Sample Masters Medicine Dissertation Proposal

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Association between Toxoplasma Gondii and Mental Disorders in Taif Region

Abstract

Background

Around 30 percent of both developing and developed countries’ populations are infected by Toxoplasma gondii. Researches have presented that in the Toxoplasma infection Initial stage, changes are made in the infected human physiology, behaviour, and animals infected artificially.

Personality shifts were observed in simple response times and psychiatric diseases and intelligence consisting of schizophrenia, dementia, and suicidal tendencies. Correspondingly changes in behaviour such as raised attraction toward feline odours and reduction in neophobia were observed in experimental studies.

Aims

Our study aims to investigate the association between latent Toxoplasma gondii infection and various mental illnesses in Taif, KSA.

Settings and Design

A cross-sectional study involving patients receiving medical care for various mental disorders in the psychiatric health hospital, Taif, KSA, has been done. And a control group of patients not suffering from any previous mental disorders.

Methods and Materials

Blood samples were drawn from patients with different mental disorders and a control group.  Toxoplasma gondii –IgG ELISA was performed.

Statistical Analysis Used

Statistical Tests Data were analyzed using the chi-square test. Statistical analyses were carried out using SPSS version 11.

Results and Conclusion

A statistically significant association between mental disorders and latent Toxoplasma infection (IgG positive) was observed. 60% of the study group were positive for Toxoplasma IgG compared to only 30% of the control group. The most frequent mental disorder marked in the positive cases was schizophrenia (55%), followed by depression with suicidal tendencies (22%).

Our results support the hypothesis of major involvement between latent T.gondii infection and mental disorders. We recommend that the Toxoplasma-IgG test be routinely performed on all patients with mental disorders and consider administering anti-Toxoplasma drugs to all positive cases.

Keywords

Toxoplasma gondii–  schizophrenia- depression- Taif- association.

Introduction

Toxoplasma gondii is a prevalent parasite that can account for infecting almost 30% of individuals of both developing and developed countries. Toxoplasma Prevalence rates can reach 80% of any population [1]. It is considered one of the most accomplished protozoan parasites due to its surprisingly wide range of mammalian hosts [2].

T. gondii might infect individuals through eating food that is either undercooked or can be considered as raw meat containing the infective stage. In this case, the tissue cysts or ingesting oocytes accidentally after manipulating cat faces [3], or if the oocysts in cat aces have contaminated drinking water [4].

Since 1994, numerous researches have presented that in the initial stage of Toxoplasma infection, that was in the past was taken as an asymptomatic disease from the perspective of medical, particularly modification made in the infected human’s physiology and behaviour and as well as in the animals.

However, some researchers had explained these behavioural alterations due to the parasite’s manipulative actions to ascertain its spread from the wide range of animals acting as intermediate hosts to their ultimate definitive host, the cat [7], [6]. Moreover, others suggest that such changes are the primary reason for Toxoplasma infection on the infected human physiology that will grow in light stress.

Several research articles have addressed the changes that can be inflicted by Toxoplasma infection and demonstrated its association with alteration in intelligence and simple reaction time [8], [6] and personality shifts [9], [10]. Others even went to the assumption that Toxoplasma infection can be related to different psychiatric disorders like suicidal behaviour, dementia, and schizophrenia [11], [12], [13]

Correspondingly, the experimental studies examined the changes in behaviour such as the neophobia reduction[14 And raised attraction towards the felin orders [15]. It has been suggested by the evidence that parasites impact the synthesis of neurotransmitters, particularly dopamine. In infected humans, that can be the reason for personality changes [16].

Meanwhile, experimental studies have revealed behavioural alterations decreased aversion to odours of feline nature [15]. Some studies suggested the Capability parasite to modify neurotransmitters’ production, central dopamine in infected persons leading to different behavioural alterations [16].

Aims

Our study aims to investigate the association between latent Toxoplasma gondii infection and various mental illnesses in the city of Taif, KSA.

