Skip to main content Accessibility help

Mood stabilisers and risk of stroke in bipolar disorder

  • Pao-Huan Chen (a1), Shang-Ying Tsai (a2), Chun-Hung Pan (a3), Chi-Kang Chang (a4), Sheng-Shiang Su (a5), Chiao-Chicy Chen (a6) and Chian-Jue Kuo (a7)...



Research on the risk of stroke following the use of mood stabilisers specific to patients with bipolar disorder is limited.


In this study, we investigated the risk of stroke following the exposure to mood stabilisers in patients with bipolar disorder.


Data for this nationwide population-based study were derived from the Taiwan National Health Insurance Research Database. Among a retrospective cohort of patients with bipolar disorder (n = 19 433), 609 new-onset cases of stroke were identified from 1999 to 2012. A case–crossover study design utilising 14-day windows was applied to assess the acute exposure effect of individual mood stabilisers on the risk of ischaemic, haemorrhagic and other types of stroke in patients with bipolar disorder.


Mood stabilisers as a group were significantly associated with the increased risk of stroke in patients with bipolar disorder (adjusted risk ratio, 1.26; P = 0.041). Among individual mood stabilisers, acute exposure to carbamazepine had the highest risk of stroke (adjusted risk ratio, 1.68; P = 0.018), particularly the ischaemic type (adjusted risk ratio, 1.81; P = 0.037). In addition, acute exposure to valproic acid elevated the risk of haemorrhagic stroke (adjusted risk ratio, 1.76; P = 0.022). In contrast, acute exposure to lithium and lamotrigine did not significantly increase the risk of any type of stroke.


Use of carbamazepine and valproic acid, but not lithium and lamotrigine, is associated with increased risk of stroke in patients with bipolar disorder.

Declaration of interest



Corresponding author

Correspondence: Chian-Jue Kuo, Department of General Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, 309 Sung-Te Road, Taipei 110, Taiwan. Email:


Hide All
1Sajatovic, M, Strejilevich, SA, Gildengers, AG, Dols, A, Al Jurdi, RK, Forester, BP, et al. A report on older-age bipolar disorder from the International Society for Bipolar Disorders Task Force. Bipolar Disord 2015; 17: 689704.
2Crump, C, Sundquist, K, Winkleby, MA, Sundquist, J. Comorbidities and mortality in bipolar disorder: a Swedish national cohort study. JAMA Psychiatry 2013; 70: 931–9.10.1001/jamapsychiatry.2013.1394
3Tsai, SY, Lee, CH, Kuo, CJ, Chen, CC. A retrospective analysis of risk and protective factors for natural death in bipolar disorder. J Clin Psychiatry 2005; 66: 1586–91.10.4088/JCP.v66n1215
4Correll, CU, Detraux, J, De Lepeleire, J, De Hert, M. Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression and bipolar disorder. World Psychiatry 2015; 14: 119–36.10.1002/wps.20204
5Lan, CC, Liu, CC, Lin, CH, Lan, TY, McInnis, MG, Chan, CH, et al. A reduced risk of stroke with lithium exposure in bipolar disorder: a population-based retrospective cohort study. Bipolar Disord 2015; 17: 705–14.10.1111/bdi.12336
6Prosser, JM, Fieve, RR. Patients receiving lithium therapy have a reduced prevalence of neurological and cardiovascular disorders. Prog Neuropsychopharmacol Biol Psychiatry 2016; 71: 3944.
7Olesen, JB, Abildstrom, SZ, Erdal, J, Gislason, GH, Weeke, P, Andersson, C, et al. Effects of epilepsy and selected antiepileptic drugs on risk of myocardial infarction, stroke, and death in patients with or without previous stroke: a nationwide cohort study. Pharmacoepidemiol Drug Saf 2011; 20: 964–71.10.1002/pds.2073
8Chuang, YC, Chuang, HY, Lin, TK, Chang, CC, Lu, CH, Chang, WN, et al. Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis. Epilepsia 2012; 53: 120–8.
9WHO. Manual of the International Statistical Classification of Diseases, Injuries and Causes of Death (9th revision) (ICD-9). World Health Organization, 1977.
10Wu, CS, Wang, SC, Gau, SS, Tsai, HJ, Cheng, YC. Association of stroke with the receptor-binding profiles of antipsychotics-a case-crossover study. Biol Psychiatry 2013; 73: 414–21.
11WHO Collaborating Centre for Drug Statistic Methodology. ATC Index with DDDs. World Health Organization, 2009.
12Charlson, ME, Pompei, P, Ales, KL, MacKenzie, CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40: 373–83.
13Chen, WY, Chen, LY, Liu, HC, Wu, CS, Yang, SY, Pan, CH, et al. Antipsychotic medications and stroke in schizophrenia: a case-crossover study. PLoS One 2017; 12: e0179424.
14Hu, HH, Sheng, WY, Chu, FL, Lan, CF, Chiang, BN. Incidence of stroke in Taiwan. Stroke 1992; 23: 1237–41.10.1161/01.STR.23.9.1237
15Lopinto-Khoury, C, Mintzer, S. Antiepileptic drugs and markers of vascular risk. Curr Treat Options Neurol 2010; 12: 300–8.
16Lorenz, MW, Polak, JF, Kavousi, M, Mathiesen, EB, Volzke, H, Tuomainen, TP, et al. Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. Lancet 2012; 379: 2053–62.
17Miao, Y, Liao, JK. Potential serum biomarkers in the pathophysiological processes of stroke. Expert Rev Neurother 2014; 14: 173–85.
18Chen, HF, Xu, LP, Luo, ZY, Yu, ZQ, Li, ZY, Cui, QY, et al. Valproic acid-associated low fibrinogen and delayed intracranial hemorrhage: case report and mini literature review. Drug Des Devel Ther 2013; 7: 767–70.10.2147/DDDT.S47718
19Nanau, RM, Neuman, MG. Adverse drug reactions induced by valproic acid. Clin Biochem 2013; 46: 1323–38.10.1016/j.clinbiochem.2013.06.012
20Choi, SE, Jang, HJ, Kang, Y, Jung, JG, Han, SJ, Kim, HJ, et al. Atherosclerosis induced by a high-fat diet is alleviated by lithium chloride via reduction of VCAM expression in ApoE-deficient mice. Vascul Pharmacol 2010; 53: 264–72.10.1016/j.vph.2010.09.004
21Wang, Z, Zhang, X, Chen, S, Wang, D, Wu, J, Liang, T, et al. Lithium chloride inhibits vascular smooth muscle cell proliferation and migration and alleviates injury-induced neointimal hyperplasia via induction of PGC-1alpha. PLoS One 2013; 8: e55471.
22Sacchetti, E, Trifiro, G, Caputi, A, Turrina, C, Spina, E, Cricelli, C, et al. Risk of stroke with typical and atypical anti-psychotics: a retrospective cohort study including unexposed subjects. J Psychopharmacol 2008; 22: 3946.
23Zornberg, GL, Jick, H. Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case-control study. Lancet 2000; 356: 1219–23.10.1016/S0140-6736(00)02784-7
24Janicak, PG. The relevance of clinical pharmacokinetics and therapeutic drug monitoring: anticonvulsant mood stabilizers and antipsychotics. J Clin Psychiatry 1993; 54(Suppl): 3541; discussion 55–6.
25Fiedorowicz, JG, Solomon, DA, Endicott, J, Leon, AC, Li, C, Rice, JP, et al. Manic/hypomanic symptom burden and cardiovascular mortality in bipolar disorder. Psychosom Med 2009; 71: 598606.10.1097/PSY.0b013e3181acee26
26Chen, PH, Chang, CK, Chiang, SJ, Lin, YK, Tsai, SY, Huang, SH. Diabetes mellitus and first episode mania associated with cardiovascular diseases in patients with older-age bipolar disorder. Psychiatry Res 2017; 249: 65–9.
27Ward, MC, White, DT, Druss, BG. A meta-review of lifestyle interventions for cardiovascular risk factors in the general medical population: lessons for individuals with serious mental illness. J Clin Psychiatry 2015; 76: e47786.


Type Description Title
Supplementary materials

Chen et al. supplementary material
e-Figure 1 and e-Tables 1-4

 Word (365 KB)
365 KB

Mood stabilisers and risk of stroke in bipolar disorder

  • Pao-Huan Chen (a1), Shang-Ying Tsai (a2), Chun-Hung Pan (a3), Chi-Kang Chang (a4), Sheng-Shiang Su (a5), Chiao-Chicy Chen (a6) and Chian-Jue Kuo (a7)...


