Affective Spectrum Disorders Current Issues

The Use of Rating Scales in Affective Disorders

a report by

Per Bech
Professor, Applied Psychometrics, University of Copenhagen

Since the paradigmatic change heralded by the release of the Diagnosis and Statistical Manual of Mental Disorders, Third Edition (DSM-III), the
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Using sophisticated software programs such as the Statistical Analysis System (SAS), the rating scale data can be analysed by the physicians themselves. However, the sections of psychometrics in the SAS9 designed to help the physician evaluate the reliability and validity of rating scales refers to a form of mathematical reasoning that may lead to a misuse of rating scale data. Thus, the reliability measure co-efficient alpha is recommended, although Feinstein wrote its obituary two decades ago.10 The factor validity of rating scales is also recommended in the SAS, although the SAS user is at the same time warned that factor analysis can be seductive in that it takes a large number of baffling variables and turns them into a clear-cut set of just a few factors.9 In the following, the use of rating scales for affective disorders, as recommended by Feinstein10 and Borsboom,8 will be outlined. The Clinimetrics of Rating Scales In his monograph on clinimetrics, Feinstein10 referred to three different types of rating scale and their rational uses. The Apgar or Global Impression Type of Rating Scales The Apgar scale was developed as a rating scale for the clinical condition of a newborn baby.11 It is probably one of the most commonly used scales in clinical medicine worldwide. It is a very short scale, containing five items, each of which can be scored from zero to two. In other words, the theoretical score range of the sum score is from zero to 10. A high score indicates a better condition. As the five items are diverse (covering heart rate, muscular tone, respiration, colour and reflex response), the total score gives only a rough global impression of the condition. An Apgar score of five, for example, indicates that the babys condition is not splendid. However, if we want to determine what is wrong with this baby, we need to check the individual items. Therefore, a profile score is often needed as the total score is not sufficient. As pointed out by Feinstein,10 the Apgar type of scale is not valid for measuring outcome of a specific treatment. The Hamilton or Factor-based Type of Rating Scales The HAM-D17 is a rating scale for assessment of the clinical condition of depressive states.12 As mentioned above, Hamilton developed his scale to measure depressive states globally, but not for the monitoring of changes due to treatment effect. It is a rather large scale, containing at least 17 items, each of which can be scored either from zero to four or from zero to two, with a theoretical score range of the sum score from zero to 52. A high score indicates higher severity of depressive states. Feinstein10 included the HAMD17 in his monograph to illustrate a scale that has been produced by factor analysis.12 Like the Apgar scale, the HAM-D contains diverse symptoms of depressive states and the total score is therefore only a global impression of the severity of depression. A score of 18 indicates a severity of depressive state as seen in major depression and a score of seven indicates remission. However, the total score is not a sufficient statistic for measuring the specific

focus in our diagnostic systems for mental disorders has been on signs and symptoms rather than aetiological factors, and has entailed a high reliance on the symptom rating scales of psychopathology, especially in the field of affective disorders. In the DSM-III (as well as in the DSM-IV2 or the International Statistical Classification of Diseases and Related Health Problems, 10th Revision [ICD-10] ), the diagnosis of depression provides a global impression of
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the severity of depressive states through their symptoms, e.g. minor versus major depression or mild, moderate and severe depression. When Hamilton developed his Hamilton Depression Rating Scale (HAM-D), he
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made an attempt to characterise the global impression of depressive states by a total score of the 17 items in the scale (HAM-D17). Since then, it has consistently been shown that the HAM-D can be used in all forms of depressive disorders.5 As summarised by Paykel:6 We all know the appropriate meaning of a Hamilton score of 17, 13 or 26. Over the last few decades, the HAM-D has been the scale most frequently used when measuring the outcome of antidepressive therapy. Rating scales for affective disorders have their major use as outcome scales, and this article will review the correct use of the various scales for affective disorders in this respect. The Mathematics of Rating Scales Fifty years ago, when the antimanic effect of chlorpromazine or the antidepressive effect of imipramine were identified but were found to be controversial by many psychiatrists, the conclusion was that when examining the effects of these new psychopharmacological drugs, the physician lacked a system of statements from which the observed facts could be derived by formal mathematical reasoning.7 Mathematical reasoning is indeed the most reliable way to measure the mind.8

