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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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
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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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
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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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
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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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
Figure 1
Figure 2
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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
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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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
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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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
11
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
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
12
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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