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Saturday 1 May 1965

TREATMENT OF DEPRESSION *

C. M. B. PAREM.D., M.R.C.P., D.P.M.

PHYSICIAN, DEPARTMENT OF PSYCHOLOGICAL MEDICINE,ST. BARTHOLOMEW’S HOSPITAL, LONDON, E.C.1

* Maudsley Bequest lecture delivered in London on Feb. 8, 1965.

THE antidepressant drugs are generally agreed to act onthe genetic or endogenous element of depressive illness(Delay and Deniker 1959). Since genes are organicchemicals and exert their action through enzymes, itfollows that depressive illnesses are likely to be bio-chemical disturbances affecting the control of mood. Thenature of the biochemical defect is unknown, but thepossible effect on mood of changes in the brain con-centrations of certain monoamines is of great theoreticalinterest and has led to big advances in therapy (seeAxelrod 1963, Kopin 1964, Pletscher 1965).

5-hydroxytryptamine (5-H.T.) and noradrenaline are

two monoamines which are thought to be necessary forthe normal functioning of the brain. Many more mono-amines are known, however, and presumably many arestill undiscovered; and some of these may turn out tobe even more important than noradrenaline and 5-H.T.(Dewhurst and Marley 1964). Monoamine oxidase(M.A.o.) is an enzyme which is concerned in the meta-bolism of this group of compounds, and the M.A.o.

inhibitors are drugs which inactivate this enzyme and sointerfere with the metabolism of the monoamines.These important monoamines can be pictured as

localised in cell granules or nerve vesicles, mainly in themidbrain. In these storage organelles they are inactivebut protected from the metabolising enzymes. Part of thestored monoamines is probably situated in the vicinity ofstructures containing M.A.O. (e.g., mitochondria), andnoradrenaline released from this " deeply bound " pool isimmediately metabolised by the surrounding M.A.o. (seeaccompanying figure). Another " readily available"pool of monoamines is thought to be located close to thenerve endings, remote from the M.A.o. but in equilibriumwith the " deeply bound " pool. On nervous stimulationnoradrenaline can be released from this store without

being inactivated, and exert its physiological effect on theadrenergic receptor.

In the laboratory animal reserpine has been shown torelease 5-H.T. and noradrenaline from binding sites, soexposing them to the inactivating enzymes. Shortly afterthe animal has been given reserpine, practically all the5-H.T. and noradrenaline disappear from the brain, andat the same time the animal’s behaviour changes to astate which is compatible with profound depression.Conversely, the brain concentrations of 5-H.T. andnoradrenaline can be increased by administering their

precursors, 5-hydroxytryptophan (5-H.T.P.) and 3,4-di-hydroxyphenylalanine (DoPA). When the concentrationsof the amines have increased sufficiently, the animal’s

behaviour changes-this time to a state of excitement.M.A.O. inhibitors are drugs which inactivate M.A.o.; themetabolism of 5-H.T. and noradrenaline is interfered with,and their concentration in the brain increases. Again, thisincrease in brain concentration of monoamines-thistime caused by decrease in their destruction-results in astate of excitation. As the accompanying figure shows,inhibition of the surrounding M.A.O. results in increasedconcentration of noradrenaline in the " deeply bound "pool and, by equilibrium, a rise in noradrenaline in the"

readily available " pool, and more is thus available forrelease at the receptor site.Whereas the M.A.o. inhibitors exert their main effect on

the "deeply bound" pool by inactivating the surroundingenzyme, the action of imipramine is related to the

" readily available " pool. When noradrenaline isliberated at the nerve-endings, over 95% is inactivated byreabsorption on to its storage sites and only 5% by theenzyme catechol-O-methyl transferase. Imipramine actsby inhibiting this reabsorption, so causing a localisedincrease in active noradrenaline at the receptor site.Thus both groups of antidepressant seem to reach the

same end-result, but by different mechanisms.Clinical

That the antidepressants are not general euphoriantsbut act against a specific biochemical type of depression issuggested by the fact that a patient’s condition may becompletely unchanged by one antidepressant yet responddramatically to another. Whereas the response to two

drugs belonging to different pharmacological groups is

quite inconsistent, drugs belonging to the same pharma-cological group tend to cause a similar clinical effect