Per Bech is a Professor of Applied Psychometrics at the University of Copenhagen. Prior to this he was a Professor of Clinical Psychiatry at Odense University and Head of the Psychiatric Unit at Frederiksborg General Hospital. He was one of the founder members of the European College of Neuropsychopharmacology (ECNP) in 1987, Past President of the Association of European Psychiatrists (AEP) (19921994) and Head of the Research Unit at the World Health Organization (WHO) Centre for Psychometrics (19852005). Professor Bech has published several books on applied psychometrics and approximately 400 papers in the field of psychometrics, clinical psychiatry and psychopharmacology. He received his MD from the University of Copenhagen in 1969, and in 1972 he received the Gold Medal in Psychiatry for studies of the doseresponse effect of cannabis on psychological tests at the University of Aarhus. He specialised in clinical psychiatry 1978, and in 1981 he obtained his DScM for rating scales of affective disorder. E: pebe@noh.regionh.dk

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The Use of Rating Scales in Affective Disorders

Table 1: Rating Scales for Affective Disorders

Scale BPRS HAM-D HAM-A SCL-90 1 Anxiety/depression Anxiety/somatisation Somatic anxiety Somatisation 2 Anergia Weight Psychic anxiety Obsessive/compulsive 3 Thought disturbance Cognitive disturbance Interpersonal sensitivity Factors 4 Activation/excitement Diurnal variation Depression

5 Hostility/suspicion Retardation Anxiety

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6 Sleep Anger/hostility

Phobic anxiety

Descriptions of rating scales for affective disorders measuring outcome of trials with psychopharmacological drugs by their factorial validation. BPRS = Brief Psychiatric Rating Scale; HAM-D = Hamilton Depression Rating Scale; HAM-A = Hamilton Anxiety Rating Scale; SCL-90 = Symptom Checklist-90.

Table 2: Items in the Hamilton Depression Rating Scale

NO Item 1 Depressed mood 2 3 4 5 6 7 Low self-esteem, feelings of guilt Suicidal thoughts Insomnia: initial Insomnia: middle Insomnia: late Social life activities and interests HAM-D17 HAM-D6 MES

Table 3: Universe of Items in the Mania Assessment Scale and the Young Mania Assessment Scale
MAS (044) Evaluated mood (04) Increased verbal activity (04) (accelerated speech) Increased social contact (04) (intrusiveness) Increased motor activity (04) Sleep (04) Social activity (04) (distractibility) Hostility (04) Noise level (04) Increased sexual interest (04) Increased self-esteem (04) Flight of thoughts (04) YMRS (044/060) Evaluated mood (04) Speech (08)

MADRS10 MADRS6 Items A=Apparent A R A R R=Reported sadness Pessimistic thoughts Suicidal thoughts

Increased motor activity (04) Sleep (04) Irritability (08) Destructive behaviour (08) Sexual interest (04) Content of thoughts (08) Thought disturbances (04) Insight (04) Appearance (04)

I L

I L

I=Inability to feel L=Lassitude

Psychomotor retardation 9 Psychomotor agitation 10 Anxiety: psychic 11 Anxiety: somatic 12 Gastrointestinal

Inner tension Reduced appetite

The universe of items in the first two mania scales released independently before the Diagnosis and Statistical Manual of Mental Disorders, Third Edition (DSM-III).19,20 In the Young Mania Rating Scale (YMRS), items with asterisks have been doubled up, hence the two score ranges. MAS = BechRafaelsen Mania Assessment Scale; YMRS = Young Mania Rating Scale.

most important handbook for psychopharmacological investigators in clinical psychiatry, the factors shown in Table 1 have been recommended when using the HAM-D17 or other rating scales in trials with patients suffering from psychotic depression (the Brief Psychiatric Rating Scale [BPRS]), major depression (HAM-D), dysthymia or general anxiety (the Hamilton Anxiety Rating Scale [HAM-A] or the Symptom Checklist-90 [SCL90]).13 Even Hamilton himself showed that the HAM-A was insufficient for the monitoring of changes due to treatment effect when total score

13 Somatic symptoms: general 14 Sexual disturbances 15 Hypochondriasis (somatisation) 16 Insight 17 Weight loss 18 Insomnia: general 19 Decreased motor activity 20 Decreased verbal activity 21 Concentration difficulties 22 Introversion 23 Tiredness Total

Reduced sleep

was used.14 The most interesting example of a HAM-D subscale produced by factor analysis is the five-item subscale identified by Gonzales-Pinto et al.,15 who used a principal component analysis to identify bipolar depression. Among

