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ANP0010.1177/0004867416664794ANZJP ArticlesSportiche et al.


Australian & New Zealand Journal of Psychiatry

Clinical factors associated with lithium 17

DOI: 10.1177/0004867416664794

response in bipolar disorders The Royal Australian and

New Zealand College of Psychiatrists 2016
Reprints and permissions:

Sarah Sportiche1,2,3, Pierre Alexis Geoffroy1,2,3,4,5,

Clara Brichant-Petitjean1,2,3, Sebastien Gard3,6,
Jean-Pierre Khan3,7,8, Jean-Michel Azorin3,9,10, Chantal Henry3,11,12,
Marion Leboyer3,11, Bruno Etain1,2,3,4, Jan Scott13,14 and Frank Bellivier1,2,3,4

Background: Bipolar disorder is a common chronic illness characterized by high levels of morbidity and all-cause
mortality. Lithium is one of the gold standard mood stabilizer treatments, but the identification of good, partial and non-
responders in clinical settings is inconsistent.
Methods: We used an established rating scale (the Alda scale) to classify the degree of lithium response (good response,
partial response, non-response) in a large, multicentre clinically representative sample of well-characterized cases of
bipolar disorders I and II. Next, we examined previously reported clinical predictors of response to determine which
factors significantly differentiated between the three response groups.
Results: Of 754 cases, 300 received lithium, for at least 6months, as a treatment for bipolar disorder (40%). Of these
cases, 17% were classified as good response, 52% as partial response and 31% as non-response. Lifetime history of mixed
episodes (p=0.017) and alcohol use disorders (p=0.015) both occurred in >20% of partial response and non-response
groups but <10% of good response cases. Family history of bipolar disorder I was of borderline statistical significance,
being more frequent in the good response group (38%) compared with the non-response group (18%). There was a
trend (p=0.06) for bipolar disorder II to be associated with non-response.
Conclusions: Only three factors previously identified as predictors of lithium response significantly differentiated the
response groups identified in our sample. Interestingly, these factors have all been found to co-occur more often than
expected by chance, and it can be hypothesized that they may represent a shared underlying factor or dimension. Further
prospective studies of predictors and the performance of the Alda scale are recommended.

Bipolar disorder, lithium response, mixed state, alcohol misuse, clinical predictors

1Inserm, U1144, Paris, France

2AP-HP, GH Saint-Louis Lariboisire F. Widal, Ple de Psychiatrie et de Mdecine Addictologique, Paris, France
3Fondation FondaMental, Crteil, France
4Universit Paris Diderot and Sorbonne Paris Cit, UMR-S 1144, Paris, France
5Universit Paris Descartes, UMR-S 1144, Paris, France
6Hpital Charles Perrens, Centre Expert Bipolaire, Ple de Psychiatrie Gnrale Universitaire, Bordeaux, France
7Service de Psychiatrie et Psychologie Clinique, CHU de Nancy, Centre Psychothrapique de Nancy-Laxou, Nancy, France
8Universit de Lorraine, Nancy, France
9Ple de psychiatrie, Hpital Sainte Marguerite, Assistance Publique Hpitaux de Marseille, Marseille, France
10EA 3279-Self-perceived Health Assessment Research Unit, School of Medicine, Timone University, Marseille, France
11Inserm, U955, Equipe de psychiatrie gntique et Universit Paris Est, Facult de mdecine et AP-HP, Ple de psychiatrie, Hpitaux Universitaires

Henri Mondor, Crteil, France

12Institut Pasteur, Unit Perception et Mmoire, Paris, France
13Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
14Centre for Affective Disorders, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), London, UK

Corresponding author:
Sarah Sportiche, AP-HP, GH Saint-Louis Lariboisire F. Widal, Ple de Psychiatrie et de Mdecine Addictologique, 75475 Paris, France.