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed

Mood stabilisers and risk of stroke in bipolar disorder

  • Pao-Huan Chen (a1), Shang-Ying Tsai (a2), Chun-Hung Pan (a3), Chi-Kang Chang (a4), Sheng-Shiang Su (a5), Chiao-Chicy Chen (a6) and Chian-Jue Kuo (a7)...
Submit a response


Response to article titled “Mood stabilizers and risk of stroke in bipolar disorder”

18 December 2018

Dear sir

We read with great interest the article titled “Mood stabilizers and risk of stroke in bipolar disorder” by Chen et al., 2018 published in your esteemed journal. The authors have assessed the association between mood stabilizers and risk of stroke in patients suffering from bipolar disorder (BD). They have addressed multiple potential confounders such as age, gender, physical illness and concomitant medication. However, we would like to discuss some important factors which could have influenced the study findings

Firstly, the study did not consider the role of psychiatric comorbidity. Only admission for BD was taken into account. Certain psychiatric illnesses are common in patients suffering from BD and are noted to be risk factors for stroke as well. For example, the lifetime prevalence of anxiety disorder in BD was found to be 42.7%. 1Further, anxiety disorders have been associated with 24% increased risk of stroke compared to general population.2

Secondly, the role of psychosocial factors in stroke is not addressed. It is important to note that BD is associated with several psychosocial factors and a recent meta-analysis mentions that the risk of stroke is increased by psychological, vocational and interpersonal factors by almost 39%, 35% and 16% respectively.3

Thirdly, BD is associated with high rates of non adherence to medication. Since, the study focuses on the association between mood stabiliser and BD, the adherence to MS is an important variable to be considered. This point is worth highlighting as the mean prevalence of non-adherence to medication was found to range from 41.5% to 43%.4

Fourthly, the role of oral contraceptive pills has not been discussed. The increased risk of stroke with oral contraceptives is well known. About 42.7% of the sample consisted of women. Oral contraceptives are used commonly by women for contraception as well as prescribed for Poly Cystic Ovarian Syndrome, which is not uncommonly seen with use of Valproate.

Fifthly the comorbidity of seizure disorder has not been considered. This is important to address mainly for two reasons. Firstly, preparations of Valproate, Carbamazepine are prescribed in patients with seizure disorder or epilepsy as well as in patients with BD. Further, literature exists that late onset epilepsy has been associated with increased risk of stroke. 5 This is a point to be noted as almost 61% of the sample was recruited at age more than 45 years.

Lastly, the term “Any mood stabilizer” is not clearly defined. For example, the number of patients on any mood stabilizer during case period is 212. However, sum of patients as per numbers given separately for Carbamazepine (35), Valproic acid (118), Lithium (62) and Lamotrigine (18) is 233.

Declaration of interest: The authors declare no source of funding or conflict of interest


1. Nabavi B, Mitchell AJ, Nutt D. A lifetime prevalence of comorbidity between bipolar affective disorder and anxiety disorders: a meta-analysis of 52 interview-based studies of psychiatric population. EBioMedicine. 2015;2(10):1405-19.

2. Perez-Pinar M, Ayerbe L, González E, Mathur R, Foguet-Boreu Q, Ayis S. Anxiety disorders and risk of stroke: a systematic review and meta-analysis. European Psychiatry. 2017; 41:102-8.

3. Lightbody CE, Clegg A, Patel K, Lucas JC, Storey H, Hackett ML, Watkins DC. Systematic Review and Meta-Analysis of Psychosocial Risk Factors for Stroke. InSeminars in neurology.2017; 37(3):294-306.

4. Chakrabarti S. Medication non-adherence in bipolar disorder: Review of rates, demographic and clinical predictors. World Journal of Meta-Analysis. 2017;5(4):103-23.

5. Ben‐Menachem E. Epilepsy as a warning sign for stroke. Epilepsy currents. 2005; 5(1):42-3.

... More

Conflict of interest: None declared

Write a reply
Show replies

to Response to article titled “Mood stabilizers and risk of stroke in bipolar disorder”


Reply to: Submit a response

Your details

Conflicting interests

Do you have any conflicting interests? *