(Dally 1960, Dally and Rhode 1961, Pare 1965). Thefact that this pharmacological grouping holds good inclinical practice is most important, not only as a basis forclinical research, but in the management of patients.With both groups of antidepressants there is a latent

period of about 2 weeks before the antidepressant effectbecomes evident, and the patient should be warned that

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improvement will be delayed. In general the earlier thebeneficial effect, the better the final outcome; and thesmaller the effective dose, the better the result. Usuallythe dosage is increased gradually; but if improvement hasnot been attained after 3-4 weeks on a dose of, for instance,isocarboxazid 10 mg. t.d.s. or imipramine 50 mg. t.d.s.,continuance of the drug or further increase of dosage isunlikely to result in more than partial improvement. Thisclinical impression is reflected by the changes in theconcentration of 5-H.T. in human brain, which reach amaximum after 4 weeks’ administration of an M.A.o.

inhibitor (MacLean et al. 1965). If no improvementoccurs, a change of antidepressant to one belonging toanother group is indicated, since a drug belonging to thesame group, even if it is thought to be more potent, isless likely to be beneficial. Any improvement which isattained is more in the way of symptom relief than cure,and the drug should be continued in a maintenance dosefor several weeks or months until either a natural remissionoccurs or the patient, now more capable of tacklingher difficulties, has overcome or adjusted to whateverenvironmental stresses precipitated the depression.Which Drug, Which Patient? ?

From a practical point of view, it is obviously importantto be able to predict in any individual patient which groupof antidepressant is likely to result in improvement, andtherefore which group to try first. Sargant (1961) hassuggested that members of the imipramine group of

drugs are the antidepressants of choice in the more typicalendogenous cases of depression, whereas the monoamine-oxidase inhibitors are indicated in the more reactive or

atypical depressions. Most clinicians would agree with

him, though realising that many typical endogenous casesrespond best to monoamine-oxidase inhibitors and manyreactive or atypical ones to the imipramine group. Butthe more that clinicians try to delineate in detail the sortof depressive illness which responds to one or other groupof antidepressants, the more the subject becomes one ofcontradiction and controversy.This question has now been approached from a genetic

point of view. Angst (1961, 1964) was the first to pointout that patients tended to respond to imipramine in thesame way as close relatives who themselves had beentreated with this drug for depression. We confirmed thissimilarity of response between patient and first degreerelative and found that it held with both the M.A.o.inhibitors and the imipramine group of drugs (Pare et al.1962). Further work is being done to see whether theseresults can be repeated; but meanwhile we have suggestedthat there may be two genetically specific types of

depression, predisposition to which will, of course, breedtrue from one generation to another, and that one typewill respond to the imipramine group of antidepressantsand the other to the M.A.o. inhibitors. We suggest thatthe " imipramine gene " may be a more penetrating oneand thus produce a more " endogenous " picture, the" M.A.o. inhibitor gene " being less penetrating, onlybecoming manifest under stress and thus resulting in amore reactive or atypical clinical picture.Side-effects

It is only by knowing why and how side-effects occurthat the doctor can decrease their incidence and severity inhis clinical practice.With the M.A.o. inhibitors the incidence of side-effects

seems to be closely related to the potency of the drug as an

antidepressant: iproniazid is the most potent and causesmost side-effects; isocarboxazid, phenelzine, and nial-amide are less potent but show few side-effects; andmebenazine comes somewhere in between. As has alreadybeen mentioned, the antidepressant effect of the M.A.O.inhibitors is thought to be due to their ability to inhibitM.A.O., which in turn results in an increase in the brainconcentrations of various monoamines. But the amineconcentrations rise at the same time in other parts of thebody, including the autonomic ganglia, and the side-effects are due in turn to this increased concentration of

body amines. -This was well illustrated in an investigationwhere, following Kety, tryptophan was used in the treat-ment of depressed patients (Pollin et al. 1961, Pare

1963). Tryptophan is the precursor of 5-hydroxy-tryptamine (5-H.T.), and, if used with an M.A.O. inhibitor,would be expected to increase further the already highlevels of brain and body 5-H.T. On the other hand, whengiven to patients receiving imipramine, tryptophanwould not be expected to have any effect since any 5-H.T.formed would be rapidly metabolised by M.A.O., which isnot inhibited by this drug. Briefly, it was found that

tryptophan did indeed potentiate the antidepressant effectof the M.A.o. inhibitors but not of the imipramine groupof drugs. Furthermore, although it was well tolerated bythose patients receiving imipramine, patients taking anM.A.O. inhibitor had a notable increase in side-effects,similar to those seen with the more potent M.A.o.

