Clozapine As Transformative Treatment In Bipolar Patients
Received 15 August 2019
Accepted for publication 19 September 2019
Published 9 October 2019 Volume 2019:15 Pages 2901—2905
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Roger Pinder
Alina Wilkowska, Wiesław J Cubała
Department of Psychiatry, Medical University of Gdańsk, Gdańsk, Poland
Correspondence: Alina Wilkowska
Department of Psychiatry, Medical University of Gdańsk, Dębinki 7, Gdańsk 80-211, Poland
Tel +48 58 349 2650
Fax +48 349 2748
Email [email protected]
Abstract: Clozapine is an atypical antipsychotic used in treatment-resistant bipolar disorder. There is evidence for its anti-suicidal, anti-aggressive properties and efficacy in substance use comorbidities. Despite guidelines, the drug is used in 1.5% of bipolar patients only. Considering its effectiveness in treatment-resistant cases as well as its epigenetic effects it may become transformative treatment in bipolar disorder impacting the clinical course and psychosocial burden of the disease.
Keywords: clozapine, transformative treatment, bipolar disorder, treatment resistance
Bipolar disorder is a chronic and severe mental disorder, characterized by irregular acute episodes of depressed, elevated, and mixed mood states often accompanied by comorbidities and suicidality-associated symptomatology.1 Bipolar disorder is a disabling illness due to its early onset, severity and chronicity. Current trends in growth and aging are leading to an increase in the burden of bipolar disorder over time. It is important that resources be directed towards more effective treatments.2
Clozapine is effective in treatment resistant and severe cases of bipolar disorder. There is growing evidence that it has impact on course modifying processes which can change the course of disease leading to significant improvement, reducing the disease burden and become a transformative treatment in psychiatry.
Clozapine In Bipolar Disorder
Clozapine has been used in treatment-resistant bipolar disorder (TRBD) for almost 30 years.3 It reduces symptom severity in manic and mixed episodes and decreases the need for use of concomitant psychotropic drugs.3,4
The treatment with clozapine in bipolar disorder is associated with the reduction in psychiatric admissions, number of psychotropic concomitant medications, and hospital contact for self-harm and overdose,3 all suggesting that clozapine exhibits strong mood-stabilizing properties. Clozapine has been shown to be useful in treatment of TRBD, decreasing the number of hospitalizations and improving symptomatic and functional improvement.5 It has anti-manic and possibly an antidepressant effect described in one case report.6–8 There is also evidence for use of clozapine in rapid-cycling bipolar disorder.9,10
According to the contemporary guidelines, clozapine is worth considering as a treatment option in cases of resistant bipolar I disorder, including rapid cycling.11 It is recommended for treatment-resistant BD,12 as the third-line treatment for acute mania and treatment-resistant mania and also as an additional agent for the maintenance treatment of BD I.13 Despite all that clozapine lacks official regulatory approval for use in any phase of bipolar disorder which is probably due to the very small number of studies on clozapine in bipolar disorder.14
Antisuicidal And Antiaggressive Effects Of Clozapine
Clozapine has been shown to have specific anti-suicidal properties in patients with schizophrenia.15–17 Some authors suggest that clozapine may exhibit anti-suicidal properties that extend beyond schizophrenia into bipolar disorder.18,19 This effect was described in one case report and our recent case series.20,21 Suicide accounts for 15% to 20% of deaths among bipolar disorder patients.22,23 For today there are no approved pharmacological interventions for suicidality in bipolar disorder.
Another interesting effect of clozapine is the reduction of violence and aggression in patients with schizophrenia and other psychiatric disorders.24 This also applies to patients with comorbid substance use disorder. There is evidence that clozapine reduces aggressive behavior in patients with bipolar disorder with psychotic symptoms25 as well as substance abuse. It may limit the use of cannabis,26 alcohol,27 both combined28 and poly-substance abuse including cocaine29 in comparison to FGA (first-generation antipsychotics) and other SGA (second-generation antipsychotics). Some authors suggest that clozapine should be evaluated for reducing abuse of alcohol and other substances in bipolar disorder patients.30 It may be hypothesized that clozapine impacts the disease itself along with the specific symptom domains like suicidality, aggression and substance use.
