BRITISH JOURNAL OF PSYCHIATRY (2000), 176, 1^5 EDITORIAL

Is psychiatry more mindful or brainier measures. More than 20 000 patients were subjected to in the USA than it was a decade ago?** between 1935 and 1950. The procedure was carried out in private as well as public hospitals, and it was endorsed by leading LEON EISENBERG academics because it sometimes `worked'. What brought about the demise of psycho- surgery was neither science nor compassion but the introduction in 1954 of chlorpro- mazine, the first in a series of drugs that made psychosurgery redundant (Pressman, 1998).1998). Academic psychiatry in the USA in the experience (Doll, 1991). Not until 1948 Good as they are, psychotropic drugs decade after the Second World War was was the first double-blind randomised con- were vastly overvalued then, as they are dominated by psychoanalytic theory. trolled trial (RCT) in medicine carried now. They were credited with emptying Psychotherapy, most of it psychodynamic out ± the Medical Research Council trial the mental hospitals, although the onset of in orientation, was the principal activity of streptomycin for treating tuberculosis de-institutionalisation had preceded the in- of clinicians in office practice. Critics like (Medical Research Council, 1948). With troduction of the drugs. In catchment areas myself who pointed out the lack of empiri- the advent of psychotropic drugs, RCTs en- where `open hospital' and `community psy- cal validation for the theory or the practice tered psychiatric research. They undoubt- chiatry' policies had been implemented, were unavailing (Eisenberg, 1962). edly improved matters, but they have not drugs had relatively little additional effect This is less surprising when considered quite taken us to the promised land. Thorn- on length of hospital stay (Shepherd et aletal,, in context: there were nono treatments of ley &ley&Adams (1998) reviewed for the 1961), but they werewere decisive in hospitals demonstrated effectiveness. Psychiatric CochraneCochraneCollaboration the first 2000 con- where patients continued to be warehoused diagnosis had low interrater reliability. trolled treatment trials in . (Odegaard, 1964). De-institutionalisation The ` sciences' were largely irrelevant Most trials were substantially flawed: they in the USA was driven more powerfully to clinical practice. To its credit, psychiatry had inadequate sample size, or too short a by economic forces (cost-shifting from state made a virtue of the failure of its biomedi- duration, uncertain blinding, inconsistent to federal budgets) than by theory or data. cal science by remaining the one medical methods of evaluation, or poor reporting. The decline of the mental hospital census speciality with a persistent interest in the Only 20 (1% of the 2000) were rated at 5 was celebrated without finding out where patient as a person in an era increasingly on a 1±5 scale of quality. Clearly, we still the former patients were. Elderly patients dominated by organ-based medical sub- have a long way to go. were `trans-institutionalised' to nursing specialities.specialities. Psychoanalysis, despite its inadequacies homes; many long-stay patients were The chance discoveries of effective as science, made a powerful contribution discharged to home addresses that no psychotropic drugs transformed the field to psychiatry. It taught trainees to listen longer existed, and became street people. in the mid-1950s. Because the new agents to patients and to try to understand their Calls to evaluate the community mental were relatively syndrome-specific, diagnos- distress ± not simply to classify them, or health movement (Eisenberg, 1968) were tic categories were defined operationally shock them, or lock them up. It made psy- as unavailing as earlier critiques of and gained reliability. The search for an chiatrists aware of the importance of mem- psychoanalysis. understanding of drug action stimulated ory, its vulnerability to distortion, and its Given the above background, is psy- research in neurobiology. Welcome as these central role in patients' stories about them- chiatry `more mindful' or `brainier' than it developments were, they embodied a peril: selves. Such narratives can be self-defeating, was a decade ago? In an immediate sense, psychiatry began to focus exclusively on and a key task of therapy was defined as the answer is a self-evident `yes'. A decade the brain as an organ. Psychiatrists found helping patients to reconstruct their auto- of imaginative research has taught us very it useful to emphasise their medical identity biographies in such a way as to foster much more about both brain and mind; for purely economic reasons. Prescribing growth. That task, no less important today, the problem that continues to bedevil us drugs and monitoring drug therapy require is being squeezed out of clinical practice conceptually is how to integrate the two a medical licence, whereas psychologists, and residency training. domains into what, for lack of a suitable social workers and counsellors can compete word, I shall have to call `brain/minded- in the psychotherapy market in the USA. ness'. The very elegance of neurobiology Mindlessness had begun to replace brain- THE EMPTYING OF MENTAL and the power of genetics dazzle us: knock lessness (Eisenberg, 1986). HOSPITALS out a gene and the effect stares you in the In the 1940s and 1950s, just about all face; study a psychosocial phenomenon medical therapeutics was based on the In the 1940s and 1950s, increasing num- and the relevant variables require sophisti- claims of expert opinion and clinical bers of severely disturbed patients were cated statistical analysis before the meaning warehoused in understaffed mental hospi- is clear. The psychosocial findings in a tals (Deutsch, 1948). No treatments given case may be more important for patient

