psychother 14: 278-282 Salkovskis P M, Westbrook D (1989) Behaviour therapy and obsessional ruminations: Can failure be turned into success? Behav Res Ther 27: 149-160 Stratton J R, Halter J B (1985) Efi'ect of a benzodiazepine (alprazolam) on plasma epinephrine and norepinephrine levels during exercise stress. Am J Cardiol 56: 136-139 Telch M J, Agras WS, Taylor C B (1985) Combined pharmacological and behavioural treatment for agora- phobia. Behav Res Ther 23: 325-335 Warwick HMC, Salkovskis P (1990) Hypochondriasis. Behav Res Ther 28: 105-117 Wesser S, David A, Butler S, Chalder T (1989) Management of chronic (post-viral) fatigue syndrome. J R Coll Gen Practitioners 39: 26-29 Wolpe J (1958) Psychotherapy by reciprocal inhibition. Stanford, California, Stanford University Press Ziegler G, Ludwig L, Klotz U (1984) Stress protective effects during steady state conditions of bromazepam. Pharmacopsychiatry 17: 194-198 Zitrin C M, Klein D F, Woerner M C (1980) Treatment of agoraphobia with group exposure in vivo and imipramine. Arch Gen Psychiatr 37: 63-72 Zitrin C M, Klein D F, Woerner M G (1983) Treatment of phobias—1. Comparison of imipramine hydrochloride and placebo. Arch Gen Psychiatr 40: 125-138 Journal of PsychOpharmacology 5(4) (1991) 299—300 ©1991 British Association for Psychopharmacology Commentary on ‘Psychology and pharmacology in the treatment of anxiety disorders: co-operation or confrontation?’ Donald F. Klein Department of Psychiatry, Columbia University, and the New York State Psychiatric Institute, New York, USA Middleton (1991) warns us against the possibility of ‘a further round in the sterile debate about the relative merits of drugs or psychological treatments for anxiety’. He does this both at the beginning and at the end of his contribution, so one would assume that this paper would document both ‘the sterile debate’ and ‘deleterious clinical consequences’ and hopefully provide us with a new synthesis that would enable us to transcend this fruitless antimony. However, instead we have a vague ramble supported by undocumented and tendentious statements. Middleton asserts that benzodiazepines have produced many casualties both clinical and professional. No documentation is attempted. The recent report of the American Psychiatric Association (Salzman et a1. , 1990) presents a far more judicious view. The author argues that psychological and pharma- cological treatments are usually given on an either/or basis. It may be true that those practitioners that are debarred from prescribing may use only psychotherapy, but it has been common practice among biological psychiatrists to use whatever works. The exact strategy for arriving at a combination, when needed, may well differ from practitioner to practitioner. One common suggestion (Muskin and Fyer, 1981) is to initially use medication, as for many anxious and depressed patients that is all that they need, besides being inexpensive and quick. For that group who require more help, a variety of adjunctive psychotherapies may be appropriate. The author argues that little has been done to explore the potential for ‘interaction between psychological and pharmacological treatments’. Certainly he is correct that more needs doing, but the difficulty in getting such studies going is not due to any sterile debate, but to the realistic problems of interdisciplinary collaboration and funding. Our research team at Columbia is currently engaged in two multisite placebo-controlled studies of specific medications, specific psychotherapies and their com- bination in the treatment of agoraphobia and social phobia. The sterility of debate seems fostered by Middleton who manages to write an entire paper concerning this very active field without ever mentioning panic as a key organizing concept. This notion has done much to foster the development of both discrete diagnostic indications for treatment as well as a variety of physiological and psychological theories. To assume that drug and psychological treatment are ‘complementary’ goes well beyond the facts. It may well turn out that for some they are, but it would not be surprising if for some, drugs alone are necessary and for others, as with simple phobics, psychological therapies are entirely sufficient. Complementarity has been most clearly demonstrated by studies indicating the utility of imipramine for the spontaneous panic and exposure for avoidance behavior (Klein and Gorman, 1987; Klein, Ross and Cohen, 1987; Klein and Klein, 1988, 1989). Middleton describes, in positive terms, the ‘cognitive revolution’. It adds to the sterility of debate when only one side of a formulation is presented. Fruitful debates come from the clash of informed opinion. Cognitive theory has yet to deal satisfactorily with the initial panic attack, the lack of data supporting catastrophizing attitudes anteceding the development of anxious states, and the fact that pregnancy, which should be easily misappraised as an endogenously stimulating and threatening period of life, is a relatively protected period against panic (R. Swinson, unpublished). Middleton’s review of pharmacotherapy does not distinguish between interesting observations and anxiety- relevant phenomena. Do we know whether reductions in cerebrospinal fluid circulating and urinary monoamine metabolite levels are of any direct importance in anxiety reduction? Might they simply be epiphenomena? Such issues are not addressed. A lack of critical assessment of the relevance of physiological findings to therapeutic effects prolongs the sterility of any debate. The discussion concerning the various structures mediating pathological anxiety and their relationship to benzodiazepines, tricyclic antidepressants and monoamine oxidase inhibitors are referred to by the author as ‘speculation’. Certainly that is correct and many other speculations are possible. What relevance this is to fostering cooperation between psychology and pharma- cology is quite unclear. What is clear is that calls for the end of debate are a waste of time. The debate can end, although guild allegiances and economic interests may prevent this, only 300 if there is