The Urgent Need of New Mood-Stabilizers: The Promising Results of
Giulia Serra1,2, Francesca Demontis3 and Gino Serra4*
1Clinical and Research fellow, Child Neuropsychiatry, Department of Neuroscience, I.R.C.C.S. Children Hospital Bambino Gesu, Rome, Italy.
2NESMOS Department, Sant'Andrea Hospital, Sapienza University, Rome Italy
3International Consortium for Bipolar Disorder Research, McLean Hospital, Belmont (MA), USA
4Dipartimento di Scienze Biomediche, University of Sassari, Italy
- Corresponding Author:
- Gino Serra
Dipartimento di Scienze Biomediche
Università di Sassari
VialeSan Pietro, 4307100, SASSARI ITALY, Italy
E-mail: [email protected]
Received date: September 08, 2015; Accepted date: September 09, 2015; Published date: September 16, 2015
Citation: Serra G, Demontis F, Serra G (2015) The Urgent Need of New Mood- Stabilizers: The Promising Results of Memantine. Bipolar Disord 1:e102. doi:10.4172/2472-1077.1000e102
Copyright: © 2015 Serra G, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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The main aim of pharmacological treatment for Bipolar Disorder (BD) patients is the prevention of manic/hypomanic and depressive episodes by the administration of mood stabilizer drugs.
Unfortunately, after several decades of its serendipitous discovery, lithium remains the only drug with consolidated evidence of moodstabilizing effect . No important therapeutic innovations (i.e., a drug with major clinical benefit compared with existing drugs, according to the definition of Motola  have been introduced in the last 60 years
Some anticonvulsant medications and atypical antipsychotics are currently approved or used off-label as lithium alternative mood stabilizers. Anticonvulsants have been shown to be of limited efficacy both as a monotherapy and in combination with lithium [1,3-7] and the mood stabilizing effect of atypical antipsychotics has been severely questioned [8,9].
Thus, the research and development of more effective moodstabilizers for the prophylaxis of bipolar patients resistant to lithium, is an urgent challenge of modern psychopharmacology.
Indeed, even with currently available treatments, patients with BD remain unwell in 50% of their time, with about 75% of this time spent in depression .
We have recently suggested that blockade of NMDA receptors by memantine, a drug with excellent safety and tolerability profile , could result in an antimanic and mood-stabilizing effect in treatmentresistant BD patients [11,12].
Our group found suggestive evidence of the mood-stabilizing effect of memantine when added to stable, ongoing but inadequately effective standard treatments in 40 BD patients in two 6 and 12-month clinical trials [13,14].
Memantine as a monotherapy also has been reported to show beneficial effects in few individual BD patients, including after discontinuation of lithium treatment [15-18].
Finally, we reported the results of a three-year naturalistic study of adding memantine to 30 treatment-resistant bipolar patients . In this trial, memantine achieves clinically meaningful long-term benefits, for both depressive and mania-like (mania, hypomania) morbidity, in outpatients who had proved resistant to standard treatments for more than 3 years, until memantine (20–30 mg/day) was added to otherwise stable regimens for another 3 years, during which patients improved progressively. Patients under memantine treatment showed a marked, statistically significant decrease of the illness morbidity (total, manic and depressive illness, on average–74.2%), the severity (CGI-BP; –63.1%), the duration (–56.3%) and the number of illness episodes (episodes/year; –55.8%). These findings indicated progressive and impressive improvement in the duration (from about 70% of total illness, 45% of depression, and 25% of mania/hypomania before memantine to less than 10% of total illness, 5% of depression, and 5% of mania hypomania after 3 years of memantine addition) and the severity of both affective phases of the disorder, with a greater improvement of depression than mania, and evidence of decreased severity of mania. Subjects with previous rapid- (≥ 4 episodes/year) or continuous-cycling were particularly improved.
As for the possible mechanism of antimanic and mood stabilizing effect of memantine, we have demonstrated that chronic treatment with antidepressants sensitizes dopamine D2 receptors in the mesolimbic system, an effect that may contribute to their therapeutic action and may be responsible of their ability to induce switch from depression to mania in humans [11,12,20-24].
Indeed, Tondo et al.  reported 12.5% of switch from depression to mania induced by antidepressants, and a great deal of evidence suggests that an increased dopaminergic transmission is associated with mania/hypomania [26-30].
The sensitization of dopamine receptors (mania) is followed by a progressive desensitization of those receptors, associated with a depressivelike behavior assessed in the forced swimming test of depression [31-33].
Thus, antidepressants induce a bipolar-like behavior, mimicking a cycle of the manic depressive illness (mania followed by depression).
Memantine prevents the bipolar-like behavior in rats. Indeed it prevents both the sensitization of dopamine receptors (mania) induced by chronic treatment with imipramine, and the ensuing desensitization associated with the depressive behavior .
Moreover it has recently been suggested that memantine, as well as lithium, has a neuroprotective action  and that mania could be associated with an excessive stimulation of NMDA receptors , which may result in an excitotoxic neurodegeneration .
