100

tinguished from true schizophrenia, supports the idea that aD.A. hypersensitivity in the mesolimbic system can produceschizophrenic symptoms.7On the pharmacological side, neuroleptics which block D.A.

receptors will decrease the increased D.A. function due to recep-tor hypersensitivity in the mesolimbic system (as they do intardive dyskinesias). Thus they should be-and are-the mostefficacious treatment for positive symptoms. Dopamine precur-sors ought to exacerbate schizophrenia short-term, but may betherapeutic long-term. Levodopa exacerbates schizophrenia,8,9but these studies were of less than 1 week’s duration and thesymptoms exacerbated were positive ones, as predicted by ourhypothesis. Chronic administration of levodopa with neurolep-tics has been of therapeutic value for negative symptoms,’"’"which would likewise be predicted by our model. Amphetamineand amphetamine-like substances exacerbate schizophrenia,but only the positive symptoms.12 Also, the fact that ampheta-mine psychosis induced by long-term amphetamine use is simi-lar to paranoid schizophrenia and does not include negativesymptoms, would be predicted by our model.

In conclusion, a more efficient way to treat schizophreniawould be to add levodopa to neuroleptics in patients with signsof D.A. hypersensitivity. For patients without hypersensitivity(those with only negative symptoms), levodopa alone mightprevent and/or reverse the development of D.A.-receptor hyper-sensitivity in addition to treating the negative symptoms.Research Department,Institut National de la Recherche

Scientifique,Hôpital Louis-H. Lafontaine;

and Department of Psychiatry,McGill University,Montréal, Québec, Canada

GUY CHOUINARD

BARRY D. JONES

ANTIDEPRESSANT DRUG LEVELS AND CLINICALRESPONSE

SIR,-Our study is in general agreement with the report ofthe World Health Organisation collaborative study’ whichfailed to find a significant relationship between plasma-tricyc-lic-antidepressant (T.C.A.) levels and clinical effects in amitrip-tyline-treated patients. Despite attempts to discount the resultsof the collaborative study, the fact remains that studies oflarger sample size, including ours, fail to find a clinically use-ful relationship between T.c.A. levels and therapeutic effects.Most of the investigations reporting positive findings have hadvery small samples and thus suffer statistical limitations.

While Potter and Goodwin2 cautioned that the W.H.O.

study may mislead the general reader, their equation of "reco-very-rate" with "response-rate" is itself misleading. Methodo-logical differences between studies make it difficult to comparea 35% recovery-rate (final Hamilton rating score 6 or less) inthe W.H.O. study with the 36-43% placebo "response-rate" ofthe M.R.C. study.3 In fact the data of Coppen et al. showedthat approximately 65% of their patients improved (finalHamilton score 15 or less), which is consistent with the litera-ture on antidepressants. The fact that depressed patients inhospital increasingly show T.C.A. resistance with the passage oftime, and therefore may not be a proper sample for detectionof T.C.A. relationship, does not establish that the blood-levels

7. Chouinard, G., Jones, B. D. Unpublished.8. Angrist, B., Sathananthan, G., Gershon, S. Psychopharmacologia, 1973, 31,

1.9. Calil, H. M., Yesavage, J. A., Hollister, L. E. Commun. Psychopharmaco.

1977, 1, 593.10. Gerlach, J., Lühdorf, K. Psychopharmacologia, 1975, 44, 105.11. Ogura, C., Kishimoto, A., Nakao, T. Curr. ther. Res. 1976, 20, 308.12. Janowsky, D. S., El-Yousef, M. K., Davis, J. M., Sekerke, H. J. Archs gen.

Psychiat. 1973, 28, 185.1. Coppen, A., and others, Lancet, 1978, i, 63.2. Potter, W. Z., Goodwin, F. K. ibid. p. 1049.3. M.R.C. Clinical Psychiatry Committee Br. med. J. 1965, i, 881.

of responding outpatients are related to degree of improve-ment.

Our study of 49 amitriptyline-treated (150 mg/day for 6weeks) outpatients, presented at the annual meeting of theAmerican Psychiatric Association, in Atlanta on May 9, will bepublished in detail elsewhere. Briefly, our findings are that62% of patients showed improvement (6 week Hamilton scoreof 12 or less). As in the W.H.O. study we also used a one-weekwashout period before treatment to reduce the numbers of pa-tients improving because of non-drug factors. The mean age ofour patients (39 years), is in the range of those studies tabu-lated by Potter and Goodwin. We failed to find a significantrelationship of plasma amitriptyline, nortriptyline, or com-bined T.C.A. levels to response in the patient group as a wholeor in a more endogenous subgroup.We must hope that efforts to explain away the negative find-

ings of the more definitive studies are not an example of thephilosophy, "if the facts don’t fit my theory, so much the worsefor the facts". We agree with the conclusion of Coppen et aUthat the evidence does not support routine monitoring of plas-ma-T.C.A. levels.

