Anticonvulsants as Calcium Antagonists in Mood Stabilization

This is a paper I wrote for a psychology course I am taking so the level of discourse is quite high, sorry about that. I promise though, it is comprehensible. What I’m basically talking about is calcium-channel blockers and other calcium antagonists (they turn calcium down). This refers to calcium in your brain and not calcium in your blood.

Mood Stabilizers and Bipolar Disorder

Because inadequate response, poor compliance, chronic recurring symptoms, and functional disability are constant challenges is the treatment of bipolar disorder, (Gitlin, 2006) efforts have been made to search out new mood stabilizing medication and determine new methods of action. There has been an effort to treat bipolar disorder with a class of medication termed “mood stabilizers”, most notably consisting of some anticonvulsants (also known as antiepileptics) in addition to the traditional lithium.[1] [push]I will show that these anticonvulsants, stabilize mood in bipolar disorder, at least partially, through their ability to act as calcium antagonists.[/push]

While anticonvulsants are widely used in the treatment of mood disorders, their method of action in mood stabilization is mostly unknown.[2] Recent research has indicated that disrupted calcium homeostasis is present in bipolar disorder, and that anticonvulsants and lithium effect calcium channels and concentration in the brain (Amann, 2005). The mood-stabilizing effects of calcium channel blockers like Nimodipine (Levy, 2000) further add to the evidence that calcium antagonism is useful in the treatment of bipolar disorder. I will show that these “mood stabilizers”, anticonvulsants, stabilize mood in bipolar disorder, at least partially, through their ability to act as calcium antagonists.

Bipolar Disorder and Calcium Levels

A review of hypercalcemia and hypocalcemia shows links from calcium blood levels to depression, irritability, delirium, and psychosis – symptoms that are similar to a bipolar disorder. Additional to calcium’s powerful abilities in the blood, it also plays a vital role both as primary and secondary messengers in the brain and according to Gargus (2009), is known to regulate “physiological systems at every level from membrane potential and ion transporters to kinases and transcription factors”. Calcium also plays a role in long-term changes to the architecture of a neuron (Amann, 2005). Disruption of intracellular calcium homeostasis is now thought to underlie many diseases such as Autism, Migraine, Seizures, and psychological disorders like bipolar (Gargus, 2009). Additionally, atrophy and glial death now found in mood disorders may be avoided by increasing cellular plasticity, accomplished through reducing intracellular calcium concentrations (Landmark, 2008).[pull]Atrophy and glial death now found in mood disorders may be avoided by increasing cellular plasticity, accomplished through reducing intracellular calcium concentrations.[/pull]

In some studies, the bipolar population has been found to have abnormally elevated intracellular calcium, elevated basal platelet and lymphocyte calcium concentrations, and elevated B-lymphoblast calcium (Silverstone, 2005). Found more consistently the bipolar population, both in the manic and depressed phase, is an enhanced calcium response to agonist stimulation (Silverstone, 2005). This may partially be explained by the enhanced platelet intracellular calcium mobilization found after stimulation by serotonin in bipolar disorder (Suzuki, 2003). This research suggests that not only are calcium levels elevated, and calcium activities dysregulated, but this may become worse if the patient is treated with a selective serotonin reuptake inhibitor (SSRI), which is often the case.

Lithium and Calcium

Lithium has long been the standard therapy for bipolar disorder both for acute and maintenance treatment due to its quality and quantity of supporting evidence (Gitlin, 2006), (Levy, 2000). Part of lithium’s biological effects is to both inhibit the entry of calcium intracellularly acting as a calcium antagonist, and to block calcium channels directly. This, in turn, inhibits other cellular responses of subtypes adrenergic, serotonergic, and cholinergic (Levy, 2000). Moreover, adding Verapamil, a calcium channel blocker, to unresponsive lithium treatment, improves outcomes, (Mallinger, 2008) suggesting that both calcium itself and calcium channels benefit from antagonists.[3]

Calcium Channel Blockers as Mood Stabilizers

A number of calcium channel antagonists have been studied with varied results likely resulting from their specific affinities to different calcium channel subtypes and their individual ability to cross the blood-brain barrier. Verapamil, one of the most studied calcium channel blockers, is not the most lipophilic and is likely not as effective as other calcium channel blockers like nimodipine (Gitlin, 2006), although Verapamil has been shown effective in some studies and does work on calcium ions in a way similar to lithium (Levy, 2000).[pull]Nimodipine is not only a calcium channel blocker but has also been shown to have anticonvulsant properties and has shown great potential as a mood-stabilizer particularly for cycling forms of bipolar disorder.[/pull]

Nimodipine is not only a calcium channel blocker but has also been shown to have anticonvulsant properties and has shown great potential as a mood-stabilizer particularly for cycling forms of bipolar disorder (Goodnick, 2000). While its efficacy needs further study, there have been positive results shown for bipolars in manic, depressed, and rapid cycling states.

