Toward Constructing an Endophenotype Strategy
for Bipolar Disorders
Gregor Hasler, Wayne C. Drevets, Todd D. Gould, Irving I. Gottesman, and Husseini K. Manji
Research aimed at elucidating the underlying neurobiology and genetics of bipolar disorder, and factors associated with treatment
response, have been limited by a heterogeneous clinical phenotype and lack of knowledge about its underlying diathesis. We used a
survey of clinical, epidemiological, neurobiological, and genetic studies to select and evaluate candidate endophenotypes for bipolar
disorder. Numerous findings regarding brain function, brain structure, and response to pharmacological challenge in bipolar patients
and their relatives deserve further investigation. Candidate brain function endophenotypes include attention deficits, deficits in verbal
learning and memory, cognitive deficits after tryptophan depletion, circadian rhythm instability, and dysmodulation of motivation
and reward. We selected reduced anterior cingulate volume and early-onset white matter abnormalities as candidate brain structure
endophenotypes. Symptom provocation endophenotypes might be based on bipolar patients’ sensitivity to sleep deprivation,
psychostimulants, and cholinergic drugs. Phenotypic heterogeneity is a major impediment to the elucidation of the neurobiology and
genetics of bipolar disorder. We present a strategy constructed to improve the phenotypic definition of bipolar disorder by elucidating
candidate endophenotypes. Studies to evaluate candidate endophenotypes with respect to specificity, heritability, temporal stability,
and prevalence in unaffected relatives are encouraged.
Key Words: Intermediate phenotype, biological marker, bipolar
disorder, genetics, twins, families, endophenotypic
course from unipolar depression (Angst 1966; Angst and Perris
1968; Perris 1966), with which it had been merged in Kraepelin’s
earlier and durable category of manic-depressive insanity since
early in the 20th century. Understanding the etiology of manic-
depressive illness, now referred to as bipolar disorder (BPD),
requires a genetic diathesis interacting with environmental, epi-
genetic and stochastic components. Bipolar disorder, affecting
approximately 1% of individuals (strictly diagnosed), is a chronic,
disabling, and often life-threatening illness (Angst and Preisig
1995). Adding broader notions of the BP spectrum (Akiskal and
Pinto 1999; Angst and Gamma 2002) would complicate our
mission at this stage, so we must omit that rich literature.
Underlying genetic diatheses and environmental, epigenetic,
and stochastic mechanisms have remained mostly uncharacter-
ized (Lenox et al 2002). Recent scientific advances suggest that
the time is at hand to begin to elucidate the genetic basis of BPD;
these advances include 1) detection of genes causal for Mende-
lian brain diseases, such as Huntington’s disease and early-onset
Alzheimer’s disease, and for some of the genes predisposing to
complex diseases, such as diabetes and coronary artery block-
age; 2) dramatic developments in molecular genetics, including
the human genome project, Hapmap project, and increasing
availability of low-cost genetic markers (single nucleotide poly-
morphisms) throughout the genome (Badner and Gershon 2002;
Craddock et al 2005; Ogden et al 2004); and 3) continued
n seminal contributions, Angst and Perris proposed bipolar
manic-depressive illness as a separate nosological group
differing significantly in genetics, gender distribution, and
consistent evidence from twin studies that concordance in BPD
identical twins ranges from 40% (strict) to 97% (spectrum), in
contrast to corresponding rates in nonidentical twins of 5%–38%
(Angst et al 1980; Bertelsen 2004; Kieseppa et al 2004; McGuffin
et al 2003).
Despite costly candidate gene association studies and ge-
nome-wide linkage scans, however, no genes for BPD have been
identified definitively, though there are many promising leads
(DePaulo 2004; Levinson et al 2003; McQueen et al 2005). The
limited success of genetic studies of complex disorders has
resulted in considerable debate regarding the reasons for the
failures in the past, as well as the most appropriate methodolog-
ical approaches to take in the future (Hirschhorn and Daly 2005;
Kendler 2005). Questions have been raised concerning the
definition of genetically relevant phenotypes and the nature of
the underlying, partially overlapping sets of susceptibility genes.
The diagnosis of BPD, as defined by current classification
schemas, including DSM-IV, is based on clusters of symptoms
and characteristics of clinical course that do not necessarily
describe homogenous disorders but that rather reflect final
common pathways of different pathophysiological processes
involving genetic and environmental contributors (Charney et al
2002; Hasler et al 2004b). In addition, there is growing evidence
that the boundaries between BPD and schizophrenia and be-
tween BPD and recurrent major depression might not be as
distinct as previously assumed (Angst 1998; Lewis 2004; Maziade
et al 2005).
In this review, we will present strategies to overcome some of
the methodological difficulties impeding the elucidation of the
genetic basis of BPD by proposing putative endophenotypes.
The term “endophenotype” was described as an internal, inter-
mediate phenotype (i.e., not obvious to the unaided eye) that
fills the gap in the causal chain between genes and distal diseases
(Gottesman and Shields 1973) and therefore might help to
resolve questions about etiology. The endophenotype concept
assumes that the number of genes involved in the variations of
endophenotypes representing more elementary phenomena (as
opposed to the behavioral macros found in the DSM) is less than
the number involved in producing the full disease (Gottesman
and Gould 2003). Endophenotypes provide a means for identi-
fying the “upstream” traits underlying clinical phenotypes, as
well as the “downstream” biological consequences of genes. The
From the Mood and Anxiety Disorders Program (GH, WCD, TDG, HKM),
ments of Psychiatry and Psychology (IIG), University of Minnesota Med-
ical School, Minneapolis, Minnesota.
Address reprint requests to Gregor Hasler, M.D., Department of Psychiatry,
University Hospital Culmannstrasse 8, 8091 Zurich, Switzerland; E-mail:
Received May 2, 2005; revised November 14, 2005; accepted November 18,
BIOL PSYCHIATRY 2006;60:93–105
© 2005 Society of Biological Psychiatry
methods available to identify endophenotypes include neuro-
psychological, cognitive, neurophysiological, neuroanatomical,
imaging, and biochemical measures (Figure 1). The evaluation
criteria are based on the endophenotype concept developed by
Gottesman and associates (Gottesman and Gould 2003; Gottes-
man and Shields 1973). Given the increasing recognition of the
importance of epigenetic transformations and developmental
factors in the expression of psychiatric phenotypes (Gottesman
and Hanson 2004; Hasler et al 2005), the criterion “state inde-
pendence” might be particularly difficult to achieve for candidate
endophenotypes. Therefore, we slightly modified this criterion,
emphasizing the role of time/age. Given the success of symptom
provocation methods in genetic studies of medical diseases with
variable course and important environmental influences over
time (Kajantie et al 2004; Tripathy et al 2003), we also referred to
these methods when claiming “state independence.” Here are the
modified criteria for the identification of endophenotypes:
1. An endophenotype is associated with illness, in the
2. An endophenotype is heritable.
3. An endophenotype is state independent (manifests in an
individual whether or not illness is active) but age-normed
and might need to be elicited by a challenge (e.g., glucose
tolerance test in relatives of diabetics).
4. Within families, endophenotype and illness co-segregate.
5. An endophenotype identified in probands is found in their
unaffected relatives at a higher rate than in the general
Apart from the criteria mentioned above, disease specificity
and clinical and biological plausibility have also been discussed
as evaluation criteria for endophenotypes (Tsuang et al 1993), to
relate phenotypic definitions to clinically relevant outcomes, to
enhance the elucidation of clinically relevant pathophysiological
mechanisms (Lavori et al 2002), and to increase prior probability
of utility in genetic studies (Freimer and Sabatti 2003, 2004). It
should be emphasized, however, that endophenotypes, reflecting
genetically relevant aspects of the heterogeneous pathophysiology
of the disease, are clearly different from diagnostic markers, which
Figure 1. A heuristic model, whereby underlying
bipolar disorders gene susceptibility loci and impli-
cated genes, modulated by environmental, epige-
netic, and stochastic events, predispose to the de-
velopment of bipolar disorder. Along this lengthy
putative bipolar endophenotypes, the identifica-
tion of which will be useful for studies of the under-
lying neurobiology and genetics of bipolar disor-
ders, in addition to clear utility in preclinical
investigations, such as the development of animal
models. This figure is meant to represent a guide to
locus. ©2005 I.I. Gottesman.
94 BIOL PSYCHIATRY 2006;60:93–105
G. Hasler et al
are evaluated by measures of sensitivity and specificity, because it
cannot be assumed that the current definitions of psychiatric
diseases are biologically valid. Claiming biological and clinical
plausibility as endophenotype criteria prematurely or a priori
might consequently impede discoveries of novel, unexpected
disease mechanisms. We are not yet able to carve nature at its
joints because we are uncertain as to what are the joints.
The Pheno–Geno Gradient of Endophenotypes
Within the broad class “endophenotypes,” there is a gradient
of closer to the gene and gene products (“geno”) versus closer to
the symptoms and the disease itself (“pheno”). In twin studies,
broader diagnostic definitions (e.g., schizophrenia plus mood-
incongruent affective disorders plus schizotypal personality dis-
order plus atypical psychosis) might provide higher heritability
estimates than narrow diagnostic definitions (e.g., pure schizophre-
nia) (Farmer et al 1987). Likewise, in longitudinal studies, broader
diagnostic categories (e.g., mood plus anxiety disorders) showed
greater stability over time than narrow diagnostic definitions (e.g.,
pure panic disorder) (Angst et al 1990). By analogy, this might
lead to the conclusion that relatively broad endophenotypes
(brain function endophenotypes, e.g., cognitive performance)
might be the most heritable and most appropriate for genetic
studies. It has to be kept in mind, however, that although broad
phenotypic constructs might show high familial transmission in
twin and family studies, they might not represent alternative
manifestations of a single liability distribution (McGue et al
1983). Genetic factors for intermediate traits that are closer to the
genotype in the developmental scheme might generally be easier to
identify because of the improved signal-to-noise ratio in the fraction
of variance explained by any single factor (Carlson et al 2004).
