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Bipolar disorder (BD) is a recurrent, life-long psychiatric illness affecting nearly 2% of the world population1,2 that is characterized by episodes of mania and depression interspersed among periods of relative mood stability.3 The illness causes an enormous health burden, which makes understanding its pathophysiology and treatment patterns a substantial priority.4 In the 1950s, lithium was found to be effective for treating acute manic episodes and preventing relapse in BD.5 Since then, valproate and carbamazepine also have been FDA-approved for treating mania.6,7 Antipsychotics have also shown evidence of efficacy in BD treatment,8,9 particularly for use in acute settings for more rapid effect or for a limited duration,10 which has led some to refer to them as “mood stabilizers.”11
In this article, we describe changes in trends of prescribing medications to treat BD, the role of ion dysregulation in the disorder, and how a better understanding of this dysregulation might impact the choice of treatment.
Changes in pharmacotherapy for bipolar disorder
From 1997 through 2016, the use of lithium for BD decreased from >30% of patients to 17.6% (with a nadir of 13.9% from 2009 to 2012).12 Over the same period, the use of nonlithium mood stabilizers decreased from 30.4% to approximately 4.8%, while second-generation antipsychotic (SGAs) use increased from 12.4% to 50.4%.12 Distressingly, antidepressant use increased from approximately 47% to 56.8%, and antidepressant use without concomitant mood stabilizers increased from 38% to 40.8%, although the rate of antidepressants without either a mood stabilizer or an antipsychotic remained relatively stable (14.9% to 16.8%).12 In randomized trials, when added to mood stabilizers, antidepressants have consistently failed to separate from placebo,13-15 but they can destabilize the illness, resulting in increases in mania, depression, and subsyndromal mixed symptoms.16-18
It is easy to understand clinicians’ attempts to address their patients’ distress due to depressive symptoms that do not resolve with mood stabilizers.19,20 Similarly, the increased use of antipsychotics is driven by evidence that antipsychotics are effective for treating bipolar depression and preventing the recurrence of manic and (for some antipsychotics) depressive episodes.21,22 However, long-term antipsychotic use causes brain volume change in patients with schizophrenia23 or major depressive disorder24 and in nonhuman primates25,26; metabolic abnormalities27-31; and cardiovascular adverse effects.32 Antipsychotics are believed to be associated with withdrawal psychosis.33,34 In the head-to-head Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study, quetiapine was as effective as lithium but associated with more adverse effects.35 Importantly, the estimated disability-adjusted life years of patients with BD increased by 54.4% from 6.02 million in 1990 to 9.29 million in 2017, which is greater than the increase in the incidence of BD (47.74%) over the same time.36 This means that despite the dramatic increase in treatment options for people with BD, functional outcomes have declined.
One major difference between antipsychotics and mood stabilizers is that antipsychotics do not alter the underlying abnormal pathology of BD.37 An ideal pharmacologic intervention is one that corrects a known pathophysiologic anomaly of the condition being treated. There are no demonstrated abnormalities in the dopamine or serotonin systems in individuals with BD, but long-term use of antipsychotics may create dopaminergic alterations.33 One of the most reproducible biomarkers associated with manic and bipolar depressed mood states is increased intracellular sodium38,39 and reduced ability to correct a sodium challenge.40-42 By normalizing intracellular sodium levels, lithium and the mood-stabilizing anticonvulsants uniquely and specifically counter known physiologic abnormalities in patients with BD.37,43
The role of ion dysregulation
The pathophysiology of BD remains elusive. A multitude of lines of evidence link BD to abnormal neuroimaging findings,22,44,45 oxidative stress,46 inflammation,47 and mitochondrial disease,48 but there is still no unifying understanding of these findings. Ion dysregulation appears to be central to understanding and treating BD.38,39
Despite extensive genetic studies, no genes have been identified that mediate >5% of the risk for BD. Nonetheless, 74% of all genes identified as mediating risk for BD code for proteins essential for the regulation of ion transport and membrane potential.49 The 2 genes that contribute the greatest risk are CACNA1C and ANK3, which code for a calcium channel and a cytoskeletal protein, respectively.50ANK3 codes for ankyrin G, which plays a role in proper coupling of the voltage-gated sodium channels to the cytoskeleton.51 An additional risk gene, TRANK1, contains multiple ankyrin-like repeat domains, which suggests some shared functions with ANK3.52 More importantly, the most reproducible pathophysiologic findings in BD are dysregulation of sodium, potassium, hydrogen, and calcium transport, with consequent alteration of depolarization potential, neuronal excitability, and calcium-mediated processes.38,39,53-56 For example, increased sodium and calcium within cells have been observed in both mania and bipolar depression, and these levels normalize during euthymia. All medications that are effective for treating BD may reduce intracellular sodium or calcium; traditional mood stabilizers do so directly by inhibiting voltage-sensitive sodium channels in an activity-dependent manner or displacing intracellular sodium,43,57 whereas antipsychotics do so indirectly by increasing sodium pump activity through inhibition of second messengers of the dopamine D2 family of receptors.37
Continue to: The extent of ion dysregulation...
The extent of ion dysregulation is directly associated with the expressed mood state of the illness. A small reduction in the activity of the sodium pump results in a small increase in intracellular sodium (approximately 10 mM).39,58 This led to the hypothesis that increased intracellular sodium causes the transmembrane potential to increase closer to membrane depolarization threshold, which increases excitability of affected neurons.38,39,58 Neurons are likely to fire and propagate signals more easily, which may manifest as symptoms of mania, such as increased energy, activity, lability, excitability, irritability, tangentiality, and looseness of associations. As the process of increased intracellular sodium progresses, a minority of neurons are expected to have their transmembrane potentials depolarize sufficiently for the resting membrane potential to go beyond threshold potential.59 Such neurons are in a state of constant depolarization (also known as depolarization block), which disrupts neuronal circuits. The difficulty in progression of these signals results in the classic bipolar depression symptoms of low energy, reduced activity, and slowing of all brain activity that is seen as psychomotor slowing.38
Implications for treatment
Medications for treating bipolar illness include lithium, anticonvulsants, benzodiazepines, first-generation antipsychotics, and SGAs.37,43
Mood stabilizers (lithium and certain anticonvulsants) correct the previously mentioned sodium abnormality by reducing sodium entry into the cell in an activity-dependent manner.43 As the only agents that directly address a known pathophysiologic abnormality, they are foundational in the treatment of BD.60 Lithium effectively treats acute mania and prevents relapse.61 It preferentially targets the active neurons, entering through both voltage-responsive and neurotransmitter-coupled channels.43,62 This results in an increase of intracellular lithium concentrations to as much as 8 times that of the extracellular concentration.63 These ions displace intracellular sodium ions in a 1:1 ratio, which results in a reduced intracellular sodium concentration that reduces the excitability of neurons.43,57,62
Substantial evidence supports the use of valproic acid for initial and maintenance treatment of BD.64 It inhibits the voltage-sensitive sodium channel when the channel is open, which results in an activity-dependent action that selectively impacts rapidly firing neurons.43 The voltage-gated sodium channels exist nearly exclusively on the axon, beyond the hillock65; as such, valproic acid will only inhibit neurons that fire, whereas lithium accumulates throughout the neuron and will affect depolarization in the neuronal soma as well as the firing in the axon.43 Additionally, valproic acid has been observed to enhance gamma-aminobutyric acid (GABA) levels and transmission.43,66,67 A meta-analysis that included 6 randomized controlled trials illustrated that, acutely, valproate was not different from lithium’s overall efficacy (RR 1.02; 95% CI, 0.87 to 1.20), but was associated with reduced dropout rates compared with placebo or lithium (RR 0.82; 95% CI, 0.71 to 0.95 and RR 0.87; 95% CI, 0.77 to 0.98, respectively).64
Lamotrigine is an anticonvulsant used for initial and maintenance treatment of BD, with greater efficacy for depressive episodes68; it also has notable effect for treating bipolar depression, although it is not FDA-approved for this indication.69 Lamotrigine inhibits sodium influx by binding to open voltage-gated sodium channels70 but also appears to reduce N-methyl-D-aspartate–mediated sodium entry,71 thereby acting both prehillock and posthillock.
Continue to: Carbamazepine is an anticonvulsant...
Carbamazepine is an anticonvulsant FDA-approved for treating BD.7 Like valproate, it acts by inhibiting voltage-gated sodium channels in an activity-dependent manner,72 which means it preferentially inhibits the most active neurons and those with higher intracellular sodium.43
Benzodiazepines, which have shown to be effective for treating acute mania,73 potentiate synaptic GABA receptors accruing an elevation in intracellular chloride influx.74 Despite acute efficacy, benzodiazepine use is limited because these agents are associated with worsening long-term, substance use–related outcomes.75,76
Antipsychotics are effective for treating mood disorders,60,76 and their use has been rising dramatically.12 The antimanic effect of all antipsychotics is believed to be mediated through dopamine D2 blockade, since use of a dose sufficient to block D2 receptors is required, and haloperidol, which acts exclusively on the D2 receptor, is equal to SGAs in its antimanic effect.77 Blockade of the D2 receptor will increase the activity of the sodium pump (sodium and potassium-activated adenosine triphosphatase) thus reducing intracellular sodium and calcium concentrations.37 When antipsychotics are used as antidepressants, they are generally used at doses lower than those used to treat mania.78
Antipsychotics are effective for treating BD, and may work more quickly than other agents for treating acute mania.79 However, maintenance or prevention trials tend to favor mood stabilizers.35,60,80 Several add-on studies have found the combination of a mood stabilizer plus an antipsychotic is superior to a mood stabilizer alone or an antipsychotic alone.81
An argument for mood stabilizers
Evidence suggests mood stabilizers and other approaches, such as antipsychotics, are almost equivalent for treating acute mania, with a small clinical advantage of mood stabilizers for preventing relapse. In general, current treatment guidelines do not distinguish mood stabilizers from antipsychotics as the first-line treatment.82 Over the past 20 years, antipsychotic use has increased while mood stabilizer use has decreased, so that presently a patient with BD is more likely to be prescribed an antipsychotic than a mood stabilizer.12 Over the same time, dysfunction among patients with BD has increased.33 Antipsychotics are appealing because they appear to be equally effective and generally well tolerated. But these agents cause problems that are difficult to see in routine visits, such as metabolic27-31 and cardiovascular adverse effects29 as well as reductions in brain volume.23-26 Mechanistic research suggests that mood stabilizers directly correct known pathophysiologic anomalies with additional protective effects, whereas antipsychotics appear to create new abnormalities and contribute to medical problems. Clinicians need to look beyond the similarities in acute efficacy and make a more broadly supported, evidence-based choice for managing BD, which clearly places mood stabilizers as the first-line agent and antipsychotics as reasonable alternatives. At a minimum, mood stabilizers should be viewed as the foundation to which antipsychotics can be added.
