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Acta Psychiatr Scand 2000: 101 (Suppl. 402): 45±51 Copyright # Munksgaard 2000 Printed in UK. All rights reserved ACTA PSYCHIATRICA SCANDINAVICA ISSN 0902-4441 : its effects as measured by the Social Adaptation Self-evaluation Scale

Healy D. Reboxetine: its effects as measured by the Social Adaptation David Healy Self-evaluation Scale. North Wales Department of Psychological Medicine, Acta Psychiatr Scand 2000: 101 (Suppl. 402): 45±51. # Munksgaard Hergest Unit, Bangor, UK 2000.

The determination of the outcome of treatment for depression is important both for the symptoms of depression and social functioning. The aim of this review is to evaluate the outcome of two clinical trials comparing reboxetine and ¯uoxetine on depressive symptoms and social functioning. These studies used both conventional measures of outcome such as the Hamilton Rating Scale for Depression (HAM-D) and the Social Adaptation Self-evaluation Scale (SASS), a patient-centred, disease non-speci®c scale of social functioning, which was developed for measuring social functioning in depressed people. These ®ndings, set against a background of all studies in which have been compared using quality of life instruments, suggest that while some Key words: reboxetine; ¯uoxetine; social functioning; patients may appear to the clinician to have recovered, they may remain quality of life; emotional blunting less than fully well and differences in selectivity for neurotransmitter Dr David Healy, North Wales Department of systems may play a part in the degree of wellbeing that recovered patients Psychological Medicine, Hergest Unit, Bangor LL57 might expect. 2PW, Wales, UK

Introduction the sort outlined by Kielholz (3), Carlsson (4) A number of critics of the current psychotropic suggested that the drive-enhancing agents were more arena (1) have argued that, given the diversity in the active on catecholamine systems while those that preclinical of agents conventionally had another, as yet less clearly characterized action, labelled , it is dif®cult to believe that had an effect on the (5-hydroxytryp- these agents are equally bene®cial in clinical tamine; 5-HT) system (2, 4). settings. It has been suggested that the pharmaceu- However, two developments supervened to create tical industry, and perhaps clinical researchers, may the impression that all antidepressants did essen- have minimized the differences between agents in tially the same thing, regardless of the system on order to secure a large market share (1). which they acted. One was the development of the Furthermore, it has been implied that clinical monoamine hypotheses, which suggested a de®- trials methods have not been designed to reveal ciency of central monoamines. More sophisticated differences that may exist between antidepressants. versions of this posited a ®nal common pathway or Such critiques have a certain face validity. This is lesion, in either catecholamine or seroto- particularly the case with the selective serotonin nergic systems, to explain antidepressant ef®cacy (5, reuptake inhibitors (SSRIs), which were developed 6). These versions of the hypothesis were able, for a because it was recognized that there were signi®cant time, to accommodate the fact that there appeared differences between the available anti- to be antidepressants that were relatively selective (2). On the basis of global clinical either for the noradrenergic system or the seroto- impressions, Kielholz (3) characterized the available nergic system. antidepressants as being variously drive-enhancing, In recent years this framework has been chal- variously and having differential effects on lenged for a number of reasons. First, the develop- something else, which seemed useful in terms of the ment of antidepressants such as and treatment of mood disorders. Faced with schemas of nomifensine, preferentially active on the