The Unique Properties Of Clozapine
Clozapine has complex binding receptor profile.31 The mechanisms employed in the anti-suicidal effect of clozapine probably involve the simultaneous modulation of dopamine, norepinephrine, and serotonin,18 regulation of the endocrine system (pregnenolone, cortisol)32 and intracellular systems-dependent modulation of N-methyl-D-aspartate (NMDA) receptor expression, brain-derived neurotrophic factor up-regulation, and regulation of the arachidonic acid cascade.33,34 Animal studies suggest that clozapine has an impact on glutamatergic transmission. Fukuyama et al found that clozapine prevents thalamocortical hyperglutamatergic transmission via activation of mPFC presynaptic III-mGluR and by the activation of astroglial l-glutamate release. The authors suggest that these actions may contribute to the unique clinical profile of clozapine.35
Clozapine is a known 5-HT2A antagonist, but it can also act as an agonist at this receptor. These mixed properties of the drug can be explained through “biased agonism.” Clozapine is an antagonist on 5-HT2A serotonin receptor in relation to the G protein activation but it is an agonist on the same receptor if AKT (protein kinase B) activation is measured. In addition, clozapine, more than other second-generation antipsychotics, activates ERK1/2 (extracellular signal-regulated kinases), which may explain, in part, the therapeutic superiority of this drug on many aspects of mental disorders. Actually, activation of ERK1/2 pathway that is involved in transcriptional regulation might contribute in improving synaptic plasticity, connectivity and neurogenesis. It might also be associated in enhancing the expression of neurotrophic factors, such as BDNF.36,37 Clozapine is the powerful drug activating ERK1/2 and part of this effect is due to the novel mechanism of 5-HT2A receptor activation. This evidence might be relevant to explain, at least in part, the superiority of clozapine among the SGAs.38
Epigenetic Effects Of Clozapine – Animal Studies
The unique properties of clozapine seem to be related to its epigenetic effects. There is growing evidence published during last few years, suggesting an important role of clozapine in epigenetic mechanisms.
Guidotti et al39 used prenatally stressed mice (PRS) model to study potential efficacy of antipsychotic drugs acting on altered epigenetic mechanisms, reducing hypermethylation which causes reduced gene expression and behavioral endophenotypes. PRS mice model turned out to be insensitive to haloperidol, but sensitive to drugs like clozapine and valproate40,41 that modulate chromatin function. Another study using this model also found that clozapine, but not haloperidol nor risperidone corrected behavioral endophenotype. In a study conducted with use of the prenatally stressed mice brains clozapine, unlike haloperidol and risperidone limited methylation in reelin, BDNF and glutamic acid decarboxylase 67 promoter regions and normalized mice behavior in the form of their social interaction.42
Ayoama et al43 suggest that the antipsychotic effect of clozapine develops, at least in part, through histone modification and this process is mediated by activation of the dopamine D1 receptor in the prefrontal cortex of PCP (Phencyclidine)-treated mice.
Epigenetic Effects Of Clozapine – Human Studies
Human studies like the one by Kinoshita et al44 investigated gene methylation in peripheral leukocytes from patients with treatment-resistant schizophrenia following 12 months clozapine treatment. Genes with clozapine-induced changes in DNA methylation were associated with cell substrate adhesion and cell matrix adhesion. The authors also observed DNA methylation changes in the CREBBP (cAMP response element-binding protein) gene, acting as a transcription factor. These changes were significantly correlated with the clinical improvements. Kouter et al45 in their recent study conducted on human suicide victims present significant differences in brain DNA methylation suggesting that this process may be involved in the pathophysiology of suicide.
