The Gut Microbiome and Treatment-Resistance in Schizophrenia
Abstract
The effect of antipsychotic medication is poor in 30–40% of patients with schizophrenia; treatment resistance is usually met with shifts to new drugs or drug augmentation strategies or a trial of clozapine. The purpose of this review was to examine the potential role of intestinal bacteria in the bioavailability of antipsychotic medication and the possibility that parenterally administered antipsychotics might be able to overcome treatment resistance. Databases were searched with appropriate terms to locate relevant papers dealing with the effect of antipsychotic drugs on the gut microbiome and the effect of bacterial metabolizing enzymes on antipsychotic drugs. Also searched were papers addressing the various current parenteral formulations of antipsychotic drugs. Sixty-five recent pertinent papers were reviewed and the results are suggestive of the premise that there is a drug refractory form of psychosis for which the composition of gut bacteria is responsible, and that parenteral drug administration could overcome the problem.
Keywords
Gut microbiome Antipsychotic drugs Treatment resistance Parenteral formulationsNotes
Compliance with Ethical Standards
Conflict of Interest
There is no conflict of interest. The author has nothing to disclose.
Ethical Approval
This is a review paper. No ethical approval was sought.
Informed Consent
This is a review paper. There was no need for consent.
Humans or Animals Participants
There was no research involving humans or animals.
References
- 1.Kane JM. Addressing non-response in schizophrenia. J Clin Psychiatry. 2012;73:e07.PubMedGoogle Scholar
- 2.Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–23.PubMedCrossRefGoogle Scholar
- 3.Beck K, McCutcheon R, Stephenson L, Schilderman M, Patel N, Ramsey R, et al. Prevalence of treatment-resistant psychoses in the community: a naturalistic study. J Psychopharmacol. 2019. https://doi.org/10.1177/0269881119855995.PubMedCrossRefGoogle Scholar
- 4.Diaz-Caneja CM, Pina-Camacho L, Rodriguez-Quiroga A, Fraguas D, Parellada M, Arango C. Predictors of outcome in early onset psychosis: a systematic review. NPJ Schizophrenia. 2015;1. Article # 14005. https://doi.org/10.1038/npjschz.2014.5.
- 5.Mouchlianitis E, McCutcheon R, Howes OD. Brain imaging studies of treatment-resistant schizophrenia: a systematic review. Lancet Psychiatry. 2016;3:451–63.PubMedPubMedCentralCrossRefGoogle Scholar
- 6.Murru A, Carpiniello B. Duration of untreated illness as a key to early intervention in schizophrenia: a review. Neurosci Lett. 2018;669:59–67.PubMedCrossRefGoogle Scholar
- 7.Samaha AN, Seeman P, Stewart J, Rajabi H, Kapur S. “Breakthrough” dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci. 2007;27:2979–86.PubMedPubMedCentralCrossRefGoogle Scholar
- 8.Hassan AN, De Luca V. The effect of lifetime adversities on resistance to antipsychotic treatment in schizophrenia patients. Schizophr Res. 2015;161:496–500.PubMedCrossRefGoogle Scholar
- 9.Lambert TJR, Velakoulis D, Pantelis C. Medical comorbidity in schizophrenia. Med J Aust. 2003;178:S67–70.PubMedGoogle Scholar
- 10.Wimberley T, Støvring H, Sørensen HJ, Horsdal HT, MacCabe JH, Gasse C. Predictors of treatment resistance in patients with schizophrenia: a population-based cohort study. 2016;3:358–66.Google Scholar
- 11.Butler R, Berry K, Varese F, Bucci S. Are family warmth and positive remarks related to outcomes in psychosis? A systematic Review. 2019;49:1250–65.Google Scholar
- 12.Arranz MJ, Munro J. Toward understanding genetic risk for differential antipsychotic response in individuals with schizophrenia. Expert Rev Clin Pharmacol. 2011;4:389–405.PubMedCrossRefGoogle Scholar
