Reducing Heterogeneity in Non–Treatment-Resistant and Treatment-Resistant Schizophrenia

Psychiatric TimesVol 39, Issue 1

Mary Long/AdobeStock

Mary Long/AdobeStock


Schizophrenia affects about 1% of the population and causes a tremendous burden on patients and families.1 Patients with schizophrenia present with diverse symptoms (ie, positive, negative, and cognitive), and the course and response to treatment varies widely. The basis of this heterogeneity is unknown but presumably results from a complex interaction of multiple genetic and environmental factors. To establish more homogeneous subpopulations, efforts have been made to use subtype based on clinical presentation or response to treatment, or by biomarkers derived from imaging, omics, or postmortem pathology (Figure). Due to the heterogeneity, subtyping approaches hold promise and should be considered when designing studies.

Figure. Addressing Heterogeneity in Schizophrenia

Figure. Addressing Heterogeneity in Schizophrenia

Definition of Response Subtypes

About 70% of patients respond at least reasonably well to treatment with standard antipsychotics (plus psychosocial interventions), and hence are considered to have non–treatment-resistant schizophrenia (non-TRS). However, up to 30% of patients do not respond to standard antipsychotic treatment and are therefore considered to have TRS, generally defined as a failed response to 2 full trials of conventional antipsychotics (see Treatment Response and Resistance in Psychosis [TRRIP] guidelines2 for more details). The only US Food and Drug Administration (FDA)-approved medicine for TRS is clozapine3; however, about 30% of TRS patients do not respond to clozapine and are considered to have ultra-TRS (UTRS).4 Currently, these definitions refer mainly to improvement in positive symptoms, reflecting the greater efficacy of available antipsychotics for treating positive symptoms compared to negative and cognitive symptoms. TRS (grouped together with UTRS in most studies) may derive from a more severe version of the same underlying pathophysiology as non-TRS. However, it is possible that TRS may be a distinct subtype of the illness with a different pathophysiology than non-TRS.5,6

Clinical Features

Analysis of clinical phenotype suggests that patients with TRS have an earlier age of onset than patients with non-TRS.7,8 Unlike non-TRS, the ratio of men to women with TRS is equal,7,8 although the extent to which this reflects a biological difference between non-TRS and TRS rather than the interaction of gender roles and age of disease onset remains to be determined. At the time of first diagnosis, patients who eventually develop TRS are more likely than future non-TRS patients to be inpatients, to require more medicine, and to spend more than 30 days in a psychiatric hospital.8 Cognitive functioning, and particularly verbal memory, is more impaired in patients with TRS than with non-TRS.9,10 TRS may also be more familial than non-TRS; first- and second-degree relatives of patients with TRS have an increased risk of developing schizophrenia compared with relatives of patients with non-TRS.11 The extent to which positive, negative, and cognitive symptoms associate with this different pattern of inheritance remains unclear.

Neurobiological Features

To understand the neurobiology of TRS, investigations have taken 2 general approaches. One is to determine the genetics of clozapine response, and the second is to identify genes and biological pathways most relevant to TRS. Initial pharmacogenetic studies of clozapine took a candidate gene approach and tended to focus on the major neurotransmitter systems implicated in the pharmacodynamics of clozapine and other antipsychotics. Response to clozapine was preliminarily associated with genetic markers linked to dopamine and serotonin receptors.12 However, these findings have not been consistently replicated, possibly due to variation in the criteria used to select subjects, inconsistencies in the definition of TRS, and ethnic differences among the populations under investigation, all in the context of small effect sizes.

Unbiased, noncandidate approaches to the neurobiology of schizophrenia provide an opportunity to identify novel pathogenic pathways. Because developing new antipsychotics based on fine-tuning the neurotransmitter profile of previously developed antipsychotics has not led to marked breakthroughs in clinical efficacy, this new approach is of critical importance. This is reflected in more recent pharmacogenomic approaches, using genome-wide association studies (GWAS) instead of data limited to markers associated with prespecified candidate genes. Findings suggest that patients with TRS, compared with patients with non-TRS, have higher polygenetic risk scores (an index of overall genetic risk of developing a disease),13 a higher frequency of disruptive mutations,14 and higher rates of chromosomal duplications and deletions.15 This approach has found an association between specific genomic loci and TRS including inter-alpha-trypsin inhibitor heavy chain 3/4 (ITIH3/4); calcium voltage-gated channel subunit alpha1 C (CACNA1C); and serologically defined colon cancer antigen 8 (SDCCAG8).16 Many of these studies have not yet been replicated, again likely a consequence small sample size, inconsistent inclusion criteria, and varying definitions of TRS.