The multifactorial threshold model of complex genetic dis-
ease assumes that 1) many factors contribute to a disorder
ontogenetically; 2) the effects of each single factor are small, but
the effects accumulate; and 3) once the combined effects of the
factors pass some critical value, perhaps triggered by signaling or
other cascades, the disorder becomes manifest (Gottesman and
Shields 1967; McGue et al 1983). This model also can be applied
to endophenotypes because we assume that multiple genetic and
nongenetic factors contribute to an endophenotype that be-
comes manifest when the combined effects of the factors pass
the endophenotype-specific threshold. Moreover, a certain en-
dophenotype (e.g., cholinergic hypersensitivity) might, together
with other endophenotypes and nongenetic factors, contribute to
endophenotypes on more symptom-related levels (e.g., rapid-
eye-movement [REM] sleep abnormality, clinical sleep character-
istics), finally summing up to effects that pass the critical value for
the macro phenotype. Again, the endophenotype approach
assumes that the underlying liability of endophenotypes repre-
senting basic biological phenomena is less complex and easier to
elucidate than the liability of complex behaviors, such as psychi-
atric diseases, irrespective of the magnitude of the phenotypic
definition’s total genetic risk.
Clinical and Preclinical Utilities of Endophenotypes
Although there exist select examples of success in psychiatry
(e.g., the schizophrenia endophenotypes described below), the
endophenotype idea remains a highly promising concept rather
than a fully validated approach. The rationale for great expecta-
tions is a consequence of informed speculation and currently
applicable procedures; specifically, endophenotypes are envi-
sioned to aid in 1) diagnosis; 2) classification; 3) treatment; 4)
clinical research; and 5) the development of preclinical models.
In contrast to other branches of medicine, psychiatry suffers
from a diagnostic and classification system that is not based on
pathophysiology and etiology, being dependent on nosological
tradition, expert consensus, psychometric reliability, and clinical
utility (First et al 2004). Therefore, it is not altogether surprising
that studies of the underlying genetics and neurobiology have
been fraught with a limited amount of success and an even more
limited breadth of consensus. Dissecting psychiatric macro pheno-
types into biologically valid components (whether they are bio-
chemical, endocrinological, neurophysiological, neuroanatomical,
cognitive, or psychopathological) presumes the ability to make
diagnosis more certain, more specific, and more amenable to
tailored treatment. Specifically, heterogeneity implicit in the
current classification schema is a likely reason for the limited
success of clinical studies, at the levels of treatment, neurobiol-
ogy, and genetics.
The reductionist approach implicit in endophenotypes has
clear parallels to the general mechanisms used in preclinical
research and molecular genetics, having been successful in
tracing pathways from potential susceptibility genes to psychiat-
ric phenotypes. Neuregulin 1 knockout mice, for example,
showed reduced expression of N-methyl-D-aspartic acid recep-
tors and abnormalities in prepulse inhibition (Stefansson et al
2002), thus relating a schizophrenia candidate gene to putative
endophenotypes of schizophrenia.
Selection of Endophenotypes
Unfortunately, there is no standardized algorithm for the
selection of endophenotypes in genetic research. Generally, a
putative endophenotype should be selected with respect to 1)
empirical evidence of meeting endophenotype criteria; 2) feasi-
bility and reliability of its measurement; and 3) possible rele-
vance for the disorder/subject under study. For this article, we
selected putative endophenotypes that seemed to be relatively
specific for BPD. For example, we did not include P300 abnor-
malities in this review because they represent general markers of
brain integrity, and their relationship to BPD is rather nonspecific
(Lenox et al 2002). Likewise, we did not include promising
putative endophenotypes that were primarily examined in major
depression (e.g., return of depressive symptoms after tryptophan
and catecholamine depletion, increased stress sensitivity, or
dysfunctions of the hypothalamic–pituitary–adrenal axis) be-
cause they were discussed in a recently published review on
endophenotypes in major depression (Hasler et al 2004b). In
addition to the specificity criterion, we selected putative endo-
phenotypes on the basis of empirical studies in euthymic patients
and in unaffected subjects at substantially increased risk for BPD.
Brain Function Endophenotypes
One of the most consistent findings in behavioral genetics is
that general intellectual functioning is highly heritable (Plomin
and Spinath 2004). Twin and family studies consistently indicate
that 65%–80% of individual differences in variation in adult
intelligence test scores is accounted for by genetic factors,
although the heritability of specific cognitive functions might be
considerably lower. Cumulative data have identified stable and
inherent cognitive impairments in psychiatric disorders (Gold-
berg and Weinberger 2004). The potentially high heritability and
the reliable measurement of cognitive functions suggest that
useful BPD endophenotypes can be derived from such impair-
G. Hasler et al
BIOL PSYCHIATRY 2006;60:93–105 95
ments, if they are not the consequence of the illness (Glahn et al
2004). In genetic studies of schizophrenia, for example, impaired
working memory has seemed to be a useful neurocognitive
endophenotype involved in schizophrenia-related functional
and structural prefrontal cortex abnormalities and to a functional
polymorphism in the catechol-O-methyl transferase (COMT)
gene, which is thought to play a role in schizophrenia vulnera-
bility (Egan et al 2001; Zammit et al 2004). In recent years, there
has been increasing recognition of the role played by particular
subcortical structures (e.g., nucleus accumbens, amygdala) in the
regulation of motivation, sleep–wake cycle, and social behavior,
domains that are prominently impaired in affective disorders
(Nestler et al 2002). Twin and family studies provide evidence for
high heritability for deficits in reward function (Fu et al 2002;
Kendler et al 1991), and longitudinal research studies have
demonstrated that symptoms of impaired reward mechanisms,
including anhedonia and antisocial traits, emerge early in life,
representing important precursors of a substantial portion of
adult mental disorders (Kim-Cohen et al 2003; Luby et al 2004).
Deficits in attention have been proposed as a neuropsycho-
logical core vulnerability marker of BPD (Clark et al 2002;
Harmer et al 2002). The specificity of this finding is questionable,
however, because attention deficits have also been reported in
patients with recurrent major depression in full remission (Wei-
land-Fiedler et al 2004), patients with schizophrenia (Addington
and Addington 1997), and subjects with attention-deficit/hyper-
activity disorder (Doyle et al 2005). In a report by Clark and
Goodwin (2004), attention deficits seemed to be present early in
the course of BPD but became more pronounced with repeated
episodes. The same deficits have been identified in euthymic
bipolar subjects (Clark et al 2002, 2005a), though the degree of
impairment might be exacerbated during acute manic episodes.
Functional neuroimaging studies have revealed several anatom-
ical networks involved in functions of attention, such as alerting,
orienting, and executive control (Fan et al 2002). Among the
different attentional functions, executive attention, a process that
involves dopamine-rich frontal areas (including the anterior
cingulate), was found to be highly heritable (Fan et al 2001; Swan
and Carmelli 2002). Executive attention has been assessed by the
Stroop paradigm, attentional set shifting tasks, or the Attention
Network Test. Impairments in executive attention were found to
be mood state independent: in euthymic patients, decreased
performance on the Stroop color and word test were not
correlated to illness severity or duration (Zubieta et al 2001), and
a functional neuroimaging study on attention in symptomatic and
euthymic subjects with BPD, using the Stroop interference task,
revealed a trait abnormality in the ventral prefrontal cortex
related to mood-independent attentional deficits (Blumberg et al
2003). Unaffected offspring of bipolar probands showed evi-
dence for deficit in tasks of ventral, but not dorsal, prefrontal
cortex function (Frangou et al 2005). Moreover, increased slow-
ness in the Stroop test, attentional set shifting, and deficits in
executive control seemed to be specifically associated with
genetic risk of BPD (Clark et al 2005b; Ferrier et al 2004; Zalla et
al 2004). Taken together, attention deficit represents a potential
endophenotype for BPD, although the neurobiological hetero-
geneity of attentional functions has to be taken into account to
further decipher the molecular and genetic determinants (Fan et
Deficits in Verbal Learning and Memory
Comparative studies on neuropsychological dysfunctions in
severe psychiatric disorders showed that impairments were
qualitatively similar in schizophrenia and BPD, with impairments
being more severe in schizophrenia than in BPD; however,
particularly poor performance on tests of verbal memory was
consistently found as a characteristic of BPD (Johnson and Magaro
1987; Seidman et al 2002). Brain lesion studies and functional
imaging studies identified a brain-wide distributed network in the
medial temporal lobe, the temporal cortex, and the frontal cortex
as a neural correlate of declarative memory function (Miyashita
2004). It has long been hypothesized that memory engrams of
declarative knowledge in the cortex develop with structural
reorganization of neural circuits. Neurobiological mechanisms
that are potentially involved in the synaptic plasticity required for
learning and memory include glutamatergic neurotransmission
(Bannerman et al 1995) and changes in gene expression brought
about by neurotrophic factors, such as cyclic adenosine
monophosphate response element binding protein (CREB)
and brain-derived neurotrophic factor (BDNF) (Bourtchuladze
et al 1994; Egan et al 2003). In healthy subjects, verbal learning
and memory were found to have a particularly high heritability:
a twin study on memory functions showed that the intraclass
correlations between monozygotic and dizygotic twins were
significantly different for verbal learning and memory, whereas
they were not different for response discrimination, learning
strategy, and recognition (Swan et al 1999). Poor performance on
measures of verbal learning and memory was found in euthymic
bipolar patients irrespective of a history of alcohol abuse (Alt-
shuler et al 2004; van Gorp et al 1998; Zubieta et al 2001), thus
providing evidence for the state independence of this dysfunc-
tion. Unaffected twins of bipolar patients performed significantly
worse than normal control subjects on short-term and long-term
verbal learning and memory tasks (Gourovitch et al 1999), and
deficits in verbal long-delay free recall and verbal recognition
were found in healthy siblings of BPD patients (Keri et al 2001;
Sobczak et al Sobczak et al 2002b, 2003). Tryptophan depletion
enhanced verbal memory deficits in unaffected relatives of BPD
patients (Sobczak et al 2002b, 2003). Some studies, however,
failed to show such impairment in relatives of subjects with BPD
(Clark et al 2005b; Ferrier et al 2004), suggesting mixed evidence
for the association between verbal memory deficit and genetic
risk of BPD. More research regarding the specific components of
learning and memory deficits associated with genetic risk of BPD
Cognitive Deficits After Tryptophan Depletion
Investigators have examined the possibility that sensitivity to
the deleterious mood and cognitive effects of lowered serotonin
might represent an endophenotype for BPD by studying unaf-
fected relatives of BPD patients. Unlike control subjects, unaf-
fected relatives showed increased impulsivity during acute tryp-
tophan depletion. Baseline measurements indicated that, relative
to control subjects, unaffected relatives exhibited lower seroto-
nin platelet concentrations, lower affinity, and fewer binding
sites of the serotonin transporter for imipramine; these differ-
ences were unaffected by tryptophan depletion (Quintin et al
2001). Sobczak et al (2002a) found that speed of information
processing on a planning task (Tower of London Task) after
tryptophan depletion was impaired in relatives of BPD patients
but not in the control group. Furthermore, subjects with a BPD
type I relative showed impairments in planning and memory,
independent of tryptophan depletion, representing potentially
96 BIOL PSYCHIATRY 2006;60:93–105
G. Hasler et al
specific familial trait abnormalities related to BPD. In concert,
these results suggest that impaired planning after reduced tryp-
tophan availability might represent an endophenotype for BPD.