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2 ANZJP Articles

Introduction number of mood episodes prior to the introduction of lith-

ium, age at onset, episode index polarity, rapid cycling,
Bipolar disorder (BD) is a common chronic illness charac- comorbidities (personality, substance use or anxiety disor-
terized by a high risk of mood recurrences, with 80% of ders) and the presence of atypical features of depression.
patients experiencing a relapse within 2years of an index However, in an extensive review of 43 studies and 42 clini-
mood episode (Goodwin and Jamison, 2007; National cal variables, Kleindienst etal. (2005) were only able to
Institute for Health and Care Excellence [NICE], 2014). identify five potential predictors of clinical response to
The disorder is also characterized by high levels of physical lithium. The two predictors of GR to lithium treatment
comorbidity, premature death and a high risk of suicide, were episodic illness pattern characterized as mania-
with a 6- to 10-fold increased risk compared to the general depression-interval (or MDI) and older age of onset of
population (Hayes etal., 2015). Unsurprisingly, BD is BD; the three predictors of poor response were higher num-
ranked as one of the 10 most burdensome disorders world- ber of pre-lithium hospitalizations, an episodic pattern of
wide (Collins etal., 2011; Lopez and Murray, 1998). depression-mania-interval (or DMI) and a continuous
Despite these levels of morbidity and all-cause mortality, cycling pattern. The authors noted that all these findings
several longitudinal observational studies have shown that should be interpreted with caution, as there were inconsist-
prophylactic treatment, especially with lithium, can reduce encies in how lithium response was defined in the different
relapse, suicide and premature death rates and improve studies. Moreover, subsequent studies have not replicated
functional outcomes compared to no treatment or sub-opti- these findings. For example, Garnham etal. (2007) reported
mal treatment (Mller-Oerlinghausen etal., 1994). that lithium responders were more likely to have an early
Furthermore, in clinical settings, lithium remains a gold rather than later age of onset, to have an episodic illness
standard treatment with a significantly greater reduction in pattern (but did not report any differences between MDI or
recurrence rates, regardless of the polarity, relative to pla- DMI) and to meet diagnostic criteria for BD I. Pfennig
cebo or to other anticonvulsant mood stabilizers etal. (2010) found that the probability of recurrence in lith-
(BALANCE Investigators and Collaborators etal., 2010; ium-treated patients was negatively associated with the
Geddes etal., 2004; Severus etal., 2014). Lithium is the presence of mood-incongruent psychotic symptoms, inter-
only mood stabilizer that has been shown empirically to be episode residual symptoms and rapid cycling. Kessing
associated with a reduction in the risk of suicide in patients etal. (2011) found that excellent lithium responders were
with BD (Cipriani etal., 2005; Goodwin etal., 2003). characterized by few earlier psychiatric hospitalizations, a
Although lithium appears to be a highly efficacious manic index polarity of BD and lower levels of somatic
treatment for BD in research settings, response rates to lith- comorbidity.
ium prophylaxis in clinical practice are highly variable Overall, there is some agreement about the proportion of
between individuals. Rybakowski etal. (2001) reported cases who are likely to show a GR (about 30%), but there is
that about 30% of individuals treated with lithium are clas- uncertainty about the putative predictors of this desired out-
sified as excellent responders (e.g. demonstrating a total come. This issue has been compounded by two factors: the
absence of affective episodes over a 10-year period of lith- heterogeneity in the definition or measurement of lithium
ium prophylaxis), while Grof etal. (2002) noted that the response and the lack of clinical representativeness and/or
response rate may be increased further in first-degree rela- small size of study samples. These issues have been par-
tives of lithium responders. However, the corollary is that, tially resolved by the introduction of the Retrospective
in day-to-day clinical practice, about 30% of cases are par- Criteria of Long-Term Treatment Response in Research
tial responders (prescription of lithium is associated with Subjects with Bipolar Disorder (also referred to as the Alda
some improvement) and up to 40% of BD cases are lithium scale) (Grof etal., 2002). The Alda scale has been used in
non-responders (i.e. the introduction of lithium does not several studies by Grof etal. (2002), Duffy etal. (2002) and
modify the course of the disease) (Baldessarini and Tondo, Garnham etal. (2007) and has recently been shown to have
2000; Garnham etal., 2007). Given these findings, there moderate but substantial inter-rater agreement and reliabil-
have been some efforts to identify the personal and clinical ity in a study of over 1000 cases recruited from 29 centres
characteristics of individuals who are more rather than less participating in the Consortium on Lithium Genetics
likely to respond to lithium prophylaxis. (ConLiGen) network (Manchia etal., 2013). We therefore
Studies that attempt to identify clinical factors associ- employed this assessment measure to a representative clini-
ated with good outcome following the introduction of lith- cal sample of adult cases of BD I and II who had been pre-
ium prophylaxis have produced conflicting results. Two of scribed lithium by clinicians at one of four clinical services
the most quoted predictors of Good Response (GR) are the located across France. In this study, we examined the demo-
history of prophylactic response to lithium in first-degree graphic and clinical characteristics associated with member-
relatives and the episodic course of the disorder with remis- ship of one of three previously defined lithium response
sion between episodes (Grof etal., 2002). Other clinical categories, namely, GR, Partial Response (PR) and Non-
predictors have also been proposed such as bipolar subtype, Response (NR) (Grof etal., 2002; Manchia etal., 2013).

