Abstract: The evidence supporting genetic factors in alcoholism comes from family studies (an alcoholic biological parent is seen in 31 per cent of alcoholics), twin studies (MZ concordance 55 per cent and 28 per cent for DZ twins), and adoption studies (alcoholism 44 per cent higher in adopted out offspring of alcoholics than controls). Once the presence or absence of a biological alcoholic parent is controlled for, rearing experiences and parental loss do not increase the risk for alcoholism. This conclusion justifies the search for genetic factors which might mediate the increased risk, particularly in groups identified as being at high risk for the development of alcoholism. The methodological assets and liabilities of the 'high risk' approach are reviewed, with reference to a detailed discussion of existing longitudinal and cross-sectional studies of high-risk populations. There is little convincing evidence that measurable personality attributes or differences in rate of ethanol breakdown contribute to alcoholism vulnerability, although high risk groups may have a unique EEG pattern in childhood, and in early adulthood decreased intensity of ethanol response, and increased acetaldehyde may be important.

Abstract: Panic disorder, comprising also agoraphobia for the purpose of this review, has a prevalence of 1.2-8.4 per cent, affecting females twice as frequently as males, and has a mean age of onset of 25. It is one of the more familial diseases in Psychiatry in that 2/3 of cases have relatives affected with the same condition, and the risk to first degree relatives is approximately 3-4 times the rate of the general population. Although some family studies have suggested an overlap in the transmission of panic disorders and depression, and a common diathesis hypothesis has been proposed, depression is more common in the families of depressives, as in panic disorder in the families of probands with panic disorder. Twin studies of anxiety disorders, although limited in number, report a 30-40 per cent concordance among MZ twins, against 0-4 per cent among DZ twins, which supports a genetic predisposition. The mode of transmission is uncertain. Studies which have used the 'ancestral pairs' method (which examines the incidence of the condition in maternal versus paternal forebears, on the assumption that single locus transmission is favored by unilateral clustering, and polygenic theories are favored by a more even spread) have favored single locus transmission, although such unilateral clustering can still be accommodated within a multifactorial-polygenic hypothesis. Potential biological markers for the condition are reviewed. The observation that lactate infusion can precipitate panic attacks in predisposed individuals is well established. The association with mitral valve prolapse suggests that perhaps 38 per cent of patients presenting with symptoms of panic disorders have mitral valve prolapse on echocardiography. The possibility of an endogenous anxiety-producing agent that binds to the benzodiazepine receptor is discussed.

Abstract: The review presents 23 studies on the action of carbamazepine (CZP) in manic-depressive disorder, some of these studies being double-blind investigations, others open investigations and some anecdotal reports. Surveys of therapeutic as well as prophylactic effects in manias and depressions are presented. There seems to be a definite antimanic and a less expressed but indubitable antidepressant therapeutic effect of CZP, and a considerable prophylactic effect in mania as well as depression, an effect which is possibly a little less than that of lithium. It must, however, be stressed that this conclusion is based on a number of different and heterogeneous studies which have been combined. In addition 5 cases are presented concerning rapid cycling cases with early onset of the disorder and without response to or bad compliance with lithium. In spite of the clinical similarity of these cases the effect of CZP was good in 3 and poor in 2 of the 5 cases presented.

Abstract: Techniques in molecular biology and genetics have made it possible to systematically study gene effects in human disease. The number of gene clusters specifically encoding human brain structure and function is probably about 1,600 or half of all clusters. Evolutionary effects such as linkage disequilibrium and conservation of exons (DNA encoding structural proteins) as well as the fact that there are a tractable number of gene clusters involved, tend to make it quite likely that DNA pathology or DNA variation (polymorphism) predisposing to mental illness can be detected. Genes involved in mental illness can be detected either by studying DNA obtained from blood samples (genomic DNA) directly or by the analysis of mRNA and proteins from suitable cell or tissue preparations. The study of gene expression in the human brain is still in its infancy, nevertheless there are some hints that non-poly-adenylated mRNAs may be important in brain development and certain transcribed sequences may have a specific role in gene expression of the brain. The advantage of studying genomic DNA by the use of linkage and association analysis in multiply affected families is that it will, in the end, almost certainly yield a positive result for a disease with a substantial genetic input. Analysis of gene products from tissues such as brain could in theory detect specific disease genes but the approach will also identify genes secondarily affected by the disease process. Differentiation of genes that are primarily causing mental illness from those that are secondarily affected can be carried out by using such candidate genes as linkage markers in multiply affected families.