45 Healy system, have been identi®ed. Secondly, there is differential effects between antidepressants have not evidence that other agents such as , which been reported. Until the use of the SASS in the have no effects on dopamine, noradrenaline or recent reboxetine±¯uoxetine studies, agents selec- serotonin, are antidepressant (7). Thirdly, there is tive for the noradrenergic system have not been evidence that , which depletes cerebral tested with such instruments. An emergence of monoamines, has antidepressant properties (8). differences between agents selective for the nora- Finally, the SSRIs have demonstrated a clinical drenergic and systems on alternative ef®cacy in a range of conditions such as obsessive± psychometric instruments such as the SASS would compulsive disorder (OCD), panic disorder and lend credence to the suggestion that the current social phobia, when there is no depressive compo- range of antidepressants are not equivalent. nent. This suggests that these agents have a non- To illustrate some of these issues, this paper will sedative or serenic action, which they do review evidence from two clinical trials conducted not share with other `antidepressants'. This is an using the SASS, along with all other studies that action that could conceivably account for their have used QoL instruments in which different antidepressant properties (9). Furthermore, there antidepressants have been compared. has been an ongoing failure to ®nd a lesion in any monoamine system. The second development that led to the impres- Material and method sion that all antidepressants were equivalent was the Patients aged 18±65 years, with a diagnosis of development of methods that exclu- Major Depressive Episode (DSM-IIIR) (19), with a sively utilized disease-speci®c observer-based rating current episode present for 1±4 months and with a scales, such as the Hamilton Rating Scale for pretreatment total score on the 21-item HAM-D Depression (HAM-D) (10). On instruments such as (10) of o22 were enrolled into two studies. In the these, all antidepressants show equivalent ef®cacy in ®rst study, 381 patients were admitted in 33 centres; mild to moderate depressive disorders. This appears 126, 127 and 128 were randomized to receive to have led to a presumption that they were, reboxetine, ¯uoxetine or placebo, respectively, for therefore, all the same, despite earlier preclinical 8 weeks (20). In the second study, 168 patients were and clinical impressions. The ef®cacy of agents with randomised to receive either ¯uoxetine or rebo- actions on the serotonin system across a wide range xetine in a 16-centre study (21). of nervous conditions did not lead to this view being Observer rating scales included the HAM-D (10), challenged, but more recent evidence that agents the Clinical Global Impression Scale (22) and the with an action on catecholamine systems appear to Montgomery±AÊ sberg Depression Rating Scale be more useful in severe depressive disorders may (MADRS) (23), while self-rating assessments do so (9). included the patient Global Impression Scale (22) A second area of measurement is the domain of and the SASS (14). The SASS has 21 questions, Clinical Global Impression instruments. These are exploring patient behaviour in four broad areas of observer-based instruments that are disease non- social functioning: work, spare time, family and speci®c. There are two other domains of measure- ability to cope with resources/®nances. The SASS ment, subject-based disease-speci®c measures and also assesses motivation, self-perception and satis- subject-based measures that are disease non- faction with a role. Each answer is scored from 0 to speci®c. Within the disease-speci®c domain, the 3 giving a total range of 0±60. Normal scores fall best-known instruments are the Beck Depression within a band from 35 to 52 (14). Inventory (BDI) (11) and the Zung self-rating scale for depression (12). With these instruments, agents selective for the noradrenergic system have Results appeared to have advantages over agents selective Of the 381 patients enrolled into the ®rst study, 302 for the serotonergic system (13). However, these (103, 100 and 99 randomized to receive reboxetine, results had little impact, in part because these ¯uoxetine or placebo, respectively) provided SASS instruments are used less frequently than the self-evaluation data at baseline and at last assess- HAM-D in clinical trials. ment. The mean values of the SASS total scores in The Social Adaptation Self-evaluation Scale the three treatment groups across the treatment (SASS) (14) measures aspects of the disease non- period are shown in Fig. 1 (20). speci®c domain from a subject-based perspective. At baseline there was no difference between the Other instruments in this area are Quality of Life three groups. At the last assessment the three (QoL) instruments (15±18), which have been used in groups were signi®cantly different (ANOVA; trials of antidepressants but on which, to date, P<0.0001) with mean SASS total scores of 35.3

46 Reboxetine and social functioning

P<0.05 Reboxetine vs. placebo Fluoxetine vs. placebo Reboxetine vs. fluoxetine Fig. 1. Mean SASS total scores over time in patients in the reboxetine, ¯uoxetine and placebo groups.

(reboxetine), 31.9 (¯uoxetine) and 27.2 (placebo), signi®cant differences between ¯uoxetine and corresponding to an average improvement with placebo were detected. respect to baseline of 41% in the reboxetine group, The results of the point±biserial correlation 31% in the ¯uoxetine group and 14% in the placebo analysis comparing reboxetine and ¯uoxetine group. At last assessment 46% of the ¯uoxetine showed a correlation coef®cient that differs from group had returned to the normal range, while 55% zero in favour of reboxetine for nine items. Values of the reboxetine-treated group had done so. were maximal for six items: community involve- A point±biserial correlation analysis was con- ment, interest in hobbies, social compliance, rejec- ducted for all items on the scale for the reboxetine, tion sensitivity, control of surroundings and ¯uoxetine and placebo series to determine which vainness. Among these items, community involve- items discriminated between treatments. In the case ment and social compliance explore active social of comparisons between reboxetine and placebo, behaviour, while most of the others, i.e. rejection the correlation coef®cient was positive and different sensitivity, control of surroundings and vainness, from zero for all items except quality of spare time. investigate self-perception aspects. The correlation was maximal for 12 items, including When the analysis was con®ned to patients in social attractiveness, external relationship apprecia- core symptom remission (HAM-D f10) (Fig. 2), tion, work enjoyment, social inquisitiveness, control the differences in favour of reboxetine were even of surroundings, family relationship quality, com- more marked with signi®cantly better outcomes munication dif®culties, interest in hobbies, external on 14 of the 21 items. The additional items were relationship quality, rejection sensitivity, intellec- family-seeking behaviour, relationship-seeking tual interest and job interest. behaviour, intellectual interest, work enjoyment In the case of comparisons between ¯uoxetine and managing of resources and ®nances. In this and placebo, the point±biserial correlation coef®- case 63% of the ¯uoxetine patients had returned cient was positive and different from zero for 12 of to normal, as de®ned by a SASS score within the the 21 items, with maximal correlations for seven normal range, while 37% of them had not, despite items: family relationship quality, social attractive- HAM-D scores indicative of remission (f). In the ness, work enjoyment, social inquisitiveness, exter- reboxetine-treated group 79% had returned to nal relationship appreciation, external relationship normal on the SASS, leaving 21% still outside the quality and job interest. However, for nine items no normal range.

