The enhancement of social functioning as a ... - Dr. David Healy

s26serotonergic systems are both effective antidepressants, thetraditional response has been to invoke a final commonpathway in p-receptor downregulation or 5-HT2 receptorchanges, implicitly locating the 'lesion' in these receptorsrather than specifying any functional consequences that mightstem from receptor alteration.An alternative response has been to postulate the notion ofnoradrenergic or serotonergic depressions with the implicationthat if the neurobiological status of particular patients couldbe pinpointed then the selection of the appropriate drug wouldenhance the chances of therapeutic success. On this basis, agood deal of research has been directed towards determiningwhether some individuals are 'noradrenergic deficient', asindicated by levels of 3-methoxy-4-hydroxyphenylglycol(MHPG) and other catecholamine metabolites, or'serotonergicdeficient', which, it is assumed, will be revealed by evidenceof reduced serotonin turnover in the form of lowered CSF 5-HIAA (Healy, 1987; Montgomery et al., 1987; Healy, 1997;'Montgomery, 1997). To date, neither efforts to distinguishdifferent biochemical depressions nor to boost therapeuticresponses by targeting those who have low levels of one orother neurotransmitter with an appropriate agent, has bornefruit. Moreover. the affective disorders have never looked likethe inborn error of metabolism disorders that the above viewof their nature would imply.Implicit in these approaches is the notion that antidepressantsare 'magic bullets' and therefore there is no need tospecify any indirect functional changes, whether behaviouralor physiological, that they need to produce in order to bringabout recoveries. An alternative way of viewing thesecompounds is that, currently, we possess a variety ofantidepressant principles or perhaps, more broadly speaking,anti-nervousness principles. If the nature of these principlescan be specified more closely, it may allow us to deploy ourtherapeutic armamentarium more rationally.Indeed, adopting this approach, it is possible to turn theargument about noradrenergic and serotonergic depressionsaround entirely and to suggesthat it is expected that drugswhich'are active on the noradrenergic system would not workproperly if there were abnormalities of the noradrenergicsystem. Equally, drugs active on the serotonergic system wouldbe least likely to work effectively in the presence ofabnormalities of that system. This argument is similar inform to the proposal that aspirin or other non-steroidal antiinflammatorydrugs would be least effective for arthriticconditions in individuals who had disorders ofthe prostaglandinpathways on which these agents act. On this basis, it mightbe argued that medications which are selective to a particularsystem are likely to be either ineffective or toxic to individualswith abnormalities of that system. Some indications of possibleoutcomes can be deduced from recent data presented byBrunner et al. (1993) on abnormal behaviour in individualswith monoamine oxidase deficiencies.A consideration of the therapeutic possibilities of aspirinpoints to the fact that it can be anti-inflammatory, anti-pyreticand antithrombotic. Its useful deployment in clinical situationsdepends on understanding the nature of these actionsrather than relying on the fact that aspirin acts onprostaglandin synthesis. What functional outcomes are therefrom actions on the noradrenergic or serotonergic systems?D. HEALYAND T. McMONAGLEIn the field ofpersonality biology, it has been traditional tosuggesthat the noradrenergic, dopaminergic and serotonergicsystems have differing functions. A number of schemes havebeen produced (Cloninger, 1986; van Praag,1992). Accordingto most schemes, noradrenaline is particularly important invigilance, serotonin in the regulation of impulse and irritability,and dopamine in the regulation of drive (Fig. l).If this scheme is followed, it becomes possible to suggesthatdrugs which act on the serotonergic system have an antiirritabilityaction of some form. This action might be expressedby a physician to a patient enquiring what the drug will do interms such as 'it will make you sanguine'. This type of actionwill be 'anxiolytic' but it might be expected to provide adifferent type of anxiolysis to the anxiolysis, for example, thatstems from the muscle relaxation provided by benzodiazepines.Benzodiazepines, in addition to other central actions, inhibitthe feedback loop from muscular tension to mental state. Thisoffers a therapeutic principle that can be expected to be useful insome but not all anxiety