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High prevalence of mental disorders in patients with inherited protein S deficiency: A case report series
Thrombosis Research 152 (2017) 1–3
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Letter to the Editors-in-Chief High prevalence of mental disorders in patients with inherited protein S deficiency: A case report series Keywords: Bipolar disorder Major depressive disorder Mental disorders Protein S deficiency Schizophrenia
Protein S, a natural anticoagulant with profibrinolytic properties, plays an important role in the central nervous system. Studies with cortical neurons showed that protein S binding to TAM (Tyro3, Axl, and Mer) receptors enhances proliferation and differentiation of adult neural stem cells. The mechanism involves increased expression of anti-apoptotic protein Bcl-2, reduced expression of pro-apoptotic protein p53, microglial inhibition and synaptic pruning [1,2]. Protein S also seems to protect ischemic mouse neurons from hypoxia/reoxygenation-induced apoptosis, in doses that do not significantly improve post-ischemic flow [3]. While inherited protein S deficiency is a rare autosomal dominant disorder, acquired deficiency is not uncommon and may result from reduced synthesis (e.g. estrogen use, pregnancy, the puerperium, hepatic insufficiency), increased excretion (e.g. nephrotic syndrome), consumption (e.g. disseminated intravascular coagulation) or autoantibodies (e.g. autoimmune disease and HIV infection). Since protein S bound to C4b-binding protein is inactive, conditions accompanied by increased levels of this complement system protein, such as systemic inflammation, are characterized by low protein S activity. Knowing that the puerperium, systemic lupus erythematosus, inflammatory bowel disease, HIV infection and other conditions characterized by low protein S activity are associated with an increased risk of psychosis, we decided to study the prevalence of psychotic symptoms and psychotic disorders in individuals with inherited protein S deficiency. From July to November 2016, adults with a thrombotic event or adverse pregnancy outcome related to protein S deficiency attending a tertiary care hospital in Rio de Janeiro, Brazil were selected. All were classified as type 1 deficiency (reduction in total and free protein S levels). Their first-degree adult relatives were screened for protein S deficiency. Index cases and their relatives with low protein S levels were invited to participate in this study. Those who accepted underwent clinical evaluation and a semistructured psychiatric interview. Since antiphospholipid antibodies may interfere with the measurement of protein S functional levels, all participants were screened for anticardiolipin antibodies and for lupus anticoagulant, but not for antiβ2 glycoprotein 1 antibodies. Mental disorders were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, DSM-5 [4]. Participants were
http://dx.doi.org/10.1016/j.thromres.2017.02.004 0049-3848/© 2017 Published by Elsevier Ltd.
diagnosed with major depression when either depressed mood or loss of pleasure were accompanied by ≥ 4 of the following manifestations over a two-week period: weight loss or gain, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, worthlessness or inappropriate guilt, and diminished concentration or indecisiveness. We decided to assess the temporal relationship between cerebral ischemia and depressive symptoms, because decreased concentration and indecisiveness are commonly seen in stroke patients. Participants were diagnosed with severe mental illness when all three criteria were met: a non-organic psychosis, such as schizophrenia, schizoaffective disorder or bipolar disorder; serious impairment in social, occupational or school functioning, as measured by the Global Assessment of Functioning scale; treatment duration of two years or more. Free protein S levels and anticardiolipin antibodies were measured by enzyme-linked immunosorbent assay (respectively, Diagnostica Stago, France and Binding Site, UK). Lupus anticoagulant testing was performed according to the guidelines of the International Society of Thrombosis and Haemostasis (Siemens Healthcare, Germany). Warfarin and estrogen were discontinued for at least 20 days before sampling. On the day of sampling, all participants were carefully