*Plenary Session Address originally presented atthe worked; Freud himself saw no role for ana- care than finesse with genes in the labora- Royal Australian and New Zealand Congress of lysis in treating the psychoses. Desperate tory, but they do not seem as `real'. Add Psychiatry,Perth, Australia,12 April1999. times were thought to justify desperate to the medical bias in favour of the tangible

11

Downloaded from https://www.cambridge.org/core. 30 Sep 2021 at 09:31:44, subject to the Cambridge Core terms of use. EISENBERG

a market that understands doctors who pre- less time with each patient, providing psy- embryogenesis, axons from both eyes mi- scribe pills but not those who listen (and chotherapy less often, and prescribing grate to, and intermingle in, the geniculate talk) to patients and it is evident why the drugs more often than they did ten years nuclei. The segregation of separate layers `neurologising tautology' ± that only those ago (Olfson et aletal, 1999). Residency training results from bursts of electrical activity aris- facts that can be reduced to terms of nerve programmes are narrowing their focus to ing in unstable retinal ganglion cells. cells are scientific ± is growing apace DSM±IV (American Psychiatric Associa- Neither the genes governing the retina nor (Eisenberg, 1986). tion, 1994) diagnosis and algorithms for the genes governing the geniculate specify drug prescribing; much less emphasis is the ocular alternation layers; they result placed on learning how to elicit the pa- fromfrom interactioninteraction between neurons in the MANAGERIAL FETTERS tient's story and how to do psychotherapy; course of development (Penn et aletal, 1998).,1998). ON EFFECTIVE CARE psychological care in mental health `carve- At the next relay, the precise targeting of outs' is being farmed out to social workers projections from the lateral geniculate to As a clinical discipline, psychiatry is thriv- and counsellors in order to save on costs. occipital cortex in turn depends on genicu- ing as it never has. Clinicians now com- Just as the intellectual underpinnings of late activity. Abolishing geniculate action mand a range of therapeutic interventions our field are becoming brainier and more potentials leads axons to project to cortical whose efficacy has been demonstrated mindful, practitioners are being pressed to areas that they ordinarily bypass, and leads through RCTs. We have an array of proven reify DSM±IV categories and employ drugs many fewer axons to project to the striate psychosocial interventions: cognitive± as panaceas ± strategies that are neither cortex (Catalano & Shatz, 1998). Finally, behavioural therapy, interpersonal psycho- brainy nor mindful! I will not say more post-natal stimulation is required for the therapy and problem-solving therapy; and, on this matter here, as I have addressed it formation of ocular dominance columns to reduce relapse in schizophrenia, family elsewhere (Eisenberg, 1999bb).). in the occipital cortex (Wiesel, 1982). Both intervention, social skills training and re- I now turn to the expanding science eyes of the newborn must receive precisely habilitation. To the standard neuroleptic base of psychiatry and what it portends focused stimulation from the visual envir- drugs have been added the `atypical' anti- for understanding the relationship between onment during the early months of post- psychotic agents which are effective in con- mind and brain. I will highlight three natal life in order to produce a fine-tuned trolling negative symptoms. The existing research areas: the role of experience in cortical structure. stock of tricyclics and monoamine oxidase constructing the anatomy of the brain; Experience moulds the brain in a pro- inhibitors has been augmented by the selec- regeneration in the cess that continues throughout life. Finger tive