Antidepressant drugs: does it matter if theyinhibit the reuptake of noradrenaline orserotonin?

Eriksson E. Antidepressant drugs: does it matter if they inhibit thereuptake of noradrenaline or serotonin?Acta Psychiatr Scand 2000: 101 (Suppl. 402): 12±17. # Munksgaard2000.

The current popularity of the selective serotonin reuptake inhibitors(SSRIs) for the treatment of depression should not conceal the fact thatnoradrenergic neurones also seem to in¯uence depressed mood. Selectivenoradrenaline reuptake inhibitors (NRIs) such as reboxetine thus seemto be at least as effective as the SSRIs. It has been suggested that NRIsin¯uence depression by indirectly facilitating serotonergic transmission,or that SSRIs act by facilitating noradrenaline; however, the markeddifferences between SSRIs and NRIs with respect to effects and side-effect pro®le do not support any of these assumptions, but rather suggestthat SSRIs and NRIs in¯uence depression by parallel, independentpathways. In this review the possibility that certain symptoms within thedepressive syndrome (and certain subtypes of depression) respond betterto NRIs, whereas other symptoms (and subtypes) respond better toSSRIs, will be discussed. In addition, the putative usefulness of NRIs forindications other than depression will be commented upon.

Elias Eriksson

Department of Pharmacology, University of Goteborg,

Sweden

Key words: noradrenaline; catecholamines; serotonin;

antidepressants; depression; behaviour; reboxetine

Elias Eriksson, Department of Pharmacology, University

of Goteborg, POB 431, S-405 30 Goteborg, Sweden

Monoamines and depression: noradrenaline or serotoninor both?

Our current understanding of the pathophysiologyof depression is, to a great extent, based on twoclinical observations which both occurred duringthe 1950s. First, in 1952, a putative tuberculostatic,iproniazid, was unexpectedly found to induce amarked symptom reduction in patients with depres-sion (1). Secondly, a few years later, the anti-depressant ef®cacy of imipramine Ð a newlysynthesized compound with some structural resem-blance to the antipsychotic drug chlorpromazine Ðwas discovered accidentally (2).

During the late 1950s and early 1960s, bothiproniazid and imipramine were found to increaseÐ by different mechanisms Ð the activity ofsynapses in the brain using noradrenaline orserotonin as transmitter. Thus, whereas iproniazidwas demonstrated to antagonize the enzymeinactivating noradrenaline, dopamine and seroto-nin (monoamine oxidase, MAO) (3), imipraminewas shown to block the transport mechanismremoving noradrenaline from the synaptic cleft,

hence increasing the synaptic availability of thetransmitter (4). A few years later it was shown thatimipramine antagonizes not only the reuptake ofnoradrenaline, but also that of serotonin (5); bothiproniazid and imipramine hence facilitate bothnoradrenaline and serotonin.

Based on the putative modes of action ofiproniazid and imipramine Ð and on the observa-tion that the monoamine-depleting drug, reserpine,may induce depression (for ref. see 6) Ð thehypothesis that serotonin and/or noradrenaline isimplicated in depression gained considerable accep-tance during the 1960s and 1970s. However,whereas some researchers (mainly American)claimed that the effect of antidepressants ismediated mainly by noradrenaline (7), others(mainly European), in contrast, emphasized thepossible importance of serotonin (5, 8, 9).

The latter theory gained support from theobservation that the bene®cial effect of tricyclicantidepressants and MAO inhibitors may becounteracted by a serotonin synthesis inhibitor(10, 11); in addition, serotonin precursors (trypto-

Acta Psychiatr Scand 2000: 101 (Suppl. 402): 12±17Printed in UK. All rights reserved

Copyright # Munksgaard 2000

ACTA PSYCHIATRICASCANDINAVICAISSN 0902-4441

12

phan, 5-hydroxytryptophan) were shown to displayantidepressant properties (12±14). Further suppor-ting the importance of serotonin, compoundsselectively inhibiting the reuptake of serotonin,without in¯uencing that of noradrenaline, suchas zimelidine and ¯uoxetine, were shown to besuperior to placebo for the treatment of depression(15, 16); indeed, during the 1980s and 1990s, theselective serotonin reuptake inhibitors (SSRIs)became the most widely prescribed antidepressantdrugs, not least in the United States. As a result ofthis development during the 1980s and 1990s thediscussion regarding the biology of depression andother mood disorders has, to a great extent, beenfocused on the putative role of serotonin, ratherthan on that of noradrenaline.

