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See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/11658377 Ethical Dilemmas in Prescribing Antidepressants Article in Archives of General Psychiatry · December 2001 DOI: 10.1001/archpsyc.58.11.1085 · Source: PubMed CITATIONS 2 READS 268 2 authors: Robert J Gregory State University of New York Upstate Medical University 60 PUBLICATIONS 1,085 CITATIONS SEE PROFILE Ripu Jindal University of Alabama at Birmingham 56 PUBLICATIONS 1,503 CITATIONS SEE PROFILE All content following this page was uploaded by Robert J Gregory on 20 September 2019. The user has requested enhancement of the downloaded file.

Depression Is an Adaptation D r Nesse, in raising the question, “Is Depression an Adaptation?” 1 has contributed greatly to un- derstanding this poorly understood, unpredict- able condition. He offers many possible functions for low mood and depression, but he stops short of firmly con- cluding that depression has adaptive significance. A strong case for the phylogenetically adaptive sig- nificance of depressive symptoms can be made, how- ever. Depression has a genetic component: parents of persons with major depressive disorder (MDD) are 2 to 3 times more likely to have had the disease themselves than parents of persons without depression. 2 Depres- sion is also common. Lifetime prevalence of MDD is 15.8%. 2 The rate of spontaneous mutation in humans is 1 per 10000 to 1 per 1000. 3 Taking the conservative values of 1 in 10 for MDD and a mutation rate of 1 per 1000, depression is observed at more than 100 times the mutation rate. Depression must have had a definite se- lective advantage in the ancestors of modern humans; otherwise, it would be rare. Not all modern depression is necessarily adaptive, of course. Depression consequent to hypothyroidism, for example, is clearly pathological. Also, even if some de- pression is strongly disadvantageous in modern condi- tions, the effect of negative selection on prevalence will not be apparent for many generations. Knowing that depression was adaptive to our an- cestors and may often still be adaptive as Nesse has shown, encourages a new view of this old disease. This evolu- tionary view implies that triggers of depression are likely to bear a recognizable relationship to situations in which depression would have improved fitness in ancestral con- ditions. Seasonal affective disorder, triggered by low light conditions 4 and enforcing reduced energy consumption at times when our ancestors would have suffered sea- sonal scarcity, may be an example of this. The typical relapsing, noncontinuous course of depression may have increased fitness by enabling be- haviors adapted to circumstances. Nesse, noting that re- peated episodes of endogenous depression often seem unrelated to life events, argues that these depressive episodes are not defenses. If previous depressive epi- sodes increase sensitivity to subsequent triggers, how- ever, heightened reactions to triggers we do not yet rec- ognize may explain the apparent absence of life events triggering recurrent endogenous depression. In any case, we can say with confidence that de- pression is an adaptation—the result of eons of positive selection. As the origins, physiology, and adaptive sig- nificance of depressive symptoms become better under- stood, it may become possible to predict and prevent de- pression in its more deleterious forms. Alison J. Longley, PhD Pacific Sciences Institute Box 85813 Seattle, WA 98145 (e-mail: longley@u.washington.edu) 1. Nesse RM. Is depression an adaptation? Arch Gen Psychiatry. 2000;57:14-20. 2. Kessler RC, Zhao SY, Blazer DG, Swartz M. Prevalence, correlates, and course of minor depression and major depression in the national comorbidity sur- vey. J Affect Disord . 1997;45:19-30. 3. EdwardsJH.Themutationrateinman.In:SteinbergAG,BearnAG,eds. Progress in Medical Genetics. Vol 10. New York, NY: Grune & Stratton; 1974:1-16. 4. Rosenthal NE, Sack DA, Gillin JC, Lewy A J, Goodwin FK, Davenport Y, Muel- ler PS, Newsome DA, Wehr TA. Seasonal affective disorder: a description of the syndrome and preliminary findings with light therapy. Arch Gen Psychia- try. 1984;41:72-80. Sex Hormones, Darwinism, and Depression T wo recent articles published in the same issue of the A RCHIVES 1,2 pose interesting questions re- garding the evolutionary roots of depression and depression in women. We would like to propose a point of view that connects the two, and examine its practical implications. Depression in Women vs Men. Women have an in- creased incidence of depression compared with men, by a ratio of 2:1. 