serotonin reuptake inhibitors (SSRIs) (CNS); and gene effects in a social context. representation in the cortex is larger on for the treatment of depression. Nirvana, the right in professional violinists, where needless to say, is not quite here; a recent it is greater than it is in the rest of us (Elbert meta-analysis of the drug treatment of et aletal, 1995); it is also enlarged in Braille depression, while showing unequivocally THE ROLE OF EXPERIENCE readers (Sterr et aletal, 1998), and it shrinks that antidepressants are effective, found a IN CONSTRUCTING THE after deafferentation (Mogilner et aletal,, response rate no better than 50% for active ANATOMYOF THE BRAIN 1993). Brain function and structure are treatment by comparison with 32% for constantly in flux. placebo (Agency for Health Care Policy The explosion in our knowledge of the Psychotherapy that makes a difference Research, 1999). Treatment-refractory neurobiological underpinnings of psychiatry changes brain function. What is the depression remains a major clinical challenge. has been extraordinary. The increase in evidence? The symptoms of obsessive± The sciences basic to psychiatry are ad- membership of the Society for Neuro- compulsive disorder (OCD) are associated vancing in dazzling fashion. New experi- science can serve as a proxy for the pace with changes in cerebral metabolism in mental techniques in permit of change since its founding in 1971, when the basal ganglia, the limbic system, and the exploration of fundamental aspects of I joined and became member number the cortical projections from both. OCD cognition and emotion. Elegant imaging 00091. By the end of the first year, mem- symptoms are reduced by cognitive±behav- methods are demonstrating that experience bership totalled 1100. By 1986, the number ioural therapy about as effectively as they shapes, as well as being shaped by, develop- had expanded ten-fold to 11 600; by the are by SSRIs. When the patient improves, ing brain structures (Eisenberg, 1998). Epi- end of 1998, it had more than doubled what happens to cerebral activity? When demiology is providing reliable population again to 29 200. treatment produces improvement, whether data on the incidence and prevalence of Data are overthrowing dogma on all by drug or by psychotherapy, the clinical mental disorders and on the extent of the sides. The conceptual CNS is no longer a change is associated with a relative `nor- illness burden they produce (Desjarlais etet hard-wired telephone switchboard based malisation' of brain metabolism (Baxter etet alal, 1995).,1995). on a blueprint in the genome. If the ground alal, 1992). The bidirectionality of the pro- At the very time that the intellectual plan follows broad genetic specifications, cess is evident from the results of symptom and therapeutic competence of psychiatry the detailed pattern of connections results provocation. Psychological stimuli identi- has expanded, psychiatric practice has been from stimulus-induced competition be- fied by individual patients as capable of sharply circumscribed. For-profit managed tween axons for common target neurons. provoking obsessions lead to an increase care dominates the medical market-place. A review of the sequential construction of in regional blood flow in the affected areas Cost control has replaced health outcomes the visual system serves to make the point. (Rauch(Rauch et aletal, 1994). Brain imaging techni- as the criterion for public policy. Office- How are the ocular alternation layers in ques reveal linkages between mind and based psychiatrists in the USA are spending the geniculate and cortex formed? Early in brain not imagined a decade ago.

22

Downloaded from https://www.cambridge.org/core. 30 Sep 2021 at 09:31:44, subject to the Cambridge Core terms of use. IS PSYCHIATRY BRAINIER THAN A DECADE AGO?