As an alternative approach to pharmacogenomic studies of clozapine using GWAS, our laboratory examined gene expression in autopsied human brains from individuals with TRS (on clozapine at time of death) and non-TRS (on conventional antipsychotics at time of death).17 A number of specific genes were differently expressed, including the genes glutamate-cysteine ligase modifier subunit (GCLM), zinc finger protein 652 (ZNF652), and glycophorin C (GYPC). Pathways associated with TRS included clathrin-mediated endocytosis, stress-activated protein kinase/c-Jun-terminal kinase signaling, 3-phosphoinositide synthesis, and paxillin signaling, each providing potential leads in the search for new therapeutic targets.

Imaging Features

Imaging studies show relative frontal and temporal grey matter volume deficits in TRS,18-21 possible white matter tract disruption,22 and disruptions of functional connectivity, particularly in frontotemporal networks, with direct and indirect involvement of the thalamus.23-25 Perfusion measured by single-photon emission computerized tomography (SPECT) appears to be reduced in multiple brain regions in TRS and is partially corrected by clozapine; clinical improvement correlates with improved perfusion in the thalamus.18,26,27

Further, treatment-resistant hallucinations correlated with increased cerebral blood flow measured by arterial spin label MRI in the temporal-parietal cortex.28 (18)F-FDOPA positron emission tomography studies detected higher striatal DA synthesis capacity in patients with non-TRS than in those with TRS and healthy control (HC) individuals, but no difference in DA synthesis capacity between TRS and HC.29 Elevated glutamate concentration in the anterior cingulate cortex was identified in the patients with TRS compared with non-TRS and HC,30 a finding that was subsequently replicated.31 The utility of these measures for determining which patients should receive clozapine remains to be determined.

Differentiating UTRS and TRS

To date, few studies separate TRS from UTRS, which is potentially a serious impediment to defining disease neurobiology, as these 2 forms of TRS may be pathologically and pathophysiologically distinct. The findings of the few studies that have directly compared TRS with UTRS, or UTRS with HC, are listed in Table 1. It is likely that these are fundamental to the illness and not a factor of disease progression because the majority of patients who develop TRS do so from the onset of symptoms,39 and the majority of patients with UTRS show limited improvement from the beginning of treatment with clozapine. So far, these findings remain preliminary and await replication. Using biochemical techniques, our laboratory has recently demonstrated increased protein insolubility, and potentially protein aggregation, in a subset of autopsied brains of individuals with schizophrenia.40 It is possible that this phenomenon, or related pathophysiological processes, may distinguish among non-TRS, TRS, and UTRS.

Table 1. Findings in Comparing UTRS and TRS

Table 1. Findings in Comparing UTRS and TRS

We performed a cross-sectional study to determine if there are differences in symptoms, cognitive functioning, or real-world functional capacity that distinguish UTRS from TRS.41 Patients who responded to clozapine performed significantly better on a validated assessment tool of function, developed by Philip Harvey, PhD, and colleagues, consisting of computer simulations of banking at an ATM, purchasing a ticket, and obtaining a prescription refill, and on overall cognition as assessed by the Brief Assessment of Cognition in Schizophrenia. The cross-sectional design did not allow us to determine if patients who eventually responded to clozapine were as impaired as eventual nonresponders but improved on clozapine, or if they were less functionally impaired at the outset of clozapine treatment. This last question will be addressed in a longitudinal study of individuals beginning treatment with clozapine.

This study highlights the potential confounding of grouping UTRS with TRS in studies of disease phenotype, pathogenesis, and treatment response. It is possible, for instance, that some—or all—of the genetic and neurobiological differences reported between non-TRS and TRS is in fact driven by UTRS. Furthermore, our work on protein homeostasis abnormalities and protein insolubility suggests that pathological processes can be identified in a subtype of patients with clinical correlations subsequently determined and eventually, specific treatments designed (Figure).40 Taken together, the available data suggests that subtyping based on treatment response is a plausible approach to understanding the heterogenous pathophysiological mechanisms related to schizophrenia. This is somewhat analogous to the past recognition that subtypes of psychotic syndromes that strongly resemble idiopathic schizophrenia could be explained by infections (eg, syphilis), nutritional deficiency (eg, niacin), or substances (eg, chronic amphetamine abuse).

