Targeting Neuroinflammation in Schizophrenia and Globalisation in Clinical Trials

             

 

ABSTRACT

 

Current therapeutic effects of schizophrenia therapy are severely limited, focusing solely on targeting positive symptoms.⁽¹⁾ Thus, the introduction of novel therapies in clinical practice could help improve patient’s overall symptoms. At present, inflammation is seen as a potential target in schizophrenia because certain anti-inflammatory novel drugs demonstrate the potential of targeting all three symptomatic domains. However, these clinical trials are not without limitations. One important example is the lack of inflammatory markers screening in studies.⁽²⁾ Moreover, the majority of clinical trials at present are not internationalised.⁽³⁾ Thus, there is a need for pharmaceutical companies to go universal and represent the world’s population as a whole in research. This could lead to an array of economical, developmental and scientific advantages.

INTRODUCTION

 

Schizophrenia is a chronic mental health condition caused by neuropathological abnormalities, resulting in disordered neurotransmission. To this day its precise aetiology remains unclear, however researchers have hypothesised plausible causes. In broad terms this includes neurodevelopment, neurodegeneration and chemical alterations. Regardless, the symptomatic profile of a schizophrenia patient includes cognitive, positive and negative symptoms (Table 1). The portrayal of the condition can differ between patient’s, but this usually consists of altered behaviours and emotions resulting in social isolation.⁽⁴⁾

	Symptomatic domain
	Cognitive	Positive	Negative
Symptoms experienced	Working, verbal and visual memory	Hallucinations	Alogia
	Attention	Delusions	Anhedonia
	Processing speed	Paranoia	Avolition
	Verbal and visual learning
	Reasoning and problem solving
	Problem solving
	Social cognition

Current pharmaceutical therapies are based on the dopaminergic theory, which consists of dysregulated dopamine receptors. The latest brain molecular imaging shows an increase of dopamine levels in the striatum, with the opposite seen in other pathways. Antipsychotics (dopamine antagonists) administered in clinical practice target this dopamine imbalance.⁽⁶⁾ They have been the mainstay treatment since the 1950’s, however they have shown superior efficacy against positive symptoms only. Thus, negative and cognitive effects are not being adequately improved in schizophrenia patients.⁽¹⁾⁽⁷⁾ Focusing on this unmet clinical need is the next step in improving schizophrenic patient’s outcomes in practice.

Recently, researchers have increasingly been supporting the involvement of neuroinflammation in schizophrenia neuropathology. They have looked at various potential causes of inflammation from subclinical inflammation to upregulated immune systems, however the precise origin remains vague. Nevertheless, there lies a potential therapeutic benefit in targeting inflammation in schizophrenia. Thus, there is a need to investigate current novel drugs development to identify potential candidates. Possible anti-inflammatory drugs include cyclooxygenase inhibitors (aspirin and celecoxib), a 2^nd generation tetracycline (minocycline) and humanised monoclonal antibodies (tocilizumab and natalizumab). Furthermore, it is also important to review previous failed clinical trials, to identify why positive results were not achieved.⁽²⁾

Identifying theoretical novel drug therapies is not the end of the line. These drugs need to be implemented into practice. Clinical trials are used to demonstrate the efficacy and safety of experimental drugs. However, they mostly represent patient populations from developed countries. Schizophrenia is a global condition affecting individuals in developing countries too, thus conducted studies need to mirror this.⁽³⁾ The availability of clinical trials in poorer countries, is a step towards globalising them.

