Do We Need New Antidepressants?

I. HINDMARCHHuman Psychopharmacology Research Unit, University of Surrey, Milford Hospital, Godalming, Surrey, GU7 1UF, UK

Tolerability and e�cacy are important factors determining the choice of an antidepressant. Older tricyclic anti-depressants (TCAs) are associated with signi®cant behavioural toxicity, notably psychomotor and cognitive impair-ment and sedation. These e�ects are not seen with newer TCAs and selective serotonin reuptake inhibitors (SSRIs).Furthermore, TCAs are associated with a variety of somatic adverse events resulting from binding to muscarinic,a1-adrenergic and H1-histaminergic receptors, including dry mouth, visual disturbances and tremor. SSRIs arelargely devoid of these e�ects, but gastrointestinal disturbances such as nausea and dyspepsia are common with theseagents. Although the two classes of agent are broadly comparable in e�cacy, there is some evidence that SSRIs maybe less e�ective than TCAs in severely depressed patients. Hence, an antidepressant that is e�ective irrespective of theseverity of depression and has a good tolerability pro®le, should o�er important therapeutic advantages. Clinicalexperience with milnacipran, a new serotonin and noradrenaline reuptake inhibitor, indicates that this agent meetsthese criteria. # 1997 John Wiley & Sons, Ltd.

Hum. Psychopharmacol. Clin. Exp. 12: S115±S119, 1997.No. of Figures: 1. No. of Tables: 2. No. of Refs: 27.

KEY WORDS Ð antidepressant therapy; tricyclic antidepressants; selective serotonin reuptake inhibitors; tolerability;behavioural toxicity; e�cacy

INTRODUCTION

The ®rst antidepressant drugs to be introducedwere the tricyclic antidepressants (TCAs) andmonoamine oxidase inhibitors (MAOIs). Today,TCAs remain widely used, whereas MAOIs arenow seldom prescribed except in patients withintractable depression, because of the risk ofinteractions with various foodstu�s. In additionto the TCAs, a range of new antidepressants havebecome available during the last decade; theseinclude the selective serotonin reuptake inhibitors(SSRIs) and reversible inhibitors of monoamineoxidase type A (RIMAs). There is, therefore, awide choice of agent for the management ofdepression and hence it may be asked whetherthere is a place for further innovations in thisarea. The guidelines issued by the British Associ-ation for Psychopharmacology (1993) are relevantin answering this question. These guidelinesidentify side-e�ects, e�cacy, safety in overdoseand price as important considerations a�ectingthe choice of antidepressant. Hence, an agent thatis e�ective regardless of the severity of depres-sion, has a good tolerability pro®le, and has noserious adverse e�ects when taken in deliberate or

accidental overdose, would be expected to o�ertherapeutic advantages.

In practice, neither the TCAs nor the SSRIs Ðcurrently the most widely used classes of anti-depressants Ð fully meet these criteria. The TCAsare e�ective in most patients with depression, butare associated with a variety of adverse e�ects,including psychomotor and cognitive impairmentand somatic e�ects such as dry mouth, tremor andvisual disturbances (de Jonghe and Swinkels,1992). The SSRIs have a better tolerabilitypro®le than the TCAs (DeVane, 1994), but thereis some evidence that they are less e�ective thanTCAs in severely depressed patients (Anderson andTomenson 1994). This paper reviews the toler-ability and e�cacy of currently available anti-depressants, with particular reference to the TCAsand SSRIs.

BEHAVIOURAL TOXICITY

Cognitive and psychomotor impairment may bethe most troublesome adverse e�ects from thepatient's point of view (Hindmarch et al., 1992),because most patients are treated in the community

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setting and about 60% continue with theirnormal occupation despite their illness (Gater andGoldberg, 1991). The behavioural toxicity of TCAsis associated with an increased risk of accidents, forexample at work (Cuvvie et al.) or when driving(Ray et al.). In addition, impaired psychomotoror cognitive function resulting from drug treat-ment may delay improvement in some of thepsychic manifestations of depression (Hindmarch,1987).

Tests of behavioural toxicity

The behavioural toxicity of antidepressant drugshas been extensively investigated in double-blind,placebo-controlled, repeated measure studies usinga battery of standard tests (Kerr et al., 1991;Sherwood and Hindmarch, 1993; Hindmarch,1995). The principal tests used are the critical¯icker fusion (CFF) test, the choice reaction time(CRT) test, and the compensatory tracking task(CTT) test. In addition, subjective impressions ofalertness or sedation are recorded by means ofvisual analogue scales.

