Field of Science

Atypically typical: The single vs multiple compound hypothesis in schizophrenia

One of the most painful parts in the book "A Beautiful Mind" narrates how the brilliant mathematician John Nash was admitted to a Trenton hospital and subjected to what was then one of the most fashionable treatments for schizophrenia- insulin shock therapy. The periodic administrations of large doses of insulin to induce convulsions and coma not only was embarrassing for the future Nobel Laureate and his family but it may have possibly damaged parts of his mind- and not just brain- beyond repair. It may have scarred a beautiful mind.

But we had lobotomy, and we had insulin shock therapy. And then we evolved. The drugs chlorpromazine and reserpine revolutionized the treatment of schizophrenia in the 1950s (recall the movie "Awakenings"). Since then a variety of drugs have been used for mitigating the symptoms of this devastating disorder. However most of these drugs target what are called the "positive symptoms" of the disease, which include delusions, agitation and hallucinations. The "negative symptoms" include social withdrawal, depression and poverty of speech, symptoms not targeted by many drugs. More importantly, many of the early drugs had nasty side effects, termed "extrapyramidal symptoms" (EPS) which included involuntary twitching of facial and other muscles, part of what is termed tardive dyskinesia. A lot of focus has been put over the years on reducing these effects as well as in mitigating negative symptoms. Medicines supposed to achieve these goals have been traditionally termed "atypical antipsychotics"

Now an article co-authored by Nobel Laureate Arvid Carlsson questions this widely accepted definition of atypical antipsychotics and suggests that the definition actually hampered the development of these drugs for more than 30 years. The article contains some rather technical commentary, but what I could get from it is the following: the most widely accepted hypothesis for the etiology of schizophrenia is the so-called "dopamine hypothesis", pioneered by Carlsson himself, that contends that high levels of dopamine in the brain are associated with psychoses. Drugs like clozapine are supposed to prevent dopamine metabolism by binding especially to the D2 family of dopamine receptors. These drugs bind to other receptors too but it's their action at dopamine D2 receptors that's important in managing the symptoms of schizophrenia.

Carlsson contends that the flaw in 30 years of antipsychotic therapy lies in searching for the perfect "atypical" antipsychotic which will tackle both positive and negative symptoms of schizophrenia as well as EPS. It was believed for many years that all these effects could not be disentangled from each other and necessarily went together. This led to the search for a "magic bullet", a single compound that could hit all symptoms. Carlsson says that recent studies on the action of antipsychotics suggests different mechanisms responsible for different symptoms, including mechanisms involving novel receptors that were not implicated before. The drugs also cause different levels of occupancy for D2 receptors in different tissues and parts of the brain, and thus provide the opportunity for designing multiple compounds that hit subtypes in different places. According to Carlsson, the "atypical" compounds used to treat psychoses should actually be called "typical" since they usually do a good job of treating the positive symptoms of the disease. The bottom line is that multiple avenues for treating the symptoms of schizophrenia arising from different molecular mechanisms should be explored, instead of focusing on a single compound that would encompass all features. Different compounds should be used for targeting positive and negative symptoms.

To me this narrative reinforced what is becoming clear about CNS disorders and the accompanying therapy; that non-selective drugs targeting different mechanisms are often more beneficial than single, selective drugs targeting only one receptor, and that multiple pathways affect the development of a disease whose symptoms and side-effects may be classified into distinct categories only with deceptive convenience. The brain is the most complex structure known to man. Its manipulation and the treatment of its disorders deserves an approach that is not too less complex and nuanced.

Gründer, G., Hippius, H., & Carlsson, A. (2009). The 'atypicality' of antipsychotics: a concept re-examined and re-defined Nature Reviews Drug Discovery, 8 (3), 197-202 DOI: 10.1038/nrd2806


  1. There's tons to say about this post, but as a clinician I quickly learned that one of the features touted about atypical neuroleptics was that they didn't produce rigidity and tremor as side effects (e.g. symptoms typical of Parkinsonism), but they did, and that another supposed benefit -- given long term atypical neuroleptics didn't produce tardive dyskinesia -- but they did.

    It is reminiscent of the combined narcotic agonists and antagonists billed to be non-addicting (but they were) -- Talwin aka pentazocine, Stadol aka butorphanol )

    As long as you are focusing on the complexity of the CNS, how many different types of serotonin receptors do you think there are? As of 1/06 there were 14, some of which had splice variants. Assuming there aren't any more, which of these receptors (and where in the CNS) demonstrate altered function or numbers or altered post-receptor responses after the administration of selective serotonin reuptake inhibitors (SSRIs)? You should distinguish acute effects from the effects seen with prolonged administration (which are more important, because no one breaks into pharmacies or sells SSRIs on the street, for the acute high they produce).


  2. Interesting experience. I would not be surprised if different levels of modulation for different receptor subtypes are observed over short-term vs long-term use. The ensuing complexity is maddening.
    P.S. You really should start your own blog to further explore such matters!

  3. Wavefunction

    You're right. It's sheer laziness on my part -- what a great excuse. It's sooo much easier to comment on blogs I enjoy (such as yours and In the pipeline) than do one of my own. This stuff really isn't chemistry (a la "The Skeptical Chymist") although an understanding of chemistry (and molecular biology) and an experience of medical practice is crucial to it. I hope to have such a blog up and running by the end of the summer. Until then . . .


  4. Why are some of symptoms of schizophrenia termed "positive" and others "negative" What are the criteria for such distinction?


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