Historically, this type of reasoning has led to advances and specific treatments, as specific causes of psychotic syndromes—including syphilis, niacin deficiency, and chronic amphetamine abuse—were identified. TRS is one way to subtype patients, but other approaches using variability in physiological parameters, such as the Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP), or protein homeostats abnormalities, as we have shown, are other ways that this problem could be addressed.

Recommendations for Treatment

Although clozapine has been clearly established as the treatment of choice for individuals with schizophrenia who do not respond to 2 trials of a standard antipsychotic, or who have other specific indications, it is vastly underused. Based on the rate of treatment failure of conventional antipsychotics, the indication of clozapine for reducing the risk of suicide, the relatively low risk of neurological disorders with clozapine, and the potential value of the drug in ameliorating schizophrenia symptoms such as polydipsia, between 30% and 40% of US patients with schizophrenia should be receiving clozapine, whereas the actual rate is approximately 4%.42 Even for those receiving clozapine, the average delay from the point in time when clozapine would have been considered indicated is 48 months.43 Patients who might respond to clozapine are instead treated with multiple antipsychotics or high-dose antipsychotics. The underuse is likely a consequence of strict guidelines for prescribing clozapine that burden both clinicians and patients, and fear of adverse effects on the part of patient, family, and clinicians.

Unfortunately, our current understanding of the neurobiology of TRS and UTRS is insufficient to predict who will respond to clozapine and who will develop adverse effects. Delay in initiating clozapine treatment is associated with poorer outcomes, and potentially with adverse effects from exposure to excess doses of ineffective medicines. Clozapine adverse effects can be monitored and mitigated, and data suggest that patients are less bothered by mandatory blood draws than prescribers tend to think and prefer clozapine to other medications.44-46

Table 2. Resources for Prescribing Clozapine

Table 2. Resources for Prescribing Clozapine

There are a number of resources to help prescribers wishing to use clozapine (Table 2). Expanding these programs and seeking advice from established clozapine clinics, such as the one we have at Johns Hopkins, and others across the country could provide instruction and consultation. Improving the ease of use of the agent and relaxing some of the Clozapine Risk Evaluation and Mitigation Strategy registry restrictions could help address the underutilization of clozapine.

Concluding Thoughts

These data suggest that subtyping patients based on treatment response (TRS or UTRS versus non-TRS) could identify more homogeneous populations of patients with distinct differences in pathophysiology. Understanding the mechanisms leading to TRS and UTRS, and the difference between the 2, may provide the opportunity to develop biomarkers of disease state and treatment response, and to develop novel treatments. Further, the available data suggests that genetic, clinical, and pathogenic studies will benefit by considering treatment response as a variable. Finally, patients with schizophrenia who do not respond well to treatment suffer considerably and place great stress on their families and the health care system. Investment in research and services for this group of patients is imperative.

Dr Nucifora is an associate professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine in Baltimore, Maryland.


1. Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med. 2005;2(5):e141.

2. Howes OD, McCutcheon R, Agid O, et al. Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am J Psychiatry. 2017;174(3):216-229.

3. Nucifora FC Jr, Mihaljevic M, Lee BJ, Sawa A. Clozapine as a model for antipsychotic development. Neurotherapeutics. 2017;14(3):750-761.

4. Siskind D, Siskind V, Kisely S. Clozapine response rates among people with treatment-resistant schizophrenia: data from a systematic review and meta-analysis. Can J Psychiatry. 2017;62(11):772-777.

5. Gillespie AL, Samanaite R, Mill J, Egerton A, MacCabe JH. Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review. BMC Psychiatry. 2017;17(1):12.

6. Nucifora FC Jr, Woznica E, Lee BJ, Cascella N, Sawa A. Treatment resistant schizophrenia: clinical, biological, and therapeutic perspectives. Neurobiol Dis. 2019;131:104257.

7. Meltzer HY, Rabinowitz J, Lee MA, Cola PA, Findling RL, Thompson PA. Age at onset and gender of schizophrenic patients in relation to neuroleptic resistance. Am J Psychiatry. 1997;154(4):475-482.

