Archives of General Psychiatry

doi: 10.1001/archpsyc.1997.01830220010001pmid: N/A

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Rapoport, Judith L.;Giedd, Jay;Kumra, Sanjiv;Jacobsen, Leslie;Smith, Amy;Lee, Paul;Nelson, Jean;Hamburger, Susan

doi: 10.1001/archpsyc.1997.01830220013002pmid: 9337768

Abstract Background: There is controversy about progression in brain abnormalities in later-onset schizophrenia. This study looked for more striking progression in brain abnormalities during adolescence in a chronically ill, treatment-refractory sample of patients with childhood-onset schizophrenia who had had more prepsychotic developmental disturbance, but clinical and neurobiological characteristics similar to those of patients with treatment-refractory adult-onset schizophrenia who have poor outcome. Methods: Anatomic brain magnetic resonance images were obtained for 16 children and adolescents with onset of schizophrenia by 12 years of age and 24 temporally yoked, age- and sex-matched healthy controls. Subjects were scanned on initial admission and rescanned after 2 years with the identical equipment and measurement methods. Results: Childhood schizophrenics showed a significantly greatenr increase in ventricular volume than did controls, for whom ventricles did not increase significantly (analysis of variance, diagnosis× time, F=16.1, P<.001). A significant decrease in midsagittal thalamic area was also seen for the schizophrenics (P=.03), which was unchanged at rescan for controls. These differential brain changes correlated significantly with each other and tended to be predicted by both prepsychotic developmental abnormality (Premorbid Assessment Scale, P=.06) and Brief Psychiatric Rating Scale at follow-up (P=.07). Conclusions: More consistent progressive ventricular enlargement was seen during adolescence for this childhood-onset sample than has been reported for adultonset populations. The brain imaging results support other clinical data showing both early and late deviations in brain development for at least this rare subgroup of treatment-refractory, very-early-onset schizophrenic patients. References 1. Asarnow J, Thompson M, Goldstein M. Childhood onset schizophrenia: a follow-up study . Schizophr Bull . 1994;20:599-617.Crossref 2. Eggers C, Bunk D. The longterm course of childhood-onset schizophrenia: a 42-year followup . Schizophr Bull . 1997;23:105-117.Crossref 3. Gordon CT, Frazier J, McKenna K, Giedd J, Zametkin A, Zahn T, Hommer D, Hong W, Kaysen D, Albus K, Rapoport J. Childhood onset schizophrenia: an NIMH study in progress . Schizophr Bull . 1994;20:697-712.Crossref 4. Alaghband-Rad J, McKenna K, Gordon CT, Albus KE, Hamburger SD, Rumsey JM, Frazier JA, Lenane MC, Rapoport JL. Childhood-onset schizophrenia: the severity of premorbid course . J Am Acad Child Adolesc Psychiatry . 1995;34:1273-1283.Crossref 5. Jacobsen LK, Rapoport JL. Childhood onset schizophrenia: implications of clinical and neurobiological research . J Child Psychol Psychiatr . In press. 6. Meltzer H, Rabinowitz J, Lee MA, Cola P, Ranjon R, Findling R, Thompson P. Age at onset and gender of schizophrenic patients in relation to neuroleptic resistance . Am J Psychiatry . 1997;154:475-482. 7. Zahn TP, Jacobsen LK, Gordon CT, McKenna K, Frazier JA, Rapoport JL. Autonomic nervous systems markers of psychopathology in childhood-onset schizophrenia . Arch Gen Psychiatry . 1997;54:904-912.Crossref 8. Jacobsen L, Hong W, Hommer DW, Castellanos FX, Frazier JA, Giedd JN, Gordon CT, Karp BI, McKenna K, Rapoport JL. Smooth pursuit eye movements in childhood-onset schizophrenia: comparison with attention-deficit hyperactivity disorder and normal controls . Biol Psychiatry . 1996;40:1144-1154.Crossref 9. Frazier J, Giedd J, Hamburger S, Albus K, Kaysen D, Vaituzis C, Rajapakse J, Lenane M, McKenna K, Jacobsen L, Gordon C, Breier A, Rapoport JL. Brain anatomic magnetic resonance in childhood onset schizophrenia . Arch Gen Psychiatry . 1996;53:617-624.Crossref 10. Bertolino A, Kumra S, Callicot J, Maltoy V, Jacobsen L, Frank J, Rapoport JL, Weinberger DA. Proton magnetic resonance imaging in childhood onset schizophrenia . Biol Psychiatry . In press. 11. Alaghband-Rad J, Hamburger SD, Giedd JN, Frazier JA, Rapoport JL. Childhood-onset schizophrenia: biological markers in relation to clinical characteristics . Am J Psychiatry . 1997;154:64-68. 12. Nasrallah J, Olson S, McCalley-Whitters M, Chapman S, Jacoby C. Cerebral ventricular enlargement in schizophrenia . Arch Gen Psychiatry . 1986;43:157-159.Crossref 13. Ilowsky B, Juliano D, Bigelow L, Weinberger D. Stability of CT scan findings in schizophrenia: results of an 8 year followup study . J Neurol Neurosurg Psychiatry . 1988;51:209-213.Crossref 14. Vita A, Sacchetti E, Valvassori C, Cazzullo CL. Brain morphology in schizophrenia: a 2-5 year CT scan followup study . Acta Psychiatr Scand . 1988;78:618-621.Crossref 15. Degreef G, Ashtari M, Wu H, Borenstein M, Geisler S, Lieberman J. Follow-up MRI study in first episode schizophrenia . Schizophr Res . 1991;5:204-206.Crossref 16. DeLisi L, Stritzke R, Riordan H. The timing of brain morphological changes in schizophrenia and their relationship to clinical outcome . Biol Psychiatry . 1992;31:241-254.Crossref 17. Jaskiw G, Juliano D, Goldberg T, Hertzman M, Urow-Hamell E, Weinberger D. Cerebral ventricular enlargement in schizophreniform disorder does not progress: a seven year followup study . Schizophr Res . 1994;14:23-28.Crossref 18. Kemali D, Maj M, Galderisi S, Milici N, Salvati A. Ventricle to brain ratio in schizophrenia: a controlled followup study . Biol Psychiatry . 1989;26:753-756.Crossref 19. Woods B, Yurgelun-Todd D, Benes FM, Frankenburg FR, Pope HG, McSparren J. Progressive ventricular enlargement in schizophrenia: comparison to bipolar affective disorder and correlation with clinical course . Biol Psychiatry . 1990;27:341-352.Crossref 20. DeLisi L, Tew W, Shu-hong X, Hoff A, Sakuma M, Kusher M, Lee G, Shedlack K, Smith A, Grimson R. A prospective follow-up study of brain morphology and cognition in first-episode schizophrenic patients: preliminary findings . Biol Psychiatry . 1995;38:349-360.Crossref 21. DeLisi L, Sakuma M, Tew W, Kushrer M, Hoff A, Grimson R. Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to onset of schizophrenia . Psychiatry Res Brain Imaging . In press. 22. Lieberman JA, Alvir JMA, Koreen A, Geisler S, Chakos M, Sheitman B, Woerner M. Psychobiotic correlates of treatment response in schizophrenia . Neuropsychopharmacology . 1996;14:13S-21S.Crossref 23. Huber G. Pneumoencephalographische undpsychopathologische Bilderbeiiendogen Psychosen . Berlin, Germany: Springer International; 1975. 24. Haug O. Pneumoencephalographic studies in mental disease . Acta Psychiatr Scand . 1962;165:1-114. 25. Giedd J, Snell J, Lange N, Rajapakse J, Kaysen D, Vaituzis C, Vauss Y, Hamburger S, Kozuch P, Rapoport J. Quantitative magnetic resonance imaging of human brain development: ages 4-18 . Cereb Cortex . 1996;6:551-560.Crossref 26. Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res . 1982-83;17:319-339.Crossref 27. Keshavan M. Neurodevelopment and schizophrenia: quo vadis? In: Keshavan M, Murray R, eds. Neurodevelopment and Adult Psychopathology . New York, NY: Cambridge University Press. In press. 28. Keshavan M, Anderson S, Pettigrew J. Is schizophrenia due to excessive pruning of the prefrontal cortex? The Feinberg hypothesis revisited . J Psychiatr Res . 1994;28:239-265.Crossref 29. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised . Washington, DC: American Psychiatric Association; 1987. 30. Kumra S, Frazier JA, Jacobsen LK, McKenna K, Gordon CT, Lenane MC, Hamburger SD, Smith AK, Albus KE, Alaghband-Rad J, Rapoport JL. Childhood-onset schizophrenia: a double-blind clozapine-haloperidol comparison . Arch Gen Psychiatry . 1996;53:1090-1097.Crossref 31. Reich W, Welner Z. Diagnostic Interview for Children and Adolescents—RC (DSM-III-R Version) . St Louis, Mo: Washington University; 1988. 32. Giedd JN, Kozuch P, Kaysen D, Vaituzis AC, Hamburger SD, Bartko J, Rapoport JL. Reliability of cerebral measures in repeated examinations with magnetic resonance imaging . Psychiatr Res Neuroimaging . 1995;61:113-119.Crossref 33. Andreasen NC. The Scale for the Assessment of Positive Symptoms (SAPS) . Iowa City, Iowa: University of Iowa; 1984. 34. Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS) . Iowa City, Iowa: University of Iowa; 1983. 35. Overall JE, Gorham DE. The Brief Psychiatric Rating Scale . Psychol Rep . 1961;10:799-812.Crossref 36. Cannon-Spoor HE, Potkin SG, Wyatt RJ. Measurement of premorbid adjustment in chronic schizophrenia . Schizophr Bull . 1982;8:470-484.Crossref 37. Snell J, Merickel M, Ortega J, Goble J, Brookerman J, Kassell N. Boundary estimation of complex objects using hierarchical active surface templates . Pattern Recognit . 1995;28:1599-1609.Crossref 38. Rasband W. Image, Version 1.6 . Bethesda, Md: National Institutes of Health; 1993. 39. Rajapakse JC, Giedd JN, DeCarli C, Snell JS, McLaughlin A, Vauss YC, Krain AL, Hamburger SD, Rapoport JL. Atechnique for single-channel MR brain tissue segmentation: application to a pediatric sample . Magn Reson Imaging . 1996;14:1053-1065.Crossref 40. Lim K, Harris D, Beal M, Hoff A, Kyungtak M, Csernansky J, Faustman W, Marsh L, Sullivan E, Pfefferbaum A. Grey matter deficits in young onset schizophrenia are independent of age of onset . Biol Psychiatry . 1996;40:4-31.Crossref 41. Frazier J, Giedd J, Kaysen D, Albus K, Hamburger SD, Alaghband-Rad J, Lenane M, McKenna K, Breier A, Rapoport J. Childhood onset schizophrenia: brain MRI rescan after 2 years of clozapine maintenance treatment . Am J Psychiatry . 1996;153:564-566. 42. Chakos MH, Lieberman JA, Bilder RM, Borenstein M, Lerner G, Bogerts B, Wu H, Kinon B, Ashtari M. Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs . Am J Psychiatry . 1994;151:1430-1436. 43. Chakos MH, Lieberman JA, Alvir J, Bilder R, Ashtari M. Caudate nuclei volumes in schizophrenic patients with typical antipsychotics or clozapine . Lancet . 1995;345:456-457.Crossref 44. Russell A, Bott L, Sammons C. The phenomenology of schizophrenia occurring in childhood . J Am Acad Child Adolesc Psychiatry . 1989;28:399-407.Crossref 45. Watkins J, Asarnow R, Tanguey P. Symptom development in childhood onset schizophrenia . J Child Psychol Psychiatry . 1988;29:865-878.Crossref 46. Waddington J, Scully P, Youssef H. Developmental trajectory and disease progression in schizophrenia: the conundrum, and insights from a 12 year prospective study in the Monaghan 101 . Schizophr Res . 1997;23:107-118.Crossref 47. Pogue-Geile M. Developmental aspects of schizophrenia . In: Keshavan M, Murray R, eds. Neurodevelopment and Adult Psychopathology . New York, NY: Cambridge University Press. In press. 48. Vicario-Abejon C, Johe K, Hazel T, Collazo D, McKay RD. Functions of basic fibroblast growth factor and neurotrophins in the differentiation of hippocampal neurons . Neuron . 1995;15:105-114.Crossref 49. Mangiarini L, Sathasiuam K, Sellar M, Cozens B, Harper A, Hetherington G, Lawton M, Trottier Y, Lehrach H, Davies S, Bates G. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurobiological phenotype in transgenic mice . Cell . 1996;87:493-506.Crossref 50. Murray R. Neurodevelopmental schizophrenia: the rediscovery of dementia praecox . Br J Psychiatry . 1994;165:6-12.

