Berghöfer et al.

International Journal of Bipolar Disorders 2013, 1:11

http://www.journalbipolardisorders.com/content/1/1/11

RESEARCH Open Access

Stability of lithium treatment in bipolar disorder -

long-term follow-up of 346 patients
Anne Berghöfer1*, Martin Alda2, Mazda Adli3, Christopher Baethge4, Michael Bauer5, Tom Bschor6, Paul Grof7,
Bruno Müller-Oerlinghausen8, Janusz K Rybakowski9, Alexandra Suwalska9 and Andrea Pfennig5

Abstract
Background: The purpose of this study was to investigate the effectiveness and stability of long-term lithium
treatment in a prospective, international, multicenter cohort of bipolar patients in a naturalistic setting.
Methods: Patients were selected according to DSM IV criteria for bipolar disorder and required long-term
treatment. They were prospectively followed and documented in five centers belonging to the International Group
for the Study of Lithium-Treated Patients. This was a prospective cohort study without a comparison group. Lithium
treatment was administered in a naturalistic and specialized outpatient setting. All patients underwent a
comprehensive psychiatric examination, which included the use of standard rating scales, as well as an evaluation
of clinical course based on the morbidity index (MI).
Wald tests were used to assess the significance of fixed effects and covariates when analyzing the relationship
between depressive, manic, and total morbidity index and several characteristics of illness course.
Results and discussion: A total of 346 patients with bipolar disorder I or II were followed for a mean period of
10.0 years (standard deviation (SD) 6.2, range 1 to 20). The morbidity index remained stable over time: the mean MI
was 0.125 (SD 0.299) in year 1 and 0.110 (SD 0.267) in year 20. The MI was not associated with the duration of
lithium treatment, the number or frequency of episodes prior to treatment, or latency from the onset of bipolar
disorder to the start of lithium treatment. The drop-out rate was high over the study period. Our findings suggest
that long-term response to lithium maintenance treatment remains stable over time.
Keywords: Bipolar disorder; Lithium; Long-term treatment; Morbidity index; Stability

Background 1989a). Maj and coworkers analyzed the course of illness

Lithium is recommended in all major international guide- in 43 bipolar patients who had been successfully treated
lines as a first-line prophylactic treatment for bipolar dis- with lithium for 2 years. During a follow-up period of 5
order (American Psychiatric Association 2002; Grunze years, a substantial number of patients experienced recur-
et al. 2004; Crossley et al. 2006; Yatham et al. 2013; DGBS, rences despite their having been initially classified as re-
DGPPN 2012; Grof and Müller-Oerlinghausen 2009), and sponders to lithium treatment. The authors interpreted
its efficacy in this context has been demonstrated in meta- this as an indication that it may not be possible to achieve
analyses of controlled studies (Burgess et al. 2001; Geddes long-term stability with lithium prophylaxis (Maj et al.
et al. 2004; Geddes and Goodwin 2006; Licht 2012). In 1989a). Post and coworkers retrospectively assessed the
naturalistic settings, however, the effectiveness of long- course of illness in 66 lithium-refractory patients with
term lithium treatment has been reported to be much affective disorder and found that a substantial number of
lower (Surtees and Barkley 1994; Harrow et al. 1990; those who initially showed a complete or partial response
Goldberg et al. 1995; Keller et al. 1993; Licht et al. 2008), to lithium experienced a gradual loss of efficacy over time
and to even diminish over time (Post et al. 1993; Maj et al. (Post et al. 1993). However, recent observational studies
show a general superiority of lithium compared to alterna-
* Correspondence: anne.berghoefer@charite.de tive mood stabilizers in clinical practice (Kessing et al.
1
Institute for Social Medicine, Epidemiology and Health Economics, Charité
University Medical Center, Berlin 10098, Germany
2012; Kessing et al. 2011; Nivoli et al. 2010; Garnham
Full list of author information is available at the end of the article et al. 2007).
© 2013 Berghöfer et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction
in any medium, provided the original work is properly cited.