8. Wimberley T, Støvring H, Sørensen HJ, et al. Predictors of treatment resistance in patients with schizophrenia: a population-based cohort study. Lancet Psychiatry. 2016;3(4):358-366. Published correction appears in Lancet Psychiatry. 2016;3(4):320.

9. Joober R, Rouleau GA, Lal S, et al. Neuropsychological impairments in neuroleptic-responder vs -nonresponder schizophrenic patients and healthy volunteers. Schizophr Res. 2002;53(3):229-238.

10. de Bartolomeis A, Balletta R, Giordano S, et al. Differential cognitive performances between schizophrenic responders and non-responders to antipsychotics: correlation with course of the illness, psychopathology, attitude to the treatment and antipsychotics doses. Psychiatry Res. 2013;210(2):387-395.

11. Joober R, Rouleau GA, Lal S, et al. Increased prevalence of schizophrenia spectrum disorders in relatives of neuroleptic-nonresponsive schizophrenic patients. Schizophr Res. 2005;77(1):35-41.

12. Sriretnakumar V, Huang E, Müller DJ. Pharmacogenetics of clozapine treatment response and side-effects in schizophrenia: an update. Expert Opin Drug Metab Toxicol. 2015;11(11):1709-1731.

13. Frank J, Lang M, Witt SH, et al. Identification of increased genetic risk scores for schizophrenia in treatment-resistant patients. Mol Psychiatry. 2015;20(7):913.

14. Ruderfer DM, Charney AW, Readhead B, Kidd BA. Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach. Lancet Psychiatry. 2016;3(4):350-357.

15. Martin AK, Mowry B. Increased rare duplication burden genomewide in patients with treatment-resistant schizophrenia. Psychol Med. 2016;46(3):469-476.

16. Hamshere ML, Walters JT, Smith R, et al. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. Mol Psychiatry. 2013;18(6):708-712. Published correction appears in Mol Psychiatry. 2013;18(6):738.

17. Lee BJ, Marchionni L, Andrews CE, et al. Analysis of differential gene expression mediated by clozapine in human postmortem brains. Schizophr Res. 2017;185:58-66.

18. Molina V, Tamayo P, Montes C, et al. Clozapine may partially compensate for task-related brain perfusion abnormalities in risperidone-resistant schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(4):948-954.

19. Anderson VM, Goldstein ME, Kydd RR, Russell BR. Extensive gray matter volume reduction in treatment-resistant schizophrenia. Int J Neuropsychopharmacol. 2015;18(7):pyv016.

20. Quarantelli M, Palladino O, Prinster A, Schiavone V. Patients with poor response to antipsychotics have a more severe pattern of frontal atrophy: a voxel-based morphometry study of treatment resistance in schizophrenia. Biomed Res Int. 2014;2014:325052.

21. Maller JJ, Daskalakis ZJ, Thomson RH, Daigle M, Barr MS, Fitzgerald PB. Hippocampal volumetrics in treatment-resistant depression and schizophrenia: the devil’s in de-tail. Hippocampus. 2012;22(1):9-16.

22. Holleran L, Ahmed M, Anderson-Schmidt H, et al. Altered interhemispheric and temporal lobe white matter microstructural organization in severe chronic schizophrenia. Neuropsychopharmacology. 2014;39(4):944-954.

23. Wolf ND, Sambataro F, Vasic N, et al. Dysconnectivity of multiple resting-state networks in patients with schizophrenia who have persistent auditory verbal hallucinations. J Psychiatry Neurosci. 2011;36(6):366-374.

24. Vercammen A, Knegtering H, den Boer JA, Liemburg EJ, Aleman A. Auditory hallucinations in schizophrenia are associated with reduced functional connectivity of the temporo-parietal area. Biol Psychiatry. 2010;67(10):912-918.

25. Alonso-Solís A, Vives-Gilabert Y, Grasa E, et al. Resting-state functional connectivity alterations in the default network of schizophrenia patients with persistent auditory verbal hallucinations. Schizophr Res. 2015;161(2-3):261-268.

26. Molina Rodríguez V, Montz Andrée R, Pérez Castejón MJ, et al. Cerebral perfusion correlates of negative symptomatology and parkinsonism in a sample of treatment-refractory schizophrenics: an exploratory 99mTc-HMPAO SPET study. Schizophr Res. 1997;25(1):11-20.