Zahn, Theodore P.;Jacobsen, Leslie K.;Gordon, Charles T.;McKenna, Kathleen;Frazier, Jean A.;Rapoport, Judith L.

doi: 10.1001/archpsyc.1997.01830220020003pmid: 9337769

Abstract Background: Consistent abnormalities in peripheral indicators of autonomic activity, ie, skin conductance (SC) and heart rate (HR), have been reported in adult-onset schizophrenia. Herein, we use these markers to test the hypothesis of continuity between childhood-onset schizophrenia and adult-onset schizophrenia. Methods: Skin conductance and HR were recorded from 21 severely ill children and adolescents (mean age, 14.1 years) with childhood-onset (>12 years) schizophrenia (patient group) and from 54 age-matched controls (control group) during a rest period, a series of innocuous tones, reaction time insructions, and a simple warned reaction time task. Results: During rest, patients had higher rates of spontaneous SC responses (SCRs) and HRs than controls, but their SC level was marginally lower and declined more slowly over time. Half of the patients, compared with 4% of the controls, failed to give SC-orienting responses to the first 2 tones. Patients who responded had impaired SCR magnitudes, and their habituation was more erratic than that of controls. The increase in SC level and SCR frequency at the onset of the task period was greatly attenuated in the patients, so that both variables were higher in controls. Patients had smaller SCRs and anticipatory HR responses to the reaction time stimuli. Skin conductance nonresponding was associated with negative and total symptoms, and spontaneous SCR frequency was associated with positive symptoms. Conclusions: The findings show similar abnormalities in autonomic nervous system activity in childhoodonset schizophrenia to those found in adult chronic schizophrenia, thus supporting the hypothesis of continuity of the childhood and adult forms of the illness. Comparisons with data from other childhood disorders suggest that the combination of low-elicited SC activity with high levels of spontaneous SC activity may be specific to schizophrenia. References 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised . Washington, DC: American Psychiatric Association; 1987. 2. Karno M, Norquist GS. Schizophrenia: epidemiology . In: Kaplan HI, Sacock BJ, eds. Comprehensive Textbook of Psychiatry . 5th ed. Baltimore, Md: Williams & Wilkins; 1989;1:699-705. 3. Kramer M. Population changes and schizophrenia, 1970-1985 . In: Wynne LC, Cromwell RL, Matthysse S, eds. The Nature of Schizophrenia: New Approaches to Research and Treatment New York, NY: John Wiley & Sons Inc; 1978:545-571. 4. Asarnow JR. Annotation: childhood-onset schizophrenia . J Child Psychol Psychiatr . 1994;35:1345-1371.Crossref 5. Rutter M. Childhood schizophrenia reconsidered . J Aut Child Schizophr . 1972;2:315-337.Crossref 6. Werry JS. Child and adolescent (early onset) schizophrenia: a review in light of DSM-III-R . J Aut Dev Dis . 1992;22:601-624.Crossref 7. Gordon CT, Frazier JA, McKenna K, Giedd J, Zametkin A, Zahn T, Hommer D, Hong W, Kaysen D, Albus KE, Rapoport JL. Childhood-onset schizophrenia: an NIMH study in progress . Schizophr Bull . 1994;20:697-712.Crossref 8. Alaghband-Rad J, McKenna K, Gordon CT, Albus KE, Hamburger SD, Rumsey JM, Frazier JA, Lenane MC, Rapoport JL. Childhood onset schizophrenia: the severity of premorbid course . J Am Acad Child Adolesc Psychiatry . 1995;34:1273-1283.Crossref 9. Asarnow RF, Grandholm E, Sherman T. Span of apprehension in schizophrenia . In: Steinhauer SR, Gruzelier JH, Zubin J, eds. Handbook of Schizophrenia . Amsterdam, the Netherlands: Elsevier Science Publishers; 1991;5:335-370. 10. Asarnow RF, Sherman T. Studies of visual information processing in schizophrenic children . Child Dev . 1984;55:249-261.Crossref 11. Strandburg RJ, Marsh JT, Brown WS, Asarnow RF, Guthrie D. Informationprocessing deficits across childhood- and adult-onset schizophrenia . Schizophr Bull . 1994;20:685-695.Crossref 12. Jacobsen LK, Hong WL, Hommer DW, Hamburger SD, Castellanos FX, Frazier JA, Giedd JN, Gordon CT, Karp BI, McKenna K, Rapoport JL. Smooth pursuit eye movements in childhood onset schizophrenia: comparison with ADHD and normal controls . Biol Psychiatry . 1996;40:1144-1154.Crossref 13. Frazier JA, Giedd JN, Hamburger SD, Albus KE, Kaysen D, Vaituzis AC, Rajapakse JC, Lenane MC, McKenna K, Jacobsen LK, Gordon CT, Breier A, Rapoport JL. Brain anatomic magnetic resonance imaging in childhood-onset schizophrenia . Arch Gen Psychiatry . 1996;53:617-624.Crossref 14. Bernstein AS, Frith CD, Gruzelier JH. An analysis of the skin conductance—orienting response in samples of American, British, and German schizophrenics . Biol Psychol . 1982;14:155-211.Crossref 15. Zahn TP, Frith CD, Steinhauer SR. Autonomic functioning in schizophrenia: electrodermal activity, heart rate, pupillography . In: Steinhauer SR, Gruzelier JH, Zubin J, eds. Handbook of Schizophrenia . Amsterdam, the Netherlands: Elsevier Science Publishers; 1991;5:185-224. 16. Ohman A. Electrodermal activity and vulnerability to schizophrenia: a review . Biol Psychol . 1981;12:87-145.Crossref 17. Frith CD, Stevens M, Johnstone EC, Crow TJ. Skin conductance responsivity during acute episodes of schizophrenia as a predictor of symptomatic improvement . Psychol Med . 1979;9:101-106.Crossref 18. Zahn TP, Carpenter WTJ, McGlashan TH. Autonomic nervous system activity in acute schizophrenia, II: relationships to short-term prognosis and clinical state . Arch Gen Psychiatry . 1981;38:260-266.Crossref 19. Iacono WG, Lykken DT, Peloquin LJ, Lumry AE, Valentine RH, Tuason VB. Electrodermal activity in euthymic unipolar and bipolar affective disorders . Arch Gen Psychiatry . 1983;40:557-565.Crossref 20. Zahn TP. Psychophysiological approaches to psychopathology . In: Coles MGH, Donchin E, Porges SW, eds. Psychophysiology: Systems, Processes, and Applications . New York, NY: Guilford Press; 1986:508-610. 21. Straube ER, Schied HW, Rein W, Breyer-Pfaff U. Autonomic nervous system differences as predictors of short-term outcome in schizophrenics . Pharmacopsychiatry . 1987;20:105-110.Crossref 22. Frazier JA, Gordon CT, McKenna K, Lenane MC, Jih D, Rapoport JL. An open trial of clozapine in 11 adolescents with childhood-onset schizophrenia . J Am Acad Child Adolesc Psychiatry . 1994;33:658-663.Crossref 23. Kumra S, Frazier JA, Jacobsen LK, McKenna K, Gordon CT, Lanane MC, Hamburger SD, Smith AK, Albus KE, Alaghband-Rad J, Rapoport JL. Childhood-onset schizophrenia: a double-blind clozapine-haloperidol comparison . Arch Gen Psychiatry . 1996;53:1090-1097.Crossref 24. Bernstein AS, Taylor KW, Starkey P, Juni S, Lubowsky J, Paley H. Bilateral skin conductance, finger pulse volume, and EEG orienting response to tones of differing intensities in chronic schizophrenics and controls . J Nerv Ment Dis . 1981;169:513-528.Crossref 25. Straube E. On the meaning of electrodermal nonresponding in schizophrenia . J Nerv Ment Dis . 1979;167:601-611.Crossref 26. Kim DK, Shin YM, Kim CE, Cho HS, Kim YS. Electrodermal responsiveness, clinical variables, and brain imaging in male chronic schizophrenics . Biol Psychiatry . 1993;33:786-793.Crossref 27. Reich W, Welner Z. DICA-RC (DSM-III-R Version), Revised Version V-R . St Louis, Mo: Washington University; 1988. 28. Orvaschell H, Tabrizi MA, Chambers W. Schedule for Affective Disorders and Schizophrenia for School-Age Children—Epidemiologic Version (Kiddie-SADSE) . 3rd ed. New York, NY: New York State Psychiatric Institute and Yale University School of Medicine; 1980. 29. McKenna K, Gordon CT, Lenane MC, Kaysen D, Rapoport JL. Looking for childhoodonset schizophrenia: the first 71 cases screened . J Am Acad Child Adolesc Psychiatry . 1994;33:636-644.Crossref 30. Herjanic B, Campbell W. Differentiating psychiatrically disturbed children on the basis of a structured interview . J Abnorm Child Psychol . 1977;5:127-134.Crossref 31. Herjanic B, Reich W. Development of a structured psychiatric interview for children: agreement between child and parent on individual symptoms . J Abnorm Child Psychol . 1982;10:307-324.Crossref 32. Overall JE, Hollister LE, Pichot P. Major psychiatric disorders: a fourdimensional model . Arch Gen Psychiatry . 1967;24:146-151.Crossref 33. Pickar D, Labarca R, Doran AR, Wolkowitz OM, Roy A, Breier A, Linnoila M, Paul SM. Longitudinal measurement of plasma homovanillic acid in schizophrenic patients: correlation with psychosis and response to neuroleptic treatment . Arch Gen Psychiatry . 1986;43:669-676.Crossref 34. Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS) . Iowa City: University of Iowa; 1983. 35. Andreasen NC. The Scale for the Assessment of Positive Symptoms (SAPS) . Iowa City: University of Iowa; 1984. 36. Zahn TP, Rosenthal D, Lawlor WG. Electrodermal and heart rate orienting reactions in chronic schizophrenia . J Psychiatr Res . 1968;6:117-134.Crossref 37. Zahn TP, Carpenter WT, McGlashan TH. Autonomic nervous system activity in acute schizophrenia, I: method and comparison with normal controls . Arch Gen Psychiatry . 1981;38:251-258.Crossref 38. Dixon WJ. BMDP Statistical Software Manual . Berkeley, Calif: University of California Press; 1992. 39. Levinson DF, Edelberg R, Bridger WH. The orienting response in schizophrenia: proposed resolution of a controversy . Biol Psychiatry . 1984;19:489-507. 40. Siegel, S. Nonparametric Statistics for the Behavioral Sciences . New York, NY: McGraw-Hill Book Co; 1956. 41. Gruzelier J, Eves F, Connolly J, Hirsch S. Orienting, habituation, sensitisation, and dishabituation in the electrodermal system of consecutive, drug free, admissions for schizophrenia . Biol Psychol . 1981;12:187-209.Crossref 42. Zahn TP, Pickar D, Haier RJ. Effects of clozapine, fluphenazine, and placebo on reaction time measures of attention and sensory dominance in schizophrenia . Schizophr Res . 1994;13:133-144.Crossref 43. Toone BK, Cooke E. Lader MH. Electrodermal activity in the affective disorders and schizophrenia . Psychol Med . 1981;11:497-508.Crossref 44. Cooklin R, Sturgeon D, Leff J. The relationship between auditory hallucinations and spontaneous fluctuations of skin conductance in schizophrenia . Br J Psychiatry . 1983;142:47-52.Crossref 45. Ohman A, Nordby H, d'Elia G. Orienting in schizophrenia: habituation to auditory stimuli of constant and varying intensity in patients high and low in skin conductance responsivity . Psychophysiology . 1989;26:48-61.Crossref 46. Bartfai A, Levander S, Edman G, Schalling D, Sedvall G. Skin conductance responses in unmedicated recently admitted schizophrenic patients . Psychophysiology . 1983;20:180-187.Crossref 47. Zahn TP. Autonomic Reactivity and Behavior in Schizophrenia: Psychiatric Research Report 19 . Washington, DC: American Psychiatric Association; 1964. 48. Zahn TP. Psychophysiological concomitants of task performance in schizophrenia . In: Kietzman ML, Sutton S, Zubin J, eds. Experimental Approaches to Psychopathology . New York, NY: Academic Press; 1975:109-131. 49. Albus M, Ackenheil M, Engel RR, Muller F. Situational reactivity of autonomic functions in schizophrenic patients . Psychiatry Res . 1982;6:361-370.Crossref 50. Kelly D. Anxiety and Emotions . Springfield, III: Charles C Thomas Publisher; 1980. 51. Gruzelier JH, Venables PH. Skin conductance orienting activity in a heterogeneous sample of schizophrenics: possible evidence of limbic dysfunction . J Nerv Ment Dis . 1972;155:277-287.Crossref 52. Spohn HE, Coyne L, Wilson JK, Hayes K. Skin-conductance orienting response in chronic schizophrenics: the role of neuroleptics . J Abnorm Psychol . 1989;98:478-486.Crossref 53. Zahn TP, Pickar D. Autonomic effects of clozapine in schizophrenia: comparison with placebo and fluphenazine . Biol Psychiatry . 1993;34:3-12.Crossref 54. Zahn TP, Pickar D. Effects of a low-anticholinergic neuroleptic on autonomic activity in schizophrenia. Presented at the meeting of the Society for Psychophysiological Research;October 13, 1995; Toronto, Ontario. 55. Iacono WG, Lykken DT. The orienting response: importance of instructions . Schizophr Bull . 1979;5:11-14.Crossref 56. Alm T, Lindstrom LH, Ost LG, Ohman A. Electrodermal non-responding in schizophrenia: relationships to attentional, clinical, biochemical, computed tomographical and genetic factors . Int J Psychophysiol . 1984;1:195-208.Crossref 57. Ohman A, Ohlund LS, Alm T, Wieselgren IM, Ost LG, Lindström LH. Electrodermal nonresponding, premorbid adjustment, and symptomatology as predictors of long-term social functioning in schizophrenics . J Abnorm Psychol . 1989;98:426-435.Crossref 58. Ohman A. The orienting response, attention and learning: an informationprocessing perspective . In: Kimmel HD, van Olst EH, Orlebeke JF, eds. The Orienting Reflex in Humans . Hillsdale, NJ: Erlbaum; 1979:443-472. 59. Frith CD. The positive and negative symptoms of schizophrenia reflect impairments in the perception and initiation of action . Psychol Med . 1987;17:631-648.Crossref 60. Raine A, Reynolds GP, Sheard C. Neuroanatomical correlates of skin conductance orienting in normal humans: a magnetic resonance imaging study . Psychophysiology . 1991;28:548-558.Crossref 61. Hazlett EA, Dawson ME, Buchsbaum MS, Nuechterlein KH. Reduced regional brain glucose metabolism assessed by positron emission tomography in electrodermal nonresponder schizophrenics: a pilot study . J Abnorm Psychol . 1993;102:39-46.Crossref 62. Levy DL, Holzman PS, Matthysse S, Mendell NR. Eye tracking dysfunction in schizophrenia: a critical perspective . Schizophr Bull . 1993;19:461-536.Crossref 63. Porges SW, Fox NA. Developmental psychophysiology . In: Coles MGH, Donchin E, Porges SW, eds. Psychophysiology: Systems, Processes, and Applications . New York, NY: Guilford Press; 1986:611-625. 64. Dawson ME, Nuechterlein KH, Schell AM, Mintz J. Concurrent and predictive electrodermal corelates of symptomatology in recent-onset schizophrenic patients . J Abnorm Psychol . 1992;101:153-164.Crossref 65. Green MF, Nuechterlein KH, Satz P. The relationship of symptomatology and medication to electrodermal activity in schizophrenia . Psychophysiology . 1989;26:148-157.Crossref 66. Olbrich R, Mussgay L. Spontaneous fluctuations of electrical skin conductance and the actual clinical state in schizophrenics . Psychopathology . 1987;20:18-22.Crossref 67. Green WH, Padron-Gayol M, Hardesty AS, Bassiri M. Schizophrenia with childhood onset: a phenomenological study of 38 cases . J Am Acad Child Adolese Psychiatry . 1992;31:968-976.Crossref 68. Russel AT. The clinical presentation of childhood-onset schizophrenia . Schizophr Bull . 1994;20:631-646.Crossref 69. Spencer EK, Campbell M. Children with schizophrenia: diagnosis, phenomenology, and pharmacotherapy . Schizophr Bull . 1994;20:713-725.Crossref 70. Zahn TP, Kruesi MJP. Autonomic activity in boys with disruptive behavior disorders . Psychophysiology . 1993;30:605-614.Crossref 71. Zahn TP, Rumsey JM, Van Kammen DP. Autonomic nervous system activity in autistic, schizophrenic, and normal men: effects of stimulus significance . J Abnorm Psychol . 1987;96:135-144.Crossref 72. Zahn TP, Leonard HL, Swedo SE, Rapoport JL. Autonomic activity in children and adolescents with obsessive-compulsive disorder . Psychiatry Res . 1996;60:67-76.Crossref 73. Berg CJ, Zahn TP, Behar D, Rapoport JL. Childhood obsessive-compulsive disorder: an anxiety disorder? In: Gittelman R, eds. Anxiety Disorders of Childhood . New York, NY: Guilford Press; 1986:126-135. 74. Bernstein AS, Riedel JA, Graae F, Seidman D, Steele H, Connolly J, Lubowsky J. Schizophrenia is associated with altered orienting activity: depression with electrodermal (cholinergic?) deficit, and normal orienting response . J Abnorm Psychol . 1988;97:3-12.Crossref 75. Bernstein AS, Schnur DB, Bernstein P, Yeager A, Wrable J, Smith S. Differing patterns of electrodermal and finger pulse responsivity in schizophrenia and depression . Psychol Med . 1995;25:51-62.Crossref 76. Thorell LH, Kjellman BF, d'Elia G. Electrodermal activity in antidepressant medicated and unmedicated depressive patients and in matched healthy subjects . Acta Psychiatr Scand . 1987;76:684-692.Crossref