Concentration difficulties

the items are obsessivecompulsive symptoms but not psychomotor retardation or anhedonia. This illustrates the point that factor analysis is very sensitive in relation to the individual sample of patients from whom the HAM-D data are collected. To test the validity of bipolar depression we

need a clinical theory of the severity of depressive states, and factor analysis has no place in this stage of inquiry.8 The Guttman or Unidimensional Type of Rating Scale Feinstein10 included the Guttman scalogram analysis to illustrate the ideal scale for measuring a specific treatment effect because a Guttman scale is unidimensional, implying that the total score is a sufficient statistic for the dimension under investigation. It is a consistently monotonic scale in which a score on a low-prevalence item has to be preceded by a score on a higher-prevalence item. The Guttman scale is sometimes called a cumulative scale; however, unidimensional is the most appropriate term.

HAM-D17 HAM-D6 MES MADRS10 MADRS6

The universe of items in the HAM-D17 with reference to the first two depression scales released independently before DSM-III.18 HAM-D17 = 17-item Hamilton Depression Rating Scale; HAM-D6 = Six-item Hamilton Depression Rating Scale; MES = Bech-Rafaelsen Melancholia Scale; MADRS10 = 10-item MontgomeryAsberg Depression Rating Scale; MADRS6 = Six-item Montgomery Asberg Depression Rating Scale.

antidepressive effect of an experimental drug compared with placebo or demonstrating the doseresponse relationship. Due to the many items included in the HAM-D17, a profile score of the individual items is too complex. In this situation, factor scores are often recommended, and surprisingly this solution seems to have been accepted by physicians.10 In the

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Affective Spectrum Disorders Current Issues

Table 4: Psychometric Description of Interview-based Rating Scales for Affective Disorders

Scales (Pearsons/Interclass) Co-efficients Classic Internal Consistency Co-efficient Alpha Modern Item Response Models Co-efficient of Homogeneity HAM-D17 HAM-D6 MES MADRS MAS YMRS 0.480.97 0.780.96 0.750.93 0.650.97 0.800.99 0.360.95 0.460.91 0.670.80 0.91 0.90 0.88 0.84 0.190.27 0.400.44 0.49 0.430.46 0.40 0.24 Rasch Analysis Acceptance + + + ?

Table 5: Standardisation of Rating Scales for Affective Disorders

Symptom Rating Scales CGI Minimum (two or fewer) Remission 7 4 6 12 6 8 CGI Moderate (four or more) Relapse 18 9 15 25 15 20

HAM-D17 HAM-D6 MES MADRS MAS YMRS

Standardisation of rating scale for affective disorders19,44 with reference to the Cinical Global Impression Scale (CGI-S).13 HAM-D17 = 17-item Hamilton Depression Rating Scale; HAM-D6 = Six-item Hamilton Depression Rating Scale; MES = Bech-Rafaelsen Melancholia Scale; MADRS = MontgomeryAsberg Depression Rating Scale ; MAS = BechRafaelsen Mania Assessment Scale; YMRS = Young Mania Rating Scale.

Psychometric description by reliability and validity (classical and modern) of the most used interview-based rating scales for affective disorders.19,4346 HAM-D17 = 17-item Hamilton Depression Rating Scale; HAM-D6 = Six-item Hamilton Depression Rating Scale; MES = BechRafaelsen Melancholia Scale; MADRS = MontgomeryAsberg Depression Rating Scale; MAS = BechRafaelsen Mania Assessment Scale; YMRS = Young Mania Rating Scale.

(BechRafaelsen Mania Assessment Scale [MAS] and Young Mania Rating Scale [YMRS]).19,20 Table 4 shows the inter-rater reliability and validity of the scales shown in Tables 2 and 3. For all the scales the reliability co-efficients are of statistical significance, although most problems have emerged with the YMRS.21

