Lithium response across generations
Much of the investigations summarized in this
manuscript follows in the footsteps of Eric Stro ¨ m-
gren?s research, in particular his focus on longitu-
dinal observations, lithium and genetic studies.
Stro ¨ mgren, one of the most outstanding European
psychiatrists of all times, initiated longitudinal
epidemiological studies from which he obtained
vital knowledge about the natural course of psy-
chiatric disorders. Studies investigating prospec-
tively the clinical course in the offspring of patients
with bipolar disorder (refer to as BD) now supply
new information about the initial manifestations of
Grof P, Duffy A, Alda M, Hajek T. Lithium response across
Objective: To describe and integrate observations from bipolar
patients responsive to lithium stabilization and their children.
Method: Selected findings are described from the clinical and
biological investigations of adults meeting research criteria for bipolar
disorder and for responsiveness to lithium stabilization; and from
prospective studies of the children of lithium responders and non-
Results: Response to prophylactic lithium identifies a valid subtype of
bipolar disorder, however the search for biological markers of lithium
response, while promising, has so far remained inconclusive. Adult
responders to lithium stabilization exhibit definable clinical features
which are also observable in their affected children. In prospective
studies the children of bipolar parents develop symptoms earlier than
reported previously, with marked differences between the offspring of
lithium responders and non-responders. The illness evolves in
predictable clinical stages, first from non-specific sleep and anxiety
disorders to mood symptoms and then, often starting in adolescence,
major depressive and later activated episodes.
Conclusion: Investigating and comparing unequivocal responders and
non-responders to long-term lithium treatment and their offspring is a
fertile research strategy for addressing a multitude of clinical and
P. Grof1,2, A. Duffy1,3, M. Alda3,
1Mood Disorders Center of Ottawa, Ottawa, ON,
Canada,2Department of Psychiatry, University of
Toronto, ON, Canada,3Department of Psychiatry,
Dalhousie University, Halifax, NS, Canada and4Prague
Psychiatric Centre, 3rd Faculty of Medicine, Charles
University, Prague, Czech Republic
Key words: bipolar disorders; offspring; children;
lithium; long-term treatment; stabilization; clinical
profile; responders; biological markers
Paul Grof MD, PhD, FRCP, Mood Disorders Center of
Ottawa, Smyth Medical Centre, 202-1929 Russell Rd.,
Ottawa, ON, K1G 4G3, Canada.
• The children of lithium responsive bipolar parents may present psychopathological symptoms in
childhood, earlier than reported previously in their parents.
• In the assessment and clinical management of afflicted offspring of bipolar parents it pays off to
consider the whole clinical profile, not just the presenting symptoms.
• Patients stabilizing well on long-term lithium treatment represent a subgroup of bipolar disorders
with particular clinical characteristics.
• The morbidity risks of children investigated in our studies may be elevated compared to other family
studies because their bipolar parents may be more interested to involve them in this research.
• The findings reported here have been condensed to meet the space requirements. Further details can
be found in the references.
Acta Psychiatr Scand 2009: 120: 378–385
All rights reserved
? 2009 John Wiley & Sons A/S
BD and about important parallels and differences
between children, adolescents and adults.
Eric Stro ¨ mgren also provided major contribu-
tions to the diagnosis and classification of psychi-
atric disorders. The lessons learned from bipolar
offspring currently indicate a pressing need to
refine the diagnostic process further, particularly in
the DSM system.
Mogens Schou never failed to remind his audi-
ences that it was Eric Stromgren who, in 1953, had
drawn his attention to John Cade?s report on
lithium (1). Subsequently, Cade?s therapeutic claim
was tested and confirmed in the first psychophar-
macological placebo-controlled trial on Strom-
gren?s home territory. While Mogens Schou is
universally considered the father of lithium pro-
phylaxis, Eric Stro ¨ mgren, with several publications
reflecting his involvement with lithium (2), would
rightfully deserve the title of its grandfather.