doi: 10.1001/archpsyc.1997.01830220028004pmid: N/A

This article is only available in the PDF format. Download the PDF to view the article, as well as its associated figures and tables. Abstract Error in Reference Section. In the article titled "Increased Concentrations of Presynaptic Proteins in the Cingulate Cortex of Subjects With Schizophrenia," published in the June Archives (1997;54:559-566), there was an error in the publication information of reference 26. It should have read: Honer WG, Falkai P, Young C, Wang T, Xie J, Bonner J, Hu L, Boulianne GL, Lu Z, Trimble WS. Cingulate cortex synaptic terminal proteins and neural cell adhesion molecule in schizophrenia. Neuroscience. 1997;78:99-110.

Nasrallah, Henry A.;Tolbert, Herman A.

doi: 10.1001/archpsyc.1997.01830220031005pmid: 9337770

Abstract The LONG-HELD notion that childhoodonset schizophrenia before the age of 12 years is a different disorder than adult-onset schizophrenia continues to crumble in the face of new data. The articles by Zahn et al1 and Rapoport et al2 not only provide important scientific data to that effect but also represent an incremental step in establishing that the psychotic clinical brain disorder that we call "schizophrenia" is one illness that may manifest throughout the life cycle. Accumulating evidence related to phenomenological, neurobiological, and pharmacological characteristics and course and outcome strongly indicate that the onset of schizophrenia may occur at age 10, 20, 30, or even 60 or 70 years.3 See also pages 897 and 904 As always, new knowledge enlightens but also provokes additional questions. The continuity of neurophysiological and neuroanatomical findings in childhood- and adult-onset schizophrenia underscores the structural and functional primary brain "lesion" in schizophrenia. For References 1. Zahn, TP, Jacobsen LK, Gordon CT, McKenna K, Frazier JA, Rapoport JL. Autonomic nervous system markers of psychopathology in childhoodonset schizophrenia . Arch Gen Psychiatry . 1997;54:904-912.Crossref 2. Rapoport JL, Giedd J, Kumra S, Jacobsen L, Smith A, Lee P, Nelson J, Hamburger S. Childhoodonset schizophrenia: progressive ventricular change during adolescence . Arch Gen Psychiatry . 1997;54:897-903.Crossref 3. Jeste DV, Harris MJ, Pearlson GD, Rabins P, Lesser I, Miller B, Coles C, Yassa R. Late-onset schizophrenia: studying clinical validity . Psychiatr Clin North Am . 1988;11:1-13. 4. Nasrallah HA, Olson SC, McCalley-Whitters M, Chapman S, Jacoby CG. Cerebral ventricular enlargement in schizophrenia: a preliminary follow-up study . Arch Gen Psychiatry . 1986;43:157-159.Crossref 5. Nowakowski RS. Basic concepts of CNS development . Child Dev . 1987;58:568-595.Crossref 6. Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res . 1982;17:319-339.Crossref 7. Chakos MH, Lieberman JA, Bilder RM, Bornstein M, Lerner G, Bogerts B, Wult, Kinon B, Ashtari M. Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs . Am J Psychiatry . 1994;151:1430-1436. 8. Nasrallah HA, Skinner TE, Schmalbrock P, Robitaille PM. In vivo 1H nuclear magnetic resonance spectroscopy of the hippocampal formation in schizophrenia . Br J Psychiatry . 1994;165:481-485.Crossref 9. Andreasen NC, Flaum M, Swayze V, O'Leary DS, Alliger R, Cohen G, Ehrhardt J, Yuh WTC. Intelligence and brain structure in normal individuals . Am J Psychiatry . 1993;150:130-134. 10. Cowell PE, Turetsky B I, Gur RC, Grossman RI, Shtasel DL, Gur RE. Sex differences in aging of the human frontal and temporal lobes . J Neurosci . 1994;14:4748-4755. 11. Nasrallah HA. Neurodevelopmental pathogenesis of schizophrenia . Psychiatr Clin North Am . 1993;16:269-280. 12. Nasrallah HA. Neurodevelopmental aspects of bipolar affective disorder . Biol Psychiatry . 1991;29:1-2.Crossref

Alexopoulos, George S.;Meyers, Barnett S.;Young, Robert C.;Campbell, Scott;Silbersweig, David;Charlson, Mary