The arguments for a role of serotonin in theregulation of mood and the popularity of the SSRIsshould, however, not conceal the fact that com-pounds selectively or preferentially inhibiting thenoradrenaline transporter (NRIs), with little or noeffect on the reuptake of serotonin such asdesipramine and maprotiline, in fact appear to beat least as effective as the SSRIs for the treatment ofdepression (17, 18). Further support for theantidepressant in¯uence of noradrenaline reuptakeinhibition was provided by the recent observationthat a very selective NRI, reboxetine, is indeed aneffective antidepressant (19). (In this paper, theabbreviation NRI (noradrenaline reuptake inhibi-tor) will be used for compounds preferentially orselectively inhibiting the noradrenaline transporter(such as some of the tricyclic antidepressants,maprotiline and reboxetine).)

Also supporting the concept that facilitation ofnoradrenergic synapses may alleviate depression,several compounds acting as antagonists at nor-adrenaline autoreceptors (idazoxane, mianserin,mirtazapine) Ð hence causing enhanced release ofnoradrenaline Ð have been shown to be effective;moreover, recent data suggest that inhibition ofcatecholamine synthesis may counteract the anti-depressant effect of certain, but not all, antidepres-sants (see below). Therefore, the fact that serotoninis probably involved in the regulation of mood doesnot preclude an involvement of noradrenaline.

Is depression due to a monoamine de®ciency?

It is often suggested that depression is actually dueto a dysfunction in brain serotonergic or norad-renergic neurotransmission. It should be empha-sized that the antidepressant effects of compoundsaugmenting the effect of serotonin and/or nor-adrenaline does not necessarily mean that any ofthese transmitters are actually involved in the

pathophysiology of the disorder. In fact, fourdecades of research in this area have failed toprove beyond doubt that depressed patients differfrom controls with respect to the activity in brainnoradrenaline or serotonin synapses; the theorythat mood is in¯uenced by serotonin and/ornoradrenaline is thus still based merely on indirectpharmacological evidence. Admittedly, subgroupsof depressed patients have been reported to displaybiological abnormalities that may re¯ect a dysfunc-tion in serotonergic or noradrenergic synapses, suchas blunted hormonal responses to noradrenergicor serotonergic agents, or reduced levels of theserotonin metabolite 5-hydroxyindoleacetic acid(5-HIAA) in the cerebrospinal ¯uid. However, thediagnostic con®dence of the abnormalities reportedhas generally been low, and data from differentlaboratories have usually been far from unanimous(for ref. see (20)). On the other hand, the failure todemonstrate clear-cut differences between patientsand controls in this regard does not exclude thepossibility that such differences may indeed exist,but are impossible to detect with the techniques thathave been available. Hopefully, during the forth-coming decade the possible role of the monoaminesin the pathophysiology of depression will be furtherelucidated by the investigation of candidate genescoding for proteins related to serotonin and/ornoradrenaline (enzymes, transporters, receptors) indepressed patients and controls, and by studies ofthe synaptic activity in depressed patients by meansof sophisticated forms of brain imaging.

Do noradrenaline reuptake inhibitors act via serotonergicsynapses (or vice versa)?

In order to explain the ®nding that depression canbe treated (equally effectively) both with SSRIs andwith NRIs, some researchers have claimed that theantidepressant effects of SSRIs are due in fact to afacilitation of noradrenergic neurotransmission;both SSRIs and NRIs should therefore exert anantidepressant effect by facilitating the noradren-ergic activity. This notion, however, contrasts withanimal studies, suggesting that the overall effect ofserotonin synapses on noradrenergic transmission isinhibitory rather than facilitatory (21, 22); also, it isrefuted by data from recent clinical studies showingthat arresting the synthesis of noradrenaline doesnot counteract the antidepressant effect of an SSRI(see below).

According to an alternative hypothesis, the effectof NRIs in depression is due to a facilitation ofserotonin release mediated, e.g. by a1-adrenoceptorson the serotonergic cell bodies, stimulating the ®ringrate of serotonergic neurones (for ref. see (23)).