Departments of Pharmacologyand Psychiatry,

Marshall University,School of Medicine,Huntington, West Virginia 25701, U.S.A.

DONALD S. ROBINSONALEXANDER NIES

DELUSIONAL VERSUS NON-DELUSIONALDEPRESSION: NEUROCHEMICAL DIFFERENCES

SIR,-Delusional unipolar depressed patients respond lesswell to tricyclic antidepressants than do non-delusional pa-tients.1, 2 Furthermore, the relationship between antidepressantconcentration in plasma and clinical response seen in non-delu-sional patients does not hold for the delusional patient.3 Per-haps there are neurobiological differences between these twogroups. Meltzer et a1.4 reported that serum dopamine-B-hyd-roxylase activity was significantly lower in psychotic unipolardepressed patients than in normal controls, a result which sup-ports the possibility that delusional depressives differ from con-trols (or from non-delusional depressives) in dopaminergicand/or noradrenergic activity. However, this hypothesis hasnot yet been directly tested by measuring dopamine and nore-pinephrine (noradrenaline) metabolites at the same time in thesame patients.We have studied fifteen female inpatients aged 25-62 with

unipolar depression, all of whom met research diagnostic cri-teria5 for primary major depressive disorder. Seven exhibitedpersistent delusional thinking, while eight patients showed noevidence of delusions. No patient took drugs during the studyand their diet excluded foods contributing to catecholaminemetabolites. After a 14-day baseline period, three successive 24h urines were collected and assayed for 3-methoxy-4-hydroxy-phenethylene glycol (M.H.P.G.),6 the major C.N.s. noradrenalinemetabolite. Within 3 days after urine collections had been

completed, probenecid was administered and cerebrospinalfluid was collected for assay of homovanillic acid (H.V.A.)1 and5-hydroxyindoleacetic acid (5-H.I.A.A .),8 C.N.S. metabolites ofdopamine and serotonin, respectively.The delusional group had significantly lower urinary

M.H.P.G. and significantly higher c.s.F. H.V.A. than did the non-

1. Glassman, A. H., Kantor, S. J., Shostak, M. Am. J. Psychiat. 1975, 132,716.

2. Simpson, G. M., Lee, J. H., Cucilic, Z., Kellner, R. Archs gen. Psychiat.1976, 33, 1093.

3. Glassman, A. H., Perel, J. M., Shostak, M. Archs gen. Psychiat. 1977, 34,197.

4. Meltzer, H. Y., Hyong, W. C., Carroll, B. J., Russo, P. ibid. 1976, 33, 585.5. Spitzer, R., Endicott, J., Robins, E. New York State Psychiatric Institute,

Biometrics Research, 1975.6. Dekirmenjian, H., Maas, J. Analyt. biochem. 1970, 35, 113.7. Bowers, M. B. Neuropharmacology, 1972, 23, 26.8. Ashcroft, G. W. clin. chim. Acta 1964, 9, 364.

101

MONOAMINE METABOLITES, AS MEAN (AND S.E.) IN DELUSIONALAND NON-DELUSIONAL UNIPOLAR DEPRESSIVES

*Non-parametric Mann-Whitney U test, because of heterogeneity ofvariance in some sample distributions.

delusional group (see table). c.s.F. 5-H.I.A.A. did not differ inthe two groups. M.H.P.G.H.V.A. ratios were significantly lowerin the delusional group. The groups did not differ significantlyin c.s.F. probenecid concentrations, age, or severity of depres-sion or agitation (rated daily by nurses).

These data support the view that delusional depression maybe a clinical state accompanied by alteration in brain systemsmediated by’both dopamine and noradrenaline. Such findingsmay provide a neurochemical rationale for clinical use of anti-psychotic-antidepressant drug combinations to treat delusionaldepression.9.,o The data also support hypotheses from animal"and clinicap2 studies regarding interactions between dopamineand noradrenaline (i.e., that functionally decreased norad-renergic activity may facilitate the "release" of dopamine-mediated behaviour). Studies of monoamine interactions maybe increasingly important for the further understanding of theneurobiological substrate of psychopathology.

Clinical Research Ward,Department of Psychiatry,Yale University,New Haven, Connecticut 06508, U.S.A.

DONALD SWEENEYCRAIG NELSONMALCOLM BOWERS

JAMES MAASGEORGE HENINGER

HYPERPROLACTINÆMIA IN CHRONICALCOHOLICS TREATED WITH PROMAZINE

SIR,-Long-acting phenothiazines have been proposed as aform of drug therapy for alcohol-dependence syndrome.1,2Alcoholism causes hyperprolactinsemia. I record here prolactinvalues found in three groups of chronic alcoholics-namely, 5with hyperprolactinsemia on admission (group A), S treatedwith non-depot promazine (group B), and 5 not treated withpromazine (group C). Serum-prolactin was estimated byradioimmunoassay on admission in all three groups and

repeated immediately after completion of treatment in groupsB and C.The table shows that hyperprolactinxmia may be a problem