doi: 10.1001/archpsyc.1997.01830220033006pmid: 9337771

Abstract We propose that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes. The "vascular depression" hypothesis is supported by the comorbidity of depression, vascular disease, and vascular risk factors and the association of ischemic lesions to distinctive behavioral symptoms. Disruption of prefrontal systems or their modulating pathways by single lesions or by an accumulation of lesions exceeding a threshold are hypothesized to be central mechanisms in vascular depression. The vascular depression concept can generate studies of clinical and heuristic value. Drugs used for the prevention and treatment of cerebrovascular disease may be shown to reduce the risk for vascular depression or improve its outcomes. The choice of antidepressants in vascular depression may depend on their effect on neurologic recovery from ischemic lesions. Research can clarify the pathways to vascular depression by focusing on the site of the lesion, the resultant brain dysfunction, the presentation of depression and time of onset, and the contribution of nonbiological factors. References 1. Alexopoulos GS. Clinical and biological findings in late-onset depression . In: Tasman A, Goldfinger SM, Kaufman CA, eds. Review of Psychiatry . Washington, DC: American Psychiatric Press; 1990;9:249-262. 2. Alexopoulos GS, Meyers BS, Young RC, Charlson M, Silversweig D. The clinical presentation of'vascular depression.' In: New research program and abstracts, annual meeting of the American Psychiatric Association; May 4-9, 1996; New York, NY. 3. Alexopoulos GS, Young RC, Meyers BS. Geriatric depression: age of onset and dementia . Biol Psychiatry . 1993;34:141-145.Crossref 4. Alexopoulos GS, Meyers BS, Young RC, Mattis S, Kakuma T. The course of geriatric depression with 'reversible dementia.' Am J Psychiatry . 1993;150:1693-1699. 5. Alexopoulos GS, Young RC, Shindledecker R. Brain computed tomography in geriatric depression and primary degenerative dementia . Biol Psychiatry . 1992;31:591-599.Crossref 6. Jacoby RJ, Levy R. Computed tomography in the elderly, 3: affective disorder . Br J Psychiatry . 1980;136:270-275.Crossref 7. Coffee CE, Figiel GS, Djang WT, Cress M, Saunders WB, Weiner RD. Leukoencephalopathy in elderly depressed patients referred for ECT . Biol Psychiatry . 1988;24:143-161.Crossref 8. Alexopoulos GS, Vrontou C, Kakuma T, Meyers BS, Young RC, Klausner E, Clarkin J. Disability in geriatric depression . Am J Psychiatry . 1996;153:877-885. 9. Roth M, Kay DWK. Affective disorders arising in the senium, II: physical disability as an etiological factor . J Ment Sci . 1956;102:141-150. 10. Jacoby RJ, Levy R, Bird JM. Computed tomography and the outcome of affective disorder: a follow-up study of elderly subjects . Br J Psychiatry . 1981;139:288-292.Crossref 11. Baron M, Mendlewicz J, Klotz J. Age of onset and genetic transmission in affective disorders . Acta Psychiatr Scand . 1981;64:373-380.Crossref 12. Conwell Y, Nelson JC, Kim KM, Majure CM. Depression in late life: age of onset as marker of a subtype . J Affect Dis . 1989;17:189-195.Crossref 13. Greenwald BS, Kramer-Ginsberg E. Age of onset in geriatric depression: relationship to clinical variables . J Affect Dis . 1988;15:61-68.Crossref 14. Herrmann N, Lieff S, Silberfeld M. The effect of age of onset on depression in the elderly . J Geriatr Psychiatry Neurol . 1989;2:182-187.Crossref 15. Wiener P, Alexopoulos GS, Kakuma T, Meyers BS, Rosendhal E, Chester J. The limits of history taking in geriatric depression . Am J Geriatr Psychiatry . 1997;5:116-125.Crossref 16. Post F. The Significance of Affective Disorders in Old Age . London, England: Institute of Psychiatry; 1962. Maudsley Monograph 10. 17. Post F, Schulman K. New views on old age affective disorder . In: Aire T, ed. Recent Advances in Psychogeriatrics . New York, NY: Churchill Livingstone Inc; 1985:119-140. 18. Luber MP, Alexopoulos GS, Hollenberg J, Charlson ME, Callahan M. Recognition, treatment, comorbidity and resource utilization of depressed patients in a general medical practice. In: Program and abstracts of the annual meeting of the Society of General Internal Medicine; May 2-4, 1996; Washington, DC. 19. Peterson JC, Williams-Russo PG, Charlson ME, Meyers BS. Longitudinal course of new onset depression after cardiac bypass surgery. In: Programs and abstracts of the 10th Annual International Conference on Mental Health Problems in the General Health Care Sector, National Institute of Mental Health; July 15-16, 1996; Bethesda, Md. 20. Rabkin JG, Charles E, Kass F. Hypertension and DSM-III depression in psychiatric outpatients . Am J Psychiatry . 1983;140:1072-1074. 21. Carney RM, Rich WM, Tevelde A, Saini J, Clark K, Jaffe AS. Major depressive disorder in coronary artery disease . Am J Cardiol . 1987;60:1273-1275.Crossref 22. Sulzer DL, Levin HS, Mahler ME, High WM, Cummings JL. A comparison of psychiatric symptoms in vascular dementia and Alzheimer's disease . Am J Psychiatry . 1993;150:1806-1812. 23. Starkstein SE, Robinson RG. Depression in cerebrovascular disease . In: Depression in Neurological Disease . Baltimore, Md: The Johns Hopkins University Press; 1993:28-49. 24. Folstein MF, Maiberger R, McHugh PR. Mood disorders as a specific complication of stroke . J Neurol Neurosurg Psychiatry . 1971;40:1018-1020.Crossref 25. Ebrahim S, Barer K, Nouri F. Affective illness after stroke . Br J Psychiatry . 1987;154:170-182. 26. Mendez MF, Adams NL, Lewandoski KS. Neurobehavioral changes associated with caudate lesions . Neurology . 1989;39:349-354.Crossref 27. Fujikawa T, Yamawaki S, Touhouda Y. Incidence of silent cerebral infarction in patients with major depression . Stroke . 1993;24:1631-1634.Crossref 28. Ryan RN, Manolio TA, Schertz LD, Jungteis C, Poirier VC, Elster AD, Kronmal RA. A method of using MR to evaluate the effects of cardiovascular disease on the brain: the cardiovascular health study . Am J Neuroradiol . 1994;15:1625-1633. 29. Krishnan KRR, GoliV, Ellinwood EH, France RD, Blazer DZ, Nemeroff CB. Leukoencephalopathy in patients diagnosed as major depressive . Biol Psychiatry . 1988;23:519-522.Crossref 30. Coffey CE, Figiel GS, Djang WT, Cross M, Saunders WB, Weiner RD. Leukoencephalopathy in elderly depressed patients referred for ECT . Biol Psychiatry . 1988;23:519-522.Crossref 31. Coffey CE, Figiel GS, Djang WT, Saunders WB, Weiner RD. White matter hyperintensity on MRI clinical and neuroanatomic correlates in the depressed elderly . J Neuropsychiatry Clin Neurosci . 1989;1:135-144. 32. Coffey CE, Figiel FS. Djang WT, Weiner RD. Subcortical hyperintensity on MRI: a comparison of normal and depressed elderly subjects . Am J Psychiatry . 1990;147:187-189. 33. Coffey CE, Wilkinson WE, Weiner RD, Paraschos IA, Djang WT, Webb MC, Figiel GS, Spritzer CE. Quantitative cerebral anatomy in depression: a controlled magnetic resonance imaging study . Arch Gen Psychiatry . 1993;50:7-16.Crossref 34. Braffman BH, Zimmerman RA, Trojanowski JQ, Gonatas NK, Hickey WF, Schlaepler WW. Brain MRI: pathologic correlation with gross and histopathology, 2: hyperintense white-matter foci in the elderly . AJNR Am J Neuroradiol . 1988;151:559-566. 35. Fazekas F, Niederkorn K, Schmidt R, Offenbacher H, Honner S, Bertha G, Lechner H. White matter signal abnormalities in normal individuals: correlation with carotid ultrasonography, cerebral blood flow, measurements, and cerebrovascular risk factors . Stroke . 1988;19:1285-1288.Crossref 36. Miller DS, Kumar A, Yousem DM, Gottlieb GL. MRI high-intensity signals in late-life depression and Alzheimer's disease: a comparison of subjects without major vascular risk factors . Am J Geriatr Psychiatry . 1994;2:332-337.Crossref 37. Lesser IM, Hill-Gutierrez E, Miller BL, Boone KB. Late-onset depression with white matter lesions . Psychosomatics . 1993;34:364-367.Crossref 38. Fujikawa T, Yamawaki S, Touhouda Y. Background factors and clinical symptoms of major depression with silent cerebral infarction . Stroke . 1994;25:798-801.Crossref 39. Baldwin RC, Tomenson B. Depression in later life: a comparison of symptoms and risk factors in early and late onset cases . Br J Psychiatry . 1995;167:649-652.Crossref 40. Krishnan KRR, Hays JC, Tupler LA, George LK, Blazer DG. Clinical and phenomenological comparisons of late-onset and early-onset depression . Am J Psychiatry . 1995;152:785-788. 41. Young RC, Klerman GL. Mania in late life: focus on age at onset . Am J Psychiatry . 1992;4:73-78. 42. Alexopoulos GS, Meyers BS, Young RC, Kakuma T, Sibersweig D, Charlson M. Clinically defined vascular depression . Am J Psychiatry . 1997;154:562-565. 43. Kokmen E, Whisnant JP, O'Fallon WM, Chu C-P, Beard CM. Dementia after ischemic stroke: a population study in Rochester, Minnesota (19601984) . Neurology . 1996;19:154-159.Crossref 44. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer's disease . JAMA . 1997;277:813-817.Crossref 45. Ferruzzi L, Guralnik JM, Salive ME, Pahor M, Corti MC, Baroni A, Havlik RJ. Cognitive impairment and risk of stroke in the older population . J Am Geriatr Soc . 1996;44:237-241. 46. Åstrom MG, Thompson RF, Hendrie HC, Norton J, Farlow MR, Edwards MK, Dean R. Foci of increased T2 signal intensity in MR images of healthy elderly subjects: a follow-up study . J Am Geriatr Soc . 1990;38:1131-1138. 47. Harell LE, Duvall E, Folks DG, Duke L, Bartolucci A, Conboy T, Callaway R, Kerns D. The relationships of high-intensity signals on magnetic resonance images to cognitive and psychiatric state in Alzheimer's disease . Arch Neurol . 1991;48:1136-1140.Crossref 48. Van Swieten JC, Geyskes GG, Derix MMA, Peeck BM, Ramos LMP, van Latum JC, van Gijn J. Hypertension in the elderly is associated with white matter lesions and cognitive decline . Ann Neurol . 1991;30:825-830.Crossref 49. Ylikoski R, ylikoski A, Erkinjuntti T, Sulkava R, Raininko R, Tilvis R. White matter changes in healthy elderly persons correlate with attention and speed of mental processing . Arch Neurol . 1993;50:818-824.Crossref 50. Fein G, van Dyke C, Davenport L, Turetsky B, Brant Zawadzki M, Zatz L, Dillon W. Preservation of normal cognitive functioning in elderly subjects with extensive white matter lesions of long duration . Arch Gen Psychiatry . 1990;47:220-223.Crossref 51. Tupler LA, Coffey CE, Logue PE, Djang WT, Fagan M. Neuropsychological importance of subcortical white matter hyperintensity . Arch Neurol . 1992;49:1248-1252.Crossref 52. Meyers JS, Kawamura J, Terayama Y. White matter lesions in the elderly . J Neurol Sci . 1992;110:1-7.Crossref 53. Lesser IM, Hill-Gutierrez E, Miller RL, Boone KB. Late-onset depression with white matter lesions . Psychosomatics . 1993;34:364-367.Crossref 54. Alexopoulos GS, Meyers BS, Young RC, Kakuma T, Feder M, Einhorn A, Rosendahl E. Recovery in geriatric depression . Arch Gen Psychiatry . 1996;53:305-312.Crossref 55. Leuchter AF, Dunkin JJ, Lufkin RB, Anzai Y, Cook IA, Newton TF. Effect of white matter disease on functional connections in the aging brain . J Neurol Neurosurg Psychiatry . 1994;57:1347-1354.Crossref 56. Leuchter A, Simon SL, Daly KA, Abrams M, Rosenberg-Thompson S, Dunkin JJ, Cook IA, Newton TF, Spar JE. Quantitative EEG correlates of outcome in older psychiatric patients, II: two-year follow-up of patients with depression . Am J Geriatr Psychiatry . 1994;2:290-299.Crossref 57. Alexopoulos GS. The subtypes of geriatric depression. In: Programs and abstracts of the annual meeting of the American Geriatric Association; March 5, 1997; Orlando, Fla. 58. Boone KB, Miller BL, Lesser IM, Merhinger CM, Hill-Gutierrez E, Goldberg M, Berman NG. Neuropsychological correlates of white matter lesions in healthy elderly subjects . Arch Neurol . 1992;49:549-554.Crossref 59. Damasio AR, Van Hoesen GW. Emotional disturbances associated with focal lesions of the limbic frontal lobe . In: Heilman KM, Satz P, eds. Neuropsychology of Human Emotion . New York, NY: Guilford Press; 1983:85-110. 60. Grafman J, Vance SC, Weingartner H, Salazar AM, Amin D. The effects of lateralized frontal lesions on mood regulation . Brain . 1986;109:1127-1148.Crossref 61. Eslinger PJ, Damasio AR. Severe bilateral disturbance of higher cognition after bilateral frontal lobe ablation: patient EVR . Neurology . 1985;35:1731-1741.Crossref 62. Mayberg HS, Solomon DH. Depression in Parkinson's disease: a biochemical and organic viewpoint . In: Weiner WJ, Lang AE, eds. Behavioral Neurology of Movement Disorders: Advances in Neurology . New York, NY: Raven Press; 1995;65:49-60. 63. Starkstein SE, Robinson RG, Berthier ML, Parikh RM, Price TR. Differential mood changes following basal ganglia vs thalamic lesions . Arch Neurol . 1988;45:725-730.Crossref 64. Krishnan KRR. Neuroanatomic substrates of depression in the elderly . J Geriatr Psychiatry Neurol . 