The CFF test provides a measure of the stateof arousal (i.e. capacity to process information) ofthe central nervous system (Hindmarch, 1982).Subjects are required to distinguish ¯icker fromfusion in a set of four light-emitting diodes held infoveal ®xation at a distance of 1 metre. The ¯ickerfusion threshold is determined from the mean of sixpresentations (three ascending, three descending).The CRT test measures sensorimotor reactions to acritical stimulus; it is regarded as a basic perform-ance skill inherent in all activities (Hindmarch,1981). A series of six red lights, each equidistantfrom the subject, are illuminated at random, andthe subject is required to extinguish the light bypressing a button next to it.

The CTT test is a more complicated task thatrequires skilled motor activity in response to com-plex visual information; it is regarded as alaboratory model of car driving performance. Thesubject is required to use a joystick to keep a curseraligned with a moving target on a VDU screen,while simultaneously responding by pressing abutton when presented with visual stimuli at theedge of the screen. Two performance measures areassessed: tracking accuracy, which is measured asthe root-mean squared (RMS) deviation of thejoystick from the target, and the mean reactiontime to the peripheral stimuli (Hindmarch, 1983,1986).

Behavioural toxicities of TCAs and SSRIsThe behavioural toxicities of the TCAs amitripty-line, dothiepin and lofepramine, and the SSRIs¯uoxetine and paroxetine, were compared in ameta-analysis by Sherwood and Hindmarch(1993). In this analysis, drug e�ects were expressedas Cohen `d ' values (Cohen, 1976) derived fromt-values calculated from a repeated-measuresanalysis of variance. The results showed that theolder TCAs (amitriptyline and dothiepin) wereassociated with signi®cant psychomotor impair-ment and sedation, whereas the e�ects of the SSRIsand lofepramine were not signi®cantly di�erentfrom those of placebo (Figure 1). CFF scores weresigni®cantly increased after treatment with parox-etine, which suggests a mild alerting (i.e. improve-ment in information processing) e�ect with thisagent.

Similar results were obtained in a review of thebehavioural toxicities of SSRIs (Kerr et al., 1991).The performance of SSRIs was consistently similarto or better than that of placebo in the CFF andCRT tests; sertraline showed an `arousing' e�ect,manifested as an increase in CFF and a decrease inCRT. Similarly, SSRIs had no signi®cant e�ect oneither tracking accuracy or response time in theCTT test and, with the paradoxical exception ofsertraline, did not produce sedation; the reasonswhy sertraline showed arousal in the CFF andCRT tests in addition to subjective sedation are notclear (Kerr et al., 1991). In contrast to the SSRIs,amitriptyline was associated with signi®cantlyimpaired responses in the CFF, CRT and CTTtests, and with increased subjective sensations ofsedation (Kerr et al., 1991).

In a separate analysis, the behavioural toxicityof 15 antidepressants was ranked according to therelative activities of each drug in a battery ofstandard tests (Hindmarch et al., 1990; Kerr et al.,1991). The mean ranks are shown in Table 1. OlderTCAs, and related compounds such as trazodoneand mianserin, were associated with substantialpsychomotor and cognitive impairment. By con-trast, SSRIs and milnacipran, a novel antidepres-sant that inhibits the reuptake of both serotoninand noradrenaline and has no anticholinergic orhistaminergic e�ects (Moret et al., 1985; Moret andBriley 1996), had no signi®cant activity in thesetests.

Although these studies have shown that SSRIsare relatively free from adverse behavioural e�ects,a number of di�erences between members of thisclass have been identi®ed (Table 2). Paroxetine and

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sertraline have both been reported to cause arousal,as measured by CFF thresholds Fluoxetineappears to reduce the e�ect of ethanol, whereas¯uvoxamine shows no such interaction.

Clinical signi®cance of behavioural toxicity

Cognitive and psychomotor impairment and seda-tion associated with older TCAs can signi®cantlylimit the clinical usefulness of these agents. As wasnoted above, these adverse events are potentiallythe most troublesome to the patient. In addition tocausing problems with normal everyday activities,they can impair the cognitive processes necessaryfor the maintenance of wellbeing. The manifesta-tions of this impairment, such as tiredness and lossof memory and the ability to concentrate, canworsen the symptoms of depression and reducecompliance with treatment. Furthermore, therelative risk of road accidents has been reported

Figure 1. Maximum drug e�ects (Cohen `d ' values) after single doses of ®ve antidepressants (Sherwood andHindmarch, 1993); placebo treatment gives a d value of zero. CFF: critical ¯icker fusion; CRT: critical reactiontime; CTT: compensatory tracking task. �p < 0�05

Table 2. Behavioural toxicity of selective serotonin reuptake inhibitors (SSRIs) (Hindmarch, 1995)

Psychomotor Cognitive Arousal Alcoholspeed processing interaction

Fluoxetine 0 ? 0 #Fluvoxamine 0 0 0 0Paroxetine 0 0 " ?Sertraline 0 0 " ?