in alcoholics on admission or in those with normal admission

serum-prolactin concentrations who are treated with proma-zine. There -may be serious consequences for the patient sincehyperprolactinsemia may lead to impotence, hypogonadism,and gynaecomastia in men and galactorrhoea, and amenorrhceain women.3 The promazine-treated patients were given ’Spar-ine’ 100 mg daily for 6 days and in all of them serum-prolactinlevels rose after treatment, post-treatment values being abovethe normal range in three. Phenothiazines are known to raise

serum-prolactin by blocking dopaminergic receptors in the

hypothalamus and thus blocking prolactin-inhibiting factor.’’In the patients not given promazine (group C) serum-prolactinlevels dropped after treatment. The relevance of these findings

9. Extein, I., Bowers, M. B. Comprehens. Psychiat. 1975, 16, 427.10. Nelson, J. C., Bowers, M. B. Archs gen. Psychiat. (in the press).11. Antelman, S. M., Caggiula, A. R. Science, 1977, 195, 646.12. Sweeney, D R., Pickar, D., Redmond, D. E., Jr., Maas, J. W. Lancet, 1978.

I, 872.1 Q. Jl. Stud Alcohol, 1966, 27, 5102. Kinnel, H G. Lancet, 1977, ii, 659.3. Majumdar, S K., Thomson, A. D., Shaw, G. K. Br. med. J. 1978, i, 409.4. Thorner, M O. Lancet, 1975, i, 662.

SERUM-PROLACTIN BEFORE AND AFTER TREATMENT

*Mean is.D. and range. Normal up to 500 VII.

to the use of slow-release injectable phenothiazines is not

known.I have seen three male alcoholics with clinical features of

hypogonadism in this unit during the past year, and all ofthem were hyperprolactinaemic on admission.

Depressive psychosis may also be associated with raised pro-lactin secretion,5 and depressive symptoms and suicide arecommon in alcoholics.6

Elmdene Alcoholic Treatment Unit,Bexley Hospital,Bexley, Kent DA5 2BW SISIR K. MAJUMDAR

FAILURE OF METHYL-C.C.N.U. AND5-FLUOROURACIL IN COLORECTAL CANCER

SIR,-A report from the Sidney Farber Cancer Institute’ oncombination chemotherapy with 5-fluorouracil and methvlchloroethyl-cyclohexyl-nitrosourea (methyl-c.c.N.U.) in

advanced colorectal cancer has failed to confirm the resultsobtained in earlier studies.2.3 However, these drugs are still

widely used and believed to be effective. We report here theresults of treatment in a group of 49 patients-37 withadvanced colorectal cancer, 11 with carcinoma of the pan-creas, and 1 with metastases from an cesophageal primary-who were treated with similar combination chemotherapy.

There were 27 males and 22 females aged 30-74. Criteria for entryto the study were histological confirmation of carcinoma, measurabledisease, and progressive disease which could not be treated by radio-therapy or surgery. 7 patients had had previous chemotherapy, 11 pre-vious radiotherapy, and 3 a combination of both. 4 received concomi-tant radiotherapy for local problems. 35 patients had liver metastases.The treatment schedule was methyl-c.c.N.U. orally 150 mg/m2 on

day 1 with 5-F.U. i.v. 325 mg/m2 and dacarbazine (D.T.I.C.) i.v. 75

mg/m2 on days 1-5. Patients with pancreatic carcinoma were treatedwith mitomycin C (3 mg/m2) on days 1-5 instead of D.T.I.C. Thesecourses were repeated every 6 weeks. Response was assessed at 10weeks and at 6 months as "complete response" (disappearance of allmeasurable disease), "partial response" (50% reduction in all measur-able lesions), "no change" (no evidence of progression), or "progres-sion" (new lesions, increasing size of indicator lesions, with or withoutrising carcinoembryonic antigen levels and biochemical abnormalities.

22 patients received one course only, 13 received two

courses, and 14 more than two courses. 4 patients with pan-creatic carcinoma had known residual disease after surgery. Ofthe patients with measurable disease 11 were unassessablebecause of insufficient follow-up data or change of chemo-therapy (though this reflected clinical evidence of progressionof disease). 25 out of 49 patients had progression of disease by10 weeks, 10 patients shows no change, and 3 showed partial

5. Horrobin, D. F. Br. J Psychiat. 1974, 124, 456.6. Merry, J., Renolds, M. C., Bailey, J., Coppen, A. Lancet, 1976, ii, 481.1. Lokich, J. J., Skarin, A. T., Mayer, R. J., Frei, E., III Cancer, 1977, 40,

2792.2. Kisner, D., Schein, P., Cohen, L., Smythe, T., Duvall, C. Am. Soc. clin.

Oncol. 1976, 17, 264.3. Moertel, C. G., Schutt, A. J., Hahn, R. G., Reitemeier, R. J. J nat. Cancer

Inst. 1975, 54, 69.