Sodium lactate response as a model for panic disorders

TINS - June 1984

188 4Ow30 8 Lembeck, F. and Gamse, R. (1982) Ciba Found. Symp. 91, 35-49 9 Tuckett, R. P. (1980) Sot. Neurosci. Absrr. 6. 428 10 Kniffki, K.-D., Mense, S. and Schmidt. R. F. (1981) Circ. Rex 4S, Supp. 1. U-131 I1 Schaible. H. G. and Schmidt. R. F. (1982) Pflltegers Arch. 394. R57 12 Kumazawa. T. and Mizumura. K. (1980) J. Phwiol. (London) 299. 233-2-U 13 Colehdge, H. M. and Coleridge. J. C. G. (1980) Annu. Rev. Physiol. 42. Jl-U27 14 Nagy. J. I., Iversen. L. L.. Goedert. M.. Chapman, D. and Hunt. S. P. (1983) 1. Neurosci. 3. 399-406 15 Hokfelt. T., Elde, R.. Johansson. 0.. Luft. R., Nilsson. G. and Arimura, A. (1976) Neuroscience 1. 131-136 16 Kawatani. M., Lowe, I. P.. Nadelhaft. I..

Morgan, C. and De Groat, W. C. (1983) Neurosci. Lea. 42, 31 l-316 C.-J., Vincent, S. R., Hokfelt. T.. 17 Dalsgaard. Lundberg. J. M.. Dahlstrom. A.. Schultzberg, M., Dockray. G. J. and Cuello, A. C. (1982) Neurosci. Lerr. 33. 153-159 18 Rosenfeld. M. G., Mermod. J.-J.. Amara. S. G., Swanson, L.. W., Sawchenko. P. E.. Rivier, J.. Vale. W.-W. and Evans, R. M. (1983) Noncre (London) 304. 129-135 19 Coimbra, A.. Sodre-Borgcs, B. P. and Magalhaes, M. M. (1974) 1. Newocyrol. 3, 199-217 20 Nagy. J. 1. and Hunt, S. P. (1982) Neuroscience 7. 89-97 21 Nagy, J. I. and Hunt, S. P. (1983) J. Corp. Newol. 218, 145-158 22 Hunt, S. P. (1983) in Chemical Neuroanarom) (Emson, P. C.. ed.), p. 54, Raven Press, New York

Sodium lactate response as a model for panic disorders An important advance in our understanding of panic disorder is the use of an infusion of sodium lactate as a biological stimulus of an attack, which should enable researchers to investigate such attach under laboratory conditions.

Before the general reader can appreciate this new development, we must describe some of the complexities of the diagnosis of anxiety disorders as conceptualized in the USA. Since 1980, the official guideline for the diagnosis of mental disorders in the USA has been the third edition of the Diagnostic and Statistical Manual (DSM-III, published by the American Psychiatric Association) ’ . This third edition substantially changed the categorization of disorders grouped under the general heading of anxiety disorders. The main subcategories are panic disorder, panic disorder with agoraphobia, generalized anxiety disorder, phobias, and obsessive+ompulsive disorder. The last disorder is not relevant to this report and will not be discussed further. Panic disorder is characterized by the frequent occurrence of panic attacks which are short-lived episodes of rapidly escalating symptoms such as terror, fear of losing control, palpitations, chest discomfort, sweating, dizziness, faintness and tingling. These symptoms are not appropriate to the situation (for example, you have not turned a comer and found yourself face to face with a lion) and do not occur in the context of some other mental disorder such as schizophrenia or depression. Frequently, symptoms of panic disorder occur with agoraphobia (see below). A phobia is an unreasonable fear and avoidance of specific situations or circum-

stances. The DSM-III subcategorizes phobias into simple phobias, social phobias, and agoraphobia. Agoraphobia is fear of an apparently unrelated set of circumstances: buses, trains, crowded stores, theatres, driving, and being alone. The common denominator to these situations is the difficulty of quickly leaving them. Social phobia is fear of being scrutinized by others. Simple phobias are all other fears, such as heights, animals, etc. Generalized anxiety disorder is a residual category for symptoms of nervousness, with hypervigilance, restlessness, insomnia, palpitations, and other common symptoms of anxiety which do not fit into any of the previously described diagnoses. Agoraphobia and panic disorder often go together. If the symptoms of anxiety only and invariably occur in the phobic situation, for example, in a train, then only a phobia is diagnosed. If panic attacks occur spontaneously, i.e. not only and invariably in certain situations, then a person can have both disorders. We have described these diagnostic distinctions at some length because similar distinctions are not used in the UK, and the current work with sodium lactate makes use of these distinctions. The distinction between panic disorder and generalized anxiety disorder is stressed in the USA because of the belief that these disorders respond differently to medication. Generalized anxiety

E. and Csiiik, B. (1981) Prog. 23 Knyihar-Csillik, Hkrochem. Cyrochem. 14, l-137 J. B., Papka, R. E., Della, N. G.. 24 Furness, Costa, M. and Eskay, R. L. (1982) Neuroscience 7, 447-459 M.. Hayashi, 25 Bennett. G. J.. Abdelmoumene. H. and Dubner, R. (1980) J. Comp. Neural. 184, 331-352 T. M. and Mesulam, M.-M. (1980) 26 Brushart. Newosci. ‘Lea. 17. l-6 Brushart, T. M.. Henry E. W. and Mesulam, 27 M.-M. (1981) Neuroscience 6. 2053-2061 28 Hunt, S. P. and Ninkovic. M. (1983) &. J. Pharniacol. 79, 414P B. LYNN *S.

