Archives of General Psychiatry

doi: 10.1001/archpsyc.1994.03950110007001pmid: N/A

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Nurnberger, John I.;Blehar, Mary C.;Kaufmann, Charles A.;York-Cooler, Carolyn;Simpson, Sylvia G.;Harkavy-Friedman, Jill;Severe, Joanne B.;Malaspina, Dolores;Reich, Theodore

doi: 10.1001/archpsyc.1994.03950110009002pmid: 7944874

Abstract This the Diagnostic Interview for Genetic Studies (DIGS), a clinical interview especially constructed for the assessment of major mood and psychotic disorders and their spectrum conditions. The DIGS, which was developed and piloted as a collaborative effort of investigators from sites in the National Institute of Mental Health (NIMH) Genetics Initiative, has the following additional features: (1) polydiagnostic capacity; (2) a detailed assessment of the course of the illness, chronology of psychotic and mood syndromes, and comorbidity; (3) additional phenomenologic assessments of symptoms; and (4) algorithmic scoring capability. The DIGS is designed to be employed by interviewers who exercise significant clinical judgment and who summarize information in narrative form as well as in ratings. A two-phase test-retest (within-site, between-site) reliability study was carried out for DSM-III-R criteria—based major depression, bipolar disorder, schizophrenia, and schizoaffective disorder. Reliabilities using algorithms were excellent (0.73 to 0.95), except for schizoaffective disorder, for which disagreement on estimates of duration of mood syndromes relative to psychosis reduced reliability. A final best-estimate process using medical records and information from relatives as well as algorithmic diagnoses is expected to be more reliable in making these distinctions. The DIGS should be useful as part of archival data gathering for genetic studies of major affective disorders, schizophrenia, and related conditions. References 1. Leckman JF, Sholomskas D, Thompson WD, Belanger A, Weissman MM. Best estimate of lifetime psychiatric diagnosis: a methodological study . Arch Gen Psychiatry . 1982;39:879-883.Crossref 2. 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Regier DA, Myers JK, Kramer M, Robins LN, Blazer DG, Hough RL, Eaton WW, Locke BZ. The NIMH Epidemiologic Catchment Area program: historical context, major objectives, and study population characteristics . Arch Gen Psychiatry . 1984;41:934-941.Crossref 13. Endicott J, Spitzer RL. A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia . Arch Gen Psychiatry . 1978;35:837-844.Crossref 14. Wing JK, Birley JLT, Cooper JE, Graham P, Isaacs AD. Reliability of a procedure for measuring and classifying 'present psychiatric state.' Br J Psychiatry . 1967;113:499-515.Crossref 15. McGuffin P, Farmer AE. Operational Criteria (OPCRIT) Checklist. Version 3.0. Cardiff: University of Wales; 1990. 16. Spitzer RL, Endicott J, Robins E. Research diagnostic criteria . Arch Gen Psychiatry . 1978;35:773-782.Crossref 17. Feighner JP, Robin SE, Guze SB, Woodruff RA, Winokur G, Munoz R. Diagnostic criteria for use in psychiatric research . 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Gershon ES, Mark A, Cohen N, Belizon N, Baron M, Knobe KE. Transmitted factors in the morbid risk of affective disorders: a controlled study . J Psychiatr Res . 1975;12:283-299Crossref 25. Nurnberger JI, Gershon ES. Genetics . In: Paykel ES, ed. Handbook of Affective Disorders . 2nd ed. Edinburgh, Scotland: Churchill Livingstone; 1992:131-148. 26. Mazure C, Gershon ES. Blindness and reliability in lifetime psychiatric diagnosis . Arch Gen Psychiatry . 1979;36:521-525.Crossref 27. Guze SB, Cloninger CR, Martin RM, Clayton PJ. A follow-up and family study of schizophrenia . Arch Gen Psychiatry . 1983;40:1273-1276.Crossref 28. Gershon ES, DeLisi LE, Hamovit J, Nurnberger JI Jr, Maxwell ME, Schreiber J, Dauphinais D, Dingman CW II, Guroff JJ. A controlled family study of chronic psychoses . Arch Gen Psychiatry . 1988;45:328-336.Crossref 29. Kendler KS, Gruenberg AM, Tsuang MT. Psychiatric illness in first-degree relatives of schizophrenic and surgical control patients . Arch Gen Psychiatry . 