Abstract: Reliable concepts of borderline disorders are a prerequisite for studies of validity. Gunderson's and DSM-III's definition of Borderline personality disorder (BPD) and DSM-III's definition of Schizotypal personality disorder (SPD) fulfill these demands. The empirical evidence for descriptive, construct and predictive validity of these disorders is presented and discussed. The review concludes that BPD has descriptive validity but lacks the 2 other stronger types of validity. SPD has both descriptive and construct validity but lacks predictive validity. Various strengths and weaknesses of the empirical studies of these borderline concepts are discussed.

Abstract: Within the last decade linkage analysis has become one of the most useful tools in the human genetics arsenal and is beginning to make substantial contributions in all areas of medicine. Its increasing popularity is a direct result of the burgeoning number of polymorphic markers that are now mapped to specific chromosomal locations. Within the near future the entire human genome is likely to be saturated. This paper is intended as an introduction to linkage analysis for non-geneticists. Basic methodological approaches, along with their strengths, weaknesses and assumptions are reviewed. A subsequent paper will critically review methodological difficulties in the application of linkage analysis to the psychiatric disorders.

Abstract: The method of clinico-pathological correlation for drawing inferences about the localization of particular cerebral functions has a long history of use, and well established theoretical limitations. Release phenomena, loss of excitatory drive, as well as non-specific tissue responses to injury may all have a bearing on observed behavioral change. Nevertheless, the consistent observation that severity of depression in stroke patients is greater for left hemispheric strokes, and greater for left frontal versus left occipital strokes is of considerable interest. Site of lesion appears to have greater explanatory power for this emotional symptom than the obvious psychological explanations in terms of loss of self-esteem and loss of function. Depression is greater for strokes in general than would be expected for equivalent loss of motor function with orthopedic etiology. Loss of cognitive function likewise is a poorer guide to severity of depression than site of lesion. On the other hand, accuracy of lesion assessment using present static anatomical methods (CAT scan), and reliability and validity of the psychopathological examination present methodological difficulties which are discussed. As newer brain imaging techniques that are sensitive to function are developed, this line of enquiry holds considerable promise for furthering our understanding of the anatomy and physiology of emotion. Language: en

Abstract: 301 first-admitted hospitalized patients with paranoid psychoses have been studied by Retterstol over a period of 5-18 years. Common Scandinavian diagnostic procedures were used. About 200 are still alive, and these subjects are at present being interviewed semistructurally by Opjordsmoen using a modification of SADS-L, and making a total follow-up period of 22-37 years. The diagnoses are confirmed according to ICD-9, RDC, DSM-III and some specific groups of delusional disorders (DD) operationalized by Winokur and Kendler. All interviews have been carried out non-blind to the diagnoses which will make a bias possible. However, in paranoid cases, it is an advantage for establishing contact and a conductive atmosphere to know something about the patient beforehand. Based upon our own experiences and reviewing the literature, we point to some important methodological aspects regarding follow-up studies in delusional persons. The suspiciousness, misinterpretation, dissimulation, rationalization and convincing argumentation seen in many paranoid cases, call for a skilled investigator and a clinical approach. However, operational criteria, new diagnostic concepts and standard procedures for follow-up interviewing and outcome assessments will make comparison for international readers easier.

Abstract: The abnormal performance of the DST in depressive illness has been shown to be one of the most reproducible findings in biological psychiatry. Initial claims of its very high diagnostic specificity for the diagnosis of endogenous depression have not been substantiated: an abnormal response appears to reflect a biological dysfunction that cuts across the clinically established boundaries of psychiatric nosology. This lack of diagnostic utility does not reduce its prognostic value and abnormal DST response may indicate or reflect a versatile component in psychiatric disturbance and could serve therefore to predict or monitor the effects of physical and psychological intervention. Contributory factors to abnormal DST response are explored: factors such as stress, nutrition and age are reviewed and discussed. Concepts of biogenetic (neurohumoral) and psychological (psychodynamic and psychosocial) vulnerability and initiation/promotion are invoked and an integrated hypothesis is suggested: emotional strain provokes neurohumoral and neuroendocrine changes; these changes lead to vegetative disturbances including loss of appetite and weight with subsequent nutritional deficiencies that promote/reverse their neurohumoral and neuroendocrine changes. The role of 5-hydroxytryptamine is emphasized. Supportive evidence for aspects of this hypothesis is provided including animal studies and studies of the clinical and biological correlates of abnormal DST response.

Abstract: The diagnosis of borderline disorders poses complex problems of a semantic and methodological nature. The various diagnostic criteria sets published are examined and compared. Gunderson's borderline personality disorder and the DSM-III schizotypal and borderline disorders are recommended, as used with the structured interviews developed for them. Problems concerning the relationship of borderline disorders to the major psychoses, the importance of brief psychotic experiences, diagnostic efficiency of items, and various cut-off levels of criteria are discussed in detail, and proposals for further research are pointed out.