- 13.Puangpetch A, Vanwong N, Nuntamool N, Hongkaew Y, Chamnanphon M, Sukasem C. CYP2D6 polymorphisms and their influence on risperidone treatment. Pharmgenomics Pers Med. 2016;9:131–47.PubMedPubMedCentralGoogle Scholar
- 14.Vandenberghe F, Guidi M, Choong E, von Gunten A, Conus P, Csajka C, et al. Genetics-based population pharmacokinetics and pharmacodynamics of risperidone in a psychiatric cohort. Clin Pharmacokinet. 2015;54:1259–72.PubMedCrossRefGoogle Scholar
- 15.Amato D, Vernon AC, Papaleo F. Dopamine, the antipsychotic molecule: a perspectve on mechanisms underlying antipsychotic response variability. Neurosci Biobehav Rev. 2018;85:146–59.PubMedCrossRefGoogle Scholar
- 16.Reynolds GP. The pharmacogenetics of symptom response to antipsychotic drugs. Psychiatry Investig. 2012;9:1–7.PubMedPubMedCentralCrossRefGoogle Scholar
- 17.Zhang JP, Lencz T, Malhotra AK. D2 receptor genetic variation and clinical response to antipsychotic drug treatment: a meta-analysis. Am J Psychiatry. 2010;167:763–72.PubMedPubMedCentralCrossRefGoogle Scholar
- 18.Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464:59–65.PubMedPubMedCentralCrossRefGoogle Scholar
- 19.Zhernakova A, Kurilshikov A, Bonder MJ, Tigchelaar EF, Schirmer M, Vatanen T, et al. LifeLines cohort study. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science. 2016;352:565–9.PubMedPubMedCentralCrossRefGoogle Scholar
- 20.Li J, Jia H, Cai X, Zhong H, Feng Q, Sunagawa S, et al. An integrated catalog of reference genes in the human gut microbiome. Nat Biotechnol. 2014;32:834–41.PubMedCrossRefPubMedCentralGoogle Scholar
- 21.Clarke G, Sandhu KV, Griffin BT, Dinan TG, Cryan JF, Hyland NP. Gut reactions: breaking down xenobiotic–microbiome interactions. Psychol Rev. 2019;71:198–224.Google Scholar
- 22.Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL. Separating host and microbiome contributions to drug pharmacokinetics and toxicity. Science. 2019;363:eaat9931.PubMedPubMedCentralCrossRefGoogle Scholar
- 23.Kurilshikov A, Wijmenga C, Fu J, Zhernakova A. Host genetics and gut microbiome: challenges and perspectives. Trends Immunol. 2017;38:633–47.PubMedCrossRefGoogle Scholar
- 24.Claesson MJ, Cusack S, O'Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, et al. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. PNAS. 2011;108:S4586–91.CrossRefGoogle Scholar
- 25.Jeffery IB, Lynch DB, O’Toole PW. Composition and temporal stability of the gut microbiota in older persons. ISME J. 2016;10:170–82.PubMedCrossRefGoogle Scholar
- 26.David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559–63.PubMedCrossRefGoogle Scholar
- 27.Portune KJ, Benítez-Páez A, Del Pulgar EM, Cerrudo V, Sanz Y. Gut microbiota, diet, and obesity-related disorders: the good, the bad, and the future challenges. Mol Nutr Food Res. 2017;61:1–17.CrossRefGoogle Scholar
- 28.Sandhu KV, Sherwin E, Schellekens H, Stanton C, Dinan TG, Cryan JF. Feeding the microbiota-gut-brain axis: diet, microbiome, and neuropsychiatry. Transl Res. 2017;179:223–44.PubMedCrossRefGoogle Scholar
- 29.Shanahan F, van Sinderen D, O’Toole PW, Stanton C. Feeding the microbiota: transducer of nutrient signals for the host. Gut. 2017;66:1709–17.PubMedCrossRefGoogle Scholar
- 30.Xu Y, Xie Z, Wang H, Shen Z, Guo Y, Gao Y, et al. Bacterial diversity of intestinal microbiota in patients with substance use disorders revealed by16S rRNA gene deep sequencing. Sci Rep. 2017;7:3628.PubMedPubMedCentralCrossRefGoogle Scholar
- 31.Cussotto S, Clarke G, Dinan TG, Cryan JF. Psychotropics and the microbiome: a chamber of secrets. Psychopharmacology (Berl). 2019;236:1411–32.CrossRefGoogle Scholar
