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David Baxter PhD

Late Founder
Probing the Biology of Psychosis, Schizophrenia, and Antipsychotics: An Expert Interview With Dr. Philip Seeman, MD, PhD
Posted 11/15/2006

Editor's Note:
Philip Seeman, MD, PhD, made the breakthrough discovery of the D2 receptor, a target for all antipsychotics. In this interview with Medscape's Jessica Gould, Dr. Seeman, Professor Emeritus, University of Toronto, explains the significance of this finding and 3 other advances he and his colleagues made that have contributed to our knowledge of dopamine.

Medscape: Since 1963, Dr. Seeman, when you were a graduate student at Rockefeller University, you have been studying the biology of psychosis and the mode of action of antipsychotic drugs. To bring us up to date, what are your main discoveries that have emerged during this span of 43 years?

Philip Seeman, MD, PhD: There have been 4 major advances in this laboratory:

First, I spent 12 years searching for a target common to the action of all antipsychotic drugs. Although I was told that the search would be fruitless, I finally discovered the antipsychotic dopamine receptor, now called the dopamine D2 receptor. These data were supported by those from the laboratory of Solomon H. Snyder, MD, Department of Neuroscience, Psychiatry and Behavioral Sciences and Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.[1,2]

The second major finding was that atypical antipsychotics such as clozapine (Clozaril) and quetiapine (Seroquel) dissociated from the D2 receptor very quickly, in contrast to traditional antipsychotics such as haloperidol (Haldol) or chlorpromazine (Thorazine), which stayed on D2 much longer. The different time course helps explain the basis of atypical antipsychotic action, a principle essential in designing better antipsychotic medication.

Third, we have recently discovered that the basis of dopamine supersensitivity is a marked increase in the proportion of D2 receptors that are in a state of high affinity for dopamine (D2High receptors). This is important because up to 75% of patients with schizophrenia are supersensitive to dopamine-like drugs (methylphenidate or amphetamine) at doses that do not affect control individuals.[3,4] This elevation of D2High receptors occurs in all animal models of psychosis, including animals that have brain lesions, have received psychosis-producing doses of amphetamine, phencyclidine, or cortisone, or have had various gene knockouts resulting in abnormal behavior.

Fourth, we have found that drugs such as ketamine, phencyclidine and memantine (data to be published), long considered to be selective for N-methyl-D-aspartate (NMDA) receptors, also all stimulate the D2High receptor at concentrations similar to those that affect the NMDA receptors.

Medscape: Although it is now established that dopamine D2 receptors are a principal target for antipsychotic drugs, what has been the overall reception to this finding?

Dr. Seeman: At first there was some disbelief that a single receptor target could accommodate drugs as disparate as haloperidol, chlorpromazine, pimozide, benzamides, or melperone, to mention only a few. For example, it was reported that the D2 target had to be wrong because metoclopramide was an antipsychotic but had no potency on D2 in vitro.[5] However, it turned out that metoclopramide required the addition of sodium ions, as do all benzamide antipsychotics, and with sodium ions was active at the D2 receptor in vitro in relation to its clinical potency.[6]

Now that the D2 target has been around since 1975, there is a major search to treat schizophrenia by means of targeting different receptors. A few of the different receptors include:

Serotonin-2A (MDL 100,907);
Serotonin-2C (SR 46349B);
Dopamine D1, D3 (BP 897), and D4(fananserine; sonepiprazole);
Cannabinoid-1 (rimonabant); and
Ampakine (CX 516).​

Although none of these particular targets and drugs has yet succeeded, it is possible that the neurokinin-3 antagonist (SR-142801; osanetant) or a neurotensin receptor agonist (not the antagonist) may have some antipsychotic action.

Medscape: The so-called atypical antipsychotics, including olanzapine, clozapine, and quetiapine, cause less or no parkinsonism as a side effect of their D2-blocking action. If they block D2, how do they avoid causing parkinsonism?

Dr. Seeman: The therapeutic action of the antipsychotics occurs when 65% to 85% of brain D2 receptors are occupied, a rule discovered by Lars Farde, Professor, Department of Psychiatry and Psychology, Karolinska Institute, Stockholm, Sweden, and colleagues.[7] However, when more than 78% or 80% of the D2 receptors are occupied, then one usually finds hyperprolactinemia and parkinsonism in the patients. These side effects are particularly troublesome with the traditional antipsychotics such as haloperidol, chlorpromazine, and trifluoperazine.

In addition to the percentage of receptors occupied, another key factor assessed to determine whether an antipsychotic elicits parkinsonism is the duration of time that the antipsychotic drug stays attached to the D2 receptor. For example, haloperidol stays attached to the D2 receptor in vitro for at least 38 minutes, while chlorpromazine stays attached for 30 minutes before coming off of D2. By contrast, clozapine dissociates from the D2 receptor in vitro in a matter of 15 seconds, while quetiapine dissociates in 16 seconds. These data match human brain imaging findings that show haloperidol constantly bound to D2 for more than 24 hours, whereas the occupation of D2 by clozapine or quetiapine rapidly falls after a few hours and has mostly disappeared after 24 hours.

