The Next Therapeutic Frontier for Schizophrenia Treatment

The Stanley Medical Research Institute (SMRI) recently awarded Dr. David Mamo and Dr. Shitij Kapur a CAN$330,000 grant to study l-stepholidine, a compound derived from of a naturally occurring Chinese herb called Stephania intermedia. The aim of this positron emission tomography (PET) study is to confirm binding of l-stepholidine to dopamine D2 receptors in healthy human subjects; obtain supporting evidence of its safety and tolerability; and predict effective dosages for future clinical trials in people with schizophrenia.

PET imaging has already contributed to our understanding of how anti-psychotics work and led to a better understanding of effective dose range in clinical practice.  More recently this group has used PET imaging in early drug development to predict clinically effective dosing strategies in clinical trials.

SMRI granted this award following a highly competitive grant application process, from which only 4 of 55 treatment trial applications were successful. In this new study, Dr. Mamo and Dr. Kapur will build on previous SMRI-funded work that showed that l-stepholidine binds to both the D1 and D2 receptors in living rodents without causing neurological side effects. These findings are consistent with previous pre-clinical work from China, suggesting that l-stepholidine is both a D2 antagonist (like standard anti-psychotics) and also a D1 agonist (which has theoretical implications for addressing cognitive and negative symptoms).  These factors make it a potentially new treatment for schizophrenia.

Anti-psychotic drugs are generally quite effective in managing delusions and hallucinations.  However, they have limited impact on other core symptoms of schizophrenia including difficulties thinking, reasoning skills, and negative symptoms such as social withdrawal and lack of interest in activities.  These cognitive and negative symptoms are closely associated with social and interpersonal functioning.  Therefore, effectively addressing these symptoms is the next therapeutic frontier in the goal of improving recovery outcomes for an otherwise devastating illness.

All available anti-psychotic drugs are antagonists at the dopamine D2 receptors, and binding to D2 receptors predicts their clinical effects on delusions and hallucinations but not their effects on cognitive and negative side effects. One of the most promising targets to enhance these cognitive difficulties in schizophrenia is a treatment that binds to another subclass of dopamine receptors, the D1 receptor.  Scientists are hopeful that their work will show that l-stepholidine will be the compound that fills this treatment gap.

When Dr. Mamo and Dr. Kapur successfully complete this study, this will mark the first time that CAMH scientists translated what they learned from their own pre-clinical animal findings to a clinical trial.  Moreover, if their work does support their hypothesis, we will have a model for a new treatment for schizophrenia that focuses on negative symptoms - a critical step that could revolutionize the management of schizophrenia.

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