98 Y I* )I Ole J. Rafaelsen, Niels Juel Christensen & Annette Gjerris

K.A.S. Herlev, Department of Medicine F, Copenhagen Herlev, Denmark)

U

-1Psychochemistry Institute, Rigshospitalet, Copenhagen, Denmark

ADRENALINE AND MAO-INHIBITION IN CSF AND BRAIN.

MAO-inhibitors (MAOI) were among the substances that heralded the psychopharmacological revolution in the early 1 9 5 0 ' e s . But after early glory their role was taken over by other drugs due to un- predictability of clinical response and troublesome unwanted effects in the form of drug-drug and food-drug interactions (White K, Simpson G. J Clin Psychopharmacol 1 9 8 1 , I, 2 6 4 - 2 8 2 ) .

After many years in near-oblivion the MAOI witness now a renewed interest. New MAOI's are more specific and reversible in their action compared to the irreversibility of the classical MAOI's.

We now know that MA0 enzyme (monoamine gxidase) exists in two forms: (1) MA0 type (MAO-A) (Its preferred substrates include serotonin and noradrenaline) and ( 2 ) MA0 type B (MAO-B)(its preferred sub- strates include 'trace' amines as phenylethylamine). Dopamine seems to be preferentially deaminated by MAO-B - at least in man, whereas tyramine is a good substrate for both forms of the mono- amine oxidase enzyme (Kline et al. J Clin Psychopharmacol 1981 , A, 410-411; Pare et al. Lancet 1982 , ii, 1 8 3 - 1 8 6 ) .

Most of the MAO-inhibitors are nonselective, i.e., they inhibit both MAO-A and MAO-B, but a few are selective (Pickar et al. Psychopharmacology 1981 , 74, 8 - 1 2 ) .

Clorgyline is a selective inhibitor of MAO-A, whereas pargyline and deprenaline (Deprenyl) are selective inhibitors of MAO-B (Lipper et al. Psychopharmacology 1979 , 62, 123-128; Potter et al. Arch Gen Psychiatry 1982 , 39, 505-510). It was hoped that one or the other type of selective MAO-inhibitors would have a more favourable ratio between wanted and unwanted effects, but these expectations have as yet not been substantiated (Pickar et al. Arch Gen Psy- chiatry 1 9 8 2 , - 39 , 525-540) . For nearly forty years clinicians have had the feeling that there were types of depressions responding better or only to MAO-inhibi- tors. But whenever it was tried to prove this tenet by comparisons in well-planned studies, the results were disappointing. The most notorious case was the British Medical Research Council from 1 9 6 5 where the MAO-inhibitor phenelzine was inferior not only to electroconvulsive therapy (ECT) and to imipramine, but also to placebo, - the latter difference was, fortunately enough, not statistically significant (Shepherd M, Br med J 1 9 6 5 , 1, 8 8 1 - 8 8 6 ) . Ever since, many clinicians has argued that it was indeed the 'atypical' depressive patients who were candidates for MAO-inhibitor treatment and that such patients did rarely enter psychiatric hospitals and departments and that it therefore was not surprising that the results with hospitalized patients were rather disappoin- ting (Quitkin et al. J Clin Psychopharmacology 1981 , Vol 1. - 2, 7 0 - 7 4 ) .

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Giller and his co-workers (1982) compared Marplan ( R, ( = isoc arboxa- zide) with placebo and found trends suggesting that the markedly improved group showed less depression, anxiety, sleep disturbance, weight loss and fewer gastrointestinal complaints, but more helplessness and worthlessness. Others have also had to conclude that there were only weak differences in the profile between a tricyclic antidepressant like amitriptyline and a MAO-inhibitor like phenelzine, amitriptyline producing greater improvement in depressive impairment of work and interests while phenelzine produced additional improvement in anxiety ratings (Rowan et al. In: Youdim MBH, Paykel ES, eds. Monoamine oxidase inhibitors. Chichester: John Wiley & Sons Ltd., 1981, 125-139). Nies and Robinson (1981) compared the same two drugs and found no differen- ces in measures of total symptom severity or in patients with 'fears of recent onset'; they suggested, however, that phenelzine might be particularly efficacious in treating patients whose symptomatology included 'social fears'.

When treating neurotic patients with phenelzine or diazepam, Martin Roth and his group found no evidence of a difference in pattern of response between the two treatment groups and it was not possible to predict response to treatment from pretreatment variables (Mountjoy et al. Prog Neuropsychopharmacol 1980, 4, 303-308).