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Sportiche et al. 3

Methods compliance during periods of stability (B4) and the use of

additional medication during the period of stability (B5).
Ethical approval was granted by an institutional review The total score (TS) on the Alda scale is obtained by sub-
board for a programme of research on BD, and all partici- tracting the B score from the A score; any negative score
pants gave written informed consent for their de-identified (i.e. the B scale score exceeds the A scale score) is recorded
data to be used in the research programme, which included as 0. For the purposes of this study, we used the three
a range of projects including database studies. reported categories of response: NR (TS<2), PR (TS=2
6) and GR (TS7).
Sample Many of the variables recorded in clinical case notes (e.g.
pre- and post-lithium recurrence rates) are used to rate the A
The original research sample comprised participants who and B scale scores for the Alda scale, so the between-group
were recruited between 1995 and 2008 from four French comparisons we report here focus on those characteristics
university affiliated departments of psychiatry (Paris XII, that were not already utilized to make the Alda rating, but
Bordeaux, Marseille and Nancy). The inclusion criteria that have been identified as potentially important in predict-
were that the person (a) was aged 18years; (b) had a mood ing likelihood of response to lithium in previously published
disorder that met Diagnostic and Statistical Manual of studies. These included age at onset of BD and polarity of
Mental DisordersFourth Edition (DSM-IV) criteria for BD first episode, duration of illness prior to lithium, subtype of
I or BD II (American Psychiatric Association, 1994); (c) BD, lifetime history of mixed episodes, psychotic symp-
currently met criteria for euthymia, which was operational- toms, rapid cycling, suicide attempts, anxiety disorders,
ized as having scores <5 on both the Montgomerysberg alcohol or substance use disorders (AUD and SUD), sea-
Depression Rating Scale (Montgomery and Asberg, 1979) sonal illness pattern and family history of BD I or II.
and the Bech Mania Rating Scale (Bech etal., 1978); and
(d) was willing and able to give written informed consent.
Statistical analysis
Mean and standard deviations (SDs) and frequency data
Assessments including number (N) and percentages (%) were calculated
Cases meeting the above inclusion criteria were assessed for each response category. These data take into account any
by psychiatrists trained in the use of the French version of missing information (so each comparison gives the number
the Diagnostic Interview for Genetic Studies (DIGS), of cases with available data). Non-parametric descriptive
which is the equivalent of the Structured Clinical Interview statistical tests (2 and MannWhitney U tests) were used to
for DSM-IV, lifetime version (SCID-1) (Nurnberger etal., compare the GR, PR and NR groups. All analyses were per-
1994). The schedule (supplemented by additional questions formed using the SPSS software package, version 20, and as
as appropriate) was used to record key socio-demographic, all variables for the comparison were selected a priori, we
family, clinical and treatment history variables in a research set statistical significance at p<0.05 for all tests.
For the purposes of the current study, we identified BD Results
cases who were prescribed lithium as a prophylactic treat-
ment for at least 6months. The records of these cases were Of the 754 cases in the research database, 300 had been
then rated using the Alda scale (Grof etal., 2002) by a psy- prescribed lithium for at least 6months (40%).
chiatrist (C.B.-P.) who had participated in the ConLiGen The study sample comprised 121 (40%) males and 179
reliability study (Manchia etal., 2013). The Alda scale was (60%) females. Their mean age was 45.4 years (SD
specifically developed to allow retrospective evaluation of 13.2years), and the mean age at onset of BD was 25.8years
prophylactic treatment response in naturalistic conditions; (SD 10.4years). In all, 240 cases (80%) met criteria for BD
it comprises two subscales (A and B). The A scale score I, while 60 cases (20%) met criteria for the BD II subtype.
(range: 010) derives from items that quantify the degree of The cases had experienced a mean of 8.5 BD episodes (SD
improvement due to lithium treatment (e.g. reduction in the 8.2), of which 4.9 (SD 5.1) were depressive, 3.2 (SD 4.3)
frequency of recurrences, reduction in residual symptoms, were manic and 0.2 (SD 0.4) were mixed episodes.
etc.). The B scale includes five criteria (each rated 02, Individual had been ill for about 1012years prior to the
with a higher score being more negative) that represent fac- introduction of lithium.
tors that undermine the likelihood that the observed As shown in Table 1, 17% of the sample was classified
improvement is really due to the introduction of lithium. as GR, 52% as PR and 31% as NR. Neither current age nor
The five potential confounders incorporated in the B scale gender was associated with response category. Family his-
are as follows: the number of episodes before receiving tory of BD I was reported in 252 cases and was of border-
lithium (B1), the frequency of episodes before receiving line statistical significance, being more frequent in the GR
lithium (B2), the duration of lithium treatment (B3), the group (17 out of 45 patients: 38%) compared with the PR