examined and a complete blood count was performed. Free protein S levels were not determined when inflammation was suspected after overnight fasting were retested after three months. Those with low levels in two or more samples were considered deficient. Deep-vein thrombosis and pulmonary embolism were respectively diagnosed by duplex ultrasound and spiral computed tomography. Strokes were classified as ischemic by computed tomography or magnetic resonance imaging. The project was approved by the local ethics committee. Written informed consent was obtained from all participants. Five index patients (all women) from five different families were identified. All their 16 first-degree adult relatives were screened for protein S deficiency and nine were found to be protein S deficient. The 14 protein S-deficient individuals agreed to participate. Eight participants (57%) had a thrombotic event or a cerebral infarct before 45 years of age. Four of the six women who ever got pregnant (67%) had at least one adverse obstetric outcome related to abnormal placentation, such as recurrent early miscarriages, a small-for gestational-age infant or a preterm delivery. Of the seven participants reporting a psychotic experience (50%), four were diagnosed with a severe mental illness (29%), two with schizophrenia and two with bipolar disorder (Table 1). Patient index 1 was recommended prolonged bed rest for threatened abortion in two pregnancies. After giving birth to full-term small-for-gestational-age girls, she was diagnosed with major postpartum depression. She responded well to medications, but two years later, she had a new onset of major depressive episodes interspersed with bouts of hypomania and was diagnosed with bipolar disorder type II. Despite being treated with antidepressants, lithium, antipsychotics and electroconvulsive therapy, she is highly symptomatic. Her mother, who had two uneventful pregnancies, was diagnosed with bipolar disorder type II, currently in remission. Patient index 2 had two psychotic episodes, characterized by delusions and marked auditory hallucinations. One year after the second
2
Letter to the Editors-in-Chief
Table 1 Patients and first-degree relatives' characteristics. Index patient age #1 39 years #2 44 years #3 43 years #4 43 years #5 31 years
Mental disorder
Systemic thrombotic First-degree relatives with low Obstetric outcome without anticoagulation events protein S levels
Two episodes of major postpartum depression. Bipolar disorder type II
None
Two full-term SGA infants
Mother: bipolar disorder type II
Two psychotic episodes
None
One preterm SGA infant
Father: DVT, auditory hallucinations
None
Stroke
Three preterm SGA infants and one uneventful pregnancy
Intrusive thoughts and auditory hallucinations
Pulmonary embolism
One uneventful pregnancy
Major depression before stroke occurred
Stroke
Six early miscarriages and one uneventful pregnancy
Father: paranoid schizophrenia Sister: stroke Father: DVT Brother: asymptomatic Two sisters: DVT Brother: paranoid schizophrenia
SGA: small for gestational age; DVT: deep-vein thrombosis.
episode, she delivered a preterm small for-gestational-age infant. Her father had a deep-vein thrombosis at the age of 40 years and was treated with warfarin for six months. He currently has auditory hallucinations. Patient index 3 had three pregnancies ending in preterm delivery with small-for gestational-age infants and one uneventful pregnancy. Six years after the last delivery, she had an unprovoked stroke. Then, she was found to have protein S deficiency and was started on warfarin. Her father was diagnosed with paranoid schizophrenia, with poor response to antipsychotic therapy. The patient and her sister, who also had an unprovoked stroke, have no mental symptoms. Patient index 4 was an athlete in adolescence and early adulthood. At the age of 21 she had an uneventful pregnancy. Protein S deficiency was diagnosed three years later, when she had a pulmonary embolism. At that time, she was placed on long-term warfarin therapy. At the age of 30, some months after she stopped exercising, she began to have mild auditory hallucinations and intrusive thoughts. Her father is on long-term warfarin therapy because of deep-vein thrombosis and her brother is asymptomatic. Neither of them have any mental symptom. Patient index 5 had six early miscarriages