AIMS

 

Schizophrenia is ranked as one of the top 25 causes of disability, affecting more than 21 million individuals worldwide.⁽⁸⁾⁽⁹⁾ The global introduction of novel drugs into schizophrenia treatment guidelines is imperative in reducing the overall burden of the condition in societies. This includes reduction of family/carer, individual and economic burden.⁽¹⁰⁾ Furthermore, new therapies could potentially lead to symptomatic remission. This would improve patient’s quality of life through improved social functioning and reduced depression.⁽¹¹⁾

This integrated analysis aims to:

• Identify anti-inflammatory drugs for use in schizophrenia:
  • Review studies conducted to single out drugs with perceived benefits with future practice implications.
  • Evaluate previous studies with null results to identify potential improvement strategies.⁽²⁾
• Explore the importance of globalising clinical trials:
  • Identify the strengths and limitations of conducting clinical trials in various regions of the world.⁽³⁾

INTEGRATED ANALYSIS and DISCUSSION

 

Novel schizophrenia management:

 

Neuroinflammation is currently a highly researched prospective schizophrenia novel therapy target.⁽²⁾ Trials conducted investigated the effects of anti-inflammatory drugs on patients’ symptoms. Results demonstrated either promising or null findings. I have explored these studies below:

1. Aspirin (Fig. 1)

Study phase	Not specified
Study type	Primary: Interventional	Secondary: Randomised
Study design	Double blind, placebo controlled, parallel group trial
Participants number	70

Aspirin, a cyclooxygenase inhibitor, has been trialled by the Utrecht university’s medical centre, as a 1000 milligram daily adjunctive dose to schizophrenia patient’s medication for 3 months (Table 2). They tested the effectiveness of adjuvant aspirin in schizophrenia symptoms. Their primary outcome measured included identifying 3-month changes in symptomatic domains using the positive and negative syndrome scale (PANSS). PANSS rates the severity of positive and negative symptoms in patients (Table 3).⁽¹⁵⁾ In comparison to baseline, patients showed significant improvements in their symptoms (Table 4). Furthermore, aspirin’s effects were trialled in high and low cytokine patient groups. Superior efficacy was identified in the cytokine rich category (p=0.018) (Table 5).^(13)(14) 

 

 

PANSS total score	Severity
58	Mildly ill
75	Moderately ill
95	Markedly ill
116	Severely ill

Primary outcome measured	Baseline results	Week 13
PANSS	73.1	71.1

Primary outcome measured	Low cytokine production group	High cytokine production group
PANSS in week 13	7.47	2.39

 

Discussion:

 

Although Laan et al.’s study showed aspirin’s potential adjuvant use in schizophrenia, the results are reflective of a 3-month study. A larger timeframe trial needs to be conducted to examine aspirin’s potential long-term therapeutic effects in schizophrenia. Furthermore, in comparison to other NSAID’s aspirin has a superior cardiovascular profile. However, further research needs to be conducted on its potential side effects profile (gastric bleeding) in schizophrenia. Furthermore, the study included moderately to severely debilitated schizophrenic patients (a minimum PANS score of 60 or above). This suggests that individuals with mild schizophrenia such as first episodic patients, were excluded. Thus, aspirin’s potential benefit in first line adjuvant and preventative therapy requires further research. Finally, aspirin’s superior efficacy in cytokine rich individuals prompts potential future clinical applications. Schizophrenia patients could potentially be screened for cytokine levels pre-aspirin therapy.⁽¹⁴⁾ 

2. Celecoxib (Fig. 2)

Study phase	Not specified
Study type	Randomised
Study design	Double blind, placebo controlled
Participants number	50

Celecoxib, a cyclooxygenase inhibitor, has been trialled by Müller et al. as a 400 milligram daily adjunctive dose to schizophrenia patient’s medication (amisulpride) for 6 weeks (Table 6). They tested the effect of celecoxib on positive and negative symptoms using the PANSS. A significant symptomatic improvement was achieved in comparison to the placebo group (p=0.02) (Table 7).⁽¹⁷⁾

Primary outcome measured	Baseline results	Week 13
PANSS	94.5	52.4

Discussion:

 

Although, this trial demonstrated celecoxib’s potential therapeutic benefits there were some limitations. Firstly, schizophrenia participants included were on a second generation antipsychotic only (amisulpride). Further trials need to be conducted to identify the adjunctive effects of celecoxib on first generation antipsychotics. Moreover, some patients were administered lorazepam during the washout phase of the study. Thus, the potential co-medication effect of lorazepam needs to be considered with the results not being solely attributed to celecoxib. Finally, this drug was trialled in early stage schizophrenia only. Further studies need to explore celecoxib’s potential therapeutic role in moderate to severe schizophrenia patients.⁽¹⁷⁾

