Treatment Approaches to Toxoplasmosis and Schizophrenia
Background: Antipsychotics as antiprotozoal agents
Antipsychotic medications have been shown to have antiprotozoal activity. As early as 1891, it was reported that the phenothiazine dye methylene blue killed Plasmodium vivax, one causative agent of malaria (Guttman P, Ehrlich P. Über die wirkung des Methylenglau bei Malaria. Berl Klin Wochenschr. 1891;39:953–956). In more recent years, in vitro studies have shown that phenothiazines such as chlorpromazine inhibit the growth of Tetrahymena pyriformis (Forrest IS, Quesada F, Deitchman GL. Unicellular organisms as model systems for the mode of action of phenothiazine and related drugs. Proc West Pharmacol Soc. 1963;6:42–44); Paramecium spp. (Saitow F, Nakaoka Y. The photodynamic action of methylene blue on the ion channels of Paramecium causes cell damage. Photochem Photobiol. 1997;65:902–907); Leishmania donovani (Pearson RD, Manian AA, Hall D, et al. Antileishmanial activity of chlorpromazine. Antimicrob Agents Chemother. 1984;25:571–574); Trypanosoma brucei and Trypanosoma cruzi (Benson TJ, McKie JH, Garforth J, et al. Rationally designed selective inhibitors of trypanothione reductase. Phenothiazines and related tricyclics as lead structures. Biochem J. 1992;286:9–11; Gutierrez-Correa J, Fairlamb AH, Stoppani AO. Trypanosoma cruzi trypanothione reductase is inactivated by peroxidase-generated phenothiazine cationic radicals. Free Radic Res. 2001;34:363–378; Seebeck T, Gehr P. Trypanocidal action of neuroleptic phenothiazines in Trypanosoma brucei. Mol Biochem Parasitol. 1983;9:197–208); Plasmodium falciparum (Kristiansen JE, Jepsen S. The susceptibility of Plasmodium falciparum in vitro to chlorpromazine and the stereo-isometric compounds cis(Z)- and trans(E)-clopenthixol. Acta Pathol Microbiol Immunol Scand B. 1985;93:249–251); and Entamoeba histolytica (Ondarza RN, Hernandez E, Itrube A, et al. Inhibitory and lytic effects of phenothiazine derivatives and related tricyclic neuroleptic compounds on Entamoeba histolytica HK9 and HM1 trophozoites. Biotechnol Appl Biochem. 2000;32:61–67). In addition, an in vivo study reported that chlorpromazine ointment was effective in treating cutaneous leishmaniasis (Henriksen T-H, Lende S. Treatment of diffuse cutaneous leishmaniasis with chlorpromazine ointment (letter). Lancet. 1983;i:26).
In vitro studies
The first report of antipsychotic inhibition of Toxoplasma gondii was an in vitro study using the phenothiazine trifluoperazine (Stelazine), which was said to have “membrane-active detergent-like effects” on T. gondii (Pezzella N, Bouchot A, Bonhomme A, et al. Involvement of calcium and calmodulin inToxoplasma gondii tachyzoite invasion. Eur J Cell Biol. 1997;74:92–101). An extensive in vitro study of eight antipsychotics and metabolites and four mood stabilizers compared their effectiveness in inhibiting T. gondii against the effectiveness of trimethroprim, a standard treatment for toxoplasmosis. Haloperidol was more effective than trimethoprim. Valproic acid and sodium valproate were equally effective to trimethoprim. Chlorpromazine, fluphenazine, risperidone, clozapine, quetiapine, and carbamazapine all showed some activity but less than trimethoprim. Lithium showed no inhibition of T. gondii (Jones-Brando L, Torrey EF, Yolken R. Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii. Schizophr Res. 2003;62:237–244). A partial replication of this study was carried out using some different methods and assays. In this study, haloperidol, clozapine and valproic acid had no measurable effect but fluphenazine, thioridazine and trifluoperazine did (Goodwin DG, Strobl J, Mitchell SM, Zajac AM, Lindsay DS. Evaluation of the mood-stabilizing agent valproic acid as a preventative for Toxoplasmosis in mice and activity against tissue cysts in mice. J Parasitol. 2008;94:555-557; Goodwin DG, Strobl JS, Lindsay DS. Evaluation of five antischizophrenic agents against Toxoplasma gondii in human cell cultures. J Parasitol. 2011;97:148-151). In another replication of this study fluphenazine and zuclopenthixol showed good inhibition of T. gondii; haloperidol, levomepromazine and loxapine showed fair inhibition; and amisulpride, risperidone and valproic acid showed poor inhibition (Fond G, Macgregor A, Tamouza R, et al. Comparative analysis of anti-toxoplasmic activity of antipsychotic drugs and valproate. Eur Arch Psychiatry Clin Neurosci. 2014;264:179-83).
Antiprotozoal agents and schizophrenia-related genes
In another study that linked schizophrenia and antiprotozoal drugs, geneticists identified the genes that have emerged in the GWAS studies as being the strongest risk genes for schizophrenia. They then identified 1,267 drugs, divided into 243 drug classes, and tested them against the schizophrenia risk genes. The drug class that was most effective against the schizophrenia risk genes was the class of antiprotozals. They scored even higher than the second most effective class, the anti-psychotics (Ruderfer DM, et al. Polygenetic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach. The Lancet Psychiatry. 2016. http://dx/doi.org/10.1016/S2215-0366(15)00553-2).