1993;6:39-58.Crossref 65. Krishnan KRR, McDonald WM. Arteriosclerotic depression . Med Hypotheses . 1995;44:111-115.Crossref 66. Krishnan KRR, McDonald WM, Escalona PR, Doraiswamy PM, Na C, Husain MM, Figiel GS, Boyko OB, Ellinwood EH, Nemeroff CB. Magnetic resonance imaging of the caudate nuclei in depression . Arch Gen Psychiatry . 1992;49:553-557.Crossref 67. Husain MM, McDonald WM, Doraiswamy PM, Figiel GS, Escalona PR, Boyko OB, Nemeroff CB, Krishnan KRR. A magnetic resonance imaging study of putamen nuclei in major depression . Psychiatry Res Neuroimaging . 1991;40:95-99.Crossref 68. Alexopoulos GS, Meyers BS, Bajulaiye R, Elkin C, Khouri P, Kakuma T. Caudate size in geriatric depression. In: New research program and abstracts, annual meeting of the American Psychiatric Association; May 20-25, 1995; Miami, Fla. 69. Baxter LR Jr, Phelps ME, Mazziotta JC, Schwartz JM, Gerner RH, Selin CE, Smida RM. Cerebral metabolic rates for glucose in mood disorders: studies with positron emission tomography and fluorodeoxyglucose . Arch Gen Psychiatry . 1985;42:441-447.Crossref 70. Martinot JL, Hardy P, Feline A, Huret JD, Mazoyer B, Attar-Levy D, Pappata S, Syrota A. Left prefrontal glucose hypometabolism in the depressed state: a confirmation . Am J Psychiatry . 1990;147:1313-1317. 71. Bench CJ, Friston KJ, Brown RG, Scott LC, Frackowiak RSJ, Dolan RJ. The anatomy of melancholia: focal abnormalities of cerebral blood flow in major depression . Psychol Med . 1992;22:607-615.Crossref 72. Dolan RJ, Bench CJ, Brown RG, Scott LC, Friston KJ, Frackowiak RSJ. Regional cerebral blood flow abnormalities in depressed patients with cognitive impairment . J Neurol Neurosurg Psychiatry . 1992;55:768-773.Crossref 73. Drevets WC, Videen TO, Preskorn SH, Price JL, Carmichael ST, Raichle ME. A functional anatomical study of unipolar depression . J Neurosci . 1992;12:3628-3641. 74. Ketter TA. Andreason PJ, George MS, Pazzaglia PJ, Marangell LM, Post RM. Blunted CBF response to procaine in mood disorders. In: New research program and abstracts, annual meeting of the American Psychiatric Association; May 22-27, 1993; San Francisco, Calif. Abstract NR297. 75. George MS, Ketter TA, Post RM. Prefrontal cortex dysfunction in clinical depression . Depression . 1994;2:59-72.Crossref 76. Baxter LR Jr, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE, Gerner RH, Sumida RM. Reduction of prefrontal cortex glucose metabolism common to three types of depression . Arch Gen Psychiatry . 1989;46:243-250.Crossref 77. Finkelstein SP, Benowitz LI, Baldessarini RJ, Arana GW, Levine D, Woo E, Bear D, Moya K, Stoll AL. Mood, vegetative disturbance, and dexamethasone suppression after stroke . Ann Neurol . 1982;12:463-468.Crossref 78. Starkstein SE, Robinson RG, Honig MA, Parikh RM, Joselyn J, Price TR. Mood changes after right hemisphere lesions . Br J Psychiatry . 1989;155:79-85.Crossref 79. Robinson RG, Starr LB, Lipsey JR, Rao K, Price TR. A two-year longitudinal study of poststroke mood disorders: dynamic changes in associated variables over the first six months of followup . Stroke . 1984;15:510-516.Crossref 80. House A, Dennis M, Warlow C, Hawton K, Molyneux A. Mood disorders after stroke and their relation to lesion location: a CT scan study . Brain . 1990;113:1113-1130.Crossref 81. Finkelstein S, Campbell A, Baldessarini R, Moya KL, Haber SN. Late changes in cerebral metabolism following focal ventrolateral cerebrocortical lesions in rats . Brain Res . 1985;344:205-210.Crossref 82. Bryer JB, Starkstein SE, Votypka V, Parikh RM, Price TR, Robinson RG. Reduction of CSF monoamine metabolites in poststroke depression: a preliminary report . J Neuropsychiatry Clin Neurosci . 1992;4:440-442. 83. Mayberg HS, Robinson RG, Wong DF, Parikh R, Bolduc P, Starkstein SE, Price T, Dannals RF, Links JM, Wilson AA, et al. PET imaging of cortical S2 serotonin receptors following stroke: lateralized changes and relationship to depression . Am J Psychiatry . 1988;145:937-943. 84. Mann JJ, Stanley M, McBride P, McEwen BS. Increased serotonin2 and β-adrenergic receptor binding in the frontal cortices of suicide victims . Arch Gen Psychiatry . 1986;43:954-959.Crossref 85. Ishii H, Stanmirovic DB, Chang CJ, Mrsulja BB, Spatz M. Dopamine metabolism and freeradical related mitochondrial injury during transient brain ischemia . Neurochem Res . 1993;18:1193-1201.Crossref 86. Bertrand N, Ishii H, Beley A, Spatz M. Biphasic striatal acetylcholine release during and after transient cerebral ischemia in gerbils . J Cereb Blood Flow Metab . 1993;13:789-795.Crossref 87. Kuroda H, Baskin DS, Matsui T, Loh HH, Hosobuchi Y, Lee NM. Effects of dynorphin 1-13 on opiate binding and dopamine and GABA uptake in stroked cat brain . Brain Res . 1986;376:68-74.Crossref 88. Lyden P, Lonzo L, Nunez S. Combination chemotherapy extends the therapeutic window to 60 minutes after stroke . J Neurotrauma . 1995;12:223-230.Crossref 89. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregation circuits linking basal ganglia and cortex . Ann Rev Neurosci . 1986;9:357-381.Crossref 90. Baxter LR Jr, Schwartz LM, Guze BH, Bergman K, Szuba MP. PET imaging in obsessivecompulsive disorder with and without depression . J Clin Psychiatry . 1990;51( (suppl) ):61-69. 91. Baxter LR Jr. Brain imaging as a tool in establishing a theory of brain pathology in obsessivecompulsive disorder . J Clin Psychiatry . 1990;51( (suppl) ):22-25. 92. Kalayam B, Alexopoulos GS, Musiek FE, Kakuma T, Toro A, Silbergsweig D, Young RC. Brainstem evoked response abnormalities in latelife depression with vascular disease . Am J Psychiatry . 1997;154:970-975. 93. Ketter TA, Andreason PJ, George MS, Marangell LM, Pazzaglia PJ, Post RM. Reduced resting frontal lobe cerebral blood flow in mood disorders. In: New research program and abstracts, annual meeting of the American Psychiatric Association; May 22-27, 1993; San Francisco, Calif. Abstract NR298. 94. George MS, Ketter TA, Gill D, Haxby JV, Ungerleider L, Herscovitch P, Post RM. Brain regions involved in recognizing facial emotion or identity: an 015 PET study . J Neuropsychiatry Clin Neurosci . 1993;54:1-10. 95. George MS, Ketter TA, Gill DS, Marangell LB, Pazzaglia PJ, Post RM. Blunted cerebral blood flow with emotion recognition in depression. In: New research program and abstracts, annual meeting of the American Psychiatric Association; May 22-27, 1993; San Francisco, Calif. Abstract NR114. 96. Berman KF, Doran AR, Pickar D, Weinberger DR. Is the mechanism of prefrontal hypofunction in depression the same as in schizophrenia: regional cerebral blood flow during cognitive activation . Br J Psychiatry . 1993;162:183-192.Crossref 97. Pardo JV, Pardo PJ, Ratchle ME. Neural correlates of self-induced dysphoria . Am J Psychiatry . 1993;150:13-19. 98. George MS, Ketter TA, Parekh PI, Horwitz B, Herscovitch P, Post RM. Regional brain activity during transient sadness or happiness in healthy women . Am J Psychiatry . 1995;152:341-351. 99. Åstrom M, Adolfson R, Asplund K. Major depression in stroke patients: a three-year longitudinal study . Stroke . 1993;24:976-982.Crossref 100. Zubenko GS, Sullivan P, Nelson JP. Brain imaging abnormalities in mental disorders of late life . Arch Neurol . 1990;47:1107-1113.Crossref 101. Figiel GS, Krishnan KRR, Doraiswamy PM, Rao VP, Nemeroff CB, Boyko OB. Subcortical hyperintensities on brain magnetic resonance imaging: a comparison between late age onset and early onset elderly depressed subjects . Neurobiol Aging . 1991;12:245-247.Crossref 102. Churchill CM, Priolo CV, Nemeroff CB, Krishnan KRR, Breitner JCS. Occult subcortical magnetic resonance imaging in elderly depressives . Int J Geriatr Psychiatry . 1991;6:213-214.Crossref 103. Krishnan KRR, McDonald WM, Doraiswamy PM, Tupler LA, Husain M, Boyko OB, Figiel GS, Ellinswood EH. Neuroanatomical substrates of depression in the elderly . Eur Arch Psychiatry Clin Neurosci . 1993;243:41-46.Crossref 104. Kannel WB, Wolf PA, Verter J, McNamara PM. Epidemiologic assessment of the role of blood pressure in stroke: the Framingham Study . JAMA . 1996;276:1269-1278.Crossref 105. Lindenstrom E, Boysen G, Nyboe J. Influence of systolic and diastolic blood pressure on stroke risk: a prospective observational study . Am J Epidemiol . 1995;142:1279-1290. 106. Kannel WB. Cardioprotection and antihypertensive therapy: the key importance of addressing the associated coronary risk factors (the Framingham experience) . Am J Cardiol . 1996;77:6B-11B.Crossref 107. Whisnant JP. Effectiveness versus efficacy of treatment of hypertension for stroke prevention . Neurology . 1996;46:301-307.Crossref 108. Sirtori CR. The treatment of hypercholesterolemia in primary and secondary prevention . Ann Ital Med Int . 1995;10( (suppl) ):48S-52S. 109. Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation Study II . Lancet . 1994;343:687-691. 110. Bellavance A. Efficacy of ticlopidine and aspirin for prevention of reversible cerebrovascular ischemic events: the ticlopidine aspirin stroke study . Stroke . 1993;24:1452-1457.Crossref 111. Sivenius J, Riekkinen PJ, Laasko M, Smets P, Lowenthal A. European Stroke Prevention Study: antithrombotic therapy is also effective in the elderly . Acta Neurol Scand . 1993;87:111-114.Crossref 112. Kusumi I, Koyama A, Yamashita I. Serotoninstimulated Ca2+ response is increased in the blood platelets of depressed patients . Biol Psychiatry . 1991;30:310-312.Crossref 113. Mikuni K, Kagaya A, Takahashi K, Meltzer HY. Serotonin but not norepinephrine-induced calcium mobilization of platelets is enhanced in affective disorders . Psychopharmacology . 1992;106:311-314.Crossref 114. Silver B, Weber J, Fisher M. Medical therapy for ischemic stroke . Clin Neuropharmacol . 1996;19:101-128.Crossref 115. Hacke W, Kaste M, Fiechi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Hoxter G, Mahagne MH, Hennerici M, for the ECASS Study Group. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS) . JAMA . 1995;274:1017-1025.Crossref 116. Gelmers HJ, Hennerici M. Effect of nimodipine in acute ischemic stroke: pooled results from five randomized trials . Stroke . 1990;21( (suppl 22) ):81-84. 117. Lenzi GL, Grigoletto F, Gent M, Roberts RS, Walker MD, Easton JD, Carolei A, Dorsey FC, Rocca WA, Bruno R, et al. Early treatment with monosialoganglioside GM-1 efficacy and safety results of the Early Stroke Trial . Stroke . 1994;25:1552-1558.Crossref 118. Svennerholm L. Gangliosides: a new therapeutic agent against stroke and Alzheimer's disease . Life Sci . 1994;55:2125-2134.Crossref 119. Goldstein LB. Pharmacologic modulation of recovery after stroke: clinical data . J Neurol Rehab . 1991;5:129-140. 120. Goldstein LB. Basic and clinical studies of pharmacologic effects on recovery from brain injury . J Neural Transplant Plast . 1993;3:175-192.Crossref 121. The Sygen in Acute Stroke Study Investigators, Goldstein LB. Common drugs may influence motor recovery after stroke . Neurology . 1995;45:865-871.Crossref 122. Finkelstein SP, Weintraub RJ, Karmouz N, Askinazi C, Davar G, Baldessarini RJ. Antidepressant drug treatment for poststroke depression: retrospective study . Arch Phys Med Rehabil . 1987;68:772-776. 123. Reding MJ, Orto LA, Winter SW, Fortuna IM, Di Ponte P, McDowell FH. Antidepressant therapy after stroke: a double-blind trial . Arch Neurol . 1986;43:763-765.Crossref 124. Lipsey JR, Spencer WC, Rabins PV, Robinson RG. Phenomenological comparison of poststroke depression and functional depression . Am J Psychiatry . 1986;143:527-529. 125. Lazarus LW, Moberg PJ, Langsley PR, Lingam V. Methylphenidate and nortriptyline in the treatment of poststroke depression: a retrospective comparison . Arch Med Rehab . 1994;75:403-406.Crossref 126. Masand P, Murray GB, Pickett P. Psychostimulants in poststroke depression . J Neurol Psychiatry Clin Neurosci . 1991;3:23-27. 127. Lingham VR, Lazarus LW, Groves L, Oh SH. Methylphenidate in treating poststroke depression . J Clin Psychiatry . 1988;49:151-153. 128. Lazarus LW, Winemiller DR, Lingam VR, Robinson RG. Efficacy and side effects of methylphenidate for poststroke depression . J Clin Psychiatry . 1992;53:447-449. 129. Boyerson MG, Harmon RL. Effects of trazodone and desipramine on motor recovery in brain-injured rats . Am J Phys Med Rehab . 1993;72:286-293.Crossref 130. Boyerson MG, Harmon RL, Jones JL. Differential effects of fluoxetine, amitriptyline and serotonin S2 antagonist markedly reduces infarct size following middle cerebral artery occlusion in the rat . Neurology . 1988;38:1667-1673.Crossref 131. Dam M, Tonon P, De Boni A, Pizzolato G, Casson S, Ermani M, Freo U, Piron L, Battistin L. Effects of fluoxetine and maprotilene on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy . Stroke . 1996;27:1211-1214.Crossref

