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low dopamine neurotransmission. This keeps prolactin levels However, as I argued in detail in my recent book (2), family, normal, spares cognition, and obviates extrapyramidal signs.
twin, and adoption studies do indeed suffer from “strong and This letter provides data on the off-rates of additional consistent methodologic biases operating across study de- newer atypical antipsychotics, using methods similar to those signs,” not the least of which is the twin method’s question- ture cells (1, 2) and drug concentrations found in the spinal Dr. Kendler noted that the “low” replication level for link- fluid of patients (4). The times for 50% dissociation from D age findings “contrasts strikingly with the high level of consis- were the following: 42 seconds for 4 nM S-(-)-amisulpride, 66 tency seen in the results of genetic epidemiologic studies— seconds for 40 nM amoxapine, 52 seconds for 10 nM aripipra- for example, the results of family and twin studies of schizo- zole, 30 minutes for 1.5 nM chlorpromazine, 15 seconds for phrenia” (p. 7). In fact, there is no “striking contrast” between 200 nM clozapine, 38 seconds for 1 nM domperidone, 38 min- these results if they are viewed as evidence supporting a utes for 2 nM haloperidol, 16 minutes for 20 nM loxapine, 17 purely environmental etiology for psychiatric disorders. Envi- minutes for 5 nM olanzapine, 24 seconds for 140 nM perlap- ronmental theories predict 1) familial clustering, 2) a higher ine, 16 seconds for 200 nM quetiapine, 23 minutes for 4 nM concordance of identical versus fraternal twins, and 3) a fail- raclopride, 13 seconds for 5 nM remoxipride, 27 minutes for 2 ure to find genes, and this is what we find (2, 3). Rather than nM risperidone, and 60 seconds for 2 nM paliperidone (9-hy- consider a purely environmental explanation as a competing paradigm, Dr. Kendler argued that linkage and association The data for the rapidly dissociating antipsychotics (amox- studies cannot be used to test “whether a twin or adoption apine, aripiprazole, clozapine, perlapine, quetiapine, remox- study was correct in its conclusion that disorder X is herita- ipride, and paliperidone) are compatible with their low ex- ble” (p. 8). I agree, but negative results could at least compel trapyramidal signs. The extent of risperidone-associated researchers to take a second look at these methods. Although extrapyramidal signs may depend on the proportions of ris- Dr. Kendler views his four strategies as “competing para- peridone and its metabolite, paliperidone, in the patient.
digms,” all four are components of the same biological/ge- netic paradigm, in contrast to what we might call the “envi- dose-dependent incidence of extrapyramidal signs; however, ronment/treatment/stress” paradigm.
the potent anticholinergic action of olanzapine (its dissocia- Finally, Dr. Kendler called for integrating his four “para- tion constant of 2.1 nM matches that of benztropine at the digms,” which would “require an appreciation of the comple- muscarinic receptor) provides an effective anti-extrapyrami- mentary sources of information obtained by genetic epidemi- ologic and gene identification approaches” (p. 9). Thus, a“striking contrast” was transformed into “complimentary References
sources of information” in the space of three pages. Dr. Ken- 1. Seeman P: Atypical antipsychotics: mechanism of action. Can J dler called his synthesis “explanatory pluralism” (p. 10), but what this means in practice is falling back on family, twin, and 2. Seeman P, Tallerico T: Rapid release of antipsychotic drugs adoption results to explain the unexpected failure to find from dopamine D2 receptors: an explanation for low receptor genes. Far better, in my view, would be a reexamination of the occupancy and early clinical relapse upon withdrawal of clo- assumptions and biases of twin and adoption studies (Dr.
zapine or quetiapine. Am J Psychiatry 1999; 156:876–884 Kendler’s paradigms 1 and 2) in the context of considering the 3. Kapur S, Seeman P: Does fast dissociation from the dopamine possibility that genes for the major psychiatric disorders do D2 receptor explain the action of atypical antipsychotics? a new hypothesis. Am J Psychiatry 2001; 158:360–369 References
4. Seeman P, Corbett R, Van Tol HHM: Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4.
1. Kendler KS: Psychiatric genetics: a methodologic critique. Am J Neuropsychopharmacology 1997; 16:93–110 2. Joseph J: The Gene Illusion: Genetic Research in Psychiatry and Psychology Under the Microscope, North American ed. New York, Algora, 2004 (Ross-on-Wye, UK, PCCS Books, 2003) 3. Joseph J: The Missing Gene: Psychiatry, Heredity, and the Fruit- Research Paradigms of Psychiatric Genetics
less Search for Genes. New York, Algora (in press) TO THE EDITOR: In his article, Kenneth S. Kendler, M.D. (1), iden- tified “four major research paradigms,” consisting of 1) “basicgenetic epidemiology,” 2) “advanced genetic epidemiology,” Dr. Kendler Replies
3) “gene finding methods,” and 4) “molecular genetics.” Dr.