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The differences observed in the degree of effectiveness Hamilton-Depression-Scale (HAMILTON 1960), Young
across studies have been variously attributed to methodo- Mania Scale (1978)); (c) performed a physical examin-
logical disparities (Deshauer et al. 2005; Coryell 2009), a ation; (d) recorded any adverse events; and (e) pre-
broadening of the diagnostic criteria for bipolar disorder scribed any clinical or pharmacological interventions he
(Grof et al. 1993; Grof et al. 1995; Grof 1998), or changes or she felt was necessary. Serum lithium levels were also
in the course of illness over long periods (Goodwin 1999). obtained. Patients averaged seven to eight visits each
The present study investigated a prospective, multi- year, depending on comorbidity, severity of illness, and
center cohort of patients with bipolar disorder. Its aim age. The number of visits per year was greater than in
was to determine whether the long-term effectiveness of normal outpatient settings, facilitating optimal control of
lithium prophylaxis remains stable over time. A sub- patients’ long-term prophylaxis. Psychiatric nurses and
group of 242 patients from this sample has been ana- social workers were available to provide support during
lyzed elsewhere with regard to the influence of atypical additional, unscheduled visits.
symptoms (Berghöfer et al. 2008). Another subgroup of Before enrolling in the prospective cohort, patients
336 patients was included in an analysis of recurrence were thoroughly informed about the study procedures,
risk that applied extended Cox regression models, which treatment, and possible side effects, and all participants
allow for the use all follow-up data on diseases with gave written, informed consent. The study was approved
multiple episodes, to examine the influence of atypical by local research ethics committees in jurisdictions in
features on time to recurrence (Pfennig et al. 2010). which such approval was necessary. In the Poznan study
center, the study was approved by the bioethics commit-
Methods tee, Poznan University of Medical Sciences. The center
Inclusion criteria in Ottawa had an umbrella approval from the Research
Patients were selected based on classical criteria for ethics committee for the analysis of clinical data of
diagnosing bipolar disorder. When the first patients were lithium-treated patients (anonymously, with names re-
included in the study in the 1980s, the eighth revision of moved). The center in Halifax had an approval from the
the International Classification of Diseases (ICD-8) ethics committee at Capital District Health Authority,
(World Health Organization 1969) was in use. The ICD- Nova Scotia. In the Berlin center, an approval was not
8 was later replaced by the ICD-9 (World Health necessary because the subjects provided written in-
Organization 1979). After 1994, all of the patients in the formed consent to the anonymous and aggregate scien-
study were rediagnosed according to DSM IV (American tific use of data from their confidential medical records
Psychiatric Association 1993). All patients required when admitted to the clinic.
long-term treatment, as defined by the presence of at The onset of bipolar disorder was defined as the first
least one manic episode or at least two episodes of any recorded diagnosis of bipolar disorder or, if this was
type in the patient's history. Patients were included in lacking, as the first recorded symptoms clearly related to
the study if they had been treated continuously with lith- bipolar disorder. In turn, a recurrent episode was de-
ium for at least 1 year and were at least 18 years of age. fined as the presence, in a previously remitted patient, of
From the time of their presentation at the clinic until symptoms that required either psychotherapeutic or psy-
2004, all patients were followed up in the outpatient de- chopharmacological treatment. All recurrences were
partments of five participating International Group for the recorded and graded in terms of severity, polarity, and
Study of Lithium-Treated Patients (IGSLi) centers (Berlin, duration. Finally, remission was defined as the absence of
Germany; Halifax, Hamilton, and Ottawa, Canada; Poznan, affective symptoms, as measured using standard mood
Poland). These centers were founded in the 1980s and rating scales. All data were collected prospectively.
