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The Neurobiology of Bipolar Disorder

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									                                                           American Journal of Medical Genetics Part C (Semin. Med. Genet.) 123C:76 – 84 (2003)

 A R T I C L E




The Neurobiology of Bipolar Disorder
GREGORY S. BERNS* AND CHARLES B. NEMEROFF


               The neurobiology of bipolar disorder is reviewed. Bipolar disorder is associated with alterations in central nervous
               system (CNS) function from the level of large-scale brain circuits to intracellular signal transduction mechanisms.
               Because of the broad spectrum over which these abnormalities appear, the causative effects are most likely
               present in the lowest common denominator of all of these systems. Current evidence points to subtle alterations
               in signal transduction that reverberate downstream both intra- and extracellularly to produce the symptoms of
               bipolar disorder. ß 2003 Wiley-Liss, Inc.

KEY WORDS: bipolar disorder; schizophrenia; magnetic resonance imaging


INTRODUCTION                                         In contrast, untreated schizophrenia is            lesser severity and termed hypomania.
                                                     generally characterized by a long pro-             Bipolar II disorder has a lifetime pre-
Bipolar disorder has been known to                   gressive decline without any significant            valence rate of 0.5% [Angst, 1998].
mankind since at least the time of the               return to the premorbid state.                     Thus, bipolar I and II disorders have a
ancient Greeks, but it was not until the                   Estimates of bipolar I disorder, or          combined prevalence rate of about 2%,
20th century that it was truly recognized            classic manic-depressive illness, have             which is equal to or greater than that of
as an illness distinct from other psychiat-          ranged from 0.8–1.6% of the population             schizophrenia. It is important to note
ric disorders. The German psychiatrist               [Kessler et al., 1994]. These patients             that one-third of patients with bipolar
Emil Kraepelin was likely the first to                experience both full-blown manic epi-              disorder have their first episode during
draw attention to the distinction be-                sodes and syndromal major depressions.             their adolescent years, and 50% exhibit
tween manic depression and schizophre-               Various subtypes have been described               comorbid drug or alcohol abuse.
nia. While the acute presentations of                that include rapid cycling bipolar dis-                 In trying to understand the biology
both illnesses can appear identical with             order and mixed states, the latter char-           of bipolar disorder, we struggle to link
delusions and hallucinations, manic de-              acterized by patients who exhibit                  the obviously complex manifestations of
pression is characterized by an abrupt               concurrent symptoms of both mania                  the illness and its cyclic nature with its
onset and a fluctuating course in which               and depression. Bipolar II disorder is             biological substrate. How can one ferret
the individual returns to a relatively               characterized by syndromal major                   out the roots of a mental illness when
normal state between episodes, particu-              depressions and manic episodes that do             we are only beginning to understand
larly early in the course of the disorder.           not fulfill criteria for mania but are of           the complex machinery of the brain?
                                                                                                        Even so, extraordinary discoveries, using
                                                                                                        techniques of molecular biology, ge-
   Gregory S. Berns, M.D., Ph.D., is an Associate Professor in the Department of Psychiatry and         netics, and neuroimaging, consistently
Behavioral Sciences at Emory University School of Medicine and the Coulter School of Biomedical         point to the fact that individuals with
Engineering at the Georgia Institute of Technology. Dr. Berns received his Ph.D. in biomedical
engineering from the University of California–Davis in 1990 and his M.D. from the University            bipolar disorder have fundamental altera-
of California–San Diego in 1994. He specializes in the use of brain imaging techniques to               tions in brain function. We present here
understand the functioning of human reward pathways and how this can be applied to                      some of the recent advances in neuro-
understand human decision making, an area that has come to be known as neuroeconomics.
   Charles B. Nemeroff, M.D., Ph.D., is the Reunette W. Harris Professor and Chairman of the            biology that firmly root the pathophy-
Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine. He             siology of bipolar disorder in the brain.
received both his Ph.D. and M.D. degrees from the University of North Carolina–Chapel Hill and
completed residency training at Duke University in 1985. He was a Professor in the Departments
of Psychiatry and Pharmacology at Duke University, relocating to Atlanta in 1991 to assume his
current position. His research has concentrated on the biological basis of the major neuro-             ALTERATIONS IN
psychiatric disorders, including affective disorders, schizophrenia, and anxiety disorders. He serves
as Editor-in-Chief of Neuropsychopharmacology and has published more than 700 research
                                                                                                        BRAIN STRUCTURE
reports and reviews. He is currently the recipient of several research grants from the NIH,
including a Conte Center for the Neurobiology of Major Mental Disorders.
                                                                                                        The idea that bipolar disorder may be
   Grant sponsor: NIH; Grant numbers: MH-61010, DA-00367, MH-42088, MH-39415, MH-                       related to an alteration in brain structure
58922.                                                                                                  was derived from the astute clinical ob-
   *Correspondence to: Gregory S. Berns, Department of Psychiatry and Behavioral Sciences,
Emory University School of Medicine, 1639 Pierce Drive, Suite 4000, Atlanta, GA 30322.