from 18 to 24 years of age. She had no significant mental symptoms until the age of 28, when she was diagnosed with major depression. Two years later, she had an ischemic stroke, and the diagnosis of protein S deficiency was made. A dramatic improvement of the mental symptoms was observed six months after she was placed on warfarin and daily physiotherapy. Two years after the stroke she became pregnant and warfarin was replaced by aspirin. She continued physiotherapy throughout pregnancy and delivered a full-term girl. Her brother has paranoid schizophrenia and two sisters, on long-term warfarin therapy for recurrent deepvein thrombosis, have no mental symptoms. 1. Discussion This study is not the first one to establish a link between severe mental illnesses and low levels of protein S. Our group has recently analyzed the levels of free protein S in a cohort of 70 patients with schizophrenia or schizoaffective disorder and 98 matched controls. Fifteen patients (21%) and no control had low protein S levels [5]. Another study, using an immunoaffinity method to detect depletion of high-abundance proteins in schizophrenia serum, revealed decreased expression of both C4b-binding protein and protein S [6]. This paper is innovative because it is the first one to report a high prevalence of psychotic symptoms (50% vs. 6% in the general population) and psychotic disorders (29% vs. 2% in the general population) in patients with inherited protein S deficiency [7,8]. The importance of stressful life events such as life-threatening thromboembolism or complicated pregnancy experiences in triggering psychosis is indisputable. The hypothesis that protein S deficiency has an important role in the pathogenesis of severe mental disorders is supported by the low prevalence of such disorders in patients with thrombotic events or
complicated pregnancies who do not have protein S deficiency. In fact, among 1559 patients attending the same hospital where this study was performed (18% with thrombotic events, 71% with complicated pregnancies and 11% with both problems), only six (o.4%) have a severe mental illness. One important issue needs to be addressed. The finding that mental symptoms are highly prevalent, but not ubiquitous among individuals with protein S deficiency suggests a multifactorial model. We postulate that low levels of tissue plasminogen activator (tPA) would be an additional element in the pathogenesis of mental disorders related to protein S deficiency. tPA mediates a number of processes essential for synaptogenesis and synapse remodeling, including degradation of adhesion molecules, activation of neurotrophins and activation of N-methyl-D-aspartate receptor [9]. Abnormalities in such processes have been consistently described in psychotic disorders. Reinforcing the hypothesis that low tPA levels might have a role in the pathogenesis of protein S deficiency-related psychotic symptoms, our group did not observe an increased prevalence of severe mental disorders in nephrotic patients (unpublished data). Nephrotic patients have lower protein S levels than controls, but their tPA levels are higher, probably because urinary excretion of protein S parallels excretion of plasminogen activator inhibitor-1, a tPA inhibitor [10]. In conclusion, we found a high prevalence of psychotic symptoms and severe mental illnesses in patients with inherited protein S deficiency. Further studies are needed to confirm our findings and to elucidate the role of protein S concentrates for refractory psychosis. Funding source This study was supported by grants from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro [FAPERJ 34/ 204.823/2014]. Disclosure The authors declare no conflict of interest. Acknowledgements The authors would like to thank Dr. Jacqueline Anita Menezes, MD, PhD for her invaluable suggestions. References [1] Z. Zhong, Y. Wang, H. Guo, A. Sagare, J.A. Fernández, R.D. Bell, T.M. Barrett, J.H. Griffin, R.S. Freeman, B.V. Zlokovic, Protein S protects neurons from excitotoxic injury by activating the TAM receptor Tyro3-phosphatidylinositol 3-kinase-Akt pathway through its sex hormone-binding globulin-like region, J. Neurosci. 30 (2010) 15521–15534. [2] R. Ji, S. Tian, H.J. Lu, Q. Lu, Y. Zheng, X. Wang, J. Ding, Q. Lu, TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation, J. Immunol. 191 (2013) 6165–6177.