Methods and Materials

The study was conducted on 30 female patients receiving medical care for various mental disorders in the psychiatric health hospital, Taif, KSA. The faculty scientific research committee approved the study and the psychiatric health hospital ethical committee. Written consent was taken from the patient or their legal guardian before enrolling in this study. No harm was promised to patients who refused to participate in the study.

The supporting staff completed a written questionnaire, including some personal data (optional), patient’s diagnosis, and data about owning or handling cats in the previous year.

A control group comprising 20 age and sex matching volunteers, not suffering from any previous mental disorder and coming to perform different laboratory tests in King Abdelaziz Hospital’s laboratory department.

From every subject, a 5-ml blood sample was taken for serological analysis. The blood samples were centrifuged at 1500 rpm for 10 minutes to acquire vibrant supernatants. The sera were maintained at -20°C Before the examination. IgG antibodies in the case and control groups were evaluated through the ELISA technique (UDI, KSA) per the manufacturer’s instructions.

A Chi-square test was carried out for the examination of quantitative data tests. .05 level of probability was taken as necessary statistically. The examination was done through SPSS version 11.

Results and Discussion

The data collected from the research participants present in the control and intervention groups was statistically analyzed. The results of the Toxoplasma IgG test are summarized in (Figure1) where a significant difference (p < 0.05) was observed. In the study group. The statistical outcomes revealed that the Toxoplasma IgG test was positive in 18 samples concerning the study group.

On the other hand, the Toxoplasma IgG test was negative in 12 samples within the study group. At the same time, when the control group samples were analyzed,  it was found that the control group revealed only six positive samples for Toxoplasma IgG. Whereas most samples for the control group, i.e., 14 samples, revealed negative results.

When the diagnosis of these 18 positive cases was reviewed, the following distribution was observed (Table 1):

The results show that the most frequent diagnosis among the positive Toxoplasma IgG study group cases was schizophrenia 10 cases of total positive Toxoplasma IgG test patients representing 55% of the total Toxoplasma positive cases. They were followed by depression with suicidal tendencies, which accounted for four patients representing 22%of total positive patients.

The statistical analysis also revealed that bipolar disorders were diagnosed in two patients among the considered study group. The statistical analysis also presented that only one patient was found to experience adjustment disorders, whereas one patient was found to possess psychotic episodes. No other common psychiatric disorders were diagnosed in the study group throughout the study period.

The results also revealed a significant association (p < 0.05)   between having a cat (or at least handling cats in the previous year) and being positive Toxoplasma-IgG in the study group (Figure2). The analysis of the questionnaire results revealed that while there were 12 cases with a positive history of owning or handling a cat in the study group, there were only 3 cases that replied positively to this question from the control group. In this regard, the statistical analysis presented that owning or handling cats within the previous year were at risk of suffering from the Toxoplasma-IgG.

  1. gondii is an apicomplexan protozoan that can complete its life cycle through two hosts: a definitive feline host through which it has to pass through sexual reproduction and a middle host in which a sexual reproduction arises. Almost any warm-blooded vertebrate can serve as its intermediate host, including humans. Inside the intermediate host, antibodies are produced as a response to the acute infection. The parasite shifts into a more quiescent phase by changing into cysts in most tissues of the body. The most affected parts are usually the brain and muscles [1].

As these mentioned infections have been taken as benign, collected evidence has been presented T. gondii infection changes human behaviour and, in few scenarios, aggravates or contributes to mental instability. Although T.gondii infection had been considered harmless, over time, much data is relating its infection with behavioural changes in humans and even augmentation of various mental disorders  [10], [5]. Moreover, Rise in the street and relation with the particular personality traits were also revealed in cases with T. gondii infection [5].

Over the years, accumulating reports had been gathered associating T. gondii infection with different changes of behavior of most species ranging from insects to mammals   [22], [23], [24], [10], [25], [26]. The best theory that explains this association so far is the ‘behavioural manipulation hypothesis’ that claims that the protozoan can control the behaviour of their hosts for raising their transmission opportunities and thus complete their life cycle [27].