Noradrenaline versus serotonin

13

Although such a mechanism may indeed contributeto the antidepressant effect of NRIs, the notion thatthe administration of an NRI leads to a robustfacilitation of serotonin neurotransmission, com-parable to that induced by clomipramine or SSRIs,is refuted by the observation that NRIs, in contrastto SSRIs, do not cause `serotonergic' side-effectssuch as nausea, reduced libido and anorgasmia (24).Also, whereas SSRIs and NRIs are probably equallyeffective for the treatment of depression, reuptakeinhibitors with a serotonergic pro®le such asclomipramine and the SSRIs, are clearly superiorto antidepressants with a noradrenergic pro®le, suchas the other tricyclics and maprotiline, for thetreatment of obsessive-compulsive disorder (OCD)(25), panic disorder (26, 27) and premenstrualdysphoria (PMD) (28). If the effects of NRIs indepression were due to a general facilitation ofserotonergic activity one would have expected theNRIs to induce sexual dysfunction and to be aseffective as the SSRIs not only for depression, butalso for OCD, panic disorder and PMD.

Also supporting the assumption that NRIs do notin¯uence depression by facilitating serotonergictransmission, a tryptophan-free diet Ð presumablyreducing the synthesis of serotonin but not that ofnoradrenaline Ð is reported to counteract theantidepressant effect of SSRIs, but not that ofNRIs. In contrast, administration of the noradrena-line (and dopamine) synthesis inhibitor a-methyl-paratyrosine has been found to counteract theantidepressant effect of NRIs, but not that of SSRIs(29). If replicated, these ®ndings clearly suggest thatthe antidepressant effect of SSRIs is largelyindependent of noradrenaline, and vice versa.

Is the antidepressant effect of an NRI different from thatof an SSRI?

Both serotonergic and noradrenergic cell bodies aresituated in the brain stem (in the raphe nuclei and inthe locus coeruleus, respectively), and the noradre-nergic and serotonergic pathways also display aconsiderable anatomical overlap; thus, in most brainareas where noradrenergic nerve terminals are abun-dant, there are also serotonergic nerve endings (andvice versa). As discussed above, it is not likely thatthe effect of NRIs is essentially mediated byserotonin, or vice versa; however, the similaritybetween the serotonergic and noradrenergic neu-rones with respect to localization, and the fact thatSSRIs and NRIs both exert an antidepressant effect,may lead to the suggestion that serotonin andnoradrenaline in¯uence depression via a common®nal pathway, and that the clinical outcome hence

will be the same regardless of whether a noradre-nergic or a serotonergic antidepressant is being used.

Contrasting this assumption, animal experimentssuggest that the in¯uence on behaviour exerted bybrain noradrenergic neurones is, in fact, completelydifferent from that exerted by serotonergic neu-rones. Rodents deprived of brain serotonergicactivity, i.e. by means of a serotonergic neurotoxinor a serotonin synthesis inhibitor, display enhancedirritability and aggression, enhanced sexual activity,enhanced pain sensitivity, enhanced eating beha-viour and a reduction in sleep (for ref. see (20)). Incontrast, none of these symptoms are prominent inrats deprived of noradrenaline. On the other hand,behaviour related to alertness, selective attentionand arousal seem to be stimulated markedly bynoradrenaline but not by serotonin (for refs, see (23,30±33)).

As discussed above, clinical data (not related todepression) also suggest that serotonergic andnoradrenergic pathways in¯uence behaviour diffe-rently. Thus, whereas the SSRIs may induce sexualside-effects such as reduced libido and anorgasmia,the NRIs probably do not; also, whereas the SSRIsand the NRIs appear to be equally effective for thetreatment of depression, the SSRIs are moreeffective than antidepressants with a noradrenergicpro®le for the treatment of obsessive compulsivedisorder, panic disorder and premenstrual irritabil-ity (for refs, see above).

