Moving at “Glacier” Speed To Find New Drugs

The National Alliance on Mental Illness recently gave its 2011 Scientific Research Award to Dr. Jeffrey A. Lieberman who has a long and impressive resume in researching schizophrenia. Among his many titles, Dr. Lieberman is chairman of Psychiatry at the Columbia University College of Physicians and Surgeons, and is Director of the New York State Psychiatric Institute. 

Before he accepted his award, Dr. Lieberman gave an hour long lecture about his research. I want to share some key points with you that he made about current medications commonly prescribed for mental illnesses.

 First, some background.

 Dr. Lieberman was the principal investigator for the Clinical Anti-psychotic Trials of Intervention Effectiveness Research Program, better known as the CATIE study, that caused an uproar in 2005 when its results were published. The reason the CATIE study was controversial was because it compared older, cheaper anti-psychotic drugs –the so-called first generation of drugs used to treat mental illnesses — with the newest generation of anti-psychotics, sometimes called a-typicals, which were and are much more expensive.

 Everyone thought the newer drugs were both safer and superior to the older medications based largely on claims by the pharmaceutical industry. What the CATIE study revealed was that the newer drugs were not substantially better than the older drugs at treating symptoms, although some had fewer side effects.  This finding led to charges that drug manufacturers had hoodwinked doctors and their patients. An editorial published in 2005 by the New York Times was typical of the public reaction:

“A government-financed study has provided the strongest evidence yet that the system for approving and promoting drugs is badly out of whack. The study compared five drugs used to treat schizophrenia and found that most of the newest, most heavily prescribed drugs were no better than an older drug that is far cheaper. The nation is wasting billions of dollars on heavily marketed drugs that have never proved themselves in head-to-head competition against cheaper competitors.”

 In his lecture, Dr. Lieberman repeated much of what he has said before — that media outlets sensationalized the CATIE results. In the American Psychiatric Journal in 2005, Dr. Lieberman summerized what the CATIE study had actually revealed:

The essential import of the CATIE study can be summarized as follows. Anti psychotic drugs, both old and new, are clearly effective and have been a boon to the treatment of schizophrenia. However, they have substantial limitations … The numerous anti psychotic drugs, however they might be classified, are more similar to than different from each other. To the extent that anti psychotics differ, it is more in their side effects than therapeutic effects. ..What works for one person may not work for another. Consequently, treatments for schizophrenia must be individualized.

 In his lecture, Dr. Lieberman elaborated on the CATIE findings. He said there are currently about 20 different drugs on the market for treating schizophrenia. Although they are different, all of them work the same way — by blocking how much dopamine is released inside the brain through what is commonly called the D2 receptor.

Simply put, all of them  focus on blocking dopamine. Switching medications, doesn’t change the process. The only difference between the medications is the side effects that they may cause and those vary from one individual to the next.

In 2007, the sale of these dopamine inhibitor drugs accounted for about $30 billion in sales worldwide.  But many of these drugs are now coming off their patent protections. What this means is that they are going to begin being sold as generic drugs and less profitable. Because of this, Dr. Lieberman said several big pharmaceutical companies are no longer interested in investing in research for new anti psychotic medications. The dopamine ” gold mine” is thought to be empty.

A handful of companies, however, are preparing new anti-psychotic medications. In the 1970s, emergency room doctors noticed that patients who had been using PCP — “angel dust” — mimicked the same symptoms as someone who had schizophrenia. By the 1980s, scientists had learned that PCP interferes with brain receptors by way of an amino acid called glutamate. Now scientists are trying to determine if regulating glutamate, rather than dopamine, might be a safer and better way to control the symptoms of mental illnesses.

Dr. Lieberman said some of these new glutamate drugs with be on the market within two to five years. The question is whether they will be any better than the dopamine drugs — or will they  just a substitute?

