Intracellular Calcium Ion Signaling in Bipolar Mood Disorders: New Data and Directions

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Internal Medicine Review
Intracellular Calcium Ion Signaling in Bipolar Mood Disorders: New Data and Directions
                                       March 2019

  Intracellular Calcium Ion Signaling in Bipolar Mood Disorders: New Data
                               and Directions

Author                               Abstract

Steven L Dubovsky
                                     Bipolar mood disorders comprise a heterogeneous group
University at Buffalo, State         of conditions all of which are characterized by
University of New York               alternations or mixtures of elevated and depressed mood
                                     and physiologic arousal. Traditional hypotheses of the
Email: dubovsky@buffalo.edu          neurobiology of bipolar disorder that have invoked
                                     increases or decreases in neurotransmitter and receptor
                                     activity do not explain the existence at the same time of
                                     contradictory emotional states or comorbidity with
                                     medical disorders such as hypertension, coronary heart
                                     disease and migraine headaches. Unitary changes in
                                     neurotransmission also do not elucidate the reason why
                                     antidepressant treatments can destabilize the mood
                                     disorder, whereas a single medication (mood stabilizer)
                                     can ameliorate both poles of this condition. In contrast,
                                     changes in basic cellular functions such as the calcium
                                     (Ca2+) second messenger system can drive multiple
                                     neuronal systems in different directions depending on
                                     the sensitivity of a particular system to activation or
                                     inhibition by increased concentrations of the second
                                     messenger. This article summarizes evidence of elevated
                                     baseline and stimulated intracellular calcium ion
                                     concentration ([Ca2+]i) in peripheral cells and neuronal
                                     cultures in mania and bipolar depression and presents
                                     new data on induction of increased lymphocyte [Ca2+]I
                                     in a primate separation model. Data are presented
                                     supporting calcium antagonist actions of some mood
                                     stabilizers and mood stabilizing actions of some calcium
                                     channel blockers. This research points to new directions
                                     in understanding mood disorders and devising more
                                     specific treatments.

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     Copyright 2019 Internal Medicine Review. All Rights Reserved. Volume 5, Issue 3.
Internal Medicine Review
Intracellular Calcium Ion Signaling in Bipolar Mood Disorders: New Data and Directions
                                       March 2019
   1. Introduction                               particularly   in     the    hippocampus.
                                                 Antidepressants can induce both mania and
                                                 recurrent depression, but mood stabilizing
                                                 medications such as lithium can ameliorate
Bipolar disorder is characterized by
                                                 and prevent recurrences of both mania and
mixtures and alternations of depressed and
                                                 depression.
pathologically     elevated   (mania     and
hypomania)       mood.      The     National
Comorbidity Study reported lifetime
prevalence rates of bipolar I (history of        One recent line of investigation into the
mania, with or without hypomania), bipolar       pathophysiology that might underlie these
II (history of hypomania only), and              complex features has focused on alterations
subthreshold (fewer criteria than necessary      in fundamental cellular mechanisms in
for formal diagnosis) bipolar disorder in the    systems that regulate mood, thought,
general population as 1%, 1.1%, and 2.4%,        behavior and neuroplasticity in bipolar
respectively, noting that subsyndromal           disorder (9). The intracellular calcium ion
forms are associated with significant            (Ca2+) is interesting in this regard because it
symptomatology and impairment (1). In a          has a biphasic effect in regulating multiple
structured interview study of patients being     cellular functions. Moderate increases of
treated for depression in two primary care       free intracellular calcium ion concentration
practices, 32.8% of the sample appeared to       ([Ca2+]i) stimulate cellular activity, whereas
have subsyndromal bipolar mood disorders,        greater elevations inhibit the same functions
19% met criteria for bipolar I disorder, and     and even higher levels within the
8.6% had bipolar II disorder (2). Bipolar        physiologic range induce cellular apoptosis
disorder causes more disability than cancer,     (10). Alterations of intracellular        Ca2+
epilepsy, and Alzheimer's disease (3).           signaling in excitatory and inhibitory
People with bipolar disorder have high rates     systems could change the balance between
of suicide, substance use, obesity, heart        these systems, leading to alternations
disease, smoking, and sedentary lifestyle,       between mania and depression (11), while
with consequent increased morbidity and          mania and depression could occur
mortality. In 2009, the direct and indirect      simultaneously if a hyperactive intracellular
costs of bipolar I and bipolar II disorder       Ca2+ signal produced behavioral and
were $30.7 and $120.3 billion, respectively      emotional activation in some systems and
(4).                                             suppression in others. Enhancement of Ca2+
                                                 signaling by antidepressants could lead to
                                                 antidepressant-induced        mania,     while
                                                 attenuation of increased intracellular
Bipolar disorder is complex psychiatrically
                                                 calcium signaling could explain why mood
and medically. Manic and depressive
                                                 stabilizers can improve both mania and
symptoms may alternate with intervening
                                                 bipolar depression. Increased intracellular
periods of normal mood (euthymia), or they
                                                 calcium signaling can induce oxidative
may cycle frequently; in large numbers of
                                                 stress and apoptosis, contributing to the
patients, they occur at the same time (5-8).
                                                 neuronal loss that has been observed with
People with bipolar disorder have increased
                                                 recurrent manic and depressive episodes (9).
rates of hypertension, hypothyroidism,
                                                 Hyperactive calcium signaling in other
migraine headaches, and cardiovascular
                                                 organs could play a role in the comorbidity
disease. Recurrent affective episodes are
                                                 of bipolar mood disorders with other
associated with loss of brain volume,