P<0.05 Reboxetine vs. placebo Reboxetine vs. fluoxetine Fig. 2. Mean SASS total scores over time in patients in remission in the reboxetine, ¯uoxetine and placebo groups.

47 Healy

Fig. 4. Mean improvement in SASS total score after 4±8 weeks of treatment in patients in remission with SASS scores below 35 at baseline receiving reboxetine or ¯uoxetine. Fig. 3. Percentage of patients classi®ed as responders or in remission after treatment with reboxetine or ¯uoxetine. better outcome for remitters in the reboxetine group It is important to note that the differences compared with those in the ¯uoxetine group between reboxetine and ¯uoxetine cannot be (P=0.04). explained in terms of differential responses, at least as assessed by conventional measures such as Discussion the HAM-D or the MADRS, where both performed similarly. In both cases, therefore, There clearly needs to be some caution when there had been a comparable response across considering results from just two clinical trials what are usually thought of as the core symptoms (20, 21). The SASS is a psychometric instrument of the disorder (Fig. 3). that is not speci®c to a particular disease. It is self- In the second study (21) 168 patients were rated by patients, covering areas of social and recruited, of whom 79 were randomized to receive personal functioning that are traditionally covered by quality of life instruments (24, 25). A number of reboxetine and 89 were randomized to receive companies have produced similar scales (26) and ¯uoxetine. Of these, 153 patients were evaluable used them in clinical trials; however, the data, for and 45 patients in the reboxetine group and 55 in the most part, have not been reported in the the ¯uoxetine group achieved remission. The literature. Therefore, a good case can be made for overall SASS scores in both groups did not the fact that the current ®ndings with reboxetine on differ signi®cantly. When remitted patients in the the SASS do not stand in isolation. reboxetine and ¯uoxetine groups were compared In fact, so few QoL results have been reported, using the SASS, reboxetine-treated patients tended where two antidepressants have been compared to do better than those treated with ¯uoxetine directly, that these results comparing reboxetine and (P=0.07). When patients who, on entry into the ¯uoxetine achieve considerable signi®cance. Simon study, had social functioning levels in the normal and co-workers (27) compared ¯uoxetine, desipra- range (35±52) were excluded, improvement in the mine and using the HAM-D and the SASS total scores tended to be better (although SF-36, and found no differences between the drugs not signi®cantly) (P=0.075) for patients in the on 3-month QoL outcomes. Souetre and co-workers reboxetine group (Fig. 4). (28) compared , and ¯u- There were signi®cant differences (Pf0.05) in oxetine, using the SF-36 questionnaire and found, in favour of reboxetine for four items including general, no differences between the drugs. When interest in leisure activities, extra-family relation- confounding factors were taken into account, there ships, management of resources and organization of were bene®ts for ¯uoxetine in the domains of general environment. When an index of improvement was health perception and social function. Wheatley and constructed by comparing remitters and non- co-workers (29) compared and ¯u- remitters in each group, there was a signi®cantly oxetine using the HAM-D and Quality of Life