 During his lecture, Dr. Lieberman used the term, “schzophrenia has run its course” when talking about patients who had gone untreated for years. When it was time for audience questions, I asked him what he meant by “run its course.” He  said that studies have found that the best time to treat someone with schizophrenia is when they have their first episode. With each episode that happens after that, there is more and more damage to the brain. Eventually, there is so much damage that a patient reaches a  “plateau.”    Hence, the illness has “run its course.”

 Dr. Lieberman said we need to develop medications that will not only control the symptoms of schizophrenia but also help a person who has reached a “plateau” actually “regenerate” and regain their loss of capacity.

Here’s what I took away from his lecture.

 (1.) Our current drugs — older ones and newer ones — only help regulate symptoms and all work the same. (2.) Each person is different so they need medication that is tailored to their individual body with the fewest side effects possible. (3.) Dr. Lieberman said, “Medication is not enough.” Persons need psycho-therapy and other wrap around services to fully recover. (4.) Glutamate inhibitors that are being invented may introduce a new “pathway” for doctors to use to treat symptoms, but whether there will be fewer side effects is still unknown. Glutamate drugs may be just another way to do what dopamine drugs now do. (5.) Despite everything that we know, scientists still don’t have a clue about what actually cause severe mental illnesses, nor how to cure them. (6.) There are blood tests being marketed that can identify people with schizophrenia but these tests are not generally reliable.

Dr. Lieberman ended his talk on a hopeful note. Progress is being made, he said, but it is coming at a “glacier rate.” Slow, slow, and slower.

On that,  I certainly agree.

About the author:

Pete Earley is the bestselling author of such books as The Hot House and Crazy. When he is not spending time with his family, he tours the globe advocating for mental health reform.

Learn more about Pete.


  1. Joann_strunk says

    Why? This is a terrible disease, both in terms of suffering …for the victim and everyone connected to them, as well as monetary costs to everyone…in terms of loss of productivity, hospitalizations and incarceration. Why not put the money into research and treatment up front? It would save billions in the longer term…not to mention unspeakable suffering.

  2. By inhibiting dopamine, what these drugs are essentially doing is sedating the brain (they are, in fact, labeled “major tranquilizers”). As we do not know the actual causes or neuroscience involved in mental illness, at the moment, this is essentially the best we can do — throw a tranquilizer at the problem that is so strong it just suppresses the symptoms (thus, you are not actually regulating anything). This, of course, is also why the side effects can be so awful: they often make one feel tired, flat, apathetic, unable to feel pleasure, etc because these things are closely linked to dopamine. Quite bluntly, the medications we have now work (to some extent); but they suck for the person taking them.

    The hope with glutamate-based drugs is that not only will they control the hallucinations and psychosis that comes along with Schizophrenia; but also the negative symptoms. Most importantly, the hope is that the drug itself won’t cause side effects that are just as bad as said negative symptoms. This is key. Negative symptoms, such as apathy and loss of ability to feel pleasure, are often the reason why even somebody who no longer hallucinates and/or is delusional still cannot regain functioning (which is also often the catch 22 with medications for many people, though not all). Things like the ability to work, take care of ones self, etc all cannot happen unless someone has some motivation to do it. This is also why just getting someone to take medication is only a quarter of the battle and not anywhere near enough for recovery.

    There are also a few scientists out there still trying to create medication that target the same receptors that nicotine does. Those with mental illness tend to smoke at higher rates than those without it and one of the ideas as to why is that nicotine, as a stimulant (activates dopamine), combats negative symptoms. If one can create a drug that works on the same receptors, you equally solve two issues: (a) negative symptoms (b) some of the worst side effects.

    On therapy: h tt p : / / health . upenn . e d u / news / News_Releases / 2011 / 10 / schizophrenia / (remove spaces). Thought it would be worth posting. Though we have no research on how therapy impacts the Schizophrenic brain — mainly because, for the longest time (and still now), most abandoned it as an intervention, even when used in conjunction with medication, for psychosis — we know that therapy has a clear impact on the brain of those suffering from other mental illnesses. In those suffering from OCD, Major Depressive Disorder and other Anxiety Disorders (the disorders therapy is most widely used and, thus, where there is the most study), therapy creates the same changes to the brain as SSRI medications do. That is huge. It is likely that the changes created by therapy are more long-lasting, too. (I can cite any of this on request).