                                                                                                        servation that certain brain lesions pro-
E-mail: gberns@emory.edu                                                                                duced by brain tumors, stroke, or head
   DOI 10.1002/ajmg.c.20016                                                                             injury resulted in manic-like behavior

ß 2003 Wiley-Liss, Inc.
ARTICLE                                                        AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)          77


                                             enlargement is typically characteristic       of white matter hyperintensities. Their
 The idea that bipolar disorder              of cell loss, such as the neurodegenera-      location suggests a potential role in dis-
                                             tions observed in Alzheimers disease          rupting communicating fibers between
      may be related to an
                                             or perhaps alterations in neural circuit      fronto-temporal regions, which lends
  alteration in brain structure              development, but issues of controlling        support to earlier observations that
   was derived from the astute               for other potentially important con-          lesions in these regions cause mania.
                                             founding factors, such as alcohol and         Follow-up postmortem studies of pa-
clinical observation that certain            drug abuse and head injury, preclude an       tients with UBOs have demonstrated a
    brain lesions produced by                easy interpretation of the results. Given     number of histologic changes in these
                                             these limitations, volumetric imaging         regions, including small vascular mal-
 brain tumors, stroke, or head               studies have provided intriguing findings      formations, dilated perivascular spaces,
        injury resulted in                   in bipolar disorder. As recently reviewed     brain cysts, infarcts, and necrosis. These
      manic-like behavior.                   by Strakowski et al. [2002a], both bipolar    are surprisingly nonspecific lesions that
                                             and unipolar depression are reportedly        can occur from multiple causes. It is
                                             associated with smaller prefrontal lobe       possible that these lesions represent
[Cummings and Mendez, 1984; Cum-             volumes, but in contrast both the basal       damage from a comorbid disease process
mings, 1993]. In general, any brain          ganglia and thalamus are larger in bi-        unrelated to bipolar disorder; however,
lesion is far more likely to cause depres-   polar patients [Aylward et al., 1994;         recent studies in children and adoles-
sion than mania, but lesions that induce     Strakowski et al., 2002a]. Moreover,          cents with mania continue to reveal an
mania occur more commonly in the             both hippocampal and amygdala enlar-          abundance of these UBOs [Lyoo et al.,
frontal and temporal lobes and sub-          gement in bipolar disorder has also been      2002; Pillai et al., 2002]. More re-
cortically in the head of the caudate and    occasionally reported [Swayze et al.,         cently, the MRI changes in bipolar
the thalamus [Cummings and Mendez,           1992; Strakowski et al., 2002a], but not      disorder have been noted to bear a
1984; Starkstein et al., 1991], so-called    consistently.                                 striking similarity to an autosomal
secondary manias. It has been repeatedly           Volumetric measurements of var-         dominant disorder called cerebral auto-
suggested that lesions of the left frontal   ious brain regions are of interest, espe-     somal dominant arteriopathy with
lobe result in depression, whereas right     cially to identify structures that deserve    subcortical infarcts and leukoencephalo-
fronto-temporal lesions produce mania.       further scrutiny, but the interpretation      pathy (CADASIL), and there is some
However, these generalizations about         of volumetric assessments remains pro-        evidence for a higher incidence of
laterality are far too simplistic, and       blematic. Specific changes in regional         bipolar disorder in CADASIL patients
many exceptions to this rule have been       volume may occur in response to a             [Ahearn et al., 1998, 2002].
observed.                                    variety of factors and may not be per-
     Before the advent of noninvasive        manent. MRI has the capability of look-
                                                                                           ALTERATIONS IN
brain imaging techniques, the only           ing beyond simple structure by yielding
                                                                                           BRAIN FUNCTION
methods available to examine patients’       information about both neurochemical
brains were autopsy, brain biopsy, and       alterations and the neural activity of spe-   Both CT and MRI yield static informa-
pneumoencephalography. There have            cific regions. When brain MR images            tion about brain structure—a kind of
been few postmortem anatomic studies         were obtained in bipolar patients, it was     snapshot—but the brain is a dynamic
of patients with confirmed bipolar dis-       quickly noted that such patients had an       organ, and to understand function we
order; however, neuroimaging using           inordinate number of hyperintense re-         must choose different techniques. Func-
both computed tomography (CT) and            gions. These unidentified bright objects       tional neuroimaging can measure subtle
magnetic resonance imaging (MRI) has         (UBOs) are typically associated with          changes in receptor density, blood flow,
revealed multiple structural alterations.    vascular diseases, including systemic hy-     and glucose metabolism. Although we
CT scans were the first noninvasive           pertension, Binswangers disease, and          cannot yet image neuronal activity
modality to systematically scrutinize        carotid arteriosclerosis. Why are they        directly, recent technological advances
brain structure, but the relatively poor     present in patients with a mental dis-        in MRI have led to the development of
demarcation between different brain          order? Further studies revealed that they     functional MRI (fMRI), which can
regions allowed for only the grossest of     tend to localize in deep white matter         detect changes in blood flow on the
observations. Several investigators have     structures. The percentage of bipolar         scale of seconds with millimeter resolu-
suggested that patients with bipolar dis-    patients exhibiting these findings has         tion, and such changes are clearly coupl-
order have larger ventricles than normal     ranged from 5–50%, compared with              ed to neuronal activity [Ogawa et al.,
controls, a finding much more clearly         about 3% for controls [Aylward et al.,        1990; Kwong et al., 1992].