Eric Stro ¨ mgren set the signposts and provided
vital contributions to the population genetic studies
of functional psychoses. Genetic research of lithium
responsive mood disorders, an outgrowth of this
approach, strives to advance the field by applying
the progressivetechniques ofmolecular biology toa
relatively homogeneous clinical population.
Aims of the study
In this manuscript we, therefore, describe and
integrate selected findings from the clinical and
biological investigations of adults meeting research
criteria for bipolar disorder and for responsiveness
to lithium stabilization, as well as from prospective
studies of the children of lithium responders and
Material and methods
Selected findings are described from the clinical
and biological investigations of adults meeting
research criteria for bipolar disorder and for
responsiveness to lithium stabilization; and from
prospective studies of the children of lithium
responders and non-responders.
Stabilization achieved through long-term lithium
treatment succeeds primarily in a particular type of
bipolar patients whose clinical characteristics are
outlined below. For these patients it is a unique
benefit that, unlike other lithium uses in psychiatry,
has not been achieved by other medications (3).
A complete or marked suppression of both manic
and depressive recurrences takes place while thera-
term prevention against recurrences, we can usually
determine with a high probability, if an individual
patient responds specifically to the given treatment.
Many observations indicate that, of patients
who are diagnosed with BD according to DSM IV,
only a proportion will respond to lithium stabil-
ization. It is therefore imperative to clarify for
clinical practice which patients should receive
stabilizing lithium salts as the treatment of
choice. Conversely, patients whose characteristics
point out that they are unlikely to benefit from
lithium stabilization should be first treated with
other mood stabilizers. The heterogeneity of BDs
has been well recognized for 30 years (4), but has
not yet been sufficiently incorporated into psycho-
The observation that numerous patients with
recurrent manic-depressive illness could be stabi-
lized on a simple element – lithium – made a
significant contribution to profound changes in
psychiatric thinking. During the following decades
the point of gravity in psychiatry moved from
psychosocial to neurobiological, from psychoanal-
ysis to pharmacotherapy, and the diagnostic
boundaries of mood disorders have been markedly
Children of lithium responders
Studying children of bipolar parents has turned out
to be a fruitful strategy. Bipolar disorder clusters in
families and first-degree relatives share an 8–12
fold risk of bipolar disorder compared to the
general population. Intriguing findings have been
emerging from the prospective studies of the
children of bipolar parents, particularly from the
scrutiny of the offspring of lithium responders.
Prior to 1970 a common recommendation to
women with BD was not to have children and
many affected women had actually followed this
advice (5). But with the widespread use of lithium
the observation of a larger number of children
became possible: now dealing with a treatable
malady, women became mothers more readily and
later started bringing their symptomatic children
forassessment and care.
assumed we would be able to help their children
in the same way.
Fifteen years ago, our research group led by Dr
Anne Duffy embarked on prospective studies of
these offspring (6–13). Parents participated in
Mood Disorders Research Program and their
bipolar clinical profile was well captured. To
Lithium response across generations
qualify, each parent had to be either an unequiv-
ocal responder or non-responder to stabilizing
lithium treatment, in order to reduce bipolar
heterogeneity, and had to have a psychiatrically
Starting at 8 year of age, the children have been
assessed and diagnosed by an independent team
blind to the parent?s clinical profile, and then seen
prospectively either when they become symptom-
atic or annually. Full information about the
child?s infant years was recovered from parents.
A control group of children born of parents free
from psychiatric illness
The longitudinal study of offspring of bipolar
parents is a productive strategy for charting the
clinical beginnings of the illness, identifying the
sources of vulnerability and protection, uncovering
the interplay of important pathophysiological fac-
tors, exploring treatment responses and investigat-
ing the onset and progression of bipolar illness not
yet contaminated by the burden of illness and
Different beginnings of bipolar disorder?