Nakazawa et al,46 using induced pluripotent stem (iPS) cell-based technology, investigated a pair of monozygotic twins with treatment-resistant schizophrenia. One twin responded well to clozapine treatment and the other twin did not. Although these iPS cells similarly differentiated into neurons, several genes encoding homophilic cell adhesion molecules showed differential expression patterns between these two patients. Long-term treatment with antipsychotics is often necessary for the improvement of schizophrenic symptoms47,48 and these improvements probably involve epigenetic changes. The evidence is mounting however, the molecular and epigenetic mechanisms underlying the therapeutic efficacy of clozapine in bipolar disorder have not yet been fully elucidated.
Neuroplasticity – Animal Studies
Clozapine is hypothesized to promote synaptic remodeling or synaptic reorganization in the hippocampus.49 In the clozapine vs haloperidol comparison study on neuroplasticity, the authors found that clozapine increases dendritic spine formation, postsynaptic spinophilin expression and up-regulates the number of post-synaptic density (PSD) sites, as indicators of synaptogenesis and synaptic maturation.49 The study describing the effects of clozapine administration on levels of SNAP-25 and synaptophysin in the hippocampus in rodents revealed changes in these proteins levels that may be related to hippocampal synaptic remodeling. Interestingly, haloperidol did not induce similar synaptic changes suggests that the exceptional effect of clozapine could be related to changes in hippocampal plasticity.50 There is also evidence for clozapine-mediated significant changes in cell composition in white matter of primates, which could lead to a partial rewiring of prefrontal circuitry.51 According to Maletic and Raison,52 morphological changes like gray matter volume reduction and its hypofunction present in bipolar patients provide strong support for the hypothetical impairment of neuroplasticity in bipolar disorder. The authors also suggest the significant role of BDNF in regulating neuroplastic processes in this disorder.
Concept Of Transformative Treatment
Clozapine is used in complicated cases of BP I disorder including treatment-resistant mania and depression, mixed episodes, rapid cycling, cases with suicidality, aggression and substance use disorders. It seems that the effect of clozapine is more pronounced in severe forms of this neuropsychiatric disorder. The great burden of this disease with highest risk of suicide among psychiatric disorders, common psychiatric and somatic comorbidities, treatment resistance and devastating psychosocial consequences calls for more effective treatments.53 Clozapine with its unique pharmacology and epigenetic and neuroplastic effects can become a transformative treatment similarly to antiviral transformative treatments for AIDS or HCV, cell therapies in oncology or gene therapies54 or ketamine in the treatment of depression. It can significantly reduce the great burden of BP I and may modify the course of the disease.
Clozapine may be associated with long-term prognosis, course and anti-suicidal effect in BP I patients impacting the course of the disease particularly in treatment-resistant, rapid cycling, suicidal subpopulations and patients with comorbidities. Transformation of the global burden of the disease may exemplify for the observed clinical improvement.
This paper was granted by the Medical University of Gdańsk, Poland (Grant No. ST-02-0039/07/221).
The authors report no conflicts of interest in this work.