2 Moreover, not only clinical depression, but also more subtle dysthymic traits have had a higher preva- lence in women after the onset of puberty. 3 In evolution- ary terms, if depression is viewed as conducive to staying out of danger in a sheltered place, 1 it may have made sense historically for women to manifest more of that trait than men. Women have traditionally been involved in child- bearing and child rearing, whereas men have tradition- ally been the providers of food, material resources, and protection. Dysthymic traits would have kept a woman shelteredfromdangertobearandcareforchildren;whereas a dysthymic man would have been impaired in perform- inghismainroleasaproviderandprotector.Assuch,traits predisposing to dysthymia may have been selected for in women, and selected against in men over time. Sex hormones may be important mediators of these evolutionarily selected behavioral differences. It is inter- esting to note the antidepressant, novelty-seeking, and ag- gression-promoting effects of testosterone. 4 It is also in- teresting to note in a woman’s life cycle, the increased incidence of first-trimester and postpartum depression. 5,6 Both are critical periods for the offspring, and a lower level of activity of the mother, keeping out of danger, may have been reproductively advantageous in times past. LETTERS TO THE EDITOR (REPRINTED) ARCH GEN PSYCHIATRY/VOL 58, NOV 2001 WWW.ARCHGENPSYCHIATRY.COM 1083 ©2001 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/11822/ by a Upstate Medical University User on 01/16/2017

Agoraphobia, 7 a condition related to depression and anxiety, has also been described in the postpartum pe- riod, as have sex differences in social anxiety disorder. 8 Depression and anxiety often coexist 9 clinically and ge- netically. It may well be that the dimensions of restraint and concern shared by both depression and anxiety 10 were evolutionarily advantageous to women in terms of child- bearing and child rearing. Depression and the Menstrual Cycle. On a smaller time scale, the menstrual cycle has a phase leading to ovula- tion and a dysphoric phase following that. The initial eu- thymic phase leading to ovulation is conducive to mating and makes evolutionary sense. Following potential im- pregnation, a lower-energy dysthymic phase would make the women stay out of danger and provide more safety for thepotentialproductofconception.Progesterone,thehor- mone that promotes pregnancy, as its name suggests, has been implicated in inducing dysthymia and overt depres- sion in susceptible individuals. 11 It seems to be the driv- ing force of premenstrual dysphoric disorder, 12 and it has been implicated in postpartum depression. 13 Practical Implications. Natural selection has selected for different traits in men and women in terms of propen- sity to mood disorders, specifically dysthymia and de- pression. The propensity varies during the menstrual cycle and life cycle of a woman, and sex hormones seem to be powerful regulators. Understanding dysthymia and de- pression in women, not as an aberration, but as some- thing that has a biological rationale, will have 2 practi- cal implications. It will remove some of the ignorance andstigmasurrounding “ moodiness ” inwomen,andmore importantly, since the evolutionary reasons that led to this biological difference are not valid anymore in mod- ern times, nature can and should be be gently corrected. Using lifestyle changes, somatic therapies, 14,15 psycho- therapy, and pharmacotherapy more proactively and in a prophylactic 16,17 fashion 13,15,18,19 at selective junctures in a woman ’ s life cycle may significantly improve their quality of life and minimize discomfort and morbidity. Alexander B. Niculescu, MD, PhD La Jolla, Calif Hagop S. Akiskal, MD Department of Psychiatry University of California San Diego School of Medicine La Jolla, CA 92093-0603 1. Nesse RM. Is depression an adaptation? Arch Gen Psychiatry. 2000;57:14-20. 2. Cyranowski JM, Frank E, Young E, Shear MK. Adolescent onset of the gender difference in rates of major depression. Arch Gen Psychiatry . 2000;57:21-28. 3. Placidi GF, Signoretta S, Liguori A, Gervasi R, Maremanni I, Akiskal HS. The semi-structured affective temperament interview (TEMPS-I): reliability prop- erties in 1010 14-26-year students. J Affect Disord. 1998;47:1-10. 4. Pope HG Jr, Kouri EM, Hudson JI. Effects of supraphysiologic doses of tes- tosterone on mood and aggression in normal men. Arch Gen Psychiatry . 2000; 57:133-140. 5. ParryBL.Reproductivefactorsaffectingthecourseofaffectiveillnessinwomen. Psychiatr Clin North Am . 