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Internal Medicine Review
Intracellular Calcium Ion Signaling in Bipolar Mood Disorders: New Data and Directions
                                       March 2019
conditions linked to hyperactive intracellular    by agonists such as neurotransmitters,
calcium signaling such as migraine                increases [Ca2+]i to stimulated levels
headaches, hypertension and cardiovascular        ([Ca2+]S), which are then returned to
disease.                                          baseline by active transport of Ca2+ into
                                                  intracellular stores and out of the cell.

   2. Intracellular calcium ion signaling
                                                  Agonist interactions with G-protein coupled
                                                  receptors activates turnover of the
                                                  membrane phosphatidylinositol (PI) system,
Within neurons, intracellular Ca2+ signaling
                                                  beginning with hydrolysis of membrane-
regulates excitability, brain rhythms, the
                                                  bound phosphatidylinositol biphosphate
sleep-wake cycle, information processing,
                                                  (PIP2) and ultimately producing two
sensory          perception,        cognition,
                                                  products       of    metabolism-       inositol
neurotransmission,       synaptic     proteins,
                                                  triphosphate (IP3) and diacylglycerol (DG).
regulation of expression of multiple genes,
                                                  IP3 acts on mitochondrial and other
consciousness, remodeling of neuronal
                                                  intracellular receptors to promote release of
architecture, and synaptic plasticity (11).
                                                  stored Ca2+, while DG attracts the
Neuroplasticity,     which      depends      on
                                                  intracellular enzyme PKC to the cell
intracellular signaling, is the capacity of the
                                                  membrane, where it is activated by free
central nervous system to develop and
                                                  intracellular Ca2+ in order to phosphorylate
sustain adaptive responses to internal and
                                                  intracellular proteins that regulate cellular
external stimuli, resulting among other
                                                  processes. IP3 and DG are then combined to
things in neuronal resilience and mood
                                                  reconstitute PIP2 through a number of steps
stabilization (9).
                                                  for another round of cellular activation.

2.1 Regulation of intracellular calcium ion
    signaling                                     2.2 Calcium channels

Free intracellular Ca2+ concentration             Calcium ions enter the cytosol from the
([Ca2+]i) is normally regulated tightly at        extracellular space through receptor-
approximately 100 nM, or 0.0001 of the            operated channels gated by receptors for
Ca2+ concentration in the extracellular fluid.    hormones and neurotransmitters, such as
Most intracellular calcium is stored in           some catecholamines and the excitatory
organelles such as mitochondria and the           amino acids, and through potential
endoplastic reticulum, or is complexed with       dependent channels (PDCs or voltage-gated
binding proteins (12). Free intracellular         channels), which are gated by membrane
calcium levels are increased rapidly by           potential (13). In the brain, potential-
release from intracellular stores; influx         dependent calcium channels are localized in
through calcium channels replenishes              regions rich in synapses, perhaps because
intracellular stores and helps to regulate the    high [Ca2+]i must be produced rapidly to
baseline level of intracellular Ca2+ ([Ca2+]B),   regulate neurotransmitter release. Additional
which in turn influences neuronal                 pathways for calcium entry include leakage
excitability. Cellular activation, for example    through an ungated channel and exchange of