established in patients with schizophre-     1994; Altshuler et al., 1995; Dupont               Most functional neuroimaging
nia [Schlegel and Krtezschmar, 1987;         et al., 1995; Norris et al., 1997;            studies take advantage of a critical ob-
Dewan et al., 1988; Swayze et al., 1990;     McDonald et al., 1999]. Elderly bipolar       servation about neuronal activity and
Strakowski et al., 1993]. Ventricular        patients have larger and a higher number      brain blood flow. When synaptic activity
78     AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)                                                                 ARTICLE


increases in a particular brain region, the   patients recovered from their depression,     system. Is there some aspect of neuro-
blood flow to that region transiently          these abnormalities disappeared. These        nal function that renders patients with
increases [Logothetis et al., 2001]. The      findings have not been completely rep-         manic-depressive illness more prone to
blood flow apparently increases beyond         licated. Some studies have reported           these shifts? The new science of chaos
the metabolic requirements of the tissue,     relatively normal cortical metabolism,        theory characterizes these states as at-
so a surfeit of oxygenated blood tem-         but more localized abnormalities in           tractors. Consider the simplistic case of
porarily bathes the region. Both positron     subcortical regions such as the caudate       three mood states: euthymia (normal
emission tomography (PET) and fMRI            or subgenual prefrontal cortex [Drevets       mood), depression, and mania. For most
can be used to measure this blood flow         et al., 1995].                                individuals, euthymia is the usual state.
increase, thereby indirectly measuring              Frontal regions, especially the dor-    Unpleasant events cause transient dys-
neuronal activity. PET can also be used       solateral prefrontal cortex (DLPFC),          phoria, but most people quickly return
to measure directly local glucose meta-       have been identified as having both            to their usual mood state. Similarly,
bolism. By using a glucose analog, 2-         decreased metabolism and blood flow            winning a lottery makes most people
deoxy-glucose (2-DG), this compound           in depression. Decreases in left DLPFC        very happy, but does not shift them to a
can be labeled with a positron emitter,       metabolism have been correlated with          permanent state of elation. Euthymia is
fluorine-18. Like glucose, 2-DG is             severity of depression, but this is not       therefore a stable state for most people—
transported into cells and metabolized.       likely to be specific to bipolar disorder      perturbations are small and the return to
Unlike glucose, 2-DG is metabolized           [Strakowski et al., 2002b]. Frontal hypo-     euthymia is invariant. Patients with bi-
through only one step of glycolysis and       metabolism has been reported repeat-          polar disorder often switch into extreme
subsequently becomes trapped in the           edly in schizophrenia. Presumably, any        mania or depression without returning
cell. Thus it serves as a marker of both      alteration in these regions is associated     to a euthymic state for a considerable
glucose uptake and metabolism. Because        with profound effects on cognition and        period of time.
the process of uptake and metabolism          emotion. These brain regions are well
takes some time, fluoro-deoxyglucose           known to be integral to many functions
                                                                                            ALTERATIONS IN
(FDG) studies are more appropriate for        that are altered in psychiatric disorders
                                                                                            BRAIN CHEMISTRY
the measurement of stable state changes       such as attention and working memory.
