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Treatment of Syndromes or ofSymptoms in Psychiatry?

THE importance of carefully designed trials oftreatment in psychiatric illness lies not only in theguidance they offer to practitioners but also in theinferences that may be drawn concerning the aetiologyof the illnesses themselves. We have lately publishedthe results of a placebo-controlled trial in Nottinghamon the acute treatment of neurotic disorders (July 30, p235) and those of a controlled trial at Northwick ParkHospital on the treatment of acute psychotic illness(July 16, p 119). In both studies treatment wasrandomised to a large group of patients irrespective ofdiagnosis. Thus the psychotic patients were

depressed, manic, or schizophrenic, and receivedlithium, a neuroleptic (pimozide), or placebo. Theneurotic outpatients were diagnosed according to

DSM III, the American system for classification ofpsychiatric illness1 which abolished the general termneurosis and, somewhat arbitrarily, created a series ofdiscrete diagnoses.2 Patients were thus diagnosed ashaving dysthymic disorder, panic disorder, or

generalised anxiety disorder, and, if randomised todrug treatment, received either diazepam, an

antidepressant (dothiepin), or placebo; a separate limbof the trial compared a package of self-help withcognitive/behaviour therapy.

Practical interpretation of the results of the

psychosis trial raises few important difficulties.Particular symptoms emerged as responsive to

particular classes of drugs. For example, delusions andhallucinations clearly responded to pimozideirrespective of diagnosis and the response to lithium ofelevated mood showed a similar trend. Few

psychiatrists are likely to be surprised by such an

1. American Psychiatric Association. Diagnostic and statistical manual of mentaldisorders, 3rd ed. Washington, DC APA, 1980.

2. Tyrer P Neurosis divisible? Lancet 1985; i: 685-88.

outcome in psychosis and many already selecttreatment on the basis of symptoms as much as on thebasis of diagnosis--eg, overactivity routinely dictatesthe choice of a sedative neuroleptic irrespective ofdiagnosis.The findings in the neurosis trial were more

controversial. Patients showed no differences between

diagnostic groups in their response to different typesof treatment. Furthermore, the responses of the entirepatient group did not reveal major differencesbetween active treatment and placebo althoughplacebo-treated patients required more rescue

treatment. Finally, diazepam seemed less effectivethan other treatments, and the researchers concludedthat an antidepressant rather than a benzodiazepine isthe appropriate choice in the drug management ofneurotic disorder. The argument against usingbenzodiazepines has rested on their potential for

dependence rather than their lack of efficacy.3 3

However, in an earlier study on the drug treatment ofneurotic outpatients the Northwick Park group alsofound a tricyclic antidepressant to be more effectivethan diazepam.4 4 The Nottingham study posesdifficulties because the doses of dothiepin prescribedseem very low. Indeed, one could be forgiven forconcluding that all treatments showed only marginalevidence of any efficacy at all.The temptation to draw inferences about aetiology

from results of therapeutic trials is difficult to resist.Differential drug treatment response may offer a wayof classifying either illnesses or symptoms in a moremeaningful way. Lithium has no major effect on thebasic pharmacology of dopamine,5 so the finding thatpimozide has a greater effect than lithium on

particular symptoms (delusions, hallucinations, andthought disorder) strongly suggests that a disorder ofdopamine receptor function underlies theiroccurrence. However, this conclusion holds not

simply in relation to schizophrenia, where parallelarguments are already familiar,6°’ but also in affectivedisorder, in which such symptoms also occur. It isinteresting that increased cortisol release, which is theonly robust biological finding in acute psychoticillness, is also seen across diagnostic categories.8

In neurosis, the competing claims of psychologicaland biological theories of aetiology and the value ofdiagnosis attract more speculation than does themechanism of individual symptoms. The lack of any

3 Committee on Safety of Medicines Benzodiazepines, dependence, and withdrawalsymptoms. Curr Probl 1988; no 21.

4. Johnstone EC, Cunningham Owens DG, Frith CD, et al. Neurotic illness and itsresponse to anxiolytic and anti-depressant treatment. Psychol Med 1980; 10:321-28.