The Guttman scale model is a deterministic version of the item response theory models, of which the Rasch analysis is a parametric version and the Mokken analysis a non-parametric version.8 Thus, statistical probability has been taken into account in the Rasch and Mokken models. According to Feinstein10 and Borsboom,8 the clinical (face) validity of rating scales is a non-statistical problem. Thus, as stated by Guttman,16 the face validity of items to be included in a rating scale is the extent to which they belong to the universe of items accepted by experienced clinicians (clinical validity). The scale function tested by the item response theory analysis is the unidimensional meaning of more or less, which is meaningful only for scales when the total score is a sufficient statistic. The first depression rating scale designed according to the Guttman type of scale for measuring changes in depressive states during antidepressive treatment was the CronholmOttosson Depression Scale.17 The BechRafaelsen Melancholia Scale (MES) was developed with reference to this scale and the HAM-D.17 In doseresponse relationship trials of antidepressants, the effect size statistic has been found to be the most sensitive response measure when comparing experimental drugs with placebo.2325 In these trials it was shown that the HAM-D6 and MADRS6 were more similar than HAM-D17 or MADRS10 in showing a doseresponse relationship. Even when analysing each single item within the HAM-D17 for its sensitivity to measure change (experimental drug versus placebo), the HAM-D6 items were found to be the most valid.26 An effect size of 0.40 or higher when comparing the experimental drug with placebo was shown to be a clinically significant response.25 It has been demonstrated that an effect size of 0.40 equals a number needed to treat (NNT) of 4.5.27 Rating Scales for Measuring Outcome of Treatment in Patients with Affective Disorders Table 2 shows a scoring sheet with the three most important clinician-rated scales for the measurement of symptom change during antidepressive treatment. All three scales (the HAM-D17, MES and Montgomery-Asberg Depression Rating Scale [MADRS]) were developed before the introduction of the DSM-III in 1980. Table 3 shows the range
18

As most investigators still show the classic co-efficient alpha for testing of internal consistency, this co-efficient is included in Table 4. However, this is not a test of unidimensionality, nor is factor analysis a test for unidimensionality. Thus, for the testing of the psychometric validity of bipolar depression, item response theory models have to be used.22 The Measure of Response to Treatment in Patients with Affective Disorders The most conservative measure of response to treatment in patients with affective disorders in the acute treatment phase is a 50% reduction or more of the baseline total score at end-point (typically after six to eight weeks with antidepressants and after two to four weeks with antimanics). This corresponds with the much improved or very much improved of the Clinical Global Impression Scale (CGI-S).13

The use of rating scales is of special interest when assessing response to treatment (e.g. in doseresponse studies) or to identify remission.

In trials with antimanics it is not possible to include placebo for ethical reasons. In such trials, the plasma level of the experimental drug in relation to the clinical effect by total rating scale score seems most convincing. In fixed-dose trials using plasma level at end-point, a negative correlation co-efficient will express the clinical relation so that higher plasma levels are associated with lower rating scale scores.19 It has been shown that a significant negative correlation between the rating scale score and plasma level of olanzapine after two weeks of therapy with a fixed dose of 20mg/day emerged in manic patients using the MAS but not using the YMRS.28 When using rating scales for affective disorders to express a

of symptoms in the two most frequently used clinician-rated scales for the measurement of symptom change during treatment with antimanic drugs. They were also developed before the introduction of the DSM-III

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The Use of Rating Scales in Affective Disorders

quantitative response, for example in doseresponse trials or plasma concentrationresponse, only scales that have been accepted by item response theory models (total score a sufficient statistic) are recommended. Self-rating Scales versus Clinician-administrated Scales The use of self-reported rating scales within affective disorders has become more and more important in depression. Scales such as the Beck Depression Inventory (BDI) or the Zung Self-rating Depression Scale (SDS) were previously often used as supplements to the HAM-D. However, recently self-reported HAM-D versions have been published.29 In order to have a closer face validity with the ICD-10 or DSM-IV than that of the BDI, the Major Depression Inventory (MDI) has been developed.30 The selfrated version of the HAM-D6 and the MDI fulfil the item response theory models, i.e. the total score is a sufficient statistic. The use of self-reported rating scales to measure manic states is limited to hypomanic states because in more severely manic states the response pattern reflects that the patients are playing the manic game. Recently, patient-reported questionnaires have been published to identify previous episodes of hypomania in depressed patients in order to test for the existence of bipolar II disorder. It seems that the Hypomanic Checklist is superior to the Mood Disorder Questionnaire in this respect.31 The most comprehensive self-reported scale covering depression and hypomania (aggression) as well as the different anxiety disorders is the SCL-90.
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XIV World Congress of Psychiatry