in the brain.                                 Other frontal regions, especially those       MR spectroscopy (MRS) has been used
      The earliest functional imaging         on the innermost folds of the brain,          extensively to measure changes in rela-
studies focused on large-scale changes        are poorly understood but seem to             tive concentrations of several important
in both cerebral blood flow and meta-          be involved in conflict monitoring             neuroregulators in the brains of bipolar
bolism [Strakowski et al., 2002b]. These      [Carter et al., 1998], reward valuation       patients. The most common method,
studies showed that bipolar-depressed         [Montague and Berns, 2002], and               proton-MRS, is used both routinely and
patients had significantly lower cortical      response inhibition. This suggests that       now clinically. Proton-MRS measures
metabolism than either controls or pa-        both state- and trait-dependent inter-        the relative concentrations of N-acetyl
tients with unipolar depression [Baxter       actions with performance on cognitive         aspartate (NAA), creatine (Cr), phos-
                                              tasks may serve as a finer probe of dys-       phocreatine (PCr), and various choline
                                              function with brain imaging [Berns            (Cho)-containing compounds. Because
The earliest functional imaging               et al., 2002].                                lithium increases Cho concentrations in
                                                    Functional neuroimaging in bi-          human red blood cells [Jope et al., 1978],
 studies focused on large-scale               polar disorder dispelled a common myth        it was reasonable to look for similar
    changes in both cerebral                  about the organization of the brain,          changes in Cho concentration in the
  blood flow and metabolism.                   namely, that specific cognitive processes      brain. The MRS data on Cho concen-
                                              can be completely localized to isolated       trations are not entirely consistent, but
      These studies showed                    brain regions. Virtually every imaging        there does seem to be a consensus that
that bipolar-depressed patients               study has identified networks of activity.     there is at least an elevated Cho/Cr ratio
                                              In this context, it becomes clear why the     in the basal ganglia of bipolar patients
     had significantly lower                   search for regional abnormalities has not     [Stoll et al., 2000; Strakowski et al.,
cortical metabolism than either               yielded consistent results. If a cognitive    2002b]. It is likely that this finding is state
                                              process requires the coordinated func-        dependent because similar elevations
       controls or patients
                                              tion of several brain regions, then a small   have been observed in depression.
   with unipolar depression.                  alteration in one region may cause dra-            Because the Cho peak in proton-
                                              matic effects on the whole circuit.           MRS represents several compounds, pho-
                                                    Both mania and depression are char-     sphorous-MRS has been used to further
et al., 1985; Buchsbaum et al., 1986].        acterized by profound global changes in       delineate the nature of these alterations.
Furthermore, these changes were state         brain function. These state changes are       Phosphorous-MRS can distinguish ATP,
dependent, meaning that when the              manifest at multiple levels in the nervous    PCr, and phosphomonoesters (PMEs)
ARTICLE                                                         AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)          79


like phosphocholine, phosphoinositol,          cult to precisely document. NE, like         its metabolite, 3-methoxy-4-hydroxy-
and phosphoethanolamine; it can also           many neurotransmitters, appears extra-       phenylethyleneglycol (MHPG), to NE,
measure indirectly intracellular pH and        cellularly in small amounts. Further-        ranged from 64–107% greater in several
free magnesium. However, because of the        more, it is metabolized to several other     cortical regions. Significant decreases
relatively low concentrations of these         compounds that appear in CSF, plasma,        in both serotonin and dopamine meta-
compounds, phosphorous-MRS is tech-            and urine. Thus, alterations in NE cir-      bolism were found in the same brain
nically demanding and suffers from limited     cuits may appear as a change in either the   regions.
sensitivity. Like the proton-MRS data,         neurotransmitter or any of its metabo-            In addition to the monoamine
there are discordant findings. Most studies     lites. Most evidence points to a defi-        neurotransmitters, others have also been
have found changes in PMEs in the frontal      ciency in depression and an excess in        implicated in the pathophysiology of
lobes of symptomatic patients, but whether     mania, but this may simply reflect the        bipolar disorder. Because of its prepon-
it is increased or decreased, or whether       global neural activity of these states, as   derance in the brain, glutamate has
there are left/right asymmetries, is not       well as contributions from the sympa-        received growing attention. Glutamate
agreed upon [Stoll et al., 2000; Strakowski    thetic nervous system, which utilizes        exerts its effects through four major
et al., 2002b]. At a minimum, these studies    NE as the neurotransmitter of post-          receptor families. Three are ionotropic:
suggest that alterations in phospholipid       ganglionic neurons. Interestingly, NE        N-methyl-D-aspartate (NMDA), a-
metabolism occur in bipolar disorder           elevations purportedly precede the           amino-3-hydroxy-5-methyl-isoxazole-
[Yildiz et al., 2001].                                                                      4-propionic acid (AMPA), and kainate.
                                                                                            The ionotropic receptors are coupled to
NEUROCHEMICAL
                                                     Changes are evident at                 different ion channels, and when gluta-
                                                                                            mate binds to them, the ionic conduc-
CHANGES                                        virtually all levels of the central
                                                                                            tances are altered. The fourth family is
Changes are evident at virtually all levels        nervous system in bipolar                metabotropic, and these receptors are
of the central nervous system (CNS) in              patients. If the illness is             coupled to intracellular G-proteins. A
bipolar patients. If the illness is manifest                                                recent postmortem of the striatum
by changes in brain attractor states, as        manifest by changes in brain                found increased expression of mRNA
opposed to lesions of a specific region,           attractor states, as opposed              transcripts for both the NR2D subtype
then we have merely shifted the search                                                      of the NMDA receptor and the AMPA
for the cause to more fundamental levels.