1989;12:207-220. 6. Downey JI. Recognizing the range of mood disorders in women. Medscape Womens Health [serial online]. 1996;1:4E. 7. Roth M. The phobic anxiety-depersonalization syndrome. Proc R Soc Med . 1959;52:587-595. 8. Weinstock LS. Gender differences in the presentation and management of social anxiety disorder. J Clin Psychiatry . 1999;60(suppl 9):9-13. 9. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. Major depression and generalized anxiety disorder: same genes, (partly) different environ- ments? Arch Gen Psychiatry. 1992;49:716-722. 10. Akiskal HS. Toward a definition of generalized anxiety disorder as an anx- ious temperament type. Acta Psychiatr Scand. 1998;393:66-73. 11. Epperson CN, Wisner KL, Yamamoto B. Gonadal steroids in the treatment of mood disorders. Psychosom Med. 1999;61:676-697. 12. Gold JH, Endicott J, Parry BI, Severino SK, Stotland N, Frank E. Late luteal phase dysphoric disorder. In: Widiger TA, ed. DSM-IV Sourcebook . Vol 2. Washington, DC: American Psychiatric Association; 1996:317-394. 13. Abou-Saleh MT, Ghubash R, Karim L, Krymski M, Bhai I. Hormonal aspects of postpartum depression. Psychoneuroendocrinology. 1998;23:465-475. 14. ParryBL,UdellC,ElliotJA,etal.Bluntedphase-shiftresponsetomorningbright light in premenstrual dysphoric disorder. J Biol Rhythms . 1997;12:443-456. 15. Parry BL, Mostofi N, LeVeau B, et al. Sleep EEG studies during early and late partial sleep deprivation in premenstrual dysphoric disorder and nor- mal control subjects. Psychiatry Res. 1999;85:127-143. 16. Niculescu AB. Prophylactic antidepressant treatment before patients are ad- mitted. Lancet. 2000;355:406-407. 17. Wisner KL, Wheeler SB. Prevention of recurrent postpartum major depres- sion. Hosp Com Psychiatry. 1994;45:1191-1196. 18. Steiner M, Steinberg S, Stewart D, et al. Fluoxetine in the treatment of pre- menstrual dysphoria. N Engl J Med. 1995;332:1529-1534. 19. Griffin LD, Mellon SM. Selective serotonin reuptake inhibitors directly af- ter activity of neurosteroidogenic enzymes. Proc Natl Acad Sci U S A . 1999; 96:13512-13517. Clinical Depression Is a Disease State, Not an Adaptation I n his recent A RCHIVES article, Nesse 1 discusses de- pression as a possible evolutionary adaptation. Dr Nesse presents some interesting arguments that in certain stressful situations, the symptoms of depression can help increase the likelihood of an individual ’ s sur- vival. One cardinal symptom of depression that Dr Nesse fails to discuss, however, is suicidal behavior. In Darwinian analyses, natural selection will tend to favor behavioral traits that will maximize an individu- al ’ s reproductive capacity. 2 It is hard to imagine a behav- ior that is less likely to maximize an individual ’ s contri- bution to his or her gene pool than suicide. There is no way that suicidal thoughts or behaviors can lead to a per- son ’ s surviving any situation. Even if suicidal behavior in an individual somehow conveyed an advantage to the species as a whole, genetically determined suicidal be- havior would rapidly be selected against as individuals who displayed it killed themselves before being able to increase the frequency of these “ suicidal ” genes in the population by reproducing. Suicide (and hence severe depression) can thus only be seen as a disease state that conveys no benefits to an individual. Fleeting suicidal thoughts (as opposed to ac- tual suicide) are common even in mildly depressed in- dividuals. Thus, the clinical depression that psychia- trists most often see and treat must be seen as primarily a disease state and not adaptation. The depression that Dr Nesse describes is part of an individual ’ s normal be- havioral repertoire. Robert Feder, MD Behavioral Health Network 1 Pillsbury St, Suite 300 Concord, NH 03301 1. Nesse RM. Is depression an adaptation? Arch Gen Psychiatry . 2000;57:14-20. 2. Dawkins R. The Selfish Gene . New York, NY: Oxford University Press; 1990. (REPRINTED) ARCH GEN PSYCHIATRY/VOL 58, NOV 2001 WWW.ARCHGENPSYCHIATRY.COM 1084 ©2001 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/11822/ by a Upstate Medical University User on 01/16/2017