Most studies suggest that the overall antidepres-sant effects of SSRIs and NRIs are approximatelythe same; the clear-cut differences between nora-drenaline and serotonin with respect to how thesetransmitters in¯uence behaviour (see above) may,however, lead to the assumption that the SSRIs andthe NRIs are not interchangeable as antidepres-sants, but may in¯uence different symptoms withinthe depressive syndrome differently. In line with thisassumption, before the reuptake inhibitors withselectivity for one or another of the two transmitterswere available, it was often suggested that tricyclicantidepressants preferentially facilitating serotonin,such as clomipramine, are particularly effective forthe treatment of depressed mood, whereas tricyclicswith a noradrenergic pro®le, such as desipramine,are more effective in reducing psychomotor retar-dation. Although subsequent trials comparingcompounds with selectivity for serotonin or nora-drenaline have not provided unequivocal supportfor this assumption, the hypothesis that SSRIs andNRIs in¯uence the depressive syndrome somewhatdifferently remains a topic of considerable interest.

If one may extrapolate from one psychiatricdisorder to another, the superiority of SSRIs overantidepressants with a noradrenergic pro®le for the

Eriksson

14

treatment of OCD, panic anxiety and various formsof aggression/irritability may lead to the suggestionthat SSRIs are more effective than NRIs for thetreatment of depressed patients displaying anxiety,obsessions/compulsions or irritability/aggression asprominent symptoms. In contrast, NRIs may Ðtentatively Ð be equally, or even more effective, forother symptoms within the depressive syndromesuch as depressed mood, reduced vigilance andreduced social functioning (19).

The concept that SSRIs and NRIs within ahomogeneous group of patients may displaydifferent clinical pro®les is lent support from arecent study showing that, in women with severePMD, a selective NRI (maprotiline) was inferior toan SSRI (paroxetine) in reducing premenstrualirritability, but equally effective in reducingdepressed mood (28). In line with this, van Praagand co-workers (34) have suggested that irritability/aggression and anxiety rather than depressed moodshould be regarded as the primary target symptomsfor SSRIs (also when used for treatment ofdepression). As yet, however, controlled studiesshowing that SSRIs are better than NRIs for acertain subtype of depression, or vice versa, aresparse; also, to what extent a patient not respondingto an SSRI is more likely to respond to an NRI thanto another SSRI remains an open question (cf. 35,18).

If SSRIs and NRIs in¯uence the depressivesyndrome in different ways it seems reasonablethat Ð for some forms of depression Ð a combinedaction on both serotonin and noradrenaline wouldprove more effective than a selective action on oneof the two transmitters only. On the other hand, ifSSRIs and NRIs act via a ®nal common pathway, asynergistic effect of serotonin and noradrenalinereuptake inhibition would not be anticipated.Supporting the assumption that inhibiting thereuptake of both serotonin and noradrenaline insome patients may indeed be more effective thaninhibiting the serotonin transporter only, in several(but not all) studies comparing non-selectiveserotonin/noradrenaline reuptake inhibitors (clomi-pramine, nortriptyline, venlafaxin, milnacepran)with SSRIs, the former compounds have beenfound to be superior to the latter for the treatmentof severely depressed patients (36±39). The assump-tion that a combined action on serotonin andnoradrenaline may be superior to an effect onserotonin only is supported also by preliminary®ndings suggesting that the antidepressant ef®cacyof SSRIs may be augmented by co-administrationof an NRI (40) or of the noradrenergic autoreceptorantagonist mianserin (41). Available data thussuggest that noradrenaline/serotonin reuptake inhi-

bition may be more effective than selective seroto-nin reuptake inhibition; to what extent the clinicaleffect of an NRI may be augmented by serotoninreuptake inhibition Ð or to what extent non-selective serotonin/noradrenaline reuptake inhibi-tors may be superior to NRIs in certain forms ofdepression Ð however, remains to be clari®ed incarefully designed trials.

A selective noradrenaline reuptake inhibitor as a tool inclinical research: which studies are warranted?

Our insight into which psychiatric symptoms andsyndromes are in¯uenced by serotonin hasincreased dramatically thanks to the introductionand extensive use of the SSRIs; in comparison, ourknowledge of the role of noradrenaline in humans isless comprehensive. Although compounds with astronger effect on noradrenergic than on serotoner-gic synapses have been available for many years(desipramine, lofepramin, maprotiline), the recentlyintroduced NRI reboxetine appears to be the ®rsttruly selective noradrenaline reuptake inhibitor(42); also, like the SSRIs, it is a drug with relativelymild side-effects. Thus there are reasons to hopethat reboxetine will not only be a valuablecontribution to the arsenal of antidepressantdrugs, but also an important tool in clinical (andpreclinical) research.

