Bipolar Disorders 2000: 2: 93–101

Printed in Ireland. All rights reser6ed

Review

The impact of lithium prophylaxis on the

course of bipolar disorder: a review of the
research evidence
Maj M. The impact of lithium prophylaxis on the course of bipolar Mario Maj
disorder: a review of the research evidence. Department of Psychiatry, University of
Bipolar Disord 2000: 2: 93 – 101. © Munksgaard, 2000 Naples SUN, Naples, Italy

A critical review is provided of the available research evidence concern-

ing the efficacy and effectiveness of lithium prophylaxis in bipolar dis-
order. It is emphasized that, in spite of the limitations of available
placebo-controlled trials and naturalistic studies, lithium is the only
drug whose prophylactic activity in bipolar disorder is convincingly Key words: bipolar disorder –
proved, and remains the first-choice medication in the long-term treat- discontinuation – lithium – naturalistic
ment of bipolar patients. The impact of lithium prophylaxis is likely to studies – placebo-controlled trials –
be less significant on atypical and comorbid cases of bipolar disorder predictors of response – prophylaxis
than in typical manic – depressive illness, but the superiority of other
medications over lithium in the long-term treatment of those cases is at Received 16 July 1999, revised and
present not convincingly proved by research. Currently available re- accepted for publication 17 September
search evidence does not seem to support the idea that lithium exerts 1999
its prophylactic effect on relapses but not on recurrences of bipolar Corresponding author: Mario Maj, Clinica
disorder. Clinicians should be aware of the fact that the drop-out rate Psichiatrica, Primo Policlinico Universitario,
in bipolar patients receiving long-term lithium prophylaxis is high even Largo Madonna delle Grazie, 80138 Napoli,
if treatment surveillance is accurate, and that complete suppression of Italy. Fax: +39 81 5666523; e-mail:
recurrences is a relatively rare outcome of prophylaxis. majmario@tin.it

Lithium is still unanimously regarded as a first-line
agent in the prophylactic treatment of bipolar dis-
order (1–4). However, the magnitude of its impact
on the course of the disorder, especially on the
long term, has been repeatedly questioned during
the last decade. For example, it has been main-
tained that the benefits conferred by the prescrip-
tion of lithium to bipolar patients in ordinary
clinical practice are modest compared with the
results of clinical trials (5); that the original con-
trolled trials of lithium prophylaxis produced spu-
rious results owing to flawed methods (6); that
lithium exerts its prophylactic activity on relapses
but not on recurrences of bipolar disorder, so that
its effect does not persist after the first year of
recovery from the index episode (7); and that
about one-third of lithium-refractory patients are
not initial non-responders, but show a pattern of
gradual loss of efficacy, suggesting the develop-
ment of tolerance (8).
Here we provide a critical review of the available
research evidence concerning the efficacy and effec-
tiveness of lithium prophylaxis in bipolar disorder,
with a special emphasis on those issues that have
been most debated in the last few years.
Placebo-controlled trials and their limitations
The efficacy of lithium in preventing the recur-
rences of bipolar disorder has been tested in several
double-blind placebo-controlled trials, all pub-
lished during the 1970s (Table 1). All these studies,
except one conducted in a very small patient sam-
ple (10), found a statistically significant superiority
of lithium over placebo in reducing the recurrence
rate during the observation period. Of the seven
studies reporting separate data for manic and de-
pressive episodes, four found a statistically signifi-
cant superiority of lithium over placebo in
preventing manic recurrences, and one a significant
superiority of lithium in preventing depressive
recurrences.
Of the above-mentioned ten double-blind stud-
ies, four were discontinuation trials, i.e., trials in
which a sample of patients already on treatment
with lithium was randomly subdivided into two
93
Maj

subsamples, one of which continued to take

lithium and the other was switched to placebo.