Bottom Line
Traditional mood stabilizers—lithium and some anticonvulsants—are the only agents that directly address physiologic abnormalities associated with both mania and bipolar depression, including mood state–associated elevations of intracellular sodium. Because of their specificity, these agents maximize mood stabilization and minimize adverse effects.
Related Resources
- Karas A, Stummer L, Freedberg A. Psychiatric and nonpsychiatric indications for mood stabilizers and select antiepileptics. Current Psychiatry. 2022;21(4):34-38. doi:10.12788/cp.0230
- Koch J. Mood stabilizers: balancing tolerability, serum levels, and dosage. Current Psychiatry. 2021;20(7):37-40. doi:10.12788/cp.0147
Drug Brand Names
Carbamazepine • Tegretol
Haloperidol • Haldol
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Quetiapine • Seroquel
Valproate • Depakote, Depakene
1. Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013;382(9904):1575-1586. doi:10.1016/S0140-6736(13)61611-6
2. Merikangas KR, Jin R, He JP, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011;68(3):241-251. doi:10.1001/archgenpsychiatry.2011.12
3. Müller JK, Leweke FM. Bipolar disorder: clinical overview. Article in English, German. Med Monatsschr Pharm. 2016;39(9):363-369.
4. Smith DJ, Whitham EA, Ghaemi SN. Bipolar disorder. Handb Clin Neurol. 2012;106:251-263. doi:10.1016/B978-0-444-52002-9.00015-2
5. Goodwin FK, Ghaemi SN. The impact of the discovery of lithium on psychiatric thought and practice in the USA and Europe. Aust N Z J Psychiatry. 1999;33 Suppl:S54-S64. doi:10.1111/j.1440-1614.1999.00669.x
6. Pope HG, McElroy SL, Keck PE, et al. Valproate in the treatment of acute mania. A placebo-controlled study. Arch Gen Psychiatry. 1991;48(1):62-68. doi:10.1001/archpsyc.1991.01810250064008
7. Weisler RH, Keck PE Jr, Swann AC, et al. Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: a multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2005;66(3):323-330. doi:10.4088/jcp.v66n0308
8. Tarr GP, Glue P, Herbison P. Comparative efficacy and acceptability of mood stabilizer and second generation antipsychotic monotherapy for acute mania--a systematic review and meta-analysis. J Affect Disord. 2011;134(1-3):14-19. doi:10.1016/j.jad.2010.11.009
9. Pahwa M, Sleem A, Elsayed OH, et al. New antipsychotic medications in the last decade. Curr Psychiatry Rep. 2021;23(12):87.
10. Correll CU, Sheridan EM, DelBello MP. Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trials. Bipolar Disord. 2010;12(2):116-141. doi:10.1111/j.1399-5618.2010.00798.x
11. Rybakowski JK. Two generations of mood stabilizers. Int J Neuropsychopharmacol. 2007;10:709-711. doi:10.1017/s146114570700795x
12. Rhee TG, Olfson M, Nierenberg AA, et al. 20-year trends in the pharmacologic treatment of bipolar disorder by psychiatrists in outpatient care settings. Am J Psychiatry. 2020;177(8):706-715. doi:10.1176/appi.ajp.2020.19091000
13. El-Mallakh RS. Adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;357(6):615; author reply 615-616.
14. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-1722. doi:10.1056/NEJMoa064135
15. Ghaemi SN, Whitham EA, Vohringer PA, et al. Citalopram for acute and preventive efficacy in bipolar depression (CAPE-BD): a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2021;82(1):19m13136. doi:10.4088/JCP.19m13136
16. El-Mallakh RS, Ghaemi SN, Sagduyu K, et al. Antidepressant-associated chronic irritable dysphoria (ACID) in STEP-BD patients. J Affect Disord. 2008;111(2-3):372-377. doi:10.1016/j.jad.2008.03.025
17. Ghaemi SN, Ostacher MM, El-Mallakh RS, et al. Antidepressant discontinuation in bipolar depression: a systematic treatment enhancement program for bipolar disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry. 2010;71(4):372-380.
18. Strejilevich SA, Martino DJ, Marengo E, et al. Long-term worsening of bipolar disorder related with frequency of antidepressant exposure. Ann Clin Psychiatry. 2011;23(3):186-192.
19. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society of Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013;170(11):1249-1262. doi:10.1176/appi.ajp.2013.13020185
20. McIntyre RS, Calabrese JR. Bipolar depression: the clinical characteristics and unmet needs of a complex disorder. Curr Med Res Opin. 2019;35(11):1993-2005.
21. Fornaro M, Stubbs B, De Berardis D, et al. Atypical antipsychotics in the treatment of acute bipolar depression with mixed features: a systematic review and exploratory meta-analysis of placebo-controlled clinical trials. Int J Mol Sci. 2016;17(2):241. doi:10.3390/ijms17020241
22. Lindström L, Lindström E, Nilsson M, et al. Maintenance therapy with second generation antipsychotics for bipolar disorder – a systematic review and meta-analysis. J Affect Disord. 2017;213:138-150. doi:10.1016/j.jad.2017.02.012
23. Ho BC, Andreasen NC, Ziebell S, et al. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry. 2011;68(2):128-137. doi:010.1001/archgenpsychiatry.2010.199
24. Voineskos AN, Mulsant BH, Dickie EW, et al. Effects of antipsychotic medication on brain structure in patients with major depressive disorder and psychotic features: neuroimaging findings in the context of a randomized placebo-controlled clinical trial. JAMA Psychiatry. 2020;77(7):674-683. doi:10.1001/jamapsychiatry.2020.0036
25. Konopaske GT, Bolo NR, Basu AC, et al. Time-dependent effects of haloperidol on glutamine and GABA homeostasis and astrocyte activity in the rat brain. Psychopharmacology (Berl). 2013;230(1):57-67. doi:10.1007/s00213-013-3136-3
26. Dorph-Petersen KA, Pierri JN, Perel JM, et al. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology. 2005;30(9):1649-1661. doi:10.1038/sj.npp.1300710
27. McIntyre RS, Mancini DA, Basile VS, et al. Antipsychotic-induced weight gain: bipolar disorder and leptin. J Clin Psychopharmacol. 2003;23(4):323-327. doi:10.1097/01.jcp.0000085403.08426.f4
28. McIntyre RS, Konarski JZ, Wilkins K, et al. Obesity in bipolar disorder and major depressive disorder: results from a national community health survey on mental health and well-being. Can J Psychiatry. 2006;51(5):274-280. doi:10.1177/070674370605100502
29. McIntyre RS, Cha DS, Kim RD, et al. A review of FDA-approved treatment options in bipolar depression. CNS Spectr. 2013;18(Suppl 1):4-20. doi:10.1017/S1092852913000746
30. Barton BB, Segger F, Fischer K, et al. Update on weight-gain caused by antipsychotics: a systematic review and meta-analysis. Expert Opin Drug Saf. 2020;19(3):295-314. doi:10.1080/14740338.2020.1713091
31. Doane MJ, Bessonova L, Friedler HS, et al. Weight gain and comorbidities associated with oral second-generation antipsychotics: analysis of real-world data for patients with schizophrenia or bipolar I disorder. BMC Psychiatry. 2022;22(1):114. doi:10.1186/s12888-022-03758-w
32. Buckley NA, Sanders P. Cardiovascular adverse effects of antipsychotic drugs. Drug Saf. 2000;23(3):215-228. doi:10.2165/00002018-200023030-00004
33. Ali Z, Roque A, El-Mallakh RS. A unifying theory for the pathoetiologic mechanism of tardive dyskinesia. Med Hypotheses. 2020;140:109682. doi:10.1016/j.mehy.2020.109682
34. Sleem A, El-Mallakh RS. Adaptive changes to antipsychotics: their consequences and how to avoid them. Curr Psychiatry. 2022;21(7):46-50,52. doi: 10.12788/cp.0262
35. Nierenberg AA, McElroy SL, Friedman ES, et al. Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness): a pragmatic 6-month trial of lithium versus quetiapine for bipolar disorder. J Clin Psychiatry. 2016;77(1):90-99. doi:10.4088/JCP.14m09349
36. He H, Hu C, Ren Z, et al. Trends in the incidence and DALYs of bipolar disorder at global, regional, and national levels: results from the global burden of disease study 2017. J Psychiatr Res. 2020;125:96-105. doi:10.1016/j.jpsychires.2020.03.015
37. Roberts RJ, Repass R, El-Mallakh RS. Effect of dopamine on intracellular sodium: a common pathway for pharmacological mechanism of action in bipolar illness. World J Biol Psychiatry. 2010;11(2 Pt 2):181-187. doi:10.1080/15622970902718774
38. El-Mallakh RS, Wyatt RJ. The Na, K-ATPase hypothesis for bipolar illness. Biol Psychiatry. 1995;37(4):235-244. doi:10.1016/0006-3223(94)00201-D
39. El-Mallakh RS, Yff T, Gao Y. Ion dysregulation in the pathogenesis of bipolar disorder. Ann Depress Anxiety. 2016;3(1):1076.
40. Li R, El-Mallakh RS. Differential response of bipolar and normal control lymphoblastoid cell sodium pump to ethacrynic acid. J Affect Disord. 2004;80(1):11-17. doi:10.1016/S0165-0327(03)00044-2
41. Woodruff DB, El-Mallakh RS, Thiruvengadam AP. Validation of a diagnostic screening blood test for bipolar disorder. Ann Clin Psychiatry. 2012;24(2):135-139.