- 32.Flowers SA, Evans SJ, Ward KM, McInnis MG, Ellingrod VL. Interaction between atypical antipsychotics and the gut microbiome in a bipolar disease cohort. Pharmacotherapy. 2017;37:261–7.PubMedCrossRefGoogle Scholar
- 33.Ticinesi A, Milani C, Lauretani F, Nouvenne A, Mancabelli L, Lugli GA, et al. Gut microbiota composition is associated with polypharmacy in elderly hospitalized patients. Sci Rep. 2017;7:11102.PubMedPubMedCentralCrossRefGoogle Scholar
- 34.Skonieczna-Zydecka K, Loniewski I, Misera A, Stachowska E, Maciejewska D, Marlicz W, et al. Second-generation antipsychotics and metabolism alterations: a systematic review of the role of the gut microbiome. Psychopharmacology. 2019;236:1491–512.PubMedCrossRefGoogle Scholar
- 35.Barton W, Penney NC, Cronin O, Garcia-Perez I, Molloy MG, Holmes E, et al. The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level. Gut. 2018;67:625–33.PubMedGoogle Scholar
- 36.Campbell SC, Wisniewski PJ II. Exercise is a novel promoter of intestinal health and microbial diversity. Exerc Sport Sci Rev. 2017;45:41–7.PubMedCrossRefGoogle Scholar
- 37.Dikongué E, Ségurel L. Latitude as a co-driver of human gut microbial diversity? BioEssays. 2017;39:1–6.CrossRefGoogle Scholar
- 38.Johnson CH, Zhao C, Xu Y, Mori T. Timing the day: what makes bacterial clocks tick? Nat Rev Microbiol. 2017;15:232–42.PubMedPubMedCentralCrossRefGoogle Scholar
- 39.Voigt RM, Forsyth CB, Green SJ, Engen PA, Keshavarzian A. Circadian rhythm and the gut microbiome. Int Rev Neurobiol. 2016;131:193–205.PubMedCrossRefPubMedCentralGoogle Scholar
- 40.Moloney RD, Desbonnet L, Clarke G, Dinan TG, Cryan JF. The microbiome: stress, health and disease. Mamm Genome. 2014;25:49–74.PubMedCrossRefGoogle Scholar
- 41.Schwarz E, Maukonen J, Hyytiäinen T, Kieseppä T, Orešič M, Sabunciyan S, et al. Analysis of microbiota in first episode psychosis identifies preliminary associations with symptom severity and treatment response. Schizophr Res. 2018;192:398–403.PubMedCrossRefGoogle Scholar
- 42.Koppel N, Maini Rekdal V, Balskus EP. Chemical transformation of xenobiotics by the human gut microbiota. Science. 2017;356:eaag2770.PubMedCrossRefGoogle Scholar
- 43.Wilson ID, Nicholson JK. Gut microbiome interactions with drug metabolism, efficacy, and toxicity. Transl Res. 2017;179:S204–22.CrossRefGoogle Scholar
- 44.Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018;555:623.PubMedPubMedCentralCrossRefGoogle Scholar
- 45.Walsh J, Griffin BT, Clarke G, Hyland NP. Drug–gut microbiota interactions: implications for neuropharmacology. Br J Pharmacol. 2018;175:4415–29.PubMedCrossRefGoogle Scholar
- 46.Al-Hilal TA, Alam F, Byun Y. Oral drug delivery systems using chemical conjugates or physical complexes. Adv Drug Deliv Rev. 2013;65:845–64.PubMedCrossRefGoogle Scholar
- 47.Zimmerman M, Zimmerman-Kogadeeva M, Wegmann R, Goodman AL. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature. 2019;570:462–7.CrossRefGoogle Scholar
- 48.Kaminsky BM, Bostwick JR, Guthrie SK. Alternate routes of administration of antidepressant and antipsychotic medications. Ann Pharmacother. 2015;49:808–17.PubMedCrossRefGoogle Scholar
- 49.Oliveira P, Fortuna A, Alves G, Amílcar F. Drug-metabolizing enzymes and efflux transporters in nasal epithelium: influence on the bioavailability of intranasally administered drugs. Current Drug Metabol. 2016;17:628–47.CrossRefGoogle Scholar
- 50.Quintana DS, Guastella AJ, Westlye LT, Andreassen OA. The promise and pitfalls of intranasally administering psychopharmacological agents for the treatment of psychiatric disorders. Mol Psychiatry. 2016;21:29–38.PubMedCrossRefGoogle Scholar