0: No di�erence from placebo control; ": increase; #: decrease; ?: data not available or ambiguous.Psychomotor speed: results from CRT studies.Cognitive processing: e�ects on information processing and memory.Arousal: information processing capacity and arousal, measured by CFF thresholds.Alcohol interaction: overall e�ects of concomitant administration of absolute alcohol (0.6 mg/kg).

Table 1. Mean ranks for behavioural toxicity of 15antidepressant drugs (Kerr et al., 1991)

Drug Mean rank

Nomifensine, 100 mg 2.6Sertraline, 100 mg 4.0Lofepramine, 140 mg 4.6Buproprion, 100 mg 5.4Paroxetine, 30 mg 5.6Zimeldine, 200 mg 6.0Jouveinal, 400 mg 6.4PlaceboMilnacipran, 100 mg 6.5Desipramine, 50 mg 7.0Fluvoxamine, 50 mg 7.6Fluoxetine, 40 mg 8.6Trazodone, 50 mg 10.8Dothiepin, 50 mg 12.6Mianserin, 10 mg 14.0Amitriptyline, 25 mg 14.8

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DO WE NEED NEWANTIDEPRESSANTS? S117

to be increased at least six-fold among patientstreated with TCAs at doses equivalent to 125 mgamitriptyline per day (Ray et al., 1992), and therisk of injury from domestic or occupationalaccidents is also increased (Cuvvie et al., 1995).There is, therefore, a strong case for the use of non-sedating antidepressants that do not producesigni®cant cognitive and psychomotor impairment;particularly in ambulant out-patients or those ingeneral practice.

SOMATIC ADVERSE EVENTS

In addition to inhibiting serotonin and noradrena-line reuptake, TCAs bind to a number of receptorsubtypes, including muscarinic, H1-histaminergicand a1-adrenergic receptors. The muscarinic andhistaminergic receptors are believed to be respons-ible for the sedation and behavioural impairmentdescribed above (Hindmarch, 1995); in addition,receptor binding results in a variety of somaticadverse events, including orthostatic hypotension,cardiac arrhythmias and tachycardia, convulsions,dry mouth, tremor and blurred vision (Sherwoodand Hindmarch, 1993). The cardiovascular e�ectsof TCAs, mediated by cholinergic receptors, makethese agents potentially dangerous when taken inoverdose. As a result of the high incidence ofadverse events during TCA treatment, suboptimaldoses may be prescribed, and compliance may beimpaired (Beaumont, 1989; Montgomery andKasper, 1995).

SSRIs are largely devoid of receptor bindingactivity, and hence are generally better toleratedthan TCAs. Furthermore, because they lacksigni®cant cardiovascular e�ects, they are relativelysafe when taken in overdose. They are, however,associated with a relatively high incidence ofgastrointestinal adverse events such as nausea,dyspepsia and diarrhoea (Ferrier et al., 1992).Although usually minor, these side-e�ects can betroublesome to the patient.

EFFICACY

Although the SSRIs are better tolerated thanthe TCAs, they have not been shown to besuperior in e�cacy (Edwards, 1992; Finley, 1994;Montgomery and Kasper, 1995). Early controlledtrials suggested that SSRIs were less e�ective thanTCAs in patients with severe depression (DanishUniversity Antidepressant Group, 1986, 1990), andthis conclusion is supported by a meta-analysis

of 55 published studies (Anderson and Tomenson,1994).

CONCLUSIONS

The clinical pro®les of the TCAs and SSRIs di�ermarkedly, and these di�erences have importantclinical consequences. TCAs are e�ective in amajority of patients, irrespective of the severity ofdepression, but their usefulness is limited bysigni®cant behavioural toxicity and a high incid-ence of somatic side-e�ects. Many of the adversee�ects of TCAs occur at doses within the thera-peutic range (Dukes and Beeley, 1988), and hence itmay be necessary to reduce the dose to suboptimallevels in an attempt to minimize these e�ects.Furthermore, compliance may be reduced if lowdoses are perceived to be ine�ective or if side-e�ectsare unacceptable to the patient (Montgomery andKasper, 1995). The SSRIs are generally bettertolerated, but there is some evidence that theirspeci®c action on serotonin reuptake leads tosome diminution of activity, particularly in severedepression. Hence, an agent that combines thee�cacy of the TCAs with a favourable tolerabilitypro®le would o�er useful therapeutic advantages.

Milnacipran is a novel serotonin and noradrena-line reuptake inhibitor (SNRI) that lacks activity atcholinergic, muscarinic or histaminergic receptors.The clinical experience with this agent, describedelsewhere in this supplement, shows that milnaci-pran is comparable in e�cacy with the TCAs,and has a tolerability pro®le similar to the SSRIs.Milnacipran appears, therefore, to be a valuableaddition to the currently available antidepressants.

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