Psychosis and the coming glutamate revolution

Dopamine has been the big player in understanding schizophrenia since antipsychotic drugs were discovered. All current antipsychotics have their main effect by blocking dopamine function in the mesolimbic pathway and there’s now significant evidence that this is the location of one of the major dysfunctions.

It’s been clear for a while that this isn’t the whole story though. Ketamine and PCP, two glutamate-focused drugs that barely touch the dopamine system directly, are heavily linked to schizophrenia and can intensify psychotic symptoms.

Findings such as these have sparked a flurry of interest in understanding the role of glutamate in psychosis, and there’s now an intense interest in developing drugs that might target this system.

One of the key hopes is that these newer drugs will have fewer side-effects, as, in some, antipsychotics are have unpleasant and unhealthy adverse consequences.

The New York Times has just published a great article on the development of these new drugs, just in mid-testing stage, and on the neuroscience that motivates them.

People who use PCP often have the hallucinations, delusions, cognitive problems and emotional flatness that are characteristic of schizophrenia. Psychiatrists noted PCP’s side effects as early as the late 1950s. But they lacked the tools to determine how PCP affected the brain until 1979, when they found that it blocked a glutamate receptor, called the NMDA receptor, that is at the center of the transmission of nerve impulses in the brain.

The PCP finding led a few scientists to begin researching glutamate’s role in psychosis and other brain disorders. By the early 1990s, they discovered that besides triggering the primary glutamate receptors — NMDA and AMPA — glutamate also triggered several other receptors.

They called these newly found receptors “metabotropic,” because the receptors modified the amount of glutamate that cells released rather than simply turning circuits on or off. Because glutamate is so central to the brain’s activity, directly blocking or triggering the NMDA and AMPA receptors can be very dangerous. The metabotropic receptors appeared to be better targets for drug treatment.

The article talks about some of the new drugs in development, and the fact that this is where drug companies are placing their (quite substantial) bets at the moment.

Link to NYT article ‘Daring to Think Differently About Schizophrenia’.

2 Comments

  1. Posted February 26, 2008 at 10:10 am | Permalink

    Javier Meana and Luis F. Callado researchers from the University of the Basque Country have been recently published an article in “Nature” describing how neurotrasmitters like serotonin and glutamate form a complex molecule that trigger psychotic symptoms when the subject ingest drugs such as LSD, in similar way to the symptoms of schizophrenia, findings that open up the path to discover new durgs to treat this mental illness (schizophrenia)

  2. Posted February 26, 2008 at 3:50 pm | Permalink

    Yes, Anibal, I stumbled upon the same news here:

    http://afp.google.com/article/ALeqM5jcUVAXeWn9Qtz5DAzKDQEzOdhigQ

    As for the glutamate drug, SRF had a great review of the initial stages of its clinical testing:

    http://www.schizophreniaforum.org/new/detail.asp?id=1342

    If you want a quick overview of the Glutamate Hypothesis of Schizophrenia, it’s also there, By Bita Moghaddam:

    http://www.schizophreniaforum.org/for/curr/Moghaddam/default.asp


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