Latency and outcome of prophylaxis inbipolar disorder: role of severity as aconfounding variable?

To the editor:

Baethge et al. (1) have systematically studied the relation oflatency (delay between onset of bipolar disorder and startinglithium prophylaxis) and outcome in bipolar disorder. Theauthors have utilized a prospective follow-up design, usedproper diagnostic assessment, and employed an objectivemeasure of age at onset, thus taking care of most of themethodological flaws that have plagued research in this area.

The authors found that latency was a predictor of response toprophylaxis but only when severity of bipolar illness was notcontrolled for (1, Table 3, p. 264). In their analysis, severity ofbipolar illness before start of prophylaxis emerged as the mostpowerful predictor of response otherwise. If true, thiswould providean important clarification for this controversial question (2, 3).

Certain issues, however, merit consideration before accept-ing the authors’ conclusions. The authors performed multipleregression analysis to identify predictors of response. Thedependent variable (measure of response to prophylaxis) intheir analysis is defined as ‘saved’ hospital days. It is computedby subtracting days/year spent in hospital after startingprophylaxis from days/year spent in hospital before startingprophylaxis. In other words, the dependent variable is meas-ured as pre-prophylaxis hospitalization days/year (say, quan-tity A) minus post-prophylaxis hospitalization days/year (say,quantity B). Using this (A ) B) as the dependent variable, theindependent variable ‘latency’ did show a significant associ-ation with it (standardized b: )0.473; P < 0.001; vide upperportion of Table 3). However, inclusion of ‘severity of illness’as another independent variable (shown in the same table as‘prior hospitalization’; column 2) immediately resulted in‘complete loss of the effect of latency on outcome (b: )0.003;P ¼ 0.925)’. However, this ‘severity’ variable showed aremarkably high association with the dependent variable (b:0.961; P < 0.001). Not only that, the model that included this‘severity’ as an independent variable explained a very highpercentage of variance of the dependent variable (R2 ¼ 0.932,i.e. 93.2% of the variance explained) as opposed to theprevious model without the ‘severity’ variable (R2 ¼ 0.206).

The point we wish to emphasize is that this so-called‘independent’ variable of severity is nothing but the pre-prophylaxis hospitalization days/year (vide p. 263, right-handcolumn, second paragraph, lines 8–11). Thus, it is the very same‘quantityA’whichwas also used to operationalize the dependentvariable (A ) B). Obviously, therefore, the ‘independent’ vari-able (A) becomes a part of the operational definition of thedependent variable itself (A ) B), and hence nomore remains anindependent variable! It is quite understandable that quantity(A ) B) will have a positive and very highly significant corre-lation with quantity A, but this computation is statisticallyinvalid as one variable is simply part of the other. This, we

suspect, is the reasonwhy both the b and theR2 (and theF-value)all turned out to be spuriously high.

Apart from the above, certain other issues, althoughrelatively minor, limit the generalizibility of the findings. Theselection of ‘saved’ hospitalization days/year as responsecriterion is perhaps too restrictive, addressing only to thesubset of patients who were severely ill. Moreover, the criteriafor both hospital admission and duration of hospital stay maybe influenced by factors other than severity (e.g. referral andadmission policies, bed availability, treatment policies, numberof disturbed patients waiting for admission, etc.). Morecomposite response criteria reflecting on psychopathologyand social adjustment perhaps could have been more appropri-ate. Finally, compliance to lithium and serum levels of lithiumwere not taken into consideration.

It should be emphasized that we are not suggesting thatseverity cannot be an intermediary or confounding variableexplaining the apparent link between latency of prophylaxisand outcome. The authors should be complemented fordrawing research attention to this point. Our concern is theway the variables have been defined and data computed.Perhaps one other way of exploring this issue could be toanalyse the data separately for the two sources of patientreferral (university hospital vs. private practice). The severitylevel of these two groups of patients is likely to be different,and it may be interesting to know if there is a differential effectof latency on the outcome of prophylaxis in these two groups.

Parveen Sharma, Debasish Basu, Satish ThaparDepartment of Psychiatry

Postgraduate Institute of MedicalEducation of ResearchChandigarh-160012

IndiaE-mail: db_sm@satyam.net.in

References

1. Baethge C, Smolka MN, Gruschka P et al. Does prophylaxis-delay in bipolar disorder influence outcome? Results from along-term study of 147 patients. Acta Psychiatr Scand2003;107:260–267.