2025 September 2008 Prague Congress Centre, Czech Republic
I would like to extend to you a warm invitation to join us at the XIV World Congress of Psychiatry, taking place in Prague in the autumn of 2008. All of our 130 Member Societies and 60 Scientific Sections are expected to be present, along with a full representation of all of our partners in mental healthcare, from our patients (who are at the centre of our work) to health professionals, health planners and relevant industry. You would not want to miss this special encounter, where new psychiatric findings and perspectives will be discussed, and where current partnerships will be strengthened and new ones forged. Professor Juan E Mezzich President, XIV World Congress of Psychiatry Topics include: addiction, affective disorders, animal models in psychiatry, anxiolytics, biological markers, clinical psychopharmacology, emergency psychiatry, public health and psychiatry, somatoform disorders, urban mental health, cultural psychiatry and molecular neurobiology. Honorary and Supervisory Committee includes: Jaroslav Blahos (Chair, Czech Medical Association), Jan Brza (Director, General Faculty Hospital, Prague), Milan Kubek (President, Czech Medical Chamber) and Mario Maj (Chair, Scientific Committee, World Congress of Psychiatry). Contact: E: wpa@guarant.cz T: +420 284 001 444 F: +420 284 001 448 www.wpa-prague2008.cz

From the SCL-90, a subscale analogue to the self-rated HAM-D6 has been derived containing the following items: feeling blue, blaming yourself for things, feeling no interests in things, feeling that everything is an effort, worrying too much about things and feeling low in energy. Like the HAM-D6, this depression SCL-90 subscale fulfils the items response theory model and the items are included in the SCL-90 factor solution by Lipman.32 Standardisation of Rating Scales for Affective Disorders As mentioned above, the HAM-D was originally developed to measure a global impression of depressive states. The CGI-S13 is probably the most frequently used global assessment of depressive or manic states. This scale has a score range from one (not at all ill) to seven (among the most extremely ill patients suffering from depression or mania).
13

However,
33

the inter-rater reliability of this CGI-S has not been found to be high,

and in most trials with antidepressants a cut-off score on HAM-D17 of 7 has been used to define remission (which implies that the signs and symptoms of illness are absent or almost absent). This cut-off score for remission was introduced by Reisby et al.34 and equals a CGI-S score of one and two (minimally depressed/manic symptomatology). A modification of the CGI scales for use in bipolar illness (the CGI-BP) has been suggested by Spearing et al.33 The CGI-BP gives a severity rating of mania, depression and overall bipolar illness during treatment of an acute episode as well as in long-term prophylaxis. The cut-off levels are based on both unipolar patients with depression and bipolar patients with depression and mania. When making such a standardisation for remission and relapse with reference to CGI-S or CGI-BP, all of the symptom rating scales in Table 5 and the CGI versions themselves refer to a global impression of illness. Therefore, the total score does not need to be a sufficient statistic. It is of interest that, while the HAM-D17 remission score of seven or lower has been found to be adequate in most studies, it is still problematic for the MADRS to establish a consensus for the cut-off score of 12 (which is a rather high score but

was recently confirmed for bipolar depression by Vieta et al.44). For unipolar depression a cut-off score on MADRS of nine or lower has recently been suggested.35 The report by the American College of Neuropsychopharmacology (ACNP) task force on response and remission in major depressive disorders35 suggests a special focus on the HAM-D symptoms of depressed mood when defining remission or the core items of the scale being used. For manic episodes the definition of remission should focus on the MAS or YMRS symptoms of elevated mood and/or hostility (destructive behaviour). In an analysis using the HAM-D item of depressed mood as index of validity, the results showed that a score of zero (depressed mood absent) corresponded to an HAM-D17 score of seven or less.36 A score on depressed mood of one (doubtful or minimal) corresponded to an HAM-D17 score of 13 or less, while a

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Affective Spectrum Disorders Current Issues

score on depressed mood of two (mild depression) corresponded to a score of 16 plus or minus four. Translation Validity of Rating Scales Although the HAM-D is the most commonly used scale worldwide in affective disorders, different translations of the scale are often used.37 The American translation13 was never accepted by Hamilton himself,38 but he did go on to accept the updated version used by the Danish University Antidepressant Group (DUAG) in their trials.39,40 This updated version has been translated into French, German and Spanish,41 but only recently has a major attempt been made (by Emmanuelle Weiller and her group) to perform a translation of the correct HAM-D version (including the Melancholia Scale) into several European and Asian languages. The World Health Organization (WHO) procedure for the translation of rating scales is recommended. Summary The rating scales for affective disorders have been classified by their psychometric or clinimetric properties as Apgar type scales (measuring a global impression of affective states), Hamilton-type scales (measuring factors or sub-scores of affective states) and Guttman-type scales (measuring outcomes of treatment by the total scale score). The use of rating scales is of special interest when assessing response to treatment (e.g. in doseresponse studies) or to identify remission. In doseresponse studies, unidimensional Guttman scales are meaningful because the total Acknowledgement This study has received an educational grant from the Lundbeck Foundation.
42

