A fuller understanding of signaling in the brain of people with this disorder offers new hope for improved therapy: “An inadequate arsenal of medications is only one of the obstacles to treating this tragic disorder effectively. Another is the theories guiding drug therapy. Brain cells (neurons) communicate by releasing chemicals called neurotransmitters that either excite or inhibit other neurons. For decades, theories of schizophrenia have focused on a single neurotransmitter: dopamine. In the past few years, though, it has become clear that a disturbance in dopamine levels is just a part of the story and that, for many, the main abnormalities lie elsewhere. In particular, suspicion has fallen on deficiencies in the neurotransmitter glutamate. Scientists now realize that schizophrenia affects virtually all parts of the brain and that, unlike dopamine, which plays an important role only in isolated regions, glutamate is critical virtually everywhere. As a result, investigators are searching for treatments that can reverse the underlying glutamate deficit.” —Scientific American The treatment of schizophrenia, to put it another way, has been constrained by the serendipitous discovery of dopamine blockers that ameliorate its symptoms; that is why the disease has for so long been conceptualized as a disorder of dopamine. I have written about an analogous problem, most recently, in my critique of a misguided critique of the biogenic amine theory of depression. However, I wonder if glutamate is not just the next great thing in schizophrenia theory, much as, in that essay, I discussed the last decade’s focus on serotonin in depression. Glutamate-modulating drugs may not address the ‘underlying deficit’ any more than serotonin-modulating ones addressed an ‘underlying deficit’ in depression; in fact, they are, as I assert, less robust antidepressants than those that work by other mechanisms. Over and over again in psychiatry, when you have a new improved hammer, it pays to start seeing more and more nails everywhere [if you will forgive me for how often I overuse that metaphor…]

There is yet another problem, which this article touches upon only in its ultimate paragraph (“…because schizophrenia’s symptoms vary so greatly, many investigators believe that multiple factors probably cause the syndrome. What physicians diagnose as schizophrenia today may prove to be a cluster of different illnesses, with similar and overlapping symptoms.”), giving the briefest of nods to what I think of as a core issue in conceptualizing schizophrenia. It may not be only that other neurotransmitters beyond dopamine are affected, to varying extents, in different patients with the disease, provoking its varied presentations. I, and a number of those who treat schizophrenia, including a number of psychiatric luminaries, are convinced that our current diagnostic concept of schizophrenia lumps together patients with diverse and heterogeneous disease processes. While controversial, a strong case may be made that in some schizophrenics, it is not necessarily a disorder of intercellular signalling (neurotransmitters) at all, but more gross “organic” disruption in the architecture of the brain as a result of perinatal insult or developmental disturbance. Schizophrenics may sort roughly into two categories, those with (a) genetic history of the disease in relatives, fair to good medication response, more normal premorbid cognitive abilities (although sometimes having shown premorbid social-interactional abnormalities), less cognitive deficiency, absence of environmental insult history, and absence of findings on brain scans or autopsy; as opposed to those with (b) no family history; poorer medication response; evidence of poorer premorbid cognitive functioning; more deficits on neurocognitive testing; evidence of environmental insults such as season-of-birth effect, antibody levels indicative of exposure to infection, or other metabolic abnormalities; and abnormal brain scans and postmortem findings. The two types of schizophrenics also have contrasting symptom patterns; the former are more paranoid and delusional (the type Javitt and Coyle are writing about) and the latter more disorganized and confused.