                                                     to lesions of a specific                receptor in bipolar patients [Meador-
Numerous biochemical abnormalities               region, then we have merely                Woodruff et al., 2001].
have been detected by measuring one                 shifted the search for the
or another neurotransmitter metabolites
                                                  cause to more fundamental                 NEUROENDOCRINE
or hormones in plasma, cerebrospinal
                                                                                            CHANGES
fluid (CSF), and postmortem tissue                       levels. Numerous
studies. Although depression has often                                                      For many years it has been recognized
been conceptualized as due to a relative           biochemical abnormalities                that certain endocrine disorders are asso-
deficiency in the activity of certain                  have been detected by                 ciated with a greater than expected
monoamine-containing systems, e.g.,                                                         occurrence in bipolar disorder. The
                                                   measuring one or another
serotonin, dopamine, and norepinephr-                                                       hypothalamic-pituitary-adrenal (HPA)
ine (NE), these have not yet been clearly       neurotransmitter metabolites                axis has received the most attention in
implicated in the pathophysiology of                or hormones in plasma,                  mood disorders. Corticotropin-releasing
bipolar disorder. Many antidepressants,                                                     factor (CRF) is released from neurons
which increase the activity of one or               cerebrospinal fluid, and                 in the paraventricular nucleus of the
more of these neurotransmitter circuits,          postmortem tissue studies.                hypothalamus, and CRF is transported
can precipitate the development of                                                          to the anterior pituitary, causing ACTH
mania.                                                                                      to be released systemically. ACTH acts
     Concentrations of NE, or its major        switch into mania. Although NE may           upon the adrenal cortex, where it re-
metabolite, are consistently altered in the    not itself be the causative mediating        leases cortisol [Wang and Nemeroff,
CSF of patients with bipolar disorder.         factor, it is further evidence for the       2003]. Mixed mania has been associated
NE was originally proposed by Schildk-         idea of unstable cortical states. In one     with both an elevated CSF and urinary
raut [1965] as the major culprit in both       comprehensive postmortem study,              free cortisol concentration [Swann et al.,
depression and mania. The catechola-           there were no differences in the con-        1992], but this has also been observed
mine hypothesis stated that depression         centration of NE, serotonin, or dopa-        in unipolar major depression. The as-
resulted from low levels of NE and mania       mine in any brain region of bipolar          sessment of HPA function has typically
resulted from high levels [Schildkraut,        patients [Young et al., 1994], but NE        been done with either of two tests: the
1965]. This has been remarkably diffi-          turnover, as measured by the ratio of        dexamethasone suppression test (DST)
80     AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)                                                             ARTICLE


and the CRF-stimulation test. The              a-subunit that typically binds to the ion    events, including calcium mobilization,
practical limitations of the DST have          channel. In addition to regulation of        cytoskeletal organization, and phos-
been covered elsewhere [Shapiro et al.,        ion channels, G-proteins interact with       phoinositol metabolism. Rap1 has also
1983], but the CRF-stimulation test            several intracellular second messengers,     been found to be involved in the re-
retains utility. In the latter, CRF is ad-     including cyclic AMP (cAMP), cyclic          gulation of signal cascades coupled to
ministered intravenously (usually 1 mg/                                                     neurotrophic factors [Bos et al., 2001].
kg or 100-mg dose), and blood samples                                                       This is very intriguing because recent
are obtained for ACTH and cortisol                                                          data also suggest a role for both anti-
at 30-min intervals for 2–3 hr. When                 The heterogeneity of                   depressants and mood stabilizers as
compared to normal control subjects,              both imaging findings and                  neuroprotective agents [Duman et al.,
the ACTH response to exogenous CRF                                                          2001; Manji and Duman, 2001]. Inter-
                                                 neurotransmitter alterations
is blunted in depression but not in mania.                                                  estingly, another downstream substrate,
When dexamethasone was combined                     has not yielded a single                cAMP response element-binding pro-
with CRF-stimulation, depressed bipo-           underlying hypothesis for the               tein (CREB) has not be found to be
lar patients were reported to have a                                                        increased in bipolar patients and may be
significantly greater elevation of cortisol        pathophysiology of bipolar                decreased in the temporal lobes [Stewart
than either normal controls or unipolar         disorder. There does, however,              et al., 2001].