inhibitors in full dosage.Another important issue is the effect of these raised

concentrations of body-amines when drugs are adminis-tered in combination or owing to the effects of certainfoodstuffs in the diet (Marks 1965). I will confine myselfto the hypertensive reaction. The crux of this reaction isa pronounced rise of blood-pressure, commonly accom-panied by a sudden, usually occipital, headache. This

may occur with any M.A.O. inhibitor and is often preci-pitated by cheese, since many cheeses have a high contentof tryamine. In a patient receiving an M.A.O. inhibitorthis tyramine may be absorbed unchanged from the gutand can then exert its action of releasing noradrenalinefrom its binding sites, which in such a patient are full tocapacity. Broad-bean pods, because of their DOPA

content, and ’ Marmite ’ and ’ Bovril’, for some unknownreason, may also precipitate these hypertensive reactions;and all these must be excluded from the diet of anypatient receiving an M.A.O. inhibitor. Intravenous

amphetamine also causes this reaction by a similar" release " mechanism, and should never be given to

patients on an M.A.o. inhibitor.These hypertensive reactions have decreased notably

since cheese was omitted from the diet; but reactions arestill occurring with tranylcypromine, and this is quite outof proportion to the comparative usage of the drug(Marks 1965). This can probably be explained by thefact that these drugs, while having a common inhibitoryeffect on M.A.o. may have other actions. Thus tranyl-cypromine, in addition to inhibiting M.A.O., has someaction in inhibiting the reabsorption of amines and alsocan itself release the amines from their storage sites-allof which would, of course, increase the tendency to

hypertensive attacks (Ashcroft 1965) (see accompanyingtable).

Increasing the total amine concentration by giving anM.A.O. inhibitor, and at the same time slowing the

reabsorption of active amines by giving a member of the

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EFFECT OF DRUGS ON CATECHOLAMINE METABOLISM (MODIFIED FROMASHCROFT 1965)

imipramine group Qf drugs, can be expected to result in agreater antidepressant effect (see figure). At the same

time, however, it will make the patient much morepredisposed to hypertensive attacks. In my experience,combining the antidepressants is justified in some

patients who are severely depressed and who have failedto respond to other forms of treatment. I use amitriptylineand combine it with isocarboxazid, which is what Icall a " pure " M.A.O. inhibitor. I do not use phenelzineor tranylcypromine, which have amine-releasing pro-

perties ; and there is some evidence that amitriptylineis safer than imipramine when given with an M.A.o.

inhibitor. If a patient is already on an M.A.o. inhibitorand his stores are full of amines, I always stop the drugfor a period and then, when the stores are somewhatdepleted, start isocarboxazid and amitriptyline togetherin gradually increasing dosage.Place of Antidepressants in Treatment of DepressionThere remains the question of when to use the anti-

depressants and how they fit in with other physical andpsychological treatments. Here two factors should beborne in mind:

(1) Antidepressants are not curative in the sense that electro-convulsive therapy (E.C.T.) is curative but simply providesymptom relief until a natural remission occurs. Thus the

drugs may have to be continued for months or even years,during which the patient is exposed to the risk of side-effects.

(2) Antidepressants are effective only in some cases, and as ageneral rule the more serious the depression the less likely arethey to be effective.

.c.T., on the other hand, is particularly effective in thepredominantly endogenous cases of depression whicharise in the involutional period of life. These illnessesare often severe and may go on for as long as two years ormore before a natural remission occurs. Such cases can be

dramatically cured with E.C.T. in a few weeks. E.C.T. isless effective in cases of recurrent depression in youngerpatients, particularly if it is applied early in the illness; it isless effective in cases with reactive or neurotic features,where improvement may be followed by relapse after afew weeks.

Each patient has to be judged separately; but, in apredominantly endogenous depression, the more seriousthe disorder and the longer the estimated course of theillness, the more inclined I am to recommend E.C.T. Onthe other hand, the milder the case and the shorter theestimated course of the illness, the more I am inclined torecommend one of the antidepressants.

E.C.T. is by far the most effective treatment in severeendogenous depression; and in such cases, particularly ifthere is any risk of suicide, most psychiatrists wouldrecommend E.C.T. rather than a less certain form of therapy.Similarly with a prolonged illness, E.C.T., which is afterall extremely safe, is preferable to antidepressants where,in addition to the demoralising effect of a needlessly

long illness, there is the risk of side-effects. This riskinevitably mounts over a long period, particularly if thedoctor relaxes his supervision or the patient herselfbecomes complacent and disregards his precautionaryinstructions.The less endogenous the case, the less effective is E.C.T.;

and it is here, I think, that antidepressants really comeinto their own. A patient whose depression is largely dueto environmental or personality difficulties sees herdifficulties enlarged out of all proportion, and her view oflife and her own capacities are coloured by her mood.Furthermore, her mental functioning is slowed, psycho-therapy is impeded, and her initiative and will to face andtackle her problems are often seriously impaired. Anti-

depressants, by removing the endogenous element of herdepression, may enable the patient, with or withoutformal psychotherapy, to tackle her difficulties and attainbetter adjustment, antidepressant therapy protectingagainst relapse meanwhile. In severe cases of this type,E.C.T. may be needed; but, in my opinion, this shouldalways be combined with an antidepressant to protectagainst the relapse which otherwise so often happenswhen E.C.T. is given alone.The first essential of treatment is diagnosis and a

proper assessment of the cause. To what extent areenvironmental factors causal, and is the patient’spersonality sound enough for her to overcome suchenvironmental difficulties herself, perhaps with some

support, provided her depressive symptoms are relievedby antidepressants ? On the other hand, are her difficultieslargely of her own making, when more formal psycho-therapy may be indicated ? Finally, to what extent is thedepression endogenous and what is the likelihood of

spontaneous remission? Only by thinking on these linescan the physical and psychological treatments be used,together, to the best effect.

"... Students often arrive at university with two distinct andcontradictory, indeed unrelated, sets of assumptions. In thefirst place they expect an elevated intellectual atmosphere andlook forward to a mysterious experience which will result inintellectual transformation: they expect to emerge with newpower. They are vague about how such transformation will beaccomplished and temperamentally ill-disposed to the idea ofits imperceptible gradualness ... Disillusionment is an almostnecessary consequence; unless, from the outset, someone withtime and sympathy is prepared to give this aspiration realisticdimensions, the strength of this pristine aspiration will neverbe harnessed. The mere experience of university routine willotherwise be enough to destroy it."-BRYAN WILSON, NewSociety, April 22, 1965, p. 8.

REFERENCES

Angst, J. (1961) Psychopharmacologia, Berlin, 2, 381.— (1964) Arzneimittel-Forsch. 14, 496.

Ashcroft, G. W. (1965) J. psychosom. Res. (in press).Axelrod, J. (1963) in The Clinical Chemistry of Monoamines (edited by

H. Varley and A. H. Gowenlock); p. 5. Amsterdam.Dally, P. J. (1960) Symposium on Depression, Royal College of Surgeons,

London, 1960.— Rhode, P. (1961) Lancet, i, 18.

Delay, J., Deniker, P. (1959) Canad. psychiat. Ass. J. 4, suppl. p. 100.Dewhurst, W. G., Marley, E. (1964) in Ciba Foundation Symposium on

Animal Behaviour and Drug Action (edited by H. Steinberg, A. V. S.de Reuck, and J. Knight). London.

Kopin, I. J. (1964) Pharmacol. Rev. 16, 179.MacLean, R., Nicholson, J. M., Pare, C. M. B., Stacey, R. S. (1965).

Unpublished.Marks, J. (1965) in Scientific Basis of Drug Treatment in Psychiatry (edited

by J. Marks and C. M. B. Pare). Oxford.Pare, C. M. B. (1963) Lancet, ii, 527.

— (1965) in Scientific Basis of Drug Treatment in Psychiatry (editedby J. Marks and C. M. B. Pare). Oxford.

— Rees, L., Sainsbury, M. J. (1962) Lancet, ii, 1340.Pletscher, A. (1965) in Proceedings of the Fourth Meeting of the Collegium

Internationale Neuro-Psychopharmacologicum, Birmingham, 1964(edited by D. Bente and P. B. Bradley). Amsterdam (in the press).

Pollin, W., Cardon, P. V., Kety, S. S. (1961) Science, 133, 104.Sargant, W. W. (1961) Brit. med. J. i, 225.