The description of the course of bipolar illness
available from the major studies of adults used to
picture the mean onset of episodes in the mid 30s
(14) and prepubertal children were spared of
symptoms; no non-specific or specific psycho-
adolescence. Similarly, when interviewed about
their childhood, adult lithium responders described
their prepubertal life as free of psychiatric prob-
lems (15). These reports were usually verified by
their relatives and clinical records. But the new
findings obtained prospectively from their off-
spring, and summed up here, present a very
First, the children of bipolar parents – lithium
responders and non-responders – become ill not
only earlier but also differently than expected
from the previous observations of their parents.
Compared to the offspring of well parents, their
morbidity is increased, but does not initially
present as major mood episodes (13). The first
manifestations in childhood are non-specific and
include various presentations of anxiety and
sleep disorders. This increased risk of non-
mood disorders is in agreement with several
other studies (16, 17). However, this non-specific
psychopathology appearing at an early age does
not mean the condition termed as pediatric BD
(18, 19). On the other hand, it is also important
to note that the vast majority of offspring who
remained completely well throughout childhood
and adolescence have stayed well into early
Second, there are qualitative differences between
the offspring of lithium responders and non-
responders. The difficulties of offspring of lithium
responders, whether non-specific or specific, run an
episodic course and in adolescence present mostly
as mood disorders. Conversely, the offspring of
non-responders show either partially remitting or
non-remitting fluctuating course of illness and not
infrequently manifest cluster A traits (social inhi-
bition, odd thinking) and cognitive problems
diagnosed as attentional problems and learning
Third, while investigating offspring of bipolar
parents, Duffy discovered that BD evolves in
stages. If the child becomes afflicted, the initial
non-specific expressions – childhood sleep and
various anxiety disorders – evolve around puberty
into minor depressive symptoms and oversensitiv-
ity to stress. The onset of major depressive episodes
follows, starting in mid-adolescence, while acti-
vated mood episodes – hypomanic or manic – trail
several years later. The pre-existing anxiety mark-
edly increases the risk of later mood episodes
(Fig. 1). The illness propensity may manifest for
the first time at any of these stages, but subsequent
manifestations then follow the expected sequence.
Other high risk studies have reported observations
that are in keeping with these clinical stages
Fig. 1. Risk of onset of mood disorder increased by pre-
existing anxiety disorder. Survival analysis. A combined
sample of Duffy et al. (The early course of bipolar disorder in a
prospective study of high-risk offspring. Br J Psychiatry 2009,
in press) and Grof et al. (Children at high risk for bipolar
disorders, Psychiatrie, 2009; in print), 307 offspring of a
bipolar parent. Red: offspring with anxiety disorder preceding
mood disorder; Black: offspring with mood disorder without
preceding anxiety disorder.
Grof et al.
Consistent with adult studies, substance use
disorders in the offspring start to appear in
adolescence, in our cohort at the same time as, or
following, the first major mood episode (Fig. 2).
Already having a mood disorder nearly doubled
the age-adjusted risk of a substance use disorder
(mostly alcohol and ⁄or cannabis). It must be
clarified that in children of parents who are not
affected with BD, childhood anxiety, sleep or
minor mood disturbances should not be considered
as predictors of BD (22).
Finally, pilot data indicate that adolescents who
develop recurrences and require stabilizing treat-
ment can respond well to monotherapy with a
stabilizer tailored to their clinical profile (11). The
accomplishment of the chosen mood stabilizer
depends on the nature of the patient?s clinical
course (episodic vs. non-episodic) and the response
to the same stabilizer in the patient?s parent. These
observations indicate that a useful diagnostic and
include a careful assessment of the patient?s clinical
course and of family history of disorders and
treatment responses. They also contradict the
conviction that adolescents, as a rule, suffer from
disorders with complex comorbidities requiring
These landmark investigations of the offspring
of parents with BD now proceed to firm up the
findings on other cohorts and to integrate findings
from clinical, genetic, biological and psychosocial
research in a unified bipolar model.
Finding non-specific psychopathology in offspring
of a parent with BD has important consequences
for later development. Having such a parent is the
strongest single risk factor for mood disorders later
and the majority of those offspring who manifest
anxiety disorders become affected with a major
mood disorder, on average 8 years later (12).
