Hope or Hype in the Treatment of Schizophrenia – What’s New? – Highlights from RCPsychIC 2019

Posted on:August 15, 2019
Last Updated: December 8, 2021
Time to read: 4 minutes

This article is based on the talk by Prof Sukhi Shergill at the RCPsych IC 2019.

1. Current drug studies for schizophrenia in phase 1 and 2 trials focus on cellular messaging to improve cellular function. Instead of a drug that works across the spectrum of psychotic symptoms, investigators are focusing much more narrowly regarding the symptom profile of what they hope to change.

2. Hope itself may be an important therapeutic tool. For example, in schizophrenia:

Whereas psychiatrists are preoccupied with reducing symptoms and attaining previous functioning, the patient’s perspective is more on achieving independence and maintaining hope. Encouraging hope means negotiating a clear understanding of the aims of treatmentthrough dialogue, mutual understanding, and a process of adjustment and acceptance. Hope may be one of most powerful therapeutic aspects of the doctor-patient relationship. [Bressan R et al., 2017]

3. Other areas of interest which have some early phase studies include:

  • Inflammation and its role in depression and how the link between inflammation and psychosis can be modulated.
  • Cannabidiol as an effective treatment for positive symptoms (statistically significant), cognitive performance and overall functioning (statistically non-significant) in schizophrenia. [McGuire P et al., 2018]
  • Roluperidone, a 5-HT2A and sigma-2 agonist, has shown positive response in schizophrenia studies.[Keefe R et al., 2018]
  • SEP-363856 is a TAAR1 (trace amine-associated receptor agonist) and also an activator of serotonin 5-HT1A receptors. It has shown positive response in schizophrenia studies. [Clinicaltrials.gov]
  • TAK-831 is a first-in-class D-amino acid oxidase (DAAO) inhibitor being explored in schizophrenia. [Takeda]

DAAO is an enzyme that breaks down serine. D-serine represents the endogenous ligand for the glycine modulatory binding site on the NR1 subunit of N-methyl-D-aspartate receptors in various brain areas.

Individuals with schizophrenia have low levels of D-serine and higher activity of DAAO. Oral administration of D serine has shown to improve positive, negative, and cognitive symptoms of schizophrenia as add-on therapy to typical and atypical antipsychotics. Thus a DAAO inhibitor may enhance NMDA receptor activity by increasing D-serine availability. [Sacchi S et al., 2013]

4. G-Protein Coupled Receptor (GPCR) mechanisms and stem cell transplants are other areas of expectation for the future in treating a wide range of CNS disorders.

5. Regarding treatments available for clinicians today, Clozapine is an evidence-based effective treatment
for TRS, with reported clinical response in 60–70% of patients and meta-analyses identifying an overall response rate of 40–60%. [Lally & Gaughran, 2018]

6. Successful clinical therapy with clozapine is highly dependent upon collaboration between specialist services, e.g. Cardiology, haematology, and neurology collaborations.  Also, research, collaborations are essential to generate and test new therapeutic avenues in patients.

7. Real-world data suggest augmenting clozapine with amisulpride or with mood stabilisers such as lithium, valproic acid and lamotrigine if mood disturbance is indicated.

8. Clozapine augmentation with aripiprazole had moderate success although augmenting with quetiapine and risperidone showed less improvement. There were poorer outcomes in patients who had clozapine stopped or who could not be treated with clozapine.

A recent review outlined the following augmentation strategies in clozapine resistant schizophrenia [Kudva and Gupta, 2019]:

Positive Symptoms

  • Risperidone
  • Amisulpride
  • Sulpiride
  • Haloperidol
  • Aripiprazole (mild)
  • Lamotrigine
  • Lithium (Schizoaffective only)
  • Raloxifene
  • Omega 3 fatty acids
  • Memantine
  • ECT

Negative Symptoms:

  • Amisulpride
  • Sulpiride
  • Aripiprazole
  • Mirtazapine
  • Gingko
  • Memantine

Cognition and social adjustment

  • Citalopram
  • Lamotrigine (anti-aggression)
  • Topiramate
  • Valproic acid
  • CX516
  • Donepezil
  • Occupational therapy

Improved clozapine side effect profile

  • Amisulpride (allows for the reduction in dose of clozapine and reduced hypersalivation)
  • Fluvoxamine (improved metabolic profile)
  • Topiramate (reduced Weight gain)
  • Valproic acid (reduced weight gain)
  • Omega 3 fatty acids (reduced triglyceride levels)

Wagner and colleagues recently published a meta-review that outlined a clinical strategy to treat clozapine-resistant schizophrenia using The Scottish Intercollegiate Guidelines Network (SIGN) [Wagner et al. 2019]. SIGN was formed in 1993 and was designed to reduce variation in clinical practice.

This meta-review included 21 publications on clozapine resistance, and each publication was reviewed using the SIGN criteria to determine scientific validity prior to grading (Grade A-D): (Read more about grading criteria)

Grade B:

  • First Generation or Second Generation Antipsychotics (FGA or SGA)
  • Antidepressants
  • ECT

Grade C:

  • Lithium
  • Valproate
  • Lamotrigine
  • Topiramate
  • rTMS

Grade D:

  • Glutamatergic agents, e.g. glycine, D-cycloserine, and CX516
  • CBT
  • Transcranial direct current stimulation (tDCS)