- 51.Katare YK, Piazza JE, Bhandari J, Daya RP, Akilan K, Simpson MJ, et al. Intranasal delivery of antipsychotic drugs. Schizophr Res. 2017;184:2–13.PubMedCrossRefGoogle Scholar
- 52.Wong YC, Zuo Z. Brain disposition and catalepsy after intranasal delivery of loxapine: role of metabolism in PK/PD of intranasal CNS drugs. Pharm Res. 2013;30:2368–84.PubMedCrossRefGoogle Scholar
- 53.Taylor DM, Velaga S, Werneke U. Reducing the stigma of long acting injectable antipsychotics: current concepts and future developments. Nord J Psychiatry. 2018;72:S36–9.PubMedCrossRefGoogle Scholar
- 54.Seeman MV. Drawbacks of long-acting intramuscular antipsychotic injections. J Clin Practical Nurs. 2017;1:12–22.Google Scholar
- 55.Ita K. Percutaneous transport of psychotropic agents. J Drug Delivery Sci Technol. 2017:247–59.CrossRefGoogle Scholar
- 56.Zun LS. Evidence-based review of pharmacotherapy for acute agitation. Part 1: onset of efficacy. J Emerg Med. 2018;54:364–74.PubMedCrossRefGoogle Scholar
- 57.Citrome L. Inhaled loxapine for agitation. Curr Psychiatr Ther. 2013;12:31–6.Google Scholar
- 58.Currier G, Walsh P. Safety and efficacy review of inhaled loxapine for treatment of agitation. Clin Schizophr Relat Psychoses. 2013;7:25–32.PubMedCrossRefGoogle Scholar
- 59.Citrome L. Asenapine for schizophrenia and bipolar disorder: a review of the efficacy and safety profile for this newly approved sublingually absorbed second-generation antipsychotic. Int J Clin Practice. 2009;63:1762–84.CrossRefGoogle Scholar
- 60.Kinon BJ, Hill AL, Liu H, Kollack-Walker S. Olanzapine orally disintegrating tablets in the treatment of acutely ill non-compliant patients with schizophrenia. Int J Neuropsychopharmacol. 2003;6:97–102.PubMedCrossRefPubMedCentralGoogle Scholar
- 61.Pratts M, Citrome L, Grant W, Leso L, Opler LA. A single-dose, randomized, double-blind, placebo-controlled trial of sublingual asenapine for acute agitation. Acta Psychiatr Scand. 2014;130:61–8.PubMedCrossRefPubMedCentralGoogle Scholar
- 62.Thulluru A, Mahammed N, Madhavi C, Nandini K, Sirisha S, Spandana D. Sublingual tablets – an updated review. Asian J Pharm Res. 2019;9:97–103.CrossRefGoogle Scholar
- 63.Abdelbary A, Bendas ER, Ramadan AA, Mostafa DA. Pharmaceutical and pharmacokinetic evaluation of a novel fast dissolving film formulation of flupentixol dihydrochloride. AAPS PharmSciTech. 2014;15:1603–10.PubMedPubMedCentralCrossRefGoogle Scholar
- 64.Nagar M, Nagar M, Chopra V. Formulation and evaluation of mouth dissolving film of antipsychotic drug aripiprazole. Pharm Lett. 2012;4:1221–7.Google Scholar
- 65.Bartlett JA, van der Voort Maarschalk K. Understanding the oral mucosal absorption and resulting clinical pharmacokinetics of asenapine. AAPS PharmSciTech. 2012;13:1110–5.PubMedPubMedCentralCrossRefGoogle Scholar
- 66.Solanki A, Gupta N, Jain S. Formulation, development and evaluation of fast dissolving oral film of antipsychotic drug. J Drug Delivery Therapeut. 2019;9:181–5.Google Scholar
- 67.Fakhar-Ud-Din KGM. Development and characterisation of levosulpiride-loaded suppositories with improved bioavailability in vivo. Pharm Dev Technol. 2019;24:63–9.PubMedCrossRefGoogle Scholar
- 68.Matsumoto K, Kimura S, Takahashi K, Yokoyama Y, Miyazawa M, Kushibiki S, et al. Pharmaceutical studies on and clinical application of olanzapine suppositories prepared as a hospital preparation. J Pharm Health Care Sci. 2016;2:20.PubMedPubMedCentralCrossRefGoogle Scholar
- 69.Isaac M, Holvey C. Transdermal patches: the emerging mode of drug delivery system in psychiatry. Ther Adv Psychopharmacol. 2012;2:255–63.PubMedPubMedCentralCrossRefGoogle Scholar
