|Year : 2020 | Volume
| Issue : 1 | Page : 12-16
Impact of type and duration of use of antipsychotic drugs on plasma levels of selected acute-phase proteins in patients with major mental illnesses
Sheu Kadiri Rahamon1, Kehinde Sola Akinlade2, Olatunbosun Ganiyu Arinola1, Saheed Ladipo Kakako3, Victor Olufolahan Lasebikan4
1 Department of Immunology, College of Medicine, University of Ibadan, Ibadan, Nigeria
2 Department of Chemical Pathology, College of Medicine, University of Ibadan, Ibadan, Nigeria
3 Department of Chemical Pathology, Faculty of Medical Laboratory Science, Usmanu Danfodio University, Sokoto, Nigeria
4 Department of Psychiatry, College of Medicine, University of Ibadan, Ibadan, Nigeria
|Date of Submission||05-Nov-2019|
|Date of Decision||27-Mar-2020|
|Date of Acceptance||14-Apr-2020|
|Date of Web Publication||12-Jun-2020|
Dr. Sheu Kadiri Rahamon
Department of Immunology, College of Medicine, University of Ibadan, Ibadan
Source of Support: None, Conflict of Interest: None
Background: Disorders of the hemostatic system such as hypercoagulation and hypofibrinolysis are clinical manifestations in patients with schizophrenia, depression, and bipolar disorder. However, the role of the type of antipsychotic medication as well as the duration of use on disturbances in the hemostatic system is poorly understood. This study was, therefore, carried out to determine the possible impact of antipsychotic treatment as well as the duration of use on selected acute-phase proteins involved in coagulation and fibrinolysis. Materials and Methods: Plasma levels of fibrinogen and plasminogen activator inhibitor-1 (PAI-1) were determined in 124 patients with major mental illnesses: schizophrenia, depression, and bipolar disorder. Thereafter, the participants were grouped based on the type of antipsychotic medication (typical vs. atypical) and the duration of antipsychotic use. Results: Patients on typical antipsychotics had a slightly elevated level of PAI-1 but a similar level of fibrinogen when compared with patients on atypical antipsychotics. Furthermore, the median plasma levels of fibrinogen and PAI-1 in patients who have been on antipsychotic use for more than 10 years were slightly higher than in patients who have been on the drug for 10 years or less. Conclusion: It could be concluded from this study that patients on typical antipsychotics and those who have used any form of antipsychotics for more than 10 years might benefit from periodic assessment of markers of prothrombosis as it could facilitate early identification of those at risk of venous thromboembolism.
Keywords: Antipsychotics, fibrinogen, hypercoagulation, hypofibrinolysis, plasminogen activator inhibitor-1, venous thromboembolism
|How to cite this article:|
Rahamon SK, Akinlade KS, Arinola OG, Kakako SL, Lasebikan VO. Impact of type and duration of use of antipsychotic drugs on plasma levels of selected acute-phase proteins in patients with major mental illnesses. Biomed Res J 2020;7:12-6
|How to cite this URL:|
Rahamon SK, Akinlade KS, Arinola OG, Kakako SL, Lasebikan VO. Impact of type and duration of use of antipsychotic drugs on plasma levels of selected acute-phase proteins in patients with major mental illnesses. Biomed Res J [serial online] 2020 [cited 2021 Sep 18];7:12-6. Available from: https://www.brjnmims.org/text.asp?2020/7/1/12/286561
| Introduction|| |
It is well known that there is a cross-talk between inflammation and coagulation systems. Cytokines which play vital roles in inflammation can also cause an imbalance in hemostatic acute-phase proteins, thereby potentiating increased thrombosis., Cytokines such as interleukin-1 beta (IL-1β) and IL-6 modulate the production and suppression of many of the proteins including the coagulation enzymes synthesized by the liver. This forms the basis for classifying certain proteins as acute-phase proteins.
Evidences continue to emerge that inflammation plays a significant role in the etiology of psychotic disorders. Similarly, there is an avalanche of reports showing that the hemostatic system plays a vital role in the pathogenesis, morbidity, and prognosis of several psychiatric disorders.
One of the major proteins whose concentrations increase with inflammation is fibrinogen. It is a glycoprotein with an important role in the downstream of the coagulation cascade. During inflammation, its concentration increases at about 2–3 fold and, in turn, affects the process of inflammation due to its ability to affect leukocyte migration, bind, and activate a number of immune cells and also through the induction of cytokine and chemokine expression., Fibrinogen, a coagulation factor and an inflammatory marker, is considered as a positive mediator between mental stress and cardiovascular diseases (CVDs). A study by Justo et al. showed that males with a history of mental health crisis have elevated fibrinogen levels and thus more prone to developing CVD. It is believed that the greater the mental stress, the higher the fibrinogen level, and the greater the risk of CVD.