42. Gao Y, Lohano K, Delamere NA, et al. Ethanol normalizes glutamate-induced elevation of intracellular sodium in olfactory neuroepithelial progenitors from subjects with bipolar illness but not nonbipolar controls: biologic evidence for the self-medication hypothesis. Bipolar Disord. 2019;21(2):179-181. doi:10.1111/bdi.12737
43. El-Mallakh RS, Huff MO. Mood stabilizers and ion regulation. Harv Rev Psychiatry. 2001;9(1):23-32. doi:10.1080/10673220127873
44. Phillips ML, Swartz HA. A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research. Am J Psychiatry. 2014;171(8):829-843. doi:10.1176/appi.ajp.2014.13081008
45. Hibar DP, Westlye LT, Doan NT, et al. Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group. Mol Psychiatry. 2018;23(4):932-942. doi:10.1038/mp.2017.73
46. Brown NC, Andreazza AC, Young LT. An updated meta-analysis of oxidative stress markers in bipolar disorder. Psychiatry Res. 2014;218(1-2):61-68. doi:10.1016/j.psychres.2014.04.005
47. Benedetti F, Aggio V, Pratesi ML, et al. Neuroinflammation in bipolar depression. Front Psychiatry. 2020;11:71. doi:10.3389/fpsyt.2020.00071
48. Andreazza AC, Duong A, Young LT. Bipolar disorder as a mitochondrial disease. Biol Psychiatry. 2018;83(9):720-721. doi:10.1016/j.biopsych.2017.09.018
49. Askland KD. Toward a biaxial model of “bipolar” affective disorders: further exploration of genetic, molecular and cellular substrates. J Affect Disord. 2006;94(1-3):35-66. doi:10.1016/j.jad.2006.01.033
50. Ferreira MA, O’Donovan MC, Meng YA, et al; Wellcome Trust Case Control Consortium. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008;40(9):1056-1058. doi:10.1038/ng.209
51. Salvi AM, Bays JL, Mackin SR, et al. Ankyrin G organizes membrane components to promote coupling of cell mechanics and glucose uptake. Nat Cell Biol. 2021;23(5):457-466. doi:10.1038/s41556-021-00677-y
52. Gargus JJ. Ion channel functional candidate genes in multigenic neuropsychiatric disease. Biol Psychiatry. 2006;60(2):177-185. doi:10.1016/j.biopsych.2005.12.008
53. Dubovsky SL, Murphy J, Thomas M, et al. Abnormal intracellular calcium ion concentration in platelets and lymphocytes of bipolar patients. Am J Psychiatry 1992;149(1):118-120. doi:10.1176/ajp.149.1.118
54. Blaustein MP. Physiological effects of endogenous ouabain: control of intracellular Ca2+ stores and cell responsiveness. Am J Physiol. 1993;264(6 Pt 1):C1367–C1387. doi:10.1152/ajpcell.1993.264.6.C1367
55. El-Mallakh RS, Li R, Worth CA, et al. Leukocyte transmembrane potential in bipolar illness. J Affect Disord. 1996;41(1):33-37. doi:10.1016/0165-0327(96)00063-8
56. El-Mallakh RS, Gao Y, You P. Role of endogenous ouabain in the etiology of bipolar disorder. Int J Bipolar Disord. 2021;9(1):6. doi:10.1186/s40345-020-00213-1
57. Huang X, Lei Z, El‐Mallakh RS. Lithium normalizes elevated intracellular sodium. Bipolar Disord. 2007;9(3):298-300. doi:10.1111/j.1399-5618.2007.00429.x
58. Shaw DM. Mineral metabolism, mania, and melancholia. Br Med J. 1966;2(5508):262-267. doi:10.1136/bmj.2.5508.262
59. Qian K, Yu N, Tucker KR, et al. Mathematical analysis of depolarization block mediated by slow inactivation of fast sodium channels in midbrain dopamine neurons. J Neurophysiol. 2014;112(11):2779-2790. doi:10.1152/jn.00578.2014
60. Sleem A, El-Mallakh RS. Advances in the psychopharmacotherapy of bipolar disorder type I. Exp Opin Pharmacother. 2021;22(10):1267-1290. doi:10.1080/14656566.2021.1893306
61. Malhi GS., Tanious M, Das P, et al. Potential mechanisms of action of lithium in bipolar disorder. CNS Drugs. 2013;27(2):135-153. doi:10.1007/s40263-013-0039-0
62. Armett CJ, Ritchie JM. On the permeability of mammalian non-myelinated fibers to sodium and to lithium ions. J Physiol. 1963;165(1):130-140. doi:10.1113/jphysiol.1963.sp007047
63. Kabakov AY, Karkanias NB, Lenox RH, et al. Synapse-specific accumulation of lithium in intracellular microdomains: a model for uncoupling coincidence detection in the brain. Synapse. 1998;28(4):271-279. doi:10.1002/(SICI)1098-2396(199804)28:4<271::AID-SYN2>3.0.CO;2-6
64. Cipriani A, Reid K, Young AH, et al. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev. 2013;2013(10):CD003196. doi:10.1002/14651858.CD003196.pub2
65. Lai HC, Jan LY. The distribution and targeting of neuronal voltage-gated ion channels. Nat Rev Neurosci. 2006;7(7):548-562. doi:10.1038/nrn1938
66. Löscher W, Schmidt D. Increase of human plasma GABA by sodium valproate. Epilepsia. 1980;21(6):611-615. doi:10.1111/j.1528-1157.1980.tb04314.x
67. Owens MJ, Nemeroff CB. Pharmacology of valproate. Psychopharmacol Bull. 2003;37(Suppl 2):17-24.
68. Calabrese JR, Vieta E, Shelton MD. Latest maintenance data on lamotrigine in bipolar disorder. Eur Neuropsychopharmacol. 2003;13(Suppl 2):S57-S66. doi:10.1016/s0924-977x(03)00079-8
69. Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194(1):4-9. doi:10.1192/bjp.bp.107.048504
70. Nakatani Y, Masuko H, Amano T. Effect of lamotrigine on Na(v)1.4 voltage-gated sodium channels. J Pharmacol Sci. 2013;123(2):203-206. doi:10.1254/jphs.13116sc
71. Ramadan E, Basselin M, Rao JS, et al. Lamotrigine blocks NMDA receptor-initiated arachidonic acid signalling in rat brain: implications for its efficacy in bipolar disorder. Int J Neuropsychopharmacol. 2012;15(7):931-943. doi:10.1017/S1461145711001003
72. Jo S, Bean BP. Sidedness of carbamazepine accessibility to voltage-gated sodium channels. Mol Pharmacol. 2014;85(2):381-387. doi:10.1124/mol.113.090472
73. Curtin F, Schulz P. Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis. J Affect Disord 2004;78(3):201-208. doi:10.1016/S0165-0327(02)00317-8
74. Edwards R, Stephenson U, Flewett T. Clonazepam in acute mania: a double blind trial. Aust N Z J Psychiatry 1991;25(2):238-242. doi:10.3109/00048679109077740
75. Lin SC, Chen CC, Chen YH, et al. Benzodiazepine prescription among patients with severe mental illness and co-occurring alcohol abuse/dependence in Taiwan. Hum Psychopharmacol. 2011;26(3):201-207. doi:10.1002/hup.1193
76. Prisciandaro JJ, Brown DG, Brady KT, et al. Comorbid anxiety disorders and baseline medication regimens predict clinical outcomes in individuals with co-occurring bipolar disorder and alcohol dependence: results of a randomized controlled trial. Psychiatry Res. 2011;188(3):361-365. doi:10.1016/j.psychres.2011.04.030
77. Ashok AH, Marques TR, Jauhar S, et al. The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Mol Psychiatry. 2017;22(5):666-679. doi:10.1038/mp.2017.16
78. Roberts RJ, Lohano KK, El-Mallakh RS. Antipsychotics as antidepressants. Asia Pac Psychiatry. 2016;8(3):179-188. doi:10.1111/appy.12186
79. Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378(9799):1306-1315. doi:10.1016/S0140-6736(11)60873-8
80. Hayes JF, Marston L, Walters K, et al. Lithium vs. valproate vs. olanzapine vs. quetiapine as maintenance monotherapy for bipolar disorder: a population-based UK cohort study using electronic health records. World Psychiatry. 2016;15(1):53-58. doi:10.1002/wps.20298
81. Geddes JR, Gardiner A, Rendell J, et al. Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial. Lancet Psychiatry. 2016;3(1):31239. doi:10.1016/S2215-0366(15)00450-2
82. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6):495-553. doi:10.1177/0269881116636545
Bipolar disorder (BD) is a recurrent, life-long psychiatric illness affecting nearly 2% of the world population1,2 that is characterized by episodes of mania and depression interspersed among periods of relative mood stability.3 The illness causes an enormous health burden, which makes understanding its pathophysiology and treatment patterns a substantial priority.4 In the 1950s, lithium was found to be effective for treating acute manic episodes and preventing relapse in BD.5 Since then, valproate and carbamazepine also have been FDA-approved for treating mania.6,7 Antipsychotics have also shown evidence of efficacy in BD treatment,8,9 particularly for use in acute settings for more rapid effect or for a limited duration,10 which has led some to refer to them as “mood stabilizers.”11
In this article, we describe changes in trends of prescribing medications to treat BD, the role of ion dysregulation in the disorder, and how a better understanding of this dysregulation might impact the choice of treatment.
Changes in pharmacotherapy for bipolar disorder
From 1997 through 2016, the use of lithium for BD decreased from >30% of patients to 17.6% (with a nadir of 13.9% from 2009 to 2012).12 Over the same period, the use of nonlithium mood stabilizers decreased from 30.4% to approximately 4.8%, while second-generation antipsychotic (SGAs) use increased from 12.4% to 50.4%.12 Distressingly, antidepressant use increased from approximately 47% to 56.8%, and antidepressant use without concomitant mood stabilizers increased from 38% to 40.8%, although the rate of antidepressants without either a mood stabilizer or an antipsychotic remained relatively stable (14.9% to 16.8%).12 In randomized trials, when added to mood stabilizers, antidepressants have consistently failed to separate from placebo,13-15 but they can destabilize the illness, resulting in increases in mania, depression, and subsyndromal mixed symptoms.16-18
It is easy to understand clinicians’ attempts to address their patients’ distress due to depressive symptoms that do not resolve with mood stabilizers.19,20 Similarly, the increased use of antipsychotics is driven by evidence that antipsychotics are effective for treating bipolar depression and preventing the recurrence of manic and (for some antipsychotics) depressive episodes.21,22 However, long-term antipsychotic use causes brain volume change in patients with schizophrenia23 or major depressive disorder24 and in nonhuman primates25,26; metabolic abnormalities27-31; and cardiovascular adverse effects.32 Antipsychotics are believed to be associated with withdrawal psychosis.33,34 In the head-to-head Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study, quetiapine was as effective as lithium but associated with more adverse effects.35 Importantly, the estimated disability-adjusted life years of patients with BD increased by 54.4% from 6.02 million in 1990 to 9.29 million in 2017, which is greater than the increase in the incidence of BD (47.74%) over the same time.36 This means that despite the dramatic increase in treatment options for people with BD, functional outcomes have declined.