Carroll, Kathleen M.

doi: 10.1001/archpsyc.1997.01830220041007pmid: 9337772

Abstract The conduct of randomized clinical trials to evaluate the efficacy of pharmacotherapies for mental disorders is guided by research standards (at a high level of rigor) that govern most design elements, including randomization of subjects, use of placebo controls, formulation and dosage of the therapeutic agent, and monitoring of serum levels. In contrast, no such widely accepted guidelines are recognized for standardization of an essential, if unacknowledged, element of all such studies: the concomitant provision of at least a minimal form of psychosocial treatment. Standardized provision of psychosocial treatments in pharmacotherapy trials will foster replicability of findings and address several common problems (eg, attrition, medication noncompliance, reduction of error variance, and ethical issues associated with placebo controls). Careful selection and standardization of the psychosocial context in which medications are delivered will improve the validity, precision, and power of pharmacotherapy efficacy research, and should be considered a virtual requirement in research design. References 1. Clum GA, Clum GA, Surls R. A meta-analysis of treatments for panic disorder . J Consult Clin Psychol . 1993;61:317-326.Crossref 2. Conte HR, Plutchik R, Wild KV, Karasu TB. Combined psychotherapy and pharmacotherapy for depression: a systematic analysis of the evidence . Arch Gen Psychiatry . 1986;43:471-479.Crossref 3. Greist J, Chouinard G, DuBoff E, Halaris A, Kim SW, Koran L, Liebowitz M, Lydierd B, Rasmussen S, White K, Sikes C. Double-blind parallel comparison of three dosages of sertraline and placebo in outpatient with obsessive-compulsive disorder . Arch Gen Psychiatry . 1995;52:289-295.Crossref 4. Mitchell JE, Raymond N, Specker S. A review of the controlled trials of pharmacotherapy and psychotherapy in the treatment of bulimia nervosa . Int J Eat Disord . 1993;14:229-247.Crossref 5. Reynolds CF, Frank E, Perel JM, lmber SD, Cernes C, Morycz RK, Mazumdar S, Miller MD, Pollock BG, Rifai AN. Combined pharmacotherapy and psychotherapy in the acute and continuation treatment of elderly patients with recurrent major depression: a preliminary report . Am J Psychiatry . 1992;149:1687-1692. 6. Stack JA, Paradis CF, Reynolds CF, Houck PR, Frank E, Anderson B, Mayo AL, Miller MD, Rifai AH, Perel JM. Does recruitment method make a difference? effects on protocol retention and treatment outcome in elderly depressed patients . Psychiatry Res . 1995;56:17-24.Crossref 7. Callahan EJ. The treatment of heroin addiction: naltrexone alone with behavior therapy . Am J Drug Alcohol Abuse . 1980;7:795-807. 8. Cornelius JR, Soloff PH, Perel JM, Ulrich RF. Continuation pharmacotherapy of borderline personality disorder with haloperidol and phenelzine . Am J Psychiatry . 1993;150:1843-1848. 9. Cowdry RW, Gardner DL. Pharmacotherapy of borderline personality disorder: alprazolam, carbamazepine, trifluoperazine, and tranylcypromine . Arch Gen Psychiatry . 1988;45:111-119.Crossref 10. Mason BJ, Ritvo EC, Morgan RO, Salvato FR, Goldberg G, Welch B, Mantero-Atienza E. A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCI for alcohol dependence . Alcohol Clin Exp Res . 1994;18:1162-1167.Crossref 11. Sackett DL, Snow JC. The magnitude of compliance and noncompliance . In: Haynes RB, Taylor DW, Sackett DL, eds. Compliance in Health Care . Baltimore, Md: Johns Hopkins University Press; 1979:chap 1. 12. Kelly GR, Scott JE. Medication compliance and health education among outpatients with chronic mental disorders . Med Care . 1990;28:1181-1197.Crossref 13. Kupfer DJ, Perel JM, Frank E. Adequate treatment with imipramine in continuation treatment . J Clin Psychiatry . 1989;50:250-255. 14. Meterissian GB, Bradwejn J. Comparative studies on the efficacy of psychotherapy, pharmacotherapy, and their combination in depression: was adequate pharmacotherapy provided? J Clin Psy-chopharmacol . 1989;9:334-339. 15. Ballenger J, Burrows G, Dupont R, Lesser IM, Noyes R, Pecknold JC, Rifkin A, Swinson RP. Al-prazolam in agoraphobia with panic attacks and panic disorder: results from a multicenter trial . Arch Gen Psychiatry . 1988;45:413-422.Crossref 16. Kane JM, Borenstein M. Compliance in the longterm treatment of schizophrenia . Psychopharmacol Bull . 1985;21:23-27. 17. Gelenberg A, Kane J, Keller M, Lavori P, Rosenbaum JF, Cole K, Lavelle J. Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. disorder . N Engl J Med . 1989;321:1489-1493.Crossref 18. Fuller RK, Branchey L, Brightwell DR, Derman RM, Emrick CD, Iber FL, James KE, Lacoursiere RB, Lee KK, Lowenstam I. Disulfiram treatment for alcoholism: a Veterans Administration cooperative study . JAMA . 1986;256:1449-1455.Crossref 19. Frank E, Kupfer DJ, Siegel LR. Alliance not compliance: a philosophy of outpatient care . J Clin Psychiatry . 1995;56( (suppl 1) ):11-16. 20. Feinstein AR. 'Compliance bias' and the interpretation of therapeutic trials . In: Haynes RB, Taylor DW, Sackett DL, eds. Compliance in Health Care . Baltimore, Md: Johns Hopkins University Press; 1979:309-322. 21. Lackin JM, Foulkes MA. Evaluation of sample size and power for analyses of survival with allowance for nonuniform patient entry, losses to followup, noncompliance, and stratification . Biometrics . 1986;42:507-519.Crossref 22. Lakatos E. Sample size determination in clinical trials with time-dependent rates of losses and noncompliance . Control Clin Trials . 1986;7:189-199.Crossref 23. Freedman LS. The effect of partial noncompliance on the power of a clinical trial . Control Clin Trials . 1990;11:157-168.Crossref 24. Pledger GW. Compliance in clinical trials: impact on design, analysis, and interpretation . In: Schmidt D, Leppick IE, eds. Compliance in Epilepsy . Amsterdam, the Netherlands: Elsevier Science Publishers; 1988. 25. Goldsmith CH. The effect of compliance distributions on therapeutic trials . In: Haynes RB, Taylor DW, Sackett DL, eds. Compliance in Health Care . Baltimore, Md: Johns Hopkins University Press; 1979:297-308. 26. Lavori PW. Clinical trials in psychiatry: should protocol deviation censor patient data? Neuropsy-chopharmacology . 1992;6:39-48. 27. Lee YJ, Ellenberg JH, Hirtz DG, Nelson KB. Analysis of clinical trials by treatment actually received: is it really an option? Stat Med . 1991:10:1595-1605.Crossref 28. Newell DJ. Intention-to-treat analysis: implications for quantitative and qualitative research . Int J Epidemiol . 1992;21:837-841.Crossref 29. Nich C, Carroll KM. Now you see it, now you don't: a comparison of traditional versus random regression models in the analysis of longitudinal follow-up data from a clinical trial . J Consult Clin Psychol . 1997;65:252-261.Crossref 30. Kraemer HC, Pruyn JP, Gibbons RD, Greenhouse JB, Grochinski VJ, Waternaux C, Kupfer DJ. Methodology in psychiatric research: report on the 1986 MacArthur Foundation Network I Methodology instititute . Arch Gen Psychiatry . 1987;44:1100-1106.Crossref 31. Rabeneck L, Viscoli CM, Horwitz RI. Problems in the conduct and analysis of randomized clinical trials:are we getting the right answers to the wrong questions? Arch Intern Med . 1992;152:507-512.Crossref 32. Lang JM. The use of a run-in to enhance compliance . Stat Med . 1990;9:87-95.Crossref 33. Hennekens CH, Buring JE. Methodologic considerations in the design and conduct of randomized trials:the U.S. Physicians' Health Study . Control Clin Trials . 1989;10:142S-150S.Crossref 34. Epstein LH, Cluss PA. A behavioral medicine perspective on adherence to long-term medical regimens . J Consult Clin Psychol . 1982;50:950-971.Crossref 35. Howard K, Rickels K, Mock JE, Lipman RS, Covi L, Baumm NC. Therapeutic syle and attrition rate from psychiatric drug treatment . J Nerv Ment Dis . 1970;150:102-110.Crossref 36. Klerman GL. Assessing the influence of the hosptial milieu upon the effectiveness of psychiatric drug therapy: problems of conceptualization and of research methodology . J Nerv Ment Dis . 1963;137:143-154.Crossref 37. Uhlenhuth EH, Lipman RS, Covi L. Combined pharmacotherapy and psychotherapy: controlled studies . J Nerv Ment Dis . 1969;148:52-64.Crossref 38. Elkin I, Pilkonis PA, DochertyJP, SotskySM. Conceptual and methodological issues in comparative studies of psychotherapy and pharmacotherapy, I: active ingredients and mechanisms of change . Am J Psychiatry . 1988;145:909-917. 39. Klein DF. Improvement of phase III psychotropic drug trials by intensive phase II work . Neuropsychopharmacology . 1991;5:251-258. 40. Ball JC, Ross A. The Effectiveness of Methadone Maintenance Treatment . New York, NY: Springer-Verlag NY Inc; 1991. 41. McLellan AT, Arndt IO, Metzger DS, Woody GE, O'Brien CP. The effects of psychosocial services in substance abuse treatment . JAMA . 1993;269:1953-1959.Crossref 42. Katon W, Von Korff MV, Lin E, Walker E, Simon GE, Bush T, Robinson P, Russo J. Collaborative managment to achieve treatment guidelines: impact on depression in primary care . JAMA . 1995;273:1026-1031.Crossref 43. DiMatteo RM, DiNicola DD. Achieving Patient Compliance . Elmsford, NY: Pergamon Press Inc; 1982. 44. Haynes RB, Taylor DW, Sackett DL, eds. Compliance in Health Care . Baltimore, Md: Johns Hopkins University Press; 1979. 45. Meichenbaum D, Turk DC, eds. Facilitating Treatment Adherence . New York, NY: Plenum Publishing Corp; 1987. 46. Horwitz RI, Horwitz SM. Adherence to treatment and health outcomes . Arch Intern Med . 1993;153:1863-1868.Crossref 47. Fawcett J, Clark DC, Aagesen CA, Pisani VD, Tilkin JM, Sellers D, McGuire M, Gibbens RD. A doubleblind, placebo-controlled trial of lithium carbonate therapy for alcoholism . Arch Gen Psychiatry . 1987;44:248-256.Crossref 48. Waskow IE. Specification of the technique variable in the NIMH Treatment of Depression Collaborative Research Program . In: Williams JBW, Spitzer RL, eds. Psychotherapy Research: Where Are We and Where Should We Go? New York, NY: Guilford Press; 1984. 49. Meyer RE, Mirin SM, Altman JL, McNamee HB. A behavioral paradigm for the evaluation of narcotic antagonists . Arch Gen Psychiatry . 1976;33:371-377.Crossref 50. Lambert MJ, Bergin AE. The effectiveness of psychotherapy . In: Bergin AE, Garfield SL, eds. Handbook of Psychotherapy and Behavior Change . 4th ed. New York, NY: John Wiley & Sons Inc; 1994: chap 7. 51. Horvath AO, Luborsky L. The role of the therapeutic alliance in psychotherapy . J Consult Clin Psychol . 1993;61:561-573.Crossref 52. Luborsky L, McLellan AT, Woody GE, O'Brien CP, Auerbach A. Therapist success and its determinants . Arch Gen Psychiatry . 1985;42:602-611.Crossref 53. Cohen J. Statistical Power Analysis for the Behavioral Sciences . 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates Inc; 1988. 54. Crits-Christoph P, Baranackie K, Kurcias J, Beck AT, Carroll K, Perry K, Luborsky L, McLellan AT, Woody GE, Thompson L, Gallagher D, Zitrin C. Meta-analysis of therapist effects in psychotherapy outcome studies . Psychother Res . 1991;1:81-91.Crossref 55. Freedman B. Equipoise and the ethics of clinical research . N Engl J Med . 1987;317:141-145.Crossref 56. Schafer A. The ethics of the randomized clinical trial . N Engl J Med . 1982;307:719-724.Crossref 57. Levine RJ. The use of placebos in randomized clinical trials . IRB Rev Hum Subst Res . 1985;7:1-4. 58. Rothman KJ, Michels KB. The continued unethical use of placebo controls . N Engl J Med . 1994;331:394-398.Crossref 59. Kraemer HC, Pruyn JP. The evaluation of different approaches to randomized clinical trials: report on the 1987 MacArthur Foundation Network I Methodology Workshop . Arch Gen Psychiatry . 1990;47:1163-1169.Crossref 60. Levin FR, Lehman AF. Meta-analysis ofdesipramine as an adjunct in the treatment of cocaine addiction . J Clin Psychopharmacol . 1991;11:374-378.Crossref 61. Meyer RE. New pharmacotherapies for cocaine dependence... revisited . Arch Gen Psychiatry . 1992;49:900-904.Crossref 62. Williams JBW, Spitzer RL, eds. Psychotherapy Research: Where Are We and Where Should We Go? New York, NY: Guilford Press; 1984. 63. Luborsky L, DeRubeis RJ. The use of psychotherapy treatment manuals: a small revolution in psychotherapy research style . Clin Psychol Rev . 1984;4:5-15.Crossref 64. Kazdin AE. Methods of psychotherapy research . In: Bongar B, Beutler LE, eds. Comprehensive Textbook of Psychotherapy: Theory and Practice . New York, NY: Oxford University Press Inc; 1995: chap 11. 65. Elkin I, Shea MT, Watkins JT, Imber SD, Sotsky SM, Collins JF, Glass DR, Pilkonis PD, Leber WR, Docherty JP, Fiester SJ, Parloff MD. National Institute of Mental Health Treatment of Depression Collaborative Research Program: general effec-tiveness of treatments . Arch Gen Psychiatry . 1989;46:971-982.Crossref 66. Hill CE, O'Grady KE, Elkin I. Applying the Collaborative Study Psychotherapy Rating Scale to rate therapist adherence in cognitive-behavior therapy, interpersonal therapy, and clinical management . J Consult Clin Psychol . 1992;60:73-79.Crossref 67. Carroll KM, Kadden R, Donovan D, Zweben D, Rounsaville BJ. Implementing treatment and protecting the validity of the independent variable in treatment matching studies . J Stud Alcohol . 1994; (suppl) 12:149-155. 68. Carroll KM, Nuro K. Treatment manuals and treatment compliance . In: Carroll KM, ed. Facilitating Compliance in Alcohol Treatment . Rockville, Md: National Institute on Alcoholism and Alcohol Abuse. In press. National Institute on Alcoholism and Alcohol Abuse Project MATCH Monograph Series. 69. Chevron E, Rounsaville BJ. Evaluating the clinical skills of psychotherapists: a comparison of techniques . Arch Gen Psychiatry . 1983;40:1129-1132.Crossref 70. Rounsaville BJ, Chevron E, Weissman MM, Pru-soff BA, Frank E. Training therapists to perform interpersonal psychotherapy in clinical trials . Compr Psychiatry . 1986;27:364-371.Crossref 71. Weissman MM, Rounsaville BJ, Chevron E. Training psychotherapists to participate in psychotherapy outcome studies . Am J Psychiatry . 1982;139:1442-1446. 72. Elkin I, Parloff MB, Hadley SW, Autry JH. NIMH Treatment of Depression Collaborative Research Program: background and research plan . Arch Gen Psychiatry . 1985;42:305-316.Crossref 73. Waltz J, Addis ME, Koerner K, Jacobson NS. Testing the integrity of a psychotherapy protocol: assessment of adherence and competence . J Consult Clin Psychol . 1993;61:620-630.Crossref 74. DiClemente C, Carroll KM, Connors G, Kadden R. Process assessment in treatment matching research . J Stud Alcohol . 1994;12( (suppl) ):156-162. 75. Carroll KM, Rounsaville BJ, Nich C. Use of observer and therapist ratings to monitor delivery of coping skills treatment for cocaine abusers: utility of therapist session checklists . Psychother Res . In press. 76. Beck AT, Rush AJ, Shaw BF, Emery G. Cognitive Therapy of Depression . New York, NY: Guilford Press; 1979. 77. Klerman GL, Weissman MM, Rounsaville BJ, Chevron ES. Interpersonal Psychotherapy of Depression . New York, NY: Basic Books Inc Publishers; 1984. 78. Luborsky L. Principles of Psychoanalytic Psychotherapy: A Manual for Supportive-Expressive (SE) Treatment . New York, NY: Basic Books Inc Publishers; 1984. 79. Fawcett J, Epstein P, Fiester SJ, Elkin I, Autry JH. Clinical management—imipramine/placebo administration manual: NIMH Treatment of Depression Collaborative Research Program . Psychopharmacol Bull . 1987;23:309-324. 80. Klerman GL, Weissman MM, Markowitz J, Glick I, Wilner PJ, Mason B, Shear MK. Medication and psychotherapy 1&2 . In: Bergin AE, Garfield SL, eds. Handbook of Psychotherapy and Behavior Change . 4th ed. New York, NY:John Wiley & Sons Inc; 1994. 81. Rounsaville BJ, Klerman GL, Weissman MM. Do psychotherapy and pharmacotherapy for depression conflict? empirical evidence from a clinical trial . Arch Gen Psychiatry . 1981;38:24-29.Crossref

Klein, Donald F.;Smith, Lauren B.

doi: 10.1001/archpsyc.1997.01830220051008pmid: 9337773

Abstract IN THIS issue of the ARCHIVES, Carroll1 argues for a psychotherapeutic context, standardized by manualization, for pharmacotherapy trials. This may well succeed in lowering the attrition rate and improving compliance,2 but the superiority of detailed manuals over goal-oriented, supportive therapy has not been demonstrated. Therefore, standardization by manuals is premature. THE ADOPTION OF MANUALS Manual-based psychotherapy has become standard in psychotherapy research, to provide a distinct, operationalized, replicable structure. In comparative psychotherapy trials, manuals ensure adequate differentiation between therapies, thus allowing strong statements as to what was actually done.3,4 However, since it has not been shown that manuals increase the treatment efficacy or diminish outcome variance, their required use See also page 923 compared with manual-free, supportive psychotherapy has not been shown to be necessary. Such a manual requirement may expensively address a nonexistent problem. RESEARCH ON THE EFFICACY OF MANUALS Schulte et al5 compared the References 1. Carroll KM. Manual-guided psychosocial treatment: a new virtual requirement for pharmacotherapy trials? Arch Gen Psychiatry . 1997;54:923-928.Crossref 2. Klein DF. Improvement of phase III psychotropic drug trials with intensive phase II work . Neuropsychopharmacology . 1991;4:251-258. 3. Luborsky L, Woody G, McLellan AT, O'Brien CP, Rosenzweig J. Can independent judges recognize different psychotherapies? J Consult Clin Psychol . 1982;50:49-62.Crossref 4. Elkin I, Parloff MB, Hadley SW, Autry JH. NIMH Treatment of Depression Collaborative Research Program: background and research program . Arch Gen Psychiatry . 1985;42:305-316.Crossref 5. Schulte D, Kunzel R, Pepping G, Schulte-Bahrenberg T. Tailor-made versus standardized therapy of phobic patients . Adv Behav Res Ther . 1992;14:67-92.Crossref 6. Emmelkamp PM, Bouman TK, Blaauw E. Individualized versus standardized therapy: a comparative evaluation with obsessive-compulsive patients . Clin Psychol Psychother . 1994;1:95-100.Crossref 7. Jacobson NS, Schmaling KB, Holtzworth-Munroe A, Katt JL, Wood LF, Follette VM. Research-structured vs clinically flexible versions of social learning—based marital therapy . Behav Res Ther . 1989;27:173-180.Crossref 8. Weisz JR, Donenberg GR, Weiss B, Han SS. Bridging the gap between laboratory and clinic in child and adolescent psychotherapy . J Clin Consult Psychol . 1995;63:688-701.Crossref 9. Wilson GT. Manual-based treatments: the clinical application of research findings . Behav Res Ther . 1996;34:295-314.Crossref 10. Luborsky L, DeRubeis, RJ. The use of psychotherapy treatment manuals: a small revolution in psychotherapy research style . Clin Psychol Rev . 1984;4:5-14.Crossref 11. Roth A, Fonagy P. What Works for Whom? A Critical Review of Psychotherapy Research . New York, NY: Guilford Press; 1996. 12. Crits-Cristoph P, Baranackie K, Kurcias JS, Beck AT, Carroll K, Perry K, Luborsky L, McLellan AT, Woody GE, Thompson L, Gallagher D, Zitrin C. Meta-analysis of therapist effects in psychotherapy outcome studies . Psychother Res . 1991;1:81-91.Crossref 13. Dobson KS, Shaw BF. The use of treatment manuals in cognitive therapy: experience and issues . J Consult Clin Psychol . 1988;56:673-680.Crossref 14. HenryWP, Strupp HH, Butler SF, Schact TE, Binder JL. Effects of training in time-limited dynamic psychotherapy: changes in therapist behavior . J Consult Clin Psychol . 1993;61:434-440.Crossref 15. Henry WP, Schact TE, Strupp HH, Butler SF, Binder JL. Effects of training in time-limited dynamic psychotherapy: mediators of therapists' responses to training . J Consult Clin Psychol . 1993;61:441-447.Crossref 16. Svartberg M, Stiles TC. Therapeutic alliance, therapist competence, and client change in short-term anxiety-provoking psychotherapy . Psychother Res . 1994;4:20-33.Crossref 17. Sifneos PE. Short-term Dynamic Psychotherapy: Evaluation and Technique . New York, NY: Plenum Publishing Corp; 1979. 18. Jacobson NS, Dobson KS, Truax PA, Addis ME, Koerner K, Gollan JK, Gortner E, Prince SE. A component analysis of cognitive-behavioral treatment for depression . J Consult Clin Psychol . 1996;64:294-304.