According to this hypothesis, it may be suggested that memantine, by blocking NMDA receptors, suppresses mania and prevents the neurodegeneration  that may be associated with depression .
Thus, we suggest that the antimanic and mood-stabilizing action of memantine might be due to its ability to “stabilize” dopamine receptor sensitivity and to its blockade of the excitotoxic effect of excessive NMDA receptor stimulation.
Interestingly, the neoroprotective/neurotrophic effect of memantine may be due not only to the blockade of the excessive glutamatergic stimulation of NMDA receptors, but also to a number of biological effects shared with lithium (the gold standard mood stabilizer), and that are considered involved in a neuroprotective/neurotrophic action, such as, for instance, promotion of neurogenesis , increased in neurotrophic factor release in brain , inhibition of protein kinase C  and glycogen synthase kinase-3 .
In keeping with these observation, it may be suggested that lithium and memantine might have a synergistic effect, so that their combination might result in a potentiation of antimanic and mood stabilizing effect.
To conclude, with the exception of lithium the available mood stabilizer drugs are of limited or severely questioned efficacy. We have recently provided very promising data suggesting that memantine, a drug with excellent safety and tolerability profile, has an acute antimanic and a long lasting and progressive mood stabilizing effect in patients with BD resistant to the available treatments.
Moreover, we suggest that memantine and lithium combination might have a synergistic effect.
Accordingly it is tempting to suggest the use of a lithium and memantine combination as a first-line treatment in the severely ill BD patients.
- Severus E, Taylor MJ, Sauer C, Pfennig A, Ritter P, et al. (2014) Lithium for prevention of mood episodes in bipolar disorders: Systematic review and meta-analysis. Int J Bipolar Disord2:15.
- Motola D, De Ponti F, Rossi P, Martini N, Montanaro N, et al. (2005)Therapeutic innovation in the European Union: Analysis of the drugs approved by the EMEA between 1995 and 2003. Br J ClinPharmacol59: 475-478.
- BaldessariniRJ (2010) Commentary: The Bipolar Affective Disorder: Lithium/Anticonvulsant Evaluation (BALANCE) study. Bipolar Disorder 12: 669-672.
- Geddes JR, Goodwin GM, Rendell J, Azorin JM, Cipriani A, et al.(2010) Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): Arandomised open-label trial. Lancet 375: 385-395.
- Post RM, Weiss SR (2011) Tolerance to the prophylactic effects of carbamazepine and related mood stabilizers in the treatment of bipolar disorders. CNS NeurosciTher 17:649-660.
- Baldessarini RJ(2013) Chemotherapy in Psychiatry, third edition. New York: Springer Press.
- Geddes JR, Miklowitz DJ (2013) Treatment of bipolar disorder. Lancet 381: 1672-1682.
- Goodwin FK, Whitham EA, Ghaemi SN (2011) Maintenance treatment study designs in bipolar disorder: Do they demonstrate that atypical neuroleptics (antipsychotics) are mood stabilizers? CNS Drugs 25: 819-827.
- Malhi GS, Chengappa KN, Gershon S, Ghaemi SN (2011) Atypical mood stabilizers: A new role for neuroleptics? Bipolar Disord13: 583-586.
- Jones RW (2010) A review comparing the safety and tolerability of memantine with the acetylcholinesterase inhibitors. Int J Geriatr Psychiatry24: 547-553.
- Serra G (2009) Uso della memantina per il trattamento dei disturbi dell'umore. N° MI2009A000174. IT Patent.
- Serra G (2010)Memantine for treating bipolar mood disorders resistant to conventional treatments. EP 2 218 450 A1. Priority: 11.02.2009 IT MI20090174. 18.08.2010 Bulletin 2010/33. EP Patent.
- Koukopoulos A, Reginaldi D, Serra G, Koukopoulos A, SaniG, et al. (2010) Antimanicand mood-stabilizing effect of memantine as an augmenting agent intreatment-resistant bipolar disorder. Bipolar Disorder 12: 348-349.
- Koukopoulos A, Serra G, Koukopoulos AE, Reginaldi D, Serra G, etal. (2012)The sustained mood-stabilizing effect of memantine in the management of treatment resistant bipolar disorders: Findings from a 12-month naturalistic trial. J Affect Disord136: 163-166.
- Serra G, De Chiara L, Koukopoulos A, Serra G (2013) Antimanic and long-lasting mood stabilizing effect of memantine in bipolar I mood disorder:Two case reports. J ClinPsychopharmacol 33:715-717.
- Serra G, De Chiara L, Manfredi G, Koukopoulos AE, Sani G, et al. (2014a) Memantine in the management of affective recurrences of bipolar disorders after the discontinuation of long-term lithium treatment: Three case histories. TherAdvPsychopharmacol 4:53-55.
- Serra G, DE Chiara L, Koukopoulos AE, Koukopoulos A, Serra G (2014b)Memantine in the treatment and prophylaxis of bipolar II disorder and comorbid fibromyalgia: A case report. J PsychiatrPract 20:232-236.