Hopefully, further studies comparing the ef®cacyof non-selective antidepressants to that of SSRIsand NRIs, given alone or in combination, willclarify in which subtypes of depression a combinedeffect on both noradrenaline and serotonin may bepreferable to a treatment selectively affecting eitherserotonin or noradrenaline; also, subtypes ofdepression responding better to NRIs than toSSRIs, and vice versa, will possibly be identi®ed.In addition, the putative role of noradrenaline for anumber of psychiatric disorders other than depres-sion may be explored by evaluating the possibleef®cacy of reboxetine; for example, studies on theeffect of selective noradrenaline reuptake inhibitionin chronic fatigue syndrome, attention de®cit/hyperactivity disorder (ADHD) in children andadults, social phobia, recurrent brief depression,eating disorders and age-related reduction in moodand vigilance would all be topics of considerableinterest. Preliminary data suggest that reboxetinemay be effective for the treatment of dysthymia(43); to have this observation con®rmed, a con-trolled trial is highly warranted. Given the super-iority of clomipramine and SSRIs over othertricyclics and maprotiline for the treatment ofOCD, panic disorder and PMD (see above) onewould not expect a selective NRI, such as

Noradrenaline versus serotonin

15

reboxetine, to be as effective as the SSRIs for theseconditions; however, the possible ef®cacy of rebox-etine in these disorders has not yet been evaluated,and certainly would be worthwhile exploring.Finally, since sexual dysfunction (reduced libido,anorgasmia) is often a problem when SSRIs areused for long-term treatment, to con®rm in well-designed studies that NRIs are indeed devoid ofsuch side-effects should be a task of high priority.

Conclusions

Although NRIs may facilitate serotonergic activityand SSRIs may interact with the noradrenergictransmission, and although SSRIs and NRIs by andlarge are equally effective as antidepressants, towhat extent a reuptake inhibitor acts primarily onthe reuptake of serotonin or on that of noradrena-line is clinically relevant. The af®nity for theserotonin transporter or for the noradrenalinetransporter, or for both, that is being displayedby a novel compound in the test-tube may thustentatively predict, for example, to what extent thedrug will induce anorgasmia, to what extent it willrelieve the symptoms of panic disorder, OCD andPMD, to what extent it will improve vigilance andsocial functioning and to what extent it will beeffective in severely depressed in-patients. Theavailability of the SSRIs have dramaticallyincreased our insight into the in¯uence of serotoninon human behaviour and on various psychiatricsymptoms; hopefully the introduction of the NRIreboxetine will entail a corresponding increase inour understanding of the functional role of brainnoradrenaline.

Acknowledgement

This paper was presented at a satellite symposium to the Scand-inavian Society for Psychopharmacology, entitled `ReboxetineÐ a novel antidepressant drug selectively inhibiting noradrena-line uptake and uniquely improving social functioning'. Thesymposium was sponsored by an unrestricted educational grantfrom Pharmacia & Upjohn.

References

1. DELAY J, LAINEÂ B, BUISSON JF. Note concernant l'action del'isonicotinylhydrazide dans le traitement des etatsdeÂpressifs. Ann MeÂd Psychol 1952;110:689±692.

2. KUHN R. The treatment of depressive states with G22355(imipramine hydrochloride). Am J Psychiatry 1958;115:459±464.

3. ZELLER EA, BARSKY J. In vivo inhibition of liver and brainmonoamine oxidase by 1-isonicotinyl-2-isopropyl hydra-zine. Proc Soc Exp Biol Med 1995;81:459±461.

4. GLOWINSKI J, ALEXROD J. Inhibition of uptake of tritiatednoradrenaline in the intact rat brain by imipramine and

structurally related compounds. Nature 1964;204:1318±1319.

5. CARLSSON A, CORRODI H, FUXE K, HOÈ KFELT T. Effect of anti-depressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-methyl-alpha-ethyl-meta-tyramine. Eur J Pharmacol 1969;5:357±366.