One major difference between antipsychotics and mood stabilizers is that antipsychotics do not alter the underlying abnormal pathology of BD.37 An ideal pharmacologic intervention is one that corrects a known pathophysiologic anomaly of the condition being treated. There are no demonstrated abnormalities in the dopamine or serotonin systems in individuals with BD, but long-term use of antipsychotics may create dopaminergic alterations.33 One of the most reproducible biomarkers associated with manic and bipolar depressed mood states is increased intracellular sodium38,39 and reduced ability to correct a sodium challenge.40-42 By normalizing intracellular sodium levels, lithium and the mood-stabilizing anticonvulsants uniquely and specifically counter known physiologic abnormalities in patients with BD.37,43
The role of ion dysregulation
The pathophysiology of BD remains elusive. A multitude of lines of evidence link BD to abnormal neuroimaging findings,22,44,45 oxidative stress,46 inflammation,47 and mitochondrial disease,48 but there is still no unifying understanding of these findings. Ion dysregulation appears to be central to understanding and treating BD.38,39
Despite extensive genetic studies, no genes have been identified that mediate >5% of the risk for BD. Nonetheless, 74% of all genes identified as mediating risk for BD code for proteins essential for the regulation of ion transport and membrane potential.49 The 2 genes that contribute the greatest risk are CACNA1C and ANK3, which code for a calcium channel and a cytoskeletal protein, respectively.50ANK3 codes for ankyrin G, which plays a role in proper coupling of the voltage-gated sodium channels to the cytoskeleton.51 An additional risk gene, TRANK1, contains multiple ankyrin-like repeat domains, which suggests some shared functions with ANK3.52 More importantly, the most reproducible pathophysiologic findings in BD are dysregulation of sodium, potassium, hydrogen, and calcium transport, with consequent alteration of depolarization potential, neuronal excitability, and calcium-mediated processes.38,39,53-56 For example, increased sodium and calcium within cells have been observed in both mania and bipolar depression, and these levels normalize during euthymia. All medications that are effective for treating BD may reduce intracellular sodium or calcium; traditional mood stabilizers do so directly by inhibiting voltage-sensitive sodium channels in an activity-dependent manner or displacing intracellular sodium,43,57 whereas antipsychotics do so indirectly by increasing sodium pump activity through inhibition of second messengers of the dopamine D2 family of receptors.37
Continue to: The extent of ion dysregulation...
The extent of ion dysregulation is directly associated with the expressed mood state of the illness. A small reduction in the activity of the sodium pump results in a small increase in intracellular sodium (approximately 10 mM).39,58 This led to the hypothesis that increased intracellular sodium causes the transmembrane potential to increase closer to membrane depolarization threshold, which increases excitability of affected neurons.38,39,58 Neurons are likely to fire and propagate signals more easily, which may manifest as symptoms of mania, such as increased energy, activity, lability, excitability, irritability, tangentiality, and looseness of associations. As the process of increased intracellular sodium progresses, a minority of neurons are expected to have their transmembrane potentials depolarize sufficiently for the resting membrane potential to go beyond threshold potential.59 Such neurons are in a state of constant depolarization (also known as depolarization block), which disrupts neuronal circuits. The difficulty in progression of these signals results in the classic bipolar depression symptoms of low energy, reduced activity, and slowing of all brain activity that is seen as psychomotor slowing.38
Implications for treatment
Medications for treating bipolar illness include lithium, anticonvulsants, benzodiazepines, first-generation antipsychotics, and SGAs.37,43
Mood stabilizers (lithium and certain anticonvulsants) correct the previously mentioned sodium abnormality by reducing sodium entry into the cell in an activity-dependent manner.43 As the only agents that directly address a known pathophysiologic abnormality, they are foundational in the treatment of BD.60 Lithium effectively treats acute mania and prevents relapse.61 It preferentially targets the active neurons, entering through both voltage-responsive and neurotransmitter-coupled channels.43,62 This results in an increase of intracellular lithium concentrations to as much as 8 times that of the extracellular concentration.63 These ions displace intracellular sodium ions in a 1:1 ratio, which results in a reduced intracellular sodium concentration that reduces the excitability of neurons.43,57,62
Substantial evidence supports the use of valproic acid for initial and maintenance treatment of BD.64 It inhibits the voltage-sensitive sodium channel when the channel is open, which results in an activity-dependent action that selectively impacts rapidly firing neurons.43 The voltage-gated sodium channels exist nearly exclusively on the axon, beyond the hillock65; as such, valproic acid will only inhibit neurons that fire, whereas lithium accumulates throughout the neuron and will affect depolarization in the neuronal soma as well as the firing in the axon.43 Additionally, valproic acid has been observed to enhance gamma-aminobutyric acid (GABA) levels and transmission.43,66,67 A meta-analysis that included 6 randomized controlled trials illustrated that, acutely, valproate was not different from lithium’s overall efficacy (RR 1.02; 95% CI, 0.87 to 1.20), but was associated with reduced dropout rates compared with placebo or lithium (RR 0.82; 95% CI, 0.71 to 0.95 and RR 0.87; 95% CI, 0.77 to 0.98, respectively).64
Lamotrigine is an anticonvulsant used for initial and maintenance treatment of BD, with greater efficacy for depressive episodes68; it also has notable effect for treating bipolar depression, although it is not FDA-approved for this indication.69 Lamotrigine inhibits sodium influx by binding to open voltage-gated sodium channels70 but also appears to reduce N-methyl-D-aspartate–mediated sodium entry,71 thereby acting both prehillock and posthillock.
Continue to: Carbamazepine is an anticonvulsant...
Carbamazepine is an anticonvulsant FDA-approved for treating BD.7 Like valproate, it acts by inhibiting voltage-gated sodium channels in an activity-dependent manner,72 which means it preferentially inhibits the most active neurons and those with higher intracellular sodium.43
Benzodiazepines, which have shown to be effective for treating acute mania,73 potentiate synaptic GABA receptors accruing an elevation in intracellular chloride influx.74 Despite acute efficacy, benzodiazepine use is limited because these agents are associated with worsening long-term, substance use–related outcomes.75,76
Antipsychotics are effective for treating mood disorders,60,76 and their use has been rising dramatically.12 The antimanic effect of all antipsychotics is believed to be mediated through dopamine D2 blockade, since use of a dose sufficient to block D2 receptors is required, and haloperidol, which acts exclusively on the D2 receptor, is equal to SGAs in its antimanic effect.77 Blockade of the D2 receptor will increase the activity of the sodium pump (sodium and potassium-activated adenosine triphosphatase) thus reducing intracellular sodium and calcium concentrations.37 When antipsychotics are used as antidepressants, they are generally used at doses lower than those used to treat mania.78
Antipsychotics are effective for treating BD, and may work more quickly than other agents for treating acute mania.79 However, maintenance or prevention trials tend to favor mood stabilizers.35,60,80 Several add-on studies have found the combination of a mood stabilizer plus an antipsychotic is superior to a mood stabilizer alone or an antipsychotic alone.81
An argument for mood stabilizers
Evidence suggests mood stabilizers and other approaches, such as antipsychotics, are almost equivalent for treating acute mania, with a small clinical advantage of mood stabilizers for preventing relapse. In general, current treatment guidelines do not distinguish mood stabilizers from antipsychotics as the first-line treatment.82 Over the past 20 years, antipsychotic use has increased while mood stabilizer use has decreased, so that presently a patient with BD is more likely to be prescribed an antipsychotic than a mood stabilizer.12 Over the same time, dysfunction among patients with BD has increased.33 Antipsychotics are appealing because they appear to be equally effective and generally well tolerated. But these agents cause problems that are difficult to see in routine visits, such as metabolic27-31 and cardiovascular adverse effects29 as well as reductions in brain volume.23-26 Mechanistic research suggests that mood stabilizers directly correct known pathophysiologic anomalies with additional protective effects, whereas antipsychotics appear to create new abnormalities and contribute to medical problems. Clinicians need to look beyond the similarities in acute efficacy and make a more broadly supported, evidence-based choice for managing BD, which clearly places mood stabilizers as the first-line agent and antipsychotics as reasonable alternatives. At a minimum, mood stabilizers should be viewed as the foundation to which antipsychotics can be added.
Bottom Line
Traditional mood stabilizers—lithium and some anticonvulsants—are the only agents that directly address physiologic abnormalities associated with both mania and bipolar depression, including mood state–associated elevations of intracellular sodium. Because of their specificity, these agents maximize mood stabilization and minimize adverse effects.
Related Resources
- Karas A, Stummer L, Freedberg A. Psychiatric and nonpsychiatric indications for mood stabilizers and select antiepileptics. Current Psychiatry. 2022;21(4):34-38. doi:10.12788/cp.0230
- Koch J. Mood stabilizers: balancing tolerability, serum levels, and dosage. Current Psychiatry. 2021;20(7):37-40. doi:10.12788/cp.0147
Drug Brand Names
Carbamazepine • Tegretol
Haloperidol • Haldol
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Quetiapine • Seroquel
Valproate • Depakote, Depakene
Bipolar disorder (BD) is a recurrent, life-long psychiatric illness affecting nearly 2% of the world population1,2 that is characterized by episodes of mania and depression interspersed among periods of relative mood stability.3 The illness causes an enormous health burden, which makes understanding its pathophysiology and treatment patterns a substantial priority.4 In the 1950s, lithium was found to be effective for treating acute manic episodes and preventing relapse in BD.5 Since then, valproate and carbamazepine also have been FDA-approved for treating mania.6,7 Antipsychotics have also shown evidence of efficacy in BD treatment,8,9 particularly for use in acute settings for more rapid effect or for a limited duration,10 which has led some to refer to them as “mood stabilizers.”11
In this article, we describe changes in trends of prescribing medications to treat BD, the role of ion dysregulation in the disorder, and how a better understanding of this dysregulation might impact the choice of treatment.
Changes in pharmacotherapy for bipolar disorder
From 1997 through 2016, the use of lithium for BD decreased from >30% of patients to 17.6% (with a nadir of 13.9% from 2009 to 2012).12 Over the same period, the use of nonlithium mood stabilizers decreased from 30.4% to approximately 4.8%, while second-generation antipsychotic (SGAs) use increased from 12.4% to 50.4%.12 Distressingly, antidepressant use increased from approximately 47% to 56.8%, and antidepressant use without concomitant mood stabilizers increased from 38% to 40.8%, although the rate of antidepressants without either a mood stabilizer or an antipsychotic remained relatively stable (14.9% to 16.8%).12 In randomized trials, when added to mood stabilizers, antidepressants have consistently failed to separate from placebo,13-15 but they can destabilize the illness, resulting in increases in mania, depression, and subsyndromal mixed symptoms.16-18
It is easy to understand clinicians’ attempts to address their patients’ distress due to depressive symptoms that do not resolve with mood stabilizers.19,20 Similarly, the increased use of antipsychotics is driven by evidence that antipsychotics are effective for treating bipolar depression and preventing the recurrence of manic and (for some antipsychotics) depressive episodes.21,22 However, long-term antipsychotic use causes brain volume change in patients with schizophrenia23 or major depressive disorder24 and in nonhuman primates25,26; metabolic abnormalities27-31; and cardiovascular adverse effects.32 Antipsychotics are believed to be associated with withdrawal psychosis.33,34 In the head-to-head Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study, quetiapine was as effective as lithium but associated with more adverse effects.35 Importantly, the estimated disability-adjusted life years of patients with BD increased by 54.4% from 6.02 million in 1990 to 9.29 million in 2017, which is greater than the increase in the incidence of BD (47.74%) over the same time.36 This means that despite the dramatic increase in treatment options for people with BD, functional outcomes have declined.