It is well established that patients with depression have an increased risk of coronary heart disease attributed to elevated plasma fibrinogen level as well as elevated cerebrospinal fluid (CSF) fibrinogen level which could cause axonal damage.,,,, Similarly, Seal et al. reported, decades ago, that hyperfibrinogenemia is a common feature in patients with schizophrenia. This is further confirmed by the report of Yegin et al. that demonstrated elevated plasma fibrinogen level in patients with schizophrenia. In the same vein, patients with bipolar disorder have been shown to have elevated plasma fibrinogen level even after correcting for gender and pharmacologic treatment. These patients, however, tend to have less severe pro-inflammatory state when compared with patients with schizophrenia.
Another acute-phase protein whose concentration increases during inflammation is plasminogen activator inhibitor-1 (PAI-1). Patients with schizophrenia, including those on long-term antipsychotic therapy, have an increased risk of venous thromboembolism (VTE) due to hypercoagulable and hypofibrinolytic states found in them. Although PAI-1 polymorphism is reported not to be associated with schizophrenia, hypofibrinolysis as a result of elevated PAI-1 is still a common observation in patients with schizophrenia. This elevation is believed to be stimulated by both insulin and triglycerides. Similarly, PAI-1 level is elevated in patients with major depression (MD), and it is implicated in its pathophysiology and CVD comorbidity., Tsai et al. showed that PAI-1 gene is associated with MD as it plays a role in MD susceptibility and in acute therapeutic response to antidepressants. Patients with bipolar disorder are also at high risk of cardiovascular morbidity and mortality just like patients with schizophrenia and MD., There is little information on the contribution of PAI-1 to the development of CVD in patients with bipolar disorder; however, Rosso et al. showed that patients with bipolar disorder have a similar level of PAI-1 when compared with apparently healthy individuals.
Although hypercoagulation and hypofibrinolysis are common features in patients with schizophrenia, depression, and bipolar disorder, there is the dearth of information on the possible impact of antipsychotic treatment as well as the duration of antipsychotic use on acute-phase proteins involved in coagulation and fibrinolysis. This study was thus carried out to fill this gap in knowledge.
| Materials and Methods|| |
Diagnosis and characteristics (anthropometric and clinical) of the study participants have earlier been reported. Briefly, 124 patients with major mental illnesses (MMIs) including schizophrenia, depression, and bipolar disorder were randomly selected from a pool of 135 adult patients with MMI participating in a study (metabolic disorders in Nigerians with MMIs). The patients were enrolled in the study at the New World Psychiatric Hospital, Ibadan, Nigeria, after an approval from the University of Ibadan/University College Hospital (UI/UCH) Joint Ethics Review Committee (UI/UCH IRC/14/0239). Furthermore, written informed consent/assent was obtained from the participants or their guardians as appropriate. Patients with severe and unstable medical conditions as well as those <18 years of age were excluded from this study.
Diagnosis of MMI was carried out by one of us (Victor, Olufolahan, Lasebikan, (VOL)) using the Structured Clinical Interview for DSM-IV Axis I Disorders version 2.0. Forty apparently healthy adults with normal body weight and with no history of mental illness, diabetes, or clotting disorders served as controls.
Plasma levels of fibrinogen and PAI-1 were determined using ELISA (Assaypro LLC, USA) following the manufacturers' instructions.
The distribution of the data was assessed, and both fibrinogen and PAI-1 levels did not obey the Gaussian distribution. Therefore, Kruskal–Wallis and Mann–Whitney U-tests were used to assess the differences in medians. Results are presented as median (interquartile range), and P < 0.05 were considered as statistically significant.
| Results|| |
The median plasma levels of fibrinogen and PAI-1 were insignificantly lower in patients with MMI compared with the controls [Table 1].
|Table 1: Plasma levels of fibrinogen and plasminogen activator inhibitor-1 in patients with major mental illnesses and controls|
Click here to view
As shown in [Table 2], the median plasma levels of fibrinogen and PAI-1 were not significantly different when the three groups of MMI were compared with one another and when compared with the controls. However, the median plasma levels of fibrinogen and PAI-1 were slightly higher in patients with depression than in patients with schizophrenia and in patients with schizophrenia than in patients with bipolar disorder.