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Internal Medicine Review
Intracellular Calcium Ion Signaling in Bipolar Mood Disorders: New Data and Directions
                                       March 2019
extracellular calcium ions for intracellular       Different calcium channels in the nervous
sodium ions (Na+). Under physiological             system perform different physiologic
conditions, PDCs can be regulated by               functions, and multiple copies of the same
receptor-mediated events, such as the              channel interact to fine tune cellular
production of inositol triphosphate, and           regulation (15). The L (for long-lasting)
receptor-operated channels can be gated by         channel requires significant depolarization
changes in membrane potential. Endogenous          for Ca2+ entry and inactivates slowly. Of the
regulators, which may be altered in disease        four members of the L-type channel family
states, appear to modulate PDC gating.             (CaV1.1-1.4), only CaV1.2 and CaV1.3 play
Furthermore, extracellular Ca2+ entering the       a prominent role in the brain, the former in
cell may release calcium ions from                 the hippocampus and the latter in the limbic
intracellular stores, and trigger amounts of       system and striatum (16). L-type calcium
calcium ions released from intracellular           channels (LTCCs) do not participate directly
stores may facilitate calcium channel              in neurotransmitter release, but they play an
opening. Even subtle alterations of the            important role in setting overall neuronal
function of one kind of calcium channel can        excitability;    CaV1.2-based        channels
therefore have significant effects on the          influence gene transcription and gene
overall balance of calcium-dependent               expression (11).
cellular activity.
                                                   The T (transient) channel is activated by
                                                   small depolarizations and inactivates
The PDC consists of a central pore-forming         rapidly. T-type calcium channels may be
CaV subunit and five allosterically linked         involved in the action of the anticonvulsants
units called α1, α2, β, γ, and δ (14). There are   ethosuximide, valproic acid and divalproex
10 CaV-α1 subunits organized into various          in the treatment of absence seizures. The N
calcium channels. The mammalian nervous            (neither L nor T) channel, which is primarily
system contains 9 of the 10 major calcium          found on central nervous system (CNS)
channel types, with even more functional           neurons, as are rapidly inactivating P
diversity related to alternative splicing          (Purkinje cell) channels in cerebellar
events, as well as association with different      Purkinje cells, Q channels, and R (resistant
subunits and regulatory proteins (15). Thus        to calcium channel blocker) channels, all
far, four separate genes coding for the α1         participate in neurotransmitter release.
subunit have been identified. The α1C
subunit of the CaV1.2 channel, a primary
source of Ca2+ entry for plasma membrane
to nucleus signaling in the brain, is coded by        3. Ca2+ signaling in bipolar disorder
the CACNA1C gene, an allele of which has
been associated with bipolar disorder (11).
The other subunits, and possibly other             The study of intracellular Ca2+ dynamics in
endogenous circulating factors, can alter the      bipolar disorder initially involved blood
conformation of the α1 subunit, changing the       platelets as a proxy for brain neurons
activity of the calcium channel and its            because of their similar function and
affinity for medications that bind to it.          common embryonic origin (10). Platelet
                                                   activators such as thrombin, platelet
                                                   activating factor (PAF) and serotonin, act
                                                   through G-proteins to activate membrane