REGENERATIONIN THE There is, of course, a great distance be- The genotype is not the phenotype. To CENTRAL NERVOUS SYSTEM tween a demonstration in a Petri dish and know completely the norm of reaction for clinical success in human infants. However, a given genotype requires placing the car- Do changes in function reflect modifica- the possibility can now be dreamt of. Will it riers of that genotype in all possible envir- tions in existing neurons or can neurons prove possible to pluripotent stem onments and observing the phenotypes multiply as well as die? The very question cells derived from foetal telencephalon or that develop. That is clearly impossible be- would have been heretical not so long ventricular ependyma stereotactically into cause the existing variety of environments ago. In 1913, the great Ramon y Cajal de- the of patients with Parkinson's dis- is immense and new environments are con- clared that nerve paths in adult brain are ease or Alzheimer's disease or after stroke stantly being produced. As the geneticist ``fixed, ended, immutable. Everything may and have function restored in part or in Dobzhansky (1995, p. 75) pointed out: ``In- die, nothing may be regenerated'' (Lowen- whole? Only careful laboratory and clinical vention of a new drug, a new diet, a new stein & Parent, 1999). Everyone believed research will yield the answer. Will that re- type of housing, a new educational system, this until the past few years. Investigators search be done? Not if `right-to-lifers' have a new political regime introduces new en- have uncovered a previously unrecognized their way. Proposals to ban research on vironments''. Statements about the herit- potential for producing new neurons in foetal tissue have been introduced before ability of a given trait without having the mammalian CNS. Progenitor cells with- many parliamentary bodies. parsed the relevant environmental variables in the dentate gyrus of the are meaningless. If a particular strain of continue to produce new granule cells wheat yields different harvests under differ- throughout life in human brains (Eriksson GENE EFFECTS IN A SOCIAL ent conditions of climate, soil and cultiva- et aletal, 1998). Granule cell proliferation is di- CONTEXT tion, how can we assume that the much minished by stress (Gould et aletal, 1998) and more complex human genome would yield enhanced by environmental enrichment The completion of the Human Genome identical behavioural phenotypes under even in aging animals (Kempermann et aletal,, Project will result in a quantum jump in different circumstances of nurture? 19981998aa,,bb). Not only are new cells produced, our ability to identify the hereditary com- We need to know what distinguishes but they migrate throughout the appropri- ponents of mental diseases. Most psychi- the gene carriers who manifest clinical dis- ate cell layers and extend axon arbours into atric disorders are non-Mendelian in ease from those who do not. To know that the furthest reaches of their normal targets inheritance; most are probably polygenic, a particular allele is a necessary condition (Lowenstein & Parent, 1999). Although and triggered by gene±environment inter- for the appearance of clinical disease does the evidence of his time led Cajal to con- actions. Under such circumstances, identi- not establish that it is a sufficient condition. clude that ``nothing may be regenerated'', fying genes that confer risk (or protection) Take the case of familial haemochromatosis, he did urge future scientists ``to work to is a formidable task. The National Human an inherited disease of iron metabolism. If impede or moderate the ...decaydecay ...and toandto Genome Research Institute expects to pro- not recognised and treated in time, iron de- re-establish normal nerve paths when dis- duce a working draft of the human genome position in the liver causes fatal cirrhosis. If ease has severed centers that were inti- by the spring of this year and the full se- the diagnosis is made before major organ mately associated''. quence by 2003 (Collins et aletal, 1998). The damage has occurred, treatment by periodic In keeping with that plea, Evan Snyder's availability of an accurate display of the phlebotomy is effective and relatively sim- laboratory has isolated stable clones of DNA base-pair sequence in all 46 human ple. When the putative gene was identified neural stem cells from the human foetal tel- chromosomes will make it feasible to iden-toiden- in 1996, enthusiasts endorsed population encephalon, clones that give rise to all of the tify incompletely penetrant risk-conferringconferringrisk- screening in order to permit early identifi- fundamental neural lineages in vitroinvitro (Flax(Flax etet genes.genes. cation. As testing proceeded, it became ap- alal, 1998). Transplanted into germinal zones At a practical level, prescribing prac- parent that only a fraction of gene carriers of a newborn mouse brain, the stem cells tices will benefit significantly. No longer manifest the clinical disease. Without migrate along established pathways, differ- will drug dosage be based on the average knowledge of the co-factors, screening entiate into multiple developmentally and response of a heterogeneous patient popu- would yield unacceptably high false regionally appropriate cell types, and inter- lation. Screening by DNA chip before treat- positive rates and lead to intervention sperse with host progenitors. Neural stem ment will enable clinicians to individualise where none is needed. Progress awaits cells are more plastic and are distributed the dose to the metabolic pattern of the pa- population-based research defining the more widely throughout the adult CNS than tient (Kleyn & Vessell, 1998). Microchips prevalence of the mutations causing haemo- anyone had thought. Cells within the epen- with tens of thousands of snippets of chromatosis, the age- and gender-related dymal lining of the adult brain ventricle are DNA will identify the genetic variation in prevalence of the various alleles, and the multipotent and can generate new neurons thethe NN-acetyltransferase alleles that underlie interactions between genotypes and environ- and glia (Johansson et aletal, 1999). They seem differential drug responses (Service, 1998). mental modifiers (Burke et aletal, 1998).,1998). to lie dormant, waiting for an activating sti- Patients who are `slow acetylators' clear The case for schizophrenia, depression mulus. Potentially, their secretory products psychotropic drugs like isoniazid and phe- or Alzheimer's disease is much more com- can replace enzymatic deficits in patients nelzine slowly and thus suffer greater toxi- plex. Twin and family studies demonstrate with inherited metabolic abnormalities. In city at a given dose. The likelihood of unequivocal genetic roots for schizophrenia tissue culture, cultivated stem cells secrete such outcomes will be minimised. and depression, yet there has been a secular enough functional hexosaminidase-A to The ability to screen the genome will be increase in the lifetime prevalence for both correct the deficiency in `Tay±Sachs' mutant a major step towards the goal of preven- disorders during this century (Cross- mouse cells. tion, but it will be no more than a first step. National Collaborative Group, 1992)

