College of Psychiatric and Neurologic Pharmacists

Stephen Stahl, MD, PhD

Stephen Stahl, MD, PhD, will deliver the closing keynote address at the 2011 CPNP Annual Meeting on the topic of Glutamate: The Emerging Frontier of Psychopharmacology for Schizophrenia and Mood Disorders. Stahl, an internationally recognized clinician, researcher and teacher in psychiatry with subspecialty expertise in psychopharmacology, will discuss the pathophysiology of schizophrenia and mood disorders in relation to glutamatergic neurotransmitter systems, relevant compounds in the pipeline and their novel mechanisms of action, and the potential clinical utility of pipeline compounds in the treatment of schizophrenia and mood disorders. CPNP Program Committee member Jodie Malhotra, PharmD, BCPP, interviewed Dr. Stahl and provides you a glimpse into the session he will be presenting on this topic on Wednesday, May 4 at the close of the CPNP Annual Meeting. Register now for the 2011 CPNP Annual Meeting where this session will be featured.

Glutamate: The Emerging Frontier of Psychopharmacology for Schizophrenia and Mood Disorders

Session to be held Wednesday, May 4 from 11:00 a.m.-12:00 p.m. at the 2011 CPNP Annual Meeting
Interview Conducted by Jodie Malhotra, PharmD, BCPP

In your opinion, is there a need for better pharmacologic treatments for schizophrenia and mood disorders? If so, why?

Yes, but for different reasons. Schizophrenia is an illness that rarely goes into remission and our current treatments address only some of its symptoms. They are most effective in treating positive symptoms, which don’t have a major impact on outcomes. The symptoms that our current treatments do not treat well, negative and cognitive symptoms, are the ones that have the most impact on treatment outcomes. We obviously need treatments that will improve patient outcomes; therefore there is an emphasis now on trying to help improve cognitive and negative symptoms.

Regarding mood disorders, there is more optimism with our current treatment options because remission is more common. We have fairly good treatments for mania. What we don’t have are good treatments for major depression, bipolar depression, or treatment resistant depression of either type. What we are finding is that these treatments work pretty well in early illness but for patients who are on their third or fourth treatment trial, very few medicines work. So, our biggest area of need is for patients who don’t get well on initial treatment choices.

Glutamate is increasingly implicated in schizophrenia and mood disorders. The glutamate system is complex and involves several receptor types. What are the clinically important aspects of this system, respective to the clinical symptoms of schizophrenia, bipolar disorder, and depression?

Glutamate is a universal excitatory neurotransmitter and there are very few neurons in the brain that aren’t excited by glutamate input. This is unlike monoamine neurotransmitters which don’t affect every cell of the brain. Glutamate is profoundly important but it makes it very difficult to be selective. However, though glutamate is the same everywhere, glutamate receptors may be different in different areas of the brain. If we design drugs that work on specific glutamate receptors, we might be more regionally selective.

Many people are confused about the glutamate system. According to the NMDA hypofunction hypothesis, schizophrenia is caused by low levels of glutamate and it is possible to mimic schizophrenia by blocking NMDA receptors. On the other hand, the theory in depression is that the level of glutamate is too high. The current focus for treatment of bipolar and treatment resistant depression is giving ketamine or creating an oral, artificial ketamine that works on NMDA receptor subtypes, one example being the NR2B subtype. So, why does an agent like ketamine which causes symptoms of schizophrenia potentially treat the symptoms of treatment resistant depression? The answer may be that the area of the brain where glutamate is low in schizophrenia is not the same place or associated with the same receptors in the area of the brain where glutamate is high in depression.

What clinical advantages do you believe glutamatergic agents will bring to our patients compared to the existing drugs we use today?

The short answer is that we don’t know. The long answer is that glutamate agents are likely to help patients with refractory or treatment resistant depression since they utilize a different mechanism of action. We don’t need more monoamine agents, we need something paradigm shifting.

What evidence is there, if any, to support the use of any already marketed glutamatergic agents for the treatment of schizophrenia, bipolar disorder, or depression?

Ketamine, riluzole and lamotrigine are the only glutamatergic agents that we really have to work with at this time. Lamotrigine is a medication that has changed my practice. I have patients with bipolar depression that respond to lamotrigine and it makes a big difference in their lives. Although lamotrigine works by blocking ion channels, likely sodium channels, the implications are that when certain sodium channels are blocked, the release of glutamate is stopped. If this theory is correct, then we need more drugs with similar mechanisms to lamotrigine.

What are the risks associated with the use of these drugs for psychiatric indications?

Approximately one in thirteen thousand patients taking lamotrigine develop a life threatening rash called toxic epidermal necrolysis or Steven’s Johnson syndrome. Other than that there really aren’t many side effects with lamotrigine. Obviously, you need to make sure you don’t have drug interactions with depakote, that you are monitoring children closer since they are more likely to develop a rash, and ensure careful titration to avoid the lamotrigine induced rash. Riluzole costs a thousand dollars a month so that is a major disadvantage with using that agent. Riluzole can also cause liver function abnormalities. Ketamine obviously has risks, especially with the short duration of action.

What glutamatergic compounds in the pipeline do you feel have promise for the treatment of schizophrenia? bipolar disorder? depression? What do you feel is an expected timeline to see a novel glutamatergic agent come to market?

There are agents in the pipeline with promise. First are the NR2B antagonsits for bipolar and unipolar depression. Also, there are the mgluR2/3 presynaptic agonists for the treatment of schizophrenia. However with one of these mgluR2/3 compounds, the first test done in Russia went well but when retested worldwide, the results not only showed that it clearly did not work but also that it can possibly cause seizures. That being said, the mgluR2/3 compounds have shown potential in animal models for the treatment of drug abuse so we will possibly see them in the future, but not for schizophrenia. So, these agents do have promise but we can’t be sure where they will end up. The timeline that we are looking at is at least five years until they are filed with the FDA. Another exciting area is the development of glycine transport inhibitors.

Dr. Stahl has edited five books and written more than twenty-five others including the best-selling textbook, "Stahl's Essential Psychopharmacology", now in its third edition along with the prescribers guide, just awarded the 2010 book of the year award by the British Medical Association. Lectures, courses and preceptorships based upon his textbooks have taken him to dozens of countries on 6 continents to speak to tens of thousands of physicians, mental health professionals and students at all levels. His lectures and scientific presentations have been distributed via more than a million CD-ROMs, internet educational programs, videotapes, audiotapes and programmed home study texts for continuing medical education to hundreds of thousands of professionals in many different languages. His courses and award-winning multimedia teaching materials are used by psychopharmacology teachers and students throughout the world. Dr. Stahl also writes didactic features for mental health professionals in numerous journals.