depressed patients [Schmider et al.,                                                              Protein kinase C (PKC) is yet
1995; Rybakowski and Twardowska,
                                                    appear to be consistent                 another second messenger-dependent
1999]. The mechanisms for these altera-           evidence pointing to signal               kinase, dependent on calcium, not
tions in the HPA axis of patients with         transduction as one major locus              cAMP. At rest, PKC isozymes exist as
affective disorders are unknown, but                                                        both cystolic and membrane-bound
glucocorticoid resistance, which is ana-              of pathophysiology.                   forms, but mostly cystolic. Activation
logous to the insulin resistance of dia-                                                    of receptors coupled to phospholipase C
betes mellitus, has been one mechanism                                                      facilitates the translocation of cystolic
proposed [Pariante and Miller, 2001;           GMP (cGMP), calcium, metabolites of          PKC to the membrane [Manji et al.,
Watson and Young, 2002].                       the phosphatidyl-inositol (PI) pathway,      1995]. Like PKA, PKC is elevated
                                               arachidonic acid, and nitric oxide. Upon     in the platelets of bipolar patients
                                               neurotransmitter binding, the bg-sub-        [Friedman et al., 1993]. Acute lithium
SIGNAL TRANSDUCTION
                                               unit separates from the receptor and         exposures apparently facilitate many
The heterogeneity of both imaging find-         modulates the activity of adenylate cy-      PKC-mediated effects, but longer expo-
ings and neurotransmitter alterations has      clase, in effect changing intracellular      sure results in downregulation of some
not yielded a single underlying hypoth-        levels of cAMP. cAMP then phosphor-          PKC isozymes. The effects of lithium-
esis for the pathophysiology of bipolar        ylates a number of cAMP-dependent            induced changes of the PKC signaling
disorder. There does, however, appear          protein kinases, activating their respec-    pathway can be measured on down-
to be consistent evidence pointing to          tive functions. Protein kinase A (PKA) is    stream products, just as in the PKA
signal transduction as one major locus of      the most prominent of these kinases and      system. Chronic lithium exposure has
pathophysiology. For historical reasons        is referred to as a third messenger.         been demonstrated to reduce the ex-
alluded to above, the signal transduction            Particular attention has been focus-   pression of myristolated alanine-rich
pathway for catecholamine receptors has        ed on the cAMP/PKA transduction              C kinase substrate (MARKS), espe-
been the most extensively characterized        pathway for several reasons. First,          cially in the hippocampus. MARKS
in mood disorder. What follows is largely      lithium exerts complex effects on ade-       has been implicated in the regulation of
related to the NE system [Duman and            nylate cyclase [Risby et al., 1991], and     neuroplastic events [Manji and Lenox,
Nestler, 1995].                                this is believed to be manifest as down-     2000].
     The neurotransmitter itself, in this      stream changes on the CAMP/PKA
case NE, is referred to as the first mes-       pathway [Manji and Lenox, 2000].
                                                                                            LITHIUM
senger, and it binds to one or more            Consistent with this notion, an increased
adrenergic receptor subtypes (see above).      concentration of Ga-subunits was re-         Because lithium revolutionized the
Depending on the receptor subtype, a           ported in the CNS in a postmortem            treatment of bipolar disorder, it also
number of different intracellular events       study of bipolar patients [Young et al.,     provided a potential window into un-
may occur. G-proteins on the intracel-         1991, 1993]. Looking farther down-           derstanding the disease-related altera-
lular side of the receptor can bind to ion     stream, Rap1, a PKA substrate, has been      tions that occur at the cellular level.
channels, thereby influencing the mem-          reported to exhibit increased levels of      Lithium was identified as an element
brane potential of the cell. The G-            phosphorylation in the platelets of bi-      more than 150 years ago, and it wasn’t
proteins are generally composed of three       polar patients [Perez et al., 2000]. Rap1    long after its discovery that it was used
subunits, labeled a, b, and g, and it is the   may be involved in several intracellular     as a therapeutic agent for a variety of
ARTICLE                                                           AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)           81


ailments. Lithium’s mood-stabilizing             has been reported to increase neurogen-      lethal doses as little as two times the
effects were demonstrated in the 1950s.          esis in the hippocampus [Chen et al.,        therapeutic dose. Lithium treatment is
Unlike other medications used to treat           2000].                                       often associated with a number of un-
psychiatric patients, lithium is a salt,                                                      toward effects, ranging from tremor
and consequently, it does not have a                                                          and gastrointestinal side effects (nausea,
                                                 CLINICAL CORRELATES
receptor to which it binds in the brain.                                                      diarrhea, and cognitive slowing) to
Rather, it is actively transported into          The term bipolar disorder is somewhat        hypothyroidism and diabetes insipidus.
the cell through the sodium channel.             misleading because it implies that indi-     Fortunately, results from studies utilizing
When a neuron depolarizes, the sodium            viduals exist in either a depressed or       biological models of bipolar disorder
channel opens and both sodium and                manic state, and that these states are at    served as an impetus for research on
lithium rush into the cell. The sodium           opposite ends of a spectrum. The reality     other pharmacologic treatments, and
is then actively pumped out, using               is more complex, and this has important      one line of research led to the anti-
the sodium-potassium-ATP pump, but               implications for treatment. While it is      convulsants carbamazepine and valproic
lithium remains in the intracellular             true that the depressed and manic states     acid; they are now accepted as effective
compartment.                                     are far beyond the realm of normal           treatments. Valproic acid is FDA-
      As described above, lithium appears        emotions, they are not at opposite ends      approved for the treatment of mania.