5. Wood AJ, Goodwin GM A review of the biochemical and neuropharmacologicalactions of lithium Psychol Med 1987; 137: 579-600.

6. Carlsson A. Antipsychotic drugs, neurotransmitters and schizophrenia. Am JPsychiatry 1978, 135: 164-73.

7. Peroutka SJ, Snyder SH. Relationship of neuroleptic drug effects at brain dopamine,serotonin, alpha-adrenergic and histamine receptors to clinical potency. Am JPsychiatry 1980, 137: 1512-22.

8. Christie JE, Whalley LJ, Dick H, Blackwood DHR, Blackburn IM, Fink G. Raisedplasma cortisol concentration a feature of drug-free psychotics and not specific fordepression Br J Psychiatry 1986, 148: 58-65.

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advantage of cognitive/behaviour therapy over drugtreatment must cast doubt over claims that cognitivedysfunction is primary in neurosis.9 Somebiochemical abnormality appears equally probable onthe basis of recent studies suggesting inheritance ofpanic disorder10 and abnormality of noradrenergicfunction in anxious patients.ll The failure to finddifferential effects between treatments for differentneurotic conditions must also weaken the view thatsuch diagnoses have a sound aetiological base.

Unfortunately, these negative fmdings leave groundsfor appeal since it is very difficult to study sample sizeslarge enough to reduce adequately the appreciable riskof type II error YBoth the Nottingham and Northwick Park

investigators seem prepared to advance the notion thata spectrum of psychotic disorder or neurotic disorderis more likely to be valid than a differentiated

diagnostic schema with discrete boundaries betweenconditions. However, there are two issues. The first iswhether the symptoms of mental illness and our

ability to describe and measure them will ever beadequate to identify a true underlying continuum or aset of bounded illnesses; this remains most uncertain.The second is whether a biological continuum can beidentified as a substrate for psychiatric symptoms andsyndromes. Disorders of dopaminergic transmissioncould perhaps provide an example of a biologicalcontinuum in psychosis. The actions of

pharmacologically specific compounds, either as

treatments or as challenge drugs, can be the basis foran assay of neurotransmitter function. Such

pharmacological investigation remains one of the fewcoherent approaches to the study of psychiatric illnessthat are available and the results will continue to be of

major importance to our understanding as well as ourpractice.

Progression of Chronic RenalFailure

Is there a degree of renal failure which inevitablyleads to progressive loss of remaining renal functioneven if the underlying disease process abates or isremoved? If so, what is the cause of this progressionand can it be modified? A series of challengingexperiments carried out in Brenner’s laboratory inBoston has led to the formulation of a simplehypothesis with major clinical implications.1 His team

9. Beck AT, Laude R, Bohnert M. Ideational components of anxiety neurosis. Arch GenPsychiatry 1974; 31: 319-25.

10. Noyes RJ, Crowe RR, Harris EL, Hamra BJ, McChesney CM, Chaudhry DR.Relationship between panic disorder and agoraphobia Arch Gen Psychiatry 1986;43: 227-32.

11. Charney DS, Heninger GR. Abnormal regulation of noradrenergic function in panicdisorders. Arch Gen Psychiatry 1986, 43: 1042-54

12. Young MJ, Bresnitz EA, Strom BL. Sample size nomograms for interpreting negativeclinical studies. Ann Intern Med 1983; 99: 248-51.

1. Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressivenature of kidney disease. N Engl J Med 1982, 307: 652-59

have used micropuncture techniques to reveal theintraglomerular events following extensive renalablation in Munich Wistar rats which have superficialglomeruli suitable for this type of study. The

remaining glomeruli hypertrophy and their bloodflow and filtration rate increase. Later, proteinuria andglomerular sclerosis develop progressively and renalfunction declines. These changes appear to be a directconsequence of a rise in the pressure of the glomerularcapillaries (PGc).2 They can be accelerated by ahigh-protein diet, particularly of animal origin,3 andameliorated by a low-protein diet* and angiotensinconverting enzyme (ACE) inhibitors5 (both of whichreduce PGc) and by heparin6 and even by exercise.’Thus, Brenner and colleagues proposed that

progressive renal failure resulted from hyperfiltrationassociated with a raised PGc in the glomeruli whichsurvived the original disease.1

Other factors that may contribute to progressiverenal failure include interstitial deposits of calciumphosphate associated with progressive interstitialfibrosis,8 hyperlipidaemia,9 and mesangial overloadleading to sclerosis.1O It is difficult, even in laboratoryanimals, to determine which factors are primary andwhich secondary. Moreover, there are differencesbetween strains of rats in their susceptibility to

progressive renal failure following extensive

nephrectomyll to which dogs appear to be immune.12The lessons derived from the surface glomeruli ofMunich Wistar rats may therefore not be generallyapplicable in clinical practice.

Observations of patients with chronic renal diseasesuggest that most progress to terminal renal failureand at a predictable rate. Two studies in the mid 1970sshowed that the reciprocal of the serum creatininedeclined linearly with time and was sufficientlyreliable to predict when dialysis would becomenecessary. 13,14 A new study from Liverpool of 108

2. Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BMHyperfiltration in remnant nephrons: a potentially adverse response to renalablation. Am J Physiol 1981, 241: F85-91.

3. Williams AJ, Walls J. Metabolic consequences of differing protein diets in

experimental renal disease Eur J Clin Invest 1987; 17: 117-22.4. Naith KA, Kren SM, Hostetter TH. Dietary protein restriction in established renal

injury in the rat J Clin Invest 1986; 78: 1199-205.5. Anderson S, Meyer TW, Rennke HG, Brenner BM. Control of glomerular

hypertension limits glomerular injury in rats with reduced renal mass. J Clin Invest1985, 76: 612-19.

6. Olson JL. Role of heparin as a protective agent following reduction of renal mass KidInt 1984; 25: 376-82.

7. Heifets M, David TA, Tegtmeyer E, Klahr S. Exercise training ameliorates

progressive renal disease in rats with subtotal nephrectomy. Kid Int 1987; 32:815-20.

8. Ibels LS, Alfrey AC, Haut L, Huffer WE. Preservation of function in experimentalrenal disease by dietary restriction of phosphate. N Engl J Med 1978; 298: 122-26.

9 Moorhead JF, Chan MK, El-Nahas M, Varghese Z. Lipid nephrotoxicity in chronicprogressive glomerular and tubulo-interstitial disease. Lancet 1982; ii: 1309-11

10. Grond J, Beukers JYB, Schilthuis MS, Weening JJ, Elema JD. Analysis of renalstructural and functional features in two rat strains with different susceptibility toglomerular sclerosis. Lab Invest 1986; 54: 77-83.

11. Weening JJ, Beukers JJB, Grond J, Elema JD. Genetic factors in focal segmentalglomerulosclerosis. Kid Int 1986; 29: 789-98.

12. Robertson JL, Goldsmidt M, Kronfeld DS, Tomaszewski JE, Hill GS, Bovee KC.Long term renal responses to high dietary protein in dogs with 75% nephrectomyKid Int 1986; 29: 511-19.

13. Mitch WE, Walser M, Buffington GA, Lemann J. A simple method of estimatingprogression of chronic renal failure Lancet 1976; ii: 1326-28.

14. Rutherford WE, Blondin J, Miller JP, Greenwalt AS, Vavra JD. Chronic progressiverenal disease: Rate of change of serum creatinine concentration. Kid Int 1977; 11:62-70