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Internal Medicine Review
Intracellular Calcium Ion Signaling in Bipolar Mood Disorders: New Data and Directions
                                       March 2019
PIP2 breakdown and generate IP3 and DG;           response to serotonin was increased in major
IP3 interacts with IP3 receptors to release       depressive disorder compared with controls,
Ca2+ from stores in the endoplasmic               the increase being significantly greater in
reticulum (ER) and mitochondria, which            depressed patients with high anxiety than in
then activates calcium influx to restore          those with low anxiety (28). Stimulation of
stores (12). Thapsigargin, which inhibits ER      olfactory receptor neurons from 7
calcium-ATPase, causes Ca2+ release from          medication free euthymic bipolar disorder
the ER (12).                                      patients, 10 euthymic bipolar patients treated
                                                  with mood stabilizers, and 17 controls, with
                                                  odorants, which increase IP3 levels, resulted
                                                  in lower [Ca2+]S in euthymic medicated
Compared with controls, elevations have
                                                  patients than controls (28.8 vs 86 nM) (18).
been found in bipolar disorder in resting free
                                                  The unusually low baseline levels of [Ca2+]i,
intracellular calcium ion concentration
                                                  small N, and use of euthymic patients
([Ca2+]B), as well as the rise in intracellular
                                                  prevent comparisons with other studies.
calcium ion concentration             ([Ca2+]S)
stimulated by agonists such as thrombin,
PAF,            serotonin,          dopamine,     To examine whether changes in [Ca2+]i are
fonnylrnethionylleucylphenylalanine,       and    inducible by the kinds of experiences
various mitogens, in blood platelets,             associated with mood disorders, lymphocyte
lymphocytes, B-lymphoblast cell lines             [Ca2+]i was measured in infant pigtail and
(BLCLs),        olfactory    neurons,      and    bonnet macaque monkeys separated from
neuroblastoma cells (17-24). Most studies         their mothers or peers during studies of
have reported similar elevations in mania         stress-induced immune suppression, which
and bipolar depression, which normalize           produces observable agitation, distress and
with normalization of mood after treatment        depression that remits with reunion (29-32).
with        various       medications        or   There were no differences in lymphocyte
electroconvulsive therapy (ECT) (20).             [Ca2+]i between animals prior to separation
Similar findings with different agonists in       and after reunion with the mother or peer
different cells from patients with bipolar        group. However, during separation, mean
disorder, along with the finding of lack of       (±SEM) [Ca2+]B (Figure 1) increased from
increase of [Ca2+]i in control platelets after    81.73 ± 2.51 nM to 139.8 ± 10.78 nM
incubation with a plasma ultrafiltrate from       (paired t-test t=5.771, df=10, p=0.0002).
bipolar disorder patients with elevated           Mean mitogen-stimulated [Ca2+]S (Figure 2)
platelet ([Ca2+]i) (25), suggest that             increased from 198.5 ± 20.81 nM to 334.2 ±
hyperactive intracellular Ca2+ signaling          36.58 nM (paired t test t=3.282, df=10,
represents a generalized primary change in        p=0.0083). Both measures of [Ca2+]i
intracellular calcium ion dynamics rather         returned to pre-separation values with
than the result of a circulating substance        reunion (Dubovsky SL, Laudenslager ML,
such as cortisol that might be elevated in        Reite ML: previously unpublished data).
bipolar disorder.                                 These results imply that loss, a precipitating
                                                  stress clearly implicated in mood disorders,
                                                  can cause reversible alterations in
Most studies find increased [Ca2+]B and
                                                  intracellular Ca2+ signaling that could alter
agonist-induced [Ca2+]s in mania and bipolar
                                                  affective and behavioral regulation and
depression, but not unipolar depression (22,
                                                  induce immune suppression.
26, 27). However, platelet [Ca2+]s in

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Internal Medicine Review
Intracellular Calcium Ion Signaling in Bipolar Mood Disorders: New Data and Directions
                                       March 2019