1. American Psychiatric Association, DSM-5 Task Force. Diagnostic and Statistical Manual of Mental Disorders: DSM-5™.
2. Ferrari AJ, Stockings E, Khoo JP, et al. The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. Bipolar Disord. 2016;18(5):440–450. doi:10.1111/bdi.12423
3. Nielsen J, Kane JM, Correll CU. Real-world effectiveness of clozapine in patients with bipolar disorder: results from a 2-year mirror-image study. Bipolar Disord. 2012;14:863–869. doi:10.1111/bdi.12018
4. Chang JS, Ha KS, Young Lee K, Sik Kim Y, Min Ahn Y. The effects of long-term clozapine add-on therapy on the rehospitalization rate and the mood polarity patterns in bipolar disorders. J Clin Psychiatry. 2006;67:461–467. doi:10.4088/JCP.v67n0318
5. Li X-B, Tang Y-L, Wang C-Y, de Leon J. Clozapine for treatment resistant bipolar disorder: a systematic review. Bipolar Disord. 2015;17:235–247. doi:10.1111/bdi.2015.17.issue-3
6. Green AI, Tohen M, Patel JK, et al. Clozapine in the treatment of refractory psychotic mania. Am J Psychiatry. 2000;157:982–986. doi:10.1176/appi.ajp.157.6.982
7. Banov MD, Zarate CA
8. Calabrese JR, Kimmel SE, Woyshville MJ, et al. Clozapine for treatment-refractory mania. Am J Psychiatry. 1996;153:759–764. doi:10.1176/ajp.153.6.759
9. Calabrese JR, Meltzer HY, Markovitz PJ. Clozapine prophylaxis in rapid cycling bipolar disorder. J Clin Psychopharmacol. 1991;11:396–397. doi:10.1097/00004714-199112000-00026
10. Chen CK, Shiah I-S, Yeh C-B, Mao W-C, Chang -C-C. Combination treatment of clozapine and topiramate in resistant rapid‐cycling bipolar disorder. Clin Neuropharmacol. 2005;28:136–138. doi:10.1097/01.wnf.0000169731.93065.ef
11. 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
12. Grunze H, Vieta E, Goodwin GM, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2012 on the long term treatment of bipolar disorder. World J Biol Psychiatry. 2013;14:154–219. doi:10.3109/15622975.2013.770551
13. Yatham LN, Kennedy SH, Schaffer A, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar Disord. 2009;11:225–255. doi:10.1111/j.1399-5618.2009.00672.x
14. Poon SH, Sim K, Baldessarini RJ. Pharmacological approaches for treatment-resistant bipolar disorder. Curr Neuropharmacol. 2015;13(5):592–604. Published online 2015 September. doi:10.2174/1570159X13666150630171954
15. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60:82–91. doi:10.1001/archpsyc.60.1.82
16. Hennen J, Baldessarini RJ. Reduced suicidal risk during treatment with clozapine: meta-analysis. Schizophrenia Res. 2005;73:139–145. doi:10.1016/j.schres.2004.05.015
17. Ciapparelli A, Dell’Osso L, Pini S, Chiavacci MC, Fenzi M, Cassano GB. Clozapine for treatment-refractory schizophrenia, schizoaffective disorder, and psychotic bipolar disorder: a 24-month naturalistic study. J Clin Psychiatry. 2000;61:329–334. doi:10.4088/JCP.v61n0502
18. Carter TD, Mundo E, Parikh SV, Kennedy JL. Early age at onset as a risk factor for poor outcome of bipolar disorder. J Psychiatr Res. 2003;37:297–303. doi:10.1016/S0022-3956(03)00052-9
19. Meltzer HY, Anand R, Alphs L. Reducing suicide risk in schizophrenia: focus on the role of clozapine. CNS Drugs. 2000;14:355–365. doi:10.2165/00023210-200014050-00003
20. Vangala VR, Brown ES, Suppes T. Clozapine associated with decreased suicidality in bipolar disorder: a case report. Bipolar Disord. 1999;1:123–124.
21. Wilkowska A, Wiglusz MS, Cubała WJ. Clozapine in treatment-resistant bipolar disorder with suicidality. Three case reports. Front Psychiatry. 2019;10:520. doi:10.3389/fpsyt.2019.00448
22. Baldessarini RJ, Pompili M, Tondo L. Suicide in bipolar disorder: risks and management. CNS Spectr. 2006;11:465–471. doi:10.1017/s1092852900014681