Fortunately, the majority of offspring of bipolar
parents remain unaffected in youth.
Furthermore, it is important to evaluate young
patients with mood symptoms for relevant family
history. When a family history and a possible stage
of BD are overlooked, the early manifestations of
latent BD are often treated as the presenting
problem, with polypharmacy including stimu-
lants, antidepressants and psychotherapy. This
approach, while not part of our treatment, can
have harmful consequences (23) including a higher
risk of suicide and of paradoxical response to
In addition, longitudinal investigations of off-
spring of lithium responsive parents do not support
either an association of this condition with ADHD
or with a so called ?pediatric bipolar disorder?
(18, 19, 25). We did not observe such symptomatic
cluster in either of our cohorts. This syndrome is
more likely a non-specific predictor of variable
psychiatric outcomes and not an early form of BD
Adult responders and their offspring: differences and similarities
When contrasting lithium-responsive parents and
their offspring, the main difference is the informa-
tion available about childhood. While the adults
described in retrospect that their illness started
with depressions and manias in adolescence or
adulthood, the prospective observations of their
offspring finds that a sizable proportion actually
begin having non-specific problems much earlier.
This difference may be either an artifact, or real, or
As for the artifact, the adults may have forgotten
or repressed the symptoms from childhood, par-
ticularly after experiencing later major episodes of
abnormal mood. In earlier studies adult patients
were usually identified for research through their
hospitalization, and they provided retrospective
information about the onset and the previous
course of illness. The fallibility of recall has been
well established. Furthermore, as the interviewers
did not expect symptoms in childhood, they may
not have been sufficiently sensitive to detect the
Fig. 2. Risk of onset of mood disorder in relation to anxiety
disorder or substance abuse. Survival analysis. A combined
sample of Duffy et al. (The early course of bipolar disorder in a
prospective study of high-risk offspring. Br J Psychiatry 2009,
in press) and Grof et al. (Children at high risk for bipolar
disorders, Psychiatrie, 2009; in print). Black: age at onset of
mood disorder in the whole sample; Red: age at onset of
anxiety disorder in subjects who experienced mood disorder;
Blue: age at onset of substance abuse in subjects who experi-
enced mood disorder.
Lithium response across generations
But the re-interviews of adult lithium respond-
ers, their parents and older siblings do not support
a simple ?artifact? of recall or repression. Further,
the discrepancy between the pristine, symptom-free
childhood of previous generation of lithium-
responders and earlier harbinger symptoms in the
offspring may also have some real roots. Klerman,
for example (26), and World Health Organization
reports also indicate a steady increase in mood
disorders in subsequent generations. The impact on
a child growing up with a bipolar parent also has
to be considered.
There are, on the other hand, striking similarities
between parents and their offspring in both lithium
responsive and non-responsive families. First, the
characteristics of the clinical course of children
mirror the ill parent. If the affected parent expe-
rienced episodic, fully remitting course, so do the ill
children. Similarly, parents with a non-episodic
course and residual symptoms have offspring with
chronic or fluctuating, non-episodic psychiatric
problems. More important, the same type of
clinical course for the parent and the afflicted
children is observed regardless of whether the
presenting psychopathology is non-specific, or
whether the manifestations are full-fledged depres-
sive or manic episodes.
Second, evidence is growing that when the
children require long-term stabilizing treatment,
they appear to respond to the same mood stabilizer
as their parent, rather than responding to the
standard treatment that is prescribed according to
their presenting symptoms (10, 11). The over-
reliance on symptom-based diagnosis and the
neglect of clinical profile, including correct family
history, may explain why so many depressed
adolescents are presumed to be treatment resistant.
These similarities strongly suggest that all the
varied psychopathological manifestations in off-
spring and their lithium-responsive parents and all
the different stages of BD may be actually arising
from one, comparable brain dysregulation.
The search for biological markers
The observed remarkable responses to stabilizing
treatment with a simple ion had generated hope for
an uncomplicated laboratory test of lithium
response. As many new laboratory techniques
were then introduced into biological psychiatry,
they were also applied to revealing lithium?s mode
of action and response.