Letter to the Editors-in-Chief [3] D. Liu, H. Guo, J.H. Griffin, J.A. Fernandez, B.V. Zlokovic, Protein S confers neuronal protection during ischemic/hypoxic injury in mice, Circulation 107 (2003) 1791–1796. [4] American Psychiatric Association, Diagnostic and statistical manual of mental disorders, fifth ed. American Psychiatric Publishing, Washington D.C., 2013 [5] S. Hoirisch-Clapauch, A.E. Nardi, Markers of low activity of tissue plasminogen activator/plasmin are prevalent in schizophrenia patients, Schizophr. Res. 159 (2014) 118–123. [6] Y. Li, K. Zhou, Z. Zhang, L. Sun, J. Yang, M. Zhang, B. Ji, K. Tang, Z. Wei, G. He, L. Gao, L. Yang, P. Wang, P. Yang, G. Feng, L. He, C. Wan, Label-free quantitative proteomic analysis reveals dysfunction of complement pathway in peripheral blood of schizophrenia patients: evidence for the immune hypothesis of schizophrenia, Mol. BioSyst. 8 (2012) 2664–2671. [7] J.J. McGrath, S. Saha, A. Al-Hamzawi, J. Alonso, E.J. Bromet, R. Bruffaerts, J.M. Caldasde-Almeida, W.T. Chiu, P. de Jonge, J. Fayyad, S. Florescu, O. Gureje, J.M. Haro, C. Hu, V. Kovess-Masfety, J.P. Lepine, C.C. Lim, M.E. Mora, F. Navarro-Mateu, S. Ochoa, N. Sampson, K. Scott, M.C. Viana, R.C. Kessler, Psychotic experiences in the general population: a cross-nationalanalysis based on 31261 respondents from 18 countries, JAMA Psychiat. 72 (2015) 697–705. [8] J. Das-Munshi, M. Ashworth, F. Gaughran, S. Hull, C. Morgan, J. Nazroo, A. Roberts, D. Rose, P. Schofield, R. Stewart, G. Thornicroft, M.J. Prince, Ethnicity and cardiovascular health inequalities in people with severe mental illnesses: protocol for the E-CHASM study, Soc. Psychiatry Psychiatr. Epidemiol. 51 (2016) 627–638.
3
[9] S. Hoirisch-Clapauch, A.E. Nardi, Improvement of psychotic symptoms and the role of tissue plasminogen activator, Int. J. Mol. Sci. 16 (2015) 27550–27560. [10] Y. Yoshida, H. Shiiki, M. Iwano, H. Uyama, K. Hamano, T. Nishino, K. Dohi, Enhanced expression of plasminogen activator inhibitor 1 in patients with nephrotic syndrome, Nephron 88 (2001) 24–29.
Silvia Hoirisch-Clapauch Hematology Department, Hospital Federal dos Servidores do Estado, Rio de Janeiro, Brazil Corresponding author at: Atlântica 434-1101 Leme, 22010-000 Rio de Janeiro, Brazil. E-mail address: [email protected]. Antonio E. Nardi Institute of Psychiatry, Federal University of Rio de Janeiro, Brazil 9 January 2017 Available online xxxx
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Letter to the Editors-in-Chief High prevalence of mental disorders in patients with inherited protein S deficiency: A case report series Keywords: Bipolar disorder Major depressive disorder Mental disorders Protein S deficiency Schizophrenia
Protein S, a natural anticoagulant with profibrinolytic properties, plays an important role in the central nervous system. Studies with cortical neurons showed that protein S binding to TAM (Tyro3, Axl, and Mer) receptors enhances proliferation and differentiation of adult neural stem cells. The mechanism involves increased expression of anti-apoptotic protein Bcl-2, reduced expression of pro-apoptotic protein p53, microglial inhibition and synaptic pruning [1,2]. Protein S also seems to protect ischemic mouse neurons from hypoxia/reoxygenation-induced apoptosis, in doses that do not significantly improve post-ischemic flow [3]. While inherited protein S deficiency is a rare autosomal dominant disorder, acquired deficiency is not uncommon and may result from reduced synthesis (e.g. estrogen use, pregnancy, the puerperium, hepatic insufficiency), increased excretion (e.g. nephrotic syndrome), consumption (e.g. disseminated intravascular coagulation) or autoantibodies (e.g. autoimmune disease and HIV infection). Since protein S bound to C4b-binding protein is inactive, conditions accompanied by increased levels of this complement system protein, such as systemic inflammation, are characterized by low protein S activity. Knowing that the puerperium, systemic lupus erythematosus, inflammatory bowel disease, HIV infection and other conditions characterized by low protein S activity are associated with an increased risk of psychosis, we decided to study the prevalence of psychotic symptoms and psychotic disorders in individuals with inherited protein S deficiency. From July to November 2016, adults with a thrombotic event or adverse pregnancy outcome related to protein S deficiency attending a tertiary care hospital in Rio de Janeiro, Brazil were selected. All were classified as type 1 deficiency (reduction in total and free protein S levels). Their first-degree adult relatives were screened for protein S deficiency. Index cases and their relatives with low protein S levels were invited to participate in this study. Those who accepted underwent clinical evaluation and a semistructured psychiatric interview. Since antiphospholipid antibodies may interfere with the measurement of protein S functional levels, all participants were screened for anticardiolipin antibodies and for lupus anticoagulant, but not for antiβ2 glycoprotein 1 antibodies. Mental disorders were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, DSM-5 [4]. Participants were
http://dx.doi.org/10.1016/j.thromres.2017.02.004 0049-3848/© 2017 Published by Elsevier Ltd.
