Current Research: Antipsychotics and Other Schizophrenia Treatments

(Part 3 of 3)

In this video, Leslie Citrome, MD, MPH, clinical professor of psychiatry and behavioral sciences at New York Medical College, Valhalla, New York, examines neurobiological targets, the current research regarding antipsychotics, and other schizophrenia treatment options.

In the previous part 1, Dr Citrome breaks down the regions of the brain responsible for symptoms and tools for assessing cognition and reviews the the Personal and Social Performance Scale (PSP) and the MATRICS Consensus Cognitive Battery (MCCB).

In part 2, he explains the severity of functional deficits in schizophrenia and the importance of psychological rehabilitation such as cognitive remediation and vocational rehabilitation.

Now, I haven't really mentioned neurobiological targets yet, but it's worth revisiting. As we are working towards improvement in the pharmacological approaches to schizophrenia, greater attention has been paid to cognition.

Let's revisit the neurobiological targets in the brain. The neurobiology of cognitive impairment in schizophrenia is complex and does involve the interplay of a number of neurotransmitter systems. They include our favorite players here, dopamine, but also glutamate and acetylcholine.

The focus, as I mentioned earlier, is the dorsolateral prefrontal cortex or DLPFC, and its interactions with other brain regions. Now, in the DLPFC, dopaminergic transmission is mainly mediated through dopamine D1 receptors, not D2, D1.

Chronic low levels of dopamine in the DLPFC in people with schizophrenia have been demonstrated. This is very different from our understanding of the positive symptoms of schizophrenia, which are thought to be due to excess amounts of dopamine in the ventral striatum, and where the dopamine D2 receptor is the target of antipsychotic medications.

It's D1 versus D2, and there's not enough dopamine versus too much dopamine. Actually, what we have in the brain is too much dopamine in one place and too little in the other. How do we remedy this? Second-generation antipsychotics also possess strong antagonistic at presynaptic serotonin 5-HT2A receptors on the dopaminergic neuron.

We've known that for years. It actually facilitates the release of dopamine and theoretically boosts the dopamine levels in the DLPFC. However, attempts to measure this effect have resulted in disappointment.

Many studies have been done with second-generation antipsychotics some years ago comparing them generally with Haloperidol. We have studies of olanzapine, and quetiapine, and risperidones, and ziprasidone, basically comparing them with each other and with Haloperidol.

The bottom line is there was small improvements compared to Haloperidol. Very little differences amongst the second-generation antipsychotics themselves. The improvement that was observed is not nearly enough to erase the gap that exists between the general population and people with schizophrenia in terms of their cognitive functioning.

Maybe, it improved cognition by half a standard deviation, but that's not nearly enough when we think about the gap of two to three standard deviations that exists in the cognitive functioning comparing people with schizophrenia with the general population.

We have to look at other biological targets. Of increasing interest system is the glutamate system, with its connections with dopamine circuitry. Glutamate is widely distributed in the brain, and it's the primary excitatory neurotransmitter in the human CNS.

Experimentally, glutamate has shown to be involved in neuroplasticity and higher cognitive functioning, such as memory. In the DLPFC, NMDA glutamate receptors are involved in high-level processes, such as executive functioning.

The final common pathway, though, is dopamine. Glutamate neurons regulate the dopamine neurons, either directly, boosting dopamine, or indirectly, acting as a brake, decreasing dopamine. Depending on where we look, we see either effect.

Now, the NMDA receptor has been a target of significant interest in terms of improving its functioning. One theory of schizophrenia is that we have the hypofunctioning NMDA receptor hypothesis. We can't give glutamate, but if we give medicines or other interventions that boost signaling in the NMDA receptor, boosts its functioning.

One of the ways is to increase glycine at the NMDA receptor. Why glycine? Glycine is necessary in terms of the NMDA receptor to function. We can boost the functioning of that NMDA hypofunctioning receptor, theoretically, we can boost it by providing more glycine.

We can do that with a glycine transporter inhibitor, GlyT1 inhibition. You're going to hear about this. There is a medicine currently being evaluated for this purpose. Others have been attempted and have failed in phase III of the clinical trial development process.

Another attempt is being made with a product being developed by Boehringer Ingelheim. It's just referred to with a number, BI 425809. A randomized, double-bind, placebo-controlled study was done with add-on oral BI 425809.

This study was published in Lancet Psychiatry earlier this year, and this intervention, when added to an antipsychotic, appeared to improve cognitive abilities of the patients who participated. This is interesting. If this holds out in the phase III part of its clinical development, we may have another intervention.

To conclude, cognition is an important determinant of function, and cognitive impairment is very common in people with schizophrenia. The effect of medications on cognition is actually independent of how well they work on the positive symptoms.

We know we can treat the positive symptoms quite well, but our second-generation antipsychotics don't quite do the job with cognition. One strategy is to improve on that. Perhaps, we can find an augmenting strategy pharmacologically.

In the meantime, we have vocational rehabilitation. We have cognitive remediation, and we should use those to the hilt while waiting for a more definitive intervention. I hope this has been useful, and I look forward to speaking with you again in the not-too-distant future.

Leslie Citrome, MD, MPH, is Clinical Professor of Psychiatry and Behavioral Sciences at New York Medical College in Valhalla, New York, and has a private practice in Pomona, New York. He graduated from the McGill University Faculty of Medicine in Montreal, Canada and completed a Residency and Chief Residency in Psychiatry at the New York University School of Medicine. He also went on to complete a Masters in Public Health at Columbia University. 

Dr Citrome was the founding Director of the Clinical Research and Evaluation Facility at the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York. After nearly 2 decades of government service, as a researcher in the psychopharmacological treatment of severe mental disorders, Dr. Citrome is now engaged as a consultant in clinical trial design and interpretation. He is a frequent lecturer on the quantitative assessment of clinical trial results using the metrics of evidence-based medicine. He is a member of the Board of Directors of the American Society of Clinical Psychopharmacology. 

Dr Citrome is the editor-in-chief of the International Journal of Clinical Practice. He has authored or co-authored over 500 published research reports, reviews, and book chapters within the biomedical literature. He is the author of the textbook, Handbook of Treatment-Resistant Schizophrenia, published in 2013 by Springer Healthcare.