Circadian Rhythm Instability
Clinical features of BPD, such as diurnal variation in mood,
early morning awakening, and cyclicity and seasonality of recur-
rences, have led to speculation that abnormalities in circadian
rhythm might play an important role in its pathophysiology.
Although circadian abnormalities have also been found in other
psychiatric disorders, including unipolar depression and schizo-
phrenia, they seemed to be particularly important in BPD:
disturbance of the sleep–wake cycle was found to be the most
common prodrome of mania (Jackson et al 2003; Wehr et al
1987); experimentally induced sleep deprivation is associated
with the onset of hypomania or mania in a considerable portion
of patients (see Response to Sleep Deprivation, below); and
antimanic drugs were shown to stabilize circadian rhythms
(Klemfuss 1992; Klemfuss and Kripke 1995). Although abnormal-
ities in the circadian rhythm of body temperature and neuroen-
docrine profiles seem to be disease state dependent (Linkowski
2003; Souetre et al 1988), there is some evidence that the
circadian rhythm in euthymic bipolar patients is persistently
unstable (Jones et al 2005) and sensitive to environmental
influences, such as weather conditions and seasonal changes
(Hakkarainen et al 2003), and that euthymic patients show
important impairments of sleep-related functioning, such as low
daytime activity levels and nocturnal insomnia (Harvey et al
2005). Twin research in healthy individuals provided evidence
for the heritability of circadian clinical characteristics (Dauvilliers
et al 2005) and for a genetic control of the human circadian clock
(Linkowski et al 1993). A mutation in a human clock gene,
hPER2, has been specifically associated with a familial variant of
human sleep behavior (Toh et al 2001), and a polymorphism in the
human CLOCK gene has been associated with circadian mood
fluctuation and illness recurrence in BPD (Benedetti et al 2003).
Lithium, which has been shown to modify the phase and
period of circadian rhythms in a variety of species, ranging from
unicellular organism and insects to mice and even humans, is a
glycogen synthase kinase 3 (GSK-3) inhibitor (Gould et al 2004;
Klein and Melton 1996). Interestingly, Martinek et al (2001)
identified the Drosophila orthologue of GSK-3, SHAGGY, as a
component of the circadian cycles. Overexpression of SHAGGY
lengthened the Drosophila free-running circadian cycle. Addi-
tionally, a decrease in SHAGGY activity resulted in an increase in
circadian period length (Martinek et al 2001), the effect (increase
in circadian period) that has been noted in numerous species,
including Drosophila, after treatment with lithium (Klemfuss
1992; Padiath et al 2004). Taken together, these data suggest that
lithium’s effect on circadian cycles (discussed in Gould and Manji
2002) might bring about some of its therapeutic effects in bipolar
patients, supporting the hypothesis that circadian rhythm insta-
bility is etiologically associated with BPD and a candidate
endophenotype. Finally, preliminary evidence on an association
between a polymorphism in the GSK-3-? promoter gene and
BPD suggest that genetic factors involved in the regulation of the
human circadian clock might represent vulnerability factors of
BPD (Benedetti et al 2004a).
Dysmodulation of Motivation and Reward
Loss of interest, lack of reactivity to positive events, and anhe-
donia are core features of the depressive phase of BPD, whereas
heightened incentive motivation and compulsiveness toward rein-
forced behaviors are characteristic symptoms of the manic phase of
the disorder. Presumed associations between dysfunction of the
brain reward system and alterations between anhedonia and
enhanced response to rewarding stimuli provide a potential
biological basis of reward-related endophenotypes in BPD.
A wide variety of evidence in humans and nonhuman pri-
mates has associated brain reward functions with neural activity
in the ventral striatum and mesial prefrontal cortex (Knutson et al
2001, 2003; Schultz 2002). Interestingly, gray matter deficits in
these brain regions have been associated with genetic risk for
BPD (McDonald et al 2004a). Euphoria has been related to
amphetamine-induced dopamine release in human ventral stria-
tum (Drevets et al 2001), and enhanced rewarding effects of
psychostimulants in patients with affective illness and induction
of mania in individuals with BPD might represent a trait-like
dysfunction of the dopaminergic system associated with impair-
ment of the brain reward function (Tremblay et al 2002). In
individuals at risk for affective disorders, depletion of dopamine
and norepinephrine by ?-methyl-para-tyrosine (AMPT) induced
anhedonia after 24 hours, followed by hypomanic symptoms,
such as increased sexual interest and decreased need for sleep,
24–48 hours after the last AMPT dose, suggesting rebound
sensitivity to AMPT depletion as an endophenotype for BPD
(Anand et al 1999; Bunney et al 1977). Preliminary evidence of
the heritability of these findings includes a functional polymor-
phism of the COMT gene that has been associated with the
individual variation in the brain response to dopaminergic
challenge (Mattay et al 2003).
In animals, the reward pathway circuitry has been intricately
studied. Dopaminergic pathways originating in the ventral teg-
mental area and substantia nigra terminate in the nucleus accum-
bens and dorsal striatum. Glutamate, in addition to dopamine, is
critical for plasticity-related events that lead to the identification
of salience to rewarding stimuli. On the molecular level, in-
creased function of the neurotrophic factor CREB in the nucleus
accumbens, in response to stress or to overstimulation by
rewarding stimuli, has been found to dampen the interest for
natural rewards, such as sucrose drinking (Nestler 2004). In
contrast, accumulations of ?-FosB, another reward-related tran-
scription factor, has been shown to increase incentive motiva-
tion. ?-FosB persists in neurons for relatively long periods of time
and might initiate and sustain changes in gene expression
(Nestler et al 2001). Transgenic mouse studies have identified a
large array of genes that regulate activity and function of brain
reward pathways, although it should be mentioned that many of
the studies were in the context of the effects of drugs of abuse
(Ogden et al 2004).
More research in animal models of impaired brain reward
pathways will be necessary to specifically address the hypothesis
that dysregulation of these transcription factors might play a role
in the intracellular pathophysiology of BPD. Future clinical
studies will determine the relevance of specific reward pathways
and brain areas to bipolar and unipolar depression.
Brain Structure Endophenotypes
The identification of pathologic lesions in specific regions of
the central nervous system has contributed importantly to rapid
progress in the understanding and treatment of neurodegenera-
tive disorders, including Parkinson’s and Alzheimer’s diseases.
Neuropathological findings are extremely useful for defining
nosological subtypes of these conditions. For example, clinical
features alone can be used to diagnose parkinsonism; postmor-
G. Hasler et al
BIOL PSYCHIATRY 2006;60:93–105 97
tem examination is needed for the definite diagnosis of the
underlying disease, including classic Parkinson’s disease, multi-
ple system atrophy, progressive supranuclear palsy, and fronto-
temporal dementia (Giasson and Lee 2003).
Increasing evidence suggests that BPD is accompanied by
brain structural changes that might be mediated by interactions
between hypercortisolemia, glutamate neurotoxicity, stress-in-
duced reduction in neurotrophic factors, and stress-induced
reduction in neurogenesis (Manji and Duman 2001). The rela-
tionship between these factors and changes in brain function on
the cellular and molecular levels has been extensively studied
and lays the foundation for most current hypotheses. Advanced
imaging technology is beginning to describe subtle changes in
brain structures that are associated with specific pathophysiolog-
ical processes and genes (Hariri and Weinberger 2003). For
example, a variation in the BDNF gene that has been found as a
vulnerability factor of BPD (Craddock et al 2005) seems to affect
the anatomy of the hippocampus and prefrontal cortex (Pezawas
et al 2004). In vivo imaging allows the potential to connect
findings in genetic neuroscience obtained from animal experi-
ments and postmortem human studies to clinical characteristics
of subjects suffering from BPD.
Anterior Cingulate Volume Reduction
Volume reductions in the anterior cingulate cortex (ACC)
located ventral (“subgenual”) and anterior (“pregenual”) to the
genu of the corpus callosum have been implicated by numerous
studies of mood disorders (Drevets 2001). Specifically, a volume
reduction in the left subgenual ACC has been associated with
familial unipolar and bipolar disorders by magnetic resonance
imaging (MRI) morphometric measures (Drevets et al 1997;
Hirayasu et al 1999) and by postmortem neuropathological
studies, which have shown glial reduction in the corresponding
gray matter (Öngür et al 1998). This reduction in volume exists
early in the illness in major depressive disorder (MDD) and BPD
(state independence) (Botteron et al 2002; Hirayasu et al 1999)
but seems to become more pronounced after illness onset,
according to preliminary evidence in twins discordant for MDD
(Botteron et al 1999). A volumetric MRI study found reduced
subgenual PFC volume in subjects at high familial risk for mood
disorders (Drevets et al 2004). Consistently, another volumetric
MRI study in healthy subjects at risk for BPD or schizophrenia
showed that alterations in the anterior ACC were specifically
associated with genetic risk of BPD (McDonald et al 2004a).