to modulate several second messenger             of a continuum. In fact, these states may    Olanzapine, a recently FDA-approved
systems, including cAMP and phosphoi-            represent two dimensions of emotion          atypical antipsychotic, is also effective
nositol pathways. Lithium may blunt              that, to a certain degree, are independent   in the treatment of mania and perhaps
receptor activation of adenylate cyclase         of each other. As many as 40% of bipolar     in the depression of bipolar disorder as
activity, although separating the effects        patients enter a mixed state, a condition    well.
of lithium from the alterations that occur       with either the coexistence or rapid              Manic-depressive cycles are neither
naturally in bipolar disorder is not always      alternation of symptoms of both depres-      random nor predictable. Many, if not
easy. Rather than causing large changes          sion and mania, sometimes called dys-        most, patients show a pattern of in-
in baseline cellular activity, lithium           phoric mania. Similarly, the depression      creasing frequency over time. This
seems to attenuate responsivity to other         of bipolar disorder is generally not the     phenomenon occurs in other areas of
neurotransmitters. One might say that it         same symptomatically as the depression       neuroscience and has suggested a model
‘‘turns down the gain.’’ This may explain        of unipolar major depression. Bipolar        based on kindling and sensitization.
its efficacy in bipolar disorder—decreas-         depression tends to be atypical with         Kindling refers to increased responsivity
ing sensitivity to both internal and             prominent fatigue, hypersomnia, and          to repeated low-level electrical stimula-
external stimuli. Lithium also affects           reverse diurnal mood variability, as         tion. This is analogous to a seizure dis-
other neurotransmitter systems, includ-          opposed to insomnia in unipolar depres-      order, in which a seizure focus becomes
ing serotonin, dopamine, and g-amino-            sion.                                        increasingly sensitive to other electrical
butyric acid (GABA) circuits, and its                 For these and other reasons, bipolar    events (i.e., the more seizures one has,
efficacy may possibly be related to its           disorder is generally more difficult to       the more likely the occurrence of ad-
wide-ranging neurobiological effects             treat than simple major depression.          ditional seizures). The kindling hypoth-
rather than to a single mechanism.               Antidepressants do not typically work        esis also explains the observation that
      One of the intriguing properties of        as well for bipolar disorder, and they can   early manic episodes tend to be triggered
lithium treatment in mania is that a time        destabilize patients by switching them       by external events, like crossing time
lag of several days is required before           into manic or mixed states. Of the           zones or drug abuse, whereas after seve-
lithium exerts its clinical effect. More-        available antidepressants, the best          ral episodes they tend to occur without
over, lithium’s beneficial effects on             choices based on the current limited         any precipitants. Certain anticonvul-
mood stabilization do not disappear              database would support the use of            sants, especially carbamazepine and val-
immediately upon its discontinuation             selective serotonin reuptake inhibitors      proic acid, are effective treatments for
[Goodwin and Jamison, 1990]. One                 (SSRIs) (fluoxetine, paroxetine, sertra-      certain patients with bipolar disorder,
possibility is that lithium exerts its effects   line, etc.) and bupropion. There is a        lending further support to the kindling
by resetting the ionic homeostasis in            growing consensus that to obtain an          hypothesis. It should be noted, however,
neurons either directly or through its           optimal response in most bipolar dis-        that not all anticonvulsants are effective
interaction with second messenger sys-           order patients, multiple-drug therapy is     in the treatment of bipolar disorder (e.g.,
tems. Lithium also protects cells from           required. Lithium is one of the few Food     phenytoin, phenobarbital). Moreover,
other chemical insults [Nonaka et al.,           and Drug Administration (FDA)-               the clinical trial data supporting the
1998]. The neuroprotective properties            approved drugs for acute treatment of        efficacy of the anticonvulsants ranges
of lithium may explain lithium-induced           mania, and it is the only FDA-approved       from valproic acid, which is FDA ap-
inhibition of NMDA receptor-mediated             maintenance treatment for bipolar dis-       proved, to gabapentin and topiramate,
calcium influx. Beyond neuropro-                  order. Lithium, however, has a disturb-      which have no published efficacy data.
tection, lithium, like antidepressants,          ingly narrow therapeutic index, with         Moreover, in spite of the attractive
82     AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)                                                                 ARTICLE


nature of the kindling hypothesis, no           or depression are usually discrete, rapid      of specific clock genes offers an excit-
convincing neurobiological data have            eye movement (REM) sleep and body              ing opportunity to bring to bear in-
provided any support that this phenom-          temperature cycles change more slowly          sights from nonlinear dynamical systems.