diagnosed with major depression when either depressed mood or loss of pleasure were accompanied by ≥ 4 of the following manifestations over a two-week period: weight loss or gain, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, worthlessness or inappropriate guilt, and diminished concentration or indecisiveness. We decided to assess the temporal relationship between cerebral ischemia and depressive symptoms, because decreased concentration and indecisiveness are commonly seen in stroke patients. Participants were diagnosed with severe mental illness when all three criteria were met: a non-organic psychosis, such as schizophrenia, schizoaffective disorder or bipolar disorder; serious impairment in social, occupational or school functioning, as measured by the Global Assessment of Functioning scale; treatment duration of two years or more. Free protein S levels and anticardiolipin antibodies were measured by enzyme-linked immunosorbent assay (respectively, Diagnostica Stago, France and Binding Site, UK). Lupus anticoagulant testing was performed according to the guidelines of the International Society of Thrombosis and Haemostasis (Siemens Healthcare, Germany). Warfarin and estrogen were discontinued for at least 20 days before sampling. On the day of sampling, all participants were carefully examined and a complete blood count was performed. Free protein S levels were not determined when inflammation was suspected after overnight fasting were retested after three months. Those with low levels in two or more samples were considered deficient. Deep-vein thrombosis and pulmonary embolism were respectively diagnosed by duplex ultrasound and spiral computed tomography. Strokes were classified as ischemic by computed tomography or magnetic resonance imaging. The project was approved by the local ethics committee. Written informed consent was obtained from all participants. Five index patients (all women) from five different families were identified. All their 16 first-degree adult relatives were screened for protein S deficiency and nine were found to be protein S deficient. The 14 protein S-deficient individuals agreed to participate. Eight participants (57%) had a thrombotic event or a cerebral infarct before 45 years of age. Four of the six women who ever got pregnant (67%) had at least one adverse obstetric outcome related to abnormal placentation, such as recurrent early miscarriages, a small-for gestational-age infant or a preterm delivery. Of the seven participants reporting a psychotic experience (50%), four were diagnosed with a severe mental illness (29%), two with schizophrenia and two with bipolar disorder (Table 1). Patient index 1 was recommended prolonged bed rest for threatened abortion in two pregnancies. After giving birth to full-term small-for-gestational-age girls, she was diagnosed with major postpartum depression. She responded well to medications, but two years later, she had a new onset of major depressive episodes interspersed with bouts of hypomania and was diagnosed with bipolar disorder type II. Despite being treated with antidepressants, lithium, antipsychotics and electroconvulsive therapy, she is highly symptomatic. Her mother, who had two uneventful pregnancies, was diagnosed with bipolar disorder type II, currently in remission. Patient index 2 had two psychotic episodes, characterized by delusions and marked auditory hallucinations. One year after the second
2
Letter to the Editors-in-Chief
Table 1 Patients and first-degree relatives' characteristics. Index patient age #1 39 years #2 44 years #3 43 years #4 43 years #5 31 years
Mental disorder
Systemic thrombotic First-degree relatives with low Obstetric outcome without anticoagulation events protein S levels
Two episodes of major postpartum depression. Bipolar disorder type II
None
Two full-term SGA infants
Mother: bipolar disorder type II
Two psychotic episodes
None
One preterm SGA infant
Father: DVT, auditory hallucinations
None
Stroke
Three preterm SGA infants and one uneventful pregnancy
Intrusive thoughts and auditory hallucinations
Pulmonary embolism
One uneventful pregnancy
Major depression before stroke occurred
Stroke
Six early miscarriages and one uneventful pregnancy
Father: paranoid schizophrenia Sister: stroke Father: DVT Brother: asymptomatic Two sisters: DVT Brother: paranoid schizophrenia
SGA: small for gestational age; DVT: deep-vein thrombosis.