followed a standard research program consisting of long- First introduced by Coppen and Abou-Saleh (1982),
term prophylactic treatment with lithium and other drugs the morbidity index (MI) was used in the present study
for the management of unipolar mood disorder, bipolar as the outcome measure and includes severity and
mood disorder, or schizoaffective disorder (www.igsli.org; length of episodes. Severity is rated in a semiquantitative
Müller-Oerlinghausen et al. 1994; Alda et al. 2000). manner using three different degrees: symptoms that do
not require treatment are rated as degree 1; symptoms
Patient assessment that require psychotherapeutic or psychopharmacologi-
During each visit, patients were evaluated by a psych- cal treatment for acute affective illness but are manage-
iatrist, who (a) performed a psychiatric assessment, tak- able in an outpatient setting are rated as degree 2; and
ing account of the patient's case history and past symptoms necessitating inpatient treatment for acute
medication; (b) administered one or more standard affective illness are rated as degree 3. We included
mood rating scales (Bech-Rafaelsen Melancholia and symptoms of degrees 2 and 3 in the analysis and calcu-
Mania Scales (Bech et al. 1979; Bech et al. 1978), lated the MI using the following formula:
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ðno:of weeks with degree 2Þ 2 þ ðno:of weeks with degree 3Þ 3
Morbidity indextotal over 1 year ¼
52 weeks

For each year, the MI was calculated for all affective Results
episodes (MItotal) and also separately for depressive epi- In the present study, a total of 346 patients were
sodes (MIdep) and manic episodes (MIman). To remain in followed up for a mean period of 10 years (range, 1 to
the study, patients were required to demonstrate suffi- 20 years) on lithium treatment (Figure 1). The number of
cient compliance, which was defined as maintaining subjects varied between the participating treatment cen-
serum lithium levels of at least 0.5 mmol/L throughout ters (Berlin n = 151, Halifax n = 35, Hamilton n = 14,
the documentation period. Ottawa n = 75, and Poznan n = 71). Patients' baseline
Antipsychotics, antidepressants, or anticonvulsants ad- characteristics are given in Table 1. The mean age at the
ministered in addition to lithium were not regarded as onset of bipolar disorder was 29, and lithium treatment
prophylactic medication and were not included in the was initiated with a mean latency of 10 years. For all 346
statistical analysis (a) if they were administered as part patients, the mean MItotal decreased slightly (i.e., from
of maintenance treatment (i.e., in addition to lithium 0.125 to 0.110) over the 20-year observation period.
during the first 3 months after remission for the purpose For long-term stabilization, a total of 152 patients re-
of stabilizing the patient) or (b) if they were adminis- ceived concomitant treatment with antidepressants, anti-
tered as acute treatment (i.e., in addition to lithium at psychotics, or anticonvulsants. The mean period of
any point 4 or more months after remission to manage concomitant treatment with a drug from one of these
new symptoms). In the latter case, weeks during which three categories was 22.4 weeks per year (Table 1).
acute treatment with antipsychotics, antidepressants, or Altogether, 194 patients remained on lithium monother-
anticonvulsants was necessary were rated as degree 2 apy for their entire follow-up period.
and were included in the morbidity index. In all other The results of the repeated measures regression did
cases, treatment with drugs from any of these three drug not show a change in the MItotal, MIdep, or MIman in the
categories was considered to be prophylactic in nature. course of the study (see Table 2). There were also no sig-
Finally, other drugs, such as benzodiazepines, were not nificant associations between the number of episodes be-
regarded as additional prophylactic medication, and no fore the start of lithium treatment, the latency between
data on their use were recorded. the onset of illness onset and the start of lithium treat-
ment, and the MItotal, MIdep, or MIman (see Table 2).
Many patients dropped out of the study during the
follow-up period. In total, 165 subjects were observed
Statistical analysis
for at least 10 years, 93 for at least 15 years, and 45 for
Data were analyzed using BMDP (Biomedical Computer
at least 20 years. Patients left the study for one of four
Programs) Statistical Software, Inc. (Cary, NC, USA), re-
reasons: (1) they had been in treatment for less than 20
lease 8.0. Unbalanced repeated measures regression
years by the end of the study; (2) lithium side effects or
models with structured covariance matrices were applied
interactions with a drug prescribed for a somatic comor-
(module 5V in BMDP) to assess the impact of treatment
bidity caused them to switch to another long-term
duration on the yearly MI (within subject measure). Sep-
prophylactic agent; (3) they switched to another out-
arate calculations were made for MItotal, MIdep, and
patient clinic or moved and were lost to follow-up; or
MIman. Maximum likelihood was used to estimate pa-
(4) they died. In patients who left the study, the MIs for
rameters, with the expected response values being
the year of drop-out were not higher than the mean MI
expressed as a linear function of the parameters. The
from the preceding years (t test, all P values = n.s.).