states. An action to reduce irritabilityoffers a quite different therapeutic principle that might beexpected to have benefits across a range of psychosyndromes,including some anxiety-based and some depression-baseddisorders. The drugs, in effect, may be operating to makesomeone sanguine, and where they are effective it may bebecause the introduction of sanguinity provides a space forother homeostatic mechanisms to come into play, which in turnpromote a resolution of the index disorder.While the monoamine hypotheses of the affective disordersembodied an implicit 'magic bullet' concept of the action ofantidepressants, the idea that these drugs might contain anumber of different therapeutic principles had been adumbratedby Kielholz (1968) and Carlsson (Carlsson et al., 1969;Carlsson, 1982) amongst others. Drugs such as desipramineand nortriptyline were recognized to be more drive-enhancingthan agents like clomipramine, which appeared to be doingsomething else. When the differing effects of these agents oncatecholamine and serotonergic systems became clearer, itbecame obvious that there was a case for synthesizing the firstSSRI, zimelidine, in the hope that a more selective action onthe serotonergic system would underpin some other functionaleffect in mood disorders.In the case of drugs active on the noradrenergic system,there is a cons€nsus that these agents act on drive and vigilanceto a much greater extent than drugs active on the serotonergicsystem. In so far as they do, they would target different aspectsof the depressive syndrome to the SSRIs. Equally though,through what may be characterized provisionally as an antianergicaction, this may impact on the disorder so thathomeostatic mechanisms can come into play to promote awider resolution of the condition. If something similar to thisscenario is correct then one might expect more severe forms ofdepression, in which psychomotor retardation is frequentlymore pronounced (Parker and Hadzi-Pavlovic, 1996; Sobinand Sackheim, 1997), to be more likely to respond to theseagents. There are a series of recent studies on reboxetine(Berzewski et al., 1997; Dubini et al., 1997a), milnacipram(Lopez-Ibor et al., 1996) and mirtazapine (Wheatley andKremer, 1997), which all point to the fact that an action on thenoradrenergic system does confer benefits in the managementof severe depression.

ENHANCEMENT OF SOCIAL FUNCTIONINGs27NORADRENALINEFigure ISchematic representation of different aspects of functioning attributed to noradrenaline, serotonin and dopamine'cocktailThis analysis does not suggesthat the use of these agentscompounds', involving polypharmacy within theshould be restricted to severe depression, merely that different one compound.therapeutic principles can be employed in different clinical If there is no 'central' mechanism in depression that is thesituaiions. A further possibility is that mild to moderate target for 'magic bullets', but rather a variety of psychophysioiogicalfunctions that we can modify to facilitate thedepression characterized by lack of energy or complaints ofbeing 'tired all the time' may be more likely to respond to restoiation of homeostasis, perhaps one of these otheragenis like reboxetine, which are active on noradrenergic functions might be amenable to modification' even by nondruginterventions, with equal therapeutic effect' A re-rather than serotonergic systems. Support for this conceptcomes from the social functioning data that demonstrates that evaluation of antidepressant actions in terms of distinctreboxetine has a stronger effect on active social behaviour (e'g' therapeutic principles therefore opens up the possibility thatgregariousness, community involvement) than fluoxetine a number of other approaches, including cognitive, interpersonalor behavioural therapies, may also be considered to offerio"tlni et al., 7997a,b). Conversely, compounds active onihe serotonergic system may be more useful in some cases of certain therapeutic principles, which may be complementary toanxious deprission. On the basis that both groups offer a pharmacotherapeutic interventions. Indeed, the possibilitytherapeutic principle in depression rather than just in some must be considered that these non-pharmacotherapeuticdepressions,-both would be equally effective for the majority of interventions may exert some of their effects through acases of depression. Depression, like ulcers, is a trap and as mobilization of biological processes.with any trap there may be a number of ways out and the wayout need not involve retracing the path of entry'If the possibility that current antidepressants offer a numberSocial