adequate, controlled, experimental, clinical and basic data that speaks directly to the issues. Vague speculations, undocumented assertions and presentation of very partial expositions will not accomplish this. Address for correspondence Donald F. Klein, MD 722 West 168th Street New York NY 10032 USA References Klein DF, Gorman J M (1987) A model of panic and D. F. KLEIN agoraphobic development. Acta Psychiatr Scand 76: (Suppl 335) 87-95 Klein D F, Klein H M (1988) The status of panic disorder. Curr Opinion Psychiatr 1: 177-183 Klein D F, Klein H M (1989) The utility of the panic disorder concept. Eur J Psychiatr Neurol Sci 238: 268-279 Klein D F, Ross D C, Cohen P (1987) Panic and avoidance in agoraphobia: Application of PATH analysis to treatment studies. Arch Gen Psychiatr 44: 377-385 Middleton H C (1991) Psychology and pharmacology in the treatment of anxiety disorders: Cooperation or con- frontation? J Psychopharmacol 5: 281-285 Muskin P, Fyer A (1981) The treatment of panic disorder. J Clin Psychopharmacol 1: 81—90 Salzman C et al. (1990) The American Psychiatric Association Task Force report on benzodiazepine dependency, toxicity and abuse. APA Press, Washington DC Journal of Psychopharmaeology 5(4) (1991) 286-287 @1991 British Association for Psychopharmaeology Towards a new integration of psychology and pharmacology David H. Barlow Department of Psychology, University at Albany, State University of New York, 1400 Washington Avenue, Albany, NY 12222, USA Middleton offers a thought—provoking and stimulating comment on potential future directions for psychological and biological investigations in the area of psycho- pathology and treatment. For too long these areas have progressed as ships passing in the night with little regard from one area for progress or discovery in the other area. This is beginning to change, and comments such as Middleton’s should hasten this process. Middleton does not make explicit his model of the psychopathology and pathophysiology of anxiety, but implicit in his comment is a systemic model. This is a crucial development if biological and psychological investigators are to cooperate more fully. At the heart of this model is the understanding that anxiety, in its pathological form, is a multidetemiined causal sequence. This system would have both psychological and biological inputs that could not be reduced to a single ‘cause’ such as a neurobiological dysfunction or a cognitive misappraisal. The history of our science has taught us that linear causal models are seldom, if ever, satisfactory in the study of psychopathology and that these simple models most often develop into complex multidetermined systems as evidence accumulates. The major implication of a multidetermined systemic model for the study of anxiety is that biological and psychological manifestations are interdependent parts of the same system and that intervention with either psychological or pharmacological approaches will affect the whole system. That is, effective pharmacological approaches will change thoughts, feelings and behavior and effective psychotherapeutic approaches will change neurotransmitter flow, receptor physiology, and perhaps even basic structures implicated in anxiety. There is much animal work to support this contention and the beginnings of some work with humans. For example, both noradrenergic and serotonergic functioning seems strongly influenced by the adequacy of coping responses as in a learned helplessness paradigm (Maser and Gallup, 1974; Anisman, 1984). We have also known for a long time that catecholamine secretion is strongly affected by psychological factors. For example, Cassens et a1. (1980) demonstrated clear increases in 3-methoxy-4-hydroxy- phenylglycol in rats after exposure to previously neutral ‘ stimuli that had been paired with stress (conditioned stimuli). In humans, Bandura et a1. (1985) demonstrated changes in perceived self-efficacy alter catecholamine secretion. On a more basic level, scientists such as Kandel (1983) using classical fear conditioning paradigms have observed profound changes in synaptic strength in number of receptors as a function of learning and experience in sea snails. Furthermore, the data indicate that at the level of individual cells, increases in both receptors and neurotransmitters involved in fear conditioning seem to be permanent as a result of learning. Kandel (1983) speculates that the very genetic structure of cells within the central nervous system changes as a result of learning. Specific inactivated genes become active during learning, leading to such changes in structure as the increase in receptors. If the behavior is extinguished, the change is reversed. More recent evidence from our clinic and elsewhere indicates that our newly developed cognitive-behavioral treatment of panic disorder, panic control treatment (PCT), effects significant changes in biological challenge procedures. For example, the provocation of panic by carbon dioxide inhalations is eliminated in most patients after completion of PCT (Brown et a1., 1990). Similar results have been obtained with lactate infusions (Shear et 01., 1991). Currently, Eric Reiman is investigating changes in blood flow in the brain using positron emission tomography scan technology after successful treatment with; PCT, a psychological procedure. In my view, this fascinating line of inquiry is only one example of the future of an integrated psychobiological approach to psychopathology. Nevertheless, we are only beginning to scratch the surface of knowledge in this area and most questions remain unanswered. Middleton alludes to the possibility raised by Akiskal (1985) as well as myself (Barlow, 1988) that exposure and tricyclic approaches to anxiety might have common biological mechanisms of action. Specifically, both tricyclic antidepressants and exposure therapy result in an increase or pooling of noradrenaline (and possibly other neurotransmitters) in the locus ceruleus which, in turn, leads to a rise in autoreceptor- mediated inhibition and therefore a drop in neuro- adrenergic transmission in the forebrain. Of course, this cannot be the whole story as anxiety would quickly return