1985;42:770-779.Crossref 30. Tsuang MT, Gilbertson MV, Faraone SV. Genetic transmission of negative and positive symptoms in the biological relatives of schizophrenics . In: Marneros A, Tsuang MT, Andreasen NC, eds. Negative Versus Positive Schizophrenia . New York, NY: Springer-Verlag; 1991. 31. Kendler KS, Lieberman JA, Walsh D. The Structured Interview for Schizotypy (SIS): a preliminary report . Schizophr Bull . 1989;15:559-571.Crossref 32. Suarez BK. Problems of replicating linkage claims in psychiatry. Presented at the Annual Meeting of the American Psychopathological Association; March 5-7, 1992; New York, NY. 33. Lander E. Mapping complex genetic traits in humans . In: Davies K, ed. Genome Analysis . Oxford, England: IRL Press; 1988. 34. Spitzer RL, Williams JB, Gibbon M, First MB. Structured Clinical Interview for DSM-III-R, Patient Edition . New York: Biometrics Research Department, New York State Psychiatric Institute; 1989. 35. Andreasen NC, Flaum M, Arndt S. The Comprehensive Assessment of Symptoms and History (CASH): an instrument for assessing diagnosis and psychopathology . Arch Gen Psychiatry . 1992;49:615-623.Crossref 36. Robins LN, Helzer JE, Croughon J, Ratcliff KS. National Institute of Mental Health Diagnostic Interview Schedule: its history, characteristics, and validity . Arch Gen Psychiatry . 1981;38:381-389.Crossref 37. Andreasen NC. Comprehensive Assessment of Symptoms and History . Iowa City: University of Iowa; 1987. 38. Spitzer RL, Williams JBW, Gibbon M, First MB. The Structured Clinical Interview for DSM-III-R (SCID) . Arch Gen Psychiatry . 1992;49:624-629.Crossref 39. Bucholz K, Cadoret R, Cloninger CR, Dinwiddie S, Hesselbrock V, Nurnberger JI Jr, Reich T, Schmidt I, Schuckit M. Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) . J Stud Alcohol . 1993:149-158. 40. National Institute of Mental Health. Molecular Genetics Initiative: Diagnostic Interview for Genetic Studies , Training Manual. Bethesda, Md: National Institute of Mental Health; May 13, 1992. 41. Cockrell JR, Folstein MF. Mini-Mental State examination (MMSE) . Psychopharmacol Bull . 1988;24:689-692. 42. Wood KA, Harris MJ, Morreale A, Rizos AL. Druginduced psychosis and depression in the elderly . Psychiatr Clin North Am . 1984;11:167-193. 43. Krauthammer C, Klerman GL. Secondary mania: manic syndromes associated with antecedent physical illness or drugs . Arch Gen Psychiatry . 1978;35:1333-1339.Crossref 44. Akiskal HS, Kheni MK, Scott-Strauss A. Cyclothymic temperamental disorders . Psychiatr Clin North Am . 1979;2:527-554. 45. Mayfield D, McLeod G, Hall P. Alcoholism screening instrument . Am J Psychiatry . 1974;131:1121-1123. 46. Bush B, Shaw S, Cleary P, Delbanco TL, Aronson MD. Screening for alcohol abuse using the CAGE questionnaire . Am J Med . 1987;82:231-235.Crossref 47. Propping P. 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How are depression and bulimia related? Am J Psychiatry . 1989;146:162-169. 56. Cloninger CR, Reich T, Guze SB. The multifactorial model of disease transmission, III: familial relationship between sociopathy and hysteria (Briquet's syndrome) . Br J Psychiatry . 1975;127:23-32.Crossref 57. 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 58. Rice J, Endicott J, Knesevich MA. The estimation of diagnostic sensitivity using stability data: an application to major depressive disorder . J Psychiatr Res . 1987;21:337-345.Crossref 59. Rice J, Reich T, Andreasen NC, Endicott J, Van Eerdeweigh M, Fishman R, Hirschfeld RMA, Klerman GL. The familial transmission of bipolar illness . Arch Gen Psychiatry . 1987;44:441-447.Crossref 60. LeBoyer M, Maier W, Teherani M, Lichtermann D, D'Amato T, Franke P, Lepine J, Minges J, McGuffin P. The reliability of the SADS-LA in a family study setting . Eur Arch Psychiatry Clin Neurosci . 1991;241:165-169.Crossref 61. Williams JBW, Gibbon M, First MB, Spitzer RL, Davies M, Borus J, Howes MJ, Kane J, Poper HG, Rousaville B, Wittchen H. The Structured Clinical Interview for DSM-III-R (SCID), II: multisite test-retest reliability . Arch Gen Psychiatry . 1992;49:630-636.Crossref