6. GOODWIN FK, BUNNEY WE JR. Depressions following reser-pine: a re-evaluation. Semin Psychiatry 1971;3:435±448.

7. SCHILDKRAUT JJ. The catecholamine hypothesis of affectivedisorders: a review of supporting evidence. Am J Psychiatry1965;122:509±552.

8. VAN PRAAG HM. Antidepressants, catecholamines and 5-hydroxyindoles. Trends towards a more speci®c research inthe ®eld of antidepressants. Psychiatr Neurol Neurochir1967;70:219±233.

9. COPPEN AJ. Biochemical aspects of depression. Int PsychiatrClin 1969;6:53±81.

10. SHOPSIN B, GERSHON S, GOLDSTEIN M, FRIEDMAN E, WILK S.Use of synthesis inhibitors in de®ning a role for biogenicamines during imipramine treatment in depressed patients.Psychopharmacol Commun 1975;1:239±249.

11. SHOPSIN B, FRIEDMAN E, GERSHON S. Parachlorophen-ylalanine reversal of tranylcypromine effects in depressedpatients. Arch Gen Psychiatry 1976;33:811±819.

12. JENSEN K, FRUENSGAARD K, AHLFORS UG et al. Tryptophan/imipramine in depression (Letter). Lancet 1975;2:920.

13. WAÊ LINDER J, SKOTT A, NAGY A, CARLSSON A, ROOS BE.Potentiation of antidepressant action of clomipramine bytryptophan. Lancet 1975;1:984.

14. VAN PRAAG HM. Serotonin percursors in the treatment ofdepression. Adv Biochem Psychopharmacol 1982;34:259±286.

15. CARLSSON A. Some current problems related to the mode ofaction of antidepressant drugs. Acta Psychiatr Scand 1981;290:63±66.

16. FULLER RW. Serotonin uptake inhibitors: uses in clinicaltherapy and in laboratory research. Prog Drug Res 1995;45:167±204.

17. BOUCHARD JM, DELAUNAY J, DELISLE JP et al. Citalopramversus maprotiline: a controlled, clinical multicentre trial indepressed patients. Acta Psychiatr Scand 1987;76:583±593.

18. NYSTROÈ M C, HAÈ LLSTROÈ M T. Comparison between a serotoninand a noradrenaline reuptake blocker in the treatment ofdepressed outpatients. A cross-over study. Acta PsychiatrScand 1987;75:377±382.

19. DUBINI A, BOSC M, POLIN V. Do noradrenaline andserotonin differentially affect social motivation and beha-viour? Eur Neuropsychopharmacol 1997;7:S49±S55.

20. ERIKSSON E, HUMBLE M. Serotonin in psychiatric pathophy-siology. A review of data from experimental and clinicalresearch. In: POHL R, GERSHON S, eds. The biological basis ofpsychiatric treatment. Prog Basic Clin Pharmacol. Basel:Karger, 1990;66±119.

21. MCRAE-DEGUEURCE A, BEROD A, MERMET A et al. Alter-ations in tyrosine hydroxylase activity elicited by raphenuclei lesions in the rat locus coeruleus: evidence for theinvolvement of serotonin afferents. Brain Res 1982;11:285±301.

22. SHIEKHATTER R, ASTON-JONES G. Sensory responsiveness ofbrain noradrenergic neurones is modulated by endogenousbrain serotonin. Brain Res 1993;623:72±76.

23. SVENSSON TH. Brain noradrenaline and the mechanisms ofaction of antidepressant drugs. Acta Psychiatr Scand 2000;101(Suppl. 402):18±27.

24. WALDINGER MD, OLIVIER B. Selective serotonin reuptakeinhibitor-induced sexual dysfunction: clinical and researchconsiderations. Int Clin Psychopharmacol 1998;13:S27±S33.

Eriksson

16

25. THOREÂ N P, AÊ SBERG M, CRONHOLM B, JOÈ RNESTEDT L,TRAÈ SKMAN L. Clomipramine treatment of obsessive-com-pulsive disorder. I. A controlled clinical trial. Arch GenPsychiatry 1980;37:1281±1285.

26. DEN BOER JA, WESTENBERG HG. Effect of a serotonin andnoradrenaline uptake inhibitor in panic disorder; a double-blind comparative study with ¯uvoxamine and maprotiline.Int Clin Psychopharmacol 1988;3:59±74.