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Table 1. Clinical characteristics of groups categorized by Good Response (GR), Partial Response (PR) and Non-Response (NR) to
lithium (see text for details).

GR (n=50) PR (n=156) NR (n=94)

Variables N a (300) Mean (SD) or N (%)b U/2 Significance (p)

Females 300 31 (62%) 95 (61%) 53 (56%) 0.63 0.73

Current age in years (mean, SD) 300 47.6 (12.7) 44.6 (13.1) 45.4 (13.7) 2.53 0.81

Age at onset in years (Mean, SD) 297 27.4 (11.9) 25.4 (10.1) 25.5 (10.2) 0.57 0.75

Duration of illness before lithium 234 10.0 (9.0) 12.0 (10.3) 13.0 (11.0) 2.59 0.27
prescribed in years (mean, SD)

Bipolar I subtype 298 37 (74%) 128 (27%) 73 (79%) 1.89 0.39

Manic polarity at onset 297 24 (48%) 55 (36%) 34 (36%) 2.54 0.28

Seasonal patternc 268 4 (9%) 27 (19%) 22 (26%) 5.37 0.068

Psychotic symptomsc 297 50 (17%) 155 (52%) 92 (31%) 0.23 0.89

Mixed episodesc 269 3 (7%) 30 (21%) 23 (28%) 8.08 0.017

Rapid cyclingc 295 2 (4%) 19 (12%) 14 (15.2) 3.99 0.14

Attempted suicidec 293 24 (48%) 69 (45%) 42 (47%) 0.22 0.90

Anxiety disordersc 225 32 (45%) 51 (44%) 19 (19%) 0.02 0.99

Alcohol use disordersc 294 4 (8%) 26 (17%) 25 (27%) 8.36 0.015

Substance use disordersc 294 8 (16%) 33 (22%) 29 (32%) 5.07 0.08

Family history of Bipolar I disorder 252 17 (38%) 40 (31%) 14 (18%) 5.98 0.05

Family history of Bipolar II disorder 266 2 (4%) 9 (7%) 13 (15%) 5.73 0.06

SD: standard deviation.

aN included in analysis,
bPercentages are rounded to whole numbers.
cLifetime history.