after recovery of these functions post-therapy. Something must be learned during this process for therapy to be long-lasting and it is very possible that this something could be learned during either exposure A NEW INTEGRATION OF PSYCHOLOGY AND PHARMACOLOGY 287 therapy, tricyclic therapy or a combination. This hypothesis may also account for the fact that exposure and tricyclics complement each other, whereas preliminary evidence indicates that benzodiazepines interfere with the effects of exposure (Barlow, 1988). Furthermore, the very different types of drug action mentioned by Middleton also seem to have a parallel in psychological interventions. For example, relaxation approaches to anxiety also may interfere with exposure-based procedures and cause the same types of cognitive and motor impairments noted with benzodiazepines. Relaxation procedures are also not well tolerated, at least initially, in anxiety patients producing anxiety and even panic (Borkovec, 1985; Adler, Craske and Barlow, 1987). Nevertheless, the fact remains that we do not know how exposure works (Barlow, 1988) just as we do not know ultimately how tricyclics or benzodiazepines work. Within psychotherapeutic approaches there has recently been great emphasis on specific cognitive change and there is no question that this is an exciting and important area of inquiry. However, just as neurobiologists in previous years were justly accused of biological reductionism, there seems to be a new cognitive reductionism occurring at the expense of the study of affect or emotion. This trend involves a tendency to ignore the richness of emotional and affective experience in an apparent attempt to reduce this experience to cognitive terms and metaphors. Psychology has long been wary of our biological colleagues who would reduce behavior and cognition to electrical impulses in the brain or biochemical activity at a cell synapse. Most people accept the inherent dangers of biological reductionism, and this acceptance has accounted in part for the healthy growth of cognitive and behavioral science. Now it seems there may be little use, in the minds of some, to continue utilizing terms and processes associated with the lOO-year-old tradition of the study of moOd and emotion. This is because little or nothing is seen as qualitatively unique in the experience of emotion and affect. Differences would only be quantitative or dimensional. This would seem to me to be as dangerous as biological reductionism which, in the past, has blinded investigators to the richness of cognitive and behavioral experience. References Adler C M, Craske M G, Barlow DH (1987) Relaxation- induced panic (RIP): When resting isn’t peaceful. Integrative Psychiatr 5; 94—112 Akiskal HS (1985) Anxiety: definition, relationship to depression, and proposal for an integrative model. In ’I‘uma AH, Maser J D (eds), Anxiety and the anxiety disorders. Erlbaum, Hillsdale, NJ Anisman H (1984) Vulnerability to depression: Contribution of stress. In Post R, Ballenger J (eds), Neurobiology of mood disorders. Williams & Wilkins, Baltimore Bandura A, Taylor C B, Williams S L, Mefford I N, Barchas J D (1985) Catecholamine secretion as a function of perceived coping self-efficacy. J Consulting Clin Psychol 53: 406-414 Barlow D H (1988) Anxiety and its disorders: The nature and treatment of anxiety and panic. Guilfond Publications, NY Borkovec T D ( 1985) The role of cognitive and somatic cues in anxiety and anxiety disorders: Worry and relaxation- induced anxiety. In Tuma A H, Maser J D (eds), Anxiety and the anxiety disorders. Erlbaum, Hillsdale NJ. Brown TA, Rapee R M, Antony M M, Barlow D H (1990) Patterns of responding to hyperventilation and carbon dioxide inhalation following behavioral treatment of panic disorder. Paper presented at the annual meeting of the Association for the Advancement of Behavior Therapy, San Francisco, CA, November 1990 Cassens G, Roffman M, Kuruc A, Orsulak P, Schildkraut J (1980) Norepinephrine metabolism induced by environ- mental stimuli previously paired with inescapable shock. Science 209: 1138—1140 Kandel ER (1983) From metapsychology to molecular biology: Explorations into the nature of anxiety. Am J Psychiatr 140: 1277—1293 Maser J D, Gallup GG (1974) Tonic immobility in the chicken: Catalepsy potentiation by uncontrollable shock and alleviation by imipramine. Psychosom Med 36: 199-205 Shear M K, Fyer, A J, Ball G, Josephson S, Fitzpatrick M, Gitlin B, Frances A, German J, Liebowitz M, Klein D F (1991) Vulnerability to sodium lactate in panic disorder patients given cognitive—behavioural therapy. Am J Psychiatr 148: 795—797 Journal of Psychopharmacology 5(4) (1991) 296-298 ©|991 British Association for Psychopharmacology WW Beyond sterile debate Michael J. Telch The University of Tacos. Austin, TX, USA Middleton raises some thought-provoking issues surrounding the pharmacological and psychological treatments of anxiety disorders. One can hardly fault his primary thesis that extreme polarization of pharmacological versus psychological views has deleterious consequences for the advancement of the field. However, the pretext offered to account for the split is wanting. I will direct my comments at two major questions: (I) what contributes to the disparity between biological and psychological approaches to the anxiety disorders? and (2) what can be done to facilitate biopsychological investigation into pathogenesis and treatment? Factors maintaining the polarization of positions Middleton argues that integration of pharmacological and psychological treatments has been hindered by two primary shortcomings of the cognitive model of anxiety disorders: (1) its questionable applicability to anxiety disorders other than panic disorder (e.g. social phobia); and (2) cognitive concepts such as ‘misinterpretation’ and ‘appraisal’ do not lend themselves to empirical testing. Upon closer examination, both of these arguments can be seen as misinterpretations in their own right as opposed to real obstacles for interactive investigation. Misinterpretation number 1: the cognitive model of panic should apply equally well across all the anxiety disorders Middleton