33

Downloaded from https://www.cambridge.org/core. 30 Sep 2021 at 09:31:44, subject to the Cambridge Core terms of use. EISENBERG

(further details available from author upon schooling received in youth and the preva- if she conceals it, possibly void her insur- request). This increase cannot be due to lence of dementia in old age (Katzman, ance cover. Until there is some action that shifts in the gene pool; the time interval is 1993). At present, there are no published can reduce that risk, learning that one car- far too short. The challenge is to identify data on whether there is an interaction be- ries a gene or genes that increase risk for the relevant environmental risk factors. A tween APO ee4 and number of years of mental disorder will add to stress and con- recent Danish population-based study of schooling.schooling. fer stigma without bringing benefit. Ethnic variables associated with risk for schizo- What accounts for the relationship be- groups express alarm at being targeted as phrenia found that family history of the dis- tween education and the prevalence of Alz- different when they are identified as carry- order in a parent or a sibling increased heimer's disease? Three possibilities suggest ing a disproportionate load of harmful relative risk nine-fold, but that being born themselves. First, is selection at work? Do genes. The notion that genes are destiny, in an urban as opposed to a rural area individuals who will develop dementia have although it is utterly untenable scientifi- doubled it, and that risk was greater for fewer cognitive resources early in life, caus- cally, is used to rationalise racism. Medical births in February and March and lower ing them to drop out of school? Second, is care, especially in the USA now that the for those in August and September (Mor- poor education merely a proxy for brain profit motive dominates, is less available tensentensen et aletal, 1999). Such a pattern suggests damage resulting from poverty and re- to patients from minority groups, even the presence of multiple genetic as well as peated episodes of malnutrition, trauma, al- when ability to pay is not at issue because non-genetic co-factors (Andreasen, 1999). cohol abuse, poor health care and the like? patients are covered by insurance (Eisen- Similarly, although depression is clearly Third, is it possible that the intellectual berg, 1999berg,1999aa).). familial, Brown et aletal (1995) have demon- stimulation provided by greater schooling strated that experiences of humiliation and leads to increased synaptic density during CONCLUSION entrapment after a severe life-threatening development and yields a brain reserve that event are major risk factors and that posi- delays the appearance of clinical symptoms Nature and nurture stand in reciprocity, tive events involving hope are instrumental even after amyloid protein has been depos- not opposition. Children inherit ± along in recovery from depression (Brown, 1993). ited? Disentangling these alternatives is a with their parents' genes ± their parents, The same team of investigators found that task for inter-disciplinary research. their peers and the places they inhabit. `befriending' ± that is, providing to de- Once we can identify vulnerability in a Neighbourhood and neighbours matter, as pressed women a female volunteer willing gene-based disorder, does providing infor- do parents and siblings. The distribution to meet and talk on a weekly basis, to go mation about risk to families necessarily of health and disease in human populations on excursions, and to promote `fresh-start' lead to prevention? Disappointingly, the reflects environmental factors (where experiences capable of creating new answer is no. A Swedish clinical trial of people live, what they eat, the work they hope ± improved outcome to a significant counselling parents of infants with an in- do, the air and water they consume, their degree (Harris et aletal, 1999).,1999). herited disorder revealed toxicity without degree of connection with others, and the benefit. Alpha-1-antitrypsin deficiency in- status they occupy in the social order) as CANCANEDUCATIONDELAY EDUCATIONDELAY creases susceptibility to chronic obstructive well as what they inherit, namely their rela- ALZHEIMER'S DISEASE?DISEASE ? pulmonary disease (COPD) from cigarette tive vulnerabilities and resistances to smoke. Detecting the gene in infancy environmental pathogens. The interplay between genes and environ- should make it possible to diminish the Biomedical knowledge is essential for ment in Alzheimer's disease once again il- likelihood of clinical disease by advising providing sound medical care but it is not lustrates the complexity of the interaction. parents not to smoke and thus avoid pas- sufficient; the doctor's transactions with Early-onset Alzheimer's disease is asso- sive exposure for their children. On evalu- the patient must also be informed by psy- ciated with defects in one of three identified ating a community trial of anticipatory chosocial understanding. Neither mindless- genes ± the amyloid precursor protein gene parental counselling, Theilin (1985) found ness nor brainlessness can be tolerated in on chromosome 21, and the presenilin that parental smoking persisted unabated, medicine. The unique role of psychiatry genes on chromosomes 14 and 1. However, even though the mothers had become much will be its contribution to a new paradigm: the great majority of cases are not familial. more anxious about their children than brain/mindfulness, integrating neurobiol- In late-onset Alzheimer's disease one of mothers in the control group. Mothers ogy with behaviour in its social context. the four alleles of the gene for apolipo- saw their children as condemned to COPD That is the intellectual challenge ahead. proteinprotein ee4 (APO4(APO ee4) on chromosome 19 rather than as being at risk for it. The inter- confers a four-fold increase in risk, an asso- vention was discontinued. REFERENCES ciation found in multiple ethnic popula- The very power of the genetic `para-