It can explain why experimentally infected mice lose their aversion to feline urine odour and increase their encounter. Thus, the parasite’s opportunity to be transmitted from the intermediate host, i.e. the mouse, to the final host, i.e., the cat [28], [29].

Can control connivingly the behaviour of their host’s for raising their transmission opportunities

In their opinion, they rely on the fact that the prevalence of T. gondii infection is much higher than the prevalence of schizophrenia (0.5-1%). Moreover, a major cause in the aetiology of schizophrenia is still genetic risk [35].

Many researchers have agreed with the association between T. gondii and schizophrenia and supported their hypothesis by relating to the role of dopamine in schizophrenia. This role was proven by the attributes which present that antipsychotic drugs minimize the brain dopamine hence reducing the symptoms of schizophrenia [36], [37].

In the same time, T. gondii replication was inhibited by antipsychotic drugs [38], [39]. T. gondii infection of the brain rases ranged of dopamine [40], [41],[42]  and caused psychotic symptoms resembling schizophrenia [18], [43]. Artemether, a potent antiparasitic drug, essentially improved symptoms In contrast to schizophrenia controls [44].

Conclusions & Recommendations

Our results come in accordance with many other pieces of research that supported the hypothesis of major involvement between latent T. gondii infection and several different mental disorders.  The high percentage of positive undiagnosed cases of Toxoplasma is surprising. Based on our findings, we recommend that the Toxoplasma-IgG test be routinely performed on all patients with mental disorders and consider administering anti-Toxoplasma drugs to all positive cases. More elaborate studies on different specific neurotransmitters and their levels in T. gondii infected group should be considered.

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References

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[2] Bhadra R, Gigley JP, Khan IA (2011). The CD8 T-cell road to immunotherapy of toxoplasmosis. Immunotherapy.;3:789–801.

[3] Kijlstra A, Jongert E. (2008):  Control of the risk of human toxoplasmosis transmitted by meat. Int J Parasitol.;38(12):1359–70.

[4] Herrmann DC, Pantchev N, Vrhovec MG, Barutzki D, Wilking H, Frohlich A, et al.,. (2010):  Atypical Toxoplasma gondii genotypes identified in oocysts shed by cats in Germany. Int J Parasitol.;40(3):285–92.

[5] Flegr J (2013a): Influence of latent Toxoplasma infection on human personality, physiology and morphology: pros and cons of the Toxoplasma-human model in studying the manipulation hypothesis. Journal of Experimental Biology 216: 127–133.

[6] McConkey GA, Martin HL, Bristow GC, Webster JP (2013): Toxoplasma gondii infection and behaviour – location, location, location? Journal of Experimental Biology 216: 113–119.

[7] Webster JP (2007): The effect of Toxoplasma gondii on animal behavior: Playing cat and mouse. Schizophr Bull 33: 752–756

[8] Havlíček J, Gašová Z, Smith AP, Zvára K, Flegr J (2001) Decrease of psychomotor performance in subjects with latent ‘asymptomatic’ toxoplasmosis. Parasitology 122: 515–520.

[9] Flegr J, Hrdý I (1994) Influence of chronic toxoplasmosis on some human personality factors. Folia Parasitol 41: 122–126.

[10] Flegr J (2010): Influence of latent toxoplasmosis on the phenotype of intermediate hosts. Folia Parasitol 57: 81–87.

[11] Flegr J (2007): Effects of Toxoplasma on human behavior. Schizophr Bull.;33(3):757-60.

[12] Pedersen MG, Mortensen PB, Norgaard-Pedersen B, Postolache TT (2012): Toxoplasma gondii infection and self-directed violence in mothers. Arch Gen Psychiatry.:1–8.

[13] Torrey EF, Bartko JJ, Yolken RH (2012):  Toxoplasma gondii and other risk factors for schizophrenia: an update. Schizophr Bull.;38:642–647.