    Not to bash medication, though — it certainly helps. The psychiatric community has just become too focused on it, forgetting the fact that someone with a mental illness is a person, not just a set of symptoms. As mental illness impacts someone cognitively and socially, you cannot just look at the symptoms.

    Joann: Money is being poured into research. This is, unfortunately, just how medical research moves — very, very slowly. No matter how good the scientist, no matter how much time and effort is put into it, biomedical research is and always has been far too complicated to move quickly.

  3. On that note, I would always encourage anybody to write to their representatives about not cutting funding for public, community based treatment programs; not cutting the funding for the government organizations that help fund them (ex, SAMHSA); and not cutting funding for research and development (ie, funding for the NIH).

  4. There is a lot of research being done exploring the role of glutamate and nicotinic receptors and glial cells and inflammation and more.    Yes, it’s slow.  Schizophrenia is an extremely complex neurobiological illness and the research is difficult.  As a psychiatrist, I am excited to see what the future holds.  Each new med holds new hope for people who are struggling.  We must work with people as early as we can when illness is recognized and wrap around services beyond medications.  In the end, we must maintain hope.  I have seen progress in people with all of these meds.  CATIE looked at atypicals and only one traditional med (Trilafon.)  We can’t extrapolate from that the all the traditional meds are “just as good” as the newer meds.  When I see a person who is writhing in his chair with tardive dyskinesia and akathesia as a result of traditional meds, I am very grateful that we have the newer meds available.  Finally, the biggest take home message from CATIE was that people do not take medications consistently.  They stop for all sorts of reasons, including tolerability issues and perceived lack of efficacy.  
    Glad you got to hear Dr. Lieberman speak.  He does a wonderful job.  

  5. @c726c42b9c0a1d180a62ae61261777f1:disqus
    Obviously, as someone who is only a patient, I admit that you know considerably more than I; however, I would not go as far as to say that atypicals are necessarily safer. More tolerable, perhaps, in that the day-to-day side effects may not be as severe; however, while on atypicals, I developed a hand tremor that was so severe I could barely hold a cup, involuntary muscle twitches (that tardive dyskinesia you mention), high blood pressure, gained an unhealthy amount of weight, developed prolonged QT-interval, developed other cognitive issues that were not there before (ie, issues with memory), apathy and an inability to focus on school work (too sedated). Needless to say, despite being terrified of the idea due to a history of moderate to severe psychosis, I tapered off of them with the support (it was his idea and not just because of the side effects) of my psychiatrist. I wouldn’t call myself symptom free; however, I am incredibly high functioning for my diagnosis and doing well. I credit the fact that my psychiatrist also does therapy — which, as shown above, is still effective and is neurobiological in its own right — with my progress, a service I would not have received had he not offered it in addition to medication (due to a history of trauma, I am slow to trust — no way I would have been able to develop trust with two separate professionals at the same time).

    That is not to say that my path is for everyone — as it obviously isn’t — and, despite my experiences, I don’t regret going on the medication, as they saved my life in a time of crisis; however, please do not assume that atypicals cannot be just as dangerous as typical medication. The day to day may be more tolerable; however, research shows that, in the long term, they can be just bad, if not worse.

  6. Erika —  Never said the atypicals are “safer.”  There is no one right medicine. They all have there advantages and disadvantages.  There is room for many different meds.  I use all meds in my practice based what is the best choice for that particular person at that time in the illness process.   It is a collaborative, shared decision making approach.  Sometimes we use no meds.  Always we use a supportive psychotherapy and educational components.  As you state, it is a combination of supports that make the difference.  So glad you have a trusting relationship with your provider.  That is key.