27. MODIGH K, WESTBERG P, ERIKSSON E. Superiority of clomi-pramine over imipramine in the treatment of panic disorder:a placebo-controlled trial. J Clin Psychopharmacol 1992;12:251±261.

28. ERIKSSON E, HEDBERG MA, ANDERSCH B, SUNDBLAD C. Theserotonin reuptake inhibitor paroxetine is superior to thenoradrenaline reuptake inhibitor maprotiline in the treat-ment of premenstrual syndrome. Neuropsychopharma-cology 1995;12:167±176.

29. HENINGER GR, DELGADO PL, CHARNEY DS. The revisedmonoamine theory of depression: a modulatory role formonoamines, based on new ®ndings from monoaminedepletion experiments in humans. Pharmacopsychiatry1996;29:2±11.

30. FOOTE SL, BLOOM FE, ASTON-JONES G. Nucleus locuscoeruleus: new evidence of anatomical and physiologicalspeci®city. Physiol Rev 1983;63:844±914.

31. JACOBS BL, ABERCROMBIE ED, FORNAL CA, LEVINE ES,MORILAK DA, STAFFORD IL. Single-unit and physiologicalanalyses of brain norepinephrine function in behavinganimals. Prog Brain Res 1991;88:159±165.

32. AL-ZAHRANI SS, AL-RUWAITEA AS, HO MY, BRADSHAW CM,SZABADI E. Effect of destruction of noradrenergic neuroneswith DSP4 on performance on a free-operant timingschedule. Psychopharmacology 1998;136:235±242.

33. ROBBINS TW, GRANON S, MUIR JL et al. Neural systemsunderlying arousal and attention. Implications for drugabuse. Ann NY Acad Sci 1998;846:222±237.

34. VAN PRAAG HM, KAHN R, ASNIS GM, LEMUS CZ, BROWN SL.

Therapeutic indications for serotonin-potentiating com-pounds: a hypothesis. Biol Psychiatry 1987;22:205±212.

35. AÊ BERG A. Controlled cross-over study of a 5-HT uptakeinhibiting and an NA uptake inhibiting antidepressant.Acta Psychiatr Scand 1981;290:244±255.

36. VESTERGAARD P, GRAM LF, KRAGH-SORENSEN P, BECH P,REISBY N, BOLWIG TG. Therapeutic potentials of recentlyintroduced antidepressants. Psychopharmacol Ser 1993;10:190±198.

37. ROOSE SP, GLASSMAN AH, ATTIA E, WOODRING S. Compar-ative ef®cacy of selective serotonin reuptake inhibitors andtricyclics in the treatment of melancholia. Am J Psychiatry1994;151:1735±1739.

38. CLERC GE, RUIMY P, VERDEAU-PALLES J. A double-blindcomparison of venlafaxine and ¯uoxetine in patientshospitalized for major depression and melancholia. IntClin Psychopharmacol 1994;9:139±143.

39. PUECH A, MONTGOMERY SA, PROST JF, SOLLES A, BRILEY M.Milnacipran, a new serotonin and noradrenaline reuptakeinhibitor: an overview of its antidepressant activity andclinical tolerability. Int Clin Psychopharmacol 1997;12:99±108.

40. NELSON JC, MAZUE CM, BOWERS MB JR, JATLOW PI. Apreliminary, open study of the combination of ¯uoxetineand desipramine for rapid treatment of major depression.Arch Gen Psychiatry 1991;48:303±307.

41. DAM J, RYDE L, SVEJSO J, LAUGE N, LAURITSEN B, BECH P.Morning ¯uoxetine plus evening mainserin versus morning¯uoxetine plus evening placebo in the acute treatment ofmajor depression. Pharmacopsychiatry 1998;31:48±54.

42. MONTGOMERY SA. Reboxetine: additional bene®ts to thedepressed patient. Psychopharmacology 1997;11:S9±S15.

43. BURROWS GD, MAGUIRE KP, NORMAN TR. Antidepressantef®cacy and tolerability of the selective norepinephrinereuptake inhibitor reboxetine: a review. J Clin Psychiatry1998;59:4±7.

Noradrenaline versus serotonin

17