[14] Webster JP, Brunton CF, MacDonald DW(1994): Effect of Toxoplasma gondii upon neophobic behaviour in wild brown rats, Rattus norvegicus. Parasitology.;109 (Pt 1):37–43.

[15] Vyas A, Kim SK, Giacomini N, Boothroyd JC, Sapolsky RM (2007). Behavioural changes induced by Toxoplasma infection of rodents are particular to aversion of cat odours. Proc Natl Acad Sci USA. 104:6442–6447.

[16] Khademvatan S, Khajeddin N, Saki J, Izadi-Mazidi S. (2013): Effect of toxoplasmosis on personality profiles of Iranian men and women. S Afr J Sci.; 109(1-2):1–4.

[17] Fuller Torrey E, Rawlings R, Yolken RH (2000): The antecedents of psychoses: a case-control study of selected risk factors. Schizophr Res.;46(1):17–23.

[18] Torrey EF, Yolken RH. (2003):Toxoplasma gondii and schizophrenia. Emerg Infect Dis.;9(11):1375–80.27.

[19] Webster JP, Lamberton PH, Donnelly CA, Torrey EF. (2006): Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii‘s ability to alter host behaviour. Proc Biol Sci.;273(1589):1023–30.29.

[20] Saraei-Sahnesaraei M, Shamloo F, Jahani Hashemi H, Khabbaz F, Alizadeh S. (2009): Relation between Toxoplasma gondii infections and schizophrenia. IJPCP.;15(1):3–9.

[21] Xiao Y, Yin J, Jiang N, Xiang M, Hao L, Lu H, et al., (2010): Seroepidemiology of human Toxoplasma gondii infection in China. BMC Infect Dis.;10:4.

[22] Fjerdingstad EJ, Gertsch PJ, Keller L (2002): Why do some social insect queens mate with several males? Testing the sex‐ratio manipulation hypothesis in Lasiusniger. Evolution 56:553–562.PMID: 11989685

[23] Adamo SA (2003): Modulating the modulators: parasites, neuromodulators and host behavioural change. Brain, behaviour and evolution 60:370–377.

[24] Klein SL (2003): Parasite manipulation of the proximate mechanisms that mediate social behaviour in vertebrates. Physiology &behavior 79:441–449.

[25] Poulin R (2010): Parasite manipulation of host behaviour: an update and frequently asked questions. Advances in the Study of Behavior 41:151–186.

[26] Libersat F, Gal R (2013): What can parasitoid wasps teach us about decision-making in insects? The Journal of experimental biology 216:47–55.doi:10.1242/jeb.073999PMID:23225867

[27] Berdoy M, Webster JP, Macdonald D (2000): Fatal attraction in rats infected with Toxoplasma gondii. Proceedings of the Royal Society of London Series B: Biological Sciences 267:1591–1594.PMID: 11007336.

[28] Ingram WM1, Goodrich LMRobey EAEisen MB (2013): Mice infected with low-virulence strains of Toxoplasma gondii lose their innate aversion to cat urine, even after extensive parasite clearance. PLoS One. Sep 18;8(9):e75246. doi: 10.1371/journal.pone.0075246.

[29] Lanchava L, Carlson K, Šebánková B,  Flegr J , Nave G (2015): No Evidence of Association between Toxoplasma gondii Infection and Financial Risk Taking in Females. PLOSONE|DOI:10.1371/journal.pone.0136716 September24.

[30] Hinze-Selch D, Daubener W, Eggert L, Erdag S, Stoltenberg R, Wilms S (2007): A controlled prospective study of Toxoplasma gondii infection in individuals with schizophrenia: beyond seroprevalence. Schizophr Bull.;33(3):782–8.

[31] Niebuhr DW, Millikan AM, Cowan DN, Yolken R, Li Y, Weber NS (2008): Selected infectious agents and risk of schizophrenia among U.S. military personnel. Am J Psychiatry.;165(1):99–106.8.

