Testing a Potential Schizophrenia Drug: Dr. Phil Corlett

In spite of a clear need, few truly innovative medications for schizophrenia have appeared in the last two decades. However, with his new theory of what causes schizophrenia's symptoms, Rising Star Award winner Phil Corlett, Ph.D, Assistant Professor of Psychiatry at Yale University School of Medicine, is planning a human trial of the drug Retigabine in schizophrenia patients. Dr. Corlett believes that Retigabine might address symptoms of delusions (persistent unhealthy unrealistic beliefs) and anhedonia (lack of pursuit of once-rewarding activities). If his trial is successful, it will not only point to a new medication for schizophrenia but also help us understand why schizophrenia symptoms appear. Preview a summary of Dr. Corlett's Rising Star proposal

Now, you can watch an interview here with Dr. Corlett about his Retigabine trial and its basis.

Although comments on this page are now closed, you can reach Dr. Corlett with questions through his website: http://medicine.yale.edu/labs/corlett/www/contact.html.

If you like Dr. Corlett's research and feel moved to donate to support research like his, feel free to visit our donate page.

 

Comments

Hi - I look forward to answering your questions
Gayle A's picture

Thank you so much for your time and insight. You have a gift for making neuroscience understandable and accessible (speaking and writing). If you don't mind, I have a couple of questions. My seventeen year old daughter has Schizoaffective Disorder/Bipolar I. We noticed an improvement with cognitive functioning/mood stabilization last year when her psychiatrist replaced Lithium with Lamictal (also used for epilepsy). Is there is a difference between improved functioning in your Retigabine trial with those taking Lithium v. Lamictal? I also have a question regarding your 1/30/13 article in Scientific American. My daughter's c-reactive protein levels have been high and her psychiatrist started her on Mobic (an anti-inflammatory medication). Since then, her auditory hallucinations have quieted (still present but less often). We will be taking her to a pediatric rheumatologist at UCLA when she visits in a couple of months (she participates in a research study there). Your article was very beneficial. Are there are any articles/books you might recommend on the subject of schizophrenia and the immune system as well? Thank you very much, Gayle

Hi Gayle – thank you for your interest and your kind comments. Like retigabine, lamictal works on ion channels, but it targets sodium channels. These channels regulate neurotransmitter release into synapses, particularly glutamate – the major excitatory neurotransmitter in the brain. We have found that glutamate release is also involved in generating psychotic symptoms and prediction error signaling – we discovered this using a model of psychosis, the anesthetic drug ketamine – which for a short period of time, safely and reversibly, can make people have experiences that are very redolent of schizophrenia (e.g. they get delusion-like ideas that people are talking about them or spying on them). Ketamine increases synaptic glutamate release and causes prediction error signals to happen to unsurprising events. The associations between the immune system and psychotic symptoms are fascinating to me and I think they might offer new ways for us to intervene and treat these debilitating symptoms. The literature is growing – particularly with regards to autoimmunity – when people raise an immune response to their own neurotransmitter receptors. There is a great book about experiencing psychosis as a result of autoimmunity called ‘Brain on Fire: My Month of Madness’ by Susannah Cahalan. I hope I have answered your questions and thanks again, Phil
Gayle A's picture

Thank you for your thoughtful response. It helps to understand how and why medications work. And thank you for the book recommendation. I will order it today. Thank you for your contribution to mental health. Your research offers encouragement and hope. :) Gayle

As a neuroscientist, could you give me some insight into some questions I have regarding my son's diagnosis of schizophrenia. I was asked by a doctor as to whether my son has ever had a seizure. I said no but I am not sure if he has. My son experimented with drugs as a teenager. He seemed to change overnight after being at a party where he smoked methanphetamine. He said he was yelling at the party and said "someone was trying to kill him". After that we had him at the phychiatrists office where they thought maybe he had asbergers (how could this appear so much later in life ). After staying up for days he fainted and hit his head. He was fine after recuperating from that but smoked something in a glass pipe at a party. He was finally Baker Acted and put on an antiphychotic med. Two and a half years later, after trying to kill himself three times he has been put in residential facility. Can you tell me if the methanphetamine use caused the phychosis or if this is common in people with schizophrenia to seek drug use? I am happy that there is new studies being done for schizophrenia. Thank you for your time in this matter.

Dear Elizabeth, Thanks for your message. I am sorry to hear about your son. Methamphetamine is a very potent drug and it can indeed induce psychosis. It blocks the re-uptake of dopamine and other neurotransmitters from synapses. Having lots of dopamine in synapses can lead people to attend to things that they would normally ignore, a sort of strange and excessive significance to the world that can be very frightening. People with schizophrenia do seem to be at greater risk of substance abuse. They commonly smoke cigarettes and many people use cannabis. We do not know why this is. It may be that whilst some parts of a brain region called the striatum have too much dopamine, causing psychotic symptoms, other parts – like the ventral striatum - have too little. Having too little dopamine in the ventral striatum may predispose towards drug taking behaviors. However, the drugs themselves change dopamine signaling and so it is hard for us to make strong claims about too much or too little dopamine ‘causing’ drug abuse, without well powered prospective studies that measure brain function before, during and after drug use. I hope this answers your questions. Do please let me know of I can be more helpful. Thanks again for your time, Phil
Gayle A's picture