Anticonvulsants spawn a broad range of medication and methods of action. Useful actions for treatment of psychiatric disorders are thought to be: increases in GABAurgic transmissions, decreases in glutamate, inhibition of voltage-gates sodium and calcium channels, and interference with intracellular modulators (Landmark, 2008). For the treatment of bipolar disorder, specifically mood stabilization, carbamazepine and Lamotrigine, have been identified, and accepted as treatments through their inhibition of voltage-gated sodium and calcium channels (Landmark, 2008).[push]Anticonvulsants that work on calcium channel blockers are also known to be helpful in the treatment of neuropathic pain, which some researchers believe is closely tied to psychological pain, here in the form of bipolar disorder.[/push]

Carbamezapine and Lamotrigine have also been seen to positively affect mood while GABAurgic transmitting anticonvulsants have not. The general decreased excitability found with Carbamezapine and Lamotrigine may also be responsible for their role in preventing affective episodes (Landmark, 2008). Valproate is also considered an accepted treatment although likely functions more from the combined actions mentioned above, making it an anti-mania treatment as well as possibly useful for mood stabilization (Landmark, 2008). The effects of anticonvulsants are compared to the therapeutic effects of lithium on calcium, calcium channel blockers, and inositol concentrations, another secondary messenger indirectly acting on calcium signals (Berridge, 1993). Anticonvulsants that work on calcium channel blockers are also known to be helpful in the treatment of neuropathic pain (Landmark, 2008), which some researchers believe is closely tied to psychological pain, here in the form of bipolar disorder.

Lithium acts in the body as a complex agent, making it difficult for scientists to specify exactly how it stabilizes mood in the bipolar population, in spite of its being used for decades. It is clear; however, that part of its biological action is to antagonize calcium concentrations as well as calcium channels. This action is shown to have positive mood stabilizing effects as proven by successful treatments with calcium blocking agents like Verapamil and Nimodipine. These same mood stabilizing effects are seen with some anticonvulsants which also act as calcium antagonists. Therefore, it is reasonable to assume that part of the reason why some anticonvulsants stabilize mood is because of their ability to work on calcium, calcium channel blockers, and inositol, as seen in Lithium and calcium channel blockers.

_________________________

[1] There are several antipsychotics also in this list but are outside the scope of this paper.
[2] Treatment of bipolar disorder and mood stabilization in this paper will refer to non-acute treatment, although some of the drugs mentioned can be used in acute treatment also. No distinction will be made between types of bipolar.
[3] It should be noted that Mallinger (2009) posited that the positive effects of combining Lithium and Verapamil may also be due to the inhibition of protein kinase C (PKC) activity provided by the Verapamil.

References

(I apologize for the departure from APA style, blog formatting issues.)

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Berridge, M. J. (1993). Inositol Trisphosphate and Calcium Signaling. Nature 361, 315-325.
doi:10.1038/361315a0
Available online: http://www.ncbi.nlm.nih.gov/pubmed/8381210

Farooq, M., Moore, P., Bhatt, A., Aburashed, R., & Kassab, M. (2008). Therapeutic Role of Zonisamide in Neuropsychiatric Disorders. Mini Reviews in Medicinal Chemistry, 8(10), 968-975.
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Gargus, J. (2009). Genetic Calcium Signaling Abnormalities in the Central Nervous System: Seizures, Migraine, and Autism. Annals of the New York Academy of Sciences, 1151133-156.
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Goodnick, P. (2000). The use of nimodipine in the treatment of mood disorders. Bipolar Disorders, 2(3), 165.
Retrieved from Academic Search Complete database.
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Levy, N., & Janicak, P. (2000). Calcium channel antagonists for the treatment of bipolar disorder. Bipolar Disorders, 2(2), 108-119.
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Mallinger, A., Thase, M., Haskett, R., Buttenfield, J., Luckenbaugh, D., Frank, E., et al. (2008). Verapamil augmentation of lithium treatment improves outcome in mania unresponsive to lithium alone: preliminary findings and a discussion of therapeutic mechanisms. Bipolar Disorders, 10(8), 856-866.
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Silverstone, P., McGrath, B., Wessels, P., Bell, E., & Ulrich, M. (2005). Current Pathophysiological Findings in Bipolar Disorder and in its Subtypes. Current Psychiatry Reviews, 1(1), 75-101.
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Suzuki, K., Kusumi, I., Akimoto, T., Sasaki, Y., & Koyama, T. (2003). Altered 5-HT-Induced Calcium Response in the Presence of Staurosporine in Blood Platelets from Bipolar Disorder Patients. Neuropsychopharmacology, 28(6), 1210-1214.
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