The dopamine hypothesis of schizophrenia, in various guises, has captivated the attention of, literally, a large army of psychiatric researchers for nearly 50 years (see, e.g., Carlsson and Lindqvist, 1963). Indeed, a PubMed search of the terms "schizophrenia" and "dopamine" elicits nearly 7,000 articles. Further, every approved antipsychotic drug modulates D2-dopamine receptors and—with the exception of aripiprazole, which is a functionally selective D2 agonist—is a D2 antagonist. Finally, despite nearly three decades of research and billions of dollars spent by the pharmaceutical industry, no drug that does not interact with D2 dopamine receptors has proven to be any more effective than haloperidol for non-treatment-resistant schizophrenia.
Despite this focused research on dopamine, dopamine receptors, and schizophrenia, no clear consensus has emerged regarding whether schizophrenia is associated with excessive dopaminergic neurotransmission. As succinctly stated many years ago:
“The dopamine hypothesis of...
“The dopamine hypothesis of schizophrenia is by definition supported by no direct evidence. No one has found anything conclusively abnormal about dopamine (DA) in body fluids or brains of schizophrenics….” (Snyder, 1976) (italics mine)
Now, Howes and colleagues provide a nice meta-analytic study and attempt to address this issue conclusively as well as make suggestions for treatment. Briefly, they find that individuals with schizophrenia have a significant enhancement of what they interpret to be presynaptic dopaminergic function. A much smaller increase in D2-dopamine receptors was also reported. Not being a statistician, I cannot comment on the validity of the approach or the conclusions, though I will provide a perspective on what this might mean for drug discovery with the assumption that their results are correct.
What does it mean for drug discovery if there is excessive presynaptic dopamine activity in schizophrenia?
In the paper the authors discuss the potential of presynaptic D2 agonists, selective inhibitors of dopamine synthesis, and the use of dopamine-depleting drugs like reserpine. All of these approaches have been attempted with varying degrees of success, though since all catecholamines share the same biosynthetic pathway it will be essentially impossible to selectively inhibit dopamine synthesis without altering the synthesis of norepinephrine and epinephrine. As well, neither selective targeting of presynaptic D2 receptors nor selective depletion of dopamine is likely to be a pharmacologically viable option.
An alternative approach might be to target receptors that regulate dopamine release presynaptically. Thus, drugs that inhibit the release of dopamine might be salutary for schizophrenia. A quick literature search reveals, however, that several failed drug classes had as their raison d’être inhibition of presynaptic dopamine release, including:
Although I list only these three classes of compounds (each of which is directed at a different molecular target implicated in regulating presynaptic dopamine release) there are likely many others in the public and private domains.
What I believe this means is that it is possible to create drugs which inhibit presynaptic dopamine release, but that the jury is still out as to whether these will offer any substantial advantage over drugs which target postsynaptic D2 signaling.
Carlsson A, Lindqvist M. Effect of chloropromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh) . 1963 Jan 1 ; 20():140-4. Abstract
Gewirtz GR, Gorman JM, Volavka J, Macaluso J, Gribkoff G, Taylor DP, Borison R. BMY 14802, a sigma receptor ligand for the treatment of schizophrenia. Neuropsychopharmacology. 1994 Feb;10(1):37-40. Abstract
Kikuchi T, Tottori K, Uwahodo Y, Hirose T, Miwa T, Oshiro Y, Morita S. 7-(4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity. J Pharmacol Exp Ther. 1995 Jul;274(1):329-36. Abstract
Snyder SH. The dopamine hypothesis of schizophrenia: Focus on the dopamine receptor. Am J Psychiatry. 1976 February; 133(2):197-202. Abstract
Spooren W, Riemer C, Meltzer H. Opinion: NK3 receptor antagonists: the next generation of antipsychotics? Nat Rev Drug Discov . 2005 Dec ; 4(12):967-75. Abstract
The meta-analysis by Howes et al. once more confirms that there are abnormalities in the dopamine system in the striatum of patients with schizophrenia.
What is new is recent evidence about the location of the dopaminergic hyperfunction. Several high-resolution imaging studies performed in the last few years suggest it to be located in the head of the caudate rather than the ventral striatum. The head of the caudate receives projections from the dorsolateral prefrontal cortex, an area important for the cognitive symptoms of schizophrenia. These new findings contradict the widely accepted hypothesis that the dopaminergic hyperfunction in the striatum is mainly in the ventral or “limbic” striatum.
Another interesting new finding is that the abnormalities in the striatal dopamine system are already present in prodromal subjects. They therefore may occur early in the disease process and could be of primary origin. Obviously, to really understand the etiology of the disorder we would have to image the dopamine system at even earlier developmental stages—something...
Another interesting new finding is that the abnormalities in the striatal dopamine system are already present in prodromal subjects. They therefore may occur early in the disease process and could be of primary origin. Obviously, to really understand the etiology of the disorder we would have to image the dopamine system at even earlier developmental stages—something that, due to practical and ethical reasons, is not currently possible.
PRIMARY NEWSDoes a Presynaptic Dopamine Surplus Cause Psychosis?