|Table 2: Plasma levels of fibrinogen and plasminogen activator inhibitor-1 in patients with schizophrenia, bipolar, and depression and controls|
Click here to view
Considering the association of MMI with plasma levels of fibrinogen and PAI-1, the proportion of patients with plasma levels of fibrinogen below, within, and above the reference range (150–400 mg/dl [equivalent to 1500–4000 μg/ml]) was similar in the three groups. However, the proportion of patients with depression with fibrinogen level above the reference range was slightly higher compared with patients with schizophrenia and bipolar. Furthermore, the proportion of patients with plasma levels of PAI-1 below, within, and above the reference range (5–40 ng/ml) was similar in the three groups with more than 90% of the patients in the three groups having plasma PAI-1 level within the reference range [Table 3].
|Table 3: Association of fibrinogen and plasminogen activator inhibitor-1 levels with major mental illnesses|
Click here to view
In order to understand the possible impact of the type of antipsychotics on the levels of fibrinogen and PAI-1, all the patients with MMI were pooled together and those on typical antipsychotics were compared with those on atypical antipsychotics. It was observed that patients on typical antipsychotics have a similar plasma level of fibrinogen when compared with those on atypical antipsychotics. Although the plasma levels of PAI-1 in both groups were insignificantly different, the PAI-1 level in patients on typical antipsychotics was slightly higher than the level in patients on atypical antipsychotics [Table 4].
|Table 4: Plasma levels of fibrinogen and plasminogen activator inhibitor-1 in patients with major mental illnesses on typical and atypical antipsychotics|
Click here to view
In addition to the type of antipsychotic use, possible impact of the duration of antipsychotic use was assessed. Progressive rise in fibrinogen level was observed in patients with MMI as the duration of antipsychotic use increases. Furthermore, plasma levels of fibrinogen and PAI-1 in patients with MMI who have been on antipsychotic use for more than 10 years were slightly higher than in patients who have been on the drug for 10 years or less [Table 5].
|Table 5: Plasma levels of fibrinogen and plasminogen activator inhibitor-1 in patients with major mental illnesses based on duration of antipsychotic use|
Click here to view
| Discussion|| |
Acute psychotic episodes are usually characterized by heightened inflammation and prothrombosis., However, these acute responses get normalized by treatment with psychotropic medication. The observed slightly lower levels of fibrinogen and PAI-1 in patients with MMI compared with the controls support the report of Maes et al. that showed that differences in acute reactants between apparently healthy individuals and patients with schizophrenia, mania, and depression disappear following chronic treatment with antipsychotics. Our observation would indicate that MMI-associated acute-phase response subsides with the use of antipsychotics.
An association between PAI-1 gene and depression has been reported. Similarly, elevated plasma and CSF levels of fibrinogen have been reported in patients with depression. The observed slight elevation in the plasma levels of fibrinogen and PAI-1 in patients with depression compared with patients with schizophrenia and bipolar indicates increased prothrombotic state in patients with depression and further confirms the propensity of the patients to develop CVD., This is further supported by the observed slightly higher proportion of patients with depression having fibrinogen level above the reference range compared with patients with schizophrenia and bipolar disorder. Our observations could suggest differential inflammation state in the various groups of MMI since components of inflammation stimulate the synthesis of acute-phase proteins. Arranz et al. showed that patients with bipolar disorder have less severe pro-inflammatory state when compared with patients with schizophrenia.
It is well known that prothrombotic factors including PAI-1 influence the development of VTE and serve as its markers., Although the occurrence of VTE during antipsychotic use is not commonly reported in clinical practice, the possible association between antipsychotic use and increased risk of VTE has been known for decades, and it is still being reported.,, The observed slight elevation in the plasma level of PAI-1 in patients on typical antipsychotics corroborates the reports of Zornberg and Jick and Andole that showed an increased risk of VTE during treatment with typical antipsychotics. The association between typical antipsychotics and increased risk of VTE persists even after adjusting for confounders, and the risk is strongly associated with low potency antipsychotic drugs.,
The association between the duration of antipsychotic use and the risk of VTE has not been well studied. Kleijer et al. reported that the duration of antipsychotic use does not increase the risk of VTE in elderly patients on antipsychotics. Our observation is in line with this report; however, our observed slight elevation of the plasma levels of fibrinogen and PAI-1 in patients who have been on antipsychotics for more than 10 years suggests that there is the need for psychiatrists to assess the risk of VTE at intervals in patients with a prolonged history of antipsychotic use.
| Conclusion|| |
It could be concluded from this study that patients on typical antipsychotics and those who have used any form of antipsychotics for more than 10 years might benefit from periodic assessment of markers of prothrombosis as it could facilitate early identification of those at risk of VTE. However, our observations require cautious interpretation because of the small number of patients with bipolar and depression, which was a limitation of the study.