But many studies struggled with the methodo-
logical complexities of the mission. Among the
main obstacles has been the correct identification
of responders and non-responders to stabilizing
lithium. As the natural course of BD is capricious,
individually highly variable, and patients waver in
their compliance with long-term medication, such a
research task is challenging. To obscure things, the
patients may also benefit from anti-manic, anti-
psychotic, anti-aggressive, anti-suicidal or aug-
menting effect of lithium, without ever stabilizing
over the long-term.
We also placed our hopes on biological markers
and over 20 years performed a series of systematic
investigations comparing unequivocal responders
and non-responders to lithium stabilization. After
correcting for confounding variables, many labo-
ratory findings emerged as negative, but a few
differences became apparent. We found character-
istic neuroendocrine responses in lithium respond-
ers (27, 28). At baseline, healthy controls and
symptom-free, remitted responders were indistin-
guishable, but only responders exhibited signifi-
cantly different responses after 3 weeks of lithium
administered to both groups. These changes in
responders were compatible with a serotonin or
endorphin trait dysfunction. Lithium responders
also differed significantly from healthy and psychi-
atrically ill controls in the MNS blood groups (29).
Unfortunately, these differences have only a lim-
ited practical value.
Many others attempted to discover a laboratory
marker of lithium response, with similar outcomes.
From a wealth of reports, we have included a few
illustrations: lithium transport in red blood cells
(30), an RBC ⁄plasma lithium ratio (31), urinary
lithium excretion (32), platelet monoaminoxidase
activity (33), urinary MHPG and other expressions
of central amine metabolism (34), serum calcium
and magnesium (35, 36), average evoked potentials
(37, 38) and HLA antigens (39). As one example of
recent studies, an investigation by Kruger et al.
(40) comparing rCBF in valproate responders,
lithium responders and their unaffected relatives
showed significant, possibly heritable differences
between the two patient groups.
The search for biological markers of response to
a simple lithium ion has turned out to be surpris-
ingly complex. Even after several decades of
intense explorations, a laboratory marker of lith-
ium response appears elusive.
The genetic studies of lithium response merit
mentioning separately because they offer great
promise and have been expanding recently (41–45).
There are good reasons for optimism: Both BD
and lithium response cluster in families (46), the
illness itself appears to have the strongest genetic
Grof et al.
contribution of all psychiatric disorders and the
responders to lithium stabilization are a relatively
homogeneous bipolar subtype (4). Furthermore,
molecular genetics has already proven its useful-
ness by major discoveries in neurology and other
branches of medicine.
During the past two decades DNA of lithium-
responsive probands and their families have been
investigated in linkage and association studies and
in genome scans. Some meta-analyses of genetic
findings in bipolar patients also included a pro-
portion of lithium responders (47). The findings
overall suggest that the bipolar subgroup respon-
sive to long-term lithium treatment has a genetic
contribution that is distinct from other subtypes of
bipolar patients. In families of lithium-responsive
probands, we have found neither support for
previously reported linkages to chromosomes 13
and 22 that have been observed in families with a
high prevalence of psychotic symptoms, nor link-
ages to regions on chromosome 18 that have been
reported in bipolar families with comorbid panic
disorder, high rates of bipolar II disorder and rapid
cycling. The observations available so far indicate
that patients with these clinical characteristics
stabilize preferentially on atypical neuroleptics
and lamotrigine respectively (15, 48). Studies
comparing lithium responders and non-responders
have also attracted attention to the serotonin
transporter gene, inositol monophosphatase gene
and mitochondrial gene XBP1. Within the assigned
space we cannot do justice to this promising,
quickly expanding area and are referring the reader
to a comprehensive overview that also contains the
references to the above mentioned studies (49).