The ACC contains abundant concentrations of glucocorticoid
receptors that have been shown to play a major role in attenu-
ating the glucocorticoid response to stress (Diorio et al 1993); in
rats, left-sided lesions of the ACC increase sympathetic arousal
and corticosterone responses to restraint stress (Sullivan and
Gratton 1999). In addition, the ventral ACC and prelimbic cortex
receive and send extensive neuronal projections from/to the
ventral tegmentum, which have been shown to modulate the
burst-firing dopamine neurons during reward learning (Drevets
et al 1998). Humans with lesions that include the ventral ACC
show abnormal autonomic responses to emotional stimuli,
an inability to experience emotion related to concepts, and
inability to use information regarding the probability of aversive
social consequences versus reward in guiding social behavior
(Damasio et al 1990). In four of six severely depressed patients,
chronic deep stimulation of white matter tracts adjacent to the
subgenual cingulate gyrus was associated with a sustained
remission of depression (Mayberg et al 2005). Together, dysfunc-
tions of this region conceivably could relate to the reductions in
incentive, motivation, and hedonic capacity in depression, as
well as the hypermotivational state and elevated hedonic capac-
ity in mania. The mechanisms and genes underlying volume loss
in the ACC have not yet been determined. Preclinical studies on
the role and genetics of neurotrophic factors and the signaling
cascade neurotrophic factor/mitogen-activated protein kinase/
bcl-2 involved in the fine balance maintained between the levels
a n d activities of cell-survival and cell-death factors (Manji et al 2003)
might inform clinical studies associating ACC volume loss to genes.
In humans, there is preliminary evidence that serotonin transporter
gene s-allele carriers have significantly reduced bilateral gray matter
volumes in the subgenual anterior cingulate (Pezawas et al 2005).
Early-Onset White Matter Abnormalities
White matter abnormalities (WMA) are abnormalities in the
brain that are seen as bright foci on T2-weighted MRI scans.
Dupont et al (1987) first reported that 8 of 14 bipolar patients had
WMA findings on MRI. Two meta-analyses revealed that the risk
of white matter abnormalities is more than threefold higher in
patients with BPD than in healthy control populations (Altshuler
et al 1995; Videbech 1997). A study in 43 bipolar patients and 39
healthy control subjects, using contiguous 3-mm-thick MR slices,
confirmed increased occurrence of WMA in BPD: deep grade-2
WMA were found in 14% of bipolar patients and in none of the
healthy control subjects (Ahn et al 2004). Alhthough WMA are
not present in all subjects with BPD, WMA are thought to be
relatively specific for BPD as compared with other primary
affective disorders arising in early to mid-life (Dupont et al 1995),
although WMA have also been found in schizophrenia (Mc-
Donald et al 2005). In addition, WMA (in contrast to gray matter
or periventricular abnormalities) were found to be predictive of
lithium response in BPD patients (Kato et al 2000), suggesting a
role of WMA in the pathophysiology of BPD; however, the
etiology of the WMA identified in BPD is unknown. White matter
abnormalities are associated with a number of events, such as
aging, cerebrovascular disorders, and migraine headaches (Alt-
shuler et al 1995). Furthermore, it is unclear whether the cause of
WMA is directly related to the pathophysiology of BPD or whether
they are simply a coincident finding. The presence of WMA in
young bipolar patients, however, is particularly noteworthy (Lyoo
et al 2002; Pillai et al 2002; Stoll et al 2000). Although the
histopathological correlates and the functional significance of
WMA have not yet been determined, these findings are poten-
tially consistent with increasing evidence suggesting that cell loss
and atrophy occur in the brains of patients with BPD (Drevets
2000; Vawter et al 2000) and the possibility that BPD might be
associated with impairments of neuroplasticity and cellular resil-
ience (Manji et al 2000).
It remains to be shown convincingly that WMA are signifi-
cantly more genetic than environmental in origin. In fact, sup-
porting an environmental cause, Moore et al (2001) reported that
WMA were correlated with season of birth in a group of bipolar
patients. To our knowledge, a single study has examined the
incidence of abnormal MRI findings in a single family with a
strong history of BPD. In a group of 21 family members (8 with
BPD), these investigators noted a “high prevalence of MRI
findings.” Of the 21 family members, 15 had abnormal findings,
including 6 of 10 non-bipolar members. These abnormalities,
however, were primarily lesions in the gray matter. One of the 10
non-bipolar members had a white matter lesion (Ahearn et al
1998). In addition to more extensive pedigree studies, experi-
ments examining postmortem brains from bipolar patients im-
aged before death will be required to fully understand the
98 BIOL PSYCHIATRY 2006;60:93–105
G. Hasler et al
etiology of WMA in BPD. Continued studies that include relatives
of patients with BPD will provide further data to make conclu-
sions about the viability of WMA as an endophenotype.
Although anterior cingulate volume reduction and WMA are
among the more consistent and specific neuroimaging findings
in BPD, others, such as increased right lateral ventricular volume
and changes in amygdala and hippocampal volume, might
equally qualify as putative brain structure endophenotypes for
BPD (McDonald et al 2004b).
Symptom Provocation Endophenotypes
In the symptom provocation (challenge) paradigm, a psycho-
pharmacological or behavioral stimulus is presented to humans
or animals under controlled conditions to elicit target psychiatric
or neurobiological responses. The target symptoms or responses
are selected to provide insight into basic biological mechanisms
or into signs and symptoms that have pathophysiological rele-
vance (e.g., the use the glucose tolerance test in the unaffected
relatives of diabetics). Variations in behavioral or neurobiological
responses might serve as quantitative endophenotypes in genetic
studies. Endophenotypes based on symptom provocation meth-
ods are usually more disorder specific than brain function and
brain structure endophenotypes, particularly when typical symp-
toms of the disorder are elicited in remitted patients. Ethical
restraints must be observed at all times and should serve as an
incentive to develop in vitro challenges to relevant tissue. In the
“bottom-up” approach, symptom provocation methods help to
test the roles played by genetically controlled neurobiological
mechanisms, mainly derived from animal research, in the patho-
physiology of a psychiatric disorder, whereas the “top-down”
approach helps to generate clinically based hypotheses on the
neurobiological and genetic underpinnings of psychiatric dis-
eases that can be tested in the laboratory. In both instances, the
use of symptom provocation endophenotypes provides a con-
ceptual bridge between basic science and clinical symptomatol-
ogy (D’Souza et al 1999).
Sensitivity to Psychostimulants
Psychostimulants, including amphetamines and cocaine, in-
duce manic symptoms in some non-bipolar individuals and
might induce full mania in individuals with BPD (Mamelak 1978).
In addition, enhanced rewarding effects of psychostimulants in
patients with affective illness have been reported (Tremblay et al
2002). Anatomically, the euphoric response to stimulants seemed
to be related to dopamine release in the human ventral striatum
(Drevets et al 2001). There is preliminary evidence for specific
genetic variance explaining some of the individual variance in
brain response to psychostimulants (Mattay et al 2003). Together,
these findings suggest that behavioral changes (i.e., manic-like
behavior) observed after exposure to amphetamines might be
useful as markers for BPD.
Studies in rodents suggest a genetic foundation to behavioral
response after stimulant administration. For example, the hyper-
active response to psychostimulants measured in open-field
models of hyperactivity might considerably differ between in-
bred rat and mouse strains (George et al 1991; Moisset and Welch
1973; Stohr et al 1998). Moisset and Welch used BALB/cJ and
C57BL/10J mice to show such a difference. In an initial control
experiment including 5 days of habituation, there was no differ-
ence in the locomotion activity in BALB/cJ and C57BL/10J mice.
After amphetamine administration, they found significantly
greater activity levels in C57BL/10J mice than in BALB/cJ mice.
Furthermore, a common model observes the response of labo-
ratory animals to amphetamine. Lithium attenuates amphet-
amine-induced hyperactivity in rodents and represents one of the
most popular and reproducible models of antimanic drug effi-
cacy (Einat et al 2003). Stimulant-induced hyperactivity is atten-
uated by antipsychotic drugs and anticonvulsants often used for
the treatment of BPD (Lamberty et al 2001). It also has face
validity in the sense that amphetamine commonly precipitates
manic episodes in susceptible bipolar individuals, presenting an
effect that seems to be attenuated by lithium (Huey et al 1981;
Van Kammen and Murphy 1975).
There is some evidence that these results from animals
generalize to humans. Johanson, Uhlenhuth, and others pro-
vided evidence for differential behavioral and discriminatory
sensitivities to amphetamine administration in a series of studies
conducted in the 1980s. They showed that among healthy
volunteers, there was a broad range of differences in the ability
to discriminate between amphetamine and placebo effects. Sub-
jects who were good at identifying amphetamine effects had
higher scores on personality measures of anxiety, depression,
and confusion. Another study by the same group investigated
differences between choosers of amphetamine and non-choos-
ers in a choice procedure (de Wit et al 1986). The response to
amphetamine was considerably different between the two
groups. Choosers experienced increased positive mood and
euphoria, whereas non-choosers experienced increased anxiety
and depression after amphetamine administration. Kavoussi and
Coccaro (1993) studied behavioral responses to amphetamine
and placebo in 11 healthy volunteers by clinical interview and
self-report. They found a positive association between the mag-
nitude of the mood response to amphetamine and scores on the
Affective Liability Scale.
There is preliminary evidence for the heritability of the
behavioral response to amphetamine from twin studies. In a
sample of 13 pairs of normal monozygotic twins, amphetamine-
induced behavioral responses were highly correlated within twin
pairs (Nurnberger et al 1982). In a sample six pairs of monozy-
gotic twins, these results were replicated. The detailed analysis of
this second twin study suggested that concordance rates were
higher on behavioral than on pharmacokinetic measures, higher
on objective behavioral measures than on self-report behavioral
measures, and that different sets of genes are likely to be
involved in the heterogeneous behavioral response to amphet-
amine (Crabbe et al 1983).
There is only limited and mixed evidence for the association
between behavioral response to amphetamine and vulnerability
to BPD. Anand et al (2000) found in 13 euthymic bipolar patients
a greater increase in scores on the Brief Psychotic Rating Scale
and the Young Mania Rating Scale after amphetamine adminis-
tration than in 13 age- and gender-matched healthy comparison
subjects, whereas there was no evidence for increased striatal
dopamine release in patients relative to control subjects. An early
study, however, did not find a difference in the behavioral
response to amphetamine administration between control sub-
jects and patients with BPD (Nurnberger et al 1982). Neverthe-
less, genes that affect variability of the responses to amphet-
amines also might reflect vulnerability to BPD. For example, a
polymorphism in the promotor of the G-protein receptor kinase
3 gene, which is involved in the brain’s homeostatic response to
dopamine/amphetamine, has been associated with risk of BPD
(Barrett et al 2003). Because psychostimulant use can also
precipitate psychosis (especially in patients with a history of
schizophrenia), it will remain critical that the specificity of any
findings be tested.