The authors appreciate the contribution and support of the resident doctors of the Metabolic Research Unit, Department of Chemical Pathology, University College Hospital, Ibadan, Nigeria, and the members of staff of the New World Psychiatric Hospital, Ibadan. Dr. Modupe A. Kuti of the Department of Chemical Pathology, University of Ibadan, is also appreciated for his valuable comments and suggestions.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Davidson SJ. Inflammation and acute phase proteins in haemostasis. InTech 2013:31-54.
Esmon CT. Inflammation and thrombosis. J Thromb Haemost 2003;1:1343-138.
Levi M, van der Poll T, Buller HR. Bidirectional relation between inflammation and coagulation. Circulation 2004;109:2698-704.
Suvisaari J, Mantere O. Inflammation theories in psychotic disorders: A critical review. Infect Dis Drug Targets 2013;13:59-70.
Hoirisch-Clapauch S, Nardi AE, Gris JC, Brenner B. Coagulation and mental disorders. Rambam Maimonides Med J 2014;5:e0036.
Jennewein C, Tran N, Paulus P, Ellinghaus P, Eble JA, Zacharowski K. Novel aspects of fibrin (ogen) fragments during inflammation. Molecu Med (Cambridge, Mass) 2011;17:568-73.
Davalos D, Akassoglou K. Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol 2012;34:43-62.
Lazzarino AI, Hamer M, Gaze D, Collinson P, Rumley A, Lowe G, et al
. The association between fibrinogen reactivity to mental stress and high-sensitivity cardiac troponin T in healthy adults. Psychoneuroendocrinology 2015;59:37-48.
Justo D, Arbel Y, Altberg G, Kinori M, Shirom A, Melamed S, et al
. Inflammation markers in individuals with history of mental health crisis. Inflammation 2008;31:254-9.
Austin AW, Wissmann T, von Kanel R. Stress and hemostasis: An update. Semin Thromb Hemost 2013;39:902-12.
Lahlou-Laforet K, Alhenc-Gelas M, Pornin M, Bydlowski S, Seigneur E, Benetos A, et al
. Relation of depressive mood to plasminogen activator inhibitor, tissue plasminogen activator, and fibrinogen levels in patients with versus without coronary heart disease. Am J Cardiol 2006;97:1287-91.
Baune BT, Neuhauser H, Ellert U, Berger K. The role of the inflammatory markers ferritin, transferrin and fibrinogen in the relationship between major depression and cardiovascular disorders-The german health interview and examination survey. Acta Psychiatr Scand 2010;121:135-42.
Wium-Andersen MK, Orsted DD, Nordestgaard BG. Association between elevated plasma fibrinogen and psychological distress, and depression in 73,367 individuals from the general population. Molecu Psychiatry 2013;18:854-5.
Wium-Andersen MK, Orsted DD, Nordestgaard BG. Elevated plasma fibrinogen, psychological distress, antidepressant use, and hospitalization with depression: two large population-based studies. Psychoneuroendocrinology 2013;38:638-47.
Hattori K, Ota M, Sasayama D, Yoshida S, Matsumura R, Miyakawa T, et al
. Increased cerebrospinal fluid fibrinogen in major depressive disorder. Sci Rep 2015;5:11412.
Seal US, Swaim WR, Eist H. Hyperfibrinogenemia in schizophrenia. Clin Chem 1967;13:160-2.
Yegin A, Ay N, Aydin O, Yargici N, Eren E, Yilmaz N. Increased oxidant stress and inflammation in patients with chronic schizophrenia. Int J Clin Med 2012;3:368.
Arranz B, Sanchez M, Garriga M, Safont G, Garcia-Portilla P, Sierra P, et al
. Differential serum acute-phase biomarker profile in schizophrenia and bipolar disorder. Europ Psychiatry 2016;33:S96.
Chow V, Reddel C, Pennings G, Scott E, Pasqualon T, Ng AC, et al
. Global hypercoagulability in patients with schizophrenia receiving long-term antipsychotic therapy. Schizophr Res 2015;162:175-82.
Yenilmez C, Ozdemir Koroglu Z, Kurt H, Yanas M, Colak E, Degirmenci I, et al
. A study of the possible association of plasminogen activator inhibitor type 1 4G/5G insertion/deletion polymorphism with susceptibility to schizophrenia and in its subtypes. J Clin Pharm Therap 2017;42:103-7.