Trials of drugs known to be effective against T. gondii on patients with schizophrenia
- Azithromycin (Zithromax) 600 mg: 56 outpatients with schizophrenia; double-blind, placebo trial; 16 weeks; add-on to regular antipsychotic; negative study (Dickerson FB, Stallings CR, Boronow JJ, et al. A double-blind trial of adjunctive azithromycin in individuals with schizophrenia who are seropositive for Toxoplasma gondii. Schizophr Bull. 2007;112:198–199).
- Trimethoprim 200 mg: 91 male outpatients with mostly chronic schizophrenia; double-blind, placebo trial; 6 months; add-on to chlorpromazine or haloperidol. Both groups improved markedly, perhaps reflecting being on a regular antipsychotic with monitoring and follow-up. The trimethoprim group improved more on the negative symptom subscale, but the difference did not achieve statistical significance (Shibre T, Alem A, Abdulahi A, et al. Trimethoprim as adjuvant treatment in schizophrenia: a double-blind, randomized, placebo-controlled clinical trial. Schizophr Bull. 2010;36:846–851).
- Artemisinin: an anti-malarial, was given 200 mg/d or placebo to 66 outpatients with schizophrenia for 10 weeks. There was no significant difference in positive or negative symptoms between groups. However, the artemisinin significantly decreased the level of antibodies to gliadin (p<0.0005) (Dickerson F, Stallings C, Vaughan C, et al. Artemisinin reduces the level of antibodies to gliadin in schizophrenia. Schizophr Res. 2011;129:196–200).
- Artemether: an anti-malarial related to artemisinin, or placebo was given for 8 weeks to 100 individuals with first-episode schizophrenia, all positive for antibodies to T. gondii, in a double-blind study. They were all also taking risperidone. On the PANSS scale for negative symptoms, but not other scales, the patients on artemether improved significantly more than controls (p<0.05) (Wang H-L, et al. The effect of artemether on psychotic symptoms and cognitive impairment in first-episode, antipsychotic drug-naïve persons with schizophrenia seropositive to Toxoplasma gondii. J Psych Res. 2013; 53: 119-124).
These preliminary treatment trials have been criticized on several grounds, including using too low a dose of the drugs . [Chorlton SD. Toxoplasma gondii and schizophrenia: a review of published RCTs. Parasitol Res. 2017; doi: 10.1007/s00436-017-5478-y]
A major limiting factor in treating humans infected with T. gondii is that so far no drug has ever been shown to be effective against the cyst stage of the organism, sequestered in the person’s muscles and brain. Research carried out by our colleagues has recently identified promising candidates which are under investigation. These include a derivative of quinolone drugs, widely used to treat malaria, which appears to be effective in inhibiting the toxoplasmosis brain cysts; these drugs are being developed in the laboratory of Mike Riscoe at the University of Oregon (Doggett JS, et al. Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis. 2012. Proc Natl Acad Sci; 109(39): 15936-41).
Another kind of drug being developed for possible use in treating T. gondii brain infections are analogues of sphingosine, a brain lipid similar to one derived from wild cherry. These are being developed in the laboratory of James McNulty at McMaster University in Ontario (McNulty J, Vemula R, Bordon C, et al. Synthesis and anti-toxoplasmosis activity of 4-arylquinoline-2-carboxylate derivatives. Org Biomol Chem. 2014;12:255-60). One drug in this group, fingolimod, is currently available for the treatment of multiple sclerosis and is undergoing a treatment trial to assess its efficacy in individuals with schizophrenia. Artemisinin derivatives which reduce the burden of T. gondii brain cysts are also being developed in the laboratory of Vern Carruthers at the University of Michigan (Schultz TL, Hencken CP, Woodard LE, et al. A thiazole derivative of artemisinin moderately reduces Toxoplasma gondii cyst burden in infected mice. J Parasitol. 2014; 100:516-21).
Given the in vitro evidence that valproate has some anti-toxoplasma effects, a group in France looked at the treatment records of 152 patients with bipolar disorder and 114 with schizophrenia. The bipolar patients who were T. gondii seropositive had fewer lifetime depressive episodes (p=.048) when treated with valproate compared to those not treated with valproate. For bipolar patient who were seronegative, and for the patients with schizophrenia who were seropositive or seronegative, being treated with valproate or other medications had no differential effect on lifetime depressive episodes (Fond G, et al. Treatment with anti-toxoplasmic activity (TATA) for toxoplasma positive patients with bipolar disorders or schizophrenia: A cross sectional study. Journal of Psychiatric Research. 2015. http://di.doi.org/10.1016/j.jpyschires.2015.02.011). Ultimately it would be desirable to develop an effective vaccine against T. gondii. Current progress on this task is summarized by Zhang N-Z et al. Recent advances in developing vaccines against toxoplasma gondii: an update. Expert Rev. Vaccines. 2015: 1-13).