(40 out of 131 patients: 31%) and NR groups (14 out of 76 identified 300 well-characterized cases of BD I and II who
patients: 18%); there was a non-significant trend (p=0.06) were prescribed lithium, for at least 6months, at four
for BD II to be associated with NR. Only two other factors French centres, making this one of the biggest independent
differed significantly between the three groups: lifetime studies of this issue. Of the previously purported predictors
history of mixed episodes (p=0.017) and AUD (p=0.015); of lithium response, only three clinical factors differed sig-
these problems both occurred in >20% of PR and NR nificantly between the three predefined response groups:
groups but <10% of GR cases. family history of BD I, lifetime history of mixed episodes
There were no statistically significant differences and lifetime history of an AUD. Furthermore, the findings
between group with regard to mean age at the onset of BD, on family history of BD I should be treated with caution as
or duration of illness prior to lithium, the characteristics of data with regard to this variable were missing in 17% of the
the clinical presentation (bipolar subtype, onset polarity, sample and the statistical significance was borderline
history of seasonal illness pattern, rapid cycling, psychotic (p<0.05) and not corrected for multiple testing.
symptoms, suicide attempts) or the lifetime history of other The finding that lifetime history of AUD and lifetime
psychiatric comorbidities (anxiety disorder or SUD). history of mixed episodes were both more common in
groups associated with lower response or NR to lithium
concurs with previous studies. For example, the response
Discussion rate to lithium prophylaxis has been shown to be poorer in
Our main objective was to identify clinical factors associ- patients with BD and AUD (Frye and Salloum, 2006; Tohen
ated with different levels of lithium response in a large, etal., 1990). The mechanism of this lithium resistance is
clinically representative sample of patients with BD. We unexplained, but there are a number of hypotheses. First,