Abstract: Recent advances in molecular biology make genetic linkage analysis an increasingly attractive tool for the identification and characterization of genes involved in the etiology of psychiatric illnesses. However, the complex nature of psychiatric illnesses engenders a host of methodological difficulties not encountered in linkage analyses of simple, Mendelian genetic traits. A previous paper reviewed the basic concepts of genetic linkage analysis. This paper focuses on the methodological difficulties associated with the application of genetic linkage methods to psychiatric illnesses.

Abstract: The study of mortality has a long tradition in Psychiatry. The specificity required to define risks associated with particular disorders and to monitor the effects of changing patterns of treatment necessitates rigorous attention to methodology. The strengths and limitations of particular study designs and how these must be considered when interpreting results are reviewed. Sampling of the study population involves deciding whether to define a group retrospectively or prospectively, the type of psychiatric population to be utilized (eg inpatients or outpatients), and whether cases are to be chosen randomly as to diagnosis or with selection for certain profiles. Ascertainment of death is critical in mortality studies. Once the index population is defined, cases lost to final ascertainment significantly weaken the study. Cause of death as determined by coroner's verdict is readily obtained but of questionable accuracy. Results may be influenced by the method of psychiatric assessment and diagnosis, especially whether case record or interview data is used, and whether multiple or only single diagnoses are determined. With computerization improved statistical analysis are now possible. There is no perfect mortality study design. Any particular design involves a trade-off of advantages and disadvantages.

Abstract: Studies which have sought to address the question of how brain dysfunction might be an etiological factor in the development of psychiatric disorders in childhood are reviewed from the point of view of the methodological issues which arise. It is argued that common forms of behavioral disturbance are more likely to have a psychosocial rather than a neurological origin, whereas epidemiologically unusual conditions are more likely to have neuro-developmental causal factors. Possible study designs are reviewed with the recommendation that cohort studies most closely approximate the ideal of the randomized control trial, whereas case control studies are weakest. The assessment of the reliability and validity of measures of brain dysfunction is discussed. Criteria for attributing causation after an association has been identified include temporal sequence, a 'dose-response' relationship, and the specificity of the cause. The clinical as opposed to the statistical significance of the association must be assessed. Confounding variables in such studies, variables which account in part for the association identified, but which undermine the etiological significance which can be attributed, are discussed. The particular importance of psychosocial disadvantage in this field is stressed as a factor to be taken into account in the critical evaluation of studies.

Abstract: Some of the methodological and conceptual issues relevant to behavior therapy treatment outcome studies for anxiety disorders are presented. The practice among behavioral researchers of measuring anxiety from 3 response systems (verbal, physiological and motoric-behavioral) is discussed. It is emphasized that many of the popular methods used to assess the 3 response systems have unknown or poor reliability or validity. From the point of view of treatment variables, it is noted that many behavioral treatment procedures are not reported in sufficient detail to allow replication or comparisons to be made across studies. In addition, it is argued that in order to improve the existing treatment procedures, it will be necessary for each study to assess the subjects' adherence to the treatment regimen, as well as their proficiency with any skills required to carry out the treatment plan. Finally, the importance of 'placebo' control groups is discussed in the context of identifying the specific factors in behavioral treatments which are responsible for change in the targeted symptoms. It is concluded that behavior therapy holds promise as an effective treatment for the anxiety disorders.

Abstract: Since its introduction in 1934, electroconvulsive therapy has been subjected to a large number of clinical trials of varying methodological sophistication. Although doubts continue to be expressed about the efficacy of ECT, there is a remarkable degree of unanimity in the findings of trials published over a period of 50 years: improvement rates in depression of 70-80 per cent, compared with 20-30 per cent in untreated controls. The principal caveat is that ECT is not a ubiquitous treatment, even in the field of depression, and only patients with endogenous illnesses, whether unipolar or bipolar, can be expected to respond. Even among these, ECT cannot be expected to prevent the relapses in an illness whose underlying course is episodic. The published studies leave little doubt that ECT is statistically more effective than any of the antidepressant drugs, although the relative difference in outcome between the 2 forms of therapy is small, and drugs are to be preferred in mild or moderate cases. However, ECT is an effective and rapidly acting treatment for severe depressive illness, and the rapidity of the response makes its early use desirable in patients at risk of suicide, and those showing marked retardation, agitation and weight loss.

Abstract: Conditions which had an historical association with Asylums in the years 1850-1950, but which are no longer commonly seen in psychiatric practice, are reviewed These include: Asylum pellagra, Erysipelas, Insane Ear and Fractured Ribs The history of each condition and its manifestation is reviewed in the context of its relationship with mental illness and its treatment as seen by authorities writing when these conditions were prevalent It is not clear why these conditions became common, why they had a particular association with Asylums, or why they have largely disappeared