References During MJ, Acworth IN, Wurtman PO (1988): An in vivo study of dopamine release in striatum: The effects ofphenylalanine and brain function. In Wurtman P,J, Walter ER (eds), Dietary Phen. ylalanine and Brain Function. Boston: Birkhauser, pp 80--86. Roberts ILl (1988): Neurological, psychiatric, and behavioral reactions to aspartame in 505 aspartame reactors. In Wurtman ILl, Walter ER (eds), Dietary Phenylalanine and Brain Function. Boston: Birkheimer, pp 373-376. Zar JH (1984): "Power and sample size in tests for difference between two means." In BiostatisticalAnalysis, 2nd ed. Englewood Cliffs, N J: Prentice-Hail, pp 134-138. Zhang C, Border S, Karoum F, Commissiong JW (1990): Effect of precursors on the synthesis of catecholamines and on neurotransmission in the superior cervical ganglion of the rat. J Neurochem 55:890--8.
Magnetic Cortex Stimulation as a Therapeutic Strategy in Schizophrenia? To the Editor: Psychological and electrophysiological studies in schizophrenia support the hypothesis that the frontal lobe is involved in this disorder, whereas left hemisphere dysfunction is especially probable (Kaplan and Sadock 1991). Whether the cortical (Weinberger 1986) or sub cortical (Robbins !990) region is crucial in the genesis of schizophrenic pathology is not clear. Nevertheless, if this model is true, activation or exhaustion of the frontal cortex may give rise to changes in the intensity of the pathology of patients suffering from schizophrenia. Since 1985 (Barker et al 1985) experience has been obtained with selective cortical stimulation by means of noninvasive, nontraumatic, easy to handle, time-varying magnetic field stimulation. When applied to the motor cortex, transcranial magnetic stimulation proved to influence higher cortical functions, such as the selection of motor programs (Ammon and Gandevia 1990). This suggests the possibility of influencing cortical performance by means of magnetic cortex stimulation. If so, and if the frontal lobe hypothesis is true, we can expect some influence on psychotic patients when stimulating the left frontal cortex by means of magnetic fields. "I~e present magnetic codex stimulators can s~mUlatC umy a small part of the cortex (Colon and Visser 1990). It may be that such a stimulation area is inadequate for influencing schizophrenic symptoms. I suggest, therefore, that it is worthwhile to develop magnetic equipment that exclusively stimulates the cerebral cortex and that can do so over a large area in search of beneficial strategies for the treatment of schizophrenia.
E.J. Colon St. Elizabeths Hospital Rielerweg 187 7416 ZE Deventer The Netherlands
References Kaplan HI, Sadock BJ (1991): Synopsis of Psychiatry. Baltimore: Williams and Wilkins.
Weinberger DR (1986): Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44:660-669. Robbins TW (1990): The case for frontostriatal dysfimcfions in schizophrenia. Schizophrenia Bull 16:391-402. Barker At, Jalinous R, Freeston IL (1985): Non invasive magnetic stimulation of the human cortex. Lancet 2:1106-1107. Ammon K, Gandevia SC (1990): Transcranial magnetic stimulation can influence the selection of motor programmes. JNeurol Neurosurg Psychimry 53:705-707. Colon EJ, Visser S (Eds) (1990): Evoked Potential Manual, 2rid ed. Boston: Kluwer Academic Publishers.
CSPT Circuitry in Affeetive Disorders To the Editor: Swerdlow et al (1993) discuss the role of dopaminergic dysfunction in affective domains functioning within integrated cortico-striato-pallido-thalamic (CSPT) circuitry (Hoover and Strick 1993; Takada 1993), The neurobiology is suggested by electroconvulsions independent of seizure activity inducing the release of dopamine (DA) (McGarvey et al 1993). It also is suggested by mania in a woman with improved parkinsonism caused by increased dopaminergic activity lateralized to the right hemisphere in which the metabofic rate is higher in females (Afonso et al ! 993; Friedman 1990). This hypothesis is supported by electroconvulsive therapy in an 88-year-old woman inducing asymmetrical enhancement of regional cerebral blood flow, especially in the motor/sensory region that was not reflected on the electroencephalogram (Sestoft et al 1993). It also is supported by hemiballismus and secondary mania following a small infarct in the right thalamus of an 81-year-old woman (Kulisevsky et al 1993) and by the correlation of dysfluency, but not volume of lesions to depression in acute left hemisphere stroke patients (Astrom et al 1993; Herrmann et al 1993). These findings and reports of gender disparities in affective disorders (Friedman 1993a) and adaptation to exercise (Friedman 1993b) prompt further research of the role of CSPT circuitry in the pathogenesis and treatment of affective disorders.
Ernest Friedman 1831 Forest Hills Boulevard l:;,~©t f~l~xral.~nrl N i l
441124313 References Afonso D, Santana C, Rodriguez M (1993): Neonatal lateralization of behavior and brain dopaminergic asymmetry. Brain Res Bull 32:11-16. Astrom M, Adolfsson R, Asplund K (1993): Major depression in stroke patients: A 3-year longitudinal study. Stroke 24:976-982. Friedman EH (1990): Dopamine and obsessive symptom expression. Neuropsychiatry Neuropsyehol Behav Neural 3:313 [Letter]. Friedman EH (1993a): The neurobiology of gender inequalities in affective disorders. Sac Sci Med 37:127 [Letter]. Friedman EH (1993b): The neurobiology of adaptation to exercise. J Psychosom Res 37:553-554 [Letter].