[32] Yuksel P, Kocazeybek B, Alpay N, Babur C, Bayar R, Karaköse AR, et al., (2008):  Establishing the Role of Latent Toxoplasmosis in the Etiopathogenesis of Schizophrenia. Int J Infect Dis.;12.7.

[33] Mahmoud SS, Hasan MS (2009). Seroprevalence of toxoplasmosis among schizophrenic patients. Yemeni J Med Sci.;1(3):1–7.6.

[34] Thomas HV, Thomas DR, Salmon RL, Lewis G, Smith AP (2004):Toxoplasma and Coxiella infection and psychiatric morbidity: a retrospective cohort analysis. BMC Psychiatry; 4: 32. 29.

[35] Eells JB, Varela-Stokes A, Guo-Ross SX, Kummari E, Smith HM, Cox E, et al.,. (2015): Chronic Toxoplasma gondii in Nurr1-Null heterozygous mice exacerbates elevated open field activity .PLoSONE 10(4): e0119280. doi:10.1371/journal.pone.0119280

[36] Richtand NM, Welge JA, Loque AD, Keck PE Jr, Strakowski SM, McNamara RK (2007). Dopamine and serotonin receptor binding and antipsychotic efficacy. Neuropsychopharmacology; 32: 1715-1726.

[37] Omar A, Bakar OC,  Adam NF, Osman H,  Osman A, Suleiman AH, Riza M,  Manaf A, Selamat MI (2015): Seropositivity and Serointensity of Toxoplasma gondii Antibodies and DNA among Patients with Schizophrenia. Korean J Parasitol Vol. 53, No. 1: 29-34

[38] Jones-Brando L, Torrey EF, Yolken R. (2003): Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii. Schizophr Res; 62: 237-244.

[39] Jones-Brando L, D’Angelo J, Posner GH, Yolken R (2006): In vitro inhibition of Toxoplasma gondii by four new derivatives of artemisinin. Antimicrob Agents Chemother. 50(12):4206-8.

[40] Gatkowska J, Wieczorek M, Dziadek B, Dzitko K, Dlugonska H (2013): Sex-dependent neurotransmitter level changes in brains of Toxoplasma gondii infected mice. Exp Parasitol; 133: 1-7.

[41] Flegr J (2013b): How and why Toxoplasma makes us crazy.  TrendsParasitol. ;29:156–163.doi:10. 1016/j.pt.2013.01.007PMID:23433494

[42] Xiao J, Li Y, Prandovszky E, Karuppagounder SS, Talbot CC Jr, Dawson VL, Dawson TM, Yolken RH (2014): MicroRNA-132 dysregulation in Toxoplasma gondii infection has implications for dopamine signalling pathway. Neuroscience; 268: 128-138.

[43] Wang T, Tang ZH, Li JF, Li XN, Wang X, Zhoa ZJ (2013): A potential association between Toxoplasma gondii infection and schizophrenia in mouse models. Exp Parasitol; 135: 497-502.

[44] Wang HL, Xiang YT, Li QY, Wang XP, Liu ZC, Hao SS, Liu X, Liu LL, Wang GH, Wang DG, Zhang PA, Bao AY, Chiu HF, Ungvari GS, Lai KY, Buchanan RW (2014): The effect of artemether on psychotic symptoms and cognitive impairment in first-episode, antipsychotic drug-naïve persons with schizophrenia seropositive to Toxoplasma gondii. J Psychiatr Res; 53: 119-124.

Tables and Figures

Fig-Toxoplasma-IgG-test-in-the-study-group-versus-the-control-group

Fig (1): Toxoplasma IgG test in the study group versus the control group

Place table here

Table (1): Frequency of the positive Toxoplasma IgG cases according to their clinical diagnosis

Fig-The-association-between-having-or-handling-a-cat-and-Toxoplasma-infection-in-the-study-group-versus-the-control-group.

Fig (2): The association between having or handling a cat and Toxoplasma infection in the study group versus the control group.

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