– L: 57, P: 64)
This design may have artificially inflated the recur-
rence rate in patients receiving placebo, and conse-
% Recurrences quently the difference between lithium and placebo
(6), since lithium discontinuation is reportedly fol-

50
L: 25, P: 42

L: 16, P: 26

L: 22, P: 62

48

44
L: 0, P: 23*
(depressive)

(bipolar II
lowed by a period of high risk of recurrences,

L: 56, P:
L: 28, P:

L: 29, P:
especially of manic episodes (see below). In sup-
port to this idea, in one of those studies (12), the
ratio between the number of manic and depressive
episodes was 0.67:1 before the beginning of lithium

(bipolar II – L: 0, P: 9)
treatment and became 3.5:1 after lithium with-
drawal. The above criticism may be extended to
% Recurrences

some of the other studies (parallel-group prospec-

L: 32, P: 68*

L: 20, P: 56*
L: 11, P: 38

L: 59, P: 94
L: 0, P: 27*

L: 8, P: 75*

L: 6, P: 25
tive trials), in which some patients were or had
(manic)

been recently treated with lithium at the moment

of recruitment. It should be pointed out, however,
that rebound after discontinuation is in itself an
evidence in favor of the mood-stabilizing effect of
lithium.
% Recurrences

18, P: 95*
33, P: 83*

43, P: 80*

L: 28, P: 77*

L: 44, P: 93*

In some of the parallel-group prospective trials,

57, P: 78
0, P: 55*

6, P: 33*

the treating physicians knew which patients were

taking lithium, and were allowed to increase the
(total)

dosage of the drug in the presence of prodromal

L:
L:
L:
L:
L:
L:

manic symptoms. This may have artificially re-

duced the recurrence rate in patients randomized
follow-up (months)

to lithium (6). In fact, in one of those studies (14),

D= discontinuation trial; PRP = parallel-group randomized prospective trial; L = lithium; P =placebo.

it is reported that part of the patients classified as

Duration of

lithium responders had prodromal symptoms of

Up to 28
Up to 36
Up to 53
Up to 5

mania during the observation period. Nevertheless,

5–24
4–6
24

24

an increase of the dosage of a medication upon the

6
6

appearance of prodromal symptoms of a new

Table 1. Double-blind placebo-controlled trials of lithium in the prophylaxis of bipolar disorder

episode of the target disorder is in itself a preven-

L: 101, P: 104 (patients hospitalized for a

L: 17, P: 18 (plus bipolar II – L: 7, P: 11)

tive strategy, which would have been ineffective if

L: 18, P: 13 (patients hospitalized for a

lithium were inactive (19).

Other limitations of the available trials compar-
ing lithium and placebo in the prophylaxis of bipo-
* Statistically significant difference between lithium and placebo.

lar disorder are the focus on patients completing

L: 16, P: 24 (all bipolar II)

the treatment period (disregarding drop-outs), the

depressive episode)

short follow-up period (no more than 6 months in

four of the studies), the fact that operational crite-
manic episode)
No. of patients

ria for patients’ diagnosis and standardized rating

L: 28, P: 22

L: 17, P: 21
L: 12, P: 12
L: 18, P: 18

L: 25, P: 27
L: 7, P: 8

scales were not used, and the extensive use of

additional drugs. Concerning this last issue, how-
ever, it is remarkable that in a trial in which
unrestricted additional use of neuroleptics, antide-
pressants, and electroconvulsive therapy was al-
Design

lowed (11), patients on lithium received

PRP

PRP

PRP

PRP
PRP
PRP

significantly less neuroleptic and antidepressant

D
D

D
D

medication than those on placebo, and no patient

on lithium (vs. 43% of those on placebo) required
Coppen et al. (11)

Stallone et al. (16)

Baastrup et al. (9)

Cundall et al. (12)

Dunner et al. (17)

Hullin et al. (13)

electroconvulsive therapy.
Fieve et al. (18)
Prien et al. (14)

Prien et al. (15)

Finally, the inclusion and exclusion criteria

Melia (10)

