Am J Psychiatry 159:7, July 2002
Effect of Abrupt Change From Standard to Low Serum
Levels of Lithium: A Reanalysis of Double-Blind
Lithium Maintenance Data
Roy H. Perlis, M.D.
Gary S. Sachs, M.D.
Beny Lafer, M.D.
Michael W. Otto, Ph.D.
Stephen V. Faraone, Ph.D.
John M. Kane, M.D.
Jerrold F. Rosenbaum, M.D.
Objective: Growing evidence suggests
that abrupt lithium discontinuation in-
creases the risk of recurrence for patients
with bipolar disorder. To assess the effect
of abrupt change in lithium dose, the au-
thors reanalyzed data from a previously
reported, randomized, double-blind trial
of standard- versus low-dose lithium for
maintenance therapy in bipolar disorder.
Method: In the original study, serum lith-
ium levels were obtained during a 2-
month open stabilization period for 94 pa-
tients with bipolar disorder who were then
randomly assigned to be maintained on a
low (serum level=0.4–0.6 meq/liter) or a
standard (0.8–1.0 meq/liter) level of lith-
ium therapy. Patients were then followed
for up to 182 weeks. This reanalysis exam-
ined the potential confounding influence
of prerandomization lithium level and
change in lithium level on the outcome of
subjects assigned to a standard or low
maintenance dose of lithium.
Results: In a Cox proportional hazards
model incorporating pre- and postran-
domization lithium levels and the interac-
tion of these factors, only the interaction
term remained significantly associated
with time to recurrence.
Conclusions: The findings indicate that
change in serum lithium level may be a
more powerful predictor of recurrence of
bipolar disorder than the absolute assign-
ment to a low or a standard dose of lith-
ium and suggest that an abrupt decrease
in lithium level should be avoided. This
reanalysis did not directly address opti-
mal maintenance lithium levels but
raises questions about the original
study’s finding of superiority for lithium
levels ≥0.8 meq/liter. The results under-
score the importance of accounting for
the possible confounding effects of
changes in the intensity of pharmaco-
therapy in studies of maintenance thera-
pies for bipolar disorder.
(Am J Psychiatry 2002; 159:1155–1159)
Lithium discontinuation may have significant nega-
tive consequences for patients with bipolar disorder, par-
ticularly in the first year after treatment is terminated (1,
2). After discontinuation, the risk of recurrence of affective
illness, and particularly of manic episodes, appears to be
greater than that expected in untreated patients (3). Over-
all morbidity and suicidal behavior in particular are also
greater (4). This elevated risk has been demonstrated in a
group of pregnant women and nonpregnant comparison
subjects (5) and in adolescents with bipolar I disorder (6).
However, not all studies have shown this elevation (7).
Abrupt lithium discontinuation may yield a particularly
great risk for relapse (2). In two studies that addressed this
concern, gradual taper (>14 days) significantly reduced
morbidity compared with a rapid taper (8, 9). A later study
noted a similar effect (5).
The consequences of rapid change in lithium levels dur-
ing treatment have not been investigated in detail. Fluctu-
ations in serum lithium levels are quite common even dur-
ing long-term treatment, particularly as compliance with
treatment may be erratic (10, 11). Poor compliance has
been independently associated with poorer outcome (12).
The purpose of this investigation was to examine the
apparent risk posed by an abrupt change in lithium level.
We reanalyzed data from a study of the efficacy of low- ver-
sus standard-dose lithium in maintenance therapy for pa-
tients with bipolar disorder (13) to examine the potential
confounding influence of rapid change in lithium dose on
the effects of the random assignment to treatment groups.
In that study, stable, euthymic patients with bipolar disor-
der who were being treated with lithium were randomly
assigned to maintenance treatment with either standard
or low serum lithium levels. However, as that study was
performed before the effects of abrupt discontinuation
were described, the original analysis did not include an in-
teraction effect between the baseline and the randomly
assigned lithium levels. On the basis of the more recent
data of Faedda and Baldessarini and colleagues (8, 9), we
hypothesized that the patients who experienced a dose re-
duction would be at greater risk for recurrence than those
who continued to receive their original dose. We investi-
gated this hypothesis by examining the interactive effects
of previous dose levels on the outcome of a standard- ver-
sus a low-dose strategy for maintenance treatment.