Figure 1

Figure 2

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Internal Medicine Review
Intracellular Calcium Ion Signaling in Bipolar Mood Disorders: New Data and Directions
                                       March 2019
3.1 Calcium channels and intracellular           One possible mediator of increased release
stores in the regulation of [Ca2+]i in           of stored intracellular calcium is amplified
bipolar disorder                                 production of IP3 as a result of increased PI
                                                 turnover that is either primary or secondary
                                                 to a hyperactive G-protein. Another
A polymorphism of the CACNA1C gene,              potential mechanism that has been a subject
which encodes the α1C subunit of the L-type      of recent research involves neuronal calcium
calcium channel CaV1.2, has been linked to       sensor-1 (NCS-1), a calcium binding protein
bipolar disorder (11, 15, 16, 33-36), as well    expressed in neurons that enhances the
as to associated alterations in intracellular    response of the IP3 receptor to IP3 in both a
calcium ion homeostasis (37) and circadian       calcium-dependent and calcium-independent
rhythms (36). This channel plays a central       manner (42). Both over-expression (43) and
role in regulating gene transcription and the    under-expression (44) of NCS-1 have been
tonic excitatory drive (11), raising the         noted in bipolar disorder.
suggestion that bipolar disorder could
represent a channelopathy, similar to
familial migraine and some seizure disorders
(38). As already noted, L-type calcium           Another line of investigation into the
channel dysfunction could contribute to          mechanism of increased release of Ca2+
elevated [Ca2+]B and resting neuronal            from intracellular stores in bipolar disorder
excitability, as well as to replenishing of      involves B-cell lymphoma-2 (Bcl-2), an
intracellular Ca2+ stores.                       antiapoptic and pro-neurotrophic protein
                                                 located on the ER and outer mitochondrial
                                                 membrane that interacts with the IP3
                                                 receptor to inhibit release of stored Ca2+ (9,
The immediate source of elevated [Ca2+]i         40). Decreased Bcl-2 activity, which has
with neuronal activation in bipolar disorder     been reported in bipolar disorder, may
appears to involve increased release from        contribute to increased Ca2+ release from
intracellular calcium stores promoted by         intracellular stores in bipolar disorder (9,
inositol triphosphate (IP3) (39, 40). Support    40). Both loss of the anti-apoptotic function
for this possibility is provided by              and increased [Ca2+]i could promote loss of
observations that thapsagargin, which            cerebral grey matter in some bipolar
promotes release of stored intracellular Ca2+,   disorder patients (40). In lymphoblasts of
increases platelet and lymphocyte [Ca2+]i in     patients with bipolar disorder, those with an
bipolar disorder (12). Along these lines,        SNP of the Bcl-2 gene associated with
IMPA2,        the    gene     for     inositol   decreased gene expression have been found
monophosphatase, the rate limiting step in       to have increased [Ca2+]B, as well as
reconstitution of membrane PIP2, is thought      increased IP3-mediated [Ca2+]S, presumably
to be a susceptibility gene for bipolar          associated with greater release from
disorder (9). Mitochondria play an essential     intracellular stores (11, 40, 45). Lithium (9,
role in regulation of intracellular Ca2+,        40), valproate (11), and ECT (9), all of
particularly in platelets, and mitochondrial     which are effective treatments for bipolar
dysfunction has been reported in parallel        disorder, have been noted to up-regulate
with intracellular Ca2+ dysregulation in         Bcl-2 gene expression, in some studies in
bipolar disorder (12, 41).                       conjunction with reducing elevated [Ca2+]i
                                                 in platelets of patients with bipolar disorder
                                                 (9, 40).

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Internal Medicine Review
Intracellular Calcium Ion Signaling in Bipolar Mood Disorders: New Data and Directions
                                       March 2019
   4. Calcium antagonist actions           of      production of PKC (9). Another pertinent
      mood stabilizing medications                 action of lithium is inhibition of thrombin
                                                   stimulated calcium flux through the transient
                                                   receptor potential canonical type 3 (TRPC3)
                                                   channel in human astroglioma cells (47). In
Lithium, the prototypical mood stabilizing
                                                   B-lymphoblast cell lines from bipolar I
medication that is effective for both poles of
                                                   patients, lithium attenuated lysophosphatidic
bipolar mood disorders, reduces elevated
                                                   acid (LPA) (agonist)- but not thapsigargin
[Ca2+]B and [Ca2+]S in peripheral cells of
                                                   (TG)- induced (store depletion) induced
patients with bipolar disorder but does not
                                                   mobilization      of    intracellular    Ca2+,
affect normal [Ca2+]i in most studies (46).
                                                   suggesting that lithium did not directly alter
One hypothesized mechanism of attenuation
                                                   release of Ca2+ from intracellular stores (48).
of hyperactive intracellular          calcium
                                                   In contrast, lithium inhibits the action of
signaling is that lithium inhibits inositol
                                                   NCS-1 on the IP3 receptor, which would be
monophosphatase, the rate limiting step in
                                                   expected to interfere with Ca2+ release from
reconstitution of PIP2 which, as noted
                                                   intracellular stores (42). Mechanisms of
earlier, is up-regulated in some cases of
                                                   calcium antagonism by lithium that could be
bipolar disorder; inhibition of the enzyme
                                                   relevant to reduction of [Ca2+]i are
would eventually deplete IP3, decreasing
                                                   summarized in Table 1 (9, 16, 17, 21, 27,
both intracellular Ca2+ release and
                                                   42, 47-49).