adopted in the above controlled trials may have

Study

reduced the representativeness of the enrolled sam-

ples of bipolar patients. Actually, in a recent natu-
94

ralistic study, Sachs et al. (20) reported that only
23% of their clinical sample would have been eligi-
ble for the double-blind trials of the 1970s. How-
ever, an alternative perspective is that the patient
samples enrolled in the above controlled trials were
more representative of ‘typical’ manic – depressive
illness, whereas those recruited in recent naturalis-
tic studies included a large proportion of bipolar
patients with atypical features (mood-incongruent
psychotic symptoms, mixed states, rapid cycling)
or comorbidities, which made them more likely to
be treatment resistant, as well as some patients
who had already been treated unsuccessfully with
lithium.
Overall, despite the above limitations, the evi-
dence provided by double-blind placebo-controlled
trials appears consistent and impressive, and
lithium is the only drug for which such substantial
evidence of a prophylactic effect in bipolar disor-
der is currently available.
Naturalistic studies and their limitations
During the 1980s and the 1990s, no further double-
blind placebo-controlled trials testing the prophy-
lactic effect of lithium have been published, but
several naturalistic studies of bipolar patients re-
ceiving lithium prophylaxis under routine clinical
conditions have appeared. Markar and Mander (5)
studied retrospectively 83 bipolar patients who had
recovered from a manic episode, of whom 41 had
received prophylactic lithium for at least 6 months
after the episode and 42 had not, and did not find
a significant difference between the two groups
with respect to the number of hospitalizations and
the time spent in hospital during a 6-year observa-
tion period. Harrow et al. (21) followed up
prospectively after discharge 73 patients hospital-
ized for a manic episode, and found that those who
took lithium throughout the 1-year period follow-
ing discharge did not differ significantly from those
who did not receive the drug throughout that
period, with respect to several outcome measures.
Sachs et al. (20) studied retrospectively 100 bipolar
patients, of whom 67 had received lithium, alone
or in combination with other drugs, and 33 had
not, and detected no significant difference between
the two groups with regard to the recurrence rate
during a 1-year period. On the other hand, some
epidemiological studies have reported that the fre-
quency of hospitalizations for mania has not de-
creased, but actually increased, in the years
following the introduction of lithium (22, 23). All
these observations have led to the conclusion that
the impact of lithium on the course of bipolar
disorder in ordinary clinical conditions is less sig-
Lithium prophylaxis of bipolar disorder
nificant than that expected on the basis of the
results of controlled trials (24).
However, the above-mentioned clinical and epi-
demiological studies have some important draw-
backs. In the study by Markar and Mander (5),
although the observation period was 6 years, the
lithium-treated group also included patients who
had received the drug for only 6 months: these
patients may well have relapsed after lithium dis-
continuation. In the study by Harrow et al. (21),
the periodic check of plasma lithium levels was not
ensured, so that some lithium-treated patients may
have not been adequately exposed to the drug.
Moreover, under naturalistic conditions, the illness
course is not only a consequence of the treatment
choice, but also a determinant of that choice (for
instance, patients with less severe or frequent affec-
tive episodes may be less likely to receive long-term
lithium prophylaxis); therefore, the lack of a sig-
nificant difference with respect to outcome, be-
tween patients who have received lithium and
those who have not, cannot be regarded as evi-
dence that the drug is not effective. On the other
hand, the above-mentioned epidemiological studies
have not documented that patients who were hos-
pitalized during the observation period had actu-
ally received lithium prophylaxis; in fact, there are
other studies (25) showing the same increase in the
hospitalization rate for mania in the years follow-
ing the introduction of lithium (ascribed to the
change in diagnostic habits, with the broadening of
the concept of mania), but a decrease of that rate
in patients treated with lithium. Finally, it is im-
portant to emphasize that a gap between the effi-
cacy of a treatment (i.e., its therapeutic potential,
as resulting from controlled trials) and its effective-
ness (i.e., its impact on the target disorder in ordi-
nary clinical conditions) is a common observation
in medicine (26), being due to such factors as
patients’ incomplete compliance, physicians’ inade-
quate supervision of treatment, and underdiagno-
sis/undertreatment of the target disorder. All these
factors are significantly at work in the case of
lithium prophylaxis.
In our prospective study (27) carried out in all
bipolar I patients (n=402) who had started
lithium prophylaxis at a lithium clinic over more
than 15 years, we found that 28% of the enrolled
patients were not on lithium anymore after 5 years,
in spite of adequate treatment surveillance. Among
patients who had interrupted prophylaxis on their