tions worldwide. Yet a full half of digm' will almost certainly reinforce biolo- Agency for Health Care Policy Research Alzheimer's disease patients do not carry gical reductionism in medicine. Moreover, (1999)(1999)Treatment of Depression ^ Newer APOAPO ee4 at all, and only one in six has two information can come at a heavy cost. Pharmacotherapies..AHCPRPublicationNo.99-E013. AHCPR Publication No. 99-E013. Washington, DC: Agency for Health Care Policy copies. The allele is neither necessary nor The woman who is told that she is positive Research. sufficient to cause Alzheimer's disease for BRAC 1 or 2 (and thus at much in- (Blacker, 1998). creased risk for breast cancer) has learned American Psychiatric Association (1994)Diagnostic and Statistical Manual of Mental Disorders (4th edn)edn)(4th At the same time, epidemiological that she faces a hazard without a certain re- (DSM^IV).Washington, DC: APA. studies in the USA, France, Italy, Sweden, medy and has been given information that Andreasen, N. C. (1999) Understanding the causes of Finland, Israel and China reveal a robust will, if it becomes public knowledge, make schizophrenia. New England Journal of Medicine,, 340340,, inverse correlation between the amount of her uninsurable and unemployable, or will, 645^647.645^647.

44

Downloaded from https://www.cambridge.org/core. 30 Sep 2021 at 09:31:44, subject to the Cambridge Core terms of use. IS PSYCHIATRY BRAINIER THAN A DECADE AGO?

Baxter, L. R., Schwartz, J. M., Bergman, K. S., et aletal (19 92)9 2) Caudate glucose metabolic rate changes with LEON EISENBERG, MD,Department of Social Medicine, Harvard Medical School, Boston, MA 02115,USA both drug and behavior therapy for obsessiveobsessive^ ^ compulsive disorder. Archives of General Psychiatry,, 49,, (First received 25 June 1999, final revision 30 July 1999, accepted 30 July 1999) 1999) 681^689.681^689.