G. Hasler et al
BIOL PSYCHIATRY 2006;60:93–105 99
Sensitivity to psychostimulants is worthy of future study
because many of the human behavioral responses to amphet-
amine, including hyperactivity, increased novelty seeking, and
changes in sleep–wake behaviors, can be modeled in animals
(Stewart and Badiani 1993). Therefore, a better understanding of
the human responses to amphetamine and their possible associ-
ations with vulnerability to BPD has the potential to improve
animal models for BPD. Conversely, insights into the genetic
factors responsible for differences in behavioral responses to
amphetamine in animals might help to elucidate the genetic
underpinnings of BPD in humans. Given the mixed evidence for
associations between the behavioral response to amphetamine
and risk of BPD, as well as ethical concerns regarding the use of
amphetamines in subjects at risk of BPD, it seems to be war-
ranted to evaluate the use of other promanic medications (Peet
and Peters 1995) as putative symptom provocation endopheno-
types in BPD.
Dysfunctions of the cholinergic–adrenergic balance might be
associated with etiologic factors of BPD. Evidence for anomalies
of the cholinergic system in affective disorders has derived from
studies conducted in symptomatic patients. Decreased cholin-
ergic activity has been found in mania and cholinergic hypersen-
sitivity in depression. Janowsky et al (1972, 1974, 1981) reported
that a cholinergic challenge (using the anticholinesterase inhib-
itor physostigmine) induced depressive symptoms in manic
subjects, and cholinergic activity induced a worsening of symp-
toms in unipolar depressed subjects; these results have been
replicated by others (Davis et al 1978; Nurnberger et al 1983b;
Risch et al 1981). The anergic–anhedonic syndrome following a
cholinergic agonist was found to be dose dependent (Fritze and
Beckmann 1988), suggesting that the percent change (and
perhaps the speed of change) in intrasynaptic acetylcholine
concentration is critical. In contrast, anticholinergic drugs, such
as scopolamine, that target the muscarinic cholinergic receptors
are associated with mood elevation and mania, and some
tricyclic antidepressant drugs have relevant antimuscarinic ef-
fects (Raisman et al 1979; Stanton et al 1993). The neuroendo-
crine and pupillary responses to cholinergic activity are in-
creased in depressed subjects (Dilsaver 1986), whereas manic
subjects are hyporesponsive to cholinergic agents with respect to
pupillary responses (Sokolski and DeMet 2000), and improve-
ment in mania with lithium and valproate is associated with
normalization of pupillary responses (Sokolski and DeMet 1999),
confirming the hypotheses that depression is associated with
cholinergic overreactivity, whereas mania is associated with a
hypocholinergic state. A recent positron emission tomography
study using [F-18]3-(3-((3-fluoropropyl)thio)-1,2,5-thiadiazol-4-
yl)-1,2,5,6-tetrahydro-1methlpyridine (FPTZTP) showed a rela-
tively specific reduction in muscarinic cholinergic-2 receptor
binding in the depressed state of BPD (Cannon et al 2004),
possibly reflecting excessive extracellular acetylcholine concen-
trations. Although there has been mixed evidence for the cho-
linergic hypothesis (Katerina et al 2004), the challenge paradigms
used to test it might be useful in identifying endophenotypes in
BPD. Given the role of the cholinergic system in the sleep–wake
cycle (Szymusiak 1995), in learning, memory, and attention
(Murray and Fibiger 1985; Wesnes and Warburton 1984), and in
motivation and reward (Picciotto 1998), dysfunctions of the
cholinergic system are likely related to circadian abnormalities,
cognitive deficits, and impaired reward function in patients with
Rapid eye movements occur during discreet periods of sleep,
and their onset can be induced by cholinergic agents (Gillin et al
1978; Sitaram et al 1978a, 1978b, 1978c, 1979). Bipolar patients
seemed to differ from control subjects regarding the induction of
REM sleep by cholinergic agents (Berger et al 1989; Nurnberger
et al 1989; Sitaram et al 1980, 1982). There is evidence for mood
state independence of this anomaly. Sitaram et al (1980) de-
scribed faster induction of REM sleep with the cholinergic agonist
arecoline in drug-free euthymic patients with BPD than in
healthy control subjects matched for age and gender. The same
research team also showed that the second REM period occurred
significantly earlier in 14 euthymic bipolar patients than in
control subjects (Sitaram et al 1982). Other researchers, however,
found that increased susceptibility to cholinergic induction of
REM sleep was state dependent (Berger et al 1989).
There is some evidence for the heritability of this trait.
Nurnberger et al (1983a) examined the induction of REM sleep
by cholinergic agents in seven monozygotic pairs. They reported
an intraclass correlation of 0.69 for REM latency time after
cholinergic stimulation, suggesting that this trait is heritable. In
first-degree relatives of patients with both major depression and
supersensitivity to cholinergic activity, Sitaram et al (1987)
showed that 66% of the depressed relatives and 22% of the
unaffected relatives also showed supersensitive REM induction,
suggesting that this marker co-segregates in families with affec-
tive illness. Because this informative study did not include
control subjects and did not rule out the effects of prior depres-
sive episodes or treatment on cholinergic sensitivity, the results
have to be interpreted with caution. Taken together, supersen-
sitive REM sleep induction by cholinergic agents has been
consistently associated with BPD; however, there is only prelim-
inary evidence regarding the mood state independence, herita-
bility, and familiality of this biological marker.
Response to Sleep Deprivation
Some symptoms of affective disorders might show diurnal
variations (mood, psychomotor activity, accessibility of memo-
ries of positive and negative experiences), and a subgroup of
patients with BPD might have a circadian rhythm disorder
(Bunney and Bunney 2000). In healthy young subjects, moderate
changes in the timing of the sleep–wake cycle had specific
effects on subsequent mood (Boivin et al 1997). The association
between phase advance of the sleep–wake cycle and phase
advances in nocturnal cortisol secretion, as well as the effect of
antidepressant and antimanic drugs on circadian rhythms of
behavior, physiology, and endocrinology suggest sleep–wake cycle
abnormalities as a source of putative endophenotypes for BPD
(Bunney and Bunney 2000; Duncan 1996). Because manipulations
of the circadian rhythms (light therapy, phase advance treatment,
sleep deprivation—though it has to be acknowledged that sleep
deprivation is more than a simple circadian manipulation) can have
antidepressant efficacy, circadian abnormalities have been hypoth-
esized to be etiologically associated with affective disorders.
Studies of sleep deprivation used as a therapy for the treatment
of BPD suggested that decreased sleep duration might play a role in
the origin of mania (Colombo et al 1999; Kasper and Wehr 1992;
Szuba et al 1991; Wehr et al 1987; Wirz-Justice and Van den
Hoofdakker 1999). T h e assessment of patients enrolled in sleep
deprivation studies is usually conducted in a controlled environ-
ment, which makes this setting scientifically attractive. There is
consistent evidence that sleep deprivation is highly effective in
the treatment of both unipolar and bipolar depression (Wirz-
Justice and Van den Hoofdakker 1999). The benefits are gener-
100 BIOL PSYCHIATRY 2006;60:93–105
G. Hasler et al
ally short lived, and chronic sleep deprivation might have
negative health consequences (Hasler et al 2004a), thus reducing
its use as a long-term treatment for depression (Wu and Bunney
1990). The risk of switching into mania during sleep deprivation
therapy in patients with BPD has not been sufficiently evaluated,
because most studies did not assess changes in manic symptoms,
and the study samples included both unipolar and bipolar
depressed patients. Colombo et al (1999) reported that 4.85%
switched into mania and 5.83% switched into hypomania in a
sample of 206 bipolar patients who underwent sleep deprivation
as antidepressive treatment. Others found much higher rates of
subjects with BPD vulnerable to mania/hypomania after dis-
rupted sleep (Kasper and Wehr 1992). The potential state
independence of hypomanic symptoms after sleep deprivation
and the clinical and biological plausibility of this marker suggest
that sleep deprivation might qualify as an endophenotype of
BPD; however, heritability and association with genetic risk of
BPD of this symptom provocation method have yet to be
determined. Because sleep deprivation is related to a potentially
heritable marker of affective illness, circadian rhythms, one might
hypothesize that the genetic underpinnings could possibly be
related to circadian cycles.
Because mania is associated with a reduced need of sleep and
reduced sleep duration, sleep deprivation might be both an
inducing and a self-reinforcing mechanism in the development
and maintenance of a manic episode (Wehr et al 1987). Sleep
deprivation might also be an important mechanism by which
other promanic behaviors, including stimulant use, increase the
risk of mania. Growing insight into the neurobiology of sleep
deprivation (Spiegel et al 1999) and studies on the differential
effects of sleep deprivation in susceptible individuals might
provide relevant cues about the pathophysiology and etiological
heterogeneity of BPD. Although sleep symptoms in affective
illness might not be familial, there is some evidence for familiality
of sleep physiological abnormalities related to affective illness
(Hasler et al 2004b). For example, a study in unaffected individ-
uals at high genetic risk for depression or BPD found abnormal-
ities in the electroencephalographic coherence that were related
to the risk of the disorders (Fulton et al 2000): beta– delta
coherence was lower bilaterally in male high-risk subjects,
whereas right-hemispheric theta–delta coherence was also lower
in the same subjects. These findings are similar to those reported
in subjects suffering from current affective illness. Further studies
are warranted to examine relationships between electroencepha-
lographic abnormalities and response to sleep deprivation. Elec-
troencephalographic studies in euthymic patients with BPD and
in unaffected relatives of patients with BPD will be necessary to
determine whether endophenotypes for BPD can be derived
from sleep physiological abnormalities.