3. Minocycline (Fig. 3)

Study phase	Not specified
Study type	Randomised
Study design	Double blind, placebo controlled
Participants number	207

Minocycline, a tetracycline antibiotic, has been trialled in several studies to investigate its effect in schizophrenia. Solmi et al. conducted a systematic review and meta-analysis of 6 randomised controlled trials, investigating minocycline’s efficacy in schizophrenia. This identified its supremacy in improving positive and negative symptoms (assessed using PANSS) in comparison to placebo.⁽²⁰⁾ However, a particular trial conducted disregarded these findings. 

The BeneMin trial, a large-scale replicative study conducted, investigated the effects of minocycline on negative symptoms (Table 8). They recruited 207 individuals over a 2-year timeframe from 12 NHS trusts. This included patients diagnosed with schizophrenia for 5 years with active positive symptoms. Minocycline’s effect on positive and negative symptoms was measured using the PANSS. This showed no significant improvement when compared to placebo.⁽¹⁹⁾ Why are minocycline clinical trials results inconsistent?

 

Discussion:

 

To date, the Benemin’ study is the largest. They’ve concluded that inter-clinical trial outcomes differences could be due to chance variation, small sample sizes (large dropout rates) and inter-country differences. Furthermore, they have emphasized the importance of screening individuals for inflammatory markers pre-clinical trial (patient’s stratification). As well as, the significance of ongoing training and adherence confirmation throughout trials. Finally, they believe clear neuroinflammatory biomarkers need to be identified before further trials are conducted. As well as, minocycline’s exact mechanism of action in the abating of neuroinflammation.⁽¹⁹⁾

4. Tocilizumab (Fig. 4)

Study phase	Not specified
Study type	Randomised
Study design	Double blind, placebo controlled
Participants number	36

Outcome measured	Baseline results	Week 12
PANSS	70.68	70.81
GAF scale	3.26	3.44
MATRICS scale	30.67	32.47

Tocilizumab, a humanised monoclonal interleukin-6 receptor antibody, has been trialled by Girgis et al. in schizophrenia patients (Table 9). This included patients with a 60 pre-trial PANSS score (stable for the past month on anti-psychotics). The trial consisted of 3 monthly 8mg/kg infusions. They investigated the effect of this drug on symptomatic improvement using the PANSS and global assessment of functioning scale (GAF). GAF rates an individual’s mental functioning from 0-100, with 100 being the healthiest.⁽²³⁾ As well as, the measurement and treatment research to improve cognition in schizophrenia scale (MATRICS). The higher the MATRICS score, the better the cognition. Their trial was supported by the potential role of interleukin-6 elevation in schizophrenia neuropathology. Based on week 12 findings, tocilizumab did not result in beneficial outcomes (Table 10).⁽²²⁾

Discussion:

Although this trial focused on a specific cytokine, this did not result in positive results. However, this was attributed to tocilizumab’s lack of blood-brain-barrier permeability. As well as, its unknown peripheral mechanism of action. Moreover, the 36 sample size was too restrictive, which affected reliability. Furthermore, tocilizumab’s therapeutic effect on first episodic schizophrenia patients was not investigated. Finally, patients were not stratified based on interleukin-6 levels.⁽²²⁾

5. Natalizumab (Fig. 5)

Study phase	Phase 1
Study type	Primary: Interventional	Secondary: Randomised
Study design	Parallel assignment
Participants number	60

Natalizumab, a humanised monoclonal antibody, is currently part of an active phase 1 clinical trial conducted by king’s college of London (Table 11). Natalizumab targets the cell adhesion molecule -4 integrin. They are investigating the effect of this drug on cognitive function, positive and negative symptoms using the PANSS, SANS and MATRICS tools. Furthermore, the effect on translocator protein activation, CRP and IL-6 is being studied. Their trial focuses on the role of microglia cell activation in schizophrenia neuroinflammation.⁽²⁵⁾

 

Discussion:

 