P. HUNT

Deparmtenr of Physiology, University College London, Cower Sweer. London WC1 E 6BT, UK. * MRC Neurochemical Pharmacology Unir. Medical Research Council Cenrre, Medical School, Hills Road. Cambridge CB2 ZQH, UK.

disorder is presumed to be most ameliorated by the benzodiazepines, such as diazepam (‘Valium’) and chlordiazepoxide (‘Librium’ and other brands) the most commonly prescribed benzodiazepines in the USA - while panic disorder has been shown to be prevented by the two classes of antidepressants, tricyclics and monoamine oxidase inhibitor?‘. Most of the many studies which have shown that benzodiazepines are effective for anxiety, when compared to placebo, were done before the distinction of panic disorder and generalized anxiety disorder was established (at least in the USA) and leave it somewhat unclear which disorder or what proportion of which disorder was treated. Nevertheless, there is considerable agreement that the benzodiazepines are effective in generalized anxiety and they are widely used. The value of antidepressants for panic disorder has had less impact on physicians, especially outside of the USA where the diagnosis is not official. Seven double-blind controlled studies have compared imipramine, a tricyclic antidepressant, to placebo in subjects with panic disorder, and six of these studies have demonstrated clearly that the drug is effective2-‘. Fewer studies have shown that monoamine oxidase inhibitors are effective5. The term ‘antidepressant’ has misled clinicians who do not think anxious persons with panic attacks who are not depressed require an ‘antidepressant’. However, the range of a drug’s efficacy must be established by empirical research and not by the label given to it. Yet it should be noted that panic disorder and depression do overlap to some extent, as described in a recent epidemiological studys, although most often the clinical pictures are quite distinct.

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TINS - Jutte I984 To complete this brief review of the drug treatment of anxiety disorders, we should mention a very recent development which makes the situation more interesting (or confusing?). A new benzodiazepine, alprazolam, which adds a triazolo ring to the basic benzodiazepine structure and which, has been shown to be effective in generalized anxiety, just as the other benzodiazepines are, has in one study’ been demonstrated to be as effective against panic disorder as imipramine, while both were better than placebo. If this finding is replicated it will raise many questions concerning the differential efficacy of drugs for anxiety disorder, and suggests that further research is necessary to sort all of this out. Alprazolam may be a unique drug not comparable to other benzodiazepines, or perhaps other benzodiazepines given in comparable dosage would be effective. The identification of persons who appear to be less able to cope with ordinary (or extraordinary) demands has been common for many centuries, but particularly noticeable at times when many young men were called up for military service. Among the many theories adduced for this vaguely described syndrome was that the conversion of lactate to pyruvate in muscle, part of the normal metabolic cycle, was abnormal so that the fatigue and poor performance of these men might be due to excessive build-up of lactic acid. This theory has never been substantiated but it did suggest to Pitts and McClure’” that an infusion of sodium lactate might induce anxiety. Sodium lactate has been used widely as an intravenous infusion to correct hyperacidity of the blood. In the experiment by Pitts and McClure a much larger dose was used over a brief period of 20 minutes. They showed that in subjects diagnosed as suffering from anxiety neurosis (old US classification) the infused was much more likely to induce an anxiety attack than in normal controls. This observation was later replicated’ ‘-13, most recently when the subjects with anxiety were those with panic disorder. This is an exciting development for several reasons, mainly because of the opportunity it provides to study a psychopathological syndrome under laboratory conditions. Under spontaneous conditions, mental disorders do not appear and disappear at will in the laboratory, At best the investigator can use as a subject someone with a disorder, examine her or him for biological or psychological changes, and hope that any changes so found are related to the