episode, she delivered a preterm small for-gestational-age infant. Her father had a deep-vein thrombosis at the age of 40 years and was treated with warfarin for six months. He currently has auditory hallucinations. Patient index 3 had three pregnancies ending in preterm delivery with small-for gestational-age infants and one uneventful pregnancy. Six years after the last delivery, she had an unprovoked stroke. Then, she was found to have protein S deficiency and was started on warfarin. Her father was diagnosed with paranoid schizophrenia, with poor response to antipsychotic therapy. The patient and her sister, who also had an unprovoked stroke, have no mental symptoms. Patient index 4 was an athlete in adolescence and early adulthood. At the age of 21 she had an uneventful pregnancy. Protein S deficiency was diagnosed three years later, when she had a pulmonary embolism. At that time, she was placed on long-term warfarin therapy. At the age of 30, some months after she stopped exercising, she began to have mild auditory hallucinations and intrusive thoughts. Her father is on long-term warfarin therapy because of deep-vein thrombosis and her brother is asymptomatic. Neither of them have any mental symptom. Patient index 5 had six early miscarriages from 18 to 24 years of age. She had no significant mental symptoms until the age of 28, when she was diagnosed with major depression. Two years later, she had an ischemic stroke, and the diagnosis of protein S deficiency was made. A dramatic improvement of the mental symptoms was observed six months after she was placed on warfarin and daily physiotherapy. Two years after the stroke she became pregnant and warfarin was replaced by aspirin. She continued physiotherapy throughout pregnancy and delivered a full-term girl. Her brother has paranoid schizophrenia and two sisters, on long-term warfarin therapy for recurrent deepvein thrombosis, have no mental symptoms. 1. Discussion This study is not the first one to establish a link between severe mental illnesses and low levels of protein S. Our group has recently analyzed the levels of free protein S in a cohort of 70 patients with schizophrenia or schizoaffective disorder and 98 matched controls. Fifteen patients (21%) and no control had low protein S levels [5]. Another study, using an immunoaffinity method to detect depletion of high-abundance proteins in schizophrenia serum, revealed decreased expression of both C4b-binding protein and protein S [6]. This paper is innovative because it is the first one to report a high prevalence of psychotic symptoms (50% vs. 6% in the general population) and psychotic disorders (29% vs. 2% in the general population) in patients with inherited protein S deficiency [7,8]. The importance of stressful life events such as life-threatening thromboembolism or complicated pregnancy experiences in triggering psychosis is indisputable. The hypothesis that protein S deficiency has an important role in the pathogenesis of severe mental disorders is supported by the low prevalence of such disorders in patients with thrombotic events or
complicated pregnancies who do not have protein S deficiency. In fact, among 1559 patients attending the same hospital where this study was performed (18% with thrombotic events, 71% with complicated pregnancies and 11% with both problems), only six (o.4%) have a severe mental illness. One important issue needs to be addressed. The finding that mental symptoms are highly prevalent, but not ubiquitous among individuals with protein S deficiency suggests a multifactorial model. We postulate that low levels of tissue plasminogen activator (tPA) would be an additional element in the pathogenesis of mental disorders related to protein S deficiency. tPA mediates a number of processes essential for synaptogenesis and synapse remodeling, including degradation of adhesion molecules, activation of neurotrophins and activation of N-methyl-D-aspartate receptor [9]. Abnormalities in such processes have been consistently described in psychotic disorders. Reinforcing the hypothesis that low tPA levels might have a role in the pathogenesis of protein S deficiency-related psychotic symptoms, our group did not observe an increased prevalence of severe mental disorders in nephrotic patients (unpublished data). Nephrotic patients have lower protein S levels than controls, but their tPA levels are higher, probably because urinary excretion of protein S parallels excretion of plasminogen activator inhibitor-1, a tPA inhibitor [10]. In conclusion, we found a high prevalence of psychotic symptoms and severe mental illnesses in patients with inherited protein S deficiency. Further studies are needed to confirm our findings and to elucidate the role of protein S concentrates for refractory psychosis. Funding source This study was supported by grants from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro [FAPERJ 34/ 204.823/2014]. Disclosure The authors declare no conflict of interest. Acknowledgements The authors would like to thank Dr. Jacqueline Anita Menezes, MD, PhD for her invaluable suggestions. References [1] Z. Zhong, Y. Wang, H. Guo, A. Sagare, J.A. Fernández, R.D. Bell, T.M. Barrett, J.H. Griffin, R.S. Freeman, B.V. Zlokovic, Protein S protects neurons from excitotoxic injury by activating the TAM receptor Tyro3-phosphatidylinositol 3-kinase-Akt pathway through its sex hormone-binding globulin-like region, J. Neurosci. 30 (2010) 15521–15534. [2] R. Ji, S. Tian, H.J. Lu, Q. Lu, Y. Zheng, X. Wang, J. Ding, Q. Lu, TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation, J. Immunol. 191 (2013) 6165–6177.