functioning in dePressionof therapeutic principles is accepted, further possibilitiesfollow. ihe broad idea of actions on noradrenergic or Following the introduction of the antidepressants and monoaminehypotheses of depression, there was an assumption thatserotonergic systems can be expanded further' In the chse ofagents like mirtazapine, for example, there may be more than antidepressants, in 'magic bullet' fashion, corrected the coreone action on the serotonergic system - an agonist action on featuris of the illness and, for a while, it seemed quixotic to5-HTlu receptors and an antagonist action on 5-HTt receptors' even consider treating a biological disorder like depressionThis iin be construed either in terms of blockade of 5-HT2 with a psychotherapeutic intervention' This divide betweenreceptors enhancing the efficiency of the action of the drug on pharmaio- and psychotherapeutic approaches to the affective5-HTl" receptors (i.e. there is only one therapeutic principle disorders began to yield, however, to work from YalemvoGd) or alternatively the action on 5-HT1" receptors is an University, USA, carried out by Paykel, Weissman andanti-irritability action while the blockade of 5-HT2 receptors Klerman. Their work was influential for two reasons' First,promotes sleep and appetite restoration, both of which can be it provided evidence that life events, or environmentalexpected to be therapeutic in depressive disorders' From this dislocations, could trigger cases that, until then, had beenpoint of view, many psychotropic agents are in essence termed endogenous depressive disorders, a form ofdepression

s28that was commonly seen as arising de novo from a biologicaldysfunction.The second set of developments resulted in the creation ofinterpersonal therapy (IPT). The original idea behind thistherapeutic approach was that in addition to the core disorder,depressive illness, like other medical illnesses, involvesdisturbances in the social network and social functioning ofthe affected individual. Tackling these could be expected toreduce the burden of disability, just as a similar approach canmake a difference in hypertension, rheumatoid arthritis orother chronic medical conditions. Initially, these ideas owedsomething to the thinking of Jerome Frank and Hany Stack-Sullivan, but they were developed by Weissman, Paykel andKlerman in the early 1970s (Klerman et al., 1974).The initial expectation was that antidepressantreatmentwould improve the core symptoms of depressive illness butthat IPT would be shown to enhance social functioning. Thefirst acute study to explore this hypothesis was confirmatory(Klerman et al., 1974; Weissman et al., 1974). This study led tosuggestions that it might be worth testing IPT against the corefeatures of depression itself, which led to a subsequent studythat demonstrated an efficacy for IPT against these features ofthe illness (Weissman et al., 1979). This breakthrough led tothe inclusion of IPT in the National Institute of Mental health(NIMH) randomized trial comparing IPT with imipramineand cognitive therapy in the management of depressivedisorders (Elkin er al., 1989). This trial demonstrated aneffectiveness of IPT in major depressive disorders and, indeed,a superiority of IPT to cognitive therapy, flndings that led toits inclusion in prophylactic studies of affective disorders(Frank et al.,1990).The findings from the NIMH study, which demonstrated anefficacy of IPT in major depressive disorders, clearly support atherapeutic principle as opposed to a 'magic bullet' argument.The data also support the hypothesis that treatments may beless likely to be effective if the system they act on isdysfunctional. When the NIMH investigators looked at whatpredicted successful outcomes with both IPT and cognitivetherapy, they found that a better social situation favoured abetter outcome with IPT while success with cognitive therapywas more likely in the presence of fewer dysfunctionalthoughts (Sotsky et al., l99l).To date, therefore, IPT has been shown to enhance socialfunctioning in major depressive disorders and to tackle theacute symptoms of the disorder. Accordingly, acting onperceived difficulties in interpersonal function offers atherapeutic principle in the management of depression. Theconverse question - whether antidepressant pharmacotherapycan impact on social functioning in addition to addressing thecore features of the illness - has not been closely addressed.One might expect there to be some enhancement of socialfunctioning simply by virtue of ameliorating the core featuresof the illness, but the differential effects found in