Hi-I hope it ok to ask another question. Elizabeth's question triggered a new question I would like to ask. My daughter experiences uncontrollable shaking of the left side of her body during particularly difficult episodes involving dissociation. Is it common to have seizure-like symptoms with dissociation? Thank you so much, Gayle

Hello Gayle - Please ask as many questions as you like. There are a number of intriguing links between epilepsy, seisure-like phenomena and psychosis - seisures are often accompanied by sensed presence, illusions and hallucinations that resemble some of the symptoms of schizophrenia. They are commonly quite dissociative in their phenomenology. One study of which I am very fond involved acquiring home movies of patients with schizophrenia from when they were children. Experienced neurologists rated the tapes for what we call 'neurological soft signs' - mild motor problems like listing to one side whilst walking and clumsiness during sensorimotor tasks (catching, throwing, riding bikes etc). Compared to those without schizophrenia, people with schizophrenia showed more of these neurological soft signs as children. Given that, as we develop, we build a model of how to interact with the world. It is possible that the symptoms of schizophrenia might arise because the model that sufferers learn is very different because their bodies and brains interact with the world very differently. Hope this helps, Phil
Gayle A's picture

Your answer helps very much. Thank you so much, Gayle

This gives us such hope. My family member with the symptoms you mentioned is highly allergic to all medications except Zyprexa Zydis. Would this medication be an adjunctive to the Zyprexa Zydis or a replacement. What are the known side effects of Retigabine. Would this type of study possibly put us closer to a cure some day. Thank you for the hope you give and your work for this devastating illness.

Dear Emma, thank you for your message. Retigabine and Zyprexa are not listed as drugs that interact. However, I am cautious to conclude that they don't. This is really a pilot study, one that I hope will be the basis of lots of future work where we explore the complex and important issues of drug-drug interaction. Retigabine is known to cause drowsiness, dizziness, slurred speech and double vision. At very high doses in a small number of cases, it caused confusion and hallucinations. This was at doses much higher than we are planning to use in our study. Surprisingly, one side effect of many antipsychotic drugs is psychotic symptoms. We neuroscientists think about this in terms of an 'inverted U' function: there is an optimum level of activity for any brain system. Stimulating it, or inhibiting it either side of this optimum can both impair its performance. I hope that this work will add to our understanding of how the brain creates the mind and how that process might be disrupted in psychotic illnesses. That might bring us a little closer to a cure. I think we need a concerted and translational effort from basic science all the way through to the clinic to really capitalize on what we know and what we need to know in order to treat this illness optimally. I hope this helps, Phil

I'd like to add my thanks to you for this amazing work. It's interesting that you brought up the "soft" neurological signs of children who went on to suffer from schizophrenia. My son was one of those "clumsy" children, in both gross and fine motor skills. We encouraged him to play sports and he "grew out of it.," becoming a rather good soccer player. His diagnosis of schizophrenia came at the age of 19, not long after ingesting a hallucinogenic mushroom (his first and only time doing that). He was a heavy cannabis user prior to that, so clearly self-medicating. He is currently doing as well as he ever has on a combo of clozapine, cymbalta and busbar, combined with lots of group therapy. Despite his anti-psychotic regimen, the delusions or thought insertions are still present, but he can discern that they are not "real." Would Retigabine replace clozapine in this case? And can you give any idea at all of how long before Retigabine is available on prescription?

Hi Maggie, Thank you for your message. I am glad to hear that your son is doing well. At the moment we are not certain that retigabine will be helpful; we are just beginning to explore and establish its antipsychotic properties. Based on what we know from preclinical basic science studies of the drug and what we understand of how the brain specifies predictions we believe it should be helpful, but we need to make sure with a carefully controlled study. A study that will be the beginning of a whole series of studies. Although retigabine is already approved by the FDA for epilepsy this study will be the beginning of a process. I'm afraid I can't give a more specific timeline on when the drug will be available on prescription. I am committed to working as hard as I can to learn what I can about the drug and its effects in schizophrenia. With very best wishes, Phil

Hello Phil, I'd like to ask you how long someone who has used methamphetamine, would it take to "repair" their brain. Do you know of any supplements, brain exercises and/or therapy to repair and also to keep them from wanting to use methamphetamine (in particular)? I appreciate your answers. Thanks again, Elizabeth

Hi Elizabeth, Thanks for your question. Methamphetamine is certainly very addictive. Different treatments work for different people and this is not my personal field of expertize. However, I know that therapies that help regulate cravings and teach alternate coping strategies can be helpful. I recommend that you talk to local healthcare professionals - they should be able to help you to find a treatment program. Best wishes, Phil
brandon.staglin@staglinfamily.com's picture

Hi Elizabeth,

I know of an addiction prevention program at UCLA. It uses cognitive training and cognitive behavioral style skill-building to empower young people to better control their lives, including potential addictive tendencies. Dr. Dara Ghahremani is involved in it. If you are interested, you may contact him through his page at http://portal.ctrl.ucla.edu/npi/institution/personnel?personnel_id=563746

brandon.staglin@staglinfamily.com's picture

And thus closes another great Brain Waves feature. A big thank you goes to Gayle, Elizabeth, Emma and Maggie for participating. Phil, thank you very much for sharing your knowledge with us! I hope to see everyone on Brain Waves in April, when Dr. Andrew Pieper will tell us about his development of original compounds to potentially treat cognitive disorders such as schizophrenia and neurodegenerative disorders such as dementia, Parkinson's and ALS. Take care! -Brandon

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