Very recent molecular and cellular biological studies have
reinvigorated the interest in sleep deprivation as a possible
model. Thus, there is now incontrovertible evidence that the
expression of selected critical genes varies dramatically during
sleep and waking events, which likely plays a major role in
regulating various, long-term neuroplastic events. Microarray,
messenger ribonucleic acid differential display, and biochemical
studies have shown that short-term sleep deprivation is associ-
ated with a rapid increase in various plasticity-related genes.
Notably, these are precisely the plasticity-related molecules
whose expression is increased by chronic antidepressant treat-
ment. In an extension of the gene expression studies, Cirelli and
Tononi (2000a, 2000b) hypothesized that a key factor responsi-
ble for the induction of the plasticity genes might be the level of
activity of the neuromodulatory noradrenergic and serotonergic
systems. Both of these systems project diffusely to most of the
brain, where they regulate gene expression and are only quies-
cent during REM sleep (Cirelli and Tononi 2000a). There is thus
a striking similarity between the effects of chronic antidepres-
sants and short-term sleep deprivation on the BDNF signaling
cascade. Do these alterations play a role in their ability to induce
switches in susceptible individuals? As discussed already, some
studies have suggested excess transmission of the valine allele of
amino acid 66 of BDNF in BPD. Interestingly, this is the form of
BDNF that has been associated with enhanced stimulated release
in vitro (Egan et al 2003) and with younger age of onset in BPD
(Rybakowski et al 2003). Thus, although quite preliminary, the
data raise the intriguing possibility that bipolar individuals with
the val/val BDNF genotype might be at greater risk for antide-
pressant- or sleep-deprivation–induced switches into mania;
studies are currently underway to address this possibility. Further
experiments have also linked the lithium target gene GSK-3 to
response to sleep deprivation (Benedetti et al 2004b).
In this article, we have discussed the advantages of applying
an endophenotype strategy to the study of BPD. The endophe-
notype approach, applied to studies of BPD, presents a heuristic
research strategy that will be necessary for major advances to
take place. Numerous domains of study deserve further investiga-
tion, including neuropsychological deficits, circadian rhythm insta-
bility, dysmodulation of motivation and reward, neuropathological
abnormalities, and symptom provocation responses. Given the
relative scarcity of well-designed twin, family, and prospective
studies evaluating candidate endophenotypes for BPD, future
research has the potential to improve the phenotypic definition
of BPD. Progress in developing economical and easy-to-apply
neurobiological markers and the feasibility of genome-wide
association studies might considerably facilitate the discovery of
biological endophenotypes. In the long run, the discovery and
systematic evaluation of BPD endophenotypes, along with iden-
tification of specific environmental risk factors, will provide the
basis of a new classification system (Hasler et al 2004b). Such a
classification system, based on etiology and pathophysiology, is
badly needed because the improvement of the phenotypic
definition of BPD will likely facilitate the identification of vulner-
ability genes and possibly the development of better preventive
strategies and treatments for this disabling and often life-threat-
Addington J, Addington D (1997): Attentional vulnerability indicators in
schizophrenia and bipolar disorder. Schizophr Res 23:197–204.
Ahn KH, Lyoo IK, Lee HK, Song IC, Oh JS, Hwang J, et al (2004): White matter
hyperintensities in subjects with bipolar disorder. Psychiatry Clin Neuro-
Altshuler LL, Curran JG, Hauser P, Mintz J, Denicoff K, Post R (1995): T2
hyperintensities in bipolar disorder: Magnetic resonance imaging com-
parison and literature meta-analysis. Am J Psychiatry 152:1139–1144.
Neurocognitive function in clinically stable men with bipolar I disorder or
Effect of catecholamine depletion on lithium-induced long-term remis-
sion of bipolar disorder. Biol Psychiatry 45:972–978.
G. Hasler et al
BIOL PSYCHIATRY 2006;60:93–105 101
Brain SPECT imaging of amphetamine-induced dopamine release in
euthymic bipolar disorder patients. Am J Psychiatry 157:1108–1114.
Angst J (1998): The emerging epidemiology of hypomania and bipolar II
Angst J, Frey R, Lohmeyer B, Zerbin-Rudin E (1980): Bipolar manic-depres-
sive psychoses: Results of a genetic investigation. Hum Genet 55:237–
Angst J, Gamma A (2002): A new bipolar spectrum concept: A brief review.
Bipolar Disord 4(suppl 1):11–14.
Angst J, Perris C (1968): Zur Nosologie endogener Psychosen. Vergleich der
Ergebnisse zweier Untersuchungen. Arch Psychiatr Nervenkr 210:373–
Angst J, Preisig M (1995): Outcome of a clinical cohort of unipolar, bipolar
depression in the Zurich Cohort Study of Young Adults. In: Maser JD,
ington, DC: American Psychiatric Press, 123–137.
of bipolar disorder and schizophrenia. Mol Psychiatry 7:405–411.
components of spatial learning revealed by prior training and NMDA
receptor blockade. Nature 378:182–186.
Barrett TB, Hauger RL, Kennedy JL, Sadovnick AD, Remick RA, Keck PE, et al
of the G protein receptor kinase 3 gene is associated with bipolar disor-
der. Mol Psychiatry 8:546–557.
3-beta promoter gene influences onset of illness in patients affected by
bipolar disorder. Neurosci Lett 355:37–40.
Benedetti F, Serretti A, Colombo C, Barbini B, Lorenzi C, Campori E, et al
tuation and illness recurrence in bipolar depression. Am J Med Genet B
A glycogen synthase kinase 3-beta promoter gene single nucleotide
polymorphism is associated with age at onset and response to total
sleep deprivation in bipolar depression. Neurosci Lett 368:123–126.
Berger M, Riemann D, Hochli D, Spiegel R (1989): The cholinergic rapid eye
movement sleep induction test with RS-86. State or trait marker of
chopathology: Thirty years of collaboration with Irving I. Gottesman. In
DiLalla LF, editor. Behavior Genetics Principles. Perspectives in Develop-
chological Association, 123–133.
Blumberg HP, Leung HC, Skudlarski P, Lacadie CM, Fredericks CA, Harris BC,
et al (2003): A functional magnetic resonance imaging study of bipolar
disorder: State- and trait-related dysfunction in ventral prefrontal corti-
Boivin DB, Czeisler CA, Dijk DJ, Duffy JF, Folkard S, Minors DS, et al (1997):
Complex interaction of the sleep-wake cycle and circadian phase mod-
ulates mood in healthy subjects. Arch Gen Psychiatry 54:145–152.
reduction in left subgenual prefrontal cortex in early onset depression.
Botteron KN, Raichle ME, Heath AC, Price A, Sternhell KE, Singer TM, et al
in early onset depression. Biol Psychiatry 45:59S.
Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ (1994):
Deficient long-term memory in mice with a targeted mutation of the
cAMP-responsive element-binding protein. Cell 79:59–68.
Bunney WE, Bunney BG (2000): Molecular clock genes in man and lower
possibly reflecting central receptor hypersensitivity following catechol-
Cannon D, Nugent AC, Carson RE, Williams JM, Wood S, Solorio G, et al
(2004): Reduced muscarinic cholinergic2 receptor binding in bipolar
disorder using PET and [F-18]FPTZTP. Biol Psychiatry 55:229S.
Carlson CS, Eberle MA, Kruglyak L, Nickerson DA (2004): Mapping complex
disease loci in whole-genome association studies. Nature 429:446–
Charney DS, Barlow DH, Botteron KN, Cohen JD, Goldman D, Gur RC, et al
DA, editors. A Research Agenda for DSM-V. Washington, DC: American
Psychiatric Association, 31–83.
in waking and sleep and their regulation by the noradrenergic system.
Cirelli C, Tononi G (2000b): Gene expression in the brain across the sleep-
waking cycle. Brain Res 885:303–321.
Clark L, Goodwin GM (2004): State- and trait-related deficits in sustained
Clark L, Kempton MJ, Scarna A, Grasby PM, Goodwin GM (2005a): Sustained
degree relatives of bipolar patients or euthymic unipolar depression.
is impaired in first-degree relatives of bipolar I patients and in euthymic
Colombo C, Benedetti F, Barbini B, Campori E, Smeraldi E (1999): Rate of
bipolar depression. Psychiatry Res 86:267–270.
Crabbe JC, Jarvik LF, Liston EH, Jenden DJ (1983): Behavioral responses to
amphetamines in identical twins. Acta Genet Med Gemellol (Roma) 32:
and bipolar disorder: Dissecting psychosis. J Med Genet 42:193–204.
Damasio AR, Tranel D, Damasio H (1990): Individuals with sociopathic be-
Dauvilliers Y, Maret S, Tafti M (2005): Genetics of normal and pathological
sleep in humans. Sleep Med Rev 9:91–100.
de Wit H, Uhlenhuth EH, Johanson CE (1986): Individual differences in the
reinforcing and subjective effects of amphetamine and diazepam. Drug
DePaulo JR Jr (2004): Genetics of bipolar disorder: Where do we stand? Am
Dilsaver SC (1986): Pathophysiology of “cholinoceptor supersensitivity” in
affective disorders. Biol Psychiatry 21:813–829.
Diorio D, Viau V, Meaney MJ (1993): The role of the medial prefrontal cortex
(cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal
responses to stress. J Neurosci 13:3839–3847.
Doyle AE, Willcutt EG, Seidman LJ, Biederman J, Chouinard VA, Silva J, et al
(2005): Attention-deficit/hyperactivity disorder endophenotypes. Biol
sion: Implications for the cognitive-emotional features of mood disor-
Amphetamine-induced dopamine release in human ventral striatum
correlates with euphoria. Biol Psychiatry 49:81–96.
Drevets WC, Ongur D, Price JL (1998): Neuroimaging abnormalities in the
subgenual prefrontal cortex: Implications for the pathophysiology of
familial mood disorders. Mol Psychiatry 3220–226, 190–191.
Subgenual prefrontal cortex abnormalities in mood disorders. Nature
Drevets WC, Ryan ND, Bogers W, Birmaher B, Axelson D, Dahl RE (2004):
Subgenual prefrontal cortex volume decreased in healthy humans at
high familial risk for mood disorders. Soc Neuroscience Abstr 79919.