notes that the threatening appraisal of somatic cues and their consequent amplification may not adequately account for those anxiety disorders when the provoking stimulus is unlikely to be amplified by _ increased arousal. He then concludes that this state of affairs discredits the cognitive model. I agree that cognitive formulations of panic (Beck and Emory, 1985; Clark, 1986) have limited applicability to other anxiety disorders. However, the specificity of the somatic misinterpretation hypothesis to panic disorder can be seen as a strength of the theory and does not discredit cognitive formulations of anxiety disorders. Middleton’s misconstrual of the cognitive model of panic may be due to his assumption that the persistence of threat misappraisal is primarily governed by the amplification of provoking stimuli. Although such amplification may contribute to the maintenance of faulty threat appraisal in some cases, it is neither a necessary condition nor the most influential one in most anxiety disorders. Indeed, avoidance and other defensive manoeuvres which are present in all the anxiety disorders reinforce threat misappraisal by reducing opportunities for threat disconfirmation. In addition to the cognitive model of panic, other prom- inent psychological theories of pathological anxiety have appeared (Foa and Kozak, I986; Bandura, 1988; Barlow, 1988; Rachman, 1988), as have theories of specific anxiety disorders such as agoraphobia (Goldstein and Chambless, 1978), post-traumatic stress disorder (Chemtob et a1. , 1988) and social phobia (Heimburg and Barlow, 1988). These formulations may prove useful for those pharmacologically minded researchers interested in the integration of psychological and pharmacological approaches. Misinterpretation number 2: cognitive concepts such as ‘misinterpretation’ and ‘appraisal’ do not lend themselves to empirical study Although acknowledging that constructs such as ‘appraisal' and ‘misinterpretation’ possess ‘considerable subjective validity’, Middleton asserts that integration of cognitive formulations by pharmacologically minded investigators has been inhibited by the ‘untestable’ nature of these constructs. Contrary to Middleton’s assertion, studies employing varied research paradigms have provided clear evidence for a linkage between threat appraisal and anxiety disorders. For instance, psychometric assessment of anxiety-relevant appraisals is being increasingly used to examine cognitive factors in the anxiety disorders (McNally and Lorenz, I987; Telch et 01., 1989a,b). Illustrative of this approach is a study demonstrating that appraisal of panic likelihood and panic consequences strongly predicted panic patients’ level of agoraphobic avoidance, whereas panic severity did not (Telch et al., 1989a). As an alternative to psychometric assessment, experi- mental manipulations have been used to examine how alterations in cognitive appraisal affect anxiety (Rapee, Mattick and Murrell, 1986; Sanderson, Rapee and Barlow, 1989). For example, appraisal of perceived control was manipulated in the context of a biological panic provocation (Sanderson, 1989). Panic patients led to believe that they BEYOND STERILE DEBATE could control the concentration of the incoming C02 displayed little COz-induced panic compared with patients administered C02 in the standard fashion. Clark, Salkovskis and Anastiasiades (1990) recently demonstrated that a brief (30 min) cognitive reappraisal manipulation markedly reduced the panicogenic effects of sodium lactate among panic disorder patients. In short, research strongly supports the testability of cognitive concepts such as perceived control. Hence, we should look elsewhere for explanations of the polarization of pharmacological and psychological positions. Although not mentioned by Middleton, economic forces clearly contribute to the biology-psychology polarization. Given that psychologists cannot prescribe drug treatments, it is little wonder that they advocate non-pharmacological interventions, especially for those conditions in which psychological treatments enjoy some success. Though I do not favor the proposal to allow psychologists to prescribe psychotropic medications, we might speculate how such a policy would affect psychologists’ attitudes and behavior toward pharmacological treatments. For psychiatry, powerful incentives undoubtedly contribute to the view of anxiety disorders as primarily biological thus requiring medical treatment. As a result, empirical evidence pointing to psychopathogenicity and the efficacy of psychological interventions is more easily discounted. Clinical research on panic disorder nicely illustrates this discounting bias. Despite the increasing evidence for the efficacy of a new genre of psychological treatments for panic attacks (Clark, Salkovskis and Chalkley, 1985; Beck, 1988; Barlow et (11.; Klosko et (11., 1990; Michelson et a1. , 1990), their recognition in psychiatry has often been slow. This cognitive bias surely contributes to the biology— psychology polarization. By selectively attending to bias-confirming data in our choice of journals, books and conferences, we impede the disconfirmatory process of scientific inquiry. Depolarization through integration? Can this sundered state of affairs be improved? Middleton implies that biological and psychological perspectives could be better integrated. Few would argue with his basic premise, but how should we proceed? As with integration of disparate psychosocial treatments (Goldfried, 1982), the integration of psychological and biological perspectives can occur at several levels of analyses. Because pros, cons and feasibility will vary with the level of analysis, dialogue will be more constructive if we consider the specific level of integration. Integration through common change mechanisms Integration of biological and psychological perspectives 297 can be attempted at the level of common change mechanisms. Middleton raises the interesting possibility that benzodiazepines and cognitive therapy may share a common mechanism of action. The pr0posed mechanism involves the alteration of activity in higher brain centers (e.g. hippocampus) which