Frances, Allen

doi: 10.1001/archpsyc.1994.03950110023003pmid: N/A

Abstract THE GOOD news is that we are probably at the brink of a revolution in our understanding of the genetics of the major psychiatric disorders. The bad news is that the steps we must take in getting there will not always be pretty or easy. We must recognize that this research enterprise is inherently a bootstrapping operation that will have to make the best of a useful but imperfect diagnostic system. Under optimal conditions, genetic studies are aimed at disorders with clear-cut diagnostic markers. Unfortunately, our classification of mental disorders is based on the definition of their descriptive characteristics and is largely uninformed by an understanding of underlying pathogenesis. For the most part, we lack diagnostic tests with sufficient sensitivity and specificity to be of much use in clinical practice or research investigations. What this means is that genetic studies of the psychiatric disorders must sort out the noise introduced References 1. Nurnberger JI Jr, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, Severe JB, Malaspina D, Reich T, the NIMH Genetics Initiative. Diagnostic Interview for Genetic Studies: rationale, development, training, and reliability . Arch Gen Psychiatry . 1994;51:849-859.Crossref

doi: 10.1001/archpsyc.1994.03950110024004pmid: 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 Reported Data. In the article "A Multicenter Investigation of Fixed Dose Fluoxetine in the Treatment of Obsessive-compulsive Disorder" published in the July 1994 issue of the Archives (1994;51:559-567), an error appears in the "Results" section on page 563. Under the "Safety" heading in the right-hand column, six lines from the top, the numbers in parentheses should read "(3.45%, 3/87)."

Delgado, Pedro L.;Price, Lawrence H.;Miller, Helen L.;Salomon, Ronald M.;Aghajanian, George K.;Heninger, George R.;Charney, Dennis S.

doi: 10.1001/archpsyc.1994.03950110025005pmid: 7944875

Abstract Objective: To investigate the effects of tryptophan depletion in untreated depressed patients. Rapid dietary depletion of the precursor of serotonin synthesis, tryptophan, causes a transient return of depression in 67% of patients who have had a therapeutic antidepressant response. Method: Forty-three untreated depressed patients underwent tryptophan depletion in a double-blind, placebocontrolled cross-over study. After testing, they received open sequential antidepressant treatment. Results: Mood did not change when tryptophan was depleted but did change on the day after the depletion test. Relative to the control test, 37% of the patients had 10-point or greater decrease in Hamilton Depression Rating Scale (Ham-D) score, while 23% had a 10-point or greater increase in Ham-D score on the day after the tryptophan depletion test. Change in mood was correlated to treatment response after testing. Patients whose condition worsened proved to be highly refractory to treatment while those who showed improvment were more likely to respond. Conclusions: That tryptophan depletion did not rapidly worsen depression argues that serotonin function is not linearly related to the level of depression and if reduced serotonin function does cause depression, then it is either as predisposing factor or due to a postsynaptic deficit in the utilization of serotonin. References 1. Heninger GR, Charney DS. Mechanism of action of antidepressant treatments: implications for the etiology and treatment of depressive disorders . In: Meltzer HY, ed. Psychopharmacology: The Third Generation of Progress . New York, NY: Raven Press; 1987:535-544. 2. Meltzer HY, Lowy MT. The serotonin hypothesis of depression . In: Meltzer HY, ed. Psychopharmacology: The Third Generation of Progress . New York, NY: Raven Press; 1987:513-526. 3. Coppen A. The biochemistry of affective disorders . 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J Affect Disord . 1987;12:91-103.Crossref 15. Stanley M, Mann JJ. Increased serotonin-2 binding sites in frontal cortex of suicide victims . Lancet . 1983;1:214-216.Crossref 16. Yates M, Leake A, Candy JM, Fairbairn AF, McKeith IG, Ferrier IN. 5-HT-2 receptor changes in major depression . Biol Psychiatry . 1990;27:489-496.Crossref 17. Arora RC, Meltzer HY. Serotonergic measures in the brains of suicide victims: 5-HT2 binding sites in the frontal cortex of suicide victims and control subjects . Am J Psychiatry . 1989;146:730-736. 18. Arango V, Ernsberger P, Marzuk PM, et al. Autoradiographic demonstration of increased serotonin 5-HT2 and β-adrenergic receptor binding sites in the brain of suicide victims . Arch Gen Psychiatry . 1990;47:1038-1047.Crossref 19. Heninger GR, Charney DS, Sternberg DE. Serotonergic function in depression: prolactin response to intravenous tryptophan in depressed patients and healthy subjects . Arch Gen Psychiatry . 1984;41:398-402.Crossref 20. 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Garbutt, James C.;Mayo, James P.;Little, Karley Y.;Gillette, Gregory M.;Mason, George A.;Dew, Bess;Prange, Arthur J.