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Sportiche et al. 5

inadequate adherence may impact the response to lithium, especially helpful in assessing each of the B scale items and
and it is well known that individuals with AUD and SUD would offer a more reliable measure of the impact of fluc-
often show lower adherence rates than other patient popula- tuating levels of mediation adherence and/or variations in
tions (Aagaard and Vestergaard, 1990; Teter etal., 2011). therapeutic levels of lithium to be monitored. In this study,
However, other evidence indicates that lithium adherence we note that only 4% of our cases (N=11) had a high score
in BD cases with comorbid AUD does not necessarily on the compliance item (B4 item score of 2). However,
improve response. For example, patients with BD and this does not mean that all other cases had good compliance
comorbid AUD often have a younger age at onset for BD throughout. Likewise, missing information from case notes
(Feinman and Dunner, 1996; Winokur etal., 1998), a higher can hamper accurate assessment of B scale items, such as
risk of self-harm, more severe symptoms and more frequent detailed recordings of nature and severity of comorbidities
episodes (OConnell etal., 1991; Tohen etal., 1990) and and their treatments.
more rapid cycling and mixed episodes (Carvalho etal., On a positive note, this study identifies several new lines
2014); all of these characteristics may be associated with for future research on predictors to lithium response, such as
poorer response to lithium. Furthermore, in animal studies, clarifying the nature of familial response (and the best ele-
a recent study has demonstrated that alcohol and lithium ment to choose to predict benefit from lithium) and the inter-
have opposing effects on behavioural circadian rhythms relationships between the most robust predictors we found. In
(Nascimento etal., 2015). addition, it is clear that while the A and B subscales of the
In line with our findings, previous studies have reported Alda scale are admirably pragmatic and make clinical sense,
poorer lithium response in BD cases with a lifetime history our experience of applying the scale to large clinical samples
of mixed episodes (Fountoulakis etal., 2012). Relatively leads us to believe that there may be some benefit in review-
few studies have investigated the long-term medication in ing the performance of the scale in more detail to determine
patients with mixed episodes, but several suggest that lith- whether further refinements could improve its ability to iden-
ium may be less effective for these patients than some of tify valid clinical phenotypes of lithium response for use in
the other mood stabilizers such as valproate (Fountoulakis genetic and other studies (Schulze etal., 2010).
etal., 2012; Freeman etal., 1992; Montgomery etal., 2000;
Yatham etal., 2013).
Finally, it is noteworthy that family history of BD I, Conclusion
AUD and mixed states often co-occur, and thus, the three In our large French sample of individuals with BD I and II
predictors we have identified may represent different who received lithium for at least 6months and who were
aspects of some underlying genetic or pathophysiological characterized for lithium response using the Alda scale, we
mechanism. A family history of BD has been noted as a observed three factors associated with lithium response:
predictor of response to lithium in several studies (Grof, family history of BD I, lifetime history of mixed episodes
2010; Maj etal., 1985; Mendlewicz etal., 1973), although and lifetime history of an AUD. These three characteristics,
it is not always clear whether the important element is sub- previously identified as predictors of lithium response in
type of BD (I or II), family history of lithium response (i.e. the literature, have also been found to co-occur more often
pharmaco-genetic aspects) or the pattern of illness in famil- than expected by chance and may represent a shared under-
ial cases (such as offspring presenting with a more classic lying factor or dimension. Future prospective studies
Kraepelian form of manic depression). However, studies should test the positive and negative predictive value of this
have also noted that alcohol misuse, especially in males cluster of characteristics on lithium prophylactic response.
with BD, is often more frequent in those with family his- Another finding, albeit weaker, is still noteworthy, namely
tory of BD (Frye etal., 2003), and AUD appears to increase that family history of BD I appeared to be associated with
the risk of syndromal or sub-syndromal mixed states improving response, but family history of BD II showed a
(Paykel etal., 2006). trend in the opposite direction suggesting the need to
Several limitations of this study must be acknowledged. explore these separately rather than as a single construct.
The major weakness is the retrospective nature of the
assessment of lithium response. Of course, to a certain Acknowledgements
extent, this is the only way to estimate the overall response
S.S., F.B. and P.A.G. were involved in the design and planning of
to lithium in a large clinical sample. However, a prospec-
the study. S.S., F.B., P.A.G. and J.S. identified the hypotheses for
tive study with contemporaneous recording of clinical data the current study. C.B.-P. undertook the lithium response assess-
pre- and post-lithium prescribing would allow more ments using the Alda Scale. S.S. carried out the literature review
detailed analysis of other potentially important predictors and drafted the main sections of the manuscript. S.S., P.A.G. and
and reduce any false-negative results that could have J.S. undertook the statistical analyses. S.G., J.P.-K., J.-M.A., C.H.,
occurred in our study because of random missing data (that B.E., M.L. and F.B. were responsible for the recruitment. F.B.,
may have reduced the statistical power of some of our anal- B.E. and M.L. were, respectively, principal investigator and scien-
yses or between-group differences). This would be tific coordinators of the research project. F.B., P.G. and J.S.