score is then a sufficient statistic. The HAM-D6 or MADRS6 subscales or the MES have been found to be unidimensional depression scales. Among the mania scales, the MAS is still the only scale found to be unidimensional. Self-rating scales are of major use in depressive states. A self-reported version of the HAM-D6 has been released, and the MD has been developed to measure depression according to ICD-10 or DSM-IV.

The use of self-reported rating scales within affective disorders has become more and more important in depression.

Standardisation of rating scales is an important aspect of their clinimetric use, especially in order to define remission in affective states during treatment. Table 5 shows standardisation, in terms of remission and relapse, of the various rating scales included in Table 4. The translation problems when using scales in Europe have been discussed and the WHO procedure for translation of rating scales has been recommended.

1.

2. 3.

4. 5.

6.

7. 8. 9. 10. 11. 12. 13. 14.

15. 16. 17.

18.

19.

American Psychiatric Association, Diagnosis and statistical manual of mental disorders , Third Edn , (DSM-III), Washington DC, 1980. American Psychiatric Association, Diagnosis and statistic manual of mental disorders , Third Edn (DSM-IV), Washington DC, 1994. World Health Organization, The ICD-10 classification of mental and behavioural disorders, Diagnostic criteria for research, World Health Organization , 1993. Hamilton M, A rating scale for depression, J Neurol Neurosurg Psychiatry , 1960;23:5662. Roth M, Hamilton M, a life devoted to psychiatric science. In: Bech P, Coppen A (eds), The Hamilton Scales , Berlin: Springer 1990;19. Paykel ES, Use of the Hamilton Depression Scale in general practice. In: Bech P, Coppen A (eds), The Health Scales , Berlin Springer 1990;4047. Editorial comments, Rose is a rose is a rose is a rose, Psychiatr Quart , 1957;31:34661. Borsboom D, Measuring the mind. Conceptual issues in contemporary psychometrics , Cambridge University Press, 2005. Cody RP, Smith JK, Applied statistics and the SAS programming language , 4th Edn , Prentice-Hall, 1997. Feinstein AR, Clinimetrics , Yale University Press, 1987 Apgar V, A proposal for a new method of evaluation of a newborn infant, Curr Res Anesth Analg , 1953;32:26067. Hamilton M, Development of a rating scale for primary depressive illness, Br J Soc Clin Psychol , 1967;6:27896. Guy W, Early clinical drug evaluation (ECDEU) assessment manual , Rockvill, National Institute Mental Health, 1976. Hamilton M, Treatment of anxiety states. Components of anxiety and their response to benactyzine, J Ment Sci , 1958;104:10628. Gonzales-Pinto A, Ballesteros J, Aldama A, Principal components of mania, J Affect Dis , 2003;76:95102. Guttman L, A basis for scaling quantitative data, American Sociological Review , 1944;9:13950. Bech P, CronholmOttosson Depression Scale: the first depression scale designed to rate changes during treatment, Acta Psychiatr Scand , 1991;84:43945. Bech P, The Bech, Hamilton and Zung Scales for Mood Disorders: Screening and Listening. A twenty years update with reference to DSM-IV and ICD-10 , SpringerVerlag, 1996. Bech P, Lunde M, Bech-Andersen G, et al., Psychiatric outcome