One major difference between antipsychotics and mood stabilizers is that antipsychotics do not alter the underlying abnormal pathology of BD.37 An ideal pharmacologic intervention is one that corrects a known pathophysiologic anomaly of the condition being treated. There are no demonstrated abnormalities in the dopamine or serotonin systems in individuals with BD, but long-term use of antipsychotics may create dopaminergic alterations.33 One of the most reproducible biomarkers associated with manic and bipolar depressed mood states is increased intracellular sodium38,39 and reduced ability to correct a sodium challenge.40-42 By normalizing intracellular sodium levels, lithium and the mood-stabilizing anticonvulsants uniquely and specifically counter known physiologic abnormalities in patients with BD.37,43
The role of ion dysregulation
The pathophysiology of BD remains elusive. A multitude of lines of evidence link BD to abnormal neuroimaging findings,22,44,45 oxidative stress,46 inflammation,47 and mitochondrial disease,48 but there is still no unifying understanding of these findings. Ion dysregulation appears to be central to understanding and treating BD.38,39
Despite extensive genetic studies, no genes have been identified that mediate >5% of the risk for BD. Nonetheless, 74% of all genes identified as mediating risk for BD code for proteins essential for the regulation of ion transport and membrane potential.49 The 2 genes that contribute the greatest risk are CACNA1C and ANK3, which code for a calcium channel and a cytoskeletal protein, respectively.50ANK3 codes for ankyrin G, which plays a role in proper coupling of the voltage-gated sodium channels to the cytoskeleton.51 An additional risk gene, TRANK1, contains multiple ankyrin-like repeat domains, which suggests some shared functions with ANK3.52 More importantly, the most reproducible pathophysiologic findings in BD are dysregulation of sodium, potassium, hydrogen, and calcium transport, with consequent alteration of depolarization potential, neuronal excitability, and calcium-mediated processes.38,39,53-56 For example, increased sodium and calcium within cells have been observed in both mania and bipolar depression, and these levels normalize during euthymia. All medications that are effective for treating BD may reduce intracellular sodium or calcium; traditional mood stabilizers do so directly by inhibiting voltage-sensitive sodium channels in an activity-dependent manner or displacing intracellular sodium,43,57 whereas antipsychotics do so indirectly by increasing sodium pump activity through inhibition of second messengers of the dopamine D2 family of receptors.37
Continue to: The extent of ion dysregulation...
The extent of ion dysregulation is directly associated with the expressed mood state of the illness. A small reduction in the activity of the sodium pump results in a small increase in intracellular sodium (approximately 10 mM).39,58 This led to the hypothesis that increased intracellular sodium causes the transmembrane potential to increase closer to membrane depolarization threshold, which increases excitability of affected neurons.38,39,58 Neurons are likely to fire and propagate signals more easily, which may manifest as symptoms of mania, such as increased energy, activity, lability, excitability, irritability, tangentiality, and looseness of associations. As the process of increased intracellular sodium progresses, a minority of neurons are expected to have their transmembrane potentials depolarize sufficiently for the resting membrane potential to go beyond threshold potential.59 Such neurons are in a state of constant depolarization (also known as depolarization block), which disrupts neuronal circuits. The difficulty in progression of these signals results in the classic bipolar depression symptoms of low energy, reduced activity, and slowing of all brain activity that is seen as psychomotor slowing.38
Implications for treatment
Medications for treating bipolar illness include lithium, anticonvulsants, benzodiazepines, first-generation antipsychotics, and SGAs.37,43
Mood stabilizers (lithium and certain anticonvulsants) correct the previously mentioned sodium abnormality by reducing sodium entry into the cell in an activity-dependent manner.43 As the only agents that directly address a known pathophysiologic abnormality, they are foundational in the treatment of BD.60 Lithium effectively treats acute mania and prevents relapse.61 It preferentially targets the active neurons, entering through both voltage-responsive and neurotransmitter-coupled channels.43,62 This results in an increase of intracellular lithium concentrations to as much as 8 times that of the extracellular concentration.63 These ions displace intracellular sodium ions in a 1:1 ratio, which results in a reduced intracellular sodium concentration that reduces the excitability of neurons.43,57,62
Substantial evidence supports the use of valproic acid for initial and maintenance treatment of BD.64 It inhibits the voltage-sensitive sodium channel when the channel is open, which results in an activity-dependent action that selectively impacts rapidly firing neurons.43 The voltage-gated sodium channels exist nearly exclusively on the axon, beyond the hillock65; as such, valproic acid will only inhibit neurons that fire, whereas lithium accumulates throughout the neuron and will affect depolarization in the neuronal soma as well as the firing in the axon.43 Additionally, valproic acid has been observed to enhance gamma-aminobutyric acid (GABA) levels and transmission.43,66,67 A meta-analysis that included 6 randomized controlled trials illustrated that, acutely, valproate was not different from lithium’s overall efficacy (RR 1.02; 95% CI, 0.87 to 1.20), but was associated with reduced dropout rates compared with placebo or lithium (RR 0.82; 95% CI, 0.71 to 0.95 and RR 0.87; 95% CI, 0.77 to 0.98, respectively).64
Lamotrigine is an anticonvulsant used for initial and maintenance treatment of BD, with greater efficacy for depressive episodes68; it also has notable effect for treating bipolar depression, although it is not FDA-approved for this indication.69 Lamotrigine inhibits sodium influx by binding to open voltage-gated sodium channels70 but also appears to reduce N-methyl-D-aspartate–mediated sodium entry,71 thereby acting both prehillock and posthillock.
Continue to: Carbamazepine is an anticonvulsant...
Carbamazepine is an anticonvulsant FDA-approved for treating BD.7 Like valproate, it acts by inhibiting voltage-gated sodium channels in an activity-dependent manner,72 which means it preferentially inhibits the most active neurons and those with higher intracellular sodium.43
Benzodiazepines, which have shown to be effective for treating acute mania,73 potentiate synaptic GABA receptors accruing an elevation in intracellular chloride influx.74 Despite acute efficacy, benzodiazepine use is limited because these agents are associated with worsening long-term, substance use–related outcomes.75,76
Antipsychotics are effective for treating mood disorders,60,76 and their use has been rising dramatically.12 The antimanic effect of all antipsychotics is believed to be mediated through dopamine D2 blockade, since use of a dose sufficient to block D2 receptors is required, and haloperidol, which acts exclusively on the D2 receptor, is equal to SGAs in its antimanic effect.77 Blockade of the D2 receptor will increase the activity of the sodium pump (sodium and potassium-activated adenosine triphosphatase) thus reducing intracellular sodium and calcium concentrations.37 When antipsychotics are used as antidepressants, they are generally used at doses lower than those used to treat mania.78
Antipsychotics are effective for treating BD, and may work more quickly than other agents for treating acute mania.79 However, maintenance or prevention trials tend to favor mood stabilizers.35,60,80 Several add-on studies have found the combination of a mood stabilizer plus an antipsychotic is superior to a mood stabilizer alone or an antipsychotic alone.81
An argument for mood stabilizers
Evidence suggests mood stabilizers and other approaches, such as antipsychotics, are almost equivalent for treating acute mania, with a small clinical advantage of mood stabilizers for preventing relapse. In general, current treatment guidelines do not distinguish mood stabilizers from antipsychotics as the first-line treatment.82 Over the past 20 years, antipsychotic use has increased while mood stabilizer use has decreased, so that presently a patient with BD is more likely to be prescribed an antipsychotic than a mood stabilizer.12 Over the same time, dysfunction among patients with BD has increased.33 Antipsychotics are appealing because they appear to be equally effective and generally well tolerated. But these agents cause problems that are difficult to see in routine visits, such as metabolic27-31 and cardiovascular adverse effects29 as well as reductions in brain volume.23-26 Mechanistic research suggests that mood stabilizers directly correct known pathophysiologic anomalies with additional protective effects, whereas antipsychotics appear to create new abnormalities and contribute to medical problems. Clinicians need to look beyond the similarities in acute efficacy and make a more broadly supported, evidence-based choice for managing BD, which clearly places mood stabilizers as the first-line agent and antipsychotics as reasonable alternatives. At a minimum, mood stabilizers should be viewed as the foundation to which antipsychotics can be added.
Bottom Line
Traditional mood stabilizers—lithium and some anticonvulsants—are the only agents that directly address physiologic abnormalities associated with both mania and bipolar depression, including mood state–associated elevations of intracellular sodium. Because of their specificity, these agents maximize mood stabilization and minimize adverse effects.
Related Resources
- Karas A, Stummer L, Freedberg A. Psychiatric and nonpsychiatric indications for mood stabilizers and select antiepileptics. Current Psychiatry. 2022;21(4):34-38. doi:10.12788/cp.0230
- Koch J. Mood stabilizers: balancing tolerability, serum levels, and dosage. Current Psychiatry. 2021;20(7):37-40. doi:10.12788/cp.0147
Drug Brand Names
Carbamazepine • Tegretol
Haloperidol • Haldol
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Quetiapine • Seroquel
Valproate • Depakote, Depakene
1. Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013;382(9904):1575-1586. doi:10.1016/S0140-6736(13)61611-6
2. Merikangas KR, Jin R, He JP, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011;68(3):241-251. doi:10.1001/archgenpsychiatry.2011.12
3. Müller JK, Leweke FM. Bipolar disorder: clinical overview. Article in English, German. Med Monatsschr Pharm. 2016;39(9):363-369.
4. Smith DJ, Whitham EA, Ghaemi SN. Bipolar disorder. Handb Clin Neurol. 2012;106:251-263. doi:10.1016/B978-0-444-52002-9.00015-2
5. Goodwin FK, Ghaemi SN. The impact of the discovery of lithium on psychiatric thought and practice in the USA and Europe. Aust N Z J Psychiatry. 1999;33 Suppl:S54-S64. doi:10.1111/j.1440-1614.1999.00669.x
6. Pope HG, McElroy SL, Keck PE, et al. Valproate in the treatment of acute mania. A placebo-controlled study. Arch Gen Psychiatry. 1991;48(1):62-68. doi:10.1001/archpsyc.1991.01810250064008
7. Weisler RH, Keck PE Jr, Swann AC, et al. Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: a multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2005;66(3):323-330. doi:10.4088/jcp.v66n0308
8. Tarr GP, Glue P, Herbison P. Comparative efficacy and acceptability of mood stabilizer and second generation antipsychotic monotherapy for acute mania--a systematic review and meta-analysis. J Affect Disord. 2011;134(1-3):14-19. doi:10.1016/j.jad.2010.11.009
9. Pahwa M, Sleem A, Elsayed OH, et al. New antipsychotic medications in the last decade. Curr Psychiatry Rep. 2021;23(12):87.