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6 ANZJP Articles

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Declaration of Conflicting Interests disorder: A systematic review. The Journal of Clinical Psychiatry 75:
The author(s) declared the following potential conflicts of interest 578586.
with respect to the research, authorship, and/or publication of this Cipriani A, Pretty H, Hawton K, etal. (2005) Lithium in the prevention of
article: S.S., C.B.-P., J.P.-K. declare that there is no conflict of inter- suicidal behavior and all-cause mortality in patients with mood disor-
est. P.A.G. has received travel awards or financial compensation ders: A systematic review of randomized trials. The American Journal
of Psychiatry 162: 18051819.
from AstraZeneca, Lundbeck, Menarini France and Otsuka. S.G.
Collins PY, Patel V, Joestl SS, etal. (2011) Grand challenges in global
has received honoraria and financial compensation as independent mental health. Nature 475: 2730.
symposium speakers from AstraZeneca, Bristol Myerrs Squib and Duffy A, Alda M, Kutcher S, etal. (2002) A prospective study of the off-
Otsuka. J.-M.A. has received research support and has acted as con- spring of bipolar parents responsive and nonresponsive to lithium
sultant and/or serves on a speakers bureau for Bristol-Myers treatment. The Journal of Clinical Psychiatry 63: 11711178.
Squibb, Eli Lilly, Lundbeck, Otsuka, Takeda, Novartis, Pfizer, Feinman JA and Dunner DL (1996) The effect of alcohol and substance
AstraZeneca, Servier and Sanofi-Aventis. C.H. has received hono- abuse on the course of bipolar affective disorder. Journal of Affective
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ers from AstraZeneca, Bristol-Myers Squibb, Otsuka. M.L. reports Fountoulakis KN, Kontis D, Gonda X, etal. (2012) Treatment of mixed
personal fees from Servier outside the submitted work. B.E. has bipolar states. The International Journal of Neuropsychopharmacology
15: 10151026.
received honoraria and financial compensation as independent
Freeman TW, Clothier JL, Pazzaglia P, etal. (1992) A double-blind com-
symposium speakers from Lundbeck, AstraZeneca, Bristol-Myers parison of valproate and lithium in the treatment of acute mania. The
Squibb, Otsuka and Servier. F.B. has received honoraria and finan- American Journal of Psychiatry 149: 108111.
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Sanofi-Aventis, Lundbeck, AstraZeneca, Eli Lilly, Bristol-Myers prevalence, risk, and clinical correlates of alcoholism comorbidity in
Squibb and Servier and has received peer review research funding bipolar disorder. The American Journal of Psychiatry 160: 883889.
from French Ministry of research, Assistance Publique Hpitaux Frye MA and Salloum IM (2006) Bipolar disorder and comorbid alcohol-
de Paris, the National Institute for Research (INSERM) and the ism: Prevalence rate and treatment considerations. Bipolar Disorders
NARSAD. J.S. is a visiting professor at Diderot University. J.S. has 8: 677685.
received grant funding from the Stanley Foundation (for work on Garnham J, Munro A, Slaney C, etal. (2007) Prophylactic treatment
response in bipolar disorder: Results of a naturalistic observation
lithium and medication adherence), from the Medical Research
study. Journal of Affective Disorders 104: 185190.
Council UK (including for projects on actigraphy and bipolar disor- Geddes JR, Burgess S, Hawton K, etal. (2004) Long-term lithium therapy
ders) and from the Research for Patient Benefit programme UK for bipolar disorder: Systematic review and meta-analysis of rand-
(PB-PG-0609-16166: Early identification and intervention in young omized controlled trials. The American Journal of Psychiatry 161:
people at risk of mood disorders). The FondaMental foundation has 217222.
received funding from Sanofi-Aventis (sponsorship of the Psy COH Goodwin FK and Jamison KR (2007) Manic-Depressive Illness. New
BP cohort project), Roche Laboratory (sponsorship of the Autism York: Oxford University Press.
InfoR cohort), Otsuka and Lundbeck laboratories (FondaMental Goodwin FK, Fireman B, Simon GE, etal. (2003) Suicide risk in bipo-
Conferences), Eli Lilly & Co. (FondaMental PhD grant) and Servier lar disorder during treatment with lithium and divalproex. Journal of
(FondaMental Post Doctoral grant). American Medical Association 290: 14671473.
Grof P (2010) Sixty years of lithium responders. Neuropsychobiology 62:
Grof P, Duffy A, Cavazzoni P, etal. (2002) Is response to prophylactic lith-
The author(s) disclosed receipt of the following financial support ium a familial trait? The Journal of Clinical Psychiatry 63: 942947.
for the research, authorship, and/or publication of this article: This Hayes JF, Miles J, Walters K, etal. (2015) A systematic review and meta-
research was funded by INSERM and Assistance Publique des analysis of premature mortality in bipolar affective disorder. Acta
Hpitaux de Paris (Research Project number C0829 and P111002, Psychiatrica Scandinavica 131: 417425.
Ethics Approval number IDRCB2008-AO1465-50). Kessing LV, Hellmund G and Andersen PK (2011) Predictors of excellent
response to lithium: Results from a nationwide register-based study.
International Clinical Psychopharmacology 26: 323328.
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