Old Dogs, New Tricks: Innovative Therapies for Schizophrenia

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Rosana Oliveira, PharmD, BCPS, BCPP

 
While schizophrenia is thought to affect only about 1% of the world’s population, because of its early onset and association with unemployment, homelessness, and early mortality, it is one of the top 15 leading causes of disability worldwide.1 Despite treatment with antipsychotic medications, clinical improvement and recovery from schizophrenia remains limited, with an estimated 30% of individuals with schizophrenia considered to be treatment-resistant.2 Given the limited treatment response, particularly in regards to the cognitive domain of schizophrenia which is strongly associated with poor functional outcomes, and unfavorable side effect profile of current antipsychotic medications whose shared mechanism of action is dopaminergic blockade, other causes of schizophrenia and potential treatment options that target different etiologies have been under investigation.3

During the CPNP 2018 Annual Meeting, Dr. Alan Breier, the Director of the Prevention and Recovery Center for Early Psychosis in Indianapolis, shared the new evidence supporting the repurposing of neuroprotective, anti-inflammatory, and hormonal agents for the treatment of schizophrenia and the role of a psychiatric pharmacist during his session entitled “Old Dogs, New Tricks: Innovative Therapies for Schizophrenia”.

Novel Treatments for Schizophrenia

Abnormal cortical synaptic architecture, accelerated gray matter loss, reduced dendritic spine density due to suspected immunologic abnormalities and inflammation, and prenatal exposures to viral or bacterial infections have been investigated as contributors to the development of schizophrenia.4-8 To save time and money in the drug development process, medications which target the aforementioned neurochemical or biologic systems which are already approved for other indications are being studied in the possible treatment of schizophrenia.

Possibly due to its reduction of inflammatory cytokines and increase in glutathione levels, N-acetylcysteine has shown some promise as an augmentation strategy in chronic schizophrenia as it has demonstrated reductions on the Positive and Negative Symptoms Scale (total, negative, and general).9-10 Anti-viral medications demonstrated improvement in working and visual memory during a small test-of-concept study, and a more robust double-blind  trial of adjunctive valacyclovir is underway to confirm and expand upon the initial study findings.11-12 Additionally, low estrogen levels have been linked to poor cognitive performance, and estradiol has been found to be an effective augmentation strategy in the treatment of women with schizophrenia with demonstrated reductions on total symptom severity.13 Ongoing research is underway to test the significance of estrogen receptor beta in working/verbal memory and negative symptoms.14

The Role of the Psychiatric Pharmacist

Dr. Breier discussed how The Prevention and Recovery Center for Early Psychosis has integrated a clinical pharmacist into their team. Functioning under a collaborative practice agreement, the psychiatric pharmacist is able to assist with medication evaluations, adherence reviews, symptom assessment, education, and insurance coverage concerns. As part of the interdisciplinary team, the psychiatric pharmacist provides coverage for other team members, facilitates the assessment of psychosocial issues, and collaborates with nursing to ensure appropriate administration of long-acting injectables. This model can be incorporated in other systems to improve the access and quality of care that patients with schizophrenia receive, especially during the prodromal stage of their illness where early intervention is critical.

Take Home Messages

  • Schizophrenia treatment remains insufficient in achieving meaningful clinical recovery for a large percentage of patients affected and ongoing research is urgently needed to find more effective treatments
  • The repurposing of medications already approved for other indications may be more cost and time effective than seeking approval of new agents, and may improve cognitive symptoms in schizophrenia more robustly than currently used antipsychotics
  • A psychiatric pharmacist can play a role both in the research of novel therapeutics, and in provision of medication therapy management to patients with schizophrenia

References

  1. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017; 390(10100): 1211-1259.
  2. Lally J, Gaughran F, Timms P, et al. Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics.  Pharmgenomics Pers Med. 2016; 9: 117-129.
  3. Savla GN, Vella L, Amstrong CA. Deficits in domains of social cognition in schizophrenia: a meta-analysis of the empirical evidence. Schizophr Bull. 2013; 39(5): 979-992.
  4. Rapoport JL, Addington AM, Frangou S, et al. The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry. 2005; 10(5): 434-449.
  5. Selemon LD, Zecevic N. Schizophrenia: a tale of two critical periods for prefrontal cortical development. Transl Psychiatry. 2015; 5e623.
  6. Glausier JR, Lewis DA. Dendritic spine pathology in schizophrenia. Neuroscience. 2013; 251: 90-107.
  7. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014; 511(7510): 421-427.
  8. Kneeland RE, Fatemi SH. Viral infection, inflammation and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2013; 42: 35-48.
  9. Berk M, Copolov D, Dean O, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia – a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2007; 64(5): 361-368.
  10. Breier A, Liffick E, Hummer TA, et al. Effects of 12-month, double-blind N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders. Schizophr Res. 2018: S0920-9964(18)30164-6.
  11. Prasad KM, Eack SM, Keshavan MS. Antiherpes virus-specific treatment and cognition in schizophrenia: A test-of-concept randomized double-blind placebo-controlled trial. Schizophr Bull 2013; 39(4): 857-866.
  12. Breier A, Dickerson F, Buchanan R, et al. A double-blind trial of valacyclovir to improve cognition in early phase schizophrenia: Results from the VISTA study. Schizophr Bull. 2018: S63.
  13. Begemann MJ, Dekker CF, van Lunenburg M, et al. Estrogen augmentation in schizophrenia: a quantitative review of current evidence. Schizophr Res. 2012; 141 (2-3): 179-184.
  14. Koehler KF, Helguero LA, Haldosen LA, et al. Reflections on the discovery and significant of estrogen receptor beta. Endocr Rev. 2005; 26(3): 465-478.
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