doi: 10.1001/archpsyc.1994.03950110035006pmid: 7944876

Abstract Background: A reduced thyrotropin (TSH) response to thyrotropin-releasing hormone (protirelin [TRH]) has been found consistently in a portion of patients with major depression. One hypothesis to explain this observation is that pituitary TRH receptors are downregulated in major depression. One prediction stemming from this hypothesis is that prolactin (PRL) as well as TSH responses to TRH should be attenuated. To adequately test the pattern of protirelin-induced TSH and PRL responses with a protirelin doseresponse design is necessary. Methods: Four doses of protirelin (25, 100, 500, and 800 μg) were infused in an ascending schedule at intervals of 3 to 7 days in patients with major depression and in control subjects. Seven women and six men with major depression were compared with ageand gender-matched controls (five women and seven men). The TSH and PRL responses were measured at regular intervals following each dose of protirelin. Results: No significant group differences in baseline levels of thyroid hormones or cortisol were present. Depressed men exhibited significant reductions in both TSH and PRL responses to protirelin across all doses compared with control men. Depressed women exhibited significant reductions in TSH responses but not in PRL responses compared with control women. Conclusions: The findings that men with major depression exhibit reductions in both protirelin-induced TSH and PRL responses support the hypothesis that TRH receptors are downregulated in depression. The findings in women are less clear and may represent the greater variance in the protirelin-induced PRL responses found in women. References 1. Prange AJ Jr, Wilson IC, Lara PP, Alltop LB, Breese OR. Effects of thyrotropinreleasing hormone in depression . Lancet . 1972;11:999-1002.Crossref 2. Kastin AJ, Ehrensing RH, Schalch DS, Anderson MS. 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Nobler, Mitchell S.;Sackeim, Harold A.;Prohovnik, Isak;Moeller, James R.;Mukherjee, Sukdeb;Schnur, David B.;Prudic, Joan;Devanand, D. P.

doi: 10.1001/archpsyc.1994.03950110044007pmid: 7944877

Abstract Background: Global and regional deficits in cerebral blood flow and glucose metabolism have been reported in major depression, but there is limited information on the effects of somatic treatment and clinical recovery on these abnormalities. Methods: We assessed cortical blood flow with the xenon 133 technique in depressed patients prior to a course of electroconvulsive therapy (ECT), 30 minutes before and 50 minutes after a single treatment, and during the week following ECT. Acute (preictal and postictal) effects of a single treatment also were studied in manic patients. Results: In the depressed and manic groups, larger blood flow reductions in the acute period, both globally and in particular patterns of brain regions, were associated with a superior clinical outcome following the treatment course. In depressed patients, similar patterns were observed for the blood flow changes over a full treatment course. Blood flow reductions in anterior cortical regions were strongly associated with a positive clinical response in both depression and mania. Conclusions: The findings indicated that cerebral blood flow abnormalities in major depression were not reversed by successful treatment with ECT. Rather, particularly in responders, ECT resulted in additional perfusion reductions. The therapeutic properties of ECT are related to reduced functional brain activity in specific neural regions. References 1. Sackeim HA, Prohovnik I. Studies of brain imaging in mood disorders . In: Mann JJ, Kupfer D, eds. The Biology of Depressive Disorders: Part A: A Systems Perspective . New York, NY: Plenum Publishing Corp; 1993:205-258. 2. Baxter LR Jr, Phelps M, Maziotta J, Schwartz J, Gerner R, Selin C, Sumida R. Cerebral metabolic rates for glucose in mood disorders . Arch Gen Psychiatry . 1985;42:441-447.Crossref 3. Baxter LR Jr, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE, Gerner RH, Sumida RM. 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Krystal, John H.;Webb, Elizabeth;Cooney, Ned;Kranzler, Henry R.;Charney, Dennis S.