10. Correll CU, Sheridan EM, DelBello MP. Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trials. Bipolar Disord. 2010;12(2):116-141. doi:10.1111/j.1399-5618.2010.00798.x
11. Rybakowski JK. Two generations of mood stabilizers. Int J Neuropsychopharmacol. 2007;10:709-711. doi:10.1017/s146114570700795x
12. Rhee TG, Olfson M, Nierenberg AA, et al. 20-year trends in the pharmacologic treatment of bipolar disorder by psychiatrists in outpatient care settings. Am J Psychiatry. 2020;177(8):706-715. doi:10.1176/appi.ajp.2020.19091000
13. El-Mallakh RS. Adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;357(6):615; author reply 615-616.
14. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-1722. doi:10.1056/NEJMoa064135
15. Ghaemi SN, Whitham EA, Vohringer PA, et al. Citalopram for acute and preventive efficacy in bipolar depression (CAPE-BD): a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2021;82(1):19m13136. doi:10.4088/JCP.19m13136
16. El-Mallakh RS, Ghaemi SN, Sagduyu K, et al. Antidepressant-associated chronic irritable dysphoria (ACID) in STEP-BD patients. J Affect Disord. 2008;111(2-3):372-377. doi:10.1016/j.jad.2008.03.025
17. Ghaemi SN, Ostacher MM, El-Mallakh RS, et al. Antidepressant discontinuation in bipolar depression: a systematic treatment enhancement program for bipolar disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry. 2010;71(4):372-380.
18. Strejilevich SA, Martino DJ, Marengo E, et al. Long-term worsening of bipolar disorder related with frequency of antidepressant exposure. Ann Clin Psychiatry. 2011;23(3):186-192.
19. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society of Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013;170(11):1249-1262. doi:10.1176/appi.ajp.2013.13020185
20. McIntyre RS, Calabrese JR. Bipolar depression: the clinical characteristics and unmet needs of a complex disorder. Curr Med Res Opin. 2019;35(11):1993-2005.
21. Fornaro M, Stubbs B, De Berardis D, et al. Atypical antipsychotics in the treatment of acute bipolar depression with mixed features: a systematic review and exploratory meta-analysis of placebo-controlled clinical trials. Int J Mol Sci. 2016;17(2):241. doi:10.3390/ijms17020241
22. Lindström L, Lindström E, Nilsson M, et al. Maintenance therapy with second generation antipsychotics for bipolar disorder – a systematic review and meta-analysis. J Affect Disord. 2017;213:138-150. doi:10.1016/j.jad.2017.02.012
23. Ho BC, Andreasen NC, Ziebell S, et al. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry. 2011;68(2):128-137. doi:010.1001/archgenpsychiatry.2010.199
24. Voineskos AN, Mulsant BH, Dickie EW, et al. Effects of antipsychotic medication on brain structure in patients with major depressive disorder and psychotic features: neuroimaging findings in the context of a randomized placebo-controlled clinical trial. JAMA Psychiatry. 2020;77(7):674-683. doi:10.1001/jamapsychiatry.2020.0036
25. Konopaske GT, Bolo NR, Basu AC, et al. Time-dependent effects of haloperidol on glutamine and GABA homeostasis and astrocyte activity in the rat brain. Psychopharmacology (Berl). 2013;230(1):57-67. doi:10.1007/s00213-013-3136-3
26. Dorph-Petersen KA, Pierri JN, Perel JM, et al. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology. 2005;30(9):1649-1661. doi:10.1038/sj.npp.1300710
27. McIntyre RS, Mancini DA, Basile VS, et al. Antipsychotic-induced weight gain: bipolar disorder and leptin. J Clin Psychopharmacol. 2003;23(4):323-327. doi:10.1097/01.jcp.0000085403.08426.f4
28. McIntyre RS, Konarski JZ, Wilkins K, et al. Obesity in bipolar disorder and major depressive disorder: results from a national community health survey on mental health and well-being. Can J Psychiatry. 2006;51(5):274-280. doi:10.1177/070674370605100502
29. McIntyre RS, Cha DS, Kim RD, et al. A review of FDA-approved treatment options in bipolar depression. CNS Spectr. 2013;18(Suppl 1):4-20. doi:10.1017/S1092852913000746
30. Barton BB, Segger F, Fischer K, et al. Update on weight-gain caused by antipsychotics: a systematic review and meta-analysis. Expert Opin Drug Saf. 2020;19(3):295-314. doi:10.1080/14740338.2020.1713091
31. Doane MJ, Bessonova L, Friedler HS, et al. Weight gain and comorbidities associated with oral second-generation antipsychotics: analysis of real-world data for patients with schizophrenia or bipolar I disorder. BMC Psychiatry. 2022;22(1):114. doi:10.1186/s12888-022-03758-w
32. Buckley NA, Sanders P. Cardiovascular adverse effects of antipsychotic drugs. Drug Saf. 2000;23(3):215-228. doi:10.2165/00002018-200023030-00004
33. Ali Z, Roque A, El-Mallakh RS. A unifying theory for the pathoetiologic mechanism of tardive dyskinesia. Med Hypotheses. 2020;140:109682. doi:10.1016/j.mehy.2020.109682
34. Sleem A, El-Mallakh RS. Adaptive changes to antipsychotics: their consequences and how to avoid them. Curr Psychiatry. 2022;21(7):46-50,52. doi: 10.12788/cp.0262
35. Nierenberg AA, McElroy SL, Friedman ES, et al. Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness): a pragmatic 6-month trial of lithium versus quetiapine for bipolar disorder. J Clin Psychiatry. 2016;77(1):90-99. doi:10.4088/JCP.14m09349
36. He H, Hu C, Ren Z, et al. Trends in the incidence and DALYs of bipolar disorder at global, regional, and national levels: results from the global burden of disease study 2017. J Psychiatr Res. 2020;125:96-105. doi:10.1016/j.jpsychires.2020.03.015
37. Roberts RJ, Repass R, El-Mallakh RS. Effect of dopamine on intracellular sodium: a common pathway for pharmacological mechanism of action in bipolar illness. World J Biol Psychiatry. 2010;11(2 Pt 2):181-187. doi:10.1080/15622970902718774
38. El-Mallakh RS, Wyatt RJ. The Na, K-ATPase hypothesis for bipolar illness. Biol Psychiatry. 1995;37(4):235-244. doi:10.1016/0006-3223(94)00201-D
39. El-Mallakh RS, Yff T, Gao Y. Ion dysregulation in the pathogenesis of bipolar disorder. Ann Depress Anxiety. 2016;3(1):1076.
40. Li R, El-Mallakh RS. Differential response of bipolar and normal control lymphoblastoid cell sodium pump to ethacrynic acid. J Affect Disord. 2004;80(1):11-17. doi:10.1016/S0165-0327(03)00044-2
41. Woodruff DB, El-Mallakh RS, Thiruvengadam AP. Validation of a diagnostic screening blood test for bipolar disorder. Ann Clin Psychiatry. 2012;24(2):135-139.
42. Gao Y, Lohano K, Delamere NA, et al. Ethanol normalizes glutamate-induced elevation of intracellular sodium in olfactory neuroepithelial progenitors from subjects with bipolar illness but not nonbipolar controls: biologic evidence for the self-medication hypothesis. Bipolar Disord. 2019;21(2):179-181. doi:10.1111/bdi.12737
43. El-Mallakh RS, Huff MO. Mood stabilizers and ion regulation. Harv Rev Psychiatry. 2001;9(1):23-32. doi:10.1080/10673220127873
44. Phillips ML, Swartz HA. A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research. Am J Psychiatry. 2014;171(8):829-843. doi:10.1176/appi.ajp.2014.13081008
45. Hibar DP, Westlye LT, Doan NT, et al. Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group. Mol Psychiatry. 2018;23(4):932-942. doi:10.1038/mp.2017.73
46. Brown NC, Andreazza AC, Young LT. An updated meta-analysis of oxidative stress markers in bipolar disorder. Psychiatry Res. 2014;218(1-2):61-68. doi:10.1016/j.psychres.2014.04.005
47. Benedetti F, Aggio V, Pratesi ML, et al. Neuroinflammation in bipolar depression. Front Psychiatry. 2020;11:71. doi:10.3389/fpsyt.2020.00071
48. Andreazza AC, Duong A, Young LT. Bipolar disorder as a mitochondrial disease. Biol Psychiatry. 2018;83(9):720-721. doi:10.1016/j.biopsych.2017.09.018
49. Askland KD. Toward a biaxial model of “bipolar” affective disorders: further exploration of genetic, molecular and cellular substrates. J Affect Disord. 2006;94(1-3):35-66. doi:10.1016/j.jad.2006.01.033
50. Ferreira MA, O’Donovan MC, Meng YA, et al; Wellcome Trust Case Control Consortium. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008;40(9):1056-1058. doi:10.1038/ng.209
51. Salvi AM, Bays JL, Mackin SR, et al. Ankyrin G organizes membrane components to promote coupling of cell mechanics and glucose uptake. Nat Cell Biol. 2021;23(5):457-466. doi:10.1038/s41556-021-00677-y
52. Gargus JJ. Ion channel functional candidate genes in multigenic neuropsychiatric disease. Biol Psychiatry. 2006;60(2):177-185. doi:10.1016/j.biopsych.2005.12.008
53. Dubovsky SL, Murphy J, Thomas M, et al. Abnormal intracellular calcium ion concentration in platelets and lymphocytes of bipolar patients. Am J Psychiatry 1992;149(1):118-120. doi:10.1176/ajp.149.1.118
54. Blaustein MP. Physiological effects of endogenous ouabain: control of intracellular Ca2+ stores and cell responsiveness. Am J Physiol. 1993;264(6 Pt 1):C1367–C1387. doi:10.1152/ajpcell.1993.264.6.C1367
55. El-Mallakh RS, Li R, Worth CA, et al. Leukocyte transmembrane potential in bipolar illness. J Affect Disord. 1996;41(1):33-37. doi:10.1016/0165-0327(96)00063-8
56. El-Mallakh RS, Gao Y, You P. Role of endogenous ouabain in the etiology of bipolar disorder. Int J Bipolar Disord. 2021;9(1):6. doi:10.1186/s40345-020-00213-1
57. Huang X, Lei Z, El‐Mallakh RS. Lithium normalizes elevated intracellular sodium. Bipolar Disord. 2007;9(3):298-300. doi:10.1111/j.1399-5618.2007.00429.x
58. Shaw DM. Mineral metabolism, mania, and melancholia. Br Med J. 1966;2(5508):262-267. doi:10.1136/bmj.2.5508.262
59. Qian K, Yu N, Tucker KR, et al. Mathematical analysis of depolarization block mediated by slow inactivation of fast sodium channels in midbrain dopamine neurons. J Neurophysiol. 2014;112(11):2779-2790. doi:10.1152/jn.00578.2014
60. Sleem A, El-Mallakh RS. Advances in the psychopharmacotherapy of bipolar disorder type I. Exp Opin Pharmacother. 2021;22(10):1267-1290. doi:10.1080/14656566.2021.1893306
61. Malhi GS., Tanious M, Das P, et al. Potential mechanisms of action of lithium in bipolar disorder. CNS Drugs. 2013;27(2):135-153. doi:10.1007/s40263-013-0039-0
62. Armett CJ, Ritchie JM. On the permeability of mammalian non-myelinated fibers to sodium and to lithium ions. J Physiol. 1963;165(1):130-140. doi:10.1113/jphysiol.1963.sp007047
63. Kabakov AY, Karkanias NB, Lenox RH, et al. Synapse-specific accumulation of lithium in intracellular microdomains: a model for uncoupling coincidence detection in the brain. Synapse. 1998;28(4):271-279. doi:10.1002/(SICI)1098-2396(199804)28:4<271::AID-SYN2>3.0.CO;2-6
64. Cipriani A, Reid K, Young AH, et al. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev. 2013;2013(10):CD003196. doi:10.1002/14651858.CD003196.pub2
65. Lai HC, Jan LY. The distribution and targeting of neuronal voltage-gated ion channels. Nat Rev Neurosci. 2006;7(7):548-562. doi:10.1038/nrn1938
66. Löscher W, Schmidt D. Increase of human plasma GABA by sodium valproate. Epilepsia. 1980;21(6):611-615. doi:10.1111/j.1528-1157.1980.tb04314.x