27. Molina V, Gispert JD, Reig S, et al. Cerebral metabolic changes induced by clozapine in schizophrenia and related to clinical improvement. Psychopharmacology (Berl). 2005;178(1):17-26.

28. Wolf ND, Grön G, Sambataro F, et al. Magnetic resonance perfusion imaging of auditory verbal hallucinations in patients with schizophrenia. Schizophr Res. 2012;134(2-3):285-287.

29. Demjaha A, Murray RM, McGuire PK, Kapur S, Howes OD. Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. Am J Psychiatry. 2012;169(11):1203-1210.

30. Demjaha A, Egerton A, Murray RM, et al. Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function. Biol Psychiatry. 2014;75(5):e11-e13.

31. Mouchlianitis E, Bloomfield MAP, Law V, et al. Treatment-resistant schizophrenia patients show elevated anterior cingulate cortex glutamate compared to treatment-responsive. Schizophr Bull. 2016;42(3):744-752.

32. Griffiths K, Millgate E, Egerton A, MacCabe JH. Demographic and clinical variables associated with response to clozapine in schizophrenia: a systematic review and meta-analysis. Psychol Med. 2021;51(3):376-386.

33. Molina Rodríguez V, Montz Andreé R, Pérez Castejón MJ, et al. SPECT study of regional cerebral perfusion in neuroleptic-resistant schizophrenic patients who responded or did not respond to clozapineAm J Psychiatry. 1996;153(10):1343-1346.

34. Goldstein ME, Anderson VM, Pillai A, et al. Glutamatergic neurometabolites in clozapine-responsive and -resistant schizophrenia. Int J Neuropsychopharmacol. 2015;18(6):pyu117.

35. Iwata Y, Nakajima S, Plitman E, et al. Glutamatergic neurometabolite levels in patients with ultra-treatment-resistant schizophrenia: a cross-sectional 3T proton magnetic resonance spectroscopy study. Biol Psychiatry. 2019;85(7):596-605.

36. McNabb CB, Tait RJ, McIlwain ME, et al. Functional network dysconnectivity as a biomarker of treatment resistance in schizophrenia. Schizophr Res. 2018;195:160-167.

37. Fond G, Godin O, Boyer L, et al; FACE-SZ (FondaMental Academic Centers of Expertise for Schizophrenia) Group. Chronic low-grade peripheral inflammation is associated with ultra resistant schizophrenia. Results from the FACE-SZ cohortEur Arch Psychiatry Clin Neurosci. 2019;269(8):985-992.

38. Kim J, Plitman E, Iwata Y, et al. Neuroanatomical profiles of treatment-resistance in patients with schizophrenia spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2020;99:109839.

39. Demjaha A, Lappin JM, Stahl D, et al. Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors. Psychol Med. 2017;47:1981-1989.

40. Nucifora LG, MacDonald ML, Lee BJ, et al. Increased protein insolubility in brains from a subset of patients with schizophrenia. Am J Psychiatry. 2019;176(9):730-743.

41. Nucifora FC Jr, Baker KK, Stricklin A, et al. Better functional capacity and cognitive performance in clozapine responders compared to non-responders: a cross-sectional study. Schizophr Res. 2021;229:134-136.

42. Meltzer HY. Clozapine: balancing safety with superior antipsychotic efficacy. Clin Schizophr Relat Psychoses. 2012;6(3):134-144.

43. Howes OD, Vergunst F, Gee S, McGuire P, Kapur S, Taylor D. Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. Br J Psychiatry. 2012;201(6):481-485.

44. Nielsen J, Dahm M, Lublin H, Taylor D. Psychiatrists’ attitude towards and knowledge of clozapine treatment. J Psychopharmacol. 2010;24(7):965-971.

45. Hodge K, Jespersen S. Side-effects and treatment with clozapine: a comparison between the views of consumers and their clinicians. Int J Ment Health Nurs. 2008;17(1):2-8.

46. Taylor DM, Shapland L, Laverick G, Bond J, Munro J. Clozapine – a survey of patient perceptions. Psychiatr Bull. 2000;24(12):450-452. ❒

Related Videos
nicotine use
brain schizophrenia
exciting, brain
© 2024 MJH Life Sciences

All rights reserved.