comparativestudies of reboxetine and fluoxetine indicate that somethingmore than simply this may be happening (Dnbini et al.,1997b). Where both agents may produce some enhancement insocial functioning simply 6y virtue of recovery from theunderlying disorder, reboxetine appears to provide additionalbenefits to the depressed patient. The alternative explanationthatfluoxetine, while proving beneficial on core features of theD. HEALYAND T. McMONAGLEdisorder, may produce subtle decrements in social functioningalsoneeds to be considered.These findings open certain possibilities. Drugs like reboxetinemight complement therapeutic approaches such as IPTparticularly well. On a broader front, however, as opposed tosimply specifying activation as a therapeutic principle, itbecomes possible to propose that reboxetine enhances socialfunctioning or social drive measured by the Social AdaptationSelf-evaluation Scale (SASS)(Bosc er al., 1997). Clinicians cantherefore begin to think about psychiatric conditions in whichsuch enhancement would appear desirable. As we have seenfrom the example of IPT, the enhancement of socialfunctioning may be a therapeutic principle in its own right.The importance of enhancing or at least not impairing socialfunctioning should not be underestimated. While it is alwaysbeneficial to treat an illness, illnesses rarely come divorcedfrom social context. An example from hypertension researchhighlights the importance of social functioning. Jachuk et al.(1982) investigated the effect of antihypertensive treatment onpatients in a novel manner. They observed satisfaction withtreatment from the point of view of the physician, the patientand the relatives. Physicians were completely satisfled with thetreatment that appeared to be 100% successful based on theircriterion for evaluating the outcome, a drop in mercury on thesphygmomanometer. Patients had mixed views on the outcome;only half reported satisfaction with treatment. Theorigins of the patients' satisfaction were poorly characterized.It may simply have reflected satisfaction at the physician'ssatisfaction. The assessment of relatives, however, wasuniformly poor. Only one of 75 relatives assessed treatmentas providing a benefit. Seventy-four considered the outcome tobe worse. Relatives'did not see the changes in the mercurycolumn, but saw instead a patient who had either become ahypochondriac or who had developed side-effects fromtreatment. They saw an individual who, for one reason oranother, had become symptomatic where they had not beenbefore, and these symptoms impinged on social functioning ina way the target illness had not (Jachuk et al.,1982).The success of treatments in many areas of medicine hasdepended on assessments that only take into account one pointof view - that of the treating physician. This bias arguablyrenders many studies less empirical and less scientific than theyoften claim to be. This is as true of the assessments oftherapeutic outcome in depression as it is for hypertension.Instruments such as the Hamilton Rating Scale for Depression(HAM-D) (Hamilton, 1960) and the Beck DepressionInventory (BDI) (Bech, 1989) are intensely individualistic intheir focus. The potential problems with an over-reliance onselective rating instruments were highlighted by Nathan Klineas early as 1956, when he suggested that taking this kind ofapproach to the evaluation of treatment rather than looking atlarger frame social outcomes risked creating a version of therabbit in the hat trick (Kline, 1959). Adapting Kline, there hasto be a hint of suspicion that the demonstrable efficacy ofcertain tricyclic antidepressants is reliant on the fact the thatHAM-D conveniently incorporates many clinical featuresrelieved by tricyclic antidepressants. A similar case can bemade for cognitive therapy and the BDLIn contrast, a range of other features related to socialfunctioning, such as sensitivity to criticism from significant

ENHANCEMENT OF SOCIAL FUNCTIONINGothers (Hooley et al., 1986), have been shown in repeatedstudies to predict chronicity of affective disorders but, to date,have not been incorporated in assessment instruments.Depression is a quite different illness to hypertension in thatin hypertensive disorders the undetected illness has little or noimpact on family or work functioning, unless it leads to strokeor cardiovascular accident. The impact of adverse effects onsocial functioning as a consequence of treatment may, therefore,be particularly salient in the case of hypertension.Depressive disorders, in contrast, necessarily have an extensiveimpact on work and family functioning. A treatment thatwould