main advantage of this approach was that all subjects
could be included regardless of their duration of treat-
ment. Model selection was based on optimization of
Akaike's information criterion (AIC) (Akaike 1973). The Discussion
significance of the independent variables was estimated In the present study, the MIs remained stable through-
using the Wald test. A 5% level of significance was out the observation period, confirming that the course
established with two-tailed tests. Using the same of illness also remained stable over time in this subgroup
method, it was possible to examine the impact of the of bipolar patients receiving prophylactic lithium treat-
number of episodes before the start of lithium treatment, ment. No association could be found between the MIs
as well as of treatment delay, on the MI. Finally, inde- and the number of episodes before the start of lithium
pendent variables were modeled in this analysis as treatment or the latency between the onset of illness and
covariates. the start of lithium treatment.
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Figure 1 Morbidity index over 20-year observation period. Black lines show mean (SD) morbidity index for all affective episodes (MItotal); gray
bars show number of subjects in the analysis contributing to the morbidity index each year.

In addition to this main finding, our study differs in

several respects to investigations that have demonstrated
poor stability with long-term lithium treatment. Many of
the previous prospective studies on lithium treatment
Table 1 Baseline characteristics of the 346 study subjects have had relatively short observation periods (i.e., less
Men, n (%) 147 (42.5)
than 2 years in duration). Indeed, only a few have had
longer observation periods, i.e., extending up to 5 years
Women, n (%) 199 (57.5)
(Maj et al. 1989b; Maj et al. 1998; Maj 2003) or 7 years
DSM IV diagnosis, n (%)
(Vestergaard and Schou 1988). In the present study,
Bipolar I 270 (78.0) however, data were collected over a much longer period,
Bipolar II 76 (22.0) covering up to 20 years.
Length of follow-up period (year, SD, range) 10.0 (6.2, 1 to 20) Although other studies have assessed large cohorts
Age at onset of bipolar disorder (year, SD, range) 29.2 (11.0, 11 to 66) over long observation periods, they have not focused on
Latency before start of lithium treatment 9.7 (9.3, 0 to 44) the long-term stability of prophylactic lithium treatment.
(year, SD, range) For example, the mood disorders center in Sardinia, a
Number of episodes before start of lithium 5.5 (4.9, 0 to 40) Stanley Foundation Bipolar Network research center
treatment (n, SD, range) (Post et al. 2001; Suppes et al. 2001), evaluated a large
Comedication in all 346 patients (mean number of cohort of lithium patients comparable in size to the
weeks [per follow-up year] during which any drugs
from three different drug categories were
IGSLI cohort. Tondo and coworkers presented compre-
administered; n, SD, range) hensive data on the long-term course of their lithium-
Total 9.8 (17.7, 0 to 91) treated patients within the Sardinian cohort (Tondo
et al. 1998; Baldessarini et al. 2000). The results of an
Antipsychotics 2.5 (7.9, 0 to 52)
analysis over a mean treatment period of 6 years show a
Antidepressants 3.5 (9.4, 0 to 52)
substantial improvement in the course of illness during
Anticonvulsants 3.8 (10.5, 0 to 52) long-term lithium treatment compared to the period be-
Comedication in 152 patients without lithium fore lithium treatment was initiated, although complete
monotherapy (mean number of weeks
[per follow-up year] during which any drugs
protection against affective episodes was uncommon.
from three different drug categories were However, the issue of stability over time in patients on
administered; n, SD, range) long-term lithium treatment was not addressed in this
Total 22.4 (20.9, 0 to 91) analysis (Tondo et al. 2001). Rybakowski and coworkers
Antipsychotics 5.6 (11.1, 0 to 52) analyzed the efficacy of long-term lithium treatment,
Antidepressants 8.0 (12.9, 0 to 52)
comparing the pre-index period with a post-index lith-
ium treatment period of 10 years (Rybakowski et al.