own initiative, the most frequently alleged reasons
for discontinuation were perceived inefficacy, trou-
ble related to side effects, the conviction of being
cured and of needing no more drugs, the annoy-
ance of taking medicines, and the loss of energy or
productivity.
95
Maj
In that prospective study, among patients who
were still on lithium after 5 years, 38% had had no
major depressive or manic episode during the
treatment period; 47% had had at least one
episode, but with a reduction of at least 50% in the
mean annual time spent in hospital during the
treatment period compared to the 2-year period
preceding the index episode and the start of pro-
phylaxis; and 15% had had at least one episode
without the above-mentioned reduction of at least
50% in the mean annual time spent in hospital.
These findings support the clinical perception that
lithium, if taken regularly for several years, has a
substantial impact on the course of illness in most
bipolar patients. However, the bias of self-selection
should not be overlooked: the figures just cited
refer only to a subgroup of the enrolled patients
(those who were still on lithium after 5 years),
whose permanence on the prophylactic regimen
may have been a consequence as well as a determi-
nant of the favorable response, and who may not
be representative of the initial study group. As a
matter of fact, patients with psychotic features in
the index episode (a possible predictor of poor
outcome in bipolar disorder) were significantly
over-represented among those who stopped lithium
before the 5-year term, and only 23% of the whole
sample of bipolar patients who had started pro-
phylaxis were still on completely successful lithium
treatment after 5 years.
In our study, we observed a significant reduction
of the mean annual number of both manic and
depressive episodes and of the mean annual time
spent in hospital for both manic and depressive
episodes, in comparison with the 2-year period
preceding the index episode and the start of pro-
phylaxis. However, on both measures, the reduc-
tion was more significant for manic than for
depressive episodes. Similar data have recently
been reported by Tondo et al. (28), who found that
the number of manic episodes was reduced 3.3-fold
and that of depressive episodes 2.1-fold during
lithium treatment. These authors also reported a
more pronounced effect of treatment (significantly
greater reduction of the number of episodes per
year and of the percentage of time ill) in bipolar II
compared with bipolar I patients, a finding that
requires confirmation.
Further research is also needed to address such
issues as the impact of long-term lithium treatment
on the severity and symptomatology of break-
through manic and depressive episodes, on the
interepisodic mood instability of bipolar patients,
and on patients’ social adjustment and family bur-
den. As a matter of fact, although it is documented
that bipolar disorder can significantly disrupt inter-
96
personal relationships and occupational function-
ing (29), functional measures of outcome have
usually been neglected in currently available
lithium research.
Loss of prophylactic effect over time?
Overall, lithium does not seem to lose its prophy-
lactic effect over time. In the 10-year follow-up of
our prospective study (30), conducted in 277 bipo-
lar I patients, we found that the mean number of
affective episodes per year and the mean time spent
in hospital per year were not significantly different
during the second versus the first 5-year observa-
tion period. Similar data have been obtained in a
retrospective study by Berghöfer et al. (31). These
findings do not support the idea, put forward by
Coryell et al. (7), that the prophylactic effect of
lithium does not persist after the first year of
recovery from the index episode. On the other
hand, a recent re-analysis of Coryell et al.’s data
(32) has shown that they do not necessarily contra-
dict the hypothesis of a sustained efficacy of
lithium.
Some patients who had displayed an optimal
response to lithium prophylaxis for several years
may subsequently present multiple recurrences in a
short period, in spite of persistently adequate com-
pliance. This phenomenon, reported by several au-
thors (8, 33–35) and confirmed by our 10-year
follow-up study (30), has been ascribed by Post et
al. (8) to the development of tolerance, but is more
convincingly explained by the increasing severity of
bipolar illness over time (36, 37), finally over-
whelming the prophylactic activity of lithium (35,
38). In fact, our patients with late recurrences,
compared to those with a persistently favorable
response to prophylaxis, had a significantly higher
number of pre-treatment episodes and hospitaliza-
tions (38), which may reflect a more pronounced
‘driving force’ of the illness (8).
Predictors of response to prophylaxis
Prediction of response to lithium prophylaxis in
bipolar disorder has been the subject of an exten-
sive literature (see (39) for a review). Among puta-
tive predictors of a favorable response are a family
history of bipolar disorder (40–43) and a course of
the mania–depression-free interval sequence type
(44–48), whereas putative predictors of a poor
response are a previous higher frequency of
episodes and hospitalizations (49, 50), rapid cy-
cling (51, 52), and concomitant drug abuse (53).