Blacker, D. (1998) The genetics of Alzheimer's disease. Harvard Review of Psychiatry,, 55, 234^237.,234^237.

__ (1999(1999bb)) Whatever happened to the faculty on the revealed by magnetoencephalography. Proceedings of the Brown, G. W. (1993) Life events and affective disorder: way to the agora? Archives of Internal Medicine,, 125125,, National Academy of Sciences of the United States of replications and limitations. Psychosomatic Medicine,, 55,, 2251^2256. AmericaAmerica,, 9090, 3593^3597. 248^259.248^259. Elbert, T., Paney, C.,Wienbruch, C., et aletal (19 95) Mortensen, P.B., Pedersen, C. B.,Westergaard,T., etet __ , Harris, T.O. & Hepworth, C. (1995) Loss,Loss, Increased cortical representation of the fingers of the al (1999)(19 9 9) Effects of family history and place and season humiliation and entrapment among women developing left hand in string players. Science,, 270270, 305^307.,305^307. of birth on the risk of schizophrenia. New England depression: a patient and non-patient comparison. Journal of Medicine,, 340,603^608.,603^608. Psychological Medicine,, 25,,7^21. 7^21. Eriksson, P. S., Perfilieva, E. & Bjork-Erisson, T. (19 9 8) Neurogenesis in the adult human hippocampus. hippocampus. Odegaard, O. (1964) Pattern of discharge from Burke,W., Thomson, E., Khoury, M. J., et aletal (19 9 8) Nature Medicine,, 44, 1313^1317.,1313^1317. Norwegian psychiatric hospitals before and after the Hereditary hemochromatosis: gene discovery and its introduction of psychotropic drugs. American Journal of implication for population-based screening.Journal of the Flax, J. D., Aurora, S.,Yang, C., et aletal (19 9 8) PsychiatryPsychiatry,, 120, 772^778. American Medical Association,, 280280,172^178. Engraftable human neural stem cells respond to developmental cues, replace neurons, and express Olfson, M., Markus, S. C. & Pincus, H. A. (1999) Catalano, S. M. & Shatz, C. J. (1998) Activity-Activity- foreign genes. Nature Biotechnology,, 1616,1033^1039.,1033^1039. dependent target selection by thalamic axons. Science,, Trends in office based psychiatric practice. American 281281, 559^562.,559^562. Gould, E.,Tanapat,E., Tanapat, P., McEwen, B., et aletal (19 9 8)8)(19 Journal of Psychiatry,, 156,451^457., 451^457. Proliferation of granule cell precursors in the dentate Penn, A. A., Riquelme, P. A., Feller, M. B., et aletal Collins, F. S., Patrinos, A., Jordan, E., et aletal (19 9 8) gyrus of adult monkeys monkeys is is diminished diminished by by stress. stress. (19 9 8) CompetitioninreticulogeniculatepatterningCompetition in reticulogeniculate patterning New goals for the US Human Genome Project: 1998^ Proceedings of the National Academy of Sciences of the driven by spontaneous activity. Science,, 279,2108^2112., 2108^2112. 2003.2003. Science,, 282282, 682^689.,682^689. United States of America,, 95,,3168^3171. 3168^3171.