Anticonvulsants 8.8 (14.4, 0 to 52)
2001). The study examined whether the effectiveness of
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Table 2 Relationship between depressive, manic, and total morbidity index and several characteristics of illness course
(Wald tests for significance of fixed effects and covariates)
Parameter Chi-square P
Total morbidity index
Year of treatment; df = 19 19.847 0.404
Year of treatment × group membership interaction; df = 19 17.658 0.545
Number of episodes before index; df = 1 0.602 0.438
Number of recurrences before index; df = 1 0.002 0.963
Latency between onset of illness and start of lithium treatment; df = 1 1.991 0.158
Depressive morbidity index
Year of treatment; df = 19 26.112 0.127
Year of treatment × group membership interaction; df = 19 12.208 0.877
Number of episodes before index; df = 1 0.304 0.581
Number of recurrences before index; df = 1 0.773 0.379
Latency between onset of illness and start of lithium treatment; df = 1 2.778 0.096
Manic morbidity index
Year of treatment; df = 19 22.963 0.239
Year of treatment × group membership interaction; df = 19 16.271 0.639
Number of episodes before index; df = 1 0.305 0.581
Number of recurrences before index; df =1 2.105 0.147
Latency between onset of illness and start of lithium treatment; df = 1 0.013 0.908

lithium treatment in patients who initiated treatment in episodic pattern of illness are systematically underrepre-
the 1980s was lower than that observed in patients who sented (Coryell 2009; Grof et al. 1995; Goodwin 1999;
initiated treatment in the 1970s. Although patients in Gershon et al. 2009). The lithium clinics involved in this
the 1970s group were maintained on higher serum lith- study, however, follow the Kraepelinian tradition of diag-
ium levels, no decrease in the effectiveness of treatment nosing bipolar disorder. As a result, it is conceivable that
was observed in the 1980s group. most of the patients in our sample were bipolar in the
Several studies have evaluated long-term outcomes in traditional and narrow sense of the term.
patients who began with lithium treatment but contin- In addition, many of the newer studies perform ana-
ued with various treatments other than lithium in the lyses that use time-to-new-episode or time-to-new-
naturalistic setting. A recent study by Licht and co- rehospitalization or hazard ratios for relapse as the main
workers found an unsatisfactory outcome after 15 years outcome measure for long-term prophylactic effective-
(Licht et al. 2008); however, their follow-up was based ness (Bowden et al. 2003; Tohen et al. 2005; Viguera
on registry data that did not contain information on et al. 2001; Geddes et al. 2010; Suppes et al. 2009). Al-
whether patients had continued to receive lithium. As a though this type of analysis is well suited to relatively
result, their findings do not allow inferences on the ef- short trials that aim at proving a single drug's efficacy, it
fectiveness of long-term lithium treatment. is inappropriate for long-term maintenance studies be-
Our study was not concerned with the efficacy or ef- cause it fails to discriminate between different types of
fectiveness of lithium, both of which have been demon- response. Outcome criteria such as relapse or recurrence
strated in a substantial body of literature. The use of the do not afford proper assessment of the course of illness
MI as our outcome measure did not allow us to com- in patients who show substantial clinical improvement
pare the pre-index and post-index course of illness, be- but still experience episodes and thus fail to consider a
cause the MI requires prospective follow-up to obtain patient-focused perspective which is relevant for clinical
valid results. Retrospective data (e.g., from patient his- practice (Murru et al. 2011). Given that bipolar disorder
tories) are insufficient in this regard. is characterized by wide variations in the length and se-
The present study also differs from other investiga- verity of episodes, the MI is an outcome measure which
tions regarding the indication for starting lithium allows different forms of response and clinical course to
prophylaxis. Most studies which have been performed be distinguished from one another in a precise fashion.