48 Reboxetine and social functioning

Enjoyment and Satisfaction Questionnaire treatment on the patient. The role of side-effects on (QLESQ) (a scale with a very similar range of the overall impact of treatment may play a greater questions to the SASS). While mirtazapine was part in the early rather than later weeks of signi®cantly more effective than ¯uoxetine using the treatment. HAM-D as an outcome measure, interestingly both As regards side-effects, there are two points to treatments did comparatively poorly on the QLESQ note. One is that side-effect data are not collected with little change from baseline (29). Lydiard and systematically, and therefore the true frequency and co-workers (30) compared with amitripty- impact of side-effects from all psychotropic drugs line and placebo using the HAM-D and the QLESQ. currently in use is not known. Secondly, a further Both active drugs were associated with greater issue with side-effects has been to devise a method improvements than placebo on QoL measurements, of assessing which are worse than others. Since the with sertraline showing a predisposition for greater release of the SSRIs, it has been commonly claimed improvements. Furthermore, Kocsis and colleagues that these agents produce less troublesome side- (31) used the QLESQ to compare 416 patients with a effects than the older tricyclic antidepressants. diagnosis of early onset primary dysthymia, treated Whether dry mouth is a greater problem than with sertraline, imipramine or placebo. They found severe nausea, sexual dysfunction and akathisia that that while both sertraline and imipramine were may lead to suicide is, however, questionable. signi®cantly better than placebo in improving Arguably, only the patient is in a position to QLESQ scores from baseline, no signi®cant differ- make this judgement. One bene®t of the SASS or ence was observed between the active drugs. other quality of life measures is that they may Finally, Lonnqvist and colleagues (32) compared perform just this function, since nausea, sexual with ¯uoxetine using conventional dysfunction or akathisia are incompatible with self- outcome measures along with the SF-20. A sig- ratings of normal social functioning. ni®cant change for the better in QoL was found in Reviewing all the pertinent studies (including the both treatment groups, even at week 2, but especially SASS studies), in general the SSRIs ¯uoxetine and after 6 weeks of treatment. Improvement was seen in sertraline do not perform better than some of the all dimensions of the scale. For moclobemide there older tricyclic antidepressants such as amitriptyline were comparatively greater increases in scores in the or clomipramine, which have traditionally been domains of social and role functioning, while for thought to have the heaviest burden of side-effects. ¯uoxetine the greatest improvements were in the It is also clear that there may be a considerable domain of perceptions of physical health. dissociation between observer-based, disease- What do these ®ndings mean? One possibility is speci®c ratings and QoL assessments. Finally, the that the SASS or other QoL instruments in some SASS studies with reboxetine are the only studies measure treatment ef®cacy and may re¯ect employing QoL type measurements that demon- nuances of ef®cacy that traditional observer-based, strate the effects of an agent selective for the disease-speci®c rating scales such as the HAM-D noradrenergic system. The ®ndings with reboxetine miss, other than in severely depressed populations. are consistent with ®ndings for drugs which have Another possibility is that the SASS gives some some selectivity for the noradrenergic system using assessment of the overall impact of treatment. As patient-based measures such as the BDI (11). with the antihypertensives, the overall impact of In later weeks of treatment, quite apart from treatment, from the point of view of the patient, is a responses of the index condition and the burden of complex mixture of treatment ef®cacy as regards the side-effects, there may be an additional QoL index disorder together with the impact of side- contribution that a selective for the noradren- effects on the individual's lifestyle and social ergic system may make in comparison to an SSRI. functioning. To date, there has been no means of The SSRIs produce a non-sedative anxiolytic effect, comparing the burden of side-effects stemming reduce (6) and take the edge off intrusive from agents active on one system with those thoughts in OCD, social phobia and other condi- stemming from agents active on another. tions. This may be the means by which they exert However, in the case of the antihypertensives, it is their antidepressant effect. However, on occasions clear that the angiotensin-converting enzyme inhi- this anxiolytic effect can produce an over- bitors are preferred by patients to the beta-blockers, unconcern, an excess sanguinity. There is no even though in terms of observer-based measures of reason to suppose that taking the edge off intrusive ef®cacy these treatments are equivalent. This must, thoughts will only happen to the intrusive thoughts in part, be caused by the impact of differing sets of associated with a depressive or obsessive disorder. It side-effects on the QoL. Similarly, the SASS may may well happen to thoughts which intrude and give some indication as to the overall impact of which are necessary for normal social functioning

49 Healy such as worries about ®nances, etc. This point was clinicians have strong indicators from the data illustrated in a recent study of healthy volunteers that there is a right and a wrong antidepressant given , where a sense of lessened concern for the individual patient facing them. All and detachment was reported (33). An effect such as antidepressants are not simply equivalent for all this could be expected to lead, in a proportion of patients. This is particularly likely to be important individuals who had otherwise responded to treat- during the post-recovery phase of treatment, ment, to perceptions of altered social performance where the level of wellbeing experienced by the or QoL that would be consistent with the ®ndings patient on treatment may signi®cantly affect their outlined for the SASS in those treated with compliance with treatment and prospects for ¯uoxetine. remaining well. As noted in the Results section the mean ®ndings reported, rather than indicating effects across all the individuals in the clinical trial, are consistent with Acknowledgement ®ndings that a greater proportion of individuals feel This paper was presented at a satellite symposium to the Scand- normal on reboxetine compared with those on inavian Society for Psychopharmacology, entitled `Reboxetine ¯uoxetine. The data suggest that a signi®cant Ð a novel antidepressant drug selectively inhibiting noradrena- proportion of individuals respond to ¯uoxetine, line uptake and uniquely improving social functioning'. The become fully well and feel quite normal on this symposium was sponsored by an unrestricted educational grant from Pharmacia & Upjohn. agent, but that over one-third of those who otherwise appear well are not as well as they may appear. One signi®cant effect of SSRIs that may account for this is their sanguinity-inducing proper- References ties outlined above. 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