A new approach was undertaken by Davidson and his group when making operational definitions of typical and atypical depression: "we define typical depression as a state which is associated with loss of any of the following: appetite, weight or libido. Atypical depression is the converse, namely a gain in any of the above" (Davidson et al. Arch Gen Psychiatry 1982, 39, 527-534). Their results applying this very simple set of distinctions were remarkable. The 'typical' depressions did not significantly better on isocarboxazide than on placebo, although a uniform trend was noted which favoured the MAO-inhibitor, whereas the 'atypical' depressions receiving isocarboxazide showed significantly greater improvement than those atypical cases receiving placebo on items of depression, anxiety, phobia, sensibility, somatisation, and obsession (Davidson et al. In: Youdim MBH, Paykel ES, eds. Monoamine oxidase inhibitors. Chichester: John Wiley & Sons Ltd., 1981, 115-124)

The last-mentioned study by its simple operationalisations of typical and atypical depression should invite for replication studies to falsify or verify this interesting tenet.

The various reviews are immediately confronted with the crucial problem: How can you discuss efficacy as long as you have not defined the patient population? (Quitkin, Rifkin & Klein, Arch Gen Psychiatry 1979, 36, 749-7591. Suffice it to say that a majority of phenelzine-placebo studies showed positive effects in non-endogenous depression, whereas the results were modest or outright not different from placebo in some important studies in endogenous depression (Greenblatt, Grosser & Wechsler, Am J Psychiatry 1964, 120, 935-943; Shepherd M, Br Med J 1965, I, 881-886; Raskin et al. Arch Gen Psychiatry 1974, - 30, 66-75).

It has been tried to explain some of the inherent problems pharmacodynamically and pharmacokinetically. Pharmacodynamics includes effective dosage and duration of treatment. Inhibition of at least 80% platelet-MA0 led to clinical improvement in 68% of phenelzine treated patients, whereas only 44% of those with lower MAO-inhibition had a favourable response (Robinson et al. In: Lipton M, DiMascio A, Killam KF (eds): Psychopharmacology, A Generation of Progress. New York, Raven Press 1978a, 961-973). The same researchers found that with 60 mg of phenelzine, maximum platelet MAO-inhibition took more than two weeks to occur (Robinson et al. Arch Gen psychiatry 1978b,35, 629-685). We here see a possible explanation for the clinicalabservation that full effect of MAO-inhibitor therapy takes four to six weeks.

It has been suggested that all MAO-inhibitor treated patients should have a platelet MAO-analysis after 3-4 weeks to ascertain whether sufficient MAO-inhibition had occurred knowing the wide interindividual variation to drugs. This has at least not yet gained widespread acceptance, but it is evident that no patient has had an optimal chance to respond to this class of drugs if he has not had phenelzine 60 mg per day, isocarboxazide 30 mg per day or other MAO-inhibitors in similar dosage, for at least four weeks and preferably six weeks.

From a pharmacokinetic viewpoint it is important that MAO-inhibitor partly are metabolized by acetylation. Individuals vary so con- siderably in their acetylation capacity that they can be divided into fast-acetylators and slow-acetylators. It was conceivable that this might influence the clinical response to MAO-inhibitor treatment, but investigations have failed to confirm this hypo- thesis.

Adrenaline has in recent years been recognized as a brain neuro- transmitter, quantitatively much more sparsely present in the brain and CSF than noradrenaline.

In collaboration with Dr. Niels Juel Christensen, also in Copenha- gen, we have performed two studies of CSF-adrenaline. Both studies showed that CSF-adrenaline was reduced by some 75 per cent in depression and normalized on clinical recovery (Christensen et al. Acta Psychiatr Scand 1980, 61, 178-182; and that the reduction was equally pronounced in endogenous and in non-endogenoc depression (Gjerris et al. I11 World Congress of Biological Psychiatry, Stockholm, 1981b; Amsterdam. Elsevier/North-Holland Biomedical Press, 565-568). CSF-noradrenaline showed no differences between depressed and recovered patients and controls.

We have next turned to animal experimentation, to study whether antidepressant drugs influenced CSF-adrenaline and noradrenaline. Isocarboxazide was administered intragastrically every day and CSF-adrenaline doubled already after 24 hours and continued to increase, reashing some 250 per cent after six weeks of continuous treatment. In contrast, rat CSF-noradrenaline increased more slowly, and the increase was percentage wise much smaller, reachinc only some 40 per cent after six weeks (Gjerris et al., VII World Congress of Psychiatry, Vienna 1983 (to be published)). I would

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like to mention the study of da Prada (1982) who using one of the new reversible MAO-inhibitors found that the increase of adrenaline in rat hypothalamus was faster, more pronounced, and longer lasting than that of noradrenaline.