during the last decade included patients within a broader This can be seen in an investigation of lithium mainten-
definition of bipolar disorder and patients with an ance treatment over a maximum of 15 years in a small
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subsample of the population in the present study: al- training. However, the influence of the abovementioned
though the MItotal remained stable throughout the study factors may have been mitigated by the similar tradition
period, the analysis of the absolute number of recur- of diagnosis and treatment followed by all of the centers
rences failed to produce any conclusive results because that participated in the present study. More specifically,
of the general shift over the study period from out- the centers agreed on a common treatment concept that
patient to inpatient treatment (Berghöfer et al. 1996). gives preference to lithium monotherapy whenever pos-
The outcome measure ‘burden of illness’ which is com- sible as a means to avoid adverse events and drug-
parable to the MI and uses a life chart method combin- induced cycling. In addition, there were no differences
ing severity and duration of episodes has recently been in the MI between the centers. As a result, any center-
presented by Backlund and coworkers in a long-term specific effect is likely to have been relatively small.
evaluation (Backlund et al. 2009 ). Secondly, the centers participating in the present study
In summary, the MI appears to be the most accurate were specialized academic outpatient clinics that, for the
approach to describing chronic illnesses and would most part, treated patients who required an above-
therefore seem to be a much more appropriate tool than average amount of care. As such, a selection bias must
survival analysis. Extended Cox regression models can be assumed. It should be noted, however, that the use of
provide a more accurate description of chronic illnesses additional medication in our sample was quite low. Out
because they focus on multiple recurrences rather than of 346 patients 152 (44%) had a mean co-medication
time to first recurrence (Pfennig et al. 2010). period of 22.4 out of 52 weeks (see Table 2), which indi-
The results of the present analysis are in agreement cates that patients with a severe course of illness were
with those of several studies from the same group of re- unlikely to have been overrepresented. The use of co-
searchers and, in part, derived from the same patient medication was higher in other long-term observations
data. Berghöfer et al. used the MI to report on long- (e.g., 15). Because the present study is not an epidemio-
term response in a subgroup of bipolar patients over a logical investigation with a representative sample of bi-
maximum of 15 years (Berghöfer et al. 1996), as noted polar patients, our results cannot be extrapolated to the
above, and in another study over a maximum of 20 years general population of these patients; similarly, it is not
(Berghöfer and Müller-Oerlinghausen 2000). In both possible to fully apply our results to routine psychiatric
studies, which included a subset of subjects from the practice.
present investigation, the severity and duration of recur- Thirdly, this analysis did not count affective symptoms
rences remained stable, and even decreased, over the ob- that had been rated as degree 1 (i.e., symptoms that do
servation period, albeit in small sample sizes. Two not require additional treatment). Recently, a substantial
recent reviews also support our finding that the effect- number of studies have been conducted to assess
iveness of lithium prophylaxis does not diminish over interepisodic subthreshold symptoms, such as cognitive
time (Burgess et al. 2001; Kleindienst et al. 1999). or affective impairment. It seems unlikely, however, that
There has been some controversy as to whether the including degree 1 symptoms in the analysis would sig-
length of time between illness onset and the start of nificantly affect the long-term stability shown by the MI.
prophylactic treatment (i.e., latency) may influence pa- Fourthly, a substantial number of patients dropped out
tients' response to long-term treatment (Franchini et al. of the study before completing 20 years of treatment,
1999). For this reason, we included latency of prophylac- and these subjects were not followed up. One might
tic treatment in our analysis. However, like the present argue that analyzing only those patients who remained
analysis, other recent studies have not shown any associ- on lithium treatment caused a selection toward higher
ation between negative outcomes and latency (Baethge stability, because non-responders may have switched to
et al. 2003a; Baethge et al. 2003b; Baldessarini et al. 2003). a different long-term medication or treatment setting.