- 70.Kayhart B, Lapid MI, Nelson S, Cunningham JL, Thompson VH, Leung JG. A lack of systemic absorption following the repeated application of topical quetiapine in healthy adults. Am J Hosp Palliat Care. 2018;35:1076–80.PubMedCrossRefGoogle Scholar
- 71.Manikkath J, Shenoy GG, Pandey S, Mutalik S. Response surface methodology for optimization of ultrasound-assisted transdermal delivery and skin retention of asenapine maleate. J Pharm Innov. 2019. https://doi.org/10.1007/s12247-019-09386-4.CrossRefGoogle Scholar
- 72.Lopez A, Rey J. Role of paliperidone palmitate 3-monthly in the management of schizophrenia: insights from clinical practice. Neuropsychiatr Dis Treat. 2019;15:449–56.PubMedPubMedCentralCrossRefGoogle Scholar
- 73.Haddad PM, Kishimoto T, Correll CU, Kane JM. Ambiguous findings concerning potential advantages of depot antipsychotics: in search of clinical relevance. Curr Opin Psychiatry. 2015;28:216–21.PubMedCrossRefGoogle Scholar
- 74.Ostuzzi G, Bighelli I, So R, Furukawa TA, Barbui C. Does formulation matter? A systematic review and meta-analysis of oral versus long-acting antipsychotic studies. Schizophr Res. 2017;183:10–21.PubMedCrossRefGoogle Scholar
- 75.Correll CU, Citrome L, Haddad PM, Lauriello J, Olfson M, Calloway SM, et al. The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry. 2016;77:S1–S24.CrossRefGoogle Scholar
- 76.Kishimoto T, Robenzadeh A, Leucht C, Leucht S, Watanabe K, Mimura M, et al. Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials. Schizophr Bull. 2014;40:192–213.PubMedCrossRefGoogle Scholar
- 77.Miyamoto S, Fleischhacker W. The use of long-acting injectable antipsychotics in schizophrenia. Curr Treat Options Psych. 2017;4:117–26.CrossRefGoogle Scholar
- 78.Tiihonen J, Mittendorfer-Rutz E, Majak M, Mehtälä J, Hoti F, Jedenius E, et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29 823 patients with schizophrenia. JAMA Psychiat. 2017;74:686–93.CrossRefGoogle Scholar
- 79.Lin CH, Chen FC, Chan HY, Hsu CC. Time to rehospitalization in patients with schizophrenia receiving long-acting injectable antipsychotics or oral antipsychotics. Int J Neuropsychopharmacol. 2019:7. https://doi.org/10.1093/ijnp/pyz035.PubMedPubMedCentralCrossRefGoogle Scholar
- 80.Olagunju AT, Clark SR, Baune BT. Long-acting atypical antipsychotics in schizophrenia: a systematic review and meta-analyses of effects on functional outcome. Austr NZ J Psychiatry. 2019;53:509–27.CrossRefGoogle Scholar
- 81.Park S-C, Young Choi MY, Choi J, Park E, Tchoe HJ, Suh JK, et al. Comparative efficacy and safety of long-acting injectable and oral second-generation antipsychotics for the treatment of schizophrenia: a systematic review and meta-analysis. Clin Psychopharmacol Neurosci. 2018;16:361–75.PubMedPubMedCentralCrossRefGoogle Scholar
- 82.Misawa F, Kishimoto T, Hagi K, Kane JM, Correll CU. Safety and tolerability of long-acting injectable versus oral antipsychotics: a meta-analysis of randomized controlled studies comparing the same oral and depot AP. Schizophr Res. 2016;176:220–30.PubMedCrossRefGoogle Scholar
- 83.Pietrini F, Albert U, Ballerini A, Calò P, Maina G, Pinna F, et al. The modern perspective for long-acting injectables antipsychotics in the patient-centered care of schizophrenia. Neuropsychiatr Dis Treat. 2019;15:1045–60.PubMedPubMedCentralCrossRefGoogle Scholar
- 84.Tveito M, Smith RL, Molden E, Haslemo T, Refsum H, Hartberg C, et al. Age impacts olanzapine exposure differently during use of oral versus long-acting injectable formulations: an observational study including 8,288 patients. J Clin Psychopharmacol. 2018;38:570–6.PubMedGoogle Scholar