Cross-National Collaborative Group (1992) The Harris, T., Brown, G.W. & Robinson, R. (1999) Pressman, J. D. (1998) Last Resort: Psychosurgery and changing rate of major depression: cross-national Befriending as an intervention for chronic depression the Limits of Medicine. New York: Cambridge University comparison. Journal of the American Medical Association,, among women in an inner city.1:Randomised controlled Press. 268268, 3098^3105. trial. 2: Role of fresh-start experiences and baseline Rauch, S. L., Jenike, M. A., Alpert, N. M., et aletal (19 94) psychosocial factors in remission from depression. BritishBritish Desjarlais, R., Eisenberg, L., Good, B., et aletal (19 95)9 5) Regional cerebral blood flow measured during symptom Journal of Psychiatry,, 174174, 219^232.,219^232. World Mental Health: Problems and Priorities in Low- provocation in obsessiveobsessive^compulsive ^ compulsive disorder using Income Countries. New York: Oxford University Press. Johansson, C. B., Momma, S., Clarke, D. L., et aletal oxygen-15 labelled carbon dioxide and positron (1999)(19 9 9) Identification of a neural stem cell in the adult emission tomography. Archives of General Psychiatry,, 51,, Deutsch, A. (1948) The Shame of the States.NewYork: mammalian central nervous system. Cell,, 96, 25^34. 62^70.62^70. Harcourt, Brace. Katzman, R. (1993) Education and the prevalence of Service, R. F. (1998) Microchip arrays put DNA on the Dobzhansky,T. (1995) Evolution, Genetics, and Man.. dementia and Alzheimer's disease. Neurology,, 43,13^20.,13^20. spot. Science,, 282,,396^399. 396^399. New York: John Wiley & Sons. Kempermann, G., Brandon, E. P. & Gage, F. H. Shepherd, M., Goodman, N. & Watt, D. C. (1961) TheThe Doll, R. (1991) Development of controlled trials in (19 9 8 aa)) Environmental stimulation of 129Sv/J mice application of hospital statistics in the evaluation of preventive and therapeutic medicine. Journal of Biosocial causes increased cell proliferation and neurogenesis in pharmacotherapy in a psychiatric population. Science,, 2323, 365^378. the adult dentate gyrus. Current Biology,, 88,939^942., 939^942. Comprehensive Psychiatry,, 22,11^19. Eisenberg, L. (1962) If not now, when? American Journal __ ,,Kuhn,H.G.&Gage,F.H.(1998 Kuhn, H. G. & Gage, F. H. (1998bb)) Experience-Experience- Sterr, A., Muller, M. M., Elbert,Elbert,T., T., et aletal (19 9 8) of Orthopsychiatry,, 3232, 781^793.,781^793. induced neurogenesis in the senescent dentate gyrus. Changed perceptions in Braille readers. Nature,, 391,, Neuroscience,, 18, 3206^3212. __ (19 6 8) The need for evaluation. American Journal of 134^135.134 ^ 135. Psychiatry,, 124,1700^1701.,1700^1701. Kleyn,Kleyn,P.W.&Vessell,E.S.(1998) P.W. & Vessell, E. S. (1998) Genetic variation as Theilin, T. (1985) Psychological Effects of Neonatal aaguidetodrugdevelopment. guide to drug development. ScienceScience,, 281, 1820^1821.,1820^1821. __ (19 8 6) Mindlessness and brainlessness in psychiatry. ScreeningScreening (thesis). Student Literature.University of of Lund, Lund, British Journal of Psychiatry,, 14 8148, 497^508.,497^508. Lowenstein, D. H. & Parent, J. M. (1999) Brain, heal Sweden.Sweden. thyself. Science,, 283283, 112 6^1127.,1126^1127. __ (19 9 8) Nature, niche and nurture: the role of social Thornley, B. & Adams, C. (1998) Content and quality experience in transforming genotype into phenotype. Medical Research Council (1948) Streptomycin of 2000 controlled trials in schizophrenia over 50 years. Academic Psychiatry,, 2222, 213^222. treatment for pulmonary tuberculosis. British Medical British Medical Journal,, 317317, 1181^118 4.4.,1181^118 JournalJournal,, ii, 769.,769. __ (1999(1999aa)) Does social medicine still matter in an era of Wiesel, T. N. (1982) The Postnatal Development of the molecular medicine? Journal of Urban Health (Bulletin of Mogilner, A., Grossman, J. A. I. & Ribary,V. (1993) and the Influence of Environment (The 1981 the New York Academy of Medicine),, 7676,164^175., 164^175. Somatosensory cortical plasticity in adult humans Nobel Prize Lecture). Stockholm: Nobel Foundation.

55

Downloaded from https://www.cambridge.org/core. 30 Sep 2021 at 09:31:44, subject to the Cambridge Core terms of use.