Jiang H, Li X, Chen S, Lu N, Yue Y, Liang J, et al
. Plasminogen activator inhibitor-1 in depression: Results from animal and clinical studies. Sci Rep 2016;6:30464.
Savoy C, Van Lieshout RJ, Steiner M. Is plasminogen activator inhibitor-1 a Physiological bottleneck bridging major depressive disorder and cardiovascular disease? Acta Physiol (Oxford, England) 2017;219:715-27.
Tsai SJ, Hong CJ, Liou YJ, Yu YW, Chen TJ. Plasminogen activator inhibitor-1 gene is associated with major depression and antidepressant treatment response. Pharm Genomics 2008;18:869-75.
Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis 2006;3:A42.
de Hert M, Cohen D, Bobes J, Cetkovich-Bakmas M, Leucht S, Ndetei DM, et al
. Physical illness in patients with severe mental disorders. II. Barriers to care, monitoring and treatment guidelines, plus recommendations at the system and individual level. World Psychiatry 2011;10:138-51.
Rosso G, Cattaneo A, Zanardini R, Gennarelli M, Maina G, Bocchio-Chiavetto L. Glucose metabolism alterations in patients with bipolar disorder. J Affect Dis 2015;184:293-8.
Akinlade KS, Rahamon SK, Lasebikan VO. Beta-cell function and metabolic clearance rate of glucose in patients with major mental health disorders on antipsychotic drug treatment. J National Med Assoc 2018;110:504-11.
Akinlade KS, Satope OO, Lasebikan VO, Rahamon SK. Metabolically healthy obesity and metabolic syndrome in Nigerian adults with major mental illness. Egypt J Psychiatry 2016;37:97-103.
Vaughan D. PAI-1 and atherothrombosis. J Thromb Haemost 2005;3:1879-83.
Hoirisch-Clapauch S, Nardi AE. Markers of low activity of tissue plasminogen activator/plasmin are prevalent in schizophrenia patients. Schizophr Res 2014;159:118-23.
Hoirisch-Clapauch S, Amaral OB, Mezzasalma MA, Panizzutti R, Nardi AE. Dysfunction in the coagulation system and schizophrenia. Trans Psychiatry 2016;6:e704.
Gaughran F, Welch J. Schizophrenia and immune responses. In: Handbook of Neurochemistry and Molecular Neurobiology. New York, USA: Springer; 2008. p. 467-88.
Maes M, Delange J, Ranjan R, Meltzer HY, Desnyder R, Cooremans W, et al
. Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs. Psychiatry Res 1997;66:1-11.
Meltzer ME, Lisman T, de Groot PG, Meijers JC, le Cessie S, Doggen CJ, et al
. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 2010;116:113-21.
Bollen L, Peetermans M, Peeters M, Van Steen K, Hoylaerts MF, Declerck PJ, et al
. Active PAI-1 as marker for venous thromboembolism: case-control study using a comprehensive panel of PAI-1 and TAFI assays. Thromb Res 2014;134:1097-102.
Masopust J, Maly R, Valis M. Risk of venous thromboembolism during treatment with antipsychotic agents. Psychiatry Clin Neurosci 2012;66:541-52.
Meier-Ewert K, Baumgart HH, Friedenberg P. Thromboembolism complications in neuro- and thymoleptic therapy. Deutsch Med Wochenschr 1967;92:2174-8.
Grahmann H, Suchenwirth R. Thrombosis hazard in chlorpromazine and reserpine therapy of endogenous psychoses. Der Nervenarzt 1959;30:224-5.
Matsumoto M, Konno T, Tamba K, Abe T, Kato S, Kajii E. Two cases of deep vein thrombosis associated with antipsychotic drug use. Psychiatry Clin Neurosci 2004;58:450-1.
Zornberg GL, Jick H. Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: A case-control study. Lancet (London, England) 2000;356:1219-23.
Andole SN. An unusual presentation of cortical venous thrombosis and its association with typical antipsychotics. BMJ Case Rep 2011;2011.
Parkin L, Skegg DC, Herbison GP, Paul C. Psychotropic drugs and fatal pulmonary embolism. Pharmacoepidemiol Drug Safety 2003;12:647-52.
Kleijer BC, Heerdink ER, Egberts TC, Jansen PA, van Marum RJ. Antipsychotic drug use and the risk of venous thromboembolism in elderly patients. J Clin psychopharmacol 2010;30:526-30.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]