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Ethical Dilemmas in Prescribing Antidepressants I n his thoughtful article, Nesse 1 provides a persua- sive argument that depression has adaptive func- tions for some patients. But this paradigm leads to an additional question. If depression is adaptive, could its treatment be maladaptive? With the wide array of ef- fective and relatively benign pharmacological treat- ments for depression, it has become almost a “ knee- jerk ” reaction among health care practitioners to prescribe antidepressant medication when patients have symp- toms of severe depression. Given the distressing and dis- abling nature of depressive illness, many patients clearly benefit from this strategy. However, on those occasions when severe depression is serving an adaptive purpose for the patient, improvement in depressive symptoms re- sults in overall net harm. The practitioner is then faced with the ethical dilemma of considering stopping the medication in the face of patient opposition. The follow- ing cases illustrate these points. Report of Cases. Case 1. A 35-year-old woman was re- ferred by her internist. The patient experienced symp- toms consistent with a major depressive episode of 1 year ’ s duration. The onset of these symptoms coincided with a worsening relationship with her boyfriend. He had be- come increasingly critical, controlling, and sometimes physically violent toward her. The patient realized that the relationship was devastating to her self-esteem and expressed a desire to leave it. She was amenable to psy- chotherapy and was given the telephone number of a clini- cal social worker. She was also administered paroxetine hydrochloride at 20 mg/d. At follow-up 4 weeks later, her depression was 50% better. She had made an ap- pointment to see the therapist, but later canceled when her symptoms improved. During the subsequent 6 months of follow-up for medication management, her depres- sion remained in partial remission, but she continued to maintain an abusive relationship with her boyfriend. She stated that she felt too frightened to leave the relation- ship, but would like to continue paroxetine. Case 2 . A 29-year-old man who had a history of al- cohol dependence reported symptoms consistent with a major depressive episode for the previous 6 months fol- lowing diagnosis of infection with the human immuno- deficiency virus. He continued to drink a 12-pack of beer daily. The patient was warned of the depressive effects of alcohol and seemed amenable to entering an alcohol rehabilitation program. This was to be further discussed at the next visit, and in the meantime, he began a trial of fluoxetine hydrochloride at 20 mg/d. By the follow-up visit 6 weeks later, the patient ’ s depressive symptoms had largely remitted despite continued heavy alcohol use. He was no longer interested in rehabilitation, but he wished to continue the fluoxetine. In one respect, these 2 cases seem to be treatment successes (ie, major depressive illness was correctly diag- nosed, and treatment with medication resulted in sub- stantial symptomatic improvement). On the other hand, these patients continued to lead dysfunctional lives, and their motivation for major lifestyle changes seemed to de- crease as depressive symptoms improved. In other words, would the 2 patients have been better off and made more definitive changes in their lives if treatment with anti- depressants had been postponed? As physicians we try to respect patient autonomy in making such decisions. How- ever, since we are responsible for writing the prescrip- tions, we are also bound by the ethic primum non nocere . 2 Robert J. Gregory, MD Ripu D. Jindal, MD Department of Psychiatry SUNY Upstate Medical University 713 Harrison St Syracuse, NY 13210 1. Nesse RM. Is depression an adaptation? Arch Gen Psychiatry. 2000;57:14-20. 2. Beauchamp TL, Childress JF. Principles of Biomedical Ethics . New York, NY: Oxford University Press; 1989. In reply I am glad to have an opportunity to reply to a few of the many letters received about my article. Dr Longley is confident that depression is an adapta- tion because such a prevalent and costly genetic predisposi- tion is difficult to explain in terms of mutation selection bal- ance. While this principle makes sense in general, geneticists have so much trouble defining exactly when it applies 1 that I do not believe it offers strong support for the adaptive sig- nificance of depression. Wilson notes that evolutionary epi- demiology can help us find new subcategories for depres- sion. 2 I agree with this, and I look forward, in particular, to further studies investigating the personalities and reproduc- tive success of individuals whose relatives have manic- depressive illness. While questions about genetic variation are of great interest, my article was restricted to the question as to why all humans seem to share a capacity for low mood (and perhaps depression). On another occasion, I will write about the very separate question as to why natural selection has not