doi: 10.1001/archpsyc.1994.03950110058008pmid: 7944878

Abstract Background: This study evaluated the specificity of the ethanollike effects of the serotonergic receptor partial agonist m-chlorophenylpiperazine hydrochloride (MCPP) relative to the α2-adrenergic receptor antagonist yohimbine hydrochloride and the placebo in recently detoxified alcoholics. It also examined the relationship between ethanollike discriminative properties and the induction of craving in these patients. Both MCPP and yohimbine are anxiogenic in humans; thus, this study evaluated the role of anxiogenic and ethanollike effects in the elicitation of craving. Methods: Twenty-two male inpatients who met DSMIII-R criteria for alcohol dependence and who had not consumed alcohol for. 12 to 26 days prior to the study completed 3 days of testing that involved the intravenous infusion of MCPP (0.1 mg/kg), yohimbine hydrochloride (0.4 mg/kg), or a saline solution over 2 weeks under double-blind conditions. Ethanollike subjective effects were assessed using the Sensation Scale and visual analog scales to measure the degree of similarity to the effects of ethanol, cocaine, and marijuana. Five components of craving for alcohol were assessed using visual analog scales. The effects of the drugs on mood were assessed using visual analog scales. Plasma levels of cortisol, prolactin, and 3-methoxy-4-hydroxyphenylethyleneglycol were also measured during the test days. Results: m-Chlorophenylpiperazine and yohimbine produced significant increases compared with placebo in Sensation Scale scores and the visual analog scale score for nervousness. However, the effects of MCPP were rated as more similar to those of ethanol, cocaine, and marijuana than were those of either yohimbine or placebo. Also, MCPP but not yohimbine or placebo significantly increased craving for alcohol. 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Rao, Peter A.;Pickar, David;Gejman, Pablo V.;Ram, Anca;Gershon, Elliot S.;Gelernter, Joel

doi: 10.1001/archpsyc.1994.03950110072009pmid: 7944879

Abstract Objective: To test the hypothesis that interindividual differences in response to clozapine therapy might be attributable to the D4 dopamine receptor (DRD4) alleles they carry. Different alleles of the D4 dopamine receptor, coded by the DRD4 gene, differ in the affinity with which they bind the atypical antipsychotic drug clozapine in vitro. This may have physiologic implications. Clinical response to clozapine therapy varies among patients. The observation that, in vitro, clozapine binds the protein products of different DRD4 alleles with differing affinity characteristics suggested this hypothesis. Method: The region of the DRD4 gene that encodes the putative third cytoplasmic loop of the D4 receptor contains a 48—base pair sequence repeated a variable number of times. With use of polymerase chain reaction amplification, we assessed this variable number of tandem repeats polymorphism in a series of schizophrenic and schizoaffective subjects who had been treated with clozapine, and related genotype with treatment response, to test the hypothesis that DRD4 alleles lead to varying response to clozapine. Results: Allelic variation at the DRD4 locus does not predict clinical response to clozapine relative to either fluphenazine hydrochloride or placebo in subjects with treatment-refractory schizophrenia or schizoaffective disorder. Conclusions: DRD4 alleles do not predict therapeutic response to clozapine in schizophrenic and schizoaffective patients. There are implications from these data for the pathophysiology of schizophrenia and the machanism of clozapine's therapeutic effect are discussed. References 1. Karno M and Norquist GS. Schizophrenia: epidemiology . In: Kaplan HI, Sadock BJ, eds. Comprehensive Textbook of Psychiatry . 5th ed. 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Barsky, Arthur J.;Barnett, Maria C.;Cleary, Paul D.

doi: 10.1001/archpsyc.1994.03950110078010pmid: 7944880

Abstract Background: To determine the nosological and phenomenological overlap and boundaries between panic disorder and hypochondriasis, we compared the symptoms, disability, comorbidity, and medical care of primary care patients with each diagnosis. Methods: Patients with DSM-III-R panic disorder were recruited by screening consecutive primary care clinic attenders and then administering a structured diagnostic interview for panic disorder. Patients also completed selfreport questionnaires, and their primary care physicians completed questionnaires about them. They were then compared with patients with DSM-III-R hypochondriasis from the same setting who had been studied previously. Results: One thousand six hundred thirty-four patients were screened; 135 (71.0% of the 190 eligible patients) completed the research battery; 100 met lifetime panic disorder criteria. Twenty-five of these had comorbid hypochondriasis. Those without comorbid hypochondriasis (n=75) were then compared with patients with hypochondriasis without comorbid panic disorder (n=51). Patients with panic disorder were less hypochondriacal (P<.001), somatized less (P<.05), were less disabled (P<.001), were more satisfied with their medical care (P<.001), and were rated by their physicians as less help rejecting (P<.05) and less demanding (P<.01). Major depression was more prevalent in the group with panic disorder (66.7% vs 45.1%; P<.05), as were phobias (76.0% vs 37.3%; P<.001), but somatization disorder symptoms (P<.0001) and generalized anxiety disorder were less prevalent (74.5% vs 16.0%; P<.001) in panic disorder than was hypochondriasis. Conclusions: While hypochondriasis and panic disorder co-occur to some extent in a primary care population, the overlap is by no means complete. These patients are phenomenologically and functionally differentiable and distinct and are viewed differently by their primary care physicians. 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