then indirectly affects medullary nuclei via projections from the hippocampus and periaqueductal gray. This mechanism assumes a reciprocal relationship between threat appraisal and certain neuro- biological activity in higher brain centers. Although reasonable, direct tests are needed, suggesting the need for collaborative efforts to clarify the effects of neuro- biological manipulations on appraisal, and similarly, the effects of appraisal manipulations on neurobiological function. We have recently examined the effects of imipramine on panic appraisals among panic disorder patients. When compared with placebo, imipramine over an 8-week period yielded only modest improvement in patients’ panic appraisals (Agras et 01., 1991). Integration at the procedural level One of the most promising areas for integration of the biological and psychological perspectives is combined pharmacological and psychological treatments, the most widely studied having been the combination of anti- depressants and exposure (Telch, Tearnan and Taylor, 1983; Telch, 1988; Marks and O’Sullivan, 1988). The rationale for this combined treatment is straightforward, namely, that the medication and the psychosocial treatment exert their most potent effects on separate facets of the syndrome. In panic disorder, for example, it has been argued that imipramine exerts its primary therapeutic effect on spontaneous panic, while exposure therapy complements the panic blockade by assisting the patient in overcoming panic-related avoidance (Klein, 1980; Sheehan, 1982). Although several studies have found combined treatments to be more effective than singular counterparts (T elch et al., 1985; Mavissakalian and Michelson, 1986), findings from clinical trials of combined treatments do not consistently support the proposed specificity of treatments (T elch, 1988). Moreover, combined drug-psychological treatments may sometimes lead to negative synergism as illustrated in a recent agoraphobia study in which imipramine plus exposure was significantly less effective than placebo plus exposure on measures of panic appraisal severity and agoraphobia severity (Agras et 01., 1991). Investigation into combined pharmacological and psychological treatments remains one of the most promising areas for cooperative work. Given the recent popularity of high potency benzodiazepines in the clinical management of the anxiety disorders (Pollack and Rosenbaum, 1988), there remains a pressing need for controlled studies to evaluate their use in combination with psychosocial treatments. 298 Also needed are studies of combined approaches involv- ing psychological treatments other than exposure. NIMH has recently funded a collaborative multi—site panic disorder treatment study to examine the singular and combined efficacy of imipramine and cognitive—behavior therapy (Barlow, personal communication). This study is note- worthy for it demonstrates the feasibility of cooperative research among biologically and psychologically oriented investigators. Conclusions Research and clinical management in the anxiety disorders have been plagued by a biology-psychology polarization. Although cooperative efforts between the two disciplines are likely to yield substantial progress, significant barriers remain. Examination of common change mechanisms and the procedural integration of biological and psychological treatments offer fertile ground for cooperative inquiry. Acknowledgements The authors would like to thank Drs Arnold Buss and David Cohen for their editorial comments. This research was supported by NIMH grant MB 44701 and a grant from the Texas Advanced Research Program. Address for correspondence Michael J. Telch Department of Psychology University of Texas Austin TX 78712 USA References Agras W S, Telch M J, Taylor C B, Roth W T, Brouillard M (1991) Imipramine and exposure therapy in agoraphobia: untangling the actions and interactions. Manuscript submitted for publication. Bandura A (1988) Selfefiicacy conceptions of anxiety. Anxiety Res 1: 77 -98 ‘ Barlow D H (1988) Anxiety and its disorders: the nature and treatment of anxiety and panic. Guilford, New York Barlow DH, Craske MG, Cerny J A, Klosko J S (1989) Behavioral treatment of panic disorder. Behav Ther 20: 261-282 Beck A T (1988) Cognitive approaches to panic disorder: Theory and therapy. In Rachman S, Maser J D (eds), Panic: psychological perspectives. Erlbaum, Hillsdale, NJ Beck A T, Emery G (1985) Anxiety disorders and phobias: a cognitive perspective. Basic Books, New York Chemtob C, Roitblat H L, Hamada R S, Carlson J G, Twentyman C T (1988) A cognitive action theory of post- traumatic stress disorder. J Anxiety Disorders 2: 253-27 5 Clark D M (1986) A cognitive approach to panic. Behav Res Ther 24: 461-470 Clark D M, Salkovskis P M, Chalkley A J (1985) Respiratory M. J. TELCH control as a treatment for panic attacks. J Behav Ther Exp Psychiatr 16: 23-30 Clark D M, Salkovskis PM, Anastiasiades P (1990) Cognitive mediation of lactate-induced panic. Presented at the Association for the Advancement of Behavior Therapy, San Francisco, CA. Foa E B, Kozak M J (1986) Emotional processing of fear: Exposure to corrective information. Psychol Bull 99: 20-35 Goldfried M R (1982) Converging themes in psychotherapy: trends in psychodynamic, humanistic, and behavioral practice. Springer, New York Goldstein A J, Chambless D L (1978) A reanalysis of agoraphobia. Behav Ther 9: 47-59 Heimburg R G, Barlow D H (1988) Psychosocial treatments for social phobia. Psychosomatics 29: 27-37. Klein D F (1980) Anxiety reconceptualized. Comp Psychiatr 21: 411-427 Klosko J S, Barlow D H, Tassinari R, Cerny J A (1990) A comparison of alprazolam and behavior therapy in the treatment of panic disorder. J Consulting Clin Psychol 58: 77 -84 Marks I, O’Sullivan G (1988) Drugs and psychological treat- ments for agoraphobia/panic and obsessive-compulsive disorders: a review. Br J Psychiatr 153: 650-658 Mavissakalian M, Michelson L (1986) Agoraphobia: Relative and combined effectiveness of therapist—assisted in vivo exposure and imipramine. J Clin Psychiatr 47: 117 -122 McNally R J, Lorenz M (1987) Anxiety sensitivity in