Treatment-resistant schizophrenia — mechanisms, awareness, and economic burden

One-third of individuals with schizophrenia develop treatment-resistant schizophrenia (TRS); and 70–84% of those with first-episode psychosis and TRS are treatment-resistant from the onset of their illness. Potential neurobiological mechanisms for TRS, a survey demonstrating a lack of awareness about TRS by psychiatrists and primary care physicians (PCPs), and a study evaluating the financial burden of TRS were presented in posters at Psych Congress.

45% of psychiatrists (n=467) and 70% of PCPs (n=188) were unable to correctly identify the criteria for identifying TRS1

Treatment-resistant schizophrenia (TRS), which is defined as persistent positive symptoms despite adherence to at least two trials of antipsychotic medications provided at an adequate dose and for an adequate duration (of at least 6 weeks each):2,3

  • occurs in approximately 30% of patients with schizophrenia4
  • may be present from the onset of symptoms of schizophrenia5
  • may develop over time, especially in those patients who relapse as a result of difficulties adhering to the antipsychotic treatment regimen or a discontinuation of their medication6

98% of psychiatrists (n=467) and 97% of PCPs (n=188) were not aware that 70-85% of the patients with TRS fulfill the criteria from disease onset1,5,7

Several neurobiological pathways may explain TRS

Hypothetical mechanisms for TRS were analyzed in a poster presented by John Kane, Professor of Psychiatry, Neurology, and Neuroscience, Hofstra/Northwell, NY. They include the following:

  • Dopamine supersensitivity, which is thought to result from increased dopamine D2 receptor density and increased dopamine activity.8 The poster also highlighted clinical data that do not support the hypothesis that dopamine supersensitivity might result from rapid antipsychotic withdrawal or dose reduction,9 or tolerance to continuous antipsychotic administration.10
  • A hypodopaminergic mechanism, which hypothesizes that patients with TRS have a lower capacity to synthesize dopamine, leading to decreased dopamine activity. In this scenario, dopamine synthesis capacity could be a useful biomarker to predict treatment responsiveness.11
  • A role for glutamate, potentially through N-methyl-D-aspartate receptor dysfunction.12 This has been suggested by neuroimaging studies, but more work is needed to provide further clarification.13

53% of psychiatrists (n=467) and 74% of PCPs (n=188) were not aware of studies showing higher brain glutamate levels in patients with TRS compared with those without TRS1

The poster concluded that future research should focus on identifying the mechanisms, potential subgroups, and biomarkers of TRS to enable optimized personalized treatment and the development of new, targeted therapies.

Early identification of TRS might improve outcomes and lower healthcare costs

Many of the current treatments available for schizophrenia provide a full blockade of dopamine at the dopamine D2 receptor. A key point highlighted by Professor Kane’s poster was that early identification of TRS will avoid unnecessary and prolonged exposure to D2 receptor blockade.

In addition, early identification of TRS and more effective treatment for patients with TRS may lead to lower healthcare costs, concluded a poster presented by Bruce Kinon, US Therapeutic Head, Psychosis, Lundbeck LLC, Deerfield, IL.

Direct medical costs for patients with TRS are 59% higher than for those without TRS

The poster described a retrospective cohort propensity matching study of patients with schizophrenia in the US (n=767 with TRS, n=767 without TRS) using the Truven Health Analytics datasets. The direct medical costs for patients with TRS were 59% higher ($15,588/year; p<0.0001) than for those without TRS, and the costs were higher even before these patients were diagnosed with schizophrenia.

Where do we go from here?

More education is needed to enable early identification of TRS and more effective therapy, and to potentially lower the economic burden. Further, more research is needed to elucidate the neurobiological mechanisms and biomarkers for TRS to enable appropriate treatment and the development of new targeted therapies.

References
  1. Lubarda J, et al. Poster 314, presented at Psych Congress, Orlando, US, October 26, 2018.
  2. Howes O, et al. Am J Psych 2017;174(3):216–29.
  3. Lehman A, et al. Am J Psych 2010;161(2 Suppl):1–156.
  4. Meltzer H. Curr Med Res Opin 1997;14(1):1–20.
  5. Lally J, et al. Psychol Med 2016;46(15):3231–40.
  6. Emsley R, et al. BMC Psych 2013;13:50–8.
  7. Demjaha A, et al. Psychol Med 2017;47(11):1981–9.
  8. Oda Y, et al. Int J Mol Sci 2015;16:30144–63.
  9. Leucht S, et al. Lancet 2012;379(9831):2063–71.
  10. Howes O, Kapur S. Br J Psych 2014;205(1):1–3.
  11. Kim E, et al. Neuropsychopharmacol 2017;42:941–50.
  12. Howes O, et al. J Psychopharmacol 2015; 29(2):97–115.
  13. Nakajima S, et al. Schizophr Res 2015; 164(0):164–75.
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