Weissman, Myrna M.;Warner, Virginia;Wickramaratne, Priya;Moreau, Donna;Olfson, Mark

doi: 10.1001/archpsyc.1997.01830220054009pmid: 9337774

Abstract Background: There have been numerous studies that have shown that offspring of depressed parents are at a high risk for major depressive disorder (MDD) and impairment. None have followed up the offspring into adulthood to obtain more precise estimates of risk. Method: One hundred eighty-two offspring from 91 families, in which 1 or more parents had MDD (high risk) or in which neither parent was depressed (low risk), were blindly reassessed in the third follow-up, using a structured diagnostic instrument 10 years after their initial identification. Results: Compared with the offspring for whom neither parent was depressed, the offspring of depressed parents had increased rates of MDD, particularly before puberty, and phobias (both at approximately a 3-fold risk), panic disorder, alcohol dependence (at a 5-fold risk), and greater social impairment. The peak age at onset for MDD in both high- and low-risk offspring ranged from 15 to 20 years. The peak age at onset for anxiety disorder was considerably earlier, especially in female offspring in the high-risk group. The onset of alcohol dependence in the offspring in the high-risk group peaked in adolescence and then after the age of 25 years. The depressed offspring of depressed parents, compared with nondepressed parents, had more serious and impairing depressions during the follow-up period but were less likely to go for treatment. Conclusions: The offspring of depressed parents are a high-risk group for onset of anxiety disorder and MDD in childhood, MDD in adolescence, and alcohol dependence in adolescence and early adulthood. The findings support the potential value of early detection in the offspring of depressed parents. References 1. Klerman GL, Weissman MM. Increasing rates of depression . JAMA . 1989;261:2229-2235.Crossref 2. Weissman MM, Klerman GL. Depression: current understanding and changing trends . Annu Rev Public Health . 1992;13:319-339.Crossref 3. Christie KA, Burke JD, Regier DA, Rae DS, Boyd JH, Locke BZ. Epidemiologic evidence for early onset of mental disorders and higher risk of drug abuse in young adults . Am J Psychiatry . 1988;145:971-975. 4. Lahey BB, Flagg EW, Bird HR, Schwab-Stone M, Canino G, Dulcan MK, Leaf PJ, Davies M, Bourdon K, Horwitz S, Rubio-Stipec M, Freeman DH, Shaffer D, Goodman SH, Narrow WE, Weissman MM, Kandel D, Jensen PS, Richters JE, Regier DA. The NIMH Methods for the Epidemiology of Children and Adolescents (MECA) Study: background and methodology . J Am Acad Child Adolesc Psychiatry . 1996;35:855-864.Crossref 5. Kessler RC, McGonagle KA, Nelson CB, Hughes M, Swartz M, Blazer DG. Sex and depression in the National Comorbidity Survey, II: cohort effects . J Affect Disord . 1994;30:15-26.Crossref 6. Kessler RC, McGonagle KA, Shanyang Z, Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler KS. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States . Arch Gen Psychiatry . 1994;51:8-19.Crossref 7. Weissman MM, Gershon ES, Kidd KK, Prusoff BA, Leckrnan JF, Dibble E, Harnovit J, Thompson WD, Pauls DL, Guroff JJ. Psychiatric disorders in the relatives of probands with affective disorders: the Yale University—National Institute of Mental Health Collaborative Study . Arch Gen Psychiatry . 1984;41:13-21.Crossref 8. Weissman MM, Olfson M. Depression in women: implications for health care research . Science . 1995;269:799-801.Crossref 9. Beardslee WR, Keller MB, Klerman GL. Children of parents with affective disorder . Int J Fam Psychiatry . 1985;6:283-299. 10. Orvaschel H, Walsh-Allis G, Ye W. Psychopathology in children of parents with recurrent depression . J Abnorm Child Psychol . 1988;16:17-28.Crossref 11. Hammen C, Burge D, Bumey E, Adrian C. Longitudinal study of diagnoses in children of women with unipolar and bipolar affective disorder . Arch Gen Psychiatry . 1990;47:1112-1117.Crossref 12. Hammen C, Burge D, Adrian C. Timing of mother and child depression in a longitudinal study of children at risk . J Consult Clin Psychol . 1991;59:341-345.Crossref 13. Lewinsohn PM, Gotlib IH, Seeley JR. Adolescent psychopathology, IV: specificity of psychosocial risk factors for depression and substance abuse in older adolescents . J Am Acad Child Adolesc Psychiatry . 1995;34:1221-1229.Crossref 14. Rao U, Weissman MM, Martin JA, Hammond RW. Childhood depression and risk of suicide: a preliminary report of a longitudinal study . J Am Acad Child Ado-lesc Psychiatry . 1993;32:21-27.Crossref 15. Rao U, Ryan ND, Birmaher B, Dahl RE, Williamson DE, Kaufman J, Rao R, Nelson B. Unipolar depression in adolescents: clinical outcome in adulthood . J Am Acad Child Adolesc Psychiatry . 1995;34:566-577.Crossref 16. Kovacs M, Feinberg TL, Crouse-Novak MA, Paulauskas SL, Finkelstein R. Depressive disorders in childhood, I: a longitudinal prospective study of characteristics and recovery . Arch Gen Psychiatry . 1984;41:229-237.Crossref 17. Kovacs M, Goldston D, Gatsonis C. Suicidal behaviors and childhood-onset depressive disorders: a longitudinal investigation . J Am Acad Child Adolesc Psychiatry . 1993;32:8-20.Crossref 18. Ferdinand RF, Verhulst FC. Psychopathology from adolescence into young adulthood: an 8-year follow-up study . Am J Psychiatry . 1995;152:1586-1594. 19. Orvaschel H, Lewinsohn PM, Seeley JR. Continuity of psychopathology in a community sample of adolescents . J Am Acad Child Adolesc Psychiatry . 1995;34:1525-1535.Crossref 20. Harrington R, Fudge H, Rutter M, Pickles A, Hill J. Adult outcomes of childhood and adolescent depression, I: psychiatric status . Arch Gen Psychiatry . 1990;47:465-473.Crossref 21. Harrington RC, Fudge H, Rutter ML, Bredenkamp CG, Pridham J. Child and adult depression: a test of continuities with data from a family study . Br J Psychiatry . 1993;162:627-633.Crossref 22. Weissman MM, John K, Merikangas KR, Prusoff BA, Wickramaratne P, Gammon GD, Angold A, Warner V. Depressed parents and their children: general health, social and psychiatric problems . AJDC . 1986;140:801-805. 23. Weissman MM, Gammon GD, John K, Merikangas KR, Warner V, Prusoff BA, Sholomskas D. Children of depressed parents: increased psychopathology and early onset of major depression . Arch Gen Psychiatry . 1987;44:847-853.Crossref 24. Weissman MM, Warner V, Wickramaratne P, Prusoff BA. Early onset major depression in parents and their children . J Affect Disord . 1988;15:269-278.Crossref 25. Chang G, Weissman MM, Warner V. Physicians' recognition of psychiatric disorders in children and adolescents . AJDC . 1988;142:736-739. 26. Fendrich M, Warner V, Weissman MM. Family risk factors, parental depression and childhood psychopathology . Dev Psychol . 1990;26:40-50.Crossref 27. Warner V, Weissman MM, Fendrich M, Wickramaratne PJ, Moreau D. The course of major depression in the offspring of depressed parents: incidence, recurrence, recovery . Arch Gen Psychiatry . 1992;49:797-801.Crossref 28. Weissman MM, Fendrich M, Warner V, Wickramaratne PJ. Incidence of psychiatric disorder in offspring at high and low risk for depression . J Am Acad Child Adolesc Psychiatry . 1992;31:640-648.Crossref 29. Fendrich M, Weissman MM, Warner V. Longitudinal assessment of major depression and anxiety disorders in children . J Am Acad Child Adolesc Psychiatry . 1991;30:67-74.Crossref 30. Fendrich M, Weissman MM, Warner V, Mufson L. Two-year recall of lifetime diagnoses in offspring at high and low risk for major depression: the stability of offspring reports . Arch Gen Psychiatry . 1990;47:1121-1127.Crossref 31. Endicott J, Spitzer RL. A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia . Arch Gen Psychiatry . 1978;35:837-844.Crossref 32. Mannuzza S, Fyer AJ, Klein DF, Endicott J. Schedule for Affective Disorders and Schizophrenia-Lifetime version modified for the study of anxiety disorders (SADSLA): rationale and conceptual development . J Psychiatr Res . 1986;20:317-325.Crossref 33. Endicott J, Spitzer RL, Fleiss JL, Cohen J. The Global Assessment Scale: a procedure for measuring overall severity of psychiatric disturbance . Arch Gen Psychiatry . 1976;33:766-771.Crossref 34. Weissman MM, Bothwell S. The assessment of social adjustment by patient self-report . Arch Gen Psychiatry . 1976;33:1111-1115.Crossref 35. Cohen JA. A coefficient of agreement for nominal scales . Educ Psychol . 1960;20:37-46. 36. Leckman JF, Sholomskas D, Thompson D, Belanger A, Weissman MM. Best estimate of lifetime psychiatric diagnosis: a methodological study . Arch Gen Psychiatry . 1982;39:879-883.Crossref 37. SAS Institute Inc. SAS/STATUser's Guide: Version 6.4th ed. Cary, NC: SAS Institute Inc; 1990:2. 38. Cox DR, Oakes D. Analysis of Survival Data . New York, NY: Chapman & Hall; 1984. 39. Kalbfeisch JD, Prentice RL. The Statistical Analysis of Failure Time Data . New York, NY: John Wiley & Sons Inc; 1980. 40. Cox DR. Regression models and life tables . J R Stat Soc Ser B . 1972;34:187-220. 41. Lewinsohn PM, Hoberman HM, Rosenbaum M. A prospective study of risk factors for unipolar depression . J Abnorm Psychol . 1988;97:251-264.Crossref 42. Ryan ND, Puig-Antich J, Ambrosini P, Rabinovich H, Robinson D, Nelson B, Ly-engar S, Twomey J. The clinical picture of major depression in children and adolescents . Arch Gen Psychiatry . 1987;44:854-861.Crossref 43. Lavori PW, Keller MB, Mueller TI, Scheftner W, Fawcett J, Corvell W. Recurrence after recovery in unipolar MDD: an observational follow-up study of clinical predictors and somatic treatment as a mediating factor . Int J Methods Psychiatr Res . 1994;4:211-229. 44. Keller MB, Beardslee WR, Dorer DJ, Lavori PW, Samuelson H, Klerman GL. Impact of severity and chronicity of parental affective illness on adaptive functioning and psychopathology in children . Arch Gen Psychiatry . 1986;43:930-937.Crossref 45. Beardslee WR, Keller MB, Seifer R, Lavori PW, Staley J, Podoresfsky D, Shera D. Prediction of adolescent affective disorder: effects of prior parental affective disorders and child psychopathology . J Am Acad Child Adolesc Psychiatry . 1996;35:279-288.Crossref 46. Weissman MM, Wickramaratne P, Merikangas KR, Leckman JF, Prusoff BA, Caruso KA, Kidd KK, Gammon GD. Onset of major depression in early adulthood: increased familial loading and specificity . Arch Gen Psychiatry . 1984;41:1136-1143.Crossref 47. Williamson DE, Ryan ND, Birmaher B, Dahl RE, Kaufman J, Rao U, Puig-Antich J. A case-control family history study of depression in adolescents . J Am Acad Child Adolesc Psychiatry . 1995;34:1596-1607.Crossref 48. Angold A. Childhood and adolescent depression, I: epidemiological and aetiological aspects . Br J Psychiatry . 1988;152:601-617.Crossref 49. Fleming J, Offord DR, Boyle MH. Prevalence of childhood and adolescent depression in the community: Ontario Child Health Study . Br J Psychiatry . 1989;155:647-654. 50. Carlson GA, Kashani JH. Phenomenology of major depression from childhood through adulthood: analysis of three studies . Am J Psychiatry . 1988;145:1222-1225. 51. Roberts RE, Lewinsohn PM, Seeley JR. Symptoms of DSM-III-R major depression in adolescence: evidence from an epidemiological survey . J Am Acad Child Adolesc Psychiatry . 1995;34:1608-1617.Crossref 52. Merikangas KR. Genetic epidemiologic studies of affective disorders in childhood and adolescence . Eur Arch Psychiatry Clin Neurosci . 1993;243:121-130.Crossref 53. Rende R, Wickramaratne P, Warner V, Weissman MM. Sibling resemblance for psychiatric disorders in offspring at high and low risk for depression . J Child Psychol Psychiatry . 1995;36:1353-1363.Crossref 54. Kendler K. Is seeking treatment for depression predicted by a history of depression in relatives? implications for family studies of affective disorder . Psychol Med . 1995;25:807-814.Crossref 55. Takeuchi DT, Bui KV, Kin L. The referral of minority adolescents to community mental health centers . J Health Soc Behav . 1993;34:153-164.Crossref 56. Weissman MM, Paykel ES, Klerman GL. The depressed woman as a mother . Soc Psychiatry Psychiatr Epidemiol . 1982;7:98-108. 57. Frankel KA, Harmon RJ. Depressed mothers: they don't always look as bad as they feel . J Am Acad Child Adolesc Psychiatry . 1996;35:289-298.Crossref 58. Keller MB, Lavori PW, Beardslee WR, Wunder J, Ryan N. Depression in children and adolescents: new data on 'undertreatment' and a literature review on the etficacy of available treatments . J Affect Disord . 1991;21:163-171.Crossref 59. Burns BJ. Mental health services use by adolescents in the 1970s and 1980s . J Am Acad Child Adolesc Psychiatry . 1991;30:144-150.Crossref 60. Bird HR, Canino G, Rubio-Stipec M, Gould MS, Ribera J, Sesman M, Woodbury M, Hertas-Goldman S, Pagan A, Sanchez-Lacay A, Moscoso M. Estimates of the prevalence of childhood maladjustment in a community survey in the relevance of childhood maladjustment in a community survey in Puerto Rico: the use of combined measures . Arch Gen Psychiatry . 1988;45:1120-1126.Crossref 61. Leaf PJ, Bruce ML, Tischler GL. The differential effect of attitudes on the use of mental health services . Soc Psychiatry Psychiatr Epidemiol . 1986;21:187-192. 62. Schowalter JE. Managed care: income to outcome . J Am Acad Child Adolesc Psychiatry . 1995;34:1123.Crossref

Glantz, Leisa A.;Lewis, David A.