disorder and are not merely epiphenomenal. For example, is the amenorrhea associated with anorexia nervosa, a disorder associated with marked weight loss, due to an endocrinological disturbance which is part of the disorder or which is secondary to weight loss? The ability to produce a panic attack at will in the laboratory resolves most of the problems of what is primary or secondary to the panic attack. Before this can be done, there must be some assurance that the panic attack induced by sodium lactate is reasonably similar to the spontaneous one. One means of determining this is to treat the subject who has had a panic attack due to sodium lactate in the usual fashion with imipramine, the most commonly used drug treatment for panic disorder, until the spontaneous attacks end, and then to re-infuse with sodium lactate. If the induced attack is similar to the spontaneous attack, then the subject who has successfully had the spontaneous attacks stopped with imipramine should not have a panic attack when re-infused with sodium lactate. This has been shown to be the case”. What remains now is to use this technique of inducing panic attacks to understand the pathophysiology of panic. So far there are no clear answers yet available, but we expect further research to be profitable. Also on the agenda is to use the infusion in other anxiety disorders to be certain that the induced panic attack is specific to persons with panic disorder. These studies have not yet been done. Hyperventilation has been posited as a cause of panic attacks16, although there are few data to support this. Dudley et al.” measured ventilation and pCOz in 22 subjects, 18 of whom had pulmonary disease, during stressful periods. They found respiratory changes associated with anger and anxiety similar to those occurring during real or ‘suggested’ exercise. They do not describe anyone having a panic attack brought on by hyperventilation. Lowenstein” asserts that hyperventilation causes agoraphobia, but does not present data. Mora et al.” found that subjects with depression or schizophrenia had increased ventilation and decreased pCOz - again not relevant to panic disorder. Finally, Lum’” reports that of 1 735 patients with anxiety caused, he says, by hyperventilation, ‘more than 1 000’ received a course of breathing retraining and relaxation, and 75% were completely free of all symptoms within a year. This brief review of the evidence

adduced to support the hypothesis that hyperventilation causes panic attacks shows that the matter is hardly well established, although it seems reasonable to test this interesting idea in a rigorous fashion. What is clear, so far, is that an old speculative notion (lactatelpyruvate being responsible for an old vague psychiatric diagnosis called neuresthenia) has led to an exciting new finding (that sodium lactate infusions produce panic attacks in some persons), which is the best bet so far that we shall be able to relate a common mental disorder to biological events.

Reading list 1 American Psychiatric Association (1980) Diagtwsric and Suaisricul Manual of Mental DLrorders. 3rd Edtl. American Psychiatric Association. Washington DC 2 Klein, D. F. (1967) Arch. GetI. fsychiarty 16, I lb126 3 Zitrin. C. M.. Klein. D. F. and Woerner, M. G. (1978) Arch. Cett. Psychiat? 3.5, 307-3 I6 4 Zitrin, C. M., Klein, D. F. and Woemer, M. G. (1980) Arch. Gen. Psychiarty 37, 51-59 5 Sheehan, D. V., Ballenaer, J. and Jacobsen, G. (1980) Arch. Getl. ffvchiarry 37, 51-59 . 6 McNair, D. M. and Kahn. R. J. (1981) in Anxiety: New Research and Chat&g cot,cepts (Klein. D. F. and Rabkin, J. G.. eds), pp. 6%80, Raven Press, New York Marks. I. M.. Gray, S., Cohen. S. D. er al. (1983) Arch. Gen. Psychiarry 40, 153-162 Weisman, M. M.. Gershon, E. E.. Kidd. K. K.. Prusoff, B. A.. Leckman, J. F., Dibble, E.. Hamovit. J.. Thomoson. W. D.. Pauls. D. L. and Guroff, J. J’. (1984) Arch. Gen. Psychiatry 4 1, 13-2 1 Sheehan, D. V. ‘Alprazolam in the treatment of panic disorder’. Presented at the Conference on Anxiety Disorders, Panic Attacks, and Phobias. Key Biscayne. FL. 9-11 December 1982 Pitts, F. N. and McClure, J. N.. Jr (1967) N. Etrgl. J. Med. 277. 1329-1336 Fink. M., Taylor, M. A. and Volavka. J. ( 1970) N. Engl. /. Med. 28 I, 1429-144U Kelly, D., Mitchell-Heggs, N. and Sherman. D. (1971) Er. J. Med. 119. 468-l70 13 -Appleby. I. L.. Klein. D. F.. Sachar. E. J. and Levitt. M. (1981) in Atrriety: New Research and Channinn Concenrs (Klein. D. F. and Rabkin, J.-G.: eds). pp. 41&!3, Raven Press, New York 14 Rifkin, A., Klein, D. F.. Dillon. D. and Levitt, M. (1981) Am. J. fsvchiar? 138. 676-677 15 Dudley. D. L.. Martin, C. J., Holmes, T. H. (1964) Psychosomatic Medicine 26, 64-W 16 Hibbert, G. A. (1984) Hvoerventilation as a cause of panic attacks. &it. Med. J. 288, 263-264 17 Lowenstein, H. (1968) Erir. J. of Psych. 114, 11961197 18 Lum, L. C. (1981) /. Roy. Sot. Med. 74, 1-4 19 Mora. J. D.. Grant, L., Kenyon, P.. Patel. M. K., Jenner. F. A. (1976) -Brir. J. Psych. 129. 457361 ARTHUR RIFKIN SAMUEL SIRIS Department of PsychiaIry, Medical Cetuer. New York,

The Mounr Sinai NY 10029, USA.