Letter to the Editors-in-Chief [3] D. Liu, H. Guo, J.H. Griffin, J.A. Fernandez, B.V. Zlokovic, Protein S confers neuronal protection during ischemic/hypoxic injury in mice, Circulation 107 (2003) 1791–1796. [4] American Psychiatric Association, Diagnostic and statistical manual of mental disorders, fifth ed. American Psychiatric Publishing, Washington D.C., 2013 [5] S. Hoirisch-Clapauch, A.E. Nardi, Markers of low activity of tissue plasminogen activator/plasmin are prevalent in schizophrenia patients, Schizophr. Res. 159 (2014) 118–123. [6] Y. Li, K. Zhou, Z. Zhang, L. Sun, J. Yang, M. Zhang, B. Ji, K. Tang, Z. Wei, G. He, L. Gao, L. Yang, P. Wang, P. Yang, G. Feng, L. He, C. Wan, Label-free quantitative proteomic analysis reveals dysfunction of complement pathway in peripheral blood of schizophrenia patients: evidence for the immune hypothesis of schizophrenia, Mol. BioSyst. 8 (2012) 2664–2671. [7] J.J. McGrath, S. Saha, A. Al-Hamzawi, J. Alonso, E.J. Bromet, R. Bruffaerts, J.M. Caldasde-Almeida, W.T. Chiu, P. de Jonge, J. Fayyad, S. Florescu, O. Gureje, J.M. Haro, C. Hu, V. Kovess-Masfety, J.P. Lepine, C.C. Lim, M.E. Mora, F. Navarro-Mateu, S. Ochoa, N. Sampson, K. Scott, M.C. Viana, R.C. Kessler, Psychotic experiences in the general population: a cross-nationalanalysis based on 31261 respondents from 18 countries, JAMA Psychiat. 72 (2015) 697–705. [8] J. Das-Munshi, M. Ashworth, F. Gaughran, S. Hull, C. Morgan, J. Nazroo, A. Roberts, D. Rose, P. Schofield, R. Stewart, G. Thornicroft, M.J. Prince, Ethnicity and cardiovascular health inequalities in people with severe mental illnesses: protocol for the E-CHASM study, Soc. Psychiatry Psychiatr. Epidemiol. 51 (2016) 627–638.
3
[9] S. Hoirisch-Clapauch, A.E. Nardi, Improvement of psychotic symptoms and the role of tissue plasminogen activator, Int. J. Mol. Sci. 16 (2015) 27550–27560. [10] Y. Yoshida, H. Shiiki, M. Iwano, H. Uyama, K. Hamano, T. Nishino, K. Dohi, Enhanced expression of plasminogen activator inhibitor 1 in patients with nephrotic syndrome, Nephron 88 (2001) 24–29.
Silvia Hoirisch-Clapauch Hematology Department, Hospital Federal dos Servidores do Estado, Rio de Janeiro, Brazil Corresponding author at: Atlântica 434-1101 Leme, 22010-000 Rio de Janeiro, Brazil. E-mail address: [email protected]. Antonio E. Nardi Institute of Psychiatry, Federal University of Rio de Janeiro, Brazil 9 January 2017 Available online xxxx