23. Goodwin FK, Jamison KR. Manic-Depressive Illness. New York: Oxford University Press; 1990.
24. Frogley C, Taylor D, Dickens G, Picchioni M. A systematic review of the evidence of clozapine’s anti-aggressive effects. Int J Neuropsychopharmacol. 2012;15:1351–1371. doi:10.1017/S146114571100201X
25. Kowatch R, Suppes T, Gilfillan SK, et al. Clozapine treatment of children and adolescents with bipolar disorder and schizophrenia: a clinical case series. J Child Adolesc Psychopharmacol. 1995;5:241–253. doi:10.1089/cap.1995.5.241
26. Brunette M, Dawson R, O’Keefe CD, et al. Clozapine vs. other antipsychotics for schizophrenia and co-occuring cannabis use disorder. Schizophr Bull. 2011;37:297.
27. Chau DT, Gulick D, Xie H, Dawson R, Green AI. Clozapine chronically suppresses alcohol drinking in Syrian golden hamsters. Neuropharmacology. 2010;58:351–356. doi:10.1016/j.neuropharm.2009.10.006
28. Green AI, Burgess ES, Dawson R, Zimmet SV, Strous RD. Alcohol and cannabis use in schizophrenia: effects of clozapine vs. risperidone. Schizophr Res. 2003;60:81–85. doi:10.1016/S0920-9964(02)00231-1
29. Zimmet SV, Strous RD, Burgess ES, Kohnstamm S, Green AI. Effects of clozapine on substance use in patients with schizophrenia and schizoaffective disorder: a retrospective survey. J Clin Psychopharmacol. 2000;20:94–98. doi:10.1097/00004714-200002000-00016
30. Zhornitsky S, Rizkallah E, Pampoulova T. Antipsychotic agents for the treatment of substance use disorders in patients with and without comorbid psychosis. J Clin Psychopharmacol. 2010;30:417–424. doi:10.1097/JCP.0b013e3181e7810a
31. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Application.
32. Marx CE, Shampine LJ, Duncan GE, et al. Clozapine markedly elevates pregnenolone in rat hippocampus, cerebral cortex, and serum: candidate mechanism for superior efficacy? Pharmacol Biochem Behav. 2006;84:598–608. doi:10.1016/j.pbb.2006.07.026
33. Leveque JC, Macías W, Rajadhyaksha A, et al. Intracellular modulation of NMDA receptor function by antipsychotic drugs. J Neurosci. 2000;20:4011–4020. doi:10.1523/JNEUROSCI.20-11-04011.2000
34. Spivak B, Shabash E, Sheitman B, Weizman A, Mester R. The effects of clozapine vs. haloperidol on measures of impulsive aggression and suicidality in chronic schizophrenia patients: an open, nonrandomized, 6-month study. J Clin Psychiatry. 2003;64:755–760. doi:10.4088/JCP.v64n0703
35. Fukuyama K, Kato R, Murata M, Shiroyama T, Okada M. Clozapine normalizes a glutamatergic transmission abnormality induced by an impaired NMDA receptor in the thalamocortical pathway via the activation of a group III metabotropic glutamate receptor. Biomolecules. 2019;9:234. doi:10.3390/biom9060234
36. Park SW, Lee JG, Ha EK, et al. Differential effects of aripiprazole and haloperidol on BDNF-mediated signal changes in SH-SY5Ycells. Eur Neuropsychopharmacol. 2009;19(5):356–362. doi:10.1016/j.euroneuro.2008.12.012
37. Maragnoli ME, Fumagalli F, Gennarelli M, Racagni G, Riva MA. Fluoxetine and olanzapine have synergistic effects in the modulation of fibroblast growth factor 2 expression within the rat brain. Biol Psychiatry. 2004;55(11):1095–1102. doi:10.1016/j.biopsych.2004.02.003
38. Aringhieri S, Kolachalam S, Gerace C, et al. Clozapine as the most efficacious antipsychotic for activating ERK 1/2 kinases: role of 5-HT2A receptor agonism. Eur Neuropsychopharmacol. 2017;27(4):383–398. doi:10.1016/j.euroneuro.2017.02.005