eliminated variation in susceptibility to depression. In gen- eral, I am impressed that most anxiety and depressive disor- ders occur in the 15% of people who are “sensitive.” I suspect that these people experience benefits as well as costs. If the benefits turn out to be related to their increased concern about the feelings of other people, this will be very important as we decide how to use our impending genetic knowledge. Niculescu and Akiskal suggest that the sex difference in rates of depression may be an adaptation that reflects the increased vulnerability of women because of childbearing and child rearing. This is certainly plausible and some- what supported by the hormonal mediators described, but it seems to me to be a better potential explanation for dif- ferences in anxiety rather than depression. A complemen- tary possibility is that sensibly cautious men have had lower reproductive success than risk takers. From this viewpoint, it is not women who have excessive anxiety, but men who have too little. Regarding sex differences in depression vul- nerability, I suspect that they arise, in part, from differ- ences in emotional relationships. Backing up a moment, it is not yet certain that sex differences in depression arise di- rectly from natural selection. For instance, it seems likely (REPRINTED) ARCH GEN PSYCHIATRY/VOL 58, NOV 2001 WWW.ARCHGENPSYCHIATRY.COM 1085 ©2001 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/11822/ by a Upstate Medical University User on 01/16/2017

that the evolved predispositions of men and women interact with the opportunities in many societies that result in many women having little power, less ability to extricate them- selves from unsatisfactory situations because of this, and a resulting greater vulnerability to depression. 3 Federnotesthehugefitnesscostsofsuicide,andconcludes thatseveredepressionmust,therefore,beadiseasestate.Idid notdiscusssuicidebecauseitoverlapsonlypartlywithdepres- sion, and because bringing up the issue would have required an assessment of the problematic theory that suicide could be anadaptationthathasbeenshapedtobenefitkinwhenresources arescarce. 4,5 Thus,whiletheincreasedriskofsuicidedoesin- deed suggest strong selection against predisposing genes, this doesnotprovidedefinitiveevidenceabouttheadaptivesignifi- cance of depression. Fawcett suggests that genes that predis- pose to depression could be selected for because of benefits to othersinthegroup.Groupselectionisnowrecognizedasanon- viable evolutionary explanation, but kin selection can, as he suggests, shape costly traits that benefit relatives. Finally, Gregory and Jindal wonder if the adaptive significance of depression should influence our prescribing habits. They cite 2 cases in which pharmacological relief of depression may have inhibited motivation to escape bad life situations. This certainly happens, and it is one good reason why high-quality pharmacological treatment requires sub- stantial psychological expertise. However, drug treatment can alsoincreaseconfidenceandinitiativeinwaysthatallowsome individualstogetoutofbadsituations.Weneedcontrolledstud- ies to determine the frequency of these responses. Meanwhile, it seems likely that the intensity and duration of low mood, like pain and the signals from smoke detectors, is often far in excess of what is needed, thus making it possible to use drugs to block it safely in many instances. 6 Randolph M. Nesse, MD Department of Psychiatry Institute for Social Research University of Michigan 426 Thompson St, 5057 ISR Ann Arbor, MI 48104 1. Chadwick D, Cardew G. Variation in the Human Genome . New York, NY: John Wiley; 1996. 2. deCatanzaro D. Human suicide: a biological perspective. Behav Brain Sci. 1980; 3:265-290. 3. Wenegrat B. Illness and Power . New York, NY: University Press; 1995. 4. Wilson DR. Evolutionary epidemiology and manic depression. Br J Med Psy- chol. 1998;71:375-395. 5. Brown R, Dahlen E, Mills C, Rick J, Biblarz A. Evaluation of an evolutionary model of self-preservation and self-destruction. Suicide Life Threat Behav . 1999; 29:58-71. 