further compromise social functioning may not be asreadily noticed against a background of prior difficulties. Theintroduction of an assessment of social functioning intopharmacotherapeutic studies of depression is, from thisperspective, welcome and may in due course be a potentinstrument for evaluating the relative pharmacoeconomicbenefits of different treatments (Weissman, 1997).Biology is socialQuite apart from illness being a social event, biology is alsoinherently social, as sexual differentiation, the organization ofsocial life in accord with circadian rhythms, and the findings ofinteraction between social rank and endocrine status(Sapolsky, 1990, 1991, 1992) all clearly indicate. In recentyears, we have been studying the role of circadian rhythms inaffective disorders. This has led to the development of a shiftworkmodel of affective disorders (Healy and Waterhouse,1991). Investigating this further, we looked at aspects ofsocial,neurobiological and psychological functioning in a group of100 healthy student nurses prior to a first block of night workand, subsequently, following a three-month block of nightwork (Healy et al., 1993; Adeniran et al., 1996). Night workproduced all of the major core symptoms of depressivedisorder - disturbances of sleep, appetite, interest, motivationand concentration. It produced hopelessness concerning thefuture and social dislocation. It also produced a sensitivity tointerpersonal criticism that had not been predicted a priori.Indeed, night work produced both an increased sensitivity tocriticism from significant others and, in addition, the level ofsensitivity to criticism from significant others prior to startingnight work predicted how symptomatic the individual wouldbecome during the subsequent block of night work. This led usto suggesthat these findings complemented the evidence thattherapeutic manoeuvres which focused on perceived socialfunctioning were of benefit in cases of depression and perhapsprovided some hints regarding mechanisms that might mediatethese effects.It was not possible to tease out the direction ofeffects fromour study, but there appeared to be a close relationshipbetween circadian rhythm disruption, the production of theirritability, and perceived changes in the quality of relationshipswith significant others. In retrospect, this should not besurprising as human biology is social. The impact of significantothers on our biology and in stabilizing that biology inproductive patterns has been neglected to date. When takeninto account. however. it should be clear that this imoact mustnecessarily be considerable.s29A new scale and treatment that offers the opportunity toexplore these relationships further is therefore welcome. Thefindings with reboxetine on the SASS are consistent withsuggestions from a range of other studies, which indicate thattreatments acting on catecholaminergic systems produce betterresults than agents acting on serotonergic systems when theoutcome measures involve self-report instruments such as theZung (Zung,1965) or the BDI (Bech, 1989). But what coulddifferences in outcome on such scales mean?One possibility is that the scale may reflect the impact of thebroad functional changes produced by the drug. This returnsus to the main argument of this paper, which is thatantidepressants are not simply antidepressants, they areantidepressant by virtue of some functional change theyinduce. In the case of drugs active on the serotonergic system,we have characterized this provisionally as inducing sanguinity.Sanguinity may be therapeutically useful but it may alsohave its drawbacks. It suggests detachment, in contrast to anaction to enhance drive. These differences may be reflected ininstruments such as the SASS or other self-report measures.A second possibility is that the differences that have beendemonstrated on self-report measures, such as the SASS,reflect speed of onset of antidepressant action. There is asubstantial body of evidence associating actions on catecholaminergicsystems with earlier onsets of antidepressant effects(Potter and Manji, 1994), despite the fact that earlier onseteffects have been difficult to demonstrate in clinical trials usingconventional assessment instruments such as the HAM-D orthe Montgomery-Asberg Depression Rating Scale (MADRS)(Montgomery and Asberg, 1979). These latter instrumentsmeasure a different domain of functioning to that measured bythe SASS or other self-report measures. The SASS may bemore sensitive to changes in functions that contribute to animpression of recovery. Further data on the effects ofreboxetine and fluoxetine on perceptions of