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studies (POS): Does treatment help the patients? A Popperian approach to research in clinical psychiatry, Nord J Psychiatry , 2007;61(Suppl. 46):180. Goodwin FK, Jamison KR, Manic-depressive illness , 2nd Edn , New York, Oxford University Press, 2007 Mackin P, Targum SD, Kalali A, et al., Culture and assessment of manic symptoms, Brit J Psychiatr , 2006;189:37980. Bech P, Eriksson H, The pure antidepressive effect of quetiapine in the acute therapy of bipolar depression , submitted for publication 2008. Bech P, Cialdella P, Haugh M, et al., A meta-analysis of randomised controlled trials of fluoxetine versus placebo and tricyclic antidepressants in the short-term treatment of major depression, Br J Psychiatry , 2000;176:4218. Bech P, Tanghj P, Andersen HF, Over K, Citalopram dose-response revisited using an alternative psychometric approach to evaluate clinical effects of four fixed citalopram doses compared to placebo in patients with major depression, Psychopharmacol , 2002;163:2025. Bech P, Andersen HF, Wade A, Effective dose of escitalopram in moderate versus severe DSM-IV major depression, Pharmacopsychiatry , 2006;39:12834. Santen G, Gomeni R, Danhof M, Della Pasqua O, Sensitivity of the individual items of the Hamilton depression rating scale to response and its consequences for the assessment of efficacy, J Psychiatr Res , 2008; in press. Kraemer HC, Kupfer DJ, Size of treatment effects and their importance to clinical research and practice, Biol Psychiatry , 2006;59:99096. Bech P, Gex-Fabry M, Aubry J-M, et al., Olanzapine plasma level in relation to antimanic effect in the acute therapy of manic states, Nord J Psychiatry , 2006;60:1812. Bent-Hansen J, Lauritzen L, Clemmensen L, et al., A definite and a semi-definite questionnaire version of the Hamilton/Melancholia scale, J Affect Dis , 1995;33:14350. Olsen LR, Jensen DV, Noerholm V, et al., The internal and external validity of the Major Depression Inventory in measuring severity of depressive states, Psychol Med , 2003;33:3516. Angst J, Adolfsson R, Benazzi F, The HCL.32: towards a selfassessment tool, J Affect Dis , 2005;88:21733. Lipman RS, Depression scales derived from the Hopkins Symptom Checklist. In: Sartorius N, Ban TA (eds), Assessment of Depression , Berlin: Springer, 1986;23248.

33. Spearling MK, Post RM, Leverich GS, et al., Modification of the Clinical Global Impression (CGI) Scale for use in bipolar illness, Psychiatry Research , 1997;73:15971. 34. Reisby N, Gram LF, Bech P, Nagy P, Imipramine: Clinical effects and pharmacokinetic variability, Psychopharmacology , 1977;54: 26372. 35. Rush AJ, Kraemer HC, Sackeim HA, et al., Report by the ACNP task force on response and remission in major depressive disorder, Neuropsychopharmacology , 2006;31:184153. 36. Bech P, Depressed mood as a core symptom of depression, Medicographia , 2008;30:1217. 37. Zitman FG, Mennen MF, Griez E, Hooijer CI, The different versions of the Hamilton Depression Rating Scale, Psychopharmacol Ser , 1990:9:2834. 38. Hamilton M, Shapiro CM, Depression, In: Peck DF, Shapiro CM (eds), Measuring Human Problems , Wiley, 1990;2565. 39. Bech P, Kastrup M, Rafaelsen OJ, Mini-compendium of rating scales for states of anxiety, depression, mania and schizophrenia with corresponding DSM-III syndromes, Acta Psychiatr Scand , 1986;73:737. 40. Bech P, Gram LF, Kragh-Srensen P, et al., Standardized assessment scales and effectiveness of antidepressants, Nord Psykiatr Tidsskr , 1988;42:51115. 41. Bischoff R, Grtelmeyer BD, Rating Scales for Psychiatry , Weinheim, Beltz Test, 1990. 42. Sartorius N, Kuyken W, Translation of health status instruments. In: Orley J, Kuyken W (eds), Quality of life assessment: international perspectives , Berlin: Springer, 1994;319. 43. Bagby RM, Ryder AG, Schiller DR, Marchall MB, The Hamilton Depression Rating Scale, Am J Psychiatry , 2004;161:216377. 44. Vieta E, Bobes J, Ballesteros J, et al., Validity and reliability of the Spanish versions of the BechRafaelsens mania and melancholia scales for bipolar disorders, 2007:19. 45. Dew MA, Switzer GE, Myaskovsky L, et al., Rating scales for mood disorders. In: Stein DJ, Kupfer JD, Schatzberg AF (eds), Textbook of mood disorders , American Psychiatric Publishing, 2005;6997. 46. Licht RW, Qvitzau S, Allerup P, Bech P, Validation of the BechRafaelsen Melancholia Scale and the Hamilton Depression Scale in patients with major depression, Acta Psychiatr Scand , 2005;111:1449.

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