102 BIOL PSYCHIATRY 2006;60:93–105
G. Hasler et al
D’Souza DC, Berman RM, Krystal JH, Charney DS (1999): Symptom provoca-
tion studies in psychiatric disorders: Scientific value, risks, and future.
illness. Pharmacol Ther 71:253–312.
Dupont RM, Butters N, Schafer K, Wilson T, Hesselink J, Gillin JC (1995):
unipolar mood disorder. Biol Psychiatry 38:482–486.
Dupont RM, Jernigan TL, Gillin JC, Butters N, Delis DC, Hesselink JR (1987):
Subcortical signal hyperintensities in bipolar patients detected by MRI.
Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE,
et al (2001): Effect of COMT Val108/158 Met genotype on frontal lobe
function and risk for schizophrenia. Proc Natl Acad Sci U S A 98:6917–
(2003): The BDNF val66met polymorphism affects activity-dependent
secretion of BDNF and human memory and hippocampal function. Cell
disorder. Psychopharmacol Bull 37:47–63.
Fan J, McCandliss BD, Sommer T, Raz A, Posner MI (2002): Testing the effi-
ciency and independence of attentional networks. J Cogn Neurosci 14:
Fan J, Wu Y, Fossella JA, Posner MI (2001): Assessing the heritability of
attentional networks. BMC Neurosci 2:14.
Farmer AE, McGuffin P, Gottesman II (1987): Twin concordance for DSM-III
cognitive function in unaffected first-degree relatives of patients with
bipolar disorder: A preliminary report. Bipolar Disord 6:319–322.
First MB, Pincus HA, Levine JB, Williams JB, Ustun B, Peele R (2004): Clinical
utility as a criterion for revising psychiatric diagnoses. Am J Psychiatry
of ventral, but not dorsal, prefrontal executive function as an endophe-
notypic marker for bipolar disorder. Biol Psychiatry 58:838–839.
Freimer N, Sabatti C (2003): The human phenome project. Nat Genet 34:
Freimer N, Sabatti C (2004): The use of pedigree, sib-pair and association
studies of common diseases for genetic mapping and epidemiology.
chological study. Neuropsychobiology 19:35–39.
Fu Q, Heath AC, Bucholz KK, Nelson E, Goldberg J, Lyons MJ, et al (2002):
Shared genetic risk of major depression, alcohol dependence, and mar-
ijuana dependence: Contribution of antisocial personality disorder in
Fulton MK, Armitage R, Rush AJ (2000): Sleep electroencephalographic co-
herence abnormalities in individuals at high risk for depression: A pilot
study. Biol Psychiatry 47:618–625.
isons indicate different sites of action for cocaine and amphetamine
locomotor stimulant effects. Psychopharmacology (Berl) 104:457–462.
Giasson BI, Lee VM (2003): Are ubiquitination pathways central to Parkin-
son’s disease? Cell 114:1–8.
Gillin JC, Sitaram N, Mendelson WB, Wyatt RJ (1978): Physostigmine alters
onset but not duration of REM sleep in man. Psychopharmacology (Berl)
Glahn DC, Bearden CE, Niendam TA, Escamilla MA (2004): The feasibility of
with bipolar affective disorder. Bipolar Disord 6:171–182.
Goldberg TE, Weinberger DR (2004): Genes and the parsing of cognitive
Gottesman II, Gould TD (2003): The endophenotype concept in psychiatry:
Etymology and strategic intentions. Am J Psychiatry 160:636–645.
Gottesman II, Hanson DR (2004): Human development: Biological and ge-
Gottesman II, Shields J (1973): Genetic theorizing and schizophrenia. Br J
Gould TD, Chen G, Manji HK (2004): In vivo evidence in the brain for lithium
Gould TD, Manji HK (2002): The Wnt signaling pathway in bipolar disorder.
Gourovitch ML, Torrey EF, Gold JM, Randolph C, Weinberger DR, Goldberg
TE (1999): Neuropsychological performance of monozygotic twins dis-
cordant for bipolar disorder. Biol Psychiatry 45:639–646.
et al (2003): Seasonal changes, sleep length and circadian preference
among twins with bipolar disorder. BMC Psychiatry 3:6.
Harmer CJ, Clark L, Grayson L, Goodwin GM (2002): Sustained attention
deficit in bipolar disorder is not a working memory impairment in dis-
guise. Neuropsychologia 40:1586–1590.
Harvey AG, Schmidt DA, Scarna A, Semler CN, Goodwin GM (2005): Sleep-
related functioning in euthymic patients with bipolar disorder, patients
with insomnia, and subjects without sleep problems. Am J Psychiatry
Hasler G, Buysse DJ, Klaghofer R, Gamma A, Ajdacic V, Eich D, et al (2004a):
The association between short sleep duration and obesity in young
adults: A 13-year prospective study. Sleep 27:661–666.
Hasler G, Drevets WC, Manji HK, Charney DS (2004b): Discovering endophe-
(2005): Depressive symptoms during childhood and adult obesity: The
Zurich Cohort Study. Mol Psychiatry 10:842–850.
Hirayasu Y, Shenton ME, Salisbury DF, Kwon JS, Wible CG, Fischer IA, et al
(1999): Subgenual cingulate cortex volume in first-episode psychosis.
Hirschhorn JN, Daly MJ (2005): Genome-wide association studies for com-
mon diseases and complex traits. Nat Rev Genet 6:95–108.
cognitive processes. Psychopharmacology (Berl) 73:161–164.
Jackson A, Cavanagh J, Scott J (2003): A systematic review of manic and
Janowsky DS, el-Yousef MK, Davis JM (1974): Acetylcholine and depression.
Janowsky DS, el-Yousef MK, Davis JM, Sekerke HJ (1972): A cholinergic-
adrenergic hypothesis of mania and depression. Lancet 2:632–635.
taking psychotropic drugs. J Clin Psychopharmacol 1:14–20.
Johnson MH, Magaro PA (1987): Effects of mood and severity on memory
processes in depression and mania. Psychol Bull 101:28–40.
Jones SH, Hare DJ, Evershed K (2005): Actigraphic assessment of circadian
Kajantie E, Rautanen A, Kere J, Andersson S, Yliharsila H, Osmond C, et al
depression and mania. Encephale 18(spec no 1):45–50.
Katerina Z, Andrew K, Filomena M, Xu-Feng H (2004): Investigation of
m1/m4 muscarinic receptors in the anterior cingulate cortex in schizo-
phrenia, bipolar disorder, and major depression disorder. Neuropsycho-
Kato T, Fujii K, Kamiya A, Kato N (2000): White matter hyperintensity de-
tected by magnetic resonance imaging and lithium response in bipolar
Kavoussi RJ, Coccaro EF (1993): The amphetamine challenge test correlates
with affective lability in healthy volunteers. Psychiatry Res 48:219–228.
Kendler KS (2005): Psychiatric genetics: A methodologic critique. Am J Psy-
Kendler KS, Ochs AL, Gorman AM, Hewitt JK, Ross DE, Mirsky AF (1991): The
structure of schizotypy: A pilot multitrait twin study. Psychiatry Res 36:
Keri S, Kelemen O, Benedek G, Janka Z (2001): Different trait markers for
Kieseppa T, Partonen T, Haukka J, Kaprio J, Lonnqvist J (2004): High concor-
G. Hasler et al
BIOL PSYCHIATRY 2006;60:93–105 103
Kim-Cohen J, Caspi A, Moffitt TE, Harrington H, Milne BJ, Poulton R (2003):
Prior juvenile diagnoses in adults with mental disorder: Developmental
follow-back of a prospective-longitudinal cohort. Arch Gen Psychiatry
Klemfuss H (1992): Rhythms and the pharmacology of lithium. Pharmacol
Klemfuss H, Kripke DF (1995): Antimanic drugs stabilize hamster circadian
rhythms. Psychiatry Res 57:215–222.
ing monetary reward selectively recruits nucleus accumbens. J Neurosci
terization with rapid event-related fMRI. Neuroimage 18:263–272.
Lamberty Y, Margineanu DG, Klitgaard H (2001): Effect of the new antiepi-
leptic drug levetiracetam in an animal model of mania. Epilepsy Behav
trials: A Department of Veterans Affairs cooperative study. Control Clin
Lenox RH, Gould TD, Manji HK (2002): Endophenotypes in bipolar disorder.
Levinson DF, Levinson MD, Segurado R, Lewis CM (2003): Genome scan
Lewis M (2004): Putting mind over matter: Rethinking current strategies for
unmasking the genetics of mental illness. Clin Genet 66:177.
Linkowski P (2003): Neuroendocrine profiles in mood disorders. Int J Neuro-
Linkowski P, Van Onderbergen A, Kerkhofs M, Bosson D, Mendlewicz J, Van
Luby JL, Mrakotsky C, Heffelfinger A, Brown K, Spitznagel E (2004): Charac-
teristics of depressed preschoolers with and without anhedonia: Evi-
dence for a melancholic depressive subtype in young children. Am J
Lyoo IK, Lee HK, Jung JH, Noam GG, Renshaw PF (2002): White matter
with psychiatric disorders. Compr Psychiatry 43:361–368.
Mamelak M (1978): An amphetamine model of manic depressive illness. Int
Manji HK, Duman RS (2001): Impairments of neuroplasticity and cellular
novel therapeutics. Psychopharmacol Bull 35:5–49.
Manji HK, Moore GJ, Rajkowska G, Chen G (2000): Neuroplasticity and cellu-
lar resilience in mood disorders. Mol Psychiatry 5:578–593.
Manji HK, Quiroz JA, Sporn J, Payne JL, Denicoff K, A Gray N, et al (2003):
Enhancing neuronal plasticity and cellular resilience to develop novel,
improved therapeutics for difficult-to-treat depression. Biol Psychiatry
Martinek S, Inonog S, Manoukian AS, Young MW (2001): A role for the
segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock.
Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, et al (2003):
ation in the brain response to amphetamine. Proc Natl Acad Sci U S A
(2005): Deep brain stimulation for treatment-resistant depression. Neu-
Maziade M, Roy MA, Chagnon YC, Cliche D, Fournier JP, Montgrain N, et al
(2005): Shared and specific susceptibility loci for schizophrenia and bi-
polar disorder: A dense genome scan in Eastern Quebec families. Mol
McDonald C, Bullmore ET, Sham P, Suckling J, MacCabe J (2005): Regional
volume deviations of brain structure in schizophrenia and psychotic
McDonald C, Bullmore ET, Sham PC, Chitnis X, Wickham H, Bramon E, et al
McDonald C, Zanelli J, Rabe-Hesketh S, Ellison-Wright I, Sham P, Kalidindi S,
et al (2004b): Meta-analysis of magnetic resonance imaging brain mor-
phometry studies in bipolar disorder. Biol Psychiatry 56:411–417.
McGue M, Gottesman II, Rao DC (1983): The transmission of schizophrenia
under a multifactorial threshold model. Am J Hum Genet 35:1161–1178.
McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A (2003): The
heritability of bipolar affective disorder and the genetic relationship to
(2005): Combined analysis from eleven linkage studies of bipolar disor-
der provides strong evidence of susceptibility loci on chromosomes 6q
Miyashita Y (2004): Cognitive memory: Cellular and network machineries
and their top-down control. Science 306:435–440.
Moisset B, Welch BL (1973): Effects of d-amphetamine upon open field
behaviour in two inbred strains of mice. Experientia 29:625–626.
Moore PB, El-Badri SM, Cousins D, Shepherd DJ, Young AH, McAllister VL, et
al (2001): White matter lesions and season of birth of patients with
bipolar affective disorder. Am J Psychiatry 158:1521–1524.
Murray CL, Fibiger HC (1985): Learning and memory deficits after lesions of
the nucleus basalis magnocellularis: Reversal by physostigmine. Neuro-
Nestler EJ (2004): Molecular mechanisms of drug addiction. Neuropharma-
cology 47(suppl 1):24–32.
Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM (2002):
Neurobiology of depression. Neuron 34:13–25.
Nurnberger J Jr, Berrettini W, Mendelson W, Sack D, Gershon ES (1989):
Nurnberger J Jr, Sitaram N, Gershon ES, Gillin JC (1983a): A twin study of
cholinergic REM induction. Biol Psychiatry 18:1161–1165.
(1982): Behavioral, biochemical and neuroendocrine responses to am-
phetamine in normal twins and ‘well-state’ bipolar patients. Psychoneu-
Nurnberger JI Jr, Jimerson DC, Simmons-Alling S, Tamminga C, Nadi NS,
Lawrence D, et al (1983b): Behavioral, physiological, and neuroendo-
crine responses to arecoline in normal twins and “well state” bipolar
patients. Psychiatry Res 9:191–200.
Ogden CA, Rich ME, Schork NJ, Paulus MP, Geyer MA, Lohr JB, et al (2004):
ics approach. Mol Psychiatry 9:1007–1029.
Öngür D, Drevets WC, Price JL (1998): Glial reduction in the subgenual
prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A 95:13290–
3beta as a likely target for the action of lithium on circadian clocks.
Peet M, Peters S (1995): Drug-induced mania. Drug Saf 12:146–153.
depressive psychoses. VI. Studies in perception: a) colour-form prefer-
Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE,
Kolachana BS, et al (2005): 5-HTTLPR polymorphism impacts human
cingulate-amygdala interactions: A genetic susceptibility mechanism
for depression. Nat Neurosci 8:828–834.
Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE,
et al (2004): The brain-derived neurotrophic factor val66met polymor-
phism and variation in human cortical morphology. J Neurosci 24:
Picciotto MR (1998): Common aspects of the action of nicotine and other
drugs of abuse. Drug Alcohol Depend 51:165–172.
Increased presence of white matter hyperintensities in adolescent pa-
tients with bipolar disorder. Psychiatry Res 114:51–56.
Plomin R, Spinath FM (2004): Intelligence: Genetics, genes, and genomics.
104 BIOL PSYCHIATRY 2006;60:93–105
G. Hasler et al
QuintinP,BenkelfatC,LaunayJM,ArnulfI,Pointereau-BellengerA,Barbault Download full-text
S, et al (2001): Clinical and neurochemical effect of acute tryptophan
der. Biol Psychiatry 50:184–190.
ing sites in rat brain. Nature 281:148–150.
Risch SC, Kalin NH, Janowsky DS (1981): Cholinergic challenges in affective
illness: Behavioral and neuroendocrine correlates. J Clin Psychopharma-
Rybakowski JK, Borkowska A, Czerski PM, Skibinska M, Hauser J (2003):
Polymorphism of the brain-derived neurotrophic factor gene and per-
Schultz W (2002): Getting formal with dopamine and reward. Neuron 36:
Seidman LJ, Kremen WS, Koren D, Faraone SV, Goldstein JM, Tsuang MT
(2002): A comparative profile analysis of neuropsychological function-
ing in patients with schizophrenia and bipolar psychoses. Schizophr Res
supersensitive cholinergic REM-induction and affective illness within
Sitaram N, Moore AM, Gillin JC (1978a): The effect of physostigmine on
normal human sleep and dreaming. Arch Gen Psychiatry 35:1239–1243.
ing of REM sleep ultradian rhythm by cholinergic agonist and antago-
nist. Nature 274:490–492.
rhythm in normal man by arecholine: Blockade by scopolamine. Sleep
Sitaram N, Moore AM, Gillin JC (1979): Scopolamine-induced muscarinic
Sitaram N, Nurnberger JI Jr, Gershon ES, Gillin JC (1980): Faster cholinergic
REM sleep induction in euthymic patients with primary affective illness.
to affective disorder. Am J Psychiatry 139:571–576.
Sobczak S, Honig A, Nicolson NA, Riedel WJ (2002a): Effects of acute trypto-
phan depletion on mood and cortisol release in first-degree relatives of
type I and type II bipolar patients and healthy matched controls. Neuro-
Sobczak S, Honig A, Schmitt JA, Riedel WJ (2003): Pronounced cognitive
Sobczak S, Riedel WJ, Booij I, Aan Het Rot M, Deutz NE, Honig A (2002b):
Cognition following acute tryptophan depletion: Difference between
first-degree relatives of bipolar disorder patients and matched healthy
control volunteers. Psychol Med 32:503–515.
Sokolski KN, DeMet EM (1999): Pupillary cholinergic sensitivity to pilocarpine
Sokolski KN, DeMet EM (2000): Cholinergic sensitivity predicts severity of
mania. Psychiatry Res 95:195–200.
Souetre E, Salvati E, Wehr TA, Sack DA, Krebs B, Darcourt G (1988): Twenty-
four-hour profiles of body temperature and plasma TSH in bipolar pa-
tients during depression and during remission and in normal control
and endocrine function. Lancet 354:1435–1439.
Stanton T, Bolden-Watson C, Cusack B, Richelson E (1993): Antagonism of
the five cloned human muscarinic cholinergic receptors expressed in
CHO-K1 cells by antidepressants and antihistaminics. Biochem Pharma-
Stewart J, Badiani A (1993): Tolerance and sensitization to the behavioral
effects of drugs. Behav Pharmacol 4:289–312.
Stohr T, Schulte Wermeling D, Weiner I, Feldon J (1998): Rat strain differ-
ing effects of amphetamine. Pharmacol Biochem Behav 59:813–818.
Stoll AL, Renshaw PF, Yurgelun-Todd DA, Cohen BM (2000): Neuroimaging
in bipolar disorder: What have we learned? Biol Psychiatry 48:505–517.
lesions on neuroendocrine and autonomic stress responses in rats.
Swan GE, Carmelli D (2002): Evidence for genetic mediation of executive
control: A study of aging male twins. J Gerontol B Psychol Sci Soc Sci
Swan GE, Reed T, Jack LM, Miller BL, Markee T, Wolf PA, et al (1999): Differ-
partial sleep deprivation on the diurnal variation of mood and motor
activity in major depression. Biol Psychiatry 30:817–829.
Szymusiak R (1995): Magnocellular nuclei of the basal forebrain: Substrates
of sleep and arousal regulation. Sleep 18:478–500.
Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, et al (2001): An hPer2
phosphorylation site mutation in familial advanced sleep phase syn-
drome. Science 291:1040–1043.
brain reward system function in major depressive disorder: Altered re-
sponse to dextroamphetamine. Arch Gen Psychiatry 59:409–416.
Tripathy D, Lindholm E, Isomaa B, Saloranta C, Tuomi T, Groop L (2003):
Uhlenhuth EH, Johanson CE, Kilgore K, Kobasa SC (1981): Drug preference
acteristics. Psychopharmacology (Berl) 74:191–194.
dependence. A preliminary study. Arch Gen Psychiatry 55:41–46.
Van Kammen DP, Murphy DL (1975): Attenuation of the euphoriant and
activating effects of d- and l-amphetamine by lithium carbonate treat-
ment. Psychopharmacologia 44:215–224.
Vawter MP, Freed WJ, Kleinman JE (2000): Neuropathology of bipolar disor-
der. Biol Psychiatry 48:486–504.
Videbech P (1997): MRI findings in patients with affective disorder: A meta-
Wehr TA, Sack DA, Rosenthal NE (1987): Sleep reduction as a final common
pathway in the genesis of mania. Am J Psychiatry 144:201–204.
Wesnes K, Warburton DM (1984): Effects of scopolamine and nicotine on
human rapid information processing performance. Psychopharmacol-
Wirz-Justice A, Van den Hoofdakker RH (1999): Sleep deprivation in depres-
sion: What do we know, where do we go? Biol Psychiatry 46:445–453.
Wu JC, Bunney WE (1990): The biological basis of an antidepressant re-
sponse to sleep deprivation and relapse: Review and hypothesis. Am J
Zalla T, Joyce C, Szoke A, Schurhoff F, Pillon B, Komano O, et al (2004):
Executive dysfunctions as potential markers of familial vulnerability to
bipolar disorder and schizophrenia. Psychiatry Res 121:207–217.
Zammit S, Jones G, Jones SJ, Norton N, Sanders RD, Milham C, et al (2004):
Polymorphisms in the MAOA, MAOB, and COMT genes and aggressive
Zubieta JK, Huguelet P, O’Neil RL, Giordani BJ (2001): Cognitive function in
euthymic bipolar I disorder. Psychiatry Res 102:9–20.
G. Hasler et al
BIOL PSYCHIATRY 2006;60:93–105 105