agoraphobics. J Behav Ther Exp Psychiatr 18: 3-11 Michelson L, Marchione K, Greenwald G, Glantz L, Testa S, Marchione N (1990) Panic disorder: Cognitive—behavioral treatment. Behav Res Ther 28: 141-153 ' Pollack MH, Rosenbaum J F (1988) Benzodiazepines in panic-related disorders. Special Issue: Perspectives on panic-related disorders. J Anxiety Disorders 2: 95-107 Rachman S J, Bichard S (1988) The overprediction of fear. Clin Psychol Rev 8: 303-312 Rapee R, Mattick R, Murrell E ( 1986) Cognitive mediation in the affective component of spontaneous panic attacks. J Behav Ther Exp Psychiatr 17: 245-253 Sanderson W C, Rapee R M, Barlow D H (1989) The in- fluence of an illusion of control on panic attacks induced by carbon dioxide inhalation. Arch Gen Psychiatr 46‘: 157 -162 Sheehan D V (1982) Panic attacks and phobias. N Engl J Med 307: 156-158 Telch M J (1988) Pharmacological and psychological approaches in the treatment of panic sufferers. In: Rachman S, Maser J (eds), Panic: Psychological per- spectives. Hillsdale, Erlbaum Telch M J, Tearnan B H, Taylor C B (1983) Antidepressant medication in the treatment of agoraphobia: A critical review. Behav Res Ther 21: 505-517 Telch M J, Agras W S, Taylor C B, Roth WT, Gallen C C (1985) Combined pharmacological and behavioral treat- ment for agoraphobia: A controlled trial. Behav Res Ther 23: 325-335 Telch M J, Brouillard M, Telch C F, Agras W S, Taylor C B (1989a) Role of cognitive appraisal in panic-related avoidance. Behav Res Ther 27: 373-383 Telch M J, Shermis M D, Lucas J A (1989b) Anxiety sensitivity: Unitary personality trait or domain-specific appraisals? J Anxiety Disorders 3: 25-32 - Journal of Psychopharmacology 5(4) (l99l) 301-304 ©1991 British Association for Psychopharmacology ‘Psychological inflammation’. Clarification of the model and a rejoinder H. C. Middleton Clinical Lecturer, Cambridge University Department of Psychiatry, Addenbrooke’s Hospital, Hills Road, Cambridge CBZ 2QQ, UK These are helpful comments which share some common themes, including the paucity of clinical data about combination therapies (Bond, Telch), the effect of economic forces upon the relationship between pharma- cology and psychology and the direction of psychiatric research (Marks, Telch), and established areas of conflict between psychology and pharmacology such as placebo effects (W ardle), conflicting rationales of treatment (Tyrer) and withdrawal/dependency (Bond, Wardle, Tyrer). These are important issues that have to be addressed at a practical level. It is to be hoped that one of the most valuable fruits of cooperation between psychologists and pharmacologists will be an effective resolution of some, if not all, of these difficulties. As well as highlighting practical issues, the commentaries also directly or otherwise emphasize a major conceptual issue; the absence of a model for anxiety which brings together psychological and pharmacological contributions. Such a model is a necessary prerequisite for cooperative research, and I will focus upon the development of such a model in this rejoinder rather than discussing less controversial though no less important practical issues. Barlow points to the need for such a model and recognizes that something of that sort is implicit in what is proposed in the original paper. Wardle cements upon my discussion of interacting brain systems in anxiety, and thus also senses the shadow of such a model. The other commentaries, in various ways, reflect its absence. Tyrer highlights the differences between pharmacological and psychological models of anxiety and refers to the practical consequences of these difficulties. Telch refers to the possibility of common change mechanisms but he does not extend his argument far enough to describe how different interventions might interact. Bond also refers to interactions between psychological and pharma- cological treatments and in particular refers to drugs influencing the actions of serotonin. There is, however, no Speculation upon how these serotonergic agents might assist psychological treatment whereas others, such as the benzodiazepines, might hinder or impair, as she acknowledges they most probably do. My original paper does, in fact, set out to build a model of pathological anxiety that offers a bridge between psychology and pharmacology, overcoming some of these problems. I must take responsibility for presenting it too obscurely, and now take the trouble to discuss what was intended more clearly. The proposed model is indeed a systemic one outlining a multidetermined causal sequence, as suggested by Barlow. It orders a positive interaction between Lang’s three components of anxiety. As an interactive psychopathological process with wide application it might merit the term ‘psychological inflammation’, and the model is illustrated under that name in Fig. 1. In clearer terms what is proposed is that the appraisal of threat is accompanied by reflexive aversive arousal and a propensity to avoid or ‘deny’; this has the effect of inhibiting closer scrutiny and thus facilitates continuing inaccurate appraisal. Two classes of drug effect, the ‘benzodiazepine effect’ and the ‘MAOl/TCA effect’ act upon the causal sequence in different places and with different effects. In his commentary, Telch points to the fact that faulty threat appraisal is often maintained by avoidance and other defensive manoeuvres. Far from misconstruing the process of cognitive therapy as he suggests I do, my initial proposal, and this more explicit model, develop it along just these lines. I argue that the essential ingredient in cognitive therapy for anxiety disorders is precisely targeted exposure. This is achieved by inhibiting threat- reducing strategies, thus increasing exposure to threatening stimuli, closer scrutiny thereof and facilitated reappraisal (page 283). Reading between the lines I think Telch and, perhaps, Barlow have a similar model of cognitive therapy for anxiety disorders in mind. It has the elegance of drawing together the otherwise conflicting claims of those advocating exposure as the essential element in psychological treatment and those with a more ‘cognitive' approach. Clark (1991) has shown that ‘misinterpretations’ of certain bodily sensations as evidence of an impending catastrophic illness are invariably present in patients with panic disorder. Successful treatment is associated with correction of these interpretations and relapse after treatment is associated with persisting misinterpretations. Not only was this true for patients treated with cognitive therapy, but also for patients treated with applied relaxation or with imipramine. What this demonstrates \ . t I . .. :lYun'ALIlm H. C. MIDDLETON “BINTBRPIETATIOH (SITUATION mllATflNlNO) AVBRSIVEAROUSA ‘ mflAgégA- REFLEX AVOIDANCB 302 ' 'o 0!