In our above-mentioned 5-year prospective
study (30), we found that a higher number of
pre-treatment episodes and hospitalizations and
rapid cycling were associated with the least favor-
able patterns of outcome of prophylaxis. However,
these variables are likely to be predictors of poor
outcome of bipolar disorder per se, independently
from treatment, rather than specific predictors of
an unfavorable response to lithium. This applies at
the moment also to rapid cycling, in the absence of
double-blind randomized trials showing the superi-
ority of other drugs over lithium in bipolar pa-
tients presenting that pattern.
Of greater interest is the association between a
longer duration of illness before the start of treat-
ment and a less favorable outcome of prophylaxis
(27, 28, 30), which seems to parallel the association
between earlier onset of antipsychotic treatment
and better outcome in patients with schizophrenia
(54).
Consequences of lithium discontinuation
The abrupt discontinuation of lithium prophylaxis
has been found to be followed by a period of high
risk of recurrences. According to a meta-analysis
of the relevant literature (55), a new episode occurs
within 5 months from lithium withdrawal in 50%
of patients; the risk for a manic recurrence is
significantly higher than that for a depressive one
(the computed time to 25% risk of recurrence is 2.7
months for mania and 14 months for depression);
and the risk of recurrence after lithium withdrawal
is significantly higher than that of bipolar patients
never treated with lithium (in 16 bipolar patients,
the shortest interepisodic euthymic period before
starting lithium prophylaxis was 11.6 months,
whereas the mean euthymic period between lithium
withdrawal and a new affective episode was 1.7
months). A more recent study (56) has found that
the recurrence risk is significantly lower if lithium
is discontinued gradually: the median time to re-
currence was 2.5 months for rapid discontinuation
(over 1–14 days) versus 14 months for gradual
discontinuation (over 15 – 30 days). Schou (57) has
recently emphasized the discrepancy between these
findings, obtained in patients diagnosed according
to the most recent editions of the DSM, and the
report of no evidence of withdrawal rebound by
several groups (31, 58 – 61) using the ICD criteria,
and has submitted the idea that the rebound phe-
nomenon does not occur in typical manic – depres-
sive illness. This hypothesis, however, requires
empirical testing.
Several clinicians (35, 62 – 65) (F. K. Goodwin
and J. Angst, personal communication, cited in
Lithium prophylaxis of bipolar disorder
(8)) have observed that some bipolar patients who
had a complete response to lithium prophylaxis for
many years present a secondary refractoriness to
prophylaxis after one or more treatment discontin-
uations. This refractoriness seems to be transient in
some of the cases (65). A recent study conducted in
a large sample of bipolar patients who had discon-
tinued lithium prophylaxis (66) has actually found
a statistically significant increase of affective mor-
bidity during a second versus a first period of
lithium treatment. This difference, however, failed
to reach statistical significance in a smaller sample
studied by the same group (67), although also in
this sample the use of additional medication was
found to be significantly more frequent during the
second lithium treatment period. In another inves-
tigation carried out in a very small patient sample
(68), the recurrence rate at 2 years was not signifi-
cantly different during two subsequent periods of
lithium prophylaxis, but the recurrence rate at 1
year was about 10% during the former period and
about 30% during the latter. This difference, which
is not discussed in the paper but is likely to be
significant, seems to support the notion of a re-
versible discontinuation effect. Further long-term
prospective studies of large patient samples are
needed in order to clarify the frequency and clini-
cal relevance of the phenomenon.
Antisuicidal effect
Lithium prophylaxis has been found to be associ-
ated with a marked decrease of suicide risk in
bipolar patients, and lithium discontinuation to be
accompanied by a pronounced increase of that
risk. Baldessarini et al. (69) have reported that
suicidal acts per year were reduced 6.5-fold during
lithium treatment, and that suicide risk increased
20-fold in the first year off lithium, being 2-fold
lower after slow versus rapid discontinuation. This
evidence does not prove conclusively that lithium
exerts an antisuicidal effect (70), because both im-
plementation and discontinuation of lithium pro-
phylaxis in bipolar patients do not occur at
random (for instance, alcohol and drug abuse may
be associated with a higher risk of suicide and at
the same time with a lower probability to remain
on long-term lithium treatment). However, it is
remarkable that, in a large multicenter randomized
open trial (71) comparing lithium with carba-
mazepine or amitriptyline in the prophylaxis of
bipolar and unipolar depressive disorder, respec-
tively, there were four completed suicides in pa-
tients receiving carbamazepine, five in those
treated with amitriptyline, and none in those re-