Kendler argued that although “a substantial portion” of gene TO THE EDITOR: In this brief letter, I cannot respond fully to the association claims “do not survive the test of replication,” fam- issues raised by Dr. Joseph or provide detailed references to ily, twin, and adoption studies have found “genetic risk fac- support my position. Dr. Joseph and I disagree in four ways in tors… for every psychiatric and drug use disorder that has ever the interpretation of the accumulating literature in psychiat- been the subject of serious study” (p. 6). Moreover, “Unless ric genetics. First, in examining family twin and adoption there are strong and consistent methodologic biases operating studies of the major psychiatric disorders, I concluded in my across study designs, this growing body of work indicates that article that the evidence strongly supports the hypothesis that genetic risk factors are of substantial etiologic importance for genetic factors play a significant role in the etiology of these all major psychiatric and drug use disorders” (p. 6).
conditions. I did not assert that individual studies are free Am J Psychiatry 162:10, October 2005 LETTERS TO THE EDITOR
from methodologic problems. Indeed, in studying human that humans would be the only species whose behavior is un- populations by observational means, there can be no such related to our genetic makeup? It is one thing to criticize the thing as a perfect study. However, in examining the studies methodology of specific studies. It is quite another to suggest, carefully and knowing—for example, that twin and adoption as Dr. Joseph does, that we reject the results of an entire field studies have different potential biases but reach the same of scientific inquiry. This might have been warranted for some conclusion for the disorders in which both methods have pseudoscientific systems, such as astrology, alchemy, and the been used—it becomes very unlikely that the pattern of ob- Ptolemaic astronomic system. It is highly unlikely that mod- served results could have arisen from methodological biases ern psychiatric genetics will be judged by future historians of Second, Dr. Joseph is concerned about the equal-environ- References
ment assumption as a significant bias in twin studies. I sharehis concern, but the equal-environment assumption has 1. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I, been examined in a number of empirical studies. Although Williams NM, Schwab SG, Pulver AE, Faraone SV, BrzustowiczLM, Kaufmann CA, Garver DL, Gurling HM, Lindholm E, Coon H, there is a bit of evidence that this bias might be operative in Moises HW, Byerley W, Shaw SH, Mesen A, Sherrington R, some disorders, studies that have corrected for its effects typ- O’Neill FA, Walsh D, Kendler KS, Ekelund J, Paunio T, Lonnqvist ically find only small changes in heritability estimates. Al- J, Peltonen L, O’Donovan MC, Owen MJ, Wildenauer DB, Maier though the equal-environment assumption is probably not W, Nestadt G, Blouin JL, Antonarakis SE, Mowry BJ, Silverman perfectly true, evidence to date strongly suggests that the bi- JM, Crowe RR, Cloninger CR, Tsuang MT, Malaspina D, Harkavy- ases introduced thereby are quite modest.
Friedman JM, Svrakic DM, Bassett AS, Holcomb J, Kalsi G, Third, Dr. Joseph argues that current efforts at gene finding McQuillin A, Brynjolfson J, Sigmundsson T, Petursson H, Jazin E, for psychiatric disorders have been unsuccessful. Although Zoega T, Helgason T: Genome scan meta-analysis of schizo- there certainly have been problems with replication, I dis- phrenia and bipolar disorder, part II: schizophrenia. Am J Hum agree with his interpretation. For example, a recent well- done meta-analysis of schizophrenia linkage studies identi- 2. Owen MJ, Williams NM, O’Donovan MC: The molecular genetics of schizophrenia: new findings promise new insights. Mol Psy- fied a number of genomic regions with substantial cross- study agreement (1). Several susceptibility genes for schizo- 3. Kendler KS: Schizophrenia genetics and dysbindin: a corner phrenia are beginning to be replicated at rates that are hard turned? (editorial). Am J Psychiatry 2004; 161:1533–1536 to explain if the original findings were false positive (2). I re- 4. Numakawa T, Yagasaki Y, Ishimoto T, Okada T, Suzuki T, Iwata cently summarized this evidence for dysbindin in the Journal N, Ozaki N, Taguchi T, Tatsumi M, Kamijima K, Straub RE, Wein- (3), and since then, two further positive reports have been berger DR, Kunugi H, Hashimoto R: Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia.
Fourth, unlike Dr. Joseph, I judged that it is a priori likely that genes do contribute to variation in human behavior and 5. Funke B, Finn CT, Plocik AM, Lake S, DeRosse P, Kane JM, the risk for psychiatric disorders. Behavior is instantiated in Kucherlapati R, Malhotra AK: Association of the DTNBP1 locus our brains, which are the product of evolution. The evidence with schizophrenia in a US population. Am J Hum Genet 2004; that genetic factors influence behavior in other animals is overwhelming. As Darwin recognized, behavior is as much the subject of evolution as physical traits. Is it really plausible Reprints are not available; however, Letters to the Editor can be downloaded at Am J Psychiatry 162:10, October 2005


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