Our study has several methodological limitations. However, it should be noted that the mean MI in pa-
Firstly, the severity of episodes may have been rated dif- tients who dropped out was not higher during their last
ferently at the various centers due to the use of different year of follow-up than it had been during the preceding
symptom thresholds for the initiation of treatment. This years. This indicates that the course of illness in subjects
clearly has the potential to affect which symptoms were who left the study was no worse than those who contin-
rated as degree 2. In addition, with multiple countries ued lithium treatment.
and cultures involved, treatment selection may have var- As a final consideration, it should be pointed out that
ied depending on factors such as the healthcare system, the MI does not fully reflect the effects and benefits of
the regional facilities available, and individual patient lithium in individual patients. A patient might show a
preferences. As in any long-term investigation, patients higher MI than another patient during lithium treatment
who receive up to 20 years of treatment were seen by a but might nevertheless experience a substantially greater
large number of therapists with varying degrees of reduction in his or her affective morbidity after starting
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Competing interests Baldessarini RJ, Tondo L, Floris G, Hennen J. Effects of rapid cycling on response
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Authors’ information Berghöfer A, Alda M, Adli M, Baethge C, Bauer M, Bschor T, Glenn T, Grof P,
All authors are members of the International Group for the Study of Lithium Müller-Oerlinghausen B, Rybakowski J, Suwalska A, Pfennig A. Long-term
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Acknowledgments ej07m03510.
The manuscript is dedicated to Prof. Hanfried Helmchen on the occasion of Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M,
his 80th birthday. We would like to thank Matthew D. Gaskins for editing this Montgomery P, Earl N, Smoot TM, DeVeaugh-Geiss J, Lamictal 606 Study
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Author details bipolar I disorder. Arch Gen Psychiatry. 2003; 60(4):392–400.
1 Burgess S, Geddes J, Hawton K, Townsend E, Jamison K, Goodwin G. Lithium for
Institute for Social Medicine, Epidemiology and Health Economics, Charité
University Medical Center, Berlin 10098, Germany. 2Department of Psychiatry, maintenance treatment of mood disorders. Cochrane Database Syst Rev.
Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada. 3Department of 2001; 3:CD003013.
Psychiatry and Psychotherapy, Charité University Medical Center, Berlin Coppen A, Abou-Saleh MT. Plasma folate and affective morbidity during long-
10098, Germany. 4Department of Psychiatry and Psychotherapy, University of term lithium therapy. Br J Psychiatry. 1982; 141:87–9.
Cologne Medical School, Cologne 50923, Germany. 5Department of Coryell W. Maintenance treatment in bipolar disorder: a reassessment of
Psychiatry and Psychotherapy, Universitätsklinikum Carl Gustav Carus lithium as the first choice. Bipolar Disord. 2009; 11(Suppl 2):77–83.
Dresden, Technische Universität Dresden, Dresden 01307, Germany. Crossley NA, Muller-Oerlinghausen B, Glenn T, Bauer M. The position of lithium
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Department of Psychiatry, Schlosspark Clinic, Berlin 14059, Germany. 7Mood in international and national guidelines for the treatment of mood
Disorders Center of Ottawa and Department of Psychiatry, University of disorders. In: Bauer M, Grof P, Muller-Oerlinghausen B, editors. Lithium in
Toronto, Toronto M5S 2E4, Canada. 8Drug Commission of the German Neuropsychiatry. The Comprehensive Guide. Abingdon: Informa healthcare;
Medical Association, Berlin 10623, Germany. 9Department of Adult Psychiatry, 2006: p. 33–42.
Poznan University of Medical Sciences, Poznan 61-701, Poland. Deshauer D, Fergusson D, Duffy A, Albuquerque J, Grof P. Re-evaluation of
randomized control trials of lithium monotherapy: a cohort effect. Bipolar
Received: 31 May 2013 Accepted: 19 July 2013 Disord. 2005; 7(4):382–7.
Published: 31 July 2013 DGBS, DGPPN. S3-Leitlinie zur Diagnostik und Therapie Bipolarer Störungen,
Langversion 1.0. Hamburg: DGBS, DGPPN; 2012. Ref Type: Edited Book.
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