Herrmann M, Barrels C, Wallesch C-W (1993): Depression in acute and chronic aphasia: symptoms, pathoanatomical-clinicat correlations and functional implications. J Nearol Nearosurg Psychiatry 56:672-678. Hoover JE, Strick PL (I 993): Multiple output channels in the basal ganglia. Science 259:819-82 I. Kulisevsky J, Berthier ML, Pujol J (1993): Hemiballismus and secondary mania following a right thalamic infarction. Neurology 43:1422-1424. McGarvey KA, Zis AP, Brown EE, Nomikos GG, Fibiger HC (1993): ECS-indnced dopamine release: effects of electrode placement, anticonvulsant treatment, and stimulus intensity. Biol Psychiatry 34: i 52- i 57. Sestoft D, Meden P, Hemmigsen R, Hancke B, Madsen PL, Friberg L (I 993): Disparity in regional blood flow during electrically induced seizure. Acta PsychiatrScand 88:140-143. Swerdlow NR, Kaput S, Mann JJ (1993): Dopamine and depression: Circuitous logic? Biol Psychiatry 33:757-758 [Letter and responsel. Takada M (1993): Widespread dopaminergic projections of the subparafascicular thalamic nucleus in the rat. Brain Res Bull 32:301-309.
PCP and Antipsychotic Drugs To the Editor: The article written by N.B. Father in Biological Psychiatry, V ol. 34, pp 119-121 entitled "Antipsychotic Drugs Block Phencyclidine Receptor-Mediated Neurotoxicity" contains very interesting data. There are aspects of this article that deserve comment, however.
The article reports information describing the pharmacology of the phencyclidine (PCP)/MK80 I-induced intracellular vacuolization response, as described by Olney in Science (244:1360, 1989). It reports that two drugs (haloperidol and thioridazine) that are dopamine and sigma ligands block this response. One drug (sulpiride), which is a dopamine antagonist and sigma ligand, falls to block this response. Another broad monoaminergic and cholinergic receptor ligand (clozapine) blocks this response. And two drugs (DTG and rimcazole) that are sigma ligands block the response. In this list, haloperidoi, thioridazine, sulpiride, and clozapine are known to be antipsychotic and are used in practice. At one time, and even today, theorists postulated that sigma figands would be antipsychotic. But, rimcazole was tested on this basis and found to lack antipsychotic effect, as did DTG. We now know that DTG and rimcazole are not antipsychotic. The authors might want to take this into account in their interpretation. The common pharmacologic feature of the drugs that they have demonstrated to block the vacuolization is not antipsychotic activity. The title of the paper "Antipsychotic Drugs Block Phencyclidine Receptor-Mediated Neurotoxicity" is incomplete, because some of these drugs do block neurotoxicity and some do not. These drugs that block the MK801 effect do not "have as their palpable common denominator, the potential for alleviating psychosis." So the claim of vacuolization blockade should not be made for the class of antipsychotic drugs, as was done here. The authors might consider whether the sigma action and/or the anticholinergic potency is important in blocking the unique PCP action ofintracellular vacuolization.
The data as presented are very interesting. The clinical fete. vance of this i ~ P effect is provocative. But, it is not possible to link intracellular vacuolization ~ t h psychosis on the basis oftbe 0ata_ presented here. Carol A. Tammmsa University of Maryland at Baltimore, Maryland Psychiatric Research Center, Baltimore, MD
Response A potential problem with Dr. Tamminsa's position th.at DTG and rimcazole "arc not antipsychotic" is that these drugs may have to be used at very high doses to show therapeutic efficacy, doses so high that toxic side effects preclude really testing the hypothesis. Interestingly, in our animal study these two agents would have been declared not antivacuole had we limited the dose to a range tolerated by humans. In any event we did not claim that DTO and rimcazole are andpsychotic; we spoke in terms of antipsychotic potential, which is a property that sigma agents have long been postulated to have and have not yet beenproven to not have. Dr. Tamminga suggests that we might consider whether the "sigma action and/or the anticholinergie potency is important" in blocking the vacuole reaction. We believe both are important: in fact, we postulate that both a sigma and musca~nic receptor are involved in mediating the vacuole reaction. Regarding anticholinergic potency, two of the antipsycbutic agents that block the vacuole reaction (clozapine and thioridazine) are particularly potent antimuscarinlcs. Clozapine is much more potent than thioridazine in blocking the vacuole reaction, however, and is slightly weaker than thioridazine in binding to muscarinlc receptors (Bolden et al 1992). Thioridazine is also a potent sigma ligand, but clozapine is not, so we still conclude that the only single common denominator of these assorted agents is their "known or putative" antipsychotic potential. Concerning Dr. Tamminga's characterization of sulpiride as a sigma ligand, we believe this is incorrect (Walker et al 1990). Dr. Tarnminga finds our title incomplete. Yes it is, but it accurately describes our data, unless one misinterprets the title (as Dr. Tamminga does) to mean "All antipsychotic chugs . . . . " o r "Only anfipsychotic drugs . . . . " To avoid further confusion, let us precisely clarify our position. We propose that a common mechanism may underly NMDA antagonist neurotoxicity in rodents and psy. chotic processes in humans. We consider this a tenable hypothesis even if there is not a perfect correlation between drugs that are effective antipsychotics and drugs that block NMDA antagonist neurotoxicity. For example, although muscarinic antagonists are not generally considered antipsychotics, if drugs in this class are administered immediately before an NMDA antagonist, this totally prevents the neurotoxic reaction (Olney et al 1991), we strongly believe this signifies involvement of a muscarinic receptor in the toxic process. If the antimuscarinic drug is administered 4 hr after the NMDA antagonist, there is no protection. Does this prove us wrong--a muscarinic receptor is not involved? No, it signifies that the treatment was ton late--the cerebrocortical neu¢ons were already swollen and vacuolated--the drug could not prevent what had already happened. When an individual comes into an emergency room manifesting an acute psychosis 4 hr after a toxic dose of PCP, an anticholinergic drug may not be therapeuti-