- De Chiara L, Serra G, Koukopoulos AE, Koukopoulos A, Serra G, et al.(2014) Memantine in the treatment and prophylaxis of bipolar type II mood disorder and co-morbid eating disorder: A case report. RivPsichiatr 49:192-194.
- Serra G, Koukopoulos A, De Chiara L, Koukopoulos AE, Tondo L, etal. (2015) Three-year, naturalistic, mirror-image assessment of adding memantine to the treatment of 30 treatment-resistant patients with bipolar disorder. J Clin Psychiatry 76:e91-97
- Serra G, ArgiolasA, Klimek V, Fadda F, Gessa GL, et al. (1979) Chronic treatment with antidepressants prevents the inhibitory effect of small doses of apomorphine on dopamine synthesis and motor activity. Life Sci25: 415-423.
- Serra G, Collu M, D’Aquila PS, Gessa GL (1992) Role of the mesolimbic dopamine system in the mechanism of action of antidepressants. Pharmacol Toxicol71 Suppl 1: 72-85
- Gessa GL, Pani L, Serra G, Fratta W (1995) Animal models of Mania. In: Gessa GL, Fratta W, Pani L, Serra G (Eds). Depression and Mania: From neurobiology to treatment.Raven Press, 43-66.
- Collu M, D’Aquila, Gessa GL, Serra G (1997) Do antidepressant treatments induce mania by activating dopaminergic transmission? Second International Conference on Bipolar Disorders, Pittsburg, USA, 77.
- D’Aquila PS, Collu M, Gessa GL, Serra G (2000) The role of dopamine in the mechanism of action of antidepressant drugs. Eur J Pharmacol405: 365-373.
- Tondo L, Vázquez G, Baldessarini RJ (2010) Mania associated with antidepressant treatment: Comprehensive meta-analytic review. ActaPsychiatrScand121: 404-414.
- Diehl DJ, Gershon S (1992) The role of dopamine in mood disorders. Compr Psychiatry33: 115-120.
- Dunlop BW, Nemeroff CB (2007)the role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry64: 327-337.
- Berk M, Dodd S, Kauer-Sant’anna M, Malhi GS, Bourin M, et al. (2007) Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder. ActaPsychiatrScandSuppl434: 41-49.
- Cousins DA, Butts K, Young AH (2009) the role of dopamine in bipolar disorder. Bipolar Disorder11: 787-806.
- VanEnkhuizen J, Geyer MA, Halberstadt AL, Zhuang X, Young JW, et al. (2013) Dopamine depletion attenuates some behavioral abnormalities in a hyper-dopaminergic mouse model of bipolar disorder. JAffectDisord 155: 247-254.
- D'Aquila PS, Peana AT, Panin F, Grixoni C, Cossu M, et al. (2003) Reversal of antidepressant-induced dopaminergic behaviouralsuper sensitivity after long-term chronic imipramine withdrawal. Eur J Pharmacol 458:129-134.
- D'Aquila PS, Panin F, Serra G (2004) Long-term imipramine withdrawal induces a depressive-like behaviour in the forced swimming test. Eur J Pharmacol 492:61-63.
- Demontis F, Falconi M, Canu D, Serra G (2015) Memantine prevents "bipolar-like" behavior induced by chronic treatment with imipramine in rats. Eur J Pharmacol752:49-54.
- La Spada AR (2009) Memantine strikes the perfect balance. Nat Med15: 1355-1356.
- Ongür D, Jensen JE, Prescot AP, Stork C, Lundy M, et al. (2008) Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania. Biol Psychiatry64: 718-726.
- Atmaca M, Yildirim H (2012) Altered neurochemical ingredient of hippocampus in patients with bipolar depression. Depress Res Treat 2012: 485249 .
- Tanovic A, Alfaro V (2006) Glutamate-related excitotoxicityneuroprotection with memantine, an uncompetitive antagonist of NMDA-glutamate receptor, in Alzheimer’s disease and vascular dementia. Rev Neurol42: 607-616.
- Lu RB, Chen SL, Lee SY, Chang YH, Chen SH, et al. (2012)Neuroprotective and neurogenesis agent for treating bipolar II disorder: add-on memantine to mood stabilizer works. Med Hypotheses79: 280-283.
- Wu HM, Tzeng NS, Qian L, Wei SJ, Hu X, et al. (2009) Novel neuroprotective mechanisms of memantine: increase in neurotrophic factor release from astroglia and anti-inflammation by preventing microglial activation. Neuropsychopharmacology34: 2344-2357.
- Lu CW, Lin TY, Wang SJ (2010) Memantine depresses glutamate release through inhibition of voltage-dependent Ca2+ entry and protein kinase C in rat cerebral cortex nerve terminals: An NMDA receptor-independent mechanism. NeurochemInt57: 168-176.
- De Sarno P, Bijur GN, Zmijewska AA, Li X, Jope RS, et al. (2006) In vivo regulation of GSK3 phosphorylation by cholinergic and NMDA receptors. Neurobiol Aging27: 413-422.