social functioningin studies with a longer trial period, or in patients who havefailed to respond as assessed on measures such as HAM-D,might help address this issue.A third possibility is the SASS may be sensitive to theimpact of side-effects. Impairments of sexual functioning, forexample, while not showing on assessments of recovery fromdepression, or indeed on formal side-effect measurements, maybe evident in areas of social functioning. Indeed, estimates ofsocial functioning may provide a means to assess the overallimpact of both primary and secondary effects of treatment. Todate, there has been no satisfactory method to weight the drymouth caused by tricyclic antidepressants against the jawdyskinesias that may be caused by SSRIs (Fitzgerald and Healy,1995). Assessments of sogial functioning, amongst others, byoffering some measure of an individual's assessment of theoverall impact of treatment, may in fact perform this function.Finally, another possibility is that the SASS measures theimpact of selective therapeutic principles on particular personalitytypes. Personality in one sense is the ultimate expression ofbiology in action in a social context. Eysenck and colleagues inthe 1950s and 1960s were able to demonstrate that a range ofsedatives and stimulants had predictably different impactsaccording to personality (Claridge and Healy,1994). Extrovertswere sedated by much smaller doses of a sedative thanintroverts. This was taken as indicatins distinct differences in

s30the constitutional/biological underpinnings of personality, aposition that has subsequently been developed by Kagan(Kagan, 1994). Eysenck's early work was recast by Gray (1982)in terms of behavioural activation and behavioural inhibitionsystems, with disturbances of either having the potential to leadto nervous disorders. Noradrenaline has traditionally beenassociated with the behavioural activation system and serotoninwith the behavioural inhibition system. Some of thedramatic 'better-than-well' responses, which appear to occurin a small proportion of patients taking agents selective to theserotonin system (Kramer, 1993), may stem from this source.Similar effects in a different set of depressed patients may occurwith agents selective to catecholamine systems. For a smallnumber of depressed patients, therefore, there may be dividendsin selecting treatments according to the premorbid personalitytype of the sufferer.In summary, using reboxetine and early clinical trials indepressive disorders as a case study, we have introduced thenotion that antidepressantreatment should be conceived asoffering a range of therapeutic principles that can best bedeployed if the nature of those principles is understood and thepotential benefits offered are matched to the disabilities of thetreatment population. As long as all antidepressants haveequivalent results on major outcome measures, a therapeuticprinciple as opposed to 'magic bullet' argument is moredifficult to sustain. In contrast, the fact that reboxetine differsfrom fluoxetine on the SASS poses problems for a 'magicbullet' argument. The full potential of an alternative therapeuticprinciple approach will require a mapping of theargument onto the profiles of action for both other antidepressantsand available antipsychotic agents.Address for correspondenceDr David HealyNorthWales Department of Psychological MedicineHergest UnitBangor LL57 2PWWalesUKReferencesAdeniran R, Healy D, Sharp H M, Williams J M G, Minors D S,Waterhouse J M (1996) Interpersonal sensitivity predicts depressivesy'mptom response to the circadian rhythms disruption ofnight work. Psych Med 26: 7211-122IBech P (1989) Clinical effects ofselective serotonin reuptake inhibitors.In Dahl SO, Gram LF (eds), Clinical pharmacology inpsychiatry. Springer-Verlag, Berlin Z 81-93Berzewski H, Van Moffaert M, Gagiano C A (1997) Efficacy andtolerability of reboxetine compared with imipramine in adouble-blind study in patients suffering from major depressiveepisodes. Eur Neuropsychopharmacol 7 (SuppL 1): S37-Sa7Bosc M, Dubini A, PolinV (1997) Development and validation of asocial functioning scale, the Social Adaptation Self-evaluationScale. Eur Neuropsychopharmacol 7 (Suppl. 1): S57-S70Brunner H G, Nelen M, Breakefield X O, Ropers H H, van Oost B A(1993) Abnormal behaviour associated with a point mutation in thestructural gene for monoamine oxidase A . Science 262:578-580Carlsson A (1982) Rationale and design of a selective inhibitor of 5-HT re-uptake. Br J Clin Pract 19 (Suppl.): 19-21D. HEALYAND T. McMONAGLECarlsson A, Corrodi H, tr\rxe K, H

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