6. Nesse RM. The smoke detector principle: natural selection and the regula- tion of defensive responses. In: Damasio AR, Harrington A, Kagan J, McEwen BS, Moss H, Shaikh R, eds. Unity of Knowledge . New York, NY: New York Academy of Sciences; 2001:77-85. Is Depression Adaptive for the Human Species? W hile Nesse 1 enumerates the possible ways in which low mood and/or depression may be adaptive for an individual, another possibil- ity is that depression, with its known increase in mor- bidity and mortality, may be maladaptive to the indi- vidual, but adaptive to the species. Cyranowski et al 2 point out the increase in depression and sensitivity to loss of relationships in females during childbearing years. It may be that in small bands of ancestral human hunter-gatherers, when a member lost her or his mate, the survival of the tribe was enhanced by the reduced food in- takeoftheremainingmemberofthepairviadepressionor ultimatelydeath,leavingmorefoodforthosewhoweresuc- cessfully reproducing. The genes enhancing a depressive reaction to loss would be carried by the close kin of a de- pressedindividual,andtheenhancedsurvivalofthesekin would promote the increase of depressogenic genes in the population. A similar mechanism has been postulated for increasingthefrequencyofgenesfor “ altruistic ” behavior. Robert G. Fawcett, MD Little Traverse Psychiatric Associates PC 2206 Mitchell Park, Suite 10 Petoskey, MI 49770 1. Nesse RM. Is depression an adaptation? Arch Gen Psychiatry . 2000;57:14-20. 2. Cyranowski JM, Frank E, Young E, Shear KM. Adolescent onset of the gen- der difference in lifetime rates of major depression: a theoretical model. Arch Gen Psychiatry. 2000;57:21-28. Depression Is an Adaptation T he article by Dr Nesse is a fine recap of issues as to possible adaptive aspects of depression. 1 It her- alds to a large audience that there is more to come as evolutionary science continues to reform and inte- grate studies in psychopathology. Nesse, who has al- ready done so much to foster the fruition of darwinian psychology and medicine, has done us another good turn. 2,3 Yet, for all the growth of “ evolutionary psychol- ogy ” thus far, it has yet to come to grips with genetic sci- ence. 4 In this context, the lack of reference to evolution- ary epidemiology as an operationalized mode for precise assessments is a regrettable omission. 4 As presently conceived, the indistinct nosological meaning of “ depression ” cannot constitute a proper unit of analysis since depression is likely a syndromic com- posite of homologous genetic traits, phenocopies, and proximal mechanisms. 4 However, family risk, twin and adoptee data, and DSM-IV definitions of major depres- sion approaches a good degree of naturalistic and ge- netic validity. 5,6 Hence, it is clear that several distinct natu- ralistic epigenes are likely embedded in the broad and fungible term “ depression. ” That genes linked to depres- sion arose as heuristic population polymorphisms evolved in phylogeny is a point elaborated on elsewhere. 4 With this in mind, application of Professor Ernst Mayr ’ s cogent algorithm for answering evolutionary ques- tions helps frame the issues more clearly. 7 An essential point is that, in evolutionary analysis, “ whether ” ques- tions should be answered before questions of “ how, when, where, and why. ” This promotes a less speculative and more falsifiable approach to questions concerning adap- tation and polymorphisms. It is clear, however, that some underlying geno- typy of depression is altogether too common to not have (REPRINTED) ARCH GEN PSYCHIATRY/VOL 58, NOV 2001 WWW.ARCHGENPSYCHIATRY.COM 1086 ©2001 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/11822/ by a Upstate Medical University User on 01/16/2017

been selected. So, the question ( “ Is depression an adap- tation? ” ) has an affirmative answer. How else to ac- count for all these genes in the human genome? Daniel R. Wilson, MD, PhD Department of Psychiatry Creighton University 3528 Dodge St Omaha, NE 68131 (e-mail: wilson@creighton.edu) 1. Nesse RM. Is depression an adaptation? Arch Gen Psychiatry . 2000;57:7-20. 2. Williams GW, Nesse RM. The dawn of Darwinian medicine. Q Rev Biol . 1991; 66:1-22. 3. Nesse RM, Williams GC. Why We Get Sick: The New Science of Darwinian Medi- cine . New York, NY: Vintage Books; 1994. 4. Wilson DR. Evolutionary epidemiology and manic-depression. Br J Med Psy- chol . 1998;71:375-396. 5. McKusick MM. Mendelian Inheritance in Man: Catalogs of Autosomal Domi- nant, Autosomal Recessive and X-linked Phenotypes . 9th ed. Baltimore, Md: The Johns Hopkins University Press; 1990:258. 6. Lalouel JM, Rao DC, Morton NE, Elston RC. A unified model for complex segregation analysis. Am J Hum Genet . 1983;35:939. 7. Mayr E. Population, Species and Evolution . Cambridge, Mass: Belknap/ Harvard Press; 1963. (REPRINTED) ARCH GEN PSYCHIATRY/VOL 58, NOV 2001 WWW.ARCHGENPSYCHIATRY.COM 1087 ©2001 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/11822/ by a Upstate Medical University User on 01/16/2017 View publication stats

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