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

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: [email protected] 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 2+ concentration ([Ca ]i) in peripheral cells and neuronal cultures in mania and bipolar depression and presents 2+ new data on induction of increased lymphocyte [Ca ]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.

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 2+ practices, 32.8% of the sample appeared to ([Ca ]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, 2 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, 2+ calcium signaling such as migraine increases [Ca ]i to stimulated levels 2+ headaches, hypertension and cardiovascular ([Ca ]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 2+ membrane phosphatidylinositol (PI) system, Within neurons, intracellular Ca 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 (IP ) and diacylglycerol (DG). regulation of expression of multiple genes, 3 IP acts on mitochondrial and other consciousness, remodeling of neuronal 3 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. IP and DG are then combined to things in neuronal resilience and mood 3 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 2+ Calcium ions enter the cytosol from the ([Ca ]i) is normally regulated tightly at extracellular space through receptor- approximately 100 nM, or 0.0001 of the 2+ operated channels gated by receptors for Ca 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 2+ 2+ 2+ high [Ca ]i must be produced rapidly to baseline level of intracellular Ca ([Ca ]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

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 2+ to nucleus signaling in the brain, is coded by 3. Ca 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

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+] in euthymic medicated Compared with controls, elevations have S patients than controls (28.8 vs 86 nM) (18). been found in bipolar disorder in resting free The unusually low baseline levels of [Ca2+] , intracellular calcium ion concentration i 2+ small N, and use of euthymic patients ([Ca ]B), as well as the rise in intracellular 2+ prevent comparisons with other studies. calcium ion concentration ([Ca ]S) stimulated by agonists such as thrombin, PAF, serotonin, dopamine, 2+ To examine whether changes in [Ca ]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 2+ [Ca ]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). 2+ [Ca ]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 2+ 2+ (±SEM) [Ca ]B (Figure 1) increased from increase of [Ca ]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 2+ 2+ Mean mitogen-stimulated [Ca ]S (Figure 2) platelet ([Ca ]i) (25), suggest that 2+ increased from 198.5 ± 20.81 nM to 334.2 ± hyperactive intracellular Ca signaling 36.58 nM (paired t test t=3.282, df=10, represents a generalized primary change in 2+ p=0.0083). Both measures of [Ca ]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,

2+ can cause reversible alterations in Most studies find increased [Ca ]B and 2+ 2+ intracellular Ca signaling that could alter agonist-induced [Ca ] in mania and bipolar s affective and behavioral regulation and depression, but not unipolar depression (22, 2+ induce immune suppression. 26, 27). However, platelet [Ca ]s in

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

Figure 1

Figure 2

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 2+ stores in the regulation of [Ca ]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 Another line of investigation into the (38). As already noted, L-type calcium 2+ channel dysfunction could contribute to mechanism of increased release of Ca 2+ from intracellular stores in bipolar disorder elevated [Ca ]B and resting neuronal 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 2+ 2+ receptor to inhibit release of stored Ca (9, The immediate source of elevated [Ca ]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 2+ and increased [Ca ]i could promote loss of observations that thapsagargin, which cerebral grey matter in some bipolar promotes release of stored intracellular Ca2+, 2+ disorder patients (40). In lymphoblasts of increases platelet and lymphocyte [Ca ]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 2+ to have increased [Ca ]B, as well as reconstitution of membrane PIP , is thought 2+ 2 increased IP3-mediated [Ca ]S, presumably to be a susceptibility gene for bipolar associated with greater release from disorder (9). Mitochondria play an essential 2+ intracellular stores (11, 40, 45). Lithium (9, role in regulation of intracellular Ca , 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 2+ disorder, have been noted to up-regulate with intracellular Ca dysregulation in Bcl-2 gene expression, in some studies in bipolar disorder (12, 41). 2+ conjunction with reducing elevated [Ca ]i in platelets of patients with bipolar disorder

(9, 40).

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 2+ 2+ acid (LPA) (agonist)- but not thapsigargin [Ca ] and [Ca ] in peripheral cells of B S (TG)- induced (store depletion) induced patients with bipolar disorder but does not 2+ 2+ mobilization of intracellular Ca , affect normal [Ca ] in most studies (46). i 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 IP receptor, which would be monophosphatase, the rate limiting step in 3 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 2+ relevant to reduction of [Ca ]i are would eventually deplete IP3, decreasing 2+ summarized in Table 1 (9, 16, 17, 21, 27, both intracellular Ca 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

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

2+ lymphocyte [Ca ]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+] in B i 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 2+ mood stabilizing effect. Further evidence in Ca from intracellular stores (48). A study 2+ favor of a role of intracellular Ca 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 2+ which is to attenuate increases in [Ca ] . calcium levels (54). Incubation of i The calcium channel blockers (CCBs), astrocytoma cells for 48 hours with 2+ which reduce Ca 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+] while slightly decreasing i 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+] or thapsagargin i 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+] in platelets of bipolar disorder i 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 IP receptor expression in rat brain 3 and cinnarizine may also antagonize T- (16), but [Ca2+] before and after ECT has i 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 9 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 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

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 2+ systems throughout the body and have been be useful to study whether elevated [Ca ]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 2+ whether increased [Ca ]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 2+ mechanisms of elevated [Ca ]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- 2+ (86)) would predict a response to that individual variability of [Ca ] are increased i medication. Studies of CCBs might be in bipolar disorder (20). Standard deviations 2+ 2+ supplemented by studies of medications that of [Ca ] and [Ca ] are significantly B S 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 2+ kinase C and had acute antimanic properties in [Ca ] parallels the heterogeneity of i 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, presence of depression, psychosis, clinical trials of sufficient size. comorbidity, intrusion of the mood disorder into the personality, traumatic experiences, 2+ course, family history, and treatment Measuring [Ca ]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 2+ 2+ Ca signaling, while others may be related ranges requires measuring [Ca ]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 2+ constellation of features correlated with challenges and expense in measuring [Ca ]i 2+ altered [Ca ]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

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

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

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

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

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