Table 1.Calcium Antagonist Actions of Lithium

      Reduced Ca2+ release from intracellular stores resulting from competitive inhibition of
       inositol-1-monophosphatase
           o Reduced production of inositol triphosphate (IP3)
           o Competitive inhibition results in increased inhibition with increased PI turnover
      Inhibition of the calcium binding protein neuronal calcium sensor-1 (NCS-1)
           o NCS-1 promotes release of Ca2+ from intracellular stores by enhancing
               responsiveness of IP3 receptors
      Reduction of calcium influx that replenishes intracellular stores
      Down-regulation of metabotropic glutamate receptors
      Enhancement of calcium efflux through an effect on sodium countertransport
      Antagonism of a hyperactive G protein by competition for magnesium ion binding
       required for G protein dissociation
      Induction of Bcl-2
      Inhibition of glycogen synthase kinase-3β
           o Enhances membrane stability
           o Inhibition of protein kinase C (PKC)

Carbamazepine, which has been in use as a          calcium-dependent potentials is comparable
mood stabilizer since 1962 (50), inhibits          to that produced by the calcium channel
Ca2+ currents in a variety of cellular models      blocker verapamil (52). In vitro incubation
(51), and the time course of suppression of        with carbamazepine significantly lowers

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Intracellular Calcium Ion Signaling in Bipolar Mood Disorders: New Data and Directions
                                       March 2019

lymphocyte [Ca2+]i in ill bipolar patients but       5. Calcium channel blockers as mood
not in controls or euthymic bipolar disorder            stabilizers
patients     (46).    Valproate,      another
anticonvulsant with mood stabilizing and
especially antimanic properties (53), was
                                                 Calcium antagonist actions of established
found to reduce lysophosphatidic acid
                                                 mood stabilizing medications tend to
(LPA)-stimulated increased [Ca2+]i in B
                                                 support an important role of calcium
lymphoblast cell lines from bipolar disorder
                                                 signaling in bipolar disorder, but such
patients to an extent similar to lithium, as
                                                 actions could be unrelated to the primary
well as thapsagargin-stimulated release of
                                                 mood stabilizing effect. Further evidence in
Ca2+ from intracellular stores (48). A study
                                                 favor of a role of intracellular Ca2+ could be
of transmitochondrial hybrid cells suggested
                                                 provided by antimanic or mood stabilizing
that valproate may reduce elevated [Ca2+]i
                                                 actions of medications the primary action of
only in cells with elevated mitochondrial
                                                 which is to attenuate increases in [Ca2+]i.
calcium levels (54). Incubation of
                                                 The calcium channel blockers (CCBs),
astrocytoma cells for 48 hours with
                                                 which reduce Ca2+ influx from the
therapeutic concentrations of valproate
                                                 extracellular space, are candidates in this
inhibited muscarinic receptor-stimulated
                                                 regard, in that reduction of tonic calcium
increased [Ca2+]i while slightly decreasing
                                                 influx may decrease baseline neuronal
PKC activity (55).                               excitability and reduce replenishment of the
                                                 intracellular pool from which more
                                                 immediate release results in rapid neuronal
Lamotrigine, another anticonvulsant that         activation (59).
may be useful in some cases of bipolar
disorder but is not as effective for mania as
for depression (56), also has calcium
                                                 There are 10 calcium channel blockers
channel blocking properties (57). Unlike
                                                 (CCBs) currently approved by the FDA,
lithium and valproate, lamotrigine did not
                                                 belonging to four chemical classes:
reduce lysophosphatidic acid (LPA)-
                                                 phenylalkylamines                (verapamil),
stimulated increased [Ca2+]i or thapsagargin
                                                 benzothiazepines                  (diltiazem),
stimulated release of Ca2+ from intracellular
                                                 dihydropyridines or DHPs (nifedipine,
stores in B lymphoblast cell lines from
                                                 amlodipine,      felodipine,       isradipine,
bipolar disorder patients (48). Interestingly,
                                                 nicardipine, nisoldipine, and nimodipine),
levetiracetam, an N-type calcium channel
                                                 and diarylaminopropylamines (bepridil) (16,
antagonist anticonvulsant that does not
                                                 35, 60). All CCBs inhibit calcium influx
appear to have reliable mood stabilizing
                                                 through potential dependent calcium
properties (58), does not alter increased
                                                 channels via activity-dependent binding to
[Ca2+]i in platelets of bipolar disorder
                                                 the α1 subunit of LTCCs. In addition to
patients (21). ECT, the most effective
                                                 binding    to    L-channels,     nimodipine,
treatment for both mania and depression,
                                                 nicardipine, methoxyverapamil, flunarizine,
decreases IP3 receptor expression in rat brain
                                                 and cinnarizine may also antagonize T-
(16), but [Ca2+]i before and after ECT has
                                                 channels, and a phenlyalkylamine binding
not been studied.
                                                 site exists on the inner mitochondrial
                                                 membrane (16). Because of their
                                                 heterogeneity of structure, binding site, and
                                                 action, these medications are not