- I I. .qui-d COGNITIVE 'Iauzlonmlgmlr -> Ill-Arum APPRAISAL or: runA'r Illbl WOUIAL Figure l and cognitive components of anxiety and providing a rationale for the influence of two different cl ‘benzodiazepine effect’ and the ‘TCA/MAOI effect’ is that among panic patients, at least, the correction of misinterpretations is a critical element in determining the long—term success of a variety of treatments. There is no doubt, too, that exposure therapy is of considerable value in the treatment of many anxious patients (Marks). Linking avoidance, and exposure therapy, to the maintenance and correction of misinterpretations through their effects upon appraisal offers a way of explaining these findings. Viewed in these terms the main ‘psychological’ aspects of pathological anxiety; overt and covert avoidance, superstitious risk-reducing strategies and misinterpreta- tions, can be understood as either direct or indirect effects of a reflexive response to threat. The reflex response to threat includes avoidance, which impairs appraisal and fosters misinterpretation. Aversive arousal and reflex avoidance in the presence of a threatening stimulus are aspects of a virtually universal vertebrate behavioural reflex. The sensitivity of this reflex will be determined by the transmission properties of the various synapses subserving it, and the properties of these synapses will therefore determine the intensity of physiological change and the probability of avoidance in response to a given appraisal of threat. According to the model, therefore, drugs which alter the transmission properties of synapses involved in this reflex will alter the intensity of reflexive aversive arousal and the propensity to avoid. As a result such drugs could be expected to influence anxiety by altering psychophysiological reactivity. At present it is not possible to dissect differences in appraisal from differences in the sensitivity of this reflex. Most psychophysiological paradigms measure the physiological response to a psychological or behavioural challenge and are thus unable to distinguish between the effects of psychological variables determining the subjective evaluation of threat, and physiological PH YSIOLOGICA I. ‘Psychological inflammation’. A model of pathological anxiety ordering a causal sequence of the physiological, behavioural asses of drug effect, the variables detemlining the intensity of the response to that threat. Hsiao and Potter (1990) outline the differences between neuronal systems that influence physiological activity directly, and those that do so indirectly. A lot of physiological activity is directly controlled by medullary nuclei such as the dorsal motor nucleus of the vagus, nucleus prepositus hypoglossi and the nucleus paragigantocellularis, where reflex visceral functions such as the control of blood pressure and the regulation of breathing are mediated. ‘Higher’ centres that are known to influence physiological activity such as the hypothalamus, the hippocampus and periaqueductal grey appear to exert their effects indirectly, by modulating the activity of these ‘lower’ centres. My proposal is that it is possible to delineate two classes of drug effect upon pathological anxiety which reflect V actions upon different brain structures and which have different implications for treatment, impinging as they do upon the model, the ‘multideterrnined causal sequence’, in different places. I have dubbed these the ‘benzodiazepine effect’ and the ‘MAOI/TCA effect’. These terms should not be understood as referring to the named compounds, but to the two broad classes of anxiolytic agent outlined in the main paper. The ‘benzodiazepine effect’ is that caused by benzo- diazepines and other agents such as barbiturates and ethanol which act upon the GABA—benzodiazepine receptor complex. These receptors are most densely located in the cortex, particularly in the hippocampus. The acute effects of agents that potentiate the activity of GABA at these sites include a reduction in circulating levels of adrenaline and noradrenaline (Stratton and Halter, 1985) and a dampening of catecholamine responses to physical and mental challenge (Ziegler, Ludwig and Klotz, 1984). Cortical structures influence the autonomic system, and thus circulating catecholamine PSYCHOLOGICAL INFLAMMATION: A REJOINDER 303 levels indirectly, via their effects upon the activity of more directly concerned subcortical structures (Blessing et al. , 1981). In terms of the proposed model the ‘benzodiazepine effect’ upon pathological anxiety is likely to be one of dampened appraisal, both of threat and of new information that might be gained by closer scrutiny. This would be consistent with evidence of a deleterious effect of benzodiazepines upon learning (Bond), their interference with exposure therapy (Barlow) and high rates of relapse following their use (Marks). The ‘MAOI/TCA effect’ is that brought about by agents that alter the transmission properties of mono- aminergic synapses. Such agents include those with an established reputation of efficacy in the treatment of anxiety disorders such as imipramine, phenelzine and clomipramine, which influence directly the activity of both noradrenergic and serotonergic systems, and newer agents such as the 5-HT, antagonists, selective 5—HT re- uptake inhibitors and buspirone. Noradrenaline and serotonin are heavily implicated in the activity of brain structures such as the locus coeruleus and its projections, raphe nuclei and the medullary nuclei subserving the regulation of