2. Franchini L, Zanardi R, Smeraldi E, Gasperini M. Early onsetof lithium prophylaxis as a predictor of good long-termoutcome. Eur Arch Psychiatry Clin Neurosci 1998;249:227–230.

3. Kusaric M, Engelsmann F. Predictors of lithium treatmentresponsiveness in bipolar patients. A two-year prospectivestudy. Neuropsychobiology 1998;55:23–25.

Acta Psychiatr Scand 2004: 109: 157–158Printed in UK. All rights reserved

Copyright � Blackwell Munksgaard 2004

ACTA PSYCHIATRICASCANDINAVICA

157

Reply:

In their letter, Dr Sharma and his colleagues appropriatelyemphasize the methodological difficulties of long-term studiesdealing with prophylaxis of affective disorders (1). We appre-ciate their thoughtful comments to our publication in the Aprilissue of Acta Psychiatrica Scandinavica 2003 (2). However, wediffer in our understanding of some aspects of statisticalmethods relevant to such studies.

Sharma and colleagues find one of three statistical approa-ches supporting the conclusions of our study to be circular. Wedo not agree with this understandable impression. Ourapproach is a pretest–post-test design in an observationalstudy. Such a design requires adjusting for the baseline orpretreatment illness-severity while investigating effects of cova-riates such as latency or factors such as family history. This typeof analysis is often called analysis of covariance (ANCOVA)and may be performed as a special case of multiple regression.The purpose of this type of analysis is to analyse the data as if allindividuals have the same baseline severity of illness. Thus,frequently such analyses are performed by taking post-testscores as dependent (outcome) variable with pretest scores asone of the independent variables. As suggested we useddifference scores as dependent variables (change in hospitaliza-tion). Note, however, that for an ANCOVA the dependentvariable and predictors may be correlated. A detailed consid-eration of the analysis of data arising from pretest–post-testdesigns is provided by Bonate (3).

In addition, we applied two other outcome measures thatwere based only on morbidity during prophylactic treatment,including time-to-first-recurrence and Morbidity Index (toaccount for illness-duration and severity). These measuresconfirmed that treatment-latency was not an importantpredictor in our study. Moreover, Baldessarini et al. (4)reported similar results using yet another statistical approachfor a non-university out-patient sample of bipolar patients, andwe reported additional evidence of a lack of effect of latency onprophylaxis outcome in unipolar (5) and schizoaffective (6)patients. In all of these studies, serum levels of mood stabilizerswere controlled. Finally, we recently presented a detailed,methodologically oriented, overview of research on this topicwith new data (7).

Christopher BaethgeMailman Research Center

McLean Division of Massachusetts General Hospital,Harvard Medical School

Belmont, MA, USA

Michael N. SmolkaCentral Institute of Mental Health

Mannheim, Germany

Peter SchlattmannDepartment of Medical Informatics, Biometry and

Epidemiology, Freie Universitat Berlin,Berlin, Germany

References

1. Sharma P, Basu D, Thapar S. Latency and outcome ofprophylaxis in bipolar disorder: role of severity as a con-founding variable? Acta Psychiatr Scand 2004;109:157.

2. Baethge C, Smolka MN, Gruschka P et al. Does prophylaxis-delay in bipolar disorder influence outcome? Results from along-term study of 147 patients. Acta Psychiatr Scand2003;107:260–267.

3. Bonate P. Analysis of pretest–posttest designs. Boca Raton,FL: Chapman & Hall/CRC 2000:91–94.

4. Baldessarini RJ, Tondo L, Hennen J, Floris G. Latency andepisodes before treatment: response to lithium maintenancein bipola I and II disorders. Bipolar Disord 1999;2:91–97.

5. Baethge C, Gruschka P, Smolka MN et al. Effectiveness andoutcome predictors of long-term lithium prophylaxis inunipolar major depressive disorder. J Psychiatr Neurosci2003;28:355–361.

6. Baethge C, Gruschka P, Berghofer A et al. Prophylaxis ofschizoaffective disorder with lithium or carbamazepine:outcome after long-term follow-up. J Affect Disord (inpress).

7. Baethge C, Tondo L, Bratti IM et al. Prophylaxis latencyand outcome in bipolar disorders. Can J Psychiatry 2003;48:449–457.

158