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Starting lithium prophylaxis early v. late in bipolar disorder

  • Lars Vedel Kessing (a1), Eleni Vradi (a2) and Per Kragh Andersen (a2)



No study has investigated when preventive treatment with lithium should be initiated in bipolar disorder.


To compare response rates among patients with bipolar disorder starting treatment with lithium early v. late.


Nationwide registers were used to identify all patients with a diagnosis of bipolar disorder in psychiatric hospital settings who were prescribed lithium during the period 1995–2012 in Denmark (n = 4714). Lithium responders were defined as patients who, following a stabilisation lithium start-up period of 6 months, continued lithium monotherapy without being admitted to hospital. Early v. late intervention was defined in two ways: (a) start of lithium following first contact; and (b) start of lithium following a diagnosis of a single manic/mixed episode.


Regardless of the definition used, patients who started lithium early had significantly decreased rates of nonresponse to lithium compared with the rate for patients starting lithium later (adjusted analyses: first v. later contact: P<0.0001; hazard ratio (HR) = 0.87, 95% CI 0.76–0.91; single manic/mixed episode v. bipolar disorder: P<0.0001; HR = 0.75, 95% CI 0.67–0.84).


Starting lithium treatment early following first psychiatric contact or a single manic/mixed episode is associated with increased probability of lithium response.

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Corresponding author

Lars Vedel Kessing, Psychiatric Center Copenhagen, Department O, 6233 Blegdamsvej 9, 2100 Copenhagen, Denmark. Email:


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NARSAD Distinguished Investigator Grant 2012, Brain & Behavior Research Foundation, New York, USA, awarded to L.V.K.

Declaration of interest

L.V.K. has within the preceding 3 years been a consultant for Lundbeck and AstraZeneca.



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Starting lithium prophylaxis early v. late in bipolar disorder

  • Lars Vedel Kessing (a1), Eleni Vradi (a2) and Per Kragh Andersen (a2)
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Early and delayed treatment of bipolar disorder

Martin Alda
12 August 2014

To the EditorUsing Danish registry data, Kessing et al. examined the relationship between lithium response and the start of treatment (early vs. delayed)(1). Early treatment was associated with an increased probability of lithium response. This is a clinically important finding, given the increasing emphasis on early intervention in bipolar disorder.The results of the Kessing et al. study are sobering. Only few patients, particularly those for whom treatment was delayed, responded to lithium. Several factors may have contributed to the reported results. The study did not -- and possibly could not -- control for cycle shortening that is observed after successive episodes of bipolar disorder. While the interpretation of such cycle shortening has been debated (2), it is well established that early cycles are significantly longer than those occurring later; consequently, early in the course of illness one would expect longer spontaneous remissions regardless of treatment. This effect may be partially responsible for the greater treatment response in patients receiving early intervention in the Kessing et al. study.Naturalistic studies typically demonstrate full response in about 30% of subjects (3) (that is, no recurrences, or the Kessing et al. criterion, incompliant patients), which is markedly greater than the response rate observed by Kessing et al. This discrepancy could be related to age at first contact. The average ages of subjects whom Kessing et al. reported as having received early and late treatment were 46.7 years and 49.1 years, respectively. The natural history of bipolar disorder includes an average age of onset in the second or third decade of life. The trajectoryof the illness, where mania typically develops as the last stage delays the diagnosis of bipolar disorders. Also, there is often a substantial delay in starting treatment even following the diagnosis of bipolar disorder (4,5). These reports, in conjunction with the advanced age at index presentation, and high rates of antidepressant, antipsychotic, and anticonvulsant use in the Kessing et al. study suggest that subjects may have been afflicted with bipolar disorder for some time before "first-contact." In a sample of 450 subjects, Baldessarini et al. reported a negative relationship between treatment latency and effect of treatment ontime spent ill (5). If the aforementioned findings are generalizable to the Danish sample, the reduced overall treatment responses may be interpreted as a consequence of relatively advanced subject age.Finally, Kessing et al. analyzed data collected since the year 1995. Is itplausible that subjects had received lithium during the years prior? This would further complicate the interpretations of sample responsiveness to lithium, regardless of early or late initiation.In conclusion, we suggest that the findings presented by Kessing et al. are limited by the lack of control for inter-subject differences in manifestation of the natural history of bipolar disorder. Such control maybe difficult, or in some cases impossible, to achieve using registry basedobservational data, but are nevertheless imperative to understand the effects of early versus late treatment prophylaxis in relapsing-remitting illnesses such as bipolar disorder.

References1. Kessing LV, Vradi E, Andersen PK. Starting lithium prophylaxis early v.late in bipolar disorder. [In Press] Br J Psychiatry 2. Oepen G, Baldessarini RJ, Salvatore P, Slater E. On the periodicity of manic-depressive insanity, by Eliot Slater (1938): translated excerpts andcommentary. J Affect Disord 2004; 78: 1-9.3. Garnham J, Munro A, Slaney C, MacDougall M, Passmore M, Duffy A, et al.Prophylactic treatment response in bipolar disorder: Results of a naturalistic observation study. J Affect Disord 2007; 104: 185-90.4. Ortiz A, Bradler K, Slaney C, Garnham J, Ruzickova M, O'Donovan C, et al. An admixture analysis of the age at index episodes in bipolar disorder. Psychiatr Res 2011; 188: 34-9.5. Baldessarini RJ, Tondo L, Hennen J. Treatment-latency and previous episodes: relationships to pretreatment morbidity and response to maintenance treatment in bipolar I and II disorders. Bipolar Disord 2003; 5: 169-79.

Abraham Nunes, MD MBA, Tomas Hajek MD PhD, Martin Alda MD FRCPC*Department of Psychiatry, Dalhousie University* correspondence5909 Veterans' memorial LaneHalifax, Nova ScotiaB3H 2E2Canada+1 902 473

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Conflict of interest: None declared

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