67. Owens MJ, Nemeroff CB. Pharmacology of valproate. Psychopharmacol Bull. 2003;37(Suppl 2):17-24.
68. Calabrese JR, Vieta E, Shelton MD. Latest maintenance data on lamotrigine in bipolar disorder. Eur Neuropsychopharmacol. 2003;13(Suppl 2):S57-S66. doi:10.1016/s0924-977x(03)00079-8
69. Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194(1):4-9. doi:10.1192/bjp.bp.107.048504
70. Nakatani Y, Masuko H, Amano T. Effect of lamotrigine on Na(v)1.4 voltage-gated sodium channels. J Pharmacol Sci. 2013;123(2):203-206. doi:10.1254/jphs.13116sc
71. Ramadan E, Basselin M, Rao JS, et al. Lamotrigine blocks NMDA receptor-initiated arachidonic acid signalling in rat brain: implications for its efficacy in bipolar disorder. Int J Neuropsychopharmacol. 2012;15(7):931-943. doi:10.1017/S1461145711001003
72. Jo S, Bean BP. Sidedness of carbamazepine accessibility to voltage-gated sodium channels. Mol Pharmacol. 2014;85(2):381-387. doi:10.1124/mol.113.090472
73. Curtin F, Schulz P. Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis. J Affect Disord 2004;78(3):201-208. doi:10.1016/S0165-0327(02)00317-8
74. Edwards R, Stephenson U, Flewett T. Clonazepam in acute mania: a double blind trial. Aust N Z J Psychiatry 1991;25(2):238-242. doi:10.3109/00048679109077740
75. Lin SC, Chen CC, Chen YH, et al. Benzodiazepine prescription among patients with severe mental illness and co-occurring alcohol abuse/dependence in Taiwan. Hum Psychopharmacol. 2011;26(3):201-207. doi:10.1002/hup.1193
76. Prisciandaro JJ, Brown DG, Brady KT, et al. Comorbid anxiety disorders and baseline medication regimens predict clinical outcomes in individuals with co-occurring bipolar disorder and alcohol dependence: results of a randomized controlled trial. Psychiatry Res. 2011;188(3):361-365. doi:10.1016/j.psychres.2011.04.030
77. Ashok AH, Marques TR, Jauhar S, et al. The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Mol Psychiatry. 2017;22(5):666-679. doi:10.1038/mp.2017.16
78. Roberts RJ, Lohano KK, El-Mallakh RS. Antipsychotics as antidepressants. Asia Pac Psychiatry. 2016;8(3):179-188. doi:10.1111/appy.12186
79. Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378(9799):1306-1315. doi:10.1016/S0140-6736(11)60873-8
80. Hayes JF, Marston L, Walters K, et al. Lithium vs. valproate vs. olanzapine vs. quetiapine as maintenance monotherapy for bipolar disorder: a population-based UK cohort study using electronic health records. World Psychiatry. 2016;15(1):53-58. doi:10.1002/wps.20298
81. Geddes JR, Gardiner A, Rendell J, et al. Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial. Lancet Psychiatry. 2016;3(1):31239. doi:10.1016/S2215-0366(15)00450-2
82. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6):495-553. doi:10.1177/0269881116636545
1. Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013;382(9904):1575-1586. doi:10.1016/S0140-6736(13)61611-6
2. Merikangas KR, Jin R, He JP, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011;68(3):241-251. doi:10.1001/archgenpsychiatry.2011.12
3. Müller JK, Leweke FM. Bipolar disorder: clinical overview. Article in English, German. Med Monatsschr Pharm. 2016;39(9):363-369.
4. Smith DJ, Whitham EA, Ghaemi SN. Bipolar disorder. Handb Clin Neurol. 2012;106:251-263. doi:10.1016/B978-0-444-52002-9.00015-2
5. Goodwin FK, Ghaemi SN. The impact of the discovery of lithium on psychiatric thought and practice in the USA and Europe. Aust N Z J Psychiatry. 1999;33 Suppl:S54-S64. doi:10.1111/j.1440-1614.1999.00669.x
6. Pope HG, McElroy SL, Keck PE, et al. Valproate in the treatment of acute mania. A placebo-controlled study. Arch Gen Psychiatry. 1991;48(1):62-68. doi:10.1001/archpsyc.1991.01810250064008
7. Weisler RH, Keck PE Jr, Swann AC, et al. Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: a multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2005;66(3):323-330. doi:10.4088/jcp.v66n0308
8. Tarr GP, Glue P, Herbison P. Comparative efficacy and acceptability of mood stabilizer and second generation antipsychotic monotherapy for acute mania--a systematic review and meta-analysis. J Affect Disord. 2011;134(1-3):14-19. doi:10.1016/j.jad.2010.11.009
9. Pahwa M, Sleem A, Elsayed OH, et al. New antipsychotic medications in the last decade. Curr Psychiatry Rep. 2021;23(12):87.
10. Correll CU, Sheridan EM, DelBello MP. Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trials. Bipolar Disord. 2010;12(2):116-141. doi:10.1111/j.1399-5618.2010.00798.x
11. Rybakowski JK. Two generations of mood stabilizers. Int J Neuropsychopharmacol. 2007;10:709-711. doi:10.1017/s146114570700795x
12. Rhee TG, Olfson M, Nierenberg AA, et al. 20-year trends in the pharmacologic treatment of bipolar disorder by psychiatrists in outpatient care settings. Am J Psychiatry. 2020;177(8):706-715. doi:10.1176/appi.ajp.2020.19091000
13. El-Mallakh RS. Adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;357(6):615; author reply 615-616.
14. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-1722. doi:10.1056/NEJMoa064135
15. Ghaemi SN, Whitham EA, Vohringer PA, et al. Citalopram for acute and preventive efficacy in bipolar depression (CAPE-BD): a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2021;82(1):19m13136. doi:10.4088/JCP.19m13136
16. El-Mallakh RS, Ghaemi SN, Sagduyu K, et al. Antidepressant-associated chronic irritable dysphoria (ACID) in STEP-BD patients. J Affect Disord. 2008;111(2-3):372-377. doi:10.1016/j.jad.2008.03.025
17. Ghaemi SN, Ostacher MM, El-Mallakh RS, et al. Antidepressant discontinuation in bipolar depression: a systematic treatment enhancement program for bipolar disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry. 2010;71(4):372-380.
18. Strejilevich SA, Martino DJ, Marengo E, et al. Long-term worsening of bipolar disorder related with frequency of antidepressant exposure. Ann Clin Psychiatry. 2011;23(3):186-192.
19. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society of Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013;170(11):1249-1262. doi:10.1176/appi.ajp.2013.13020185
20. McIntyre RS, Calabrese JR. Bipolar depression: the clinical characteristics and unmet needs of a complex disorder. Curr Med Res Opin. 2019;35(11):1993-2005.
21. Fornaro M, Stubbs B, De Berardis D, et al. Atypical antipsychotics in the treatment of acute bipolar depression with mixed features: a systematic review and exploratory meta-analysis of placebo-controlled clinical trials. Int J Mol Sci. 2016;17(2):241. doi:10.3390/ijms17020241
22. Lindström L, Lindström E, Nilsson M, et al. Maintenance therapy with second generation antipsychotics for bipolar disorder – a systematic review and meta-analysis. J Affect Disord. 2017;213:138-150. doi:10.1016/j.jad.2017.02.012
23. Ho BC, Andreasen NC, Ziebell S, et al. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry. 2011;68(2):128-137. doi:010.1001/archgenpsychiatry.2010.199
24. Voineskos AN, Mulsant BH, Dickie EW, et al. Effects of antipsychotic medication on brain structure in patients with major depressive disorder and psychotic features: neuroimaging findings in the context of a randomized placebo-controlled clinical trial. JAMA Psychiatry. 2020;77(7):674-683. doi:10.1001/jamapsychiatry.2020.0036
25. Konopaske GT, Bolo NR, Basu AC, et al. Time-dependent effects of haloperidol on glutamine and GABA homeostasis and astrocyte activity in the rat brain. Psychopharmacology (Berl). 2013;230(1):57-67. doi:10.1007/s00213-013-3136-3
26. Dorph-Petersen KA, Pierri JN, Perel JM, et al. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology. 2005;30(9):1649-1661. doi:10.1038/sj.npp.1300710
27. McIntyre RS, Mancini DA, Basile VS, et al. Antipsychotic-induced weight gain: bipolar disorder and leptin. J Clin Psychopharmacol. 2003;23(4):323-327. doi:10.1097/01.jcp.0000085403.08426.f4
28. McIntyre RS, Konarski JZ, Wilkins K, et al. Obesity in bipolar disorder and major depressive disorder: results from a national community health survey on mental health and well-being. Can J Psychiatry. 2006;51(5):274-280. doi:10.1177/070674370605100502
29. McIntyre RS, Cha DS, Kim RD, et al. A review of FDA-approved treatment options in bipolar depression. CNS Spectr. 2013;18(Suppl 1):4-20. doi:10.1017/S1092852913000746
30. Barton BB, Segger F, Fischer K, et al. Update on weight-gain caused by antipsychotics: a systematic review and meta-analysis. Expert Opin Drug Saf. 2020;19(3):295-314. doi:10.1080/14740338.2020.1713091
31. Doane MJ, Bessonova L, Friedler HS, et al. Weight gain and comorbidities associated with oral second-generation antipsychotics: analysis of real-world data for patients with schizophrenia or bipolar I disorder. BMC Psychiatry. 2022;22(1):114. doi:10.1186/s12888-022-03758-w
32. Buckley NA, Sanders P. Cardiovascular adverse effects of antipsychotic drugs. Drug Saf. 2000;23(3):215-228. doi:10.2165/00002018-200023030-00004
33. Ali Z, Roque A, El-Mallakh RS. A unifying theory for the pathoetiologic mechanism of tardive dyskinesia. Med Hypotheses. 2020;140:109682. doi:10.1016/j.mehy.2020.109682
34. Sleem A, El-Mallakh RS. Adaptive changes to antipsychotics: their consequences and how to avoid them. Curr Psychiatry. 2022;21(7):46-50,52. doi: 10.12788/cp.0262
35. Nierenberg AA, McElroy SL, Friedman ES, et al. Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness): a pragmatic 6-month trial of lithium versus quetiapine for bipolar disorder. J Clin Psychiatry. 2016;77(1):90-99. doi:10.4088/JCP.14m09349
36. He H, Hu C, Ren Z, et al. Trends in the incidence and DALYs of bipolar disorder at global, regional, and national levels: results from the global burden of disease study 2017. J Psychiatr Res. 2020;125:96-105. doi:10.1016/j.jpsychires.2020.03.015
37. Roberts RJ, Repass R, El-Mallakh RS. Effect of dopamine on intracellular sodium: a common pathway for pharmacological mechanism of action in bipolar illness. World J Biol Psychiatry. 2010;11(2 Pt 2):181-187. doi:10.1080/15622970902718774
38. El-Mallakh RS, Wyatt RJ. The Na, K-ATPase hypothesis for bipolar illness. Biol Psychiatry. 1995;37(4):235-244. doi:10.1016/0006-3223(94)00201-D
39. El-Mallakh RS, Yff T, Gao Y. Ion dysregulation in the pathogenesis of bipolar disorder. Ann Depress Anxiety. 2016;3(1):1076.