enon actually occurs in patients with           and have been documented to precede
bipolar disorder.                               the switch in mood [Goodwin and
      Manic-depressives suffer profound         Jamison, 1990]. Although these cycles               The recent elucidation
alterations in sleep-wake cycles during         change slowly, it appears that once some
                                                                                                 of both afferent and efferent
both the manic and depressive phases of         threshold is reached, the bipolar patient
their illness, but subtle disturbances in       is catapulted into either mania or de-                pathways from the
circadian rhythms often precede the             pression. The outward manifestations of         central clock in the SCN and
full-scale shift in mood state. Mania is        mood may therefore appear to change
characterized by a markedly decreased           quite suddenly, even though the under-             the roles of specific clock
need for sleep. It is well known that sleep     lying dynamics are more subtle.                     genes offers an exciting
deprivation [Wehr, 1989] or even travel-
ing across time zones may trigger a
                                                                                                     opportunity to bring
                                                PUTTING IT                                     to bear insights from nonlinear
manic episode in vulnerable individuals
                                                ALL TOGETHER
[Jauhar and Weller, 1982; Young, 1995].                                                               dynamical systems.
Here again is evidence for some basic           In reviewing the data ranging from
circuit instability that is subject to          behavior to brain state to intracellular
transient changes in sleep patterns. The        events, one is struck both by the diversity    Although largely qualitative at this
normal sleep-wake cycle is determined           and discordance of the extant findings in       point, much is known about what
by a combination of internal circadian          bipolar disorder. Although there is no         happens when collections of oscillators,
rhythms and external cues—day and               smoking gun, there is a biological crime       like the SCN and its slaves, interact with
night. The basic internal rhythm can            scene. Our job is to sift through the          each other. It will now be possible to
be observed across many biologic mea-           evidence and determine what happened.          model how even subtle alterations in
sures: body temperature, heart and re-          Continuing the analogy, we deal with a         clock synchronization might lead to
spiration rate, and secretion of various        contaminated crime scene. The diag-            chaotic behavior, both biologically and
hormones (e.g., growth hormone, cor-            nosis of bipolar disorder is never straight-   behaviorally. At this point, we do not
tisol). The discovery of a ‘‘master clock’’     forward, sometimes being confused with         know which is cause and effect, but
in the suprachiasmatic nucleus (SCN)            schizophrenia, and frequently it is over-      one lesson from dynamical systems
has revolutionized our understand-              laid against a background of substance         theory is that any alteration in the func-
ing of the coordination of circadian            use. The panoply of medications used to        tion of a complex system will be
rhythms [Reppert and Weaver, 2002].             treat the illness wreak further havoc on       manifest throughout the system. This
It is now known that the SCN entrains           the CNS changes, making it increasingly        occurs precisely because all the parts are
a multitude of pacemakers both in the           difficult to sort out nascent brain changes     interconnected.
brain and out (e.g., liver). The basic          from pharmacologically induced ones.                 If we continue looking into smaller
oscillatory function depends on two             Nevertheless, it is worthwhile to attempt      scales in the brain, then we run into
transcriptional factors, termed CLOCK           at least some generalizations about the        the most incontrovertible evidence of
and BMAL1. Emerging data in both                neurobiology.                                  systemic dysfunction at the level of
depression and bipolar disorder are                  The fact that there are not grossly       signal transduction. Although the cate-
suggestive of mutations in these genes          consistent alterations in regional brain       cholamine hypothesis may be correct
[Bunney and Bunney, 2000; Mitterauer,           function is the clearest evidence that         roughly in the extreme, it too should
2000], but further research is neces-           bipolar disorder is not localized to a         be considered as part of the endophe-
sary to investigate this exciting link.         specific part of the brain. Although            notype and not causative. Alterations
Interestingly, lithium has been reported        strokes can induce manic behavior, these       in signal transduction appear to offer
to lengthen the circadian period of             are more likely syndromic expressions of       the most explanatory power for the
individual SCN neurons [Abe et al.,             a final behavioral phenotype that coin-         range of symptomatology in bipolar
2000].                                          cidentally resembles the manic state of        disorder. The symptoms manifest them-
      Phase instability, that is, sensitivity   bipolar disorder. What functional altera-      selves as amplifications of the range of
to perturbations in the circadian rhythm,       tions do exist in the brains of bipolar        both human emotion and behavior.
appears to be one characteristic of bi-         patients seemingly represent an exten-         Unlike schizophrenia, the fact that
polar disorder. This is concordant with         sion of the phenotype, the so-called           most bipolar patients return to a state
the idea of a chaotic system that is more       endophenotype.                                 of relative normality, even in the ab-
sensitive to slight changes—changes that             The recent elucidation of both            sence of treatment, is strongly sugges-
throw the entire system from one state to       afferent and efferent pathways from the        tive for alterations in a modulatory
another. Although transitions to mania          central clock in the SCN and the roles         mechanism.
ARTICLE                                                                    AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)                         83


ACKNOWLEDGMENTS                                            hippocampal neurogenesis by lithium. J           Manji HK, Lenox RH. 2000. Signaling: cellular
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