No comments can be made on the results as it is currently an ongoing study. However, based on the inclusion criteria, individuals with other psychotic disorders besides schizophrenia were included. Thus, results achieved in this study cannot be solely linked to schizophrenia pathology. Moreover, this trial is limited to first episodic patients only. Neither, ultra-high risk individuals nor relapsed patients were included which leads to potential future research implications. Finally, patients were not stratified based on inflammatory marker levels thus natalizumab’s effect in various inflammatory profile groups will not be explored.⁽²⁵⁾

Globalising clinical trials

 

As previously mentioned, schizophrenia is a global mental health condition affecting individuals across the globe. Thus, moving forward research institutes need to focus on one initiative- globalising clinical trials. I have summarised the advantages and disadvantages below:

With an ageing, diverse population, there is a growing need for personalised therapies. Clinical trials conducted need to include individuals from various ethnic and genetic backgrounds as this affects the efficacy and safety of certain drugs.^(3)(26) As well as, the risk of schizophrenia development.⁽²⁷⁾ One such example is inter-ethnic CYP2D6 polymorphisms differences. This results in poor, extensive or ultra-rapid metabolisers of antipsychotics. Thus, poor and ultra-rapid metabolisers can experience overdose or no therapeutic effects respectively (Fig. 6).⁽²⁸⁾ Another case is the potential human leukocyte antigen susceptible allele in schizophrenia- this demonstrates intercountry expression differences (Fig. 7).⁽²⁷⁾ Moreover, although clinical trials initially increase short term costs, it results in a higher amount of clinical knowledge gained earlier on in trials.⁽³⁾ Furthermore, it would also increase the inclusion of developing countries populations in research- they represent 90% of the global disease burden but are involved in only 20% of clinical trials.^(3)(29) As well as, increase investment, development and job opportunities within poorer regions of the world. Furthermore, conducting clinical trials comes with great expenses. Thus, carrying them out in cost-friendly developing countries would lead to cost reductions. One such example is the availability of cheaper labour forces in developing countries.⁽³⁾

However, globalising clinical trials could result in challenges. These include the potential exploitation of participants in developing countries. Thus, there is a need to ensure overseas trials are conducted in a safe and ethical manner. Furthermore, trials need adequately trained participants and labour. Thus, this could potentially increase the cost and effort of conducting research. Moreover, clinical trial laboratories need to be standardised. Achieving this in developing countries, further leads to an increase in cost. However, the creation of laboratory standards applicable internationally could lead to a reduction in overall costs.⁽³⁾

I believe the benefits of globalising clinical trials outweigh the challenges, and these needs to be taken into consideration when conducting schizophrenia or other clinical conditions studies.

 

 

CONCLUSION

 

Although research findings of current anti-inflammatory novel drugs show undeniable promising results, work remains to be done. The mechanism of anti-inflammatory action of certain therapies need to be identified, as well as the incorporation of inflammatory markers screening in clinical studies. Moreover, trials with beneficial outcomes need to be replicated in optimum research conditions to ensure the validity and reliability of findings. Also, a “one size fits all approach” cannot be applied in the pharmaceutical industry. Thus, personalised medication considering individuals various attributes needs to be the focus of future research.

References:

 