doi: 10.1001/archpsyc.1997.01830220065010pmid: 9337775

Abstract Background: Multiple lines of evidence indicate that the prefrontal cortex is a site of dysfunction in schizophrenia. However, the apparent absence of gross structural abnormalities in this area suggests that the pathophysiological characteristics of schizophrenia may involve more subtle disturbances in prefrontal cortical circuitry, such as alterations in synaptic connectivity and transmission. In this study, immunoreactivity for synaptophysin, an integral membrane protein of small synaptic vesicles, was used to assess the integrity of cortical synaptic circuitry in schizophrenia. Methods: Using immunocytochemical techniques and adjusted optical density measurements, we examined synaptophysin immunoreactivity in prefrontal cortical areas 9 and 46 and in area 17. (the primary visual cortex) from 10 pairs of case subjects with schizophrenia and control subjects matched on a pairwise basis for age, sex, race, and postmortem interval, and in 5 matched pairs of nonschizophrenic psychiatric case subjects and normal control subjects. Results: Compared with levels found in matched control subjects, synaptophysin immunoreactivity in areas 46 and 9 was significantly decreased (P<.001 and P<.008, respectively) across all cortical layers in the case subjects with schizophrenia. In contrast, no differences were observed in area 17. In addition, levels of synaptophysin immunoreactivity in areas 46, 9, and 17 did not differ between 5 nonschizophrenic psychiatric case subjects and their matched controls, suggesting that decreased synaptophysin levels in the prefrontal cortex of patients with schizophrenia may be specific to that disorder. Conclusions: Additional studies are required to determine if the decrease in levels of synaptophysin immunoreactivity is caused by a decrease in the number or size of presynaptic terminals, a decrease in the number of synaptic vesicles per terminal, or a decrease in the expression of synaptophysin. However, all of these potential explanations are consistent with a disturbance in synaptic transmission in the prefrontal cortex of patients with schizophrenia. References 1. Levin S. Frontal lobe dysfunctions in schizophrenia, II: impairments of psychological and brain functions . J Psychiat Res . 1984;18:57-72.Crossref 2. Berman KF, Torrey EF, Daniel DG, Weinberger DR. Regional cerebral blood flow in monozygotic twins discordant and concordant for schizophrenia . Arch Gen Psychiatry . 1992;49:927-934.Crossref 3. Buchsbaum MS, Haier RJ, Potkin SG, Neuchterlein K, Bracha HS, Katz M, Lohr J, Wu J, Lottenberg S, Jerabek PA, Trenary M, Tafalla R, Reynolds C, Bunney WE Jr. Frontrostriatal disorder of cerebral metabolism in never-medicated schizophrenics . Arch Gen Psychiatry . 1992;49:935-942.Crossref 4. Ingvar DH, Franzen G. Abnormalities of cerebral blood flow distribution in patients with chronic schizophrenia . Acta Psychiat Scand . 1974;50:425-462.Crossref 5. Park S, Holzman PS. Schizophrenics show spatial working memory deficits . Arch Gen Psychiatry . 1992;49:975-982.Crossref 6. Rubin P, Holm S, Friberg L, Videbech P, Anderson HS, Bendsen BB, Stromso N, Larsen JK, Lassen NA, Hemmingsen R. Altered modulation of prefrontal and subcortical brain activity in newly diagnosed schizophrenia and schizophreniform disorder: a regional cerebral blood flow study . Arch Gen Psychiatry . 1991;48:987-995.Crossref 7. Wolkin A, Sanfilipo M, Wolf AP, Angrist B, Brodie JD, Rotrosen J. Negative symptoms and hypofrontality in chronic schizophrenia . Arch Gen Psychiatry . 1992;49:959-965.Crossref 8. Weinberger DR, Berman KF, Zec RF. Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia, I: regional cerebral blood flow evidence . Arch Gen Psychiatry . 1986;43:114-124.Crossref 9. Andreasen NC, Flashman L, Flaum M, Arndt S, Swayze V II, O'Leary DS, Ehrhardt JC, Yuh WT. Regional brain abnormalities in schizophrenia measured with magnetic resonance imaging . JAMA . 1994;272:1763-1769.Crossref 10. Breier A, Buchanan RW, Elkashef A, Munson RC, Kirkpatrick B, Gellad F. Brain morphology and schizophrenia: a magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures . Arch Gen Psychiatry . 1992;49:921-926.Crossref 11. Schlaepfer TE, Harris GJ, Tien AY, Peng LW, Lee S, Federman EB, Chase GA, Barta PE, Pearlson GD. Decreased regional cortical gray matter volume in schizophrenia . Am J Psychiatry . 1994;151:842-848. 12. Shelton RC, Karson CN, Doran AR, Pickar D, Bigelow LB, Weinberger DR. Cerebral structural pathology in schizophrenia: evidence for a selective prefrontal cortical defect . Am J Psychiatry . 1988;145:154-163. 13. Zipursky RB, Lim KO, Sullivan EV, Brown BW, Pfefferbaum A. Widespread cerebral gray matter volume deficits in schizophrenia . Arch Gen Psychiatry . 1992;49:195-205.Crossref 14. Wible CG, Shenton ME, Hokama H, Kikinis R, Jolesz FA, Metcalf D, McCarley RW. Prefrontal cortex and schizophrenia: a quantitative magnetic resonance imaging study . Arch Gen Psychiatry . 1995;52:279-288.Crossref 15. Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE Jr, Jones EG. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics . Arch Gen Psychiatry . 1995;52:258-266.Crossref 16. Pakkenberg B. Post-mortem study of chronic schizophrenic brains . Br J Psychiatry . 1987;151:744-752.Crossref 17. Pakkenberg B. Total nerve cell number in neocortex in chronic schizophrenics and controls estimated using optical disectors . Biol Psychiatry . 1993;34:768-772.Crossref 18. Selemon LD, Rajkowska G, Goldman-Rakic PS. Abnormally high neuronal density in the schizophrenic cortex: a morphometric analysis of prefrontal area 9 and occipital area 17 . Arch Gen Psychiatry . 1995;52:805-818.Crossref 19. Benes FM, Davidson J, Bird ED. Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics . Arch Gen Psychiatry . 1986;43:31-35.Crossref 20. Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL. Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients . Arch Gen Psychiatry . 1991;48:996-1001.Crossref 21. Bourgeois J-P, Goldman-Rakic PS, Rakic P. Synaptogenesis in the prefrontal cortex of rhesus monkeys . Cereb Cortex . 1994;4:78-96.Crossref 22. Jahn R, Schiebler W, Ouimet C, Greengard P. A 38, 000-dalton membrane protein (p38) present in synaptic vesicles . Proc Natl Acad Sci U S A . 1985;82:4137-4141.Crossref 23. Navone F, Jahn R, DiGioia G, Stukenbrok H, Greengard P, DeCamilli P. Protein p38: an integral membrane protein specific for small vesicles of neurons and neuroendocrine cells . J Cell Biol . 1986;103:2511-2527.Crossref 24. Wiedenmann B, Franke WW. Identification and localization of synaptophysin, an integral membrane glycoprotein of Mr 38,000 characteristic of presynaptic vesicles . Cell . 1985;41:1017-1028.Crossref 25. Alder J, Lu B, Valtorta F, Greengard P, Poo M. Calcium-dependent transmitter secretion reconstituted in Xenopus oocytes: requirement for synaptophysin . Science . 1992;257:657-661.Crossref 26. Alder J, Kanki H, Valtorta F, Greengard P, Poo M. Overexpression of synaptophysin enhances neurotransmitter secretion at xenopus neuromuscular synapses . J Neurosci . 1995;15:511-519. 27. Hamos JE, DeGennaro LJ, Drachman DA. Synaptic loss in Alzheimer's disease and other dementias . Neurology . 1989;39:355-361.Crossref 28. Masliah E, Terry RD, Alford M, DeTeresa R. Quantitative immunohistochemistry of synaptophysin in human neocortex: an alternative method to estimate density of pre-synaptic terminals in paraffin sections . J Histochem Cytochem . 1990;38:837-844.Crossref 29. Masliah E, Terry RD, Alford M, DeTeresa R, Hansen LA. Cortical and subcortical patterns of synaptophysinlike immunoreactivity in Alzheimer's disease . Am J Pathol . 1991;138:235-246. 30. Khachaturian ZS. Diagnosis of Alzheimer's disease . Arch Neurol . 1985;42:1097-1105.Crossref 31. Dixon L, Haas G, Weiden PJ, Sweeney J, Frances AJ. Drug abuse in schizophrenic patients: clinical correlates and reasons for use . Am J Psychiatry . 1991;148:224-230. 32. Daviss SR, Lewis DA. Local circuit neurons of the prefrontal cortex in schizophrenia: selective increase in the density of calbindin-immunoreactive neurons . Psychiatry Res . 1995;59:81-96.Crossref 33. Rosenberg DR, Lewis DA. Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: a tyrosine hydroxylase immunohistochemical analysis . J Comp Neurol . 1995;358:383-400.Crossref 34. Lewis DA, Campbell MJ, Terry RD, Morrison JH. The laminar and regional distribution of neurofibrillary tangles and neuritic plaques in Alzheimer's disease: a quantitative study of visual and auditory cortices . J Neurosci . 1987;7:1799-1808. 35. Rajkowska G, Goldman-Rakic PS. Cytoarchitectonic definition of prefrontal areas in the normal human cortex, I: remapping of areas 9 and 46 using quantitative criteria . Cereb Cortex . 1995;5:307-322.Crossref 36. Devoto SH, Barnstable CJ. SVP38: a synaptic vesicle protein whose appearance correlates closely with synaptogenesis in the rat nervous system . Ann N Y Acad Sci . 1987;493:493-496.Crossref 37. Smolen AJ. Image analytic techniques for quantification of immunohistochemical staining in the nervous system . In: Conn PM, ed. Quantitative and Qualitative Microscopy . Orlando, Fla: Academic Press Inc; 1990:208-229. 38. Perrone-Bizzozero NI, Sower AC, Bird ED, Benowitz LI, Ivins KJ, Neve RL. Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia . Proc Natl Acad Sci U S A . 1996;93:14182-14187.Crossref 39. Browning MD, Dudek EM, Rapier JL, Leonard S, Freedman R. Significant reductions in synapsin but not synaptophysin specific activity in the brains of some schizophrenics . Biol Psychiatry . 1993;34:529-535.Crossref 40. Eastwood SL, Harrison PJ. Decreased synaptophysin in the medial temporal lobe in schizophrenia demonstrated using immunoautoradiography . Neuroscience . 1995;69:339-343.Crossref 41. Peretti-Renucci R, Feuerstein C, Manier M, Lorimier P, Savasta M, Thibault J, Mons N, Geffard M. Quantitative image analysis with densitometry for immunohistochemistry and autoradiography of receptor binding sites—methodological considerations . J Neurosci Res . 1991;28:583-600.Crossref 42. Duvernoy H, Delon S, Vannson JL. Cortical blood vessels of the human brain . Brain Res Bull . 1981;7:519-579.Crossref 43. Vincent SL, McSparren J, Wang RY, Benes FM. Evidence for ultrastructural changes in cortical axodendritic synapses following long-term treatment with haloperidol or clozapine . Neuropsychopharmacology . 1991;5:147-155. 44. Deicken RF, Calabrese G, Merrin EL, Meyerhoff DJ, Dillon WP, Weiner MW, Fein G. 31Phosphorus magnetic resonance spectroscopy of the frontal and parietal lobes in chronic schizophrenia . Biol Psychiatry . 1994;36:503-510.Crossref 45. Pettegrew JW, Keshavan MS, Panchalingam K, Strychor S, Kaplan DB, Tretta MG, Allen M. Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics: a pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance imaging . Arch Gen Psychiatry . 1991;48:563-568.Crossref 46. Stanley JA, Williamson PC, Drost DJ, Carr TJ, Rylett RJ, Malla A, Thompson RT. An in vivo study of the prefrontal cortex of schizophrenic patients at different stages of illness via phosphorus magnetic resonance spectroscopy . Arch Gen Psychiatry . 1995;52:399-406.Crossref 47. Williamson P, Drost D, Stanley J, Carr T, Morrison S, Merskey H. Localized phosphorous 31 magnetic resonance spectroscopy in chronic schizophrenic patients and normal controls . Arch Gen Psychiatry . 1991;48:578.Crossref 48. Glantz LA, Lewis DA. Assessment of spine density on layer III pyramidal cells in the prefrontal cortex of schizophrenic subjects . Soc Neurosci Abstr . 1995;21:239. 49. Garey LJ, Ong WY, Patel TS, Kanani M, Davis A, Hornstein C, Bauer M. Reduction in dendritic spine number on cortical pyramidal neurons in schizophrenia . Soc Neurosci Abstr . 1995;21:237. 50. Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiat Res . 1982;17:319-334.Crossref 51. Hoffman RE, Dobscha SK. Cortical pruning and the development of schizophrenia: a computer model . Schizophr Bull . 1989;15:477-490.Crossref 52. Hoffman RE, McGlashan TH. Parallel distributed processing and the emergence of schizophrenic symptoms . Schizophr Bull . 1993;19:119-140.Crossref 53. Pierce JP, Lewin GR. An ultrastructural size principle . Neuroscience . 1994;58:441-446.Crossref 54. Giguere M, Goldman-Rakic PS. Mediodorsal nucleus: areal, laminar, and tangential distribution of afferents and efferents in the frontal lobe of rhesus monkeys . J Comp Neurol . 1988;277:195-213.Crossref 55. Goldman-Rakic PS, Schwartz ML. Interdigitation of contralateral and ipsilateral columnar projections to frontal association cortex in primates . Science . 1982;216:755-757.Crossref 56. Lund JS, Lewis DA. Local circuit neurons of developing and mature macaque prefrontal cortex: golgi and immunocytochemical characteristics . J Comp Neurol . 1993;328:282-312.Crossref 57. Sherman AD, Davidson AT, Baruah S, Hegwood TS, Waziri R. Evidence of glutamatergic deficiency in schizophrenia . Neurosci Lett . 1991;121:77-80.Crossref 58. Benes FM, Vincent SL, Alsterberg G, Bird ED, SanGiovanni JP. Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics . J Neurosci . 1992;12:924-929. 59. Benes FM, Vincent SL, Marie A, Khan Y. Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects . Neurosci-ence . 1996;75:1021-1031.Crossref