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Intracellular Calcium Ion Signaling in Bipolar Mood Disorders: New Data and Directions
                                       March 2019

interchangeable. However, they all have the      nervous system disease (80). In trials with
capacity to reduce excessive excitability of     varying levels of blinding, nimodipine was
diverse cellular systems. CCB binding to L-      found to be effective for complex and
channels is enhanced by depolarization and       refractory bipolar disorder, both alone (81-
reduced by hyperpolarization (14), resulting     86) and in combination with lithium (87) or
in greater activity in hyperactive tissue.       carbamazepine (83), including in some
While CCBs are primarily used to treat           patients with neurological disorders. A
cardiovascular disorders, verapamil and          retrospective analysis of open administration
norverapamil can be recovered from human         diltiazem suggested benefit in treatment-
cerebrospinal fluid (CSF) after oral             resistant bipolar disorder (79), and a single-
administration (61), and the concentration of    blind trial suggested benefit of isradipine for
phenylalkylamines and other CCBs in the          bipolar depression (35), but no further
brain is sufficient to be protective after       research has been reported on either drug.
cerebral ischemia in animal models (62, 63).     Two negative trials of verapamil in mania
The lipophilic nimodipine crosses the            (88, 89) had larger sample sizes, but they
blood–brain barrier readily and is approved      were limited by brief treatment and use of
for the treatment of stroke.                     doses that were lower than doses that have
                                                 been found effective in other experience.

5.1. Studies of CCBs in bipolar disorder
                                                     6. Conclusions
Following a double blind, placebo-
controlled trial of verapamil in a single
manic patient (64), case reports appeared of     Traditional neurobiological hypotheses that
prevention by verapamil of antidepressant-       emphasize altered neurotransmitter and
induced hypomania (65, 66), and prevention       receptor function have failed to explain the
of affective recurrence in bipolar disorder      rapidly changing alternations and mixtures
(67). Open trials of verapamil were effective    of depressed and elevated mood in
in 4 of 7 manic patients (68), and in all        conditions like bipolar disorder, and they do
patients with mania, ¾ of patients with          not predict response to particular treatments
mixed episodes, and about 1/3 of acutely         or explain why the same treatment can be
depressed patients in a sample of 28 women       effective for both mania and bipolar
(69). Formal studies of CCBs have generally      depression. Another limitation of these
been small and relatively brief, with an         hypotheses is that they do not explain
emphasis on acute treatment of mania. For        common medical comorbidities of mood
example,     in    double-blind    protocols,    disorders such as hypertension, coronary
verapamil was superior to placebo in six         heart disease, and migraine headaches.
manic patients (70) and 7 manic or
schizoaffective-manic patients (71). Double-
blind comparisons reported equivalent            Newer lines of investigation addresses
antimanic efficacy to lithium (72-75) and        fundamental changes in cellular activity that
clonidine (76). In open trials, addition of      impact multiple downstream functions. In
verapamil (77, 78) or diltiazem (79, 80)         particular, intracellular Ca2+ has a biphasic
improved the response to lithium in primary      effect on cellular activities, with the
mania, but not mania secondary to central        potential to produce contradictory changes

