Molecular Psychopharmacology
Suresh Sundram

Principal focus: schizophrenia, bipolar disorder

The Molecular Psychopharmacology Laboratory is working to:

• Understand the molecular pathology of psychotic disorders
• Develop better and more effective markers and interventions for these illnesses
• Investigate how psychotropic medications and drugs interact with receptors and intracellular signaling mechanisms in nerve cells
  (neurons).
• Test results in clinical populations through the Northern Psychiatry Research Centre (NPRC)
• Collect clinical material and relevant biological samples to examine in the laboratory to better understand these disorders.

HIGHLIGHTS

Investigating how antipsychotic drugs work

The mainstay of treatment for psychotic disorders including schizophrenia and bipolar disorder are the antipsychotic drugs (APD). These agents have been in use for over 50 years but we still have only a limited understanding of how they work.

Suresh Sundram and his team are trying to understand why one APD,
clozapine, is effective in people for whom other APDs are not. From this, Suresh hopes to gain insight into the pathology of psychotic disorders and more effective ways of treating them.

Suresh has previously described a novel pathway of action where clozapine interacts with the epidermal growth factor (EGF) system to signal intracellularly to the MAPK-ERK cascade in brain cells. The EGF system has been implicated in the pathology of schizophrenia and is involved in regulating many cell and brain processes postulated to be disturbed in the illness.

The team are now:

• Investigating which proteins are activated in the brain consequent to clozapine treatment.
• Creating cells that express receptors that the group proposes may be involved in mediating the interaction between clozapine and the EGF system
• Providing a platform to explore what may be the critical determinants of APD action and, in turn, how these may be altered in psychotic disorders.
• Collecting clinical data and biological samples from people who are receiving treatment with clozapine, to be used to determine whether there are specific genetic variants (SNP) that can predict response to clozapine treatment.

This work has demonstrated a different profile of activation for clozapine compared to other APDs, but also showed differences between the other APDs. These various patterns of activation between APDs may provide clues to explain the different clinical and side effect profiles of these agents.

Ultimately, a screening test could be developed to streamline potential responders to earlier and more effective intervention and prevent unnecessary exposure to the toxic effects of clozapine.

This work is sustained by the generous and ongoing support of One in Five and the Woods Family.

Lipoproteins and psychosis

People with schizophrenia die at a rate 2.5 times that of people without the disorder.

This is not due to the increased risk of suicid,e but to a higher death rate from cardiovascular disease. Many reasons for this increased risk have been proposed, including smoking, obesity and diabetes mellitus.

Initial work by Jagath Bandara at the NPRC established that 60% of patients with chronic schizophrenia that he examined had metabolic syndrome, a cluster of risk factors with strong links to diabetes and heart disease.

The team investigated whether these people, many of whom receive clozapine, may be predisposed to this through alterations in levels of a lipid carrying protein called apolipoprotein E (apoE).

Collaborating with Ralph Martins from the Edith Cowan University, researchers demonstrated that apoE levels were increased in patients receiving clozapine treatment compared to other antipsychotic drugs and that this did not appear to be influenced by the gene for apoE. The implications of this for exacerbating cardiovascular risk are currently being considered.

In parallel with this study we are collaborating with Elizabeth Thomas from the Scripps Institute in the USA to measure a different protein, apoD, in these patients and a subset who have started on the antipsychotic
medicine, clozapine. As well as being tremendously effective, clozapine is notorious for inducing weight gain, high blood lipids and diabetes in those who take it. This project may shed light on why people with schizophrenia have more cardiovascular disease and die younger than their contemporaries, and thus open avenues for effective interventions.

Sensory integration in schizophrenia

Together with Olivia Carter and honours student Tabitha Nash, we are examining sensory deficits in schizophrenia. Previous research has shown that healthy individuals are both accurate and fast when it comes to integrating visual information in different areas of visual space. In contrast, people with schizophrenia tend to be selectively impaired on tasks that assess visual integration.

The study aims to determine whether this impairment is purely a deficit of integration capacity or if a portion of the impairment is attributable to slower rates of sensory processing. Researchers will also test whether this deficit is specific to vision or if analogous impairments exist in auditory integration and whether the deficits are influenced by antipsychotic medications. The study will also include the first detailed assessment of auditory spatial integration in healthy control subjects.

Improved health care delivery

Russell D’Souza at the NPRC is about to undertake a major study examining a new treatment for people with schizophrenia. The NPRC team has just completed a study examining the outcomes of people with schizophrenia as well as two studies examining a new type of antidepressant, results of which are pending and may provide a new therapeutic option in treating these disorders.

NorthWest Mental Health have funded Suresh Sundram and Allison Harrington to expand their new model of nursing for people in psychiatric inpatient units, which significantly reduced the risk of aggression to staff and other patients as well as reducing the rate of absconding
without increasing other adverse measures. NorthWest Mental Health covers over a million people in Melbourne and is in the process of implementing this model across all their inpatient units.

Suresh Sundram with the NPRC received a beyondblue grant to examine the effects of acculturation on psychiatric symptoms in people with chronic physical disorders.