39. Alessandro G, Erbo D, Grayson DR. Epigenetic basis of clozapine action. J Drug Des Res. 2017;4(6):1055.
40. Matrisciano F, Tueting P, Dalal I, et al. Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice. Neuropharmacology. 2013;68:184–194. doi:10.1016/j.neuropharm.2012.04.013
41. Dong E, Tueting P, Matrisciano F, Grayson DR, Guidotti A. Behavioral and molecular neuroepigenetic alterations in prenatally stressed mice: relevance for the study of chromatin remodeling properties of antipsychotic drugs. Transl Psychiatry. 2016;6:e711.
42. Dong E, Locci V, Gatta E, Grayson DR, Guidotti A. N-Phthalyl-l-Tryptophan (RG108), like Clozapine (CLO), induces chromatin remodeling in brains of prenatally stressed mice. Mol Pharmacol. 2019;95(1):62–69. doi:10.1124/mol.118.113415
43. Aoyama Y, Mouri A, Toriumi K, et al. Clozapine ameliorates epigenetic and behavioral abnormalities induced by phencyclidine through activation of dopamine D1 receptor. Int J Neuropsychopharmacol. 2014;17:723–737. doi:10.1017/S1461145713001466
44. Kinoshita M, Numata S, Tajima A, et al. Effect of clozapine on DNA methylation in peripheral leukocytes from patients with treatment-resistant schizophrenia Int J Mol Sci. 2017;18:632. doi:10.3390/ijms18030632
45. Kouter K, Zupanc T, Paska V. A genome-wide DNA methylation in suicide victims revealing impact on gene expression. J Affect Disord. 2019;15(253):419–425. doi:10.1016/j.jad.2019.04.077
46. Nakazawa T, Kikuchi M, Ishikawa M, et al. Differential gene expression profiles in neurons generated from lymphoblastoid B cell line-derived iPS cells from monozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine. Schizophr Res. 2017;181:75–82. doi:10.1016/j.schres.2016.10.012
47. Lieberman JA, Stroup TS, McEvoy JP, et al. Clinical antipsychotic trials of intervention effectiveness I effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–1223. doi:10.1056/NEJMoa051688
48. Lewis DA, Gonzalez-Burgos G. Pathophysiologically based treatment interventions in schizophrenia. Nat Med. 2006;12:1016–1022. doi:10.1038/nm1478
49. Critchlow HM, Maycox PR, Skepper JN, Krylova O. Clozapine and haloperidol differentially regulate dendritic spine formation and synaptogenesis in rat hippocampal neurons. Mol Cell Neurosci. 2006;32(4):356–365. doi:10.1016/j.mcn.2006.05.007
50. Ozdemir H, Ertugrul A, Basar K, Saka E. Differential effects of antipsychotics on hippocampal presynaptic protein expressions and recognition memory in a schizophrenia model in mice. Progress in Neuro-psychopharmacology & Biological Psychiatry. 2012;39(1):62–68.
51. Halene TB, Kozlenkov A, Jiang Y, et al. NeuN+ neuronal nuclei in non-human primate prefrontal cortex and subcortical white matter after clozapine exposure. Schizophr Res. 2016;170:235–244. doi:10.1016/j.schres.2015.12.016
52. Maletic V, Raison C. Integrated neurobiology of bipolar disorder. Front Psychiatry. 2014;5:98. doi:10.3389/fpsyt.2014.00098
53. Miller S, Dell’Osso B, Ketter TA. The prevalence and burden of bipolar depression. J Affect Disord. 2014;169(Suppl 1):S3–S11. doi:10.1016/S0165-0327(14)70003-5
54. Faulkner E, Spinner DS, Ringo M, Carroll M. Are global health systems ready for transformative therapies? Value Health. 2019;22(6):627–641. doi:10.1016/j.jval.2019.04.1911
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