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Internal Medicine Review
Intracellular Calcium Ion Signaling in Bipolar Mood Disorders: New Data and Directions
                                       March 2019

at different concentrations in different          effective for some patients and not others.
locations. Such universal intracellular           Thus far, there are no consensual markers to
signals have a potential impact on organ          guide treatment choice. It would therefore
systems throughout the body and have been         be useful to study whether elevated [Ca2+]i
linked to the pathophysiology of associated       predicts a preferential response to
medical conditions that involve cellular          established mood stabilizers with prominent
hyperactivity. It remains to be determined        calcium antagonist properties such as
whether increased [Ca2+]i is a downstream         lithium or possibly to CCBs. This question
effector arm of a primary change in cellular      could be addressed with prospective follow-
function, or whether it is an intermediate        up of a sufficient number of patients with
step in a cascade of changes. A number of         and without this finding. Since the
issues amplify widely replicated findings of      heterogeneity of CCB binding sites provides
increased intracellular Ca2+ signaling in a       for different spectra of action of different
variety of peripheral cells and some              CCBs, another informative line of research
neuronal     preparations   and     possible      would be to determine whether binding of a
mechanisms of elevated [Ca2+]i.                   particular medication to calcium channels
                                                  that are more localized to the central
                                                  nervous system (e.g., dihydropyridine CCBs
                                                  that act on T- as well as L-type channels
One issue is that both the mean and inter-
                                                  (86)) would predict a response to that
individual variability of [Ca2+]i are increased
                                                  medication. Studies of CCBs might be
in bipolar disorder (20). Standard deviations
                                                  supplemented by studies of medications that
of [Ca2+]B and [Ca2+]S are significantly
                                                  act on mediators of intracellular Ca2+
greater in bipolar disorder than in controls,
                                                  signaling such as tamoxifen, an estrogen
and both decrease to the control range with
                                                  receptor antagonist that inhibits protein
normalization of mood (20, 90). Variability
                                                  kinase C and had acute antimanic properties
in [Ca2+]i parallels the heterogeneity of
                                                  in a small controlled trial (92). Absence of
bipolar (and most psychiatric) disorders
                                                  reliable sources of funding for such research
(91). Cases of bipolar disorder vary in
                                                  makes it challenge to conduct systematic
features such as specific symptoms, severity,
                                                  clinical trials of sufficient size.
presence     of     depression,      psychosis,
comorbidity, intrusion of the mood disorder
into the personality, traumatic experiences,
course, family history, and treatment             Measuring [Ca2+]i with intracellular calcium
response. It seems likely that some bipolar       chelating dyes is tedious and time
phenotypes involve changes in intracellular       consuming. Lack of established reference
Ca2+ signaling, while others may be related       ranges requires measuring [Ca2+]i in controls
to a different pathophysiology. Studies           contemporaneously with patients, generally
correlating specific clinical features with       at the same time of day and year to
specific biological findings would help to        minimize the potential impact of circadian
elucidate whether there is a particular           and seasonal changes. Given the technical
constellation of features correlated with         challenges and expense in measuring [Ca2+]i
altered [Ca2+]i.                                  in peripheral cells, such measures are not
                                                  likely to prove practical in the clinic, even if
                                                  further research clarifies some of the
                                                  questions raised here. From a scientific
No established treatment is universally
                                                  standpoint,     however,       this    research
effective. Any given treatment will be

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Internal Medicine Review
Intracellular Calcium Ion Signaling in Bipolar Mood Disorders: New Data and Directions
                                       March 2019

exemplifies a conceptual shift away from         intracellular systems in the brain and the
neurotransmitters and receptors to more          body assort to produce constellations of
fundamental elements of cellular function. A     features that may be addressed more
parallel change in direction has involved a      efficiently by directing treatments at
shift in focus from specific regions of the      measurable cellular derangements rather
brain to neuronal networks that integrate        than diagnoses that are not yet specific
information from multiple locations (93).        enough to direct us to inform specific choice
These lines of investigation help us to learn    of therapy.
more about ways in which dysfunction of

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      Copyright 2019 Internal Medicine Review. All Rights Reserved. Volume 5, Issue 3.
Internal Medicine Review
Intracellular Calcium Ion Signaling in Bipolar Mood Disorders: New Data and Directions
                                       March 2019

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