1. Tandon R, Nasrallah AH, Keshavan SM. Schizophrenia. “Just the Facts” 5. Treatment and prevention Past, present, and future. Schizophrenia Research. 2010;122(1-3):23.
2. Keller WR, Kum LM, Wehring HJ, Koola MM, Buchanan RW, Kelly DL. A review of anti-inflammatory agents for symptoms of schizophrenia. J Psychopharmacol. 2013;27(4):337-42.
3. Lang T, Siribaddana S. Clinical Trials Have Gone Global: Is This a Good Thing? PloS Med. 2012.
4. Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. P T. 2014;39(9):638-45.
5. Tripathi A, Kar SK, Shukla R. Cognitive Deficits in Schizophrenia: Understanding the Biological Correlates and Remediation Strategies. Clin Psychopharmacol Neurosci. 2018;16(1):7-17.
6. Weinstein JJ, O.Cohan M, Slifstein M, Kegeles SL, Moore H, Abi-Dargham A. Pathway-Specific Dopamine Abnormalities in Schizophrenia. Biological Psychiatry. 2017;81(1):42.
7. Haddad P, Kirk R, Green R. Chlorpromazine, the first antipsychotic medication: history, controversy and legacy. British Association for Psychopharmacology. 2016.
8. Chong HY, Chaiyakunapruk N, D B C W, K K C L, Chiou CF. Global Economic Burden of Schizophrenia: A Systematic Review. Value Health. 2014;17(7):A767.
9. Organization WH. Schizophrenia World Health Organization 2018
10. Chan SW. Global perspective of burden of family caregivers for persons with schizophrenia. Arch Psychiatr Nurs. 2011;25(5):339-49.
11. Brissos S, Dias VV, Balanzá-Martinez V, Carita AI, Figueira ML. Symptomatic remission in schizophrenia patients: relationship with social functioning, quality of life, and neurocognitive performance. Schizophr Res. 2011;129(2-3):133-6.
12. Information NCfB. Aspirin PubChem: PubChem; 2018.
13. Central B. Acetylsalicylic acid as an adjuvant therapy for schizophrenia. BMC Springer Nature: Springer Nature; 2010.
14. Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2010;71(5):520-7.
15. Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel RR. What does the PANSS mean? Schizophr Res. 2005;79(2-3):231-8.
16. Information NCfB. Celecoxib PubChem: PubChem; 2018.
17. Müller N, Krause D, Dehning S, Musil R, Schennach-Wolff R, Obermeier M, et al. Celecoxib treatment in an early stage of schizophrenia: Results of a randomized, double-blind, placebo controlled trial of celecoxib augmentation of amisulpride treatment. Schizophrenia Research. 2010;121(1-3):124.
18. Information NCfB. Minocycline PubChem: PubChem; 2018.
19. Deakin B, Suckling J, Barnes TRE, Byrne K, Chaudhry IB, Dazzan P, et al. The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial. Lancet Psychiatry. 2018;5(11):885-94.
20. Solmi M, Veronese N, Thapa N, Facchini S, Stubbs B, Fornaro M, et al. Systematic review and meta-analysis of the efficacy and safety of minocycline in schizophrenia. CNS Spectrums. 2017;22(5):426.
21. DrugBank. Tocilizumab DrugBank: DrugBank; 2018.
22. Girgis RR, Ciarleglio A, Choo T, Haynes G, Bathon MJ, Cremers S, et al. A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial of Tocilizumab, An Interleukin-6 Receptor Antibody, For Residual Symptoms in Schizophrenia. Neuropsychopharmacology. 2018;43:1323.
23. Aas IH. Global Assessment of Functioning (GAF): properties and frontier of current knowledge. Ann Gen Psychiatry. 2010;9:20.
24. DrugBank. Natalizumab DrugBank: DrugBank; 2018.
25. London KsC. Inflammatory Response in Schizophrenia (IRIS) Clinicaltrials.gov: Clinical trials.gov; 2017.
26. Adminipi. Globalising Clinical Trials. International Pharmaceutical Industry. 2017;9(3):68.
27. Dos Santos Francisco R, Buhler S, Nunes JM, Bitarello BD, França GS, Meyer D, et al. HLA supertype variation across populations: new insights into the role of natural selection in the evolution of HLA-A and HLA-B polymorphisms. Immunogenetics. 2015;67(11-12):651-63.
28. Fleeman N, Dundar Y, Dickson R, Jorgensen A, Pushpakom S, McLeod C, et al. Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses. Pharmacogenomics J. 2011;11(1):1-14.
29. Alemayehu C, Mitchell G, Nikles J. Barriers for conducting clinical trials in developing countries- a systematic review. Int J Equity Health. 2018;17(1):37.
30. Gaedigk A, Sangkuhl K, Whirl-Carrillo M, Klein T, Leeder JS. Prediction of CYP2D6 phenotype from genotype across world populations. Genet Med. 2017;19(1):69-76.