Clinical profile of lithium responders
While we searched extensively for biological expla-
nations of lithium response, the analyses of the
accumulated clinical database revealed a charac-
teristic clinical profile of excellent responders (50–
52). Coincidentally, the first presentation of our
results on multivariate analyses took place on Eric
Stro ¨ mgren?s home turf, at the Institute in Risskov
(50). The clinical features that emerged were later
confirmed independently in controlled clinical
studies (48) as well as in other naturalistic studies
(53, 54) and can be summarized as follows.
The most useful indicator of future success with
lithium stabilization is the clinical profile of the
bipolar patient (55). The fully remitting course of
illness is the strongest predictor, and is supported
by a family history of episodic bipolar and
depressive disorders, and no comorbidity with
other psychiatric disorders. During remissions,
the future responders not only return to their
premorbid work and family functioning, but they
are also free of any residual symptoms, affective or
non-affective. Concomitant comorbidity with other
psychiatric disorders in excellent responders does
not exceed that expected in the general population.
Provided the above features from the patient?s
history are present, the symptoms of classical
depression and mania in acute episodes also aid
in the prediction of response.
Patients with this characteristic profile who need
stabilizing treatment benefit from lithium as the
monotherapy of choice. An excellent, sustained
response to lithium prophylaxis is one of the most
gratifying outcomes a psychiatrist may experience.
To estimate in practice whether a particular
patient with a recurrent mood disorder is likely to
stabilize well on lithium, it is vital to obtain the
information about the patient?s clinical profile
comprehensively and to interpret it carefully.
While the quality of remissions is especially
important, many psychiatrists must first learn to
assess it correctly because psychiatric training has
been focusing on identifying acute psychopathol-
ogy, not its complete absence. The lack of residual
symptoms and the good quality of remission can be
also measured by MMPI profile that differs signif-
icantly between responders and non-responders
(56) as well as between their children (57).
There are three recent studies focusing on
detecting the clinical
response. Kleindienst et al. (58) analyzed data
from 43 suitable clinical trials of lithium by meta-
analytic aggregation based on a random effects
model and effect size measure. The authors con-
cluded that none of the investigated variables alone
actually predicted lithium response which seemed
to be related to a multitude of variables. They felt
that past history of a patient predicts the response
to prophylactic lithium better than the patient?s
presenting clinical picture. Two analyses of the
longitudinal observations gathered by the Interna-
tional Group for the Study of Lithium-Treated
Patients (59) have demonstrated that in bipolar
patients with mainly classical profile the response is
stable over time. When tested with models that
account for the interdependence of clinical fea-
tures, the predictors that emerged are essentially
compatible with the described clinical predictors.
The history of the use of lithium in psychiatry has
been marked by delays, misunderstandings and
controversies and the research of response to
lithium stabilization has appeared as methodolog-
Lithium response across generations
ically tricky, challenging and complicated as the
history of lithium use itself. A massive body of
investigations attempted to discover a biological
marker of lithium response and some promising
linkages have been recently emerging from genetic
studies. However, if we want to identify patients
who will likely benefit from lithium stabilization,
we still need to base this on the patient?s clinical
Most intriguing have been the prospective stud-
ies of offspring of lithium responders. The obser-
vations indicate that early manifestations of BD
may now actually start in childhood, with non-
specific symptoms, which evolve in a series of
predictable clinical stages. The patient may expe-
rience the first manifestations during any stage, but
then proceeds through the anticipated sequence.
In combination with the new studies of pre-
psychotic states (60), these findings challenge some
of the historically based assumptions of diagnos-
ing, classifying and treating primarily on the basis
of psychopathological symptoms.
The third generation – grandchildren of the
adult lithium responders – is now emerging and
may offer new insights. As measurements showed
that only a few mothers pass lithium into their milk
in concerning amounts, we now follow a cohort of
children that have been breastfed from their first
day of life by lithium-treated mothers. A body of
animal research indicates that the reactivity of the
brain can be changed profoundly by nutritional
changes imprinted during the first weeks of life.
A systematic follow-up of this generation might
offer some new insights, perhaps even into primary
Declaration of interests
None of the authors has any conflict of interest in connection
with the content of this manuscript.
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