Acta Psychiatr Scand 2000: 101 (Suppl. 402): 45±51 Copyright # Munksgaard 2000 Printed in UK. All rights reserved ACTA PSYCHIATRICA SCANDINAVICA ISSN 0902-4441 Reboxetine: 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 antidepressants 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 pharmacology of agents conventionally had another, as yet less clearly characterized action, labelled antidepressant, it is dif®cult to believe that had an effect on the serotonin (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 receptor 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 tricyclic anti- to be antidepressants that were relatively selective depressants (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 sedative 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 bupropion and treatment of mood disorders. Faced with schemas of nomifensine, preferentially active on the dopamine 45 Healy system, have been identi®ed. Secondly, there is differential effects between antidepressants have not evidence that other agents such as isoniazid, 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 reserpine, 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 serotonergic 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 anxiolytic 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 clinical trial 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