ceiving lithium, and the frequency of suicidal acts
97
Maj
was significantly lower in lithium-treated patients
than in the other two patient groups (72).
Alternatives to lithium and combination treatments
At present, there is only one double-blind placebo-
controlled trial of carbamazepine in the prevention
of recurrences of bipolar disorder (73), which
found a 1-year recurrence rate of 40% in patients
treated with the drug and of 78% in those receiving
placebo (a non-significant difference). Moreover,
there are several double-blind trials of carba-
mazepine versus lithium (74 – 77), whose interpreta-
tion is made difficult by the heterogeneity of the
enrolled patients (only one of them included exclu-
sively bipolar patients) and the peculiarity of the
designs (one of them was a discontinuation trial,
while in another the length of the observation
period in some patients was less than 6 months).
Of these studies, three found carbamazepine to be
as effective as lithium, while one (75) found lithium
to be significantly superior in increasing the time in
remission.
The above-mentioned multicenter randomized
open trial (71), comparing carbamazepine and
lithium in 144 bipolar patients, found a non-signifi-
cant superiority of lithium in terms of recurrence
rate during the 2.5-year observation period (28 vs.
47%). However, the difference in favor of lithium
became significant when, in addition to recur-
rences, the need for neuroleptics and/or antidepres-
sants for at least 6 months was considered as
failure.
It has been maintained that bipolar patients who
respond to carbamazepine prophylaxis, compared
with those responding to lithium, are more fre-
quently rapid cyclers (78). However, a retrospec-
tive study conducted in 215 bipolar patients treated
with lithium or carbamazepine for 2 years (79)
found that rapid cycling predicts a poor response
to both drugs.
The combination of lithium and carbamazepine
may be useful in some bipolar patients who do not
respond satisfactorily to either drug. In a double-
blind crossover study, Denicoff et al. (80) found
that the total number of recurrences was signifi-
cantly lower in the period in which patients were
on the combination compared with the lithium and
carbamazepine phases. The mean survival time to
the first manic episode was 179.3 days on the
combination, 89.8 days on lithium alone, and 66.2
days on carbamazepine alone (a statistically signifi-
cant difference).
No controlled trial of valproate in the preven-
tion of recurrences of bipolar disorder has been
published as yet. The preliminary results of a 1-
98
year double-blind placebo-controlled trial (81) sug-
gest a significant superiority of the drug over
placebo in increasing the time in remission, and
several open trials indicate that the drug may re-
duce the frequency and severity of affective
episodes, also in rapid cyclers (82, 83). In a ran-
domized trial in which 12 bipolar patients received
either valproate or placebo in association with
lithium, those treated with lithium and valproate
were significantly less likely to suffer a recurrence
(84).
No placebo-controlled trial is available of the
prophylactic effect of other anticonvulsants and of
atypical antipsychotics in bipolar disorder, al-
though many promising open trials have been pub-
lished (see (85) for a review).
Conclusions
The current emphasis on the limitations of the
research evidence concerning the impact of lithium
prophylaxis on the course of bipolar disorder
should not divert our attention from the fact that
lithium is the only drug for which such substantial
evidence is currently available, and remains, there-
fore, the first-choice medication in the long-term
prophylactic treatment of bipolar patients.
The impact of lithium prophylaxis is likely to be
less significant on the atypical and comorbid cases
of bipolar disorder, increasingly seen in clinical
practice, than it is on typical cases of manic–de-
pressive illness, but the superiority of other medi-
cations over lithium in the long-term treatment of
those atypical or comorbid cases is at present not
convincingly proved by research. This applies also
to rapidly cycling bipolar disorder, in the absence
of double-blind randomized trials documenting a
significantly greater effect of other drugs compared
with lithium on the recurrence rate in rapid cyclers.
Currently available research evidence does not
support the idea that lithium exerts its prophylactic
activity on relapses but not on recurrences of bipo-
lar disorder, or that tolerance to lithium develops
over time.
Clinicians should be aware of the fact that the
drop-out rate in bipolar patients receiving long-
term lithium treatment is substantial even if treat-
ment surveillance is accurate, and that complete
suppression of recurrences is a relatively rare out-
come of prophylaxis. The addition of one or more
other mood stabilizers is likely to improve the
outcome of several bipolar patients who have dis-
played an unsatisfactory response to lithium pro-
phylaxis, but further research is needed in order to
clarify in how many and in which patients this
combination treatment is required.

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