The data for the rapidly dissociating antipsychotics (amoxapine, aripiprazole, clozapine, perlapine, quetiapine, remoxipride, and paliperidone) are compatible with their low extrapyramidal signs. This is primarily because the interruption of dopamine neurotransmission is sufficiently brief to allow some pulses of dopamine to get through from one neuron to the next without the extended blockade caused by the traditional antipsychotics. Moreover, it appears that only a few hours per day of 60% to 70% occupancy of D2 may be needed to obtain the antipsychotic action.

Olanzapine is a different story because it does not have the fast-off-D2 property of clozapine. But, olanzapine has a potent anticholinergic action with a dissociation constant of 2.1 nanomoles per liter at the muscarinic receptor, matching that of benztropine and, thereby, preventing parkinsonism.

Medscape: You mentioned that patients with schizophrenia are supersensitive to dopamine, and that you have found a biomarker in animal models of psychosis that reflects this dopamine supersensitivity. What is the basis for this supersensitivity in psychosis?

Dr. Seeman: There are many animal models of psychosis, including animals sensitized to amphetamine, phencyclidine, cortisone, or ethanol; animals that have received neonatal lesions of the hippocampus; animals born by cesarean section with anoxia; and mice born with knockouts of genes such as the dopamine D4 receptor, catechol-O-methyltransferase (COMT), G protein-coupled receptor kinase 6 (GPRK-6), dopamine beta-hydroxylase (DBH), regulator of G-protein signaling (RGS-9), RII-beta protein kinase A, and trace amine receptors. All of these animals are supersensitive to dopamine, as shown by their supersensitive response to a test injection of amphetamine. In each of these cases, the total number of dopamine D2 receptors is not changed; only the proportion of D2High receptors is dramatically increased, by 200% to 900%.

These elevated D2High states appear to serve as the final common pathway for many injuries to the brain, whether by lesions, drugs, or gene alteration. These D2High states, therefore, appear to be directly related to the psychotic signs and symptoms in patients. This interpretation is compatible with the fact that D2 blockade is an effective treatment for psychotic signs and symptoms, even though cognitive difficulties may remain.

The multiple pathways to elevated D2High states suggest that there may be multiple causes for schizophrenia, including altered brain development, and multiple types of altered genes. The multiple causes may explain why many genes have been found associated or linked to schizophrenia; yet, all of the psychotic patients are treated by D2 antagonists.

These data also suggest that elevated D2High receptors may be a possible biomarker for psychosis in humans. Another biomarker of schizophrenia may be the enhanced release of dopamine caused by amphetamine, a useful method based on the interfering action of endogenous dopamine vs radioactive raclopride.

Medscape: If D2High reflects the state of psychosis, can this be measured in humans?

Dr. Seeman: Yes. This is now being done in collaboration with ****ij Kapur, MD, PhD, FRCPC, Vice-President, Research, and Alan Wilson, MD, PET Centre at the Centre for Addiction and Mental Health in Toronto. We are using trace amounts of carbon-11 propyl-9-hydroxynaphthoxazine ([11C]PHNO) to tag the D2High state in first-episode psychotic subjects. The project is at an early stage and no final results are yet available.

Medscape: As you mentioned, ketamine and phencyclidine are often used as models of psychosis. Moreover, memantine is used in Alzheimer patients to activate NMDA receptors. Do these 3 drugs act specifically on NMDA receptors?

Dr. Seeman: Yes, they do, but at the same time and at the same concentrations, these 3 drugs also act on the D2High dopamine receptor. The drugs, therefore, yield a mixed picture of NMDA antagonism and dopamine D2 stimulation.

Medscape: Thank you, Dr. Seeman, for your time. This has been interesting and informative.

Dr. Seeman: Thank you for having me.

Sawa A, Snyder SH. Schizophrenia: diverse approaches to a complex disease. Science. 2002;296:692-695. Abstract
Snyder SH. Forty years of neurotransmitters: a personal account. Arch Gen Psychiatry. 2002;59:983-994. Abstract
Curran C, Byrappa N, McBride A. Stimulant psychosis: systematic review. Br J Psychiatry. 2004;185:196-204. Abstract
Lieberman JA, Kane JM, Alvir J. Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology (Berl). 1987;91:415-433. Abstract
Stanley M, Wazer D, Virgilio J, Kuhn CM, Benson DI, Meyerson LR. Lack of potency of metoclopramide's metabolites in various dopaminergic models. Pharmacol Biochem Behav. 1983;18:263-266.
Makman MH, Dvorkin B, Klein PN. Sodium ion modulates D2 receptor characteristics of dopamine agonist and antagonist binding sites in striatum and retina. Neurobiology. 1982;79:4212-4216.
Farde L, Wiesel FA, Halldin C, Sedvall G. Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry. 1988;45:71-76. Abstract

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