40. Li R, El-Mallakh RS. Differential response of bipolar and normal control lymphoblastoid cell sodium pump to ethacrynic acid. J Affect Disord. 2004;80(1):11-17. doi:10.1016/S0165-0327(03)00044-2
41. Woodruff DB, El-Mallakh RS, Thiruvengadam AP. Validation of a diagnostic screening blood test for bipolar disorder. Ann Clin Psychiatry. 2012;24(2):135-139.
42. Gao Y, Lohano K, Delamere NA, et al. Ethanol normalizes glutamate-induced elevation of intracellular sodium in olfactory neuroepithelial progenitors from subjects with bipolar illness but not nonbipolar controls: biologic evidence for the self-medication hypothesis. Bipolar Disord. 2019;21(2):179-181. doi:10.1111/bdi.12737
43. El-Mallakh RS, Huff MO. Mood stabilizers and ion regulation. Harv Rev Psychiatry. 2001;9(1):23-32. doi:10.1080/10673220127873
44. Phillips ML, Swartz HA. A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research. Am J Psychiatry. 2014;171(8):829-843. doi:10.1176/appi.ajp.2014.13081008
45. Hibar DP, Westlye LT, Doan NT, et al. Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group. Mol Psychiatry. 2018;23(4):932-942. doi:10.1038/mp.2017.73
46. Brown NC, Andreazza AC, Young LT. An updated meta-analysis of oxidative stress markers in bipolar disorder. Psychiatry Res. 2014;218(1-2):61-68. doi:10.1016/j.psychres.2014.04.005
47. Benedetti F, Aggio V, Pratesi ML, et al. Neuroinflammation in bipolar depression. Front Psychiatry. 2020;11:71. doi:10.3389/fpsyt.2020.00071
48. Andreazza AC, Duong A, Young LT. Bipolar disorder as a mitochondrial disease. Biol Psychiatry. 2018;83(9):720-721. doi:10.1016/j.biopsych.2017.09.018
49. Askland KD. Toward a biaxial model of “bipolar” affective disorders: further exploration of genetic, molecular and cellular substrates. J Affect Disord. 2006;94(1-3):35-66. doi:10.1016/j.jad.2006.01.033
50. Ferreira MA, O’Donovan MC, Meng YA, et al; Wellcome Trust Case Control Consortium. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008;40(9):1056-1058. doi:10.1038/ng.209
51. Salvi AM, Bays JL, Mackin SR, et al. Ankyrin G organizes membrane components to promote coupling of cell mechanics and glucose uptake. Nat Cell Biol. 2021;23(5):457-466. doi:10.1038/s41556-021-00677-y
52. Gargus JJ. Ion channel functional candidate genes in multigenic neuropsychiatric disease. Biol Psychiatry. 2006;60(2):177-185. doi:10.1016/j.biopsych.2005.12.008
53. Dubovsky SL, Murphy J, Thomas M, et al. Abnormal intracellular calcium ion concentration in platelets and lymphocytes of bipolar patients. Am J Psychiatry 1992;149(1):118-120. doi:10.1176/ajp.149.1.118
54. Blaustein MP. Physiological effects of endogenous ouabain: control of intracellular Ca2+ stores and cell responsiveness. Am J Physiol. 1993;264(6 Pt 1):C1367–C1387. doi:10.1152/ajpcell.1993.264.6.C1367
55. El-Mallakh RS, Li R, Worth CA, et al. Leukocyte transmembrane potential in bipolar illness. J Affect Disord. 1996;41(1):33-37. doi:10.1016/0165-0327(96)00063-8
56. El-Mallakh RS, Gao Y, You P. Role of endogenous ouabain in the etiology of bipolar disorder. Int J Bipolar Disord. 2021;9(1):6. doi:10.1186/s40345-020-00213-1
57. Huang X, Lei Z, El‐Mallakh RS. Lithium normalizes elevated intracellular sodium. Bipolar Disord. 2007;9(3):298-300. doi:10.1111/j.1399-5618.2007.00429.x
58. Shaw DM. Mineral metabolism, mania, and melancholia. Br Med J. 1966;2(5508):262-267. doi:10.1136/bmj.2.5508.262
59. Qian K, Yu N, Tucker KR, et al. Mathematical analysis of depolarization block mediated by slow inactivation of fast sodium channels in midbrain dopamine neurons. J Neurophysiol. 2014;112(11):2779-2790. doi:10.1152/jn.00578.2014
60. Sleem A, El-Mallakh RS. Advances in the psychopharmacotherapy of bipolar disorder type I. Exp Opin Pharmacother. 2021;22(10):1267-1290. doi:10.1080/14656566.2021.1893306
61. Malhi GS., Tanious M, Das P, et al. Potential mechanisms of action of lithium in bipolar disorder. CNS Drugs. 2013;27(2):135-153. doi:10.1007/s40263-013-0039-0
62. Armett CJ, Ritchie JM. On the permeability of mammalian non-myelinated fibers to sodium and to lithium ions. J Physiol. 1963;165(1):130-140. doi:10.1113/jphysiol.1963.sp007047
63. Kabakov AY, Karkanias NB, Lenox RH, et al. Synapse-specific accumulation of lithium in intracellular microdomains: a model for uncoupling coincidence detection in the brain. Synapse. 1998;28(4):271-279. doi:10.1002/(SICI)1098-2396(199804)28:4<271::AID-SYN2>3.0.CO;2-6
64. Cipriani A, Reid K, Young AH, et al. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev. 2013;2013(10):CD003196. doi:10.1002/14651858.CD003196.pub2
65. Lai HC, Jan LY. The distribution and targeting of neuronal voltage-gated ion channels. Nat Rev Neurosci. 2006;7(7):548-562. doi:10.1038/nrn1938
66. Löscher W, Schmidt D. Increase of human plasma GABA by sodium valproate. Epilepsia. 1980;21(6):611-615. doi:10.1111/j.1528-1157.1980.tb04314.x
67. Owens MJ, Nemeroff CB. Pharmacology of valproate. Psychopharmacol Bull. 2003;37(Suppl 2):17-24.
68. Calabrese JR, Vieta E, Shelton MD. Latest maintenance data on lamotrigine in bipolar disorder. Eur Neuropsychopharmacol. 2003;13(Suppl 2):S57-S66. doi:10.1016/s0924-977x(03)00079-8
69. Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194(1):4-9. doi:10.1192/bjp.bp.107.048504
70. Nakatani Y, Masuko H, Amano T. Effect of lamotrigine on Na(v)1.4 voltage-gated sodium channels. J Pharmacol Sci. 2013;123(2):203-206. doi:10.1254/jphs.13116sc
71. Ramadan E, Basselin M, Rao JS, et al. Lamotrigine blocks NMDA receptor-initiated arachidonic acid signalling in rat brain: implications for its efficacy in bipolar disorder. Int J Neuropsychopharmacol. 2012;15(7):931-943. doi:10.1017/S1461145711001003
72. Jo S, Bean BP. Sidedness of carbamazepine accessibility to voltage-gated sodium channels. Mol Pharmacol. 2014;85(2):381-387. doi:10.1124/mol.113.090472
73. Curtin F, Schulz P. Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis. J Affect Disord 2004;78(3):201-208. doi:10.1016/S0165-0327(02)00317-8
74. Edwards R, Stephenson U, Flewett T. Clonazepam in acute mania: a double blind trial. Aust N Z J Psychiatry 1991;25(2):238-242. doi:10.3109/00048679109077740
75. Lin SC, Chen CC, Chen YH, et al. Benzodiazepine prescription among patients with severe mental illness and co-occurring alcohol abuse/dependence in Taiwan. Hum Psychopharmacol. 2011;26(3):201-207. doi:10.1002/hup.1193
76. Prisciandaro JJ, Brown DG, Brady KT, et al. Comorbid anxiety disorders and baseline medication regimens predict clinical outcomes in individuals with co-occurring bipolar disorder and alcohol dependence: results of a randomized controlled trial. Psychiatry Res. 2011;188(3):361-365. doi:10.1016/j.psychres.2011.04.030
77. Ashok AH, Marques TR, Jauhar S, et al. The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Mol Psychiatry. 2017;22(5):666-679. doi:10.1038/mp.2017.16
78. Roberts RJ, Lohano KK, El-Mallakh RS. Antipsychotics as antidepressants. Asia Pac Psychiatry. 2016;8(3):179-188. doi:10.1111/appy.12186
79. Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378(9799):1306-1315. doi:10.1016/S0140-6736(11)60873-8
80. Hayes JF, Marston L, Walters K, et al. Lithium vs. valproate vs. olanzapine vs. quetiapine as maintenance monotherapy for bipolar disorder: a population-based UK cohort study using electronic health records. World Psychiatry. 2016;15(1):53-58. doi:10.1002/wps.20298
81. Geddes JR, Gardiner A, Rendell J, et al. Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial. Lancet Psychiatry. 2016;3(1):31239. doi:10.1016/S2215-0366(15)00450-2
82. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6):495-553. doi:10.1177/0269881116636545