physiological activity. All of these structures are likely to be implicated in reflexive aversive arousal. Chronic, but not acute, TCA or MAOI administration leads to a reduction in catecholamine turnover in the brain and in the rest of the body (Potter et al. , 1985; Charney et al., 1981; Linnoila, Karoum and Potter, 1982), suggesting that one effect of long—term treatment with these agents is a reduction in sympathetic activity. In parallel the therapeutic effect of these agents is a delayed one; given acutely these drugs are anxiogenic, which contrasts sharply with the nature of the ‘benzodiazepine effect’. It thus seems reasonable to propose that the ‘MAOI/TCA effect’ upon anxiety is a change in the sensitivity or reactivity of the primitive, reflex response to threat. In terms of the model this would amount to a reduced probability of avoidance, facilitating exposure and reappraisal. This would fit with what evidence we have of an improvement in exposure therapy with imipramine (Zitrin, Klein and Woerner, 1980, 1983: Mavissakalian, Michelson and Dealy, 1983; Telch, Agras and Taylor, 1985; Mavissakalian and Michelson, 1986) despite little evidence of an effect of imipramine upon panic appraisal (Telch). It is also consistent with ‘cognitive’ findings. When reappraisal does occur in panic patients who have been treated with imipramine, there is a low risk of relapse when the drug is withdrawn (Clark, 1991). I am unable to counter Klein’s criticism of these proposals as ‘speculative’ but by clarifying them I hope I have been able to demonstrate that they are more than ‘a vague ramble supported’ by undocumented and tendentious statements’. A model such as this offers a framework for cooperative research which could provide the ‘controlled, experimental, clinical and basic data’ that he so rightly seeks. Amongst other things it points to the need for information about the effects of different classes of drug upon differing aspects of pathological anxiety rather than the condition as a whole, and to the need of a more detailed exploration of the interactions between avoidance strategies, appraisal of threat and ‘mis- interpretations’. It is a credit to the power of ‘panic’ as an organizing concept that most of the research upon which these ‘speculations’ are based arises from the study of patients with panic disorder. The establishment of ‘panic’ as a research tool in the investigation of anxiety disorders has had such far reaching and productive effects that it does tend to be assumed without citation. Even so it is appropriate to reiterate the view that cognitive theory does not need to explain the initial panic attack in order to be of considerable value in explaining the illness we call panic disorder. Occasional panic attacks are a common finding (Norton, Doward and Lox, 1986). What distinguishes otherwise unafflicted people who have experienced the occasional panic attack from those who develop panic disorder with all its morbid consequences is not the occurrence of the initial panic attack but the presence of some other quality which causes their panic attacks to become recurrent, particularly threatening, or both. There is no reason why this might not be an enhanced propensity to aversive arousal and avoidance, a quality that might well have a ‘biological’ substrate, even though one of its effects would be to generate misinterpretations in the manner proposed. Address for correspondence Dr H C Middleton Cambridge University Department of Psychiatry Addenbrooke’s Hospital Hills Road Cambridge 0132 2QQ UK References Blessing W W, Goodchild A K, Dampney R A L, Chalmers J P (1981) Cell groups in the lower brain stem of the rabbit projecting to the spinal cord, with special reference to catecholamine-containing neurons. Brain Res 221 : 35-55 Charney D S, Heninger G R, Stemberg D E, Roth R H (1981) Plasma MHPG in depression: effects of acute and chronic desipramine treatment. Psychiatr Res 5: 217-229 Clark DM (1991) Proceedings of American Psychiatric Association, New Orleans, 1991 Hsiao JK, Potter WZ (1990) Mechanisms of action of antipanic drugs. In Ballenger J C (ed.), Clinical aspects of panic disorder. Wiley-Lisa, New York, pp. 297-317 Linnoila M, Karoum F, Potter W Z (1982) Efi‘ect of lowdose clorgyline on 24 hour urinary monoamine excretion in patients with rapidly cycling bipolar affective disorder. Arch Gen Psychiatr 39: 513-516 304 Mavissakalian M, Michelson L, Dealy R S (1983) Pharma- cological treatment of agoraphobia: imipramine vs imipramine with programmed practice. Br J Psychiatr 143: 348—355 Mavissakalian M, Michelson L (1986) Relative and combined effectiveness of therapist-assisted in vivo exposure and imipramine treatment of agoraphobia. Am J Psychiatr 143: 1106-1112 Norton GR, Doward J, Cox B J (1986) Factors associated with panic attacks in nonclinical subjects. Behav Ther 17: 239—252 Potter W Z, Sceinin M, Golden R N, Rudorfer M V, Cowdry R, Cali] H M, Ross R J, Linnoila M (1985) Selective anti~ depressants and cerebrospinal fluid. Arch Gen Psychiatr 42: 1171-1177 H. C. MIDDLETON Stratton J R, Halter J B (1985) Efi'ect of a benzodiazepine (alprazolam) on plasma epinephrine and norepineph— rine levels during exercise stress. Am J Cardiol 56: 136-139 Telch M J, Agras W S, Taylor C B (1985) Combined pharma- cological and behavioural treatment for agoraphobia. Behav Res Ther 23: 325-335 Ziegler G, Ludwig L, Klotz U (1984) Stress protective efi‘ects during steady state conditions of bromazepam. Pharmaco- psychiatry 17: 194-198 Zitrin C M, Klein D F, Woerner M C (1980) Treatment of agoraphobia with group exposure in vivo and imipramine. Arch Gen Psychiatr 37: 63-72 Zitrin C M, Klein D F, Woerner M G (1983) Treatment of phobias—1. Comparison of imipramine hydrochloride and placebo. Arch Gen Psychiatr 40: 125-138 ...
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This note was uploaded on 08/12/2008 for the course PSY 364 taught by Professor Telch during the Fall '06 term at University of Texas at Austin.

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AnxietyDisorders - Journal of Psychopharmacology 5(4)...

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