We hope in CSF-adrenaline to have found a state-dependent marker related to the presence of depression, but not to its clinical subtype, a marker useful in the differential diagnosis of depression and in assessing the effect of various treatments.

In a parallel investigation of CSF peptides we have found a fifty per cent reduction of vasoactive intestinal polypeptide (VIP), but with a different characteristic: CSF-VIP is only low in non-endogenous depressions (but not in classical endogenous depressions), and it remains low after clinical recovery. This may thus be a state-independent (i.e. a trait-) marker of a subtype of depression (Gjerris et al. In: Perris C, Struwe G, Jansson B, eds. Biological Psychiatry 1981a. Amsterdam: Elsevier/North-Holland Biomedical Press, 359-361).

The combination of state- and trait-markers will be of paramount importance for future psychochemical and psychopharmacological research. It will perhaps also, at long last, give us the tools in hand to tell us which patients will respond - preferentially or only - to MAOI's and thus make us realize a differentiation in therapy that will further a differentiation in our understanding of the biology of depression.

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Christensen NJ, Vestergaard P, SQrensen T, Rafaelsen OJ. Cerebrospinal fluid adrenaline and noradrenaline in depressed patients. Acta Psychiatr Scand 1980, 61, 178-182. da Prada M, Kettler R, Keller HH, Haefely WE. Neurochemical effects in vitro and in vivo of the antidepressant Ro 11-1163, a specific and short-acting MAO-A inhibitor. Mod Probl Pharmacopsychiatry 1983, 19, 231-245. Davidson J, McLoed M, Law-Yone B, Linnoila M. A comparison of electroconvulsive therapy and combined phenelzine-amitriptyline in refractory depression. Arch Gen Psychiatry 1978, - 35, 639-642.

Davidson JRT, Miller RD, Turnbull CD, Sullivan JL. Atypical depression. Arch Gen Psychiatry 1982, - 39, 527-534.

Davidson J, Weiss J, Sullivan, J. Turnbull C, Linnoila M. A placebo controlled evaluation of isocarboxazid in outpatients. In: Youdim MBH, Paykel ES, eds. Monoamine oxidase inhibitors. Chichester: John Wiley & Sons Ltd., 1981, 115-124.

Gjerris A, Barry DI, Christensen NJ, Rafaelsen OJ. MAO-inhibitor revisited I: Adrenaline (A) and noradrenaline (NA) in cerebrospinal fluid (CSF) in isocarboxazide treated rats. VII World Congress of Psychiatry, Vienna 1983, to be published

Gjerris A, Fahrenkrug J, Bajholm S, Rafaelsen OJ. Vasoactive intestinal polypeptide (VIP) in cerebrospinal fluid in psychiatric disorders. In: Perris C, Struwe G, Jansson B, eds. Biological Psychiatry 1981. Amsterdam: Elsevier/North-Holland Biomedical Press, 1981a, 359-361.

Gjerris A, Jensen E, Christensen NJ, Rafaelsen OJ. Adrenaline and noradrenaline in psychiatric disorders. I11 World Congress of Biological Psychiatry, Stockholm, 1981. Amsterdam: Elsevier/North-Holland Biomedical Press, 1981b, 565-568.

Giller E, Bialos D, Riddle M, Sholomskas A, Harkness L. Monoamine oxidase inhibitor-responsive depression. Psychiatry Res 1982, - 6, 41-48.

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Mountjoy CQ, Marshall EF, Campbell IC, Garside RE', Roth M. Prediction of response to treatment with phenelzine in neurotic patients. Prog Neuropsychopharmacol 1980, 4, 303-308. Pergamon Press Ltd. Great Britain.

Nies A, Robinson DS. Comparison of clinical effects of amitriptyline and phenelzine treatment. In: Youdim MBH, Peykal ES, eds. Monoamine oxidase inhibitors. Chichester: John Wiley & Sons Ltd., 1981, 141-148.

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23. Rowan PR, Paykel ES, Parker RR, Gatehouse JM, Rao BM. Tricyclic anti-depressant and MAO-inhibitor: Are there differential effects? In: Youdim MBH, Paykel ES, eds. Monoamine oxidase inhibitors. Chichester: John Wiley & Sons